CHEMOTHERAPEUTIC AGENTS

[0001] This application claims the benefit under 35 U.S. C. § 119(e) of U.S. Provisional Application No. 61/935,235, filed on February 3, 2014, which is incorporated by reference in its entirety.

Field

[0002] Disclosed herein are β-substituted γ-amino acid derivatives and β-substituted γ- amino acid analogs and (bio)isosteres and their use as therapeutic agents. The β-substituted γ- amino acid derivatives and β-substituted γ-amino acid analogs and (bio)isosteres are selective substrates for LATl/4F2hc, capable of passing through the blood-brain barrier, and exhibit rapid uptake and retention in tissue such as tumors expressing the LATl/4F2hc transporter. Pharmaceutical compositions comprising the β-substituted γ-amino acid derivatives and β- substituted γ-amino acid analogs and (bio)isosteres and uses thereof are also disclosed.

Background

[0003] The ability to selectively target chemotherapy has immense value in clinical practice. Cancer is a leading cause of death in the developed world, with one in every three people developing cancer during his or her lifetime. There are many treatment options for cancer including surgery, chemotherapy, radiation therapy, immunotherapy, and monoclonal antibody treatment. Unfortunately, for many patients cancer treatment options are limited and response rates remain low.

[0004] Surgery is the oldest effective form of tumor therapy and can often result in a complete cure, depending of the type and nature of the tumor. Many tumors, however, occur in locations and/or number that make surgery impossible or impractical. Also, surgical debulking is not guaranteed to remove all abnormal cells, particularly in the case of tumors located in the brain where maximum preservation of normal tissue is desired. Residual abnormal cells pose an increased risk of tumor re-growth and/or metastasis.

[0005] Radiation therapy is often used as an adjunct to surgery. Various types of radiation, both from external and implanted sources, have been used with some success. Low linear-energy-transfer (LET) sources, such as β-particles and γ-rays, require repeated treatments over extended periods of time to produce any significant reduction in tumor cells. High LET sources, such as neutrons, protons or a-particles, do not require oxygen to enhance their biological effectiveness. External beam therapy has been available for decades, however, significant radiation damage occurs to normal tissues, and patients often succumb to widespread radiation-induced necrosis (Laramore, et al, Cancer, 1978, 42(1), 96-103).

[0006] Chemotherapy is used in attempts to cure or palliate cancer. Small molecule chemotherapeutics target rapidly dividing cells, halting cell proliferation by interfering with DNA replication, cytoskeletal rearrangements and/or signaling pathways that promote cell growth. Disruption of cell division slows the growth of malignant cells and may also kill tumor cells by triggering apoptosis. Alkylating agents, such as bis(2-chloroethyl)amine derivatives, act by covalent interaction with nucleophilic heteroatoms in DNA or proteins. It is believed that these difunctional agents are able to crosslink a DNA chain within a double helix in an intrastrand or interstrand fashion, or to crosslink between DNA, proteins or other vital macromolecules. The crosslinking results in inhibitory effects on DNA replication and transcription with subsequent cell death. Since these drugs also indiscriminately kill normal populations of rapidly proliferating cells, such as those found in the immune system and in the gastrointestinal tract, side effects that limit tolerated doses, are common.

[0007] The harsh side effects and the ultimate failure of most chemotherapy regimens have motivated investigation of alternatives, including drugs that target specifically tumor cells. Normal cells and tumor cells differ markedly in nutrient and energy metabolism, a phenomenon known as the Warburg effect (Ganapathy, et al., Pharmacol Ther, 2009, 121(1), 29-40; and Vander Heiden, et al, Science, 2009, 324(5930), 1029-1033). Enhanced proliferation in tumor cells places increased demand for nutrients to serve as building blocks for the biosynthesis of macromolecules and as sources of energy. Tumor-selective nutrient accumulation is most clearly evident in imaging studies of human tumors using positron emission tomography (PET) and [ ¹⁸ F]-fluorodeoxyglucose (FDG). FDG accumulates at high levels in many kinds of solid tumors and is thought to be taken up into tumor cells by sugar transporters. Amino acids are the primary source of cellular nitrogen, used for nucleotide, glutathione, amino sugar, and protein synthesis. In addition, tumors often utilize the carbon skeletons of amino acids as an oxidative fuel source for ATP generation in addition to glucose and fatty acids (Baggetto and Biochimie, 1992, 74(11), 959-974; Mazurek and Eigenbrodt, 2003, Anticancer Res, 2003, 23(2A), 1149-1154; and DeBerardinis, et al, Proc Natl Acad Sci USA, 2007, 104(49), 19345-19350). Therefore, tumor cells must express select specific transporters to satisfy maintenance and growth requirements for nutritional amino acids. To compete with surrounding tissue for nutrients, tumor cells up-regulate levels of certain transporters to allow for more efficient extraction of nutrients than that of the host tissue. [0008] Amino acid transport across the plasma membrane in mammalian cells is mediated by different transport "systems" such as the sodium-dependent systems A, ASC and N, and sodium-independent system L (Christensen, Phys Rev, 1990, 70, 43-77). System L is a ubiquitous plasma membrane amino acid transport system that is characterized by the sodium-independent uptake of bulky, hydrophobic amino acids and its high affinity interaction with 2-amino-bicyclo[2,2,l]heptane-2-carboxylic acid (BCH). System L activity is presently attributed to four sodium-independent transporters (LAT1-4). However, most cancers over-express only one member, the large amino acid transporter 1 (LATl/4F2hc). This transporter is a heterodimer consisting of a light chain (LAT1) that constitutes the transporter and a heavy chain 4F2hc (also known as CD98, or Tumor Antigene TA1) that is required for proper targeting of the light chain to the plasma membrane. The expression and activity of LATl/4F2hc correlates with cell proliferation and cancer growth; and up- regulation of LATl/4F2hc has been observed, for example, in cancers of brain, colon, lung, liver, pancreas, and skin (Jager, et al, J Nucl Med, 1998, 39(10), 1736-1743; Ohkame, et al, J Surg Oncol, 2001,78(4), 265-267; Tamai, et al, Cancer Detect Prev, 2001, 25(5), 439-445; Kim, et al, Anticancer Res, 2004, 24(3a),1671-1675; Kobayashi, et al, Neurosurgery, 2008, 62(2), 493-503; Imai, et al, Histopathology, 2009, 54(7), 804-813; and Kaira, et al, 2009, Lung Cancer, 66(1), 120-126). Furthermore, the expression of LATl/4F2hc has been used as an independent factor to predict poor prognoses in patients with astrocytic brain tumors, lung cancer, and prostate cancer (Nawashiro, et al, Int J Cane, 2006, 119(3), 484-492; Kaira, et al, Lung Cancer, 2009, 66(1), 120-126; Kaira, et al, Cancer Sci, 2008, 99(12), 2380-2386; and Sakata, et al, Pathol Int, 2009, 59(1), 7-18). Inhibition of LATl/4F2hc-mediated transport with non-metabolizable amino acids such as BCH can reduce growth and induce apoptosis in cancer cells in vitro (Kim, et al, Biol Pharm Bull, 2008, 31(6), 1096-1 100; Shennan and Thomson, Oncol Rep, 2008, 20(4), 885-889; and Kaji, et al, Int J Gynecol Cancer, 2010, 20(3), 329-336). Clinical studies have shown that the specificity and positive predictive value of L-[3- ¹⁸ F]-a-methyltyrosine ([ ¹⁸ F]-FAMT) PET is superior to [ ¹⁸ F]-FDG PET. The uptake of [ ¹⁸ F]-FAMT in tumors has been closely correlated with LAT1 expression (Haase, et al, J Nucl Med, 2007, 48(12), 2063-2071; Kaira, et al, Clin Cancer Res, 2007, 13(21), 6369-6378; and Urakami, et al, Nucl Med Biol, 2009, 36(3), 295-303).

[0009] In particular, melphalan is an effective chemotherapy drug used in treating multiple myeloma, ovarian cancer, retinoblastoma, and other hematopoietic tumors.

However, substrates such as gabapentin are reported to be transported much more rapidly than melphalan (Uchino, et al., Mol Pharmacol 2002, 61(4), 729-737). It is widely believed that uptake of melphalan (Alkeran , otherwise known as L-Phenylalanine Mustard, or L- PAM) into cells is mediated by amino acid transporters. Melphalan is an alkylating agent linked to the essential amino acid phenylalanine. Because normal cells and tumor cells differ markedly in nutrient and energy metabolism (Warburg effect) (Vander Heiden, et al., Science, 2009, 324(5930), 1029-1033), melphalan was introduced into clinical practice with the expectation that it would preferentially accumulate in rapidly dividing tumor cells compared to normal cells, thereby increasing its overall therapeutic index. Surprisingly, melphalan caused many of the same side effects as other conventional alkylation agents, including myelosuppression. In a series of publications, Vistica et al. examined melphalan transport in different cell types and identified two independent transport systems for melphalan. One system, presumed to be System L, is characterized by the sodium- independent uptake of bulky, hydrophobic amino acids and its sensitivity toward inhibition with 2-amino-bicyclo[2,2,l]heptane-2-carboxylic acid (BCH) (Vistica, Biochim Biophys Acta, 1979, 550(2), 309-317). A second transport system is sodium-dependent, exhibits its highest affinity for leucine, but is insensitive to both BCH and the system A-specific inhibitor a-amino-isobutyric acid (A1B) (Vistica, Biochim Biophys Acta, 1979, 550(2), 309-317). Although LAT1 is overexpressed on the cell surface of almost all tumor cells regardless of the tissue of origin, response rates to melphalan are low for most cancer types, and the drug is only approved for the treatment of multiple myeloma and ovarian cancer. Melphalan is a poor substrate for LAT1 compared to other large amino acids such as phenylalanine and leucine (Uchino, et al, Mol Pharmacol 2002, 61(4), 729-737; and Hosoya, et al, Biol Pharm Bull, 2008, 31(11), 2126-2130). Nitrogen mustard derivatives with higher selectivity toward the LATl/4F2hc system could reduce side effects associated with nitrogen mustard therapy, allow for an increase in dose, and extend the use into other areas of cancer treatment.

[0010] Although the potential for active transport strategies for increasing drug uptake into tumor cells is known and generally accepted, chemotherapeutics and tumor imaging agents have in general not been optimized for transporters known to be over-expressed in tumor cells. While the general concept of using LATl/2Fhc-selective compounds to deliver therapeutic agents to tumors is appreciated, the existing art gives no guidance as to how one prepares a composition that exploits LATl/4F2hc selective compounds. Thus, there is a need for new therapeutic agents that are more selective toward LATl/4F2hc.

[0011] Several amino acid-related drugs that are substrates of the LATl/4F2hc transporter are known, including L-Dopa, 3-O-methyldopa, droxidopa, carbidopa, 3,3', 5'- triiodothyronine, thyroxine, gabapentin, and melphalan (Uchino, et al., Mol Pharm 2002, 61(4), 729-737; and del Amo et al, Eur J Pharm Sci, 2008, 35(3), 161-174).

Summary

[0012] Differentiation of malignant cancer tissue from neighboring nonmalignant tissue can be accomplished by exploiting changes in biochemical fluxes that occur in response to metabolic, genetic, and/or microstructural changes in the malignant cells. Compounds provided by the present disclosure substantially improve chemotherapy of tissue expressing the LATl/4F2hc transporter including malignant tumors. The β-substituted γ-amino acid derivatives, β-substituted γ-amino acid analogs, and β-substituted γ-amino acid carboxylic acid (bio)isosteres provided by the present disclosure provide greater uptake selectivity for the target tissue or cells expressing the LATl/4F2hc transporter with low non-specific uptake for non-target tissues or cells.

[0013] Embodiments provided by the present disclosure provide novel β-substituted γ- amino acid derivatives and β-substituted γ-amino acid analogs, and methods of using such derivatives, for example, as chemotherapeutic agents. Certain embodiments further relate to methods of synthesizing β-substituted γ-amino acid derivatives and β-substituted γ-amino acid analogs and to pharmaceutical compositions comprising such derivatives. The β- substituted γ-amino acid derivatives and β-substituted γ-amino acid analogs provided by the present disclosure exhibit selectivity for LATl/4F2hc and therefore accumulate in cancerous cells when administered to a subject in vivo. Advantages provided by compounds of the present disclosure reflect the properties of LATl/4F2hc substrates, namely, blood brain- barrier (BBB) permeability, rapid uptake, and prolonged retention in tumors and further serve as chemotherapeutic agents with improved therapeutic index and safety.

[0014] In a first aspect, compounds of Formula (1) are provided:

(1) or a pharmaceutically acceptable salt thereof, wherein:

at least one of R ¹ and R ⁵ is independently selected from halogen, -N(R ¹⁰ ) ₂ , -N ⁺ (-CT )(R ¹⁰ ) ₂ , -N(OR ¹⁰ )(R ¹⁰ ), -NO ₂ , -NO, -N(R ¹⁰ )(S(=O)R ¹⁰ ), -N(R ¹⁰ )(S(=O) ₂ R ¹⁰ ), - N(R ¹⁰ )(C(O)R ¹⁰ ), -N(R ¹⁰ )(C(O)OR ¹⁰ ), -N(R ¹⁰ )(C(O)N(R ¹⁰ ) ₂ , -CN, -COOR ¹⁰ , -CON(R ¹⁰ ) ₂ , -OH, -SH, Ci_4 alkylsulfanyl, Ci_ ₄ alkylsulfmyl, Ci_ ₄ alkylsulfonyl, -S(O)N(R ¹⁰ ) ₂ , - S(O) ₂ N(R ¹⁰ ) ₂ , Ci_4 fluoroalkyl, Ci_ ₄ fluoroalkoxy, Ci_ ₆ alkyl, substituted Ci_ ₆ alkyl, Ci_ ₆ alkoxy, substituted Ci_ ₆ alkoxy, C3-6 cycloalkyl, substituted C3-6 cycloalkyl, C3-6

cycloalkyloxy, substituted C ₃ _ ₆ cycloalkyloxy, C ₄ _i ₂ cycloalkylalkyl, substituted C ₄ _i ₂ cycloalkylalkyl, C _6-1 o aryl, substituted C ₆ -io aryl, C _7-16 arylalkyl, substituted C _7-16 arylalkyl, Ci_6 heteroalkyl, substituted Ci_ ₆ heteroalkyl, Ci_ ₆ heteroalkoxy, substituted Ci_ ₆ heteroalkoxy, C3-6 heterocycloalkyl, substituted C ₃ _ ₆ heterocycloalkyl, C _4-12 heterocycloalkylalkyl, substituted C ₄ _i ₂ heterocycloalkylalkyl, C ₅ _i ₀ heteroaryl, substituted C ₅ _i ₀ heteroaryl, C ₆ _i6 heteroarylalkyl, and substituted C _6-1 6 heteroarylalkyl;

one of R ¹ , R ² , R ³ , R ⁴ , and R ⁵ comprises a chemotherapeutic moiety;

each of the other of R ¹ , R ² , R ³ , R ⁴ , and R ⁵ is independently selected from hydrogen, deuterio, halogen, -OH, -N(R ¹⁰ ) ₂ , -N0 ₂ , -NO, -CN, -COOR ¹⁰ , -CON(R ¹⁰ ) ₂ , Ci_ ₄ alkylsulfanyl, Ci_ ₄ alkylsulfinyl, Ci_ ₄ alkylsulfonyl, Ci_ ₆ alkyl, substituted Ci_ ₆ alkyl, C ₃ _ ₆ cycloalkyl, substituted C ₃ _ ₆ cycloalkyl, Ci_ ₆ heteroalkyl, substituted Ci_ ₆ heteroalkyl, Ci_ ₆ alkoxy, substituted Ci_ ₆ alkoxy, Ci_ ₆ heteroalkoxy, substituted Ci_ ₆ heteroalkoxy, C ₄ _8 cycloalkylalkyl, and C ₄ _8 cycloalkylheteroalkyl;

R ⁶ is selected from a carboxylic acid (-COOH), a carboxylic acid analog, and a carboxylic acid (bio)isostere;

each R ⁷ is independently selected from hydrogen, deuterio, halogen, hydroxyl, Ci_ ₆ alkyl, C ₃ _ ₆ cycloalkyl, benzyl, and phenyl; or two R ⁷ together with the carbon to which they are bonded form a ring selected from a C ₃ _ ₆ cycloalkyl ring and a C ₃ _ ₆ heterocycloalkyl ring;

R ⁸ is selected from hydrogen, deuterio, halogen, Ci_ ₆ alkyl, substituted Ci_ ₆ alkyl, Ci_ ₆ heteroalkyl, substituted Ci_ ₆ heteroalkyl, Ci_ ₆ alkoxy, substituted Ci_ ₆ alkoxy, Ci_ ₆

heteroalkoxy, substituted Ci_ ₆ heteroalkoxy, C ₃ _ ₆ cycloalkyl, substituted C ₃ _ ₆ cycloalkyl, C ₃ _ ₆ cycloalkyloxy, substituted C ₃ _ ₆ cycloalkyloxy, -OH, -COOR ¹⁰ , Ci_ ₄ fluoroalkyl, Ci_ ₄ fluoroalkoxy, C ₃ _ ₆ cycloalkyl, and phenyl;

each R ¹⁰ is independently selected from hydrogen, deuterio, Ci_ ₄ alkyl, and Ci_ ₄ alkoxy, or two geminal R ¹⁰ together with the nitrogen to which they are bonded form a 3- to 6-membered heterocyclic ring; and

L is -(X) _a -, wherein, each X is independently selected from a bond ("-"),-C(R ) ₂ -, wherein each R ¹⁶ is independently selected from hydrogen, deuterio, halogen, hydroxyl, Ci_ ₄ alkyl, and Ci_ ₄ alkoxy, or two R ¹⁶ together with the carbon to which they are bonded form a C ₃ _6 cycloalkyl ring or a C ₃ _ ₆ heterocycloalkyl ring, -0-, -S-, -SO-, -S0 ₂ -, -CO-, and -N(R ¹⁷ )-, wherein R ¹⁷ is selected from hydrogen and Ci_ ₄ alkyl; and

a is selected from 0, 1, 2, 3, and 4.

[0015] In a second aspect, chemotherapeutic moieties are provided, comprising a chemotherapeutic moiety of chemotherapeutic drugs known in the art that retains cytotoxic activity when bonded through a spacing moiety, e.g., an aryl ring and a linker L, to a γ-amino acid derivative, γ-amino acid analog, or γ-amino acid carboxylic acid (bio)isostere as a LATl recognition element provided by the present disclosure. The conjugate or fusion product of the chemotherapeutic moiety with the γ-amino acid derivative, γ-amino acid analog, or γ- amino acid carboxylic acid (bio)isostere is a selective substrate for the LATl/4F2hc transporter.

[0016] In a third aspect, chemotherapeutic moieties are provided wherein the

chemotherapeutic moiety is selected from a nitrogen mustard -N(-CR ₂ -CR ₂ -X) ₂ , a N- monoalkyl or N,N-dialkyl triazene (-N=N-NR ₂ ), a haloacetamide (-NR-CO-CH ₂ -X), an epoxide (-CROCR-R), an aziridine (-NC ₂ H ₄ ), a Michael acceptor (-CR=CR-EWG-), a sulfonate or a bissulfonate ester (-OS0 ₂ R or ROS0 ₂ -), an N-nitrosourea (-NR-CO- N(NO)R), a bissulfonyl hydrazine (R"S0 ₂ -NR-N(-)-S0 ₂ R ^* ", -S0 ₂ -NR-NR-S0 ₂ R ^m , or R"S0 ₂ -NR-NR-S0 ₂ -), a phosphoramidate (-0-P(=0)(N(R)-CH ₂ -CH ₂ -X) ₂ or -O- P(=0)(N(-CH ₂ -CH ₂ -X) ₂ ) ₂ , and a radionuclide such as, for example, 131-iodine ( ¹³¹ [I] -) or 211-astatine ( ²¹¹ [At] -).

[0017] In a fourth aspect, chemotherapeutic moieties of Formula (2) are proviced:

(2)

wherein, A is selected from a bond ("-"), oxygen (-0-), sulfur (-S-), amino (-NR -), methylene (-CH ₂ -), methyleneoxy (-CH ₂ -0-), oxycarbonyl (-0-C(=0)-), thiocarbonyl (- S-C(=0)-), aminocarbonyl (-NR ¹⁰ -C(=O)-), oxythiocarbonyl (-0-C(=S)-),

thiothiocarbonyl (-S-C(=S)-), aminothiocarbonyl (-NR ¹⁰ -C(=S)-), methyleneoxycarbonyl (-CH ₂ -0-C(=0)-), methylenethiocarbonyl (-CH ₂ -S-C(=0)-), methyleneammocarbonyl (- CH ₂ -NR ¹⁰ -C(=O)-), methyleneoxythiocarbonyl (-CH ₂ -0-C(=S)-),

methylenethiothiocarbonyl (-CH ₂ -S-C(=S)-), methyleneaminothiocarbonyl (-CH ₂ -NR ¹⁰ - C(=S)-), carbonyl (-C(=0)-), methylencarbonyl (-CH ₂ -C(=0)-), thiocarbonyl (-C(=S)-), and methylenthiocarbonyl (-CH ₂ -C(=S)-);

Z is selected from a bond ("-") and oxygen (-0-);

Q is selected from -0 ^~ (a negatively charged oxygen atom) that is bound to a positively charged nitrogen atom) and a free electron pair (:), with the proviso that when Q is -0 ^~ (a negatively charged oxygen atom that is bound to a positively charged nitrogen atom), A is selected from a bond ("-") and methylene (-CH ₂ -),Z is a bond ("-"), and the chemotherapeutic moiety of Formula (2) is an N-oxide (-A-N ⁺ (-0 )(-C(R ¹ QR ¹

R ⁹ ) ₂ );

each R ¹¹ is independently selected from hydrogen, deuterio, and Ci_ ₃ alkyl; and each R ⁹ is independently selected from fluoro (-F), chloro (-C1), bromo (-Br), iodo (- I), alkyl sulfonate (-OS0 ₂ R ⁴⁰ , wherein R ⁴⁰ is selected from Ci_ ₄ alkyl), Ci_ ₄ (per)fluoroalklyl sulfonate (-OS0 ₂ R ⁴⁰ , wherein R ⁴⁰ is selected from Ci_ ₄ (per)fluoroalkyl), and (substituted) aryl sulfonate (-OS0 ₂ R ⁴⁰ , wherein R ⁴⁰ is selected from C ₆ _io aryl).

[0018] In a fifth aspect, pharmaceutical compositions are provided comprising a compound of Formula (1) and at least one pharmaceutically acceptable vehicle.

[0019] In a sixth aspect, methods for treating cancer in a patient comprising,

administering a compound of Formula (1) or a pharmaceutical composition comprising a compound of Formula (1) to a patient in need of such treatment comprising administering a therapeutically effective amount of the compound to the patient are provided.

Detailed Description

Definitions

[0020] A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a moiety or substituent. For example, -CONH ₂ is attached through the carbon atom.

[0021] "Alkyl" refers to a saturated or unsaturated, branched, or straight-chain, monovalent hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane, alkene, or alkyne. Examples of alkyl groups include methyl; ethyls such as ethanyl, ethenyl, and ethynyl; propyls such as propan-l-yl, propan-2-yl, prop-l-en-l-yl, prop-l-en-2-yl, prop-2-en-l-yl (allyl), prop-l-yn-l-yl, prop-2-yn-l-yl, etc.; butyls such as butan-l-yl, butan-2-yl, 2-methyl-propan-l-yl, 2-methyl-propan-2-yl, but-l-en-l-yl, but-l-en-2-yl, 2-methyl-prop-l-en-l-yl, but-2-en-l-yl, but-2-en-2-yl, buta-l ,3-dien-l-yl, buta-l ,3-dien-2-yl, but-l-yn-l-yl, but-l-yn-3-yl, but-3-yn-l-yl, etc. ; and the like. The term "alkyl" is specifically intended to include groups having any degree or level of saturation, i.e., groups having exclusively carbon-carbon single bonds, groups having one or more carbon-carbon double bonds, groups having one or more carbon-carbon triple bonds, and groups having combinations of carbon-carbon single, double, and triple bonds. Where a specific level of saturation is intended, the terms alkanyl, alkenyl, and alkynyl are used. In certain embodiments, an alkyl group is Ci_ ₆ alkyl, Ci_ ₅ alkyl, Ci_ ₄ alkyl, Ci_ ₃ alkyl, and in certain embodiments, ethyl or methyl.

[0022] "Alkylsulfanyl" also referred to as "alkylthio", refers to a radical -SR where R is alkyl or cycloalkyl as defined herein. Examples of alkylsulfanyl groups include

methylsulfanyl, ethylsulfanyl, propylsulfanyl, isopropylsulfanyl, butylsulfanyl, and cyclohexylsulfanyl. In certain embodiments, an alkylsulfanyl group is Ci_ ₆ alkylsulfanyl, in certain embodiments, Ci_ ₅ alkylsulfanyl, in certain embodiments, Ci_ ₄ alkylsulfanyl, in certain embodiments, Ci_ ₃ alkylsulfanyl, in certain embodiments, ethylsulfanyl (ethylthio), and in certain embodiments, methylsulfanyl (methylthio).

[0023] "Alkylsulfmyl'' refers to a radical -S(0)R where R is alkyl or cycloalkyl as defined herein. Examples of alkylsulfmyl groups include methylsulfmyl, ethylsulfinyl, propylsulfinyl, isopropylsulfmyl, butylsulfmyl, and cyclohexylsulfinyl. In certain

embodiments, an alkylsulfmyl group is Ci_ ₆ alkylsulfmyl, in certain embodiments, Ci_ ₅ alkylsulfmyl, in certain embodiments, Ci_ ₄ alkylsulfmyl, in certain embodiments, Ci_ ₃ alkylsulfmyl, in certain embodiments, ethylsulfinyl, and in certain embodiments,

methylsulfmyl.

[0024] "Alkylsulfonyl" refers to a radical -S(0) ₂ R where R is alkyl or cycloalkyl as defined herein. Examples of alkylsulfonyl groups include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, and cyclohexylsulfonyl. In certain embodiments, an alkylsulfonyl group is Ci_ ₆ alkylsulfonyl, in certain embodiments, Ci_ ₅ alkylsulfonyl, in certain embodiments, Ci_ ₄ alkylsulfonyl, in certain embodiments, Ci_ ₃ alkylsulfonyl, in certain embodiments, ethylsulfonyl, and in certain embodiments, methylsulfonyl. [0025] "Alkoxy" refers to a radical -OR where R is alkyl as defined herein. Examples of alkoxy groups include methoxy, ethoxy, propoxy, and butoxy. In certain embodiments, an alkoxy group is Ci_ ₆ alkoxy, in certain embodiments, Ci_ ₅ alkoxy, in certain embodiments, Ci_ 4 alkoxy, in certain embodiments, Ci_ ₃ alkoxy, and in certain embodiments, ethoxy or methoxy.

[0026] "Aryl" by itself or as part of another substituent refers to a monovalent aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. Aryl encompasses 5- and 6-membered carbocyclic aromatic rings, for example, benzene; bicyclic ring systems wherein at least one ring is carbocyclic and aromatic, for example, naphthalene, indane, and tetralin; and tricyclic ring systems wherein at least one ring is carbocyclic and aromatic, for example, fluorene. Aryl encompasses multiple ring systems having at least one carbocyclic aromatic ring fused to at least one carbocyclic aromatic ring, cycloalkyl ring, or heterocycloalkyl ring. For example, aryl includes a phenyl ring fused to a 5- to 7-membered heterocycloalkyl ring containing one or more heteroatoms selected from N, O, and S. For such fused, bicyclic ring systems wherein only one of the rings is a carbocyclic aromatic ring, the radical carbon atom may be at the carbocyclic aromatic ring or at the heterocycloalkyl ring. Examples of aryl groups include groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s- indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene, and the like. In certain embodiments, an aryl group is C _6-1 o aryl, C ₆ _ aryl, C ₆ -8 aryl, and in certain embodiments, phenyl. Aryl, however, does not encompass or overlap in any way with heteroaryl, separately defined herein.

[0027] "Arylalkyl" refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom is replaced with an aryl group. Examples of arylalkyl groups include benzyl, 2-phenylethan-l-yl, 2-phenylethen-l-yl, naphthylmethyl, 2-naphthylethan-l-yl, 2-naphthylethen-l-yl, naphthobenzyl, 2-naphthophenylethan-l-yl and the like. Where specific alkyl moieties are intended, the nomenclature arylalkanyl, arylalkenyl, or arylalkynyl is used. In certain embodiments, an arylalkyl group is C _7-16 arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is Ci_ ₆ and the aryl moiety is C ₆ -io, in certain embodiments, an arylalkyl group is C ₇ _i6 arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is Ci_ ₆ and the aryl moiety is C ₆ -io. In certain embodiments an arylalkyl group is C ₇ _9 arylalkyl, wherein the alkyl moiety is Ci_ ₃ alkyl and the aryl moiety is phenyl. In certain embodiments, an arylalkyl group is C ₇ _i ₆ arylalkyl, C ₇ _i ₄ arylalkyl, C ₇ _i ₂ arylalkyl, C ₇ _io arylalkyl, C ₇ _8 arylalkyl, and in certain embodiments, benzyl.

[0028] Bioisosteres are atoms or molecules that fit the broadest definition for isosteres. The concept of bioisosterism is based on the notion that single atom, groups, moieties, or whole molecules, which have chemical and physical similarities produce similar biological effects. A bioisostere of a parent compound can still be recognized and accepted by its appropriate target, but its functions will be altered as compared to the parent molecule.

Parameters affected with bioisosteric replacements include, for example, size, conformation, inductive and mesomeric effects, polarizability, capacity for electrostatic interactions, charge distribution, H-bond formation capacity, pKa (acidity), solubility, hydrophobicity, lipophilicity, hydrophilicity, polarity, potency, selectivity, reactivity, or chemical and metabolic stability, ADME (absorption, distribution, metabolism, and excretion). Although common in pharmaceuticals, carboxyl groups or carboxylic acid functional groups ( ^~ C0 ₂ H) in a parent molecule may be replaced with a suitable surrogate or (bio)isostere to overcome chemical or biological shortcomings while retaining the desired attributes of the parent molecule bearing one or more carboxyl groups or carboxylic acid functional groups

(-C0 ₂ H). Examples of suitable surrogates or (bio)isosteres of carboxyl groups or carboxylic acid functional groups ( ^~ C0 ₂ H) include hydroxamic acids (-CONR ¹² OH); boronic acids (- B(OH)(OR ¹² ), phosphinic acids or derivatives thereof (-PO(OH)R ¹² ), phosphonic acid or derivatives thereof (-PO(OH)(OR ¹² ), sulfuric acid (-SOOH), sulfonic acid (-S0 ₂ OH), sulfonamide (-S0 ₂ NHR ¹² or -NHS0 ₂ R ¹² ), sulfonimide or acyl sulfonimide (-S0 ₂ NHCOR ¹² or -CONHS0 ₂ R ¹² ), sulfonylureas (-S0 ₂ NHCONHR ¹² or -NHCONHS0 ₂ R ¹² ), amide (- CONHR ¹² or -NHCOR ¹² ), wherein R ¹² in any of the foregoing is selected from hydrogen, Ci_ 6 alkyl, Ci_ ₄ fluoroalkyl, C ₃ _ ₆ cycloalkyl, and C ₆ _io aryl, acylcyanamide (-CONHCN); 2,2,2- trifluoroethan-l-ols (-CH(CF ₃ )OH), 2,2,2-trifluoromethyl ketones and hydrates thereof (- COCF ₃ and -C(OH) ₂ CF ₃ ), acidic heterocycles and their annular tautomers such as, for example, tetrazole, 5-oxo-l ,2,4-oxadiazole, 5-oxo-l ,2,4-thiadiazole, 5-thioxo-l ,2,4- oxadiazole, thiazolidinedione, oxazolidinedione, oxadiazolidinedione, 3-hydroxyisoxazole, 3- hydroxyisothiazole, 1 -hydroxy-imidazole, 1-hydroxy-pyrazole, 1-hydroxy-triazole, 1H- imidazol-2-ol, tetrazole-5 -thiol, 3 -hydroxy quinolin-2-ones, 4-hydroxyquinolin-2-ones, tetronic acid, tetramic acid, mercaptoazoles such as sulfanyl-lH-imidazole, sulfmyl-lH- imidazole, sulfonyl-lH-imidazole, sulfanyl-lH-triazole, sulfinyl-lH-triazole, sulfonyl-lH- triazole, sulfanyl-lH-l ,2,4-triazole, sulfinyl-lH-l ,2,4-triazole, sulfonyl-lH-l ,2,4-triazole, sulfanyl- 1 ,4-dihydro-l ,2,4-triazol-5-one, sulfmyl- 1 ,4-dihydro- 1 ,2,4-triazol-5-one, sulfonyl- l,4-dihydro-l,2,4-triazol-5-one, sulfanyl lH-tetrazole, sulfanyl 2H-tetrazole, sulfmyl 1H- tetrazole, sulfinyl 2H-tetrazole, sulfonyl lH-tetrazole, sulfonyl 2H-tetrazole, or

sulfonimidamides; and acidic oxocarbocycles or cyclic polyones and their resonance forms such as, for example, cyclopentane-l,3-diones, squaric acids, squareamides, mixed squaramates, or 2,6-difluorophenols.

[0029] "Compounds" of Formula (1) disclosed herein include any specific compounds within these formulae. Compounds may be identified either by their chemical structure and/or chemical name. Compounds are named using the ChemDraw Ultra 12.0 (CambridgeSoft, Cambridge, MA) nomenclature program. When the chemical structure and chemical name conflict the chemical structure is determinative of the identity of the compound. The compounds described herein may comprise one or more stereogenic centers and/or double bonds and therefore may exist as stereoisomers such as double-bond isomers (i.e., geometric isomers), enantiomers, diastereomers, or atropisomers. Accordingly, any chemical structures within the scope of the specification depicted, in whole or in part, with a relative

configuration encompass all possible enantiomers and stereoisomers of the illustrated compounds including the stereoisomerically pure form (e.g., geometrically pure,

enantiomerically pure, or diastereomerically pure) and enantiomeric and stereoisomeric mixtures. Enantiomeric and stereoisomeric mixtures may be resolved into their component enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known to the skilled artisan.

[0030] Compounds of Formula (1) include optical isomers of compounds of Formula (1), racemates thereof, and other mixtures thereof. In such embodiments, the single enantiomers or diastereomers may be obtained by asymmetric synthesis or by resolution of the racemates. Resolution of the racemates may be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral high-pressure liquid chromatography (HPLC) column with chiral stationary phases. In addition, compounds of Formula (1) include (Z)- and (E)-forms (or cis- and transforms) of compounds with double bonds either as single geometric isomers or mixtures thereof.

[0031] Compounds of Formula (1) may also exist in several tautomeric forms including the enol form, the keto form, and mixtures thereof. Accordingly, the chemical structures depicted herein encompass all possible tautomeric forms of the illustrated compounds.

Compounds may exist in unsolvated forms as well as solvated forms, including hydrated forms. Certain compounds may exist in multiple crystalline, co-crystalline, or amorphous forms. Compounds of Formula (1) include pharmaceutically acceptable salts thereof, or pharmaceutically acceptable solvates of the free acid form of any of the foregoing, as well as crystalline forms of any of the foregoing

[0032] Compounds of Formula (1) are also referred to herein as β-substituted γ-amino acid derivatives and/or as β-substituted γ-amino acid analogs or (bio)isosteres.

[0033] "Chemotherapeutic moiety" refers to a moiety effective in treating cancer including, any of those disclosed herein. In certain embodiments, a chemotherapeutic moiety may be any suitable chemotherapeutic moiety of a chemotherapeutic drug known in the art that retains cytotoxic activity when bonded either directly or indirectly through a suitable spacing moiety to a γ-amino acid derivative, γ-amino acid analog, or γ-amino acid carboxylic acid (bio)isostere as a LAT1 recognition element provided by the present disclosure. The conjugate or fusion product of the chemotherapeutic moiety with the γ-amino acid derivative, β-amino acid analog, or β-amino acid carboxylic acid (bio)isostere is simultaneous a selective substrate for the LATl/4F2hc transporter.

[0034] In certain embodiments, the chemotherapeutic moiety, is selected from a nitrogen mustard (-N(-CR ₂ -CR ₂ -X) ₂ ), a N-monoalkyl or N,N-dialkyl triazene (-N=N-NR ₂ ), a haloacetamide (-NR-CO-CH ₂ -X), an epoxide (-CROCR-R), an aziridine (-NC ₂ H ₄ ), a Michael acceptor (-CR=CR-EWG-), a sulfonate or a bissulfonate ester (-OS0 ₂ R or ROS0 ₂ - ), an N-nitrosourea (-NR-CO-N(NO)R), a bissulfonyl hydrazine (R"S0 ₂ -NR-N(-)-S0 ₂ R ^m , -S0 ₂ -NR-NR ^, -S0 ₂ R ^m , or R"S0 ₂ -NR-NR-S0 ₂ -), a phosphoramidate (-0-P(=0)(N(R)- CH ₂ -CH ₂ -X) ₂ or -0-P(=0)(N(-CH ₂ -CH ₂ -X) ₂ ) ₂ , and a radionuclide such as, for example, 131-iodine ( ¹³¹ [I] -) or 211-astatine ( ²¹¹ [At] -).

[0035] In certain embodiments of a compound of Formula (1), the chemotherapeutic moiety is a moiety Formula (2a):

-A-NQ(-Z-C(R ¹ -CiR ¹ ^-R'X-QR ¹¹ ) ₂ -C(R ¹ ^-R ⁹ ) (2a) wherein,

A is selected from a bond ("-"), oxygen (-0-), sulfur (-S-), amino (-NR ¹⁰ -), methylene (-CH ₂ -), methyleneoxy (-CH ₂ -0-), oxycarbonyl (-0-C(=0)-), thiocarbonyl (- S-C(=0)-), aminocarbonyl (-NR ¹⁰ -C(=O)-), oxythiocarbonyl (-0-C(=S)-),

thiothiocarbonyl (-S-C(=S)-), aminothiocarbonyl (-NR ¹⁰ -C(=S)-), methyleneoxycarbonyl (-CH ₂ -0-C(=0)-), methylenethiocarbonyl (-CH ₂ -S-C(=0)-), methyleneaminocarbonyl (- CH ₂ -NR ¹⁰ -C(=O)-), methyleneoxythiocarbonyl (-CH ₂ -0-C(=S)-),

methylenethiothiocarbonyl (-CH ₂ -S-C(=S)-), methyleneaminothiocarbonyl (-CH ₂ -NR ¹⁰ - C(=S)-), carbonyl (-C(=0)-), methylencarbonyl (-CH ₂ -C(=0)-), thiocarbonyl (-C(=S)-), and methylenthiocarbonyl (-CH ₂ -C(=S)-);

Z is selected from a bond ("-") and oxygen (-0-);

Q is selected from -0 ^~ (a negatively charged oxygen atom) that is bound to a positively charged nitrogen atom) and a free electron pair (:), with the proviso that when Q is -0 ^~ (a negatively charged oxygen atom that is bound to a positively charged nitrogen atom), A is selected from a bond ("-") and methylene (-CH ₂ -),Z is a bond ("-"), and the chemotherapeutic moiety of Formula (2) is an N-oxide (-A-N ⁺ (-0 )(-C(R ¹ QR ¹

R ⁹ ) ₂ );

each R ¹¹ is independently selected from hydrogen, deuterio, and Ci_ ₃ alkyl; and each R ⁹ is independently selected from fluoro (-F), chloro (-C1), bromo (-Br), iodo (- I), alkyl sulfonate (-OS0 ₂ R ⁴ °, wherein R ⁴⁰ is selected from Ci_ ₄ alkyl), Ci_ ₄ (per)fluoroalklyl sulfonate (-OS0 ₂ R ⁴ °, wherein R ⁴⁰ is selected from Ci_ ₄ (per)fluoroalkyl), and (substituted) aryl sulfonate (-OS0 ₂ R ⁴ °, wherein R ⁴⁰ is selected from C _6-1 o aryl).

[0036] "Cycloalkyl" refers to a saturated or partially unsaturated cyclic alkyl radical. In certain embodiments, a cycloalkyl group is C ₃ _ ₆ cycloalkyl, C ₃ _ ₅ cycloalkyl, C ₅ _ ₆ cycloalkyl, cyclopropyl, cyclopentyl, and in certain embodiments, cyclohexyl. In certain embodiments, cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0037] "Cycloalkylalkyl" refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom is replaced with a cycloalkyl group as defined herein. Where specific alkyl moieties are intended, the nomenclature cycloalkylalkyl, cycloalkylalkenyl, or cycloalkylalkynyl is used. In certain embodiments, a cycloalkylalkyl group is C ₄ _ ₃ o cycloalkylalkyl, e.g., the alkanyl, alkenyl, or alkynyl moiety of the cycloalkylalkyl group is Ci_io and the cycloalkyl moiety of the cycloalkylalkyl moiety is C ₃ _ ₂ o, and in certain embodiments, an cycloalkylalkyl group is C ₄ _ ₂ o cycloalkylalkyl, e.g., the alkanyl, alkenyl, or alkynyl moiety of the cycloalkylalkyl group is Ci_8 and the cycloalkyl moiety of the cycloalkylalkyl group is C ₃ _i ₂ . In certain embodiments, cycloalkylalkyl is C ₄ _9

cycloalkylalkyl, wherein the alkyl moiety of the cycloalkylalkyl group is Ci_ ₃ alkyl, and the cycloalkyl moiety of the cycloalkylalkyl group is C ₃ _ ₆ cycloalkyl. In certain embodiments, a cycloalkylalkyl group is C _4-12 cycloalkylalkyl, C _4-10 cycloalkylalkyl, C ₄ -8 cycloalkylalkyl, and C ₄ _6 cycloalkylalkyl. In certain embodiments a cycloalkylalkyl group is cyclopropylmethyl (- CH ₂ -cyclo-C ₃ H ₅ ), cyclopentylmethyl or cyclohexylmethyl (-CH ₂ - cyclo-CeHn). In certain embodiments a cycloalkylalkyl group is cyclopropylethenyl (- CH=CH-cyclo-C ₃ H ₅ ), cyclopentylethynyl (-C≡C-cyclo-C ₅ H ₉ ), or the like. [0038] "Cycloalkylheteroalkyl" by itself or as part of another substituent refers to a heteroalkyl group in which one or more of the carbon atoms (and certain associated hydrogen atoms) of an alkyl group are independently replaced with the same or different heteroatomic group or groups and in which one of the hydrogen atoms bonded to a carbon atom is replaced with a cycloalkyl group. Where specific alkyl moieties are intended, the nomenclature cycloalkylheteroalkanyl, cycloalkylheteroalkenyl, and cycloalkylheteroalkynyl is used. In certain embodiments of cycloalkylheteroalkyl, the heteroatomic group is selected from -0-, -S-, -NH-, -N(-CH ₃ )-, -SO-, and -S0 ₂ -, in certain embodiments, the heteroatomic group is selected from -O-and -NH-, and in certain embodiments the heteroatomic group is -O- or -NH-.

[0039] "Cycloalkyloxy" refers to a radical -OR where R is cycloalkyl as defined herein. Examples of cycloalkyloxy groups include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy. In certain embodiments, a cycloalkyloxy group is C ₃ _ ₆ cycloalkyloxy, in certain embodiments, C ₃ _ ₅ cycloalkyloxy, in certain embodiments, C ₅ _6 cycloalkyloxy, and in certain embodiments, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, or cyclohexyloxy.

[0040] "Disease" refers to a disease, disorder, condition, or symptom of any of the foregoing.

[0041] "Fluoroalkyl" refers to an alkyl group as defined herein in which one or more of the hydrogen atoms is replaced with a fluoro. In certain embodiments, a fluoroalkyl group is Ci_6 fluoroalkyl, Ci_ ₅ fluoroalkyl, Ci_ ₄ fluoroalkyl, Ci_ ₃ fluoroalkyl. In certain embodiments, the fluoroalkyl group is pentafluoroethyl (-CF ₂ CF ₃ ), in certain embodiments, trifluoromethyl (-CF ₃ ).

[0042] "Fluoroalkoxy" refers to an alkoxy group as defined herein in which one or more of the hydrogen atoms is replaced with a fluoro. In certain embodiments, a fluoroalkoxy group is Ci_6 fluoroalkoxy, Ci_ ₅ fluoroalkoxy, Ci_ ₄ fluoroalkoxy Ci_ ₃ fluoroalkoxy, and in certain embodiments, -OCF ₂ CF ₃ or -OCF ₃ .

[0043] "β-Substituted γ-amino acid derivative" refers to β-substituted γ-amino acid derivatives having a carboxyl group.

[0044] "β-Substituted γ-amino acid analog" refers to β-substituted γ-amino acid derivatives in which the carboxyl group is replaced with a phosphinic acid group, a sulfuric acid group, a lH-tetrazole, or any of the other suitable carboxylic acid (bio)isosteres as defined herein, e.g., 3-aminopropylphosphinic acids, 3-aminopropylsulfmic acids, and others.

[0045] "Halogen" refers to a fluoro, chloro, bromo, or iodo group. [0046] "Heteroalkoxy" refers to an alkoxy group in which one or more of the carbon atoms are replaced with a heteroatom. In certain embodiments, the heteroalkoxy group is Ci_ ₆ heteroalkoxy, in certain embodiments, Ci_ ₅ heteroalkoxy, in certain embodiments, Ci_ ₄ heteroalkoxy, and in certain embodiments, Ci_ ₃ heteroalkoxy. In certain embodiments of heteroalkoxy, the heteroatomic group is selected from -0-, -S-, -NH-, -NR-, -S0 ₂ -, and - S0 ₂ -, in certain embodiments, the heteroatomic group is selected from -O- and -NH-, and in certain embodiments the heteroatomic group is -O- and -NH-. In certain embodiments, a heteroalkoxy group is Ci_ ₆ heteroalkoxy, Ci_5 heteroalkoxy, Ci_ ₄ heteroalkoxy, and in certain embodiments Ci_ ₃ heteroalkoxy.

[0047] "Heteroalkyl" by itself or as part of another substituent refer to an alkyl group in which one or more of the carbon atoms (and certain associated hydrogen atoms) are independently replaced with the same or different heteroatomic group or groups. Examples of heteroatomic groups include -0-, -S-, -NH-, -NR-, -0-0-, -S-S-, =N-N=, -N=N- - N=N-NR- -PR-, -P(0)OR- -P(0)R- -POR-, -SO-, -S0 ₂ - -Sn(R) ₂ - and the like, where each R is independently selected from hydrogen, Ci_ ₆ alkyl, substituted Ci_ ₆ alkyl, C _6-12 aryl, substituted C _6-12 aryl, C ₇ _i ₈ arylalkyl, substituted C ₇ _i ₈ arylalkyl, C ₃ _ ₇ cycloalkyl, substituted C ₃ _ ₇ cycloalkyl, C ₃ _ ₇ heterocycloalkyl, substituted C ₃ _ ₇ heterocycloalkyl, Ci_ ₆ heteroalkyl, substituted Ci_ ₆ heteroalkyl, C _6-12 heteroaryl, substituted C _6-12 heteroaryl, C ₇ _ig heteroarylalkyl, and substituted C ₇ _is heteroarylalkyl. In certain embodiments, each R is independently selected from hydrogen and Ci_ ₃ alkyl. Reference to, for example, a Ci_ ₆ heteroalkyl, means a Ci_ ₆ alkyl group in which at least one of the carbon atoms (and certain associated hydrogen atoms) is replaced with a heteroatom. For example, Ci_ ₆ heteroalkyl includes groups having five carbon atoms and one heteroatom, groups having four carbon atoms and two heteroatoms, etc. In certain embodiments of heteroalkyl, the heteroatomic group is selected from -0-, -S-, -NH-, -N(-CH ₃ )-, -SO-,and -S0 ₂ -, in certain

embodiments, the heteroatomic group is selected from -O- and -NH-, and in certain embodiments, the heteroatomic group is -O- and -NH-. In certain embodiments, a heteroalkyl group is Ci_ ₆ heteroalkyl, Ci_ ₅ heteroalkyl, Ci_ ₄ heteroalkyl, and in certain embodiments Ci_ ₃ heteroalkyl.

[0048] "Heteroaryl" by itself or as part of another substituent refers to a monovalent heteroaromatic radical derived by the removal of one hydrogen atom from a single atom of a parent heteroaromatic ring system. Heteroaryl encompasses multiple ring systems having at least one heteroaromatic ring fused to at least one other ring, which may be aromatic or non- aromatic. For example, heteroaryl encompasses bicyclic rings in which one ring is heteroaromatic and the second ring is a heterocycloalkyl ring. For such fused, bicyclic heteroaryl ring systems wherein only one of the rings contains one or more heteroatoms, the radical carbon may be at the aromatic ring or at the heterocycloalkyl ring. In certain embodiments, when the total number of N, S, and O atoms in the heteroaryl group exceeds one, the heteroatoms may or may not be adjacent to one another. In certain embodiments, the total number of heteroatoms in the heteroaryl group is not more than two. In certain embodiments of heteroaryl, the heteroatomic group is selected from -0-, -S-, -NH-, -N(- CH ₃ )-, -SO-, and -S0 ₂ -, in certain embodiments, the heteroatomic group is selected from - O- and -NH-, and in certain embodiments the heteroatomic group is -O- or -NH-. In certain embodiments, a heteroaryl group is selected from C _5-10 heteroaryl, C5-9 heteroaryl, C _5- 8 heteroaryl, C ₅ _ ₇ heteroaryl, C ₅ _6 heteroaryl, and in certain embodiments, is C ₅ heteroaryl or C ₆ heteroaryl.

[0049] Examples of heteroaryl groups include groups derived from acridine, arsindole, carbazole, a-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, thiazolidine, oxazolidine, and the like. In certain embodiments, heteroaryl groups are those derived from thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole, oxazole, or pyrazine. For example, in certain embodiments, heteroaryl is C ₅ heteroaryl and is selected from furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl. In certain embodiments, heteroaryl is C ₆ heteroaryl, and is selected from pyridinyl, pyrazinyl, pyrimidinyl, and pyridazinyl.

[0050] "Heteroarylalkyl" refers to an arylalkyl group in which one of the carbon atoms (and certain associated hydrogen atoms) is replaced with a heteroatom. In certain

embodiments, a heteroarylalkyl group is C _6-1 6 heteroarylalkyl, C _6-14 heteroarylalkyl, C _6-12 heteroarylalkyl, C _6-10 heteroarylalkyl, C ₆ _8 heteroarylalkyl, C ₇ heteroarylalkyl, and in certain embodiments, C ₆ heteroarylalkyl. In certain embodiments of heteroarylalkyl, the

heteroatomic group is selected from -0-, -S-, -NH-, -N(-CH ₃ )-, -SO-, and -S0 ₂ -, in certain embodiments, the heteroatomic group is selected from -O-and -NH-, and in certain embodiments the heteroatomic group is -O- or -NH-. [0051] "Heterocycloalkyl" by itself or as part of another substituent refers to a saturated or unsaturated cyclic alkyl radical in which one or more carbon atoms (and certain associated hydrogen atoms) are independently replaced with the same or different heteroatom; or to a parent aromatic ring system in which one or more carbon atoms (and certain associated hydrogen atoms) are independently replaced with the same or different heteroatom such that the ring system violates the Huckel-rule. Examples of heteroatoms to replace the carbon atom(s) include N, P, O, S, and Si. Examples of heterocycloalkyl groups include groups derived from epoxides, azirines, thiiranes, imidazolidine, morpholine, piperazine, piperidine, pyrazolidine, pyrrolidine, quinuclidine, and the like. In certain embodiments,

heterocycloalkyl is C ₅ heterocycloalkyl and is selected from pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, doxolanyl, and dithiolanyl. In certain embodiments, heterocycloalkyl is C ₆ heterocycloalkyl and is selected from piperidinyl, tetrahydropyranyl, piperizinyl, oxazinyl, dithianyl, and dioxanyl. In certain embodiments a heterocycloalkyl group is C3-6 heterocycloalkyl, C3-5 heterocycloalkyl, C5-6 heterocycloalkyl, and in certain embodiments, C ₅ heterocycloalkyl or C ₆ heterocycloalkyl. In certain embodiments of heterocycloalkyl, the heteroatomic group is selected from -0-, -S-, -NH-, -N(-CH ₃ )-, -SO-, and -S0 ₂ -, in certain embodiments, the heteroatomic group is selected from -O-and -NH-, and in certain embodiments the heteroatomic group is -O- or - NH-.

[0052] "Heterocycloalkylalkyl" refers to a cycloalkylalkyl group in which one or more carbon atoms (and certain associated hydrogen atoms) of the cycloalkyl ring are

independently replaced with the same or different heteroatom. In certain embodiments, the heterocycloalkylalkyl is C ₄ _i ₂ heterocycloalkylalkyl, C ₄ _io heterocycloalkylalkyl, C ₄ _8 heterocycloalkylalkyl, C ₄ _ ₆ heterocycloalkylalkyl, C ₆ _ ₇ heterocycloalkylalkyl, and in certain embodiments, C ₆ heterocycloalkylalkyl or C ₇ heterocycloalkylalkyl. In certain embodiments of heterocycloalkylalkyl, the heteroatomic group is selected from -0-, -S-, -NH-, -N(- CH ₃ )-, -SO-, and -S0 ₂ -, in certain embodiments, the heteroatomic group is selected from - O- and -NH-, and in certain embodiments the heteroatomic group is -O- or -NH-.

[0053] "Mesyl" refers to the group -OS(0) ₂ Me or -OMs.

[0054] "Parent aromatic ring system" refers to an unsaturated cyclic or polycyclic ring system having a cyclic conjugated π (pi) electron system with 4n+2 electrons (Hiickel rule). Included within the definition of "parent aromatic ring system" are fused ring systems in which one or more of the rings are aromatic and one or more of the rings are saturated or unsaturated, such as, for example, fluorene, indane, indene, phenalene, etc. Examples of parent aromatic ring systems include aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene, and the like.

[0055] "Parent heteroaromatic ring system" refers to an aromatic ring system in which one or more carbon atoms (and any associated hydrogen atoms) are independently replaced with the same or different heteroatom in such a way as to maintain the continuous π-electron system characteristic of aromatic systems and a number of π-electrons corresponding to the Huckel rule (4n +2). Examples of heteroatoms to replace the carbon atoms include N, P, O, S, and Si, etc. Specifically included within the definition of "parent heteroaromatic ring systems" are fused ring systems in which one or more of the rings are aromatic and one or more of the rings are saturated or unsaturated, such as, for example, arsindole, benzodioxan, benzofuran, chromane, chromene, indole, indoline, xanthene, etc. Examples of parent heteroaromatic ring systems include arsindole, carbazole, β-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran,

isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, thiazolidine, oxazolidine, and the like.

[0056] "Patient" refers to a mammal, for example, a human. The term "patient" is used interchangeably with "subject."

[0057] "Pharmaceutically acceptable" refers to approved or approvable by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans.

[0058] "Pharmaceutically acceptable salt" refers to a salt of a compound, which possesses the desired pharmacological activity of the parent compound. Such salts include acid addition salts, formed with inorganic acids and one or more protonable functional groups such as primary, secondary, or tertiary amines within the parent compound or formed with an organic acids. Examples for inorganic acids are hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Examples of organic acids include acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethane-disulfonic acid,

2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid,

2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid,

4-methylbicyclo[2.2.2]-oct-2-ene-l-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like. In certain embodiments, a pharmaceutically acceptable salt is a salt formed when one or more acidic protons present in the parent compound are replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion, or combinations thereof; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine,

N-methylglucamine, and the like. In certain embodiments, a pharmaceutically acceptable salt is the hydrochloride salt. In certain embodiments, a pharmaceutically acceptable salt is the sodium salt. In certain embodiments wherein a compound has two or more ionizable groups, a pharmaceutically acceptable salt comprises one or more counterions, such as a bi-salt, for example, a dihydrochloride salt.

[0059] The term "pharmaceutically acceptable salt" includes hydrates and other solvates, as well as salts in crystalline or non-crystalline form. Where a particular pharmaceutically acceptable salt is disclosed, it is understood that the particular salt (e.g., a hydrochloride salt) is an example of a salt, and that other salts may be formed using techniques known to one of skill in the art. Additionally, one of skill in the art would be able to convert the

pharmaceutically acceptable salt to the corresponding compound, free base and/or free acid, using techniques generally known in the art. See also: Stahl and Wermuth (Editors),

Handbook of Pharmaceutical Salts, Wiley-VCH, Weinheim, Germany, 2008.

[0060] "Pharmaceutically acceptable vehicle" refers to a pharmaceutically acceptable diluent, a pharmaceutically acceptable adjuvant, a pharmaceutically acceptable excipient, a pharmaceutically acceptable carrier, or a combination of any of the foregoing with which a compound provided by the present disclosure may be administered to a patient and which does not destroy the pharmacological activity thereof and which is non-toxic when administered in doses sufficient to provide a therapeutically effective amount of the compound. [0061] "Pharmaceutical composition" refers to a compound of Formula (1) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable vehicle, with which the compound of Formula (1) or a pharmaceutically acceptable salt thereof is administered to a patient. Pharmaceutically acceptable vehicles are known in the art.

[0062] "Solvate" refers to a molecular complex of a compound with one or more solvent molecules in a stoichiometric or non-stoichiometric amount. Such solvent molecules are those commonly used in the pharmaceutical arts, which are known to be innocuous to a patient, e.g., water, ethanol, and the like. A molecular complex of a compound or moiety of a compound and a solvent can be stabilized by non-covalent intra-molecular forces such as, for example, electrostatic forces, van der Waals forces, or hydrogen bonds. The term "hydrate" refers to a solvate in which the one or more solvent molecules is water.

[0063] "Substituted" refers to a group in which one or more hydrogen atoms are independently replaced with the same or different substituent(s). In certain embodiments, each substituent is independently selected from halogen, -OH, -CN, -CF ₃ , -OCF ₃ , =0, - N0 ₂ , Ci_6 alkoxy, Ci_ ₆ alkyl, -COOR, -NR ₂ , and -CONR ₂ ; wherein each R is independently selected from hydrogen and Ci_ ₆ alkyl. In certain embodiments, each substituent is independently selected from halogen, -NH ₂ , -OH, Ci_ ₃ alkoxy, and Ci_ ₃ alkyl,

trifluoromethoxy, and trifluoromethyl. In certain embodiments, each substituent is independently selected from -OH, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, and trifluoromethoxy. In certain embodiments, each substituent is selected from Ci_ ₃ alkyl, =0, Ci_ ₃ alkyl, Ci_ ₃ alkoxy, and phenyl. In certain embodiments, each substituent is selected from -OH, -NH ₂ , Ci_ ₃ alkyl, and Ci_ ₃ alkoxy.

[0064] "Treating" or "treatment" of a disease refers to arresting or ameliorating a disease or at least one of the clinical symptoms of a disease or disorder, reducing the risk of acquiring a disease or at least one of the clinical symptoms of a disease, reducing the development of a disease or at least one of the clinical symptoms of the disease or reducing the risk of developing a disease or at least one of the clinical symptoms of a disease. "Treating" or "treatment" also refers to inhibiting the disease, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both, and to inhibiting at least one physical parameter or manifestation that may or may not be discernible to the patient. In certain embodiments, "treating" or "treatment" refers to delaying the onset of the disease or at least one or more symptoms thereof in a patient who may be exposed to or predisposed to a disease or disorder even though that patient does not yet experience or display symptoms of the disease. [0065] "Therapeutically effective amount" refers to the amount of a compound that, when administered to a subject for treating a disease, or at least one of the clinical symptoms of a disease, is sufficient to affect such treatment of the disease or symptom thereof. The

"therapeutically effective amount" may vary depending, for example, on the compound, the disease and/or symptoms of the disease, severity of the disease and/or symptoms of the disease or disorder, the age, weight, and/or health of the patient to be treated, and the judgment of the prescribing physician. An appropriate amount in any given instance may be ascertained by those skilled in the art or capable of determination by routine experimentation.

[0066] "Therapeutically effective dose" refers to a dose that provides effective treatment of a disease or disorder in a patient. A therapeutically effective dose may vary from compound to compound, and from patient to patient, and may depend upon factors such as the condition of the patient and the route of delivery. A therapeutically effective dose may be determined in accordance with routine pharmacological procedures known to those skilled in the art.

[0067] "Triflyl" refers to the group -OS(0) ₂ CF ₃ or -OTf.

[0068] Reference is now made in detail to certain embodiments of compounds, compositions, and methods. The disclosed embodiments are not intended to be limiting of the claims. To the contrary, the claims are intended to cover all alternatives, modifications, and equivalents.

LATl/4F2hc Transporter

[0069] The GenBank accession number for human LATl/4F2hc is

NP_003477/NP_002385. Unless otherwise apparent from the context, reference to a transporter such as LATl/4F2hc (as well as other transporters disclosed herein) includes the amino acid sequence described in or encoded by the GenBank reference number, and, allelic, cognate and induced variants and fragments thereof retaining essentially the same transporter activity. Usually such variants show at least 90% sequence identity to the exemplary

Genbank nucleic acid or amino acid sequence. Allelic variants at the DNA level are the result of genetic variation between individuals of the same species. Some allelic variants at the DNA level that cause substitution, deletion or insertion of amino acids in proteins encoded by the DNA result in corresponding allelic variation at the protein level. Cognate forms of a gene refer to variation between structurally and functionally related genes between species. For example, the human gene showing the greatest sequence identity and closest functional relationship to a mouse gene is the human cognate form of the mouse gene. [0070] For sequence comparison, typically one sequence acts as a reference sequence, to which test sequences are compared. When using a sequence comparison algorithm, test and reference sequences are entered into a computer, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated. The sequence comparison algorithm enables calculation of the percent sequence identity for the test sequence(s) relative to the reference sequence, based on the designated program parameters. Optimal alignment of sequences for comparison may be conducted by methods known to those skilled in the art.

Compounds

[0071] In certain embodiments, anti-cancer agents provided by the present disclosure are compounds of Formula (1):

(1)

or a pharmaceutically acceptable salt thereof, wherein:

at least one of R ¹ and R ⁵ is independently selected from halogen, -N(R ¹⁰ ) ₂ , -N ⁺ (-0 )(R ¹⁰ ) ₂ , -N(OR ¹⁰ )(R ¹⁰ ), -N0 ₂ , -NO, -N(R ¹⁰ )(S(=O)R ¹⁰ ), -N(R ¹⁰ )(S(=O) ₂ R ¹⁰ ), - N(R ¹⁰ )(C(O)R ¹⁰ ), -N(R ¹⁰ )(C(O)OR ¹⁰ ), -N(R ¹⁰ )(C(O)N(R ¹⁰ ) ₂ , -CN, -COOR ¹⁰ , -CON(R ¹⁰ ) ₂ , -OH, -SH, Ci_4 alkylsulfanyl, Ci_ ₄ alkylsulfmyl, Ci_ ₄ alkylsulfonyl, -S(O)N(R ¹⁰ ) ₂ , - S(O) ₂ N(R ¹⁰ ) ₂ , Ci_4 fluoroalkyl, Ci_ ₄ fluoroalkoxy, Ci_ ₆ alkyl, substituted Ci_ ₆ alkyl, Ci_ ₆ alkoxy, substituted Ci_ ₆ alkoxy, C3-6 cycloalkyl, substituted C3-6 cycloalkyl, C3-6

cycloalkyloxy, substituted C3-6 cycloalkyloxy, C ₄ _i ₂ cycloalkylalkyl, substituted C ₄ -i ₂ cycloalkylalkyl, C ₆ -io aryl, substituted C ₆ -io aryl, C7-16 arylalkyl, substituted C7-16 arylalkyl, Ci_6 heteroalkyl, substituted Ci_ ₆ heteroalkyl, Ci_ ₆ heteroalkoxy, substituted Ci_ ₆ heteroalkoxy, C3-6 heterocycloalkyl, substituted C3-6 heterocycloalkyl, C ₄ -i ₂ heterocycloalkylalkyl, substituted C ₄ -i ₂ heterocycloalkylalkyl, C5-10 heteroaryl, substituted C5-10 heteroaryl, C ₆ -i6 heteroarylalkyl, and substituted C ₆ -i6 heteroarylalkyl; one of R ¹ , R ² , R ³ , R ⁴ , and R ⁵ comprises a chemotherapeutic moiety; each of the other of R ¹ , R ² , R ³ , R ⁴ , and R ⁵ is independently selected from hydrogen, deuterio, halogen, -OH, -N(R ¹⁰ ) ₂ , -N0 ₂ , -NO, -CN, -COOR ¹⁰ , -CON(R ¹⁰ ) ₂ , Ci_ ₄ alkylsulfanyl, Ci_ ₄ alkylsulfinyl, Ci_ ₄ alkylsulfonyl, Ci_ ₆ alkyl, substituted Ci_ ₆ alkyl, C ₃ _ ₆ cycloalkyl, substituted C ₃ _ ₆ cycloalkyl, Ci_ ₆ heteroalkyl, substituted Ci_ ₆ heteroalkyl, Ci_ ₆ alkoxy, substituted Ci_ ₆ alkoxy, Ci_ ₆ heteroalkoxy, substituted Ci_ ₆ heteroalkoxy, C ₄ _g cycloalkylalkyl, and C ₄ _8 cycloalkylheteroalkyl;

R ⁶ is selected from a carboxylic acid (-COOH), a carboxylic acid analog, and a carboxylic acid (bio)isostere;

each R ⁷ is independently selected from hydrogen, deuterio, halogen, hydroxyl, Ci_ ₆ alkyl, C ₃ _ ₆ cycloalkyl, benzyl, and phenyl; or two R ⁷ together with the carbon to which they are bonded form a ring selected from a C ₃ _ ₆ cycloalkyl ring and a C ₃ _ ₆ heterocycloalkyl ring;

R ⁸ is selected from hydrogen, deuterio, halogen, Ci_ ₆ alkyl, substituted Ci_ ₆ alkyl, Ci_ ₆ heteroalkyl, substituted Ci_ ₆ heteroalkyl, Ci_ ₆ alkoxy, substituted Ci_ ₆ alkoxy, Ci_ ₆ heteroalkoxy, substituted Ci_ ₆ heteroalkoxy, C ₃ _ ₆ cycloalkyl, substituted C ₃ _ ₆ cycloalkyl, C ₃ _ ₆ cycloalkyloxy, substituted C ₃ _ ₆ cycloalkyloxy, -OH, -COOR ¹⁰ , Ci_ ₄ fluoroalkyl, Ci_ ₄ fluoroalkoxy, C ₃ _ ₆ cycloalkyl, and phenyl;

each R ¹⁰ is independently selected from hydrogen, Ci_ ₄ alkyl, and Ci_ ₄ alkoxy, or two geminal R ¹⁰ together with the nitrogen to which they are bonded form a 3- to 6-membered heterocyclic ring;

L is -(X) _a -, wherein each X is independently selected from a bond ("-"), -C(R ¹⁶ ) ₂ -, wherein each R ¹⁶ is independently selected from hydrogen, deuterio, halogen, hydroxyl, Ci_ ₄ alkyl, and Ci_ ₄ alkoxy, or two R ¹⁶ together with the carbon to which they are bonded form a C ₃ _6 cycloalkyl ring or a C ₃ _ ₆ heterocycloalkyl ring, -0-, -S-, -SO-, -S0 ₂ -, -CO-, and - N(R ¹⁷ )- wherein R ¹⁷ is selected from hydrogen and Ci_ ₄ alkyl;

a is selected from 0, 1 , 2, 3, and 4; and

each substituent is independently selected from halogen, -OH, -NH ₂ , -N(R ¹⁰ ) ₂ , - N0 ₂ , -CF ₃ , =0 (oxo), Ci_ ₃ alkyl, Ci_ ₃ alkoxy, and phenyl; wherein each R ¹⁰ is independently selected from hydrogen and Ci_ ₃ alkyl.

[0072] In certain embodiments in compounds of Formula (1), R ¹ comprises a

chemotherapeutic moiety, R ² comprises a chemotherapeutic moiety, R ³ comprises a chemotherapeutic moiety, R ⁴ comprises a chemotherapeutic moiety, and in certain embodiments, R ⁵ comprises a chemotherapeutic moiety. [0073] In certain embodiments of a compound of Formula (1), a chemotherapeutic moiety may be any suitable chemotherapeutic moiety of a chemotherapeutic drug known in the art that retains cytotoxic activity when bonded either directly or indirectly through a suitable spacing moiety, e.g., an aryl ring and a linker L, to na γ-amino acid derivative, γ- amino acid analog, or γ-amino acid carboxylic acid (bio)isostere as a LAT1 recognition element provided by the present disclosure. The conjugate or fusion product of the chemotherapeutic moiety with the γ-amino acid derivative, γ-amino acid analog, or γ-amino acid carboxylic acid (bio)isostere is simultaneous a selective substrate for the LATl/4F2hc transporter.

[0074] In certain embodiments of a compound of Formula (1), the chemotherapeutic moiety, is selected from a nitrogen mustard (-N(-CR ₂ -CR ₂ -X) ₂ ), a N-monoalkyl or N,N- dialkyl triazene (-N=N-NR ₂ ), a haloacetamide (-NR-CO-CH ₂ -X), an epoxide (-CROCR- R), an aziridine (-NC ₂ H ₄ ), a Michael acceptor (-CR=CR-EWG-), a sulfonate or a bissulfonate ester (-OS0 ₂ R or ROS0 ₂ -), an N-nitrosourea (-NR-CO-N(NO)R), a bissulfonyl hydrazine (R"S0 ₂ -NR-N(-)-S0 ₂ R", -S0 ₂ -NR-NR-S0 ₂ R", or R"S0 ₂ -NR- NR-S0 ₂ -), a phosphoramidate (-0-P(=0)(N(R)-CH ₂ -CH ₂ -X) ₂ or -0-P(=0)(N(-CH ₂ - CH ₂ -X) ₂ ) ₂ , and a radionuclide such as, for example, 131 -iodine ( ¹³¹ [I] -) or 211 -astatine

[0075] In certain embodiments of a compound of Formula (1), the chemotherapeutic moiety is a moiety Formula (2):

(2)

wherein,

A is selected from a bond ("-"), oxygen (-0-), sulfur (-S-), amino (-NR -), methylene (-CH ₂ -), methyleneoxy (-CH ₂ -0-), oxycarbonyl (-0-C(=0)-), thiocarbonyl (- S-C(=0)-), aminocarbonyl (-NR ¹⁰ -C(=O)-), oxythiocarbonyl (-0-C(=S)-),

thiothiocarbonyl (-S-C(=S)-), aminothiocarbonyl (-NR ¹⁰ -C(=S)-), methyleneoxycarbonyl (-CH ₂ -0-C(=0)-), methylenethiocarbonyl (-CH ₂ -S-C(=0)-), methyleneammocarbonyl (- CH ₂ -NR ¹⁰ -C(=O)-), methyleneoxythiocarbonyl (-CH ₂ -0-C(=S)-),

methylenethiothiocarbonyl (-CH ₂ -S-C(=S)-), methyleneaminothiocarbonyl (-CH ₂ -NR ¹⁰ - C(=S)-), carbonyl (-C(=0)-), methylencarbonyl (-CH ₂ -C(=0)-), thiocarbonyl (-C(=S)-), and methylenthiocarbonyl (-CH ₂ -C(=S)-);

Z is selected from a bond ("-") and oxygen (-0-);

Q is selected from -0 ^~ (a negatively charged oxygen atom) that is bound to a positively charged nitrogen atom) and a free electron pair (:), with the proviso that when Q is -0 ^~ (a negatively charged oxygen atom that is bound to a positively charged nitrogen atom), A is selected from a bond ("-") and methylene (-CH ₂ -),Z is a bond ("-"), and the chemotherapeutic moiety of Formula (2) is an N-oxide (-A-N ⁺ (-0 )(-C(R ¹ QR ¹

R ⁹ ) ₂ );

each R ¹¹ is independently selected from hydrogen, deuterio, and Ci_ ₃ alkyl; and each R ⁹ is independently selected from fluoro (-F), chloro (-C1), bromo (-Br), iodo (- I), alkyl sulfonate (-OS0 ₂ R ⁴⁰ , wherein R ⁴⁰ is selected from Ci_ ₄ alkyl), Ci_ ₄ (per)fluoroalklyl sulfonate (-OS0 ₂ R ⁴⁰ , wherein R ⁴⁰ is selected from Ci_ ₄ (per)fluoroalkyl), and (substituted) aryl sulfonate (-OS0 ₂ R ⁴⁰ , wherein R ⁴⁰ is C _6-1 o aryl).

[0076] In certain embodiments, a chemotherapeutic moiety of Formula (2) is selected from the structure -A-N(-Z-C(R ¹¹ ) ₂ -C(R ¹¹ ) ₂ -R ⁹ )(-C(R ¹¹ ) ₂ -C(R ¹¹ ) ₂ -R ⁹ ) and -A-N ⁺ (-CQ(- C(R ⁿ ) ₂ -C(R ^u ) ₂ -R ⁹ ) ₂ ,

wherein A is selected from a bond ("-"), methylene (-CH ₂ -), oxygen (-0-),

methyleneoxy (-CH ₂ -0-), oxycarbonyl (-0-C(=0)-), methyleneoxycarbonyl (-CH ₂ -0- C(=0)-), carbonyl (-C(=0)-), and methylenecarbonyl (-CH ₂ -C(=0)-);

each R ¹¹ is independently selected from hydrogen and deuterio; and

each R ⁹ is independently selected from fluoro (-F), chloro (-C1), bromo (-Br), iodo (-1), alkyl sulfonate (-OS0 ₂ R ⁴⁰ , wherein R ⁴⁰ is selected from Ci_ ₄ alkyl), Ci_ ₄ (per)fluoroalklyl sulfonate (-OS0 ₂ R ⁴⁰ , wherein R ⁴⁰ is selected from Ci_ ₄ (per)fluoroalkyl), and (substituted) aryl sulfonate (-OS0 ₂ R ⁴⁰ , wherein R ⁴⁰ is selected from C ₆ -io aryl).

[0077] In certain embodiments, a chemotherapeutic moiety of Formula (2) has the structure -A-NQ(-Z-C(R ¹¹ ) ₂ -C(R ¹¹ ) ₂ -R ⁹ )(-C(R ¹¹ ) ₂ -C(R ¹¹ ) ₂ -R ⁹ , wherein A is a bond ("-"); Q is a free electron pair (:); Z is a bond ("-"); each R ¹¹ is independently selected from hydrogen and deuterio; and each R ⁹ is independently selected from chloro (-C1), bromo (- Br), iodo (-1), alkyl sulfonate (-OS0 ₂ R ⁴⁰ , wherein R ⁴⁰ is selected from Ci_ ₄ alkyl), and Ci_ ₄ (per)fluoroalklyl sulfonate (-OS0 ₂ R ⁴⁰ , wherein R ⁴⁰ is selected from Ci_ ₄ (per)fluoroalkyl); and the chemotherapeutic moiety is -N(-CH ₂ - _m D _m -CH ₂ - _n D _n -R ⁹ ) ₂ , wherein m and n are independently selected from 0, 1, and 2.

[0078] In certain embodiments, a chemotherapeutic moiety of Formula (2) has the structure -A-NQ(-Z-C(R ¹¹ ) ₂ -C(R ¹¹ ) ₂ -R ⁹ )(-C(R ¹¹ ) ₂ -C(R ¹¹ ) ₂ -R ⁹ ), wherein A is methylene (- CH ₂ -); Q is a free electron pair (:); Z is a bond ("-"); each R ¹¹ is independently selected from hydrogen and deuterio; and each R ⁹ is independently selected from chloro (-C1), bromo (- Br), iodo (-1), alkyl sulfonate (-OSO ₂ R ⁴⁰ , wherein R ⁴⁰ is selected from Ci_ ₄ alkyl), and Ci_ ₄ (per)fluoroalklyl sulfonate (-OS0 ₂ R ⁴ °, wherein R ⁴⁰ is selected from Ci_ ₄ (per)fluoroalkyl); and the chemotherapeutic moiety is -CH ₂ -N(-CH ₂ - _m D _m -CH ₂ - _n D _n -R ⁹ ) ₂ , wherein m and n are independently selected from 0, 1, and 2.

[0079] In certain embodiments, a chemotherapeutic moiety of Formula (2) has the structure -A-NQ(-Z-C(R ¹¹ ) ₂ -C(R ¹¹ ) ₂ -R ⁹ )(-C(R ¹¹ ) ₂ -C(R ¹¹ ) ₂ -R ⁹ ), wherein A is a bond ("-"); Q is a negatively charged oxygen (-CT); Z is a bond ("-"); each R ¹¹ is independently selected from hydrogen and deuterio; and each R ⁹ is independently selected from chloro (-C1), bromo (-Br), iodo (-1), alkyl sulfonate (-OSO ₂ R ⁴⁰ , wherein R ⁴⁰ is selected from Ci_ ₄ alkyl), and Ci_ ₄ (per)fluoroalklyl sulfonate (-OS0 ₂ R ⁴ °, wherein R ⁴⁰ is selected from Ci_ ₄ (per)fluoroalkyl); and the chemotherapeutic moiety is -N ⁺ (-C )(-CH ₂ - _m D _m -CH ₂ - _n D _n -R ⁹ ) ₂ , wherein m and n are independently selected from 0, 1, and 2.

[0080] In certain embodiments, a chemotherapeutic moiety of Formula (2) has the structure -A-NQ(-Z-C(R ¹¹ )2-C(R ¹¹ ) ₂ -R ⁹ )(-C(R ¹¹ )2-C(R ¹¹ ) ₂ -R ⁹ ), wherein A is methylene (- CH ₂ -); Q is a negatively charged oxygen (-CT); Z is a bond ("-"); each R ¹¹ is independently selected from hydrogen and deuterio; and each R ⁹ is independently selected from chloro (- CI), bromo (-Br), iodo (-1), alkyl sulfonate (-OSO ₂ R ⁴⁰ , wherein R ⁴⁰ is selected from Ci_ ₄ alkyl), and Ci_ ₄ (per)fluoroalklyl sulfonate (-OSO ₂ R ⁴⁰ , wherein R ⁴⁰ is selected from Ci_ ₄ (per)fluoroalkyl); and the chemotherapeutic moiety is -CH ₂ -N ⁺ (-0 )(-CH ₂ _ _m D _m -CH ₂ _ _n D _n - R ⁹ ) ₂ , wherein m and n are independently selected from 0, 1, and 2.

[0081] In certain embodiments, a chemotherapeutic moiety of Formula (2) has the structure -A-NQ(-Z-C(R ¹¹ )2-C(R ¹¹ ) ₂ -R ⁹ )(-C(R ¹¹ )2-C(R ¹¹ ) ₂ -R ⁹ ), wherein A is a bond ("-"); Q is a free electron pair (:); Z is oxygen; each R ¹¹ is independently selected from hydrogen and deuterio; and each R ⁹ is independently selected from chloro (-C1), bromo (-Br), iodo (- I), alkyl sulfonate (-OSO ₂ R ⁴⁰ , wherein R ⁴⁰ is selected from Ci_ ₄ alkyl), and Ci_ ₄

(per)fluoroalklyl sulfonate (-OSO ₂ R ⁴⁰ , wherein R ⁴⁰ is selected from Ci_ ₄ (per)fluoroalkyl); and the chemotherapeutic moiety is -N(-0-CH ₂ _ _m D _m -CH ₂ _ _n D _n -R ⁹ )(-CH ₂ _ _m D _m - CH ₂ _ _n D _n - R ⁹ ), wherein m and n are independently selected from 0, 1, and 2. [0082] In certain embodiments, a chemotherapeutic moiety of Formula (2) has the structure -A-NQ(-Z-C(R ¹¹ ) ₂ -C(R ¹¹ ) ₂ -R ⁹ )(-C(R ¹¹ ) ₂ -C(R ¹¹ ) ₂ -R ⁹ ), wherein A is methylene (- CH ₂ -); Q is a free electron pair (:); Z is oxygen; each R ¹¹ is independently selected from hydrogen and deuterio; and each R ⁹ is independently selected from chloro (-C1), bromo (- Br), iodo (-1), alkyl sulfonate (-OS0 ₂ R ⁴⁰ , wherein R ⁴⁰ is selected from Ci_ ₄ alkyl), anf Ci_ ₄ (per)fluoroalklyl sulfonate (-OS0 ₂ R ⁴⁰ , wherein R ⁴⁰ is selected from Ci_ ₄ (per)fluoroalkyl); and the chemotherapeutic moiety is -CH ₂ -N(-0-CH ₂ _ _m D _m -CH ₂ _ _n D _n -R ⁹ )(-CH ₂ _ _m D _m - CH ₂ _ _n D _n -R ⁹ ), wherein m and n are independently selected from 0, 1, and 2.

[0083] In certain embodiments, a chemotherapeutic moiety of Formula (2) has the structure -A-NQ(-Z-C(R ¹¹ ) ₂ -C(R ¹¹ ) ₂ -R ⁹ )(-C(R ¹¹ ) ₂ -C(R ¹¹ ) ₂ -R ⁹ ), wherein A is oxygen (-0- ); Q is a free electron pair (:); Z is a bond ("-"); each R ¹¹ is independently selected from hydrogen and deuterio; and each R ⁹ is independently selected from chloro (-C1), bromo (- Br), iodo (-1), alkyl sulfonate (-OS0 ₂ R ⁴⁰ , wherein R ⁴⁰ is selected from Ci_ ₄ alkyl), and Ci_ ₄ (per)fluoroalklyl sulfonate (-OS0 ₂ R ⁴⁰ , wherein R ⁴⁰ is selected from Ci_ ₄ (per)fluoroalkyl) and the chemotherapeutic moiety is -0-N(-CH ₂ _ _m D _m -CH ₂ _ _n D _n -R ⁹ ) ₂ , wherein m and n are independently selected from 0, 1, and 2.

[0084] In certain embodiments, a chemotherapeutic moiety of Formula (2) has the structure -A-NQ(-Z-C(R ¹¹ ) ₂ -C(R ¹¹ ) ₂ -R ⁹ )(-C(R ¹¹ ) ₂ -C(R ¹¹ ) ₂ -R ⁹ ), wherein A is

methyleneoxy (-CH ₂ -0-); Q is a free electron pair (:); Z is a bond ("-"); each R ¹¹ is independently selected from hydrogen and deuterio; and each R ⁹ is independently selected from chloro (-C1), bromo (-Br), iodo (-1), alkyl sulfonate (-OS0 ₂ R ⁴⁰ , wherein R ⁴⁰ is selected from Ci_ ₄ alkyl), and Ci_ ₄ (per)fluoroalklyl sulfonate (-OS0 ₂ R ⁴⁰ , wherein R ⁴⁰ is selected from Ci_ ₄ (per)fluoroalkyl); and the chemotherapeutic moiety is -CH ₂ -0-N(-CH ₂ _ _m D _m -CH ₂ _ _n D _n - R ⁹ ) ₂ , wherein m and n are independently selected from 0, 1, and 2.

[0085] In certain embodiments, a chemotherapeutic moiety of Formula (2) has the structure -A-NQ(-Z-C(R ¹¹ ) ₂ -C(R ¹¹ ) ₂ -R ⁹ )(-C(R ¹¹ ) ₂ -C(R ¹¹ ) ₂ -R ⁹ ), wherein A is a carbonyl (- CO-), Q is a free electron pair (:), Z is a bond ("-"), each R ¹¹ is independently selected from hydrogen and deuterio; and each R ⁹ is independently selected from chloro (-C1), bromo (- Br), iodo (-1), alkyl sulfonate (-OS0 ₂ R ⁴⁰ , wherein R ⁴⁰ is selected from Ci_ ₄ alkyl), Ci_ ₄ (per)fluoroalklyl sulfonate ((-OS0 ₂ R ⁴⁰ , wherein R ⁴⁰ is selected from Ci_ ₄ (per)fluoroalkyl) and the chemotherapeutic moiety is (-CO-N(-CH ₂ _ _m D _m -CH ₂ _ _n D _n -R ⁹ ) ₂ ), wherein m and n are independently selected integers of 0, 1, and 2.

[0086] In certain embodiments, a chemotherapeutic moiety of Formula (2) has the structure -A-NQ(-Z-C(R ¹¹ ) ₂ -C(R ¹¹ ) ₂ -R ⁹ )(-C(R ¹¹ ) ₂ -C(R ¹¹ ) ₂ -R ⁹ ), wherein A is methylenecarbonyl (-CH ₂ -CO-); Q is a free electron pair (:); Z is a bond ("-"); each R ¹¹ is independently selected from hydrogen and deuterio; and each R ⁹ is independently selected from chloro (-C1), bromo (-Br), iodo (-1), alkyl sulfonate (-OS0 ₂ R ⁴⁰ , wherein R ⁴⁰ is selected from Ci_4 alkyl), and Ci_ ₄ (per)fluoroalklyl sulfonate (-OS0 ₂ R ⁴ °, wherein R ⁴⁰ is selected from Ci_4 (per)fluoroalkyl); and the chemotherapeutic moiety is -CH ₂ -CO-N(-CH ₂ _ _m D _m -CH ₂ _ _n D _n -R ⁹ ) ₂ , wherein m and n are independently selected from 0, 1 , and 2.

[0087] In certain embodiments, a chemotherapeutic moiety of Formula (2) has the structure -A-NQ(-Z-C(R ^{1 1} )2-C(R ¹¹ ) ₂ -R ⁹ )(-C(R ^{1 1} )2-C(R ¹¹ ) ₂ -R ⁹ ), wherein A is oxycarbonyl (-0-CO-); Q is a free electron pair (:); Z is a bond ("-"); each R ¹¹ is independently selected from hydrogen and deuterio; and each R ⁹ is independently selected from chloro (-C1), bromo (-Br), iodo (-1), alkyl sulfonate (-OS0 ₂ R ⁴⁰ , wherein R ⁴⁰ is selected from Ci_ ₄ alkyl), and Ci_ ₄ (per)fluoroalklyl sulfonate (-OS0 ₂ R ⁴⁰ , wherein R ⁴⁰ is selected from Ci_ ₄ (per)fluoroalkyl); and the chemotherapeutic moiety is -0-CO-N(-CH ₂ _ _m D _m -CH ₂ _ _n D _n -R ⁹ ) ₂ , wherein m and n are independently selected from 0, 1 , and 2.

[0088] In certain embodiments, a chemotherapeutic moiety of Formula (2) has the structure -A-NQ(-Z-C(R ¹¹ ) ₂ -C(R ¹¹ ) ₂ -R ⁹ )(-C(R ¹¹ ) ₂ -C(R ¹¹ ) ₂ -R ⁹ ), wherein A is a

methyleneoxycarbonyl (-CH ₂ -0-CO-); each R ¹¹ is independently selected from hydrogen and deuterio; and each R ⁹ is independently selected from chloro (-C1), bromo (-Br), iodo (- I), alkyl sulfonate (-OS0 ₂ R ⁴⁰ , wherein R ⁴⁰ is selected from Ci_ ₄ alkyl), and Ci_ ₄

(per)fluoroalklyl sulfonate (-OS0 ₂ R ⁴⁰ , wherein R ⁴⁰ is selected from Ci_ ₄ (per)fluoroalkyl); and the chemotherapeutic moiety is -CH ₂ -0-CO-N(-CH ₂ _ _m D _m -CH ₂ _ _n D _n -R ⁹ ) ₂ , wherein m and n are independently selected from 0, 1 , and 2.

[0089] In certain embodiments of a compound of Formula (1), the chemotherapeutic moiety comprises -N(-CH ₂ _ _m D _m -CH ₂ _ _n D _n -R ⁹ ) ₂ , wherein m and n are independently selected from 0, 1 , and 2; and each R ⁹ is independently selected from chloro ( ^~ C1), bromo ( ^~ Br), iodo (-1), methylsulfonyloxy (-OS0 ₂ CH ₃ ), and trifluoromethylsulfonyloxy (-OS0 ₂ CF ₃ ).

[0090] In certain embodiments of a compound of Formula (1), the chemotherapeutic moiety comprises -CH ₂ -N(-CH ₂ _ _m D _m -CH ₂ _ _n D _n -R ⁹ ) ₂ , wherein m and n are independently selected fromO, 1 , and 2; and each R ⁹ is independently selected from chloro ( ^~ C1), bromo (-Br), iodo (-1), methylsulfonyloxy (-OS0 ₂ CH ₃ ), and trifluoromethylsulfonyloxy

(-OS0 ₂ CF ₃ ).

[0091] In certain embodiments of a compound of Formula (1), the chemotherapeutic moiety comprises -N ⁺ (-C )(-CH ₂ _ _m D _m -CH ₂ _ _n D _n -R ⁹ ) ₂ , wherein m and n are independently selected from 0, 1 , and 2; and each R ⁹ is independently selected from chloro ( ^~ C1), bromo (-Br), iodo (-1), methylsulfonyloxy (-OSO ₂ CH3), and trifluoromethylsulfonyloxy

(-OS0 ₂ CF ₃ ).

[0092] In certain embodiments of a compound of Formula (1), the chemotherapeutic moiety comprises -CH ₂ -N ⁺ (-0 )(-CH ₂ _ _m D _m -CH ₂ _ _n D _n -R ⁹ ) ₂ , wherein m and n are independently selected from 0, 1, and 2; and each R ⁹ is independently selected from chloro (-C1), bromo ( ^~ Br), iodo (-1), methylsulfonyloxy (-OSO ₂ CH ₃ ), and

trifluoromethylsulfonyloxy (-OS0 ₂ CF ₃ ).

[0093] In certain embodiments of a compound of Formula (1), the chemotherapeutic moiety comprises -N(-0-CH ₂ - _m D _m -CH ₂ - _n D _n -R ⁹ )(-CH ₂ - _m D _m -CH ₂ - _n D _n -R ⁹ ), wherein m and n are independently selected from 0, 1, and 2; and each R ⁹ is independently selected from chloro (-C1), bromo ( ^~ Br), iodo (-1), methylsulfonyloxy (-OS0 ₂ CH ₃ ), and

trifluoromethylsulfonyloxy (-OS0 ₂ CF ₃ ).

[0094] In certain embodiments of a compound of Formula (1), the chemotherapeutic moiety comprises -CH ₂ -N(-0-CH ₂ - _m D _m -CH ₂ - _n D _n -R ⁹ )(-CH ₂ - _m D _m -CH ₂ - _n D _n -R ⁹ ), wherein m and n are independently selected from 0, 1, and 2; and each R ⁹ is independently selected from chloro (-C1), bromo ( ^~ Br), iodo (-1), methylsulfonyloxy (-OS0 ₂ CH ₃ ), and

trifluoromethylsulfonyloxy (-OS0 ₂ CF ₃ ).

[0095] In certain embodiments of a compound of Formula (1), the chemotherapeutic moiety comprises -0-N(-CH ₂ - _m D _m -CH ₂ - _n D _n -R ⁹ ) ₂ , wherein m and n are independently selected integers of 0, 1, and 2; and each R ⁹ is independently selected from chloro ( ^~ C1), bromo ( ^~ Br), iodo (-1), methylsulfonyloxy (-OS0 ₂ CH ₃ ), and trifluoromethylsulfonyloxy (-OS0 ₂ CF ₃ ).

[0096] In certain embodiments of a compound of Formula (1), the chemotherapeutic moiety comprises -CH ₂ -0-N(-CH ₂ _ _m D _m -CH ₂ _ _n D _n -R ⁹ ) ₂ , wherein m and n are independently selected from 0, 1, and 2; and each R ⁹ is independently selected from chloro ( ^~ C1), bromo (-Br), iodo (-1), methylsulfonyloxy (-OS0 ₂ CH ₃ ), and trifluoromethylsulfonyloxy

(-OS0 ₂ CF ₃ ).

[0097] In certain embodiments of a compound of Formula (1), the chemotherapeutic moiety comprises -CO-N(-CH ₂ _ _m D _m -CH ₂ _ _n D _n -R ⁹ ) ₂ , wherein m and n are independently selected from 0, 1, and 2; and each R ⁹ is independently selected from chloro ( ^~ C1), bromo (-Br), iodo (-1), methylsulfonyloxy (-OS0 ₂ CH ₃ ), and trifluoromethylsulfonyloxy

(-OS0 ₂ CF ₃ ).

[0098] In certain embodiments of a compound of Formula (1), the chemotherapeutic moiety comprises -CH ₂ -CO-N(-CH ₂ _ _m D _m -CH ₂ _ _n D _n -R ⁹ ) ₂ , wherein m and n are independently selected from 0, 1, and 2; and each R ⁹ is independently selected from chloro (-C1), bromo ( ^~ Br), iodo (-1), methylsulfonyloxy (-OSO ₂ CH3), and

trifluoromethylsulfonyloxy (-OSO ₂ CF3).

[0099] In certain embodiments of a compound of Formula (1), the chemotherapeutic moiety comprises -0-CO-N(-CH ₂ - _m D _m -CH ₂ - _n D _n -R ⁹ ) ₂ , wherein m and n are independently selected from 0, 1, and 2; and each R ⁹ is independently selected from chloro ( ^~ C1), bromo (-Br), iodo (-1), methylsulfonyloxy (-OSO ₂ CH ₃ ), and trifluoromethylsulfonyloxy

(-OSO ₂ CF ₃ ).

[0100] In certain embodiments of a compound of Formula (1), the chemotherapeutic moiety comprises -CH ₂ -0-CO-N(-CH ₂ - _m D _m -CH ₂ - _n D _n -R ⁹ ) ₂ , wherein m and n are independently selected from 0, 1, and 2; and each R ⁹ is independently selected from chloro (-C1), bromo ( ^~ Br), iodo (-1), methylsulfonyloxy (-OS0 ₂ CH ₃ ), and

trifluoromethylsulfonyloxy (-OSO ₂ CF ₃ ).

[0101] In certain embodiments of a compound of Formula (1), the chemotherapeutic moiety comprises -N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , wherein each R ⁹ is independently selected from chloro (-C1), bromo ( ^~ Br), iodo (-1), methylsulfonyloxy (-OS0 ₂ CH ₃ ), and

trifluoromethylsulfonyloxy (-OSO ₂ CF ₃ ).

[0102] In certain embodiments of a compound of Formula (1), the chemotherapeutic moiety comprises -CH ₂ -N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , wherein each R ⁹ is independently selected from chloro (-C1), bromo ( ^~ Br), iodo (-1), methylsulfonyloxy (-OSO ₂ CH ₃ ), and

trifluoromethylsulfonyloxy (-OS0 ₂ CF ₃ ).

[0103] In certain embodiments of a compound of Formula (1), the chemotherapeutic moiety comprises -N ⁺ (-0 )(-CH ₂ -CH ₂ -R ⁹ ) ₂ , wherein each R ⁹ is independently selected from chloro ( ^~ C1), bromo ( ^~ Br), iodo (-1), methylsulfonyloxy (-OSO ₂ CH ₃ ), and trifluoromethylsulfonyloxy (-OS0 ₂ CF ₃ ).

[0104] In certain embodiments of a compound of Formula (1), the chemotherapeutic moiety comprises -CH ₂ -N ⁺ (-CTX-CFl2-CFl2-R ⁹ )2, wherein each R ⁹ is independently selected from chloro ( ^~ C1), bromo ( ^~ Br), iodo (-1), methylsulfonyloxy (-OSO ₂ CH ₃ ), and trifluoromethylsulfonyloxy (-OS0 ₂ CF ₃ ).

[0105] In certain embodiments of a compound of Formula (1), the chemotherapeutic moiety comprises -N(-0-CH ₂ -CH ₂ -R ⁹ )(-CH ₂ -CFl ₂ -R ⁹ ), wherein each R ⁹ is independently selected from chloro ( ^~ C1), bromo ( ^~ Br), iodo (-1), methylsulfonyloxy (-OSO ₂ CH ₃ ), and trifluoromethylsulfonyloxy (-OS0 ₂ CF ₃ ). [0106] In certain embodiments of a compound of Formula (1), the chemotherapeutic moiety comprises -CH ₂ -N(-0-CH ₂ -CH ₂ -R ⁹ )(-CH ₂ -CH ₂ -R ⁹ ), wherein each R ⁹ is independently selected from chloro ( ^~ C1), bromo ( ^~ Br), iodo (-1), methylsulfonyloxy (-OSO ₂ CH ₃ ), and trifiuoromethylsulfonyloxy (-OS0 ₂ CF ₃ ).

[0107] In certain embodiments of a compound of Formula (1), the chemotherapeutic moiety comprises -0-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , wherein each R ⁹ is independently selected from chloro (-C1), bromo ( ^~ Br), iodo (-1), methylsulfonyloxy (-OSO ₂ CH3), and

trifiuoromethylsulfonyloxy (-OS0 ₂ CF ₃ ).

[0108] In certain embodiments of a compound of Formula (1), the chemotherapeutic moiety comprises -CH2-0-N(-CH2-CH ₂ -R ⁹ )2, wherein each R ⁹ is independently selected from chloro ( ^~ C1), bromo ( ^~ Br), iodo (-1), methylsulfonyloxy (-OSC^CF ), and

trifiuoromethylsulfonyloxy (-OS0 ₂ CF ₃ ).

[0109] In certain embodiments of a compound of Formula (1), the chemotherapeutic moiety comprises -CO-N(-CH ₂ - CH ₂ -R ⁹ ) ₂ , wherein each R ⁹ is independently selected from chloro (-C1), bromo ( ^~ Br), iodo (-1), methylsulfonyloxy (-OS0 ₂ CH ₃ ), and

trifiuoromethylsulfonyloxy (-OS0 ₂ CF ₃ ).

[0110] In certain embodiments of a compound of Formula (1), the chemotherapeutic moiety comprises -CH ₂ -CO-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , wherein each R ⁹ is independently selected from chloro ( ^~ C1), bromo ( ^~ Br), iodo (-1), methylsulfonyloxy (-OS0 ₂ CH ₃ ), and

trifiuoromethylsulfonyloxy (-OS0 ₂ CF ₃ ).

[0111] In certain embodiments of a compound of Formula (1), the chemotherapeutic moiety comprises -0-CO-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , wherein m and n are independently selected from 0, 1, and 2, and each of R ⁹ is independently selected from chloro ( ^~ C1), bromo ( ^~ Br), iodo (-1), methylsulfonyloxy (-OS0 ₂ CH ₃ ), and trifiuoromethylsulfonyloxy (-OS0 ₂ CF ₃ ).

[0112] In certain embodiments of a compound of Formula (1), the chemotherapeutic moiety comprises -CH ₂ -0-CO-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , wherein each R ⁹ is independently selected from chloro ( ^~ C1), bromo ( ^~ Br), iodo (-1), methylsulfonyloxy (-OS0 ₂ CH ₃ ), and trifiuoromethylsulfonyloxy (-OS0 ₂ CF ₃ ).

[0113] In certain embodiments of a compound of Formula (1), R ⁶ is selected from carboxylic acid (-COOH), hydroxamic acids (-CONR ¹² OH), boronic acids (-B(OH)(OR ¹² ), phosphinic acids or derivatives thereof (-PO(OH)R ¹² ), and phosphonic acid or derivatives thereof (-PO(OH)(OR ¹² )), sulfmic acid (-SOOH), sulfonic acid (-S0 ₂ OH), sulfonamide (- SO ₂ NHR ¹² or -NHSO ₂ R ¹² ), sulfonimide or acyl sulfonimide (-S0 ₂ NHCOR ¹² or - CONHSO2R ¹² ), sulfonylureas (-SO2NHCONHR ¹² or -NHCONHS0 ₂ R ¹² ), amide (- CONHR or -NHCOR ¹ ), acylcyanamide (-CONHCN), 2,2,2-trifiuoroethan-l-ols (- CH(CF ₃ )OH), 2,2,2-trifluoromethyl ketones and hydrates thereof (-COCF ₃ and - C(OH) ₂ CF ₃ ), acidic heterocycles and annular tautomers of any of the foregoing, and acidic oxocarbocycles or cyclic polyones and resonance forms of any of the foregoing; wherein R ¹² is selected from hydrogen, Ci_ ₆ alkyl, Ci_ ₄ fluoroalkyl, C ₃ _ ₆ cycloalkyl, and C _6-1 o aryl.

[0114] In certain embodiments of a compound of Formula (1), the acidic heterocycle and annular tautomers thereof is selected from IH-tetrazole, 5-oxo-l,2,4-oxadiazole, 5-oxo-l,2,4- thiadiazole, 5-thioxo-l,2,4-oxadiazole, thiazolidinedione, oxazolidinedione,

oxadiazolidinedione, 3-hydroxyisoxazole, 3-hydroxyisothiazole, 1 -hydroxy-imidazole, 1- hydroxy-pyrazole, 1-hydroxy-triazole, lH-imidazol-2-ol, tetrazole-5 -thiol, 3- hydroxyquinolin-2-one, 4-hydroxyquinolin-2-ones, tetronic acid, tetramic acid,

mercaptoazoles such as sulfanyl-lH-imidazole, sulfinyl-lH-imidazole, sulfonyl- 1H- imidazole, sulfanyl-lH-triazole, sulfinyl-lH-triazole, sulfonyl-lH-triazole, sulfanyl- 1H- 1,2,4- triazole, sulfinyl-lH-l,2,4-triazole, sulfonyl-lH-l,2,4-triazole, sulfanyl- 1,4-dihydro- 1,2,4- triazol-5-one, sulfinyl- 1 ,4-dihydro- 1 ,2,4-triazol-5-one, sulfonyl-1 ,4-dihydro- 1 ,2,4-triazol-5- one, sulfanyl IH-tetrazole, sulfanyl 2H-tetrazole, sulfinyl IH-tetrazole, sulfinyl 2H-tetrazole, sulfonyl IH-tetrazole, sulfonyl 2H-tetrazole, and sulfonimidamide.

[0115] In certain embodiments of a compound of Formula (1), the acidic oxocarbocycle or cyclic polyone and resonance forms thereof is selected from cyclopentane-l,3-dione, squaric acid, squareamide, mixed squaramate, and 2,6-difluorophenol.

[0116] In certain embodiments of a compound of Formula (1), R ⁶ is selected from - COOH, -S(0)OH, -S0 ₂ OH, -P(0)(OH)R ¹² , -P(0)(OH)(OR ¹² ), -S0 ₂ NHR ¹² , -NHS0 ₂ R ¹² , - S0 ₂ NHCOR ¹² , -CONHS0 ₂ R ¹² , -S0 ₂ NHCONHR ¹² , -CONHCN, lH-tetrazol-yl, 5-oxo- 1,2,4-oxadiazole, 5-oxo-l,2,4-thiadiazole, 5-thioxo-l,2,4-oxadiazole, thiazolidinedione, oxazolidinedione, oxadiazolidinedione, 3-hydroxyisoxazole, 3-hydroxyisothiazole, cyclopentane-l,3-dione, squaric acid, squareamide, and mixed squaramate; wherein R ¹² is selected from hydrogen, Ci_ ₄ alkyl, and C ₃ _ ₅ cycloalkyl.

[0117] In certain embodiments of a compound of Formula (1), R ⁶ is selected from - COOH, -S(0)OH, -P(0)(OH)H, -CONHS0 ₂ CH ₃ , -CONHS0 ₂ CF ₃ , -S0 ₂ NHCOCH ₃ , - S0 ₂ NHCOCF ₃ , -NHS0 ₂ CH ₃ , -NHS0 ₂ CF ₃ , lH-tetrazol-yl, 5-oxo-l,2,4-oxadiazole-yl, 5- oxo- 1 ,2,4-thiadiazole-yl, 5-thioxo- 1 ,2,4-oxadiazole-yl, thiazolidinedione-yl,

oxazolidinedione -yl, oxadiazolidinedione-yl, 3-hydroxyisoxazole-yl, 3-hydroxyisothiazole- yl, tetronic acid-yl, tetramic acid-yl, and cyclopentane-l,3-dione-yl. [01 18] In certain embodiments of a compound of Formula (1), R ⁶ is selected from - COOH, -S(0)OH, -P(0)(OH)H, -CONHS0 ₂ CH ₃ , -CONHS0 ₂ CF ₃ , -S0 ₂ NHCOCH ₃ , - S0 ₂ NHCOCH ₃ , -S0 ₂ NHCOCF ₃ , -NHS0 ₂ CF ₃ , -NHS0 ₂ CF ₃ , and lH-tetrazol-5-yl.

[01 19] In certain embodiments of a compound of Formula (1), R ⁶ is selected from - COOH, -S(0)OH, -P(0)(OH)H, and lH-tetrazol-yl.

[0120] In certain embodiments of a compound of Formula (1), R ⁶ is -COOH.

[0121] In certain embodiments of a compound of Formula (1), each R ⁷ is independently selected from hydrogen, deuterio, halogen, hydroxyl, and Ci_ ₄ alkyl, or two germinal R ⁷ together with the carbon atom to which they are bonded form a C ₃ _ ₅ cycloalkyl ring.

[0122] In certain embodiments of a compound of Formula (1), each R ⁷ is independently selected from hydrogen, deuterio, fluoro, hydroxyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl, or two germinal R ⁷ together with the carbon atom to which they are bonded form a cyclopropyl ring or a cyclobutyl ring.

[0123] In certain embodiments of a compound of Formula (1), each R ⁷ is independently selected from hydrogen, deuterio, fluoro, hydroxyl, and methyl.

[0124] In certain embodiments of a compound of Formula (1), each R ⁷ is independently selected from hydrogen and deuterio.

[0125] In certain embodiments of a compound of Formula (1), each R ⁷ is hydrogen.

[0126] In certain embodiments of a compound of Formula (1), R ⁸ is selected from hydrogen, deuterio, halogen, hydroxyl, Ci_ ₄ alkyl, Ci_ ₄ alkoxy, Ci_ ₄ fluoroalkyl, Ci_ ₄ fluoroalkoxy, and cyclopropyl.

[0127] In certain embodiments of a compound of Formula (1), R ⁸ is selected from hydrogen, deuterio, halogen, hydroxyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert- butyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, and cyclopropyl.

[0128] In certain embodiments of a compound of Formula (1), R ⁸ is selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, tert-butyl, hydroxyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, and trifluoromethoxy.

[0129] In certain embodiments of a compound of Formula (1), R ⁸ is methyl.

[0130] In certain embodiments of a compound of Formula (1), R ⁸ is hydrogen.

[0131] In certain embodiments of a compound of Formula (1), each R ¹⁰ is independently selected from hydrogen and Ci_ ₄ alkyl, or two R ¹⁰ together with the nitrogen atom to which they are bonded form a 3- to 5-membered heterocycle.

[0132] In certain embodiments of a compound of Formula (1), L is (-X-) _a wherein a is selected from 0, 1 , 2, 3, and 4 and X is selected from oxygen (-0-), sulfur (-S-), sulfinyl (- SO-), sulfonyl (-S0 ₂ -), carbonyl (-CO-), -C(R ) ₂ - wherein R is independently selected from hydrogen, deuterio, halogen, hydroxyl, Ci_ ₄ alkyl, and amino (-NR ¹⁷ -), wherein R ¹⁷ is selected from hydrogen, methyl, and ethyl.

[0133] In certain embodiments of a compound of Formula (1), a is 1 , X and L are the same, and each of X and L is selected from a bond ("-"), methylene (-CH ₂ -),

fluoromethylene (-CFH-), difluoromethylene (-CF ₂ -), hydroxymethylene (-C(OH)H-), ethane- 1 , 1-diyl (-CHCH3-), propane-2,2-diyl (-C(CH ₃ ) ₂ -), propane -1 , 1-diyl (-CH(CH ₂ - CH ₃ )-), oxygen (-0-), sulfur (-S-), sulfmyl (-SO-), sulfonyl (-S0 ₂ -), carbonyl (-CO-), and amino (-NR ¹⁷ -), wherein R ¹⁷ is selected from hydrogen, methyl, and ethyl.

[0134] In certain embodiments of a compound of Formula (1), a is 2, each X is methylene (-CH ₂ -), and L is ethane- 1 ,2-diyl (-CH ₂ -CH ₂ -); one X is methylene (-CH ₂ -) and one X is ethane- 1 , 1-diyl (-CHCH ₃ -) and L is propane- 1 ,2-diyl (-CH ₂ -CHCH ₃ -); one X is ethane- 1 , 1- diyl (-CHCH3-) and one X is methylene (-CH ₂ -) and L is propane- 1 ,2-diyl (-CHCH ₃ - CH ₂ - ); one X is methylene (-CH ₂ -) and one X is hydroxymethylene (-CHOH-) and L is hydroxyethane- 1 ,2-diyl (-CH ₂ -CHOH-); one X is hydroxymethylene (-CHOH-) and one X is methylene (-CH ₂ -) and L is hydroxyethane- 1 ,2-diyl (-CHOH- CH ₂ -); one X is methylene (-CH ₂ -) and one X is fluoromethylene (-CFH-), and L is fluoroethane- 1 ,2-diyl (-CH ₂ - CHF-); one X is fluoromethylene (-CFH-), and one X is methylene (-CH ₂ -) and L is fluoroethane- 1 ,2-diyl (-CHF-CH ₂ -); one X is methylene (-CH ₂ -) and one X is

difluoromethylene (-CF ₂ -), and L is difluoroethane- 1 ,2-diyl (-CH ₂ -CF ₂ -); one X is difluoromethylene (-CF ₂ -), and one X is methylene (-CH ₂ -) and L is difluoroethane- 1 ,2-diyl (-CF ₂ -CH ₂ -); one X is carbonyl (-CO-) and one X is amino (-NR ¹⁷ -) and L is carbonyl amino (-CO-NR ¹⁷ -); one X is amino (-NR ¹⁷ -) and one X is carbonyl (-CO-) and L is amino carbonyl (-NR ¹⁷ -CO-); one X is methylene (-CH ₂ -) and one X is amino (-NR ¹⁷ -) and L is methyleneamino (-CH ₂ -NR ¹⁷ -); one X is amino (-NR ¹⁷ -) and one X is methylene (-CH ₂ -) and L is aminomethylene (-NR ¹⁷ -CH ₂ -); one X is methylene (-CH ₂ -) and one X is oxygen (-0-) and L is methyleneoxy (-CH ₂ -0-); one X is oxygen (-0-) and one X is methylene (- CH ₂ -) and L is oxymethylen (-0-CH ₂ -); one X is methylene (-CH ₂ -) and one X is sulfur (- S-) and L is methylenethiyl (-CH ₂ -S-); one X is sulfur (-S-) and one X is methylene (- CH ₂ -) and L is thiylmethylene (-S-CH ₂ -); one X is methylene (-CH ₂ -) and one X is sulfmyl (-SO-) and L is methylenesulfmyl (-CH ₂ -SO-); one X is sulfmyl (-SO-) and one X is methylene (-CH ₂ -) and L is sulfmylmethylene (-SO-CH ₂ -); one X is methylene (-CH ₂ -) and one X is sulfonyl (-S0 ₂ -) and L is methylenesulfonyl (-CH ₂ -S0 ₂ -); one X is sulfonyl (- S0 ₂ -) and one X is methylene (-CH ₂ -) and L is sulfonylmethylene (-S0 ₂ -CH ₂ -); one X is methylene (-CH ₂ -) and one X is carbonyl (-CO-) and L is methylenescarbonyl (-CH ₂ -CO- ); and in certain embodiments, one X is carbonyl (-CO-) and one X is methylene (-CH ₂ -) and L is carbonylmethylene (-CO-CH ₂ -), wherein R ¹⁷ is selected from hydrogen, methyl, and ethyl.

[0135] In certain embodiments of a compound of Formula (1), a is 1, X and L are the same, and each of X and L is selected from a bond ("-"), methylene (-CH ₂ -),

hydroxymethylene (-C(OH)H-), ethane- 1,1-diyl (-CHCH3-), propane-2,2-diyl (-C(CH ₃ ) ₂ -), oxygen (-0-), sulfonyl (-S0 ₂ -), and amino (-NR ¹⁷ -), wherein R ¹⁷ is selected from hydrogen and methyl.

[0136] In certain embodiments of a compound of Formula (1), a is 2; and L is selected from ethane- 1,2-diyl (-CH ₂ -CH ₂ -), propane- 1,2-diyl (-CH ₂ -CHCH ₃ - or -CHCH ₃ - CH ₂ -), hydroxyethane-l,2-diyl (-CH ₂ -CHOH-) or (-CHOH-CH ₂ -), carbonyl amino (-CO-NR ¹⁷ -), amino carbonyl (-NR ¹⁷ -CO-), methyleneamino (-CH ₂ -NR ¹⁷ -), aminomethylene (-NR ¹⁷ - CH ₂ -), methyleneoxy (-CH ₂ -0-), oxymethylene (-0-CH ₂ -), methylenethiyl (-CH ₂ -S-), thiylmethylene (-S-CH ₂ -), methylenesulfonyl (-CH ₂ -S0 ₂ -), and sulfonylmethylene (-S0 ₂ - CH ₂ -), wherein R ¹⁷ is selected from hydrogen and methyl.

[0137] In certain embodiments of a compound of Formula (1),

at least one of R ¹ and R ⁵ is independently selected from, halogen, -N(R ¹⁰ ) ₂ , -N ⁺ (-0 )(R ¹⁰ ) ₂ , -N(R ¹⁰ )(OR ¹⁰ ), -NO ₂ , -NO, -CN, -COOR ¹⁰ , -CON(R ¹⁰ ) ₂ , -OH, Ci_ ₄ alkyl, substituted Ci_ ₄ alkyl, Ci_ ₄ alkoxy, substituted Ci_ ₄ alkoxy, Ci_ ₄ alkylsulfanyl, Ci_ ₄

alkylsulfinyl, Ci_ ₄ alkylsulfonyl, Ci_ ₄ heteroalkyl, Ci_ ₄ heteroalkoxy, Ci_ ₄ fluoroalkyl, Ci_ ₄ fluoroalkoxy, C ₃ _ ₅ cycloalkyl, C ₃ _ ₅ cycloalkyloxy, and C ₄ _g cycloalkylalkyl;

each R ¹⁰ is independently selected from hydrogen, deuterio, Ci_ ₄ alkyl, and Ci_ ₄ alkoxy, or two geminal R ¹⁰ together with the nitrogen to which they are bonded form a 3- to 6-membered heterocyclic ring; and

one of R ¹ , R ² , R ³ , R ⁴ , and R ⁵ is selected from -N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CH ₂ -N(-CH ₂ - CH ₂ -R ⁹ ) ₂ , -N ⁺ (-0 )(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CH ₂ -N ⁺ (-0 )(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -N(-0-CH ₂ -CH ₂ - R ⁹ )(-CH ₂ -CH ₂ -R ⁹ ), -CH ₂ -N(-0-CH ₂ -CH ₂ -R ⁹ )(-CH ₂ -CH ₂ -R ⁹ ), -0-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , - CH ₂ -0-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CO-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CH ₂ -CO-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -O- CO-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , and -CH ₂ -0-CO-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , wherein each R ⁹ is independently selected from -CI, -Br, -I, -OS0 ₂ CH ₃ , and -OS0 ₂ CF ₃ .

[0138] In certain embodiments of a compound of Formula (1), at least one of R ¹ and R ⁵ is independently selected from halogen, -N(R ¹⁰ ) ₂ , - NR ¹⁰ (OR ¹⁰ ), -NO2, -NO, -OH, Ci_4 alkyl, Ci_ ₄ alkoxy, Ci_ ₄ alkylsulfanyl, Ci_ ₄ alkylsulfmyl, Ci_4 fluoroalkyl, Ci_ ₄ fluoroalkoxy, C3-5 cycloalkyl, and C3-5 cycloalkyloxy;

each R ¹⁰ is independently selected from hydrogen and Ci_ ₃ alkyl, or two R ¹⁰ together with the nitrogen to which they are bonded form a 3- to 5-membered heterocyclic ring; and one of R ¹ , R ² , R ³ , R ⁴ , and R ⁵ is selected from -N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CH ₂ -N(-CH ₂ - CH ₂ -R ⁹ ) ₂ , -N ⁺ (-0 )(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CH ₂ -N ⁺ (-0 )(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -N(-0-CH ₂ -CH ₂ - R ⁹ )(-CH ₂ -CH ₂ -R ⁹ ), -CH ₂ -N(-0-CH ₂ -CH ₂ -R ⁹ )(-CH ₂ -CH ₂ -R ⁹ ), -0-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , - CH ₂ -0-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CO-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CH ₂ -CO-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -O- CO-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , and -CH ₂ -0-CO-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , wherein each R ⁹ is independently selected from -CI, -Br, -I, -OS0 ₂ CH ₃ , and -OS0 ₂ CF ₃ .

[0139] In certain embodiments of a compound of Formula (1),

each of R ¹ and R ⁵ is independently selected from halogen, -N(R ¹⁰ ) ₂ , -N ⁺ (-O ^~ )(R ¹⁰ ) ₂ , -N(R ¹⁰ )(OR ¹⁰ ), -NO2, -NO, -CN, -COOR ¹⁰ , -CON(R ¹⁰ ) ₂ , -OH, Ci_ ₄ alkyl, Ci_ ₄ alkoxy, Ci_ ₄ alkylsulfanyl, Ci_ ₄ alkylsulfinyl, Ci_ ₄ alkylsulfonyl, Ci_ ₄ heteroalkyl, Ci_ ₄ heteroalkoxy, Ci_ ₄ fluoroalkyl, Ci_ ₄ fluoroalkoxy, C ₃ _ ₅ cycloalkyl, C ₃ _ ₅ cycloalkyloxy, and C ₄ _ ₈ cycloalkylalkyl; each R ¹⁰ is independently selected from hydrogen, deuterio, Ci_ ₄ alkyl, and Ci_ ₄ alkoxy, or two geminal R ¹⁰ together with the nitrogen to which they are bonded form a 3- to 6-membered heterocyclic ring; and

one of R ² , R ³ , and R ⁴ is selected from -N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CH ₂ -N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -N ⁺ (-0 )(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CH ₂ -N ⁺ (-0 )(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -N(-0-CH ₂ -CH ₂ -R ⁹ )(-CH ₂ - CH ₂ -R ⁹ ), -CH ₂ -N(-0-CH ₂ -CH ₂ -R ⁹ )(-CH ₂ -CH ₂ -R ⁹ ), -0-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CH ₂ -0- N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CO-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CH ₂ -CO-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -0-CO-N(- CH ₂ -CH ₂ -R ⁹ ) ₂ , and -CH ₂ -0-CO-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , wherein each R ⁹ is independently selected from -CI, -Br, -I, -OS0 ₂ CH ₃ , and -OS0 ₂ CF ₃ .

[0140] In certain embodiments of a compound of Formula (1),

each of R ¹ and R ⁵ is independently selected from halogen, -N(R ¹⁰ ) ₂ , -NR ¹⁰ (OR ¹⁰ ), - N0 ₂ , -NO, -OH, Ci_4 alkyl, Ci_ ₄ alkoxy, Ci_ ₄ alkylsulfanyl, Ci_ ₄ alkylsulfinyl, Ci_ ₄

fluoroalkyl, Ci_ ₄ fluoroalkoxy, C ₃ _ ₅ cycloalkyl, and C ₃ _ ₅ cycloalkyloxy;

each R ¹⁰ is independently selected from hydrogen and Ci_ ₃ alkyl, or two R ¹⁰ together with the nitrogen to which they are bonded form a 3- to 5-membered heterocyclic ring; and one of R ² , R ³ , and R ⁴ is selected from -N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CH ₂ -N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -N ⁺ (-0 )(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CH ₂ -N ⁺ (-0 )(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -N(-0-CH ₂ -CH ₂ -R ⁹ )(-CH ₂ - CH ₂ -R ⁹ ), -CH ₂ -N(-0-CH ₂ -CH ₂ -R ⁹ )(-CH ₂ -CH ₂ -R ⁹ ), -0-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CH ₂ -0- N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CO-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CH ₂ -CO-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -0-CO-N(- CH ₂ -CH ₂ -R ⁹ ) ₂ , and -CH ₂ -0-CO-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , wherein each R ⁹ is independently selected from -CI, -Br, -I, -OS0 ₂ CH ₃ , and -OS0 ₂ CF ₃ .

[0141] In certain embodiments of a compound of Formula ( 1 ),

one of R ¹ and R ⁵ is selected from halogen, -N(R ¹⁰ ) ₂ , -N ⁺ (-CQ(R ¹⁰ ) ₂ , -N(R ¹⁰ )(OR ¹⁰ ), -N0 ₂ , -NO, -CN, -COOR ¹⁰ , -CON(R ¹⁰ ) ₂ , -OH, Ci_ ₄ alkyl, Ci_ ₄ alkoxy, Ci_ ₄ alkylsulfanyl, Ci_ ₄ alkylsulfinyl, Ci_ ₄ alkylsulfonyl, Ci_ ₄ heteroalkyl, Ci_ ₄ heteroalkoxy, Ci_ ₄ fluoroalkyl, Ci_ ₄ fluoroalkoxy, C ₃ _ ₅ cycloalkyl, C ₃ _ ₅ cycloalkyloxy, and C ₄ _ ₈ cycloalkylalkyl;

each R ¹⁰ is independently selected from hydrogen, deuterio, Ci_ ₄ alkyl, and Ci_ ₄ alkoxy, or two geminal R ¹⁰ together with the nitrogen to which they are bonded form a 3- to 6-membered heterocyclic ring; and

one of R ¹ , R ² , R ³ , R ⁴ , and R ⁵ is selected from -N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CH ₂ -N(-CH ₂ - CH ₂ -R ⁹ ) ₂ , -N ⁺ (-0 )(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CH ₂ -N ⁺ (-0 )(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -N(-0-CH ₂ -CH ₂ - R ⁹ )(-CH ₂ -CH ₂ -R ⁹ ), -CH ₂ -N(-0-CH ₂ -CH ₂ -R ⁹ )(-CH ₂ -CH ₂ -R ⁹ ), -0-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , - CH ₂ -0-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CO-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CH ₂ -CO-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -O- CO-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , and -CH ₂ -0-CO-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , wherein each R ⁹ is independently selected from -CI, -Br, -I, -OS0 ₂ CH ₃ , and -OS0 ₂ CF ₃ .

[0142] In certain embodiments of a compound of Formula (1),

one of R ¹ and R ⁵ is selected from halogen, -N(R ¹⁰ ) ₂ , -NR ¹⁰ (OR ¹⁰ ), -N0 ₂ , -NO, -OH, Ci_ ₄ alkyl, Ci_ ₄ alkoxy, Ci_ ₄ alkylsulfanyl, Ci_ ₄ alkylsulfinyl, Ci_ ₄ fluoroalkyl, Ci_ ₄

fluoroalkoxy, C ₃ _ ₅ cycloalkyl, and C ₃ _ ₅ cycloalkyloxy;

each R ¹⁰ is independently selected from hydrogen and Ci_ ₃ alkyl, or two R ¹⁰ together with the nitrogen to which they are bonded form a 3- to 5-membered heterocyclic ring; and one of R ¹ , R ² , R ³ , R ⁴ , and R ⁵ is selected from -N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CH ₂ -N(-CH ₂ - CH ₂ -R ⁹ ) ₂ , -N ⁺ (-0 )(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CH ₂ -N ⁺ (-0 )(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -N(-0-CH ₂ -CH ₂ - R ⁹ )(-CH ₂ -CH ₂ -R ⁹ ), -CH ₂ -N(-0-CH ₂ -CH ₂ -R ⁹ )(-CH ₂ -CH ₂ -R ⁹ ), -0-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , - CH ₂ -0-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CO-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CH ₂ -CO-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -O- CO-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , and -CH ₂ -0-CO-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , wherein each R ⁹ is independently selected from -CI, -Br, -I, -OS0 ₂ CH ₃ , and -OS0 ₂ CF ₃ .

[0143] In certain embodiments of a compound of Formula (1),

each of the other of R ¹ , R ² , R ³ , R ⁴ , and R ⁵ is independently is selected from hydrogen, deuterio, halogen, -N(R ¹⁰ ) ₂ , -N(R ¹⁰ )(OR ¹⁰ ), -N0 ₂ , -NO, -OH, -COOR ¹⁰ , -CON(R ¹⁰ ) ₂ , - OH, Ci_ ₄ alkylsulfanyl, Ci_ ₄ alkylsulfinyl, Ci_ ₄ alkylsulfonyl, Ci_ ₄ fluoroalkyl, Ci_ ₄ fluoroalkoxy, Ci_ ₄ alkyl, Ci_ ₄ alkoxy, Ci_ ₄ heteroalkyl, Ci_ ₄ heteroalkoxy, and C ₄ _g cycloalkylalkyl; and

each R ¹⁰ is independently selected from hydrogen and Ci_ ₄ alkyl, or two R ¹⁰ together with the nitrogen to which they are bonded form a 3- to 6-membered heterocyclic ring.

[0144] In certain embodiments of a compound of Formula (1),

each of the other of R ¹ , R ² , R ³ , R ⁴ , and R ⁵ is independently selected from hydrogen, deuterio, halogen, -NR ¹⁰ ₂ , -N(R ¹⁰ )(OR ¹⁰ ), -OH, Ci_ ₄ alkyl, Ci_ ₄ alkoxy, Ci_ ₄ alkylsulfanyl, Ci_ ₄ fluoroalkyl, and Ci_ ₄ fluoroalkoxy, and

each R ¹⁰ is independently selected from hydrogen and Ci_ ₄ alkyl, or two R ¹⁰ together with the nitrogen to which they are bonded form a 3- to 5-membered heterocyclic ring.

[0145] In certain embodiments of a compound of Formula (1), each of R ¹ and R ⁵ is hydrogen.

[0146] In certain embodiments of a compound of Formula (1), each of the other of R ¹ , R ² , R ³ , R ⁴ , and R ⁵ is hydrogen.

[0147] In certain embodiments of a compound of Formula (1), each of R ² , R ³ , and R ⁵ is hydrogen.

[0148] In certain embodiments of a compound of Formula (1), Rl is selected from halogen, -N(R10)2, -N+(-O-)(R ¹⁰ ) ₂ , -N(OR ¹⁰ )(R ¹⁰ ), -N0 ₂ , -NO, -N(R ¹⁰ )(S(=O)R ¹⁰ ), - N(R ¹⁰ )(S(=O) ₂ R ¹⁰ ), -N(R ¹⁰ )(C(O)R ¹⁰ ), -N(R ¹⁰ )(C(O)OR ¹⁰ ), -N(R ¹⁰ )(C(O)N(R ¹⁰ ) ₂ , -CN, - COOR ¹⁰ , -CON(R ¹⁰ ) ₂ , -OH, -SH, Ci_ ₄ alkylsulfanyl, Ci_ ₄ alkylsulfinyl, Ci_ ₄ alkylsulfonyl, - S(O)N(R ¹⁰ ) ₂ , -S(O) ₂ N(R ¹⁰ ) ₂ , Ci_ ₄ fluoroalkyl, Ci_ ₄ fluoroalkoxy, Ci_ ₆ alkyl, substituted Ci_ ₆ alkyl, Ci_ ₆ alkoxy, substituted Ci_ ₆ alkoxy, C ₃ -6 cycloalkyl, substituted C ₃ -6 cycloalkyl, C ₃ -6 cycloalkyloxy, substituted C ₃ -6 cycloalkyloxy, C ₄ _i ₂ cycloalkylalkyl, substituted C ₄ _i ₂ cycloalkylalkyl, C ₆ -io aryl, substituted C ₆ -io aryl, C7-16 arylalkyl, substituted C7-16 arylalkyl, Ci_6 heteroalkyl, substituted Ci_ ₆ heteroalkyl, Ci_ ₆ heteroalkoxy, substituted Ci_ ₆ heteroalkoxy, C ₃ -6 heterocycloalkyl, substituted C ₃ -6 heterocycloalkyl, C ₄ _i ₂ heterocycloalkylalkyl, substituted C ₄ _i ₂ heterocycloalkylalkyl, C ₅ -10 heteroaryl, substituted C ₅ -10 heteroaryl, C ₆ -i6 heteroarylalkyl, and substituted C ₆ -i6 heteroarylalkyl; wherein each R ¹⁰ is independently selected from hydrogen, deuterio, Ci_ ₄ alkyl, and Ci_ ₄ alkoxy, or two geminal R ¹⁰ together with the nitrogen to which they are bonded form a 3- to 6-membered heterocyclic ring; and R ⁵ is hydrogen.

[0149] In certain embodiments of a compound of Formula (1),

R ¹ selected from halogen, -N(R ¹⁰ ) ₂ , -N ⁺ (-CQ(R ¹⁰ ) ₂ , -N(R ¹⁰ )(OR ¹⁰ ), -N0 ₂ , -NO, - CN, -COOR ¹⁰ , -CON(R ¹⁰ ) ₂ , -OH, Ci_ ₄ alkyl, Ci_ ₄ alkoxy, Ci_ ₄ alkylsulfanyl, Ci_ ₄ alkylsulfinyl, Ci_ ₄ alkylsulfonyl, Ci_ ₄ heteroalkyl, Ci_ ₄ heteroalkoxy, Ci_ ₄ fluoroalkyl, Ci_ ₄ fluoroalkoxy, C3_ ₅ cycloalkyl, C3_ ₅ cycloalkyloxy, and C ₄ _8 cycloalkylalkyl; wherein each R ¹⁰ is independently selected from hydrogen, deuterio, Ci_ ₄ alkyl, and Ci_ ₄ alkoxy, or two geminal R ¹⁰ together with the nitrogen to which they are bonded form a 3- to 6-membered heterocyclic ring; and

R ⁵ is hydrogen.

[0150] In certain embodiments of a compound of Formula (1),

R ¹ is selected from halogen, -N(R ¹⁰ ) ₂ , -NR ¹⁰ (OR ¹⁰ ), -N0 ₂ , -NO, -OH, Ci_ ₄ alkyl, Ci_ 4 alkoxy, Ci_ ₄ alkylsulfanyl, Ci_ ₄ alkylsulfinyl, Ci_ ₄ fluoroalkyl, Ci_ ₄ fluoroalkoxy, C3-5 cycloalkyl, and C3-5 cycloalkyloxy; wherein each R ¹⁰ is independently selected from hydrogen and Ci_3 alkyl, or two R ¹⁰ together with the nitrogen to which they are bonded form a 3- to 5-membered heterocyclic ring; and

R ⁵ is hydrogen.

[0151] In certain embodiments of a compound of Formula ( 1 ),

each of R ¹ and R ⁵ is independently selected from halogen, -N(R ¹⁰ ) ₂ , -N ⁺ (-O ^~ )(R ¹⁰ ) ₂ , -N(R ¹⁰ )(OR ¹⁰ ), -NO ₂ , -NO, -CN, -COOR ¹⁰ , -CON(R ¹⁰ ) ₂ , -OH, Ci_ ₄ alkyl, Ci_ ₄ alkoxy, Ci_ ₄ alkylsulfanyl, Ci_ ₄ alkylsulfinyl, Ci_ ₄ alkylsulfonyl, Ci_ ₄ heteroalkyl, Ci_ ₄ heteroalkoxy, Ci_ ₄ fluoroalkyl, Ci_ ₄ fluoroalkoxy, C3-5 cycloalkyl, C3-5 cycloalkyloxy, and C ₄ _8 cycloalkylalkyl; wherein each R ¹⁰ is independently selected from hydrogen, deuterio, Ci_ ₄ alkyl, and Ci_ ₄ alkoxy, or two geminal R ¹⁰ together with the nitrogen to which they are bonded form a 3- to 6-membered heterocyclic ring;

one of R ² , R ³ , and R ⁴ is -N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CH ₂ -N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -N ⁺ (-0 )(- CH ₂ -CH ₂ -R ⁹ ) ₂ , -CH ₂ -N ⁺ (-0 )(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -N(-0-CH ₂ -CH ₂ -R ⁹ )(-CH ₂ -CH ₂ -R ⁹ ), - CH ₂ -N(-0-CH ₂ -CH ₂ -R ⁹ )(-CH ₂ -CH ₂ -R ⁹ ), -0-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CH ₂ -0-N(-CH ₂ - CH ₂ -R ⁹ ) ₂ , -CO-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CH ₂ -CO-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -0-CO-N(-CH ₂ -CH ₂ - R ⁹ ) ₂ , and -CH ₂ -0-CO-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , wherein each R ⁹ is independently selected from -CI, -Br, -I, -OS0 ₂ CH ₃ , and -OS0 ₂ CF ₃ ;

each of the other of R ² , R ³ , and R ⁴ is hydrogen;

R ⁶ is selected from -COOH, -S(0)OH, -P(0)(OH)H, and lH-tetrazole;

each R ⁷ is independently selected from hydrogen, methyl, hydroxyl, and fluoro;

R ⁸ is selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, cyclobutyl, tert-butyl, hydroxyl, Ci_ ₄ alkoxy, Ci_ ₄ fluoroalkyl, and Ci_ ₄ fluoroalkoxy; and L is selected from a bond -CH ₂ - -C(OH)H- -CHCH ₃ - -C(CH ₃ ) ₂ -, -CF ₂ - - 0-, -SO ₂ -, -NR ¹⁷ -, -CH ₂ -CH ₂ -, -CH ₂ -CHCH ₃ -, -CHCH ₃ - CH ₂ -, -CH ₂ -CHOH-, - CHOH-CH ₂ -, -CH ₂ -CF ₂ -, -CF ₂ -CH ₂ -, -CO-NR ¹⁷ -, -NR ¹⁷ -CO-, -CH ₂ -NR ¹⁷ -, -NR ¹⁷ - CH ₂ - -CH ₂ -O-, -O-CH ₂ -, -CH ₂ -S-, -S-CH ₂ -, -CH ₂ -SO ₂ -, and -S0 ₂ -CH ₂ -, wherein R ¹⁷ is selected from hydrogen, methyl, and ethyl.

[0152] In certain embodiments of a compound of Formula (1),

each of R ¹ and R ⁵ is independently selected from halogen, -N(R ¹⁰ ) ₂ , -NR ¹⁰ (OR ¹⁰ ), - N0 ₂ , -NO, -OH, Ci_4 alkyl, Ci_ ₄ alkoxy, Ci_ ₄ alkylsulfanyl, Ci_ ₄ alkylsulfmyl, Ci_ ₄

fluoroalkyl, Ci_ ₄ fluoroalkoxy, C ₃ _ ₅ cycloalkyl, and C ₃ _ ₅ cycloalkyloxy; wherein each R ¹⁰ is independently selected from hydrogen and Ci_ ₃ alkyl, or two R ¹⁰ together with the nitrogen to which they are bonded form a 3- to 5-membered heterocyclic ring;

one of R ² , R ³ , and R ⁴ is selected from-N(-CH2-CH ₂ -R ⁹ )2, -CH2-N(-CH ₂ -CH ₂ -R ⁹ )2, -N ⁺ (-0 )(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CH ₂ -N ⁺ (-0 )(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -N(-0-CH ₂ -CH ₂ -R ⁹ )(-CH ₂ - CH2-R ⁹ ), -CH ₂ -N(-0-CH2-CH2-R ⁹ )(-CH2-CH ₂ -R ⁹ ), -0-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CH ₂ -0- N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CO-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CH2-CO-N(-CH ₂ -CH ₂ -R ⁹ )2, -0-CO-N(- CH ₂ -CH ₂ -R ⁹ ) ₂ , and -CH ₂ -0-CO-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , wherein each R ⁹ is independently selected from -CI, -Br, -I, -OS0 ₂ CH ₃ , and -OS0 ₂ CF ₃ .

each of the other R ² , R ³ , and R ⁴ is hydrogen;

R ⁶ is -COOH;

each R ⁷ is independently selected from hydrogen, methyl, hydroxyl, and fluoro;

R ⁸ is selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, tert-butyl, hydroxyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, and trifluoromethoxy; and

L is selected from a bond -CH ₂ - -C(OH)H-, -CHCH ₃ - -0-, -NR ¹⁷ -, -CH ₂ - CH ₂ -), -CH ₂ -CHCH ₃ - -CHCH ₃ - CH ₂ -, -CH ₂ -CHOH-, -CHOH-CH ₂ -, -CO-NR ¹⁷ -, - NR ¹⁷ -CO- -CH ₂ -NR ¹⁷ -, -NR ¹⁷ -CH ₂ -, -CH ₂ -O-, -O-CH ₂ -, -CH ₂ -S-, -S-CH ₂ -, -CH ₂ - SO ₂ -, and -SO ₂ -CH ₂ -, wherein R ¹⁷ is selected from hydrogen and methyl.

[0153] In certain embodiments of a compound of Formula (1),

R ¹ is selected from halogen, -N(R ¹⁰ ) ₂ , -N ⁺ (-CQ(R ¹⁰ ) ₂ , -N(R ¹⁰ )(OR ¹⁰ ), -N0 ₂ , -NO, - CN, -COOR ¹⁰ , -CON(R ¹⁰ ) ₂ , -OH, Ci_ ₄ alkyl, Ci_ ₄ alkoxy, Ci_ ₄ alkylsulfanyl, Ci_ ₄

alkylsulfinyl, Ci_ ₄ alkylsulfonyl, Ci_ ₄ heteroalkyl, Ci_ ₄ heteroalkoxy, Ci_ ₄ fluoroalkyl, Ci_ ₄ fluoroalkoxy, C ₃ _ ₅ cycloalkyl, C ₃ _ ₅ cycloalkyloxy, and C ₄ _8 cycloalkylalkyl; wherein each R ¹⁰ is independently selected from hydrogen, deuterio, Ci_ ₄ alkyl, and Ci_ ₄ alkoxy, or two geminal R ¹⁰ together with the nitrogen to which they are bonded form a 3- to 6-membered heterocyclic ring; one of R ² , R ³ , R ⁴ , and R ⁵ is selected from -N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CH ₂ -N(-CH ₂ -CH ₂ - R ⁹ ) ₂ , -N ⁺ (-0 )(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CH ₂ -N ⁺ (-0 )(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -N(-0-CH ₂ -CH ₂ -R ⁹ )(- CH ₂ -CH ₂ -R ⁹ ), -CH ₂ -N(-0-CH ₂ -CH ₂ -R ⁹ )(-CH ₂ -CH ₂ -R ⁹ ), -0-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CH ₂ - 0-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CO-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CH ₂ -CO-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -O-CO- N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , and -CH ₂ -0-CO-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , wherein each R ⁹ is independently selected from -CI, -Br, -I, -OS0 ₂ CH ₃ , and -OS0 ₂ CF ₃ ;

each of the other of R ² , R ³ , R ⁴ , and R ⁵ is hydrogen;

R ⁶ is selected from -COOH, -S(0)OH, -P(0)(OH)H, and lH-tetrazole;

each R ⁷ is independently selected from hydrogen, methyl, hydroxyl, and fluoro;

R ⁸ is selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, cyclobutyl, tert-butyl, hydroxyl, Ci_ ₄ alkoxy, Ci_ ₄ fluoroalkyl, and Ci_ ₄ fluoroalkoxy; and

L is selected from a bond -CH ₂ - -C(OH)H- -CHCH ₃ - -C(CH ₃ ) ₂ -, -CF ₂ - - 0-, -SO ₂ -, -NR ¹⁷ -, -CH ₂ -CH ₂ -, -CH ₂ -CHCH ₃ -, -CHCH ₃ - CH ₂ -, -CH ₂ -CHOH-, - CHOH-CH ₂ -, -CH ₂ -CF ₂ - -CF ₂ -CH ₂ - -CO-NR ¹⁷ -, -NR ¹⁷ -CO-, -CH ₂ -NR ¹⁷ -, -NR ¹⁷ - CH ₂ - -CH ₂ -O-, -O-CH ₂ -, -CH ₂ -S-, -S-CH ₂ -, -CH ₂ -S0 ₂ -, and -S0 ₂ -CH ₂ -, wherein R ¹⁷ is selected from hydrogen, methyl, and ethyl.

[0154] In certain embodiments of a compound of Formula (1),

R ¹ is selected from halogen, -N(R ¹⁰ ) ₂ , -NR ¹⁰ (OR ¹⁰ ), -N0 ₂ , -NO, -OH, Ci_ ₄ alkyl, Ci_ 4 alkoxy, Ci_ ₄ alkylsulfanyl, Ci_ ₄ alkylsulfmyl, Ci_ ₄ fluoroalkyl, Ci_ ₄ fluoroalkoxy, C ₃ _ ₅ cycloalkyl, and C ₃ _ ₅ cycloalkyloxy; wherein each R ¹⁰ is independently selected from hydrogen and Ci_ ₃ alkyl, or two R ¹⁰ together with the nitrogen to which they are bonded form a 3- to 5-membered heterocyclic ring;

one of R ² , R ³ , R ⁴ , and R ⁵ is selected from -N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CH ₂ -N(-CH ₂ -CH ₂ - R ⁹ ) ₂ , -N ⁺ (-0 )(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CH ₂ -N ⁺ (-0 )(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -N(-0-CH ₂ -CH ₂ -R ⁹ )(- CH ₂ -CH ₂ -R ⁹ ), -CH ₂ -N(-0-CH ₂ -CH ₂ -R ⁹ )(-CH ₂ -CH ₂ -R ⁹ ), -0-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CH ₂ - 0-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CO-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CH ₂ -CO-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -O-CO- N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , and -CH ₂ -0-CO-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , wherein each R ⁹ is independently selected from -CI, -Br, -I, -OS0 ₂ CH ₃ , and -OS0 ₂ CF ₃ .

each of the other of R ² , R ³ , R ⁴ , and R ⁵ is hydrogen;

R ⁶ is -COOH;

each R ⁷ is independently selected from hydrogen, methyl, hydroxyl, and fluoro;

R ⁸ is selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, tert-butyl, hydroxyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, and trifluoromethoxy; and L is selected from a bond -CH ₂ - -C(OH)H- -CHCH ₃ - -0-, -NR -, -CH ₂ - CH ₂ -), -CH ₂ -CHCH ₃ -, -CHCH ₃ - CH ₂ - -CH ₂ -CHOH-, -CHOH-CH ₂ -, -CO-NR ¹⁷ -, - NR ¹⁷ -CO- -CH ₂ -NR ¹⁷ -, -NR ¹⁷ -CH ₂ -, -CH ₂ -0-, -0-CH ₂ - -CH ₂ -S- -S-CH ₂ - -CH ₂ - S0 ₂ -, and -S0 ₂ -CH ₂ -, wherein R ¹⁷ is selected from hydrogen and methyl.

[0155] In certain embodiments of a compound of Formula (1),

R ⁵ is selected from halogen, -N(R ¹⁰ ) ₂ , -N ⁺ (-CQ(R ¹⁰ ) ₂ , -N(R ¹⁰ )(OR ¹⁰ ), -N0 ₂ , -NO, - CN, -COOR ¹⁰ , -CON(R ¹⁰ ) ₂ , -OH, Ci_ ₄ alkyl, Ci_ ₄ alkoxy, Ci_ ₄ alkylsulfanyl, Ci_ ₄

alkylsulfmyl, Ci_ ₄ alkylsulfonyl, Ci_ ₄ heteroalkyl, Ci_ ₄ heteroalkoxy, Ci_ ₄ fluoroalkyl, Ci_ ₄ fluoroalkoxy, C ₃ _ ₅ cycloalkyl, C ₃ _ ₅ cycloalkyloxy, and C ₄ _8 cycloalkylalkyl; wherein each R ¹⁰ is independently selected from hydrogen, deuterio, Ci_ ₄ alkyl, and Ci_ ₄ alkoxy, or two geminal R ¹⁰ together with the nitrogen to which they are bonded form a 3- to 6-membered heterocyclic ring;

one of R ¹ , R ² , R ³ , and R ⁴ is selected from -N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CH ₂ -N(-CH ₂ -CH ₂ - R ⁹ ) ₂ , -N ⁺ (-0 )(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CH ₂ -N ⁺ (-0 )(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -N(-0-CH ₂ -CH ₂ -R ⁹ )(- CH ₂ -CH ₂ -R ⁹ ), -CH ₂ -N(-0-CH ₂ -CH ₂ -R ⁹ )(-CH ₂ -CH ₂ -R ⁹ ), -0-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CH ₂ - 0-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CO-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CH ₂ -CO-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -O-CO- N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , and -CH ₂ -0-CO-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , wherein each R ⁹ is independently selected from -CI, -Br, -I, -OS0 ₂ CH ₃ , and -OS0 ₂ CF ₃ ;

each of the other of R ¹ , R ² , R ³ , and R ⁴ is hydrogen;

R ⁶ is selected from -COOH, -S(0)OH, -P(0)(OH)H, and lH-tetrazole;

each R ⁷ is independently selected from hydrogen, methyl, hydroxyl, and fluoro;

R ⁸ is selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, cyclobutyl, tert-butyl, hydroxyl, Ci_ ₄ alkoxy, Ci_ ₄ fluoroalkyl, and Ci_ ₄ fluoroalkoxy; and

L is selected from a bond -CH ₂ - -C(OH)H-, -CHCH ₃ - -C(CH ₃ ) ₂ - -CF ₂ - - 0-, -S0 ₂ - -NR ¹⁷ -, -CH ₂ -CH ₂ - -CH ₂ -CHCH ₃ -, -CHCH ₃ - CH ₂ -, -CH ₂ -CHOH- - CHOH-CH ₂ -, -CH ₂ -CF ₂ -, -CF ₂ -CH ₂ - -CO-NR ¹⁷ -, -NR ¹⁷ -CO- -CH ₂ -NR ¹⁷ -, -NR ¹⁷ - CH ₂ - -CH ₂ -0- -0-CH ₂ - -CH ₂ -S-, -S-CH ₂ -, -CH ₂ -S0 ₂ -, and -S0 ₂ -CH ₂ - wherein R ¹⁷ is selected from hydrogen, methyl, and ethyl.

[0156] In certain embodiments of a compound of Formula (1),

R ⁵ is selected from halogen, -N(R ¹⁰ ) ₂ , -NR ¹⁰ (OR ¹⁰ ), -N0 ₂ , -NO, -OH, Ci_ ₄ alkyl, Ci_ 4 alkoxy, Ci_ ₄ alkylsulfanyl, Ci_ ₄ alkylsulfinyl, Ci_ ₄ fluoroalkyl, Ci_ ₄ fluoroalkoxy, C ₃ _ ₅ cycloalkyl, and C ₃ _ ₅ cycloalkyloxy; wherein each R ¹⁰ is independently selected from hydrogen and Ci_ ₃ alkyl, or two R together with the nitrogen to which they are bonded form a 3- to 5-membered heterocyclic ring;

one of R ¹ , R ² , R ³ , and R ⁴ is selected from -N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CH ₂ -N(-CH ₂ -CH ₂ - R ⁹ ) ₂ , -N ⁺ (-0 )(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CH ₂ -N ⁺ (-0 )(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -N(-0-CH ₂ -CH ₂ -R ⁹ )(- CH ₂ -CH ₂ -R ⁹ ), -CH ₂ -N(-0-CH ₂ -CH ₂ -R ⁹ )(-CH ₂ -CH ₂ -R ⁹ ), -0-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CH ₂ - 0-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CO-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CH ₂ -CO-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -O-CO- N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , and -CH ₂ -0-CO-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , wherein each R ⁹ is independently selected from -CI, -Br, -I, -OS0 ₂ CH ₃ , and -OS0 ₂ CF ₃ .

each of the other of R ¹ , R ² , R ³ , and R ⁴ is hydrogen;

R ⁶ is -COOH;

each R ⁷ is independently selected from hydrogen, methyl, hydroxyl, and fluoro;

R ⁸ is selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, tert-butyl, hydroxyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, and trifluoromethoxy; and

L is selected from a bond -CH ₂ - -C(OH)H- -CHCH ₃ - -0-, -NR ¹⁷ -, -CH ₂ - CH ₂ -), -CH ₂ -CHCH ₃ -, -CHCH ₃ - CH ₂ -, -CH ₂ -CHOH-, -CHOH-CH ₂ - -CO-NR ¹⁷ -, - NR ¹⁷ -CO-, -CH ₂ -NR ¹⁷ -, -NR ¹⁷ -CH ₂ - -CH ₂ -0-, -0-CH ₂ -, -CH ₂ -S-, -S-CH ₂ - -CH ₂ - S0 ₂ -, and -S0 ₂ -CH ₂ -, wherein R ¹⁷ is selected from hydrogen and methyl.

[0157] In certain embodiments of a compound of Formula (1),

one of R ¹ and R ⁵ is selected from -N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CH ₂ -N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , - N ⁺ (-0 )(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CH ₂ -N ⁺ (-0 )(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -N(-0-CH ₂ -CH ₂ -R ⁹ )(-CH ₂ - CH ₂ -R ⁹ ), -CH ₂ -N(-0-CH ₂ -CH ₂ -R ⁹ )(-CH ₂ -CH ₂ -R ⁹ ), -0-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CH ₂ -0- N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CO-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CH ₂ -CO-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -0-CO-N(- CH ₂ -CH ₂ -R ⁹ ) ₂ , and -CH ₂ -0-CO-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , wherein each R ⁹ is independently selected from -CI, -Br, -I, -OS0 ₂ CH ₃ , and -OS0 ₂ CF ₃ ;

each of the other of R ¹ , R ² , R ³ , R ⁴ , and R ⁵ is hydrogen;

R ⁶ is selected from -COOH, -S(0)OH, -P(0)(OH)H, and lH-tetrazole;

each R ⁷ is independently selected from hydrogen, methyl, hydroxyl, and fluoro;

R ⁸ is selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, cyclobutyl, tert-butyl, hydroxyl, Ci_ ₄ alkoxy, Ci_ ₄ fluoroalkyl, and Ci_ ₄ fluoroalkoxy; and

L is selected from a bond -CH ₂ - -C(OH)H-, -CHCH ₃ - -C(CH ₃ ) ₂ -, -CF ₂ -, - 0-, -S0 ₂ - -NR ¹⁷ -, -CH ₂ -CH ₂ -, -CH ₂ -CHCH ₃ - -CHCH ₃ - CH ₂ -, -CH ₂ -CHOH-, - CHOH-CH ₂ - -CH ₂ -CF ₂ -, -CF ₂ -CH ₂ - -CO-NR ¹⁷ -, -NR ¹⁷ -CO-, -CH ₂ -NR ¹⁷ -, -NR ¹⁷ - CH ₂ - -CH2-O-, -O-CH2-, -CH2-S-, -S-CH2-, -CH2-SO2-, and -S0 ₂ -CH ₂ -, wherein R is selected from hydrogen, methyl, and ethyl.

[0158] In certain embodiments of a compound of Formula (1),

one of R ¹ and R ⁵ is selected from-N(-CH ₂ -CH ₂ -R ⁹ )2, -CH2-N(-CH ₂ -CH ₂ -R ⁹ )2, - N ⁺ (-0 )(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CH ₂ -N ⁺ (-0 )(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -N(-0-CH ₂ -CH ₂ -R ⁹ )(-CH ₂ - CH2-R ⁹ ), -CH ₂ -N(-0-CH2-CH2-R ⁹ )(-CH2-CH ₂ -R ⁹ ), -0-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CH ₂ -0- N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CO-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CH2-CO-N(-CH ₂ -CH ₂ -R ⁹ )2, -0-CO-N(- CH ₂ -CH ₂ -R ⁹ ) ₂ , and -CH ₂ -0-CO-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , wherein each R ⁹ is independently selected from -CI, -Br, -I, -OS0 ₂ CH ₃ , and -OS0 ₂ CF ₃ ;

each of the other of R ¹ , R ² , R ³ , R ⁴ , and R ⁵ is hydrogen;

R ⁶ is -COOH;

each R ⁷ is independently selected from hydrogen, methyl, hydroxyl, and fluoro;

R ⁸ is selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, tert-butyl, hydroxyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, and trifluoromethoxy; and

L is selected from a bond -CH ₂ - -C(OH)H-, -CHCH ₃ - -0-, -NR ¹⁷ -, -CH ₂ - CH ₂ -), -CH ₂ -CHCH ₃ -, -CHCH ₃ - CH ₂ -, -CH ₂ -CHOH-, -CHOH-CH ₂ -, -CO-NR ¹⁷ -, - NR ¹⁷ -CO- -CH ₂ -NR ¹⁷ -, -NR ¹⁷ -CH ₂ -, -CH ₂ -O-, -O-CH ₂ -, -CH ₂ -S-, -S-CH ₂ -, -CH ₂ - SO ₂ -, and -SO ₂ -CH ₂ -, wherein R ¹⁷ is selected from hydrogen and methyl.

[0159] In certain embodiments of a compound of Formula (1),

R ¹ is selected from halogen, -N(R ¹⁰ ) ₂ , -N ⁺ (-CQ(R ¹⁰ ) ₂ , -N(R ¹⁰ )(OR ¹⁰ ), -N0 ₂ , -NO, - CN, -COOR ¹⁰ , -CON(R ¹⁰ ) ₂ , -OH, Ci_ ₄ alkyl, Ci_ ₄ alkoxy, Ci_ ₄ alkylsulfanyl, Ci_ ₄

alkylsulfinyl, Ci_ ₄ alkylsulfonyl, Ci_ ₄ heteroalkyl, Ci_ ₄ heteroalkoxy, Ci_ ₄ fluoroalkyl, Ci_ ₄ fluoroalkoxy, C ₃ _ ₅ cycloalkyl, C ₃ _ ₅ cycloalkyloxy, and C ₄ _8 cycloalkylalkyl; wherein each R ¹⁰ is independently selected from hydrogen, deuterio, Ci_ ₄ alkyl, and Ci_ ₄ alkoxy, or two geminal R ¹⁰ together with the nitrogen to which they are bonded form a 3- to 6-membered heterocyclic ring;

R ⁴ is selected from -N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CH ₂ -N(-CH ₂ -CH ₂ -R ⁹ )2, -N ⁺ (-0 )(-CH ₂ - CH ₂ -R ⁹ ) ₂ , -CH ₂ -N ⁺ (-0 )(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -N(-0-CH2-CH ₂ -R ⁹ )(-CH2-CH ₂ -R ⁹ ), -CH ₂ - N(-0-CH2-CH ₂ -R ⁹ )(-CH2-CH ₂ -R ⁹ ), -0-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CH2-0-N(-CH ₂ -CH ₂ -R ⁹ )2, -CO-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CH ₂ -CO-N(-CH ₂ -CH ₂ -R ⁹ )2, -0-CO-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , and - CH ₂ -0-CO-N(-CH ₂ -CH ₂ -R ⁹ )2, wherein each R ⁹ is independently selected from -CI, -Br, -I, -OS0 ₂ CH ₃ , and -OS0 ₂ CF ₃ .

each of R ² , R ³ , and R ⁵ is hydrogen;

R ⁶ is selected from -COOH, -S(0)OH, -P(0)(OH)H, and lH-tetrazole; each R is independently selected from hydrogen, methyl, hydroxyl, and fluoro;

R ⁸ is selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, cyclobutyl, tert-butyl, hydroxyl, Ci_ ₄ alkoxy, Ci_ ₄ fluoroalkyl, and Ci_ ₄ fluoroalkoxy; and

L is selected from a bond -CH ₂ - -C(OH)H- -CHCH ₃ - -C(CH ₃ ) ₂ -, -CF ₂ - - 0-, -SO ₂ -, -NR ¹⁷ -, -CH ₂ -CH ₂ -, -CH ₂ -CHCH ₃ -, -CHCH ₃ - CH ₂ -, -CH ₂ -CHOH-, - CHOH-CH ₂ -, -CH ₂ -CF ₂ -, -CF ₂ -CH ₂ -, -CO-NR ¹⁷ -, -NR ¹⁷ -CO-, -CH ₂ -NR ¹⁷ -, -NR ¹⁷ - CH ₂ - -CH ₂ -O-, -O-CH ₂ -, -CH ₂ -S-, -S-CH ₂ -, -CH ₂ -SO ₂ -, and -S0 ₂ -CH ₂ -, wherein R ¹⁷ is selected from hydrogen, methyl, and ethyl.

[0160] In certain embodiments of a compound of Formula (1),

R ¹ is selected from halogen, -N(R ¹⁰ ) ₂ , -NR ¹⁰ (OR ¹⁰ ), -N0 ₂ , -NO, -OH, Ci_ ₄ alkyl, Ci_ ₄ alkoxy, Ci_ ₄ alkylsulfanyl, Ci_ ₄ alkylsulfmyl, Ci_ ₄ fluoroalkyl, Ci_ ₄ fluoroalkoxy, C ₃ _ ₅ cycloalkyl, and C ₃ _ ₅ cycloalkyloxy; wherein each R ¹⁰ is independently selected from hydrogen and Ci_ ₃ alkyl; or two R ¹⁰ together with the nitrogen to which they are bonded to form a 3- to 5-membered heterocyclic ring;

R ⁴ is selected from -N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CH2-N(-CH ₂ -CH ₂ -R ⁹ )2, -N ⁺ (-0 )(-CH ₂ - CH ₂ -R ⁹ ) ₂ , -CH ₂ -N ⁺ (-0 )(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -N(-0-CH2-CH ₂ -R ⁹ )(-CH2-CH ₂ -R ⁹ ), -CH ₂ - N(-0-CH2-CH ₂ -R ⁹ )(-CH2-CH ₂ -R ⁹ ), -0-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CH2-0-N(-CH ₂ -CH ₂ -R ⁹ )2, -CO-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , -CH ₂ -CO-N(-CH ₂ -CH ₂ -R ⁹ )2, -0-CO-N(-CH ₂ -CH ₂ -R ⁹ ) ₂ , and - CH ₂ -0-CO-N(-CH ₂ -CH ₂ -R ⁹ )2, wherein each R ⁹ is independently selected from -CI, -Br, -I, -OS0 ₂ CH ₃ , and -OS0 ₂ CF ₃ .

each of R ² , R ³ , and R ⁵ is hydrogen;

R ⁶ is -COOH;

each R ⁷ is independently selected from hydrogen, methyl, hydroxyl, and fluoro;

R ⁸ is selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, tert-butyl, hydroxyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, and trifluoromethoxy;

L is selected from a bond -CH ₂ - -C(OH)H- -CHCH ₃ - -0-, -NR ¹⁷ -, -CH ₂ - CH ₂ -), -CH ₂ -CHCH ₃ -, -CHCH ₃ - CH ₂ -, -CH ₂ -CHOH-, -CHOH-CH ₂ -, -CO-NR ¹⁷ -, - NR ¹⁷ -CO- -CH ₂ -NR ¹⁷ -, -NR ¹⁷ -CH ₂ -, -CH ₂ -O-, -O-CH ₂ -, -CH ₂ -S-, -S-CH ₂ -, -CH ₂ - SO ₂ -, and -SO ₂ -CH ₂ -, wherein R ¹⁷ is selected from hydrogen and methyl.

[0161] In certain embodiments of a compound of Formula (1), the absolute

stereochemistry of the beta-carbon atom is (R).

[0162] In certain embodiments of a compound of Formula (1), the absolute

stereochemistry of the beta-carbon atom is (S). [0163] In certain embodiments of a compound of Formula (1), the absolute stereochemistry of the β carbon atom is of the (R) configuration, the absolute axial stereochemistry (atropisomerism) is R _a , and the absolute stereochemistry of a compound of Formula (1) is (R,R _a ).

[0164] In certain embodiments of a compound of Formula (1), the absolute

stereochemistry of the β carbon atom is of the (R) configuration, the absolute axial stereochemistry (atropisomerism) is S _a , and the absolute stereochemistry of a compound of Formula (1) is (R,S _a ).

[0165] In certain embodiments of a compound of Formula (1), the absolute

stereochemistry of the β carbon atom is of the (S) configuration, the absolute axial stereochemistry (atropisomerism) is R _a , and the absolute stereochemistry of a compound of Formula (1) is (S,R _a ).

[0166] In certain embodiments of a compound of Formula (1), the absolute

stereochemistry of the β carbon atom is of the (S) configuration, the absolute axial stereochemistry (atropisomerism) is S _a , and the absolute stereochemistry of a compound of Formula (1) is (S,S _a ).

[0167] In certain embodiments, a compound of Formula (1) is selected from:

4-Amino-3-[3-[bis(2-chloroethyl)amino]phenyl]butanoic acid (1);

4-Amino-3-[5-[bis(2-chloroethyl)amino]-2-methyl-phenyl]butan oic acid (2);

4-Amino-3-[3-[bis(2-chloroethyl)amino]-2,6-dimethyl-phenyl]b utanoic acid (3); 4-Amino-3-[3-[bis(2-chloroethyl)amino]phenyl]-3-methyl-butan oic acid (4);

4- Amino-3 - [5 - [bis(2-chloroethyl)amino]-2-methyl-pheny 1] -3 -methyl-butanoic acid (5);

4- Amino-3 - [3 - [bis(2-chloroethyl)amino]-2-methyl-phenyl] -3 -methyl-butanoic acid

(6);

4- Amino-3 - [4- [bis(2-chloroethyl)amino]-2-methyl-phenyl] -3 -methyl-butanoic acid

(V);

4-Amino-3-[5-[bis(2-chloroethyl)carbamoyl]-2-methyl-phenyl]b utanoic acid (8); 4- Amino-3 - [5 -(bis(2-methylsulfonyloxyethyl)amino)-2-methyl-phenyl]butano ic acid

(9);

4-Amino-3-[5-(bis(2-bromoethyl)amino)-2-methyl-phenyl]butano ic acid (10);

4-Amino-3-[5-(bis(2-iodoethyl)amino)-2-methyl-phenyl]butanoi c acid (11);

4- Amino-3 - [5 -(2-chloroethyl(2-methylsulfonyloxyethyl)amino)-2-methyl- phenyl]butanoic acid (12); 4- Amino-3 - [5 -(2-bromoethyl(2-chloroethyl)amino)-2-methyl-phenyl]butanoic acid

(13);

4- Amino-3 - [5 -(2-bromoethyl(2-methylsulfonyloxyethyl)amino)-2-methyl- phenyljbutanoic acid (14);

4-Amino-3-[5-[bis(2-chloroethyl)amino]-2-methyl-phenyl]butan oic acid (15);

4-Amino-3-[5-[bis(2-chloroethyl)amino]-2-methyl-phenyl]-2-fl uoro-butanoic acid

(16);

3 -(Aminomethyl)-4- [5 -[bis(2-chloroethyl)amino]-2-methyl-phenyl] -4-hydroxy- butanoic acid (17);

4-Amino-3-[5-[bis(2-chloroethyl)amino]-2-nitro-phenyl]butano ic acid (18);

[3-Amino-2-[5-[bis(2-chloroethyl)amino]-2-methyl-phenyl]prop yl]phosphinic acid

(19);

3- [l-(Aminomethyl)-2-(lH-tetrazol-5-yl)ethyl]-N,N-bis(2-chloro ethyl)-4-methyl- aniline (20);

4- Amino-3-[5-[bis(2-chloroethyl)amino]-2-methoxy-phenyl]butano ic acid (21);

4- Amino-3 - [5 - [bis(2-chloroethyl)aminomethyl] -2-methyl-phenyl]butanoic acid (22);

4-Amino-3-[5-[bis(2-chloroethyl)carbamoyloxy]-2-methyl-ph enyl]butanoic acid (23);

4- Amino-3 - [4-(2-chloroethoxy(2-chloroethyl)amino)-2-methyl-phenyl] -3 -methyl- butanoic acid (24); and

4- [ 1 -(Aminomethyl)-3 -hydroxy- 1 -methyl-3 -oxo-propyl] -N,N-bis(2-chloroethyl)-3 - methyl-benzeneamine oxide (25);

or a pharmaceutically acceptable salt of any of the foregoing.

[0168] In certain embodiments of any of the foregoing compounds, a pharmaceutically acceptable salt is the hydrochloride salt.

[0169] In certain embodiments of any of the foregoing compounds, a pharmaceutically acceptable salt is the dihydrochloride salt.

[0170] In certain embodiments of a compound of Formula (1), a pharmaceutically acceptable salt is the hydrochloride salt.

[0171] In certain embodiments of a compound of Formula ( 1 ), a pharmaceutically acceptable salt is the dihydrochloride salt.

[0172] In certain embodiments, compounds of Formula (1) are selective substrates for the LATl/4F2hc transporter.

[0173] In certain embodiments, compounds provided by the present disclosure exhibit a LATl/4F2hc-dependent V _max of at least 10% the V _max of gabapentin. In certain embodiments, compounds provided by the present disclosure exhibit a LATl/4F2hc-dependent V _max of at least 20% the V _max of gabapentin. In certain embodiments, compounds provided by the present disclosure exhibit a LATl/4F2hc-dependent V _max of at least 30% the V _max of gabapentin. In certain embodiments, compounds provided by the present disclosure exhibit a LATl/4F2hc-dependent V _max of at least 40%> the V _max of gabapentin. In certain embodiments, compounds provided by the present disclosure exhibit a LATl/4F2hc-dependent V _max of at least 50%) the V _max of gabapentin. In certain embodiments, compounds provided by the present disclosure exhibit a LATl/4F2hc-dependent V _max of at least 60%> the V _max of gabapentin. In certain embodiments, compounds provided by the present disclosure exhibit a LATl/4F2hc-dependent V _max of at least 70%> the V _max of gabapentin. In certain embodiments, compounds provided by the present disclosure exhibit a LATl/4F2hc-dependent V _max of at least 80%o the V _max of gabapentin. In certain embodiments, compounds provided by the present disclosure exhibit a LATl/4F2hc-dependent V _max of at least 90%> the V _max of gabapentin. In certain embodiments, compounds provided by the present disclosure exhibit a LATl/4F2hc-dependent V _max of at least 100% the V _max of gabapentin.

[0174] In certain embodiments, compounds provided by the present disclosure exhibit a LATl/4F2hc-dependent uptake of at least 10% that of gabapentin measured at an

extracellular concentration of 1 mM (1 mmol/L) and a system A-, system N-, a system ASC-, and a LAT2/4F2hc-dependent uptake of less than 50% that of L-leucine measured at an extracellular concentration of 1 mM (1 mmol/L). In certain embodiments, compounds provided by the present disclosure exhibit a LATl/4F2hc-dependent uptake of at least 10%> that of gabapentin measured at an extracellular concentration of 1 mM (1 mmol/L); and a system A-, system N-, a system ASC-, and a LAT2/4F2hc-dependent uptake of less than 40%> that of L-leucine measured at an extracellular concentration of 1 mM (1 mmol/L). In certain embodiments, compounds provided by the present disclosure exhibit a LATl/4F2hc- dependent uptake of at least 10% that of gabapentin measured at an extracellular

concentration of 1 mM (1 mmol/L); and a system A-, system N-, a system ASC-, and a LAT2/4F2hc-dependent uptake of less than 30% that of L-leucine measured at

anextracellular concentration of 1 mM (mmol/L). In certain embodiments, compounds provided by the present disclosure exhibit a LATl/4F2hc-dependent uptake of at least 10%> that of gabapentin measured at an extracellular concentration of 1 mM (1 mmol/L); and a system A-, system N-, a system ASC-, and a LAT2/4F2hc-dependent uptake of less than 20%> that of L-leucine measured at an extracellular concentration of 1 mM (1 mmol/L). In certain embodiments, compounds provided by the present disclosure exhibit a LATl/4F2hc- dependent uptake of at least 10% that of gabapentin measured at an extracellular concentration of 1 mM (1 mmol/L); and a system A-, system N-, a system ASC-, and a LAT2/4F2hc-dependent uptake of less than 10% that of L-leucine measured at an

extracellular concentration of 1 mM (1 mmol/L). In certain embodiments, compounds provided by the present disclosure exhibit a LATl/4F2hc-dependent uptake of at least 10%> that of gabapentin measured at an extracellular concentration of 1 mM (1 mmol/L); and a system A-, system N-, a system ASC-, and a LAT2/4F2hc-dependent uptake of less than 5% that of L-leucine measured at an extracellular concentration of 1 mM (1 mmol/L). In certain embodiments, compounds provided by the present disclosure exhibit a LATl/4F2hc- dependent uptake of at least 10% that of gabapentin measured at an extracellular

concentration of 1 mM (1 mmol/L); and a system A-, system N-, a system ASC-, and a LAT2/4F2hc-dependent uptake of less than 1% that of L-leucine measured at an extracellular concentration of 1 mM (1 mmol/L).

[0175] Compounds of Formula (1) may be adapted as prodrugs to achieve desirable pharmacokinetic properties. For example, suitable prodrugs of β-substituted γ-amino acid derivatives and β-substituted γ-amino acid analogs are disclosed by Gallop, et al, U.S. Patent No. 7,109,239, U.S. Patent No. 6,972,341, U.S. Patent No. 6,818,787 and U.S. Patent No. 7,227,028. Prodrugs of compounds of Formula (1) include the prodrug systems disclosed by Gallop, et al., as well as others known in the art.

Synthesis of Compounds

[0176] Compounds disclosed herein may be obtained via the general synthetic methods illustrated in Schemes 1-10. General synthetic methods useful in the synthesis of compounds, precursors, and starting materials described herein are available in the art. Starting materials useful for preparing compounds and intermediates thereof, and/or for practicing methods described herein, are commercially available or may be prepared by well-known synthetic methods (March's Advanced Organic Chemistry: Reactions, Mechanisms, M. B.Smith, 7 ^th Edition, John Wiley & Sons, Hoboken, New Jersey, USA, 2013; Advanced Organic

Chemistry: Part B: Reaction and Synthesis, Carey and Sundberg, 5 ^th Edition, Springer, Germany, 2010; Comprehensive Organic Transformations, 2 ^nd Edition, Larock, Wiley- VCH, Weinheim, Germany, 1999; Science of Synthesis: Houben-Weyl Methods of Moleculer Transformations, Thieme, Germany (www.thieme.de).

[0177] Additionally, as will be apparent to those skilled in the art, use of conventional protecting groups or protecting strategies may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art (Wuts and Greene, Greene's Protective Groups in Organic Synthesis, ^4th Ed, 2007, Wiley-Interscience, John Wiley & Sons, Inc., Hoboken, New Jersey).

[0178] It will be appreciated that where typical or preferred process conditions, e.g., reaction temperatures, reaction times, molar ratios of reactants, solvents, pressures, etc., are given other process conditions may also be used. Optimal reaction conditions may vary with the particular reactants, solvents, functional groups, and protecting groups used, but such conditions may be determined by one skilled in the art by routine optimization procedures.

[0179] Furthermore, certain compounds provided by the present disclosure may contain one or more stereogenic centers. Accordingly, and if desired, such compounds may be prepared or isolated as pure stereoisomers, e.g., as individual enantiomers, diastereomers, atropisomers, rotamers, or as stereoisomer enriched mixtures or racemates. All such stereoisomers are included within the scope of this disclosure. Pure stereoisomers (or enriched mixtures thereof) may be prepared using, for example, optically active starting materials, stereoselective reagents such as chiral catalysts and auxiliaries well known in the art. Alternatively, racemic mixtures of such compounds may be separated or partially enriched using, for example, chromatographic methods with chiral stationary phases, chiral resolving agents, and the like, also well known in the art and easily adaptable to the particular compound to be separated.

[0180] Methods of preparing (protected) 3-, 4-, and/or 5 -ring-substituted and ring- unsubstituted pyrrolidin-2-ones (γ-lactams) from commercial or known starting materials are well known in the art (Huang, in New Methods for the Asymmetric Synthesis of Nitrogen Heterocycles; Research Signpost: Trivandrum, India, 2005, pp 197-222; Smith, in Science of Synthesis (S. Weinreb, et. al (Ed.s)), Georg Thieme Verlag: Stuttgart, Germany, 2005, Vol. 21, pp 647-711). In particular, methods of preparing (protected) 4-aryl-, 4-alkylaryl-, 4- heteroalkylaryl, 4-aryloxy substituted pyrrolidin-2-ones from commercial or known starting materials are well known in the art. In certain embodiments, 3-, 4-, and/or 5-ring substituted and unsubstituted pyrrolidin-2-ones may be used as starting materials for the preparation of N-mustard β-substituted γ-amino acid derivatives and β-substituted γ-amino acid analogs or (bio)isosteres provided by the present disclosure.

[0181] Methods of synthetic manipulations and modifications of the underlying pyrrolidin-2-one ring (γ-lactam ring) of 3-, 4-, and/or 5 -ring-substituted and -unsubstituted pyrrolidin-2-ones are also well known in the art (Huang, in New Methods for the Asymmetric Synthesis of Nitrogen Heterocycles; Research Signpost: Trivandrum, India, 2005, pp 197- 222; Smith, in Science of Synthesis (S. Weinreb, et. al (Ed.s)), Georg Thieme Verlag:

Stuttgart, Germany, 2005, Vol. 21, pp 647-711). In certain embodiments, the underlying pyrrolidin-2-one ring (γ-lactam) may be modified to allow for regio- and/or stereoselective incorporation of auxiliary molecular functionalities into the resulting β-substituted γ-amino acid scaffold of the final N-mustard functionalized β-substituted γ-amino acid derivatives or β-substituted γ-amino acid analogs or (bio)isosteres. Auxiliary molecular functionalities may, for example, be incorporated to modulate interaction with LATl transporter proteins, e.g., efficacy of translocation through biological membranes, modulate physiochemical or ADMET properties, or to modulate the activity of the physiologically active N-mustard moiety, e.g., cytotoxicity.

[0182] Methods of synthetic manipulations and modifications of the aryl ring of

(protected) 4-aryl-, 4-alkylaryl-, 4-heteroalkylaryl, 4-aryloxy substituted pyrrolidin-2-ones are also well known in the art (Xu, et al., US 8,344,028 (2013)). In certain embodiments, the underlying aryl ring may be modified to allow for regioselective incorporation of functional groups that can be converted to N-mustards by using reagents, methods, and protocols well known in the art. In certain embodiments, the underlying aryl ring may also be modified to allow for regio- and/or stereoselective incorporation of auxiliary molecular functionalities into the arene scaffold. Auxiliary molecular functionalities may, for example, be incorporated to modulate interaction with LATl transporter proteins, e.g., efficacy of translocation through biological membranes (binding to the LATl -transporter protein and capacity of LATl - mediated transport), modulate physiochemical or ADMET properties, or to modulate the activity of the physiologically active N-mustard moiety, e.g., cytotoxicity.

[0183] Methods of functionalizing the amino acid scaffold of 3-aryl-, 3-alkylaryl-, 3- heteroalkylaryl, 3-aryloxy substituted 2-, 3-, and/or 4-substituted and unsubstituted γ-amino acid amino acid derivatives (β-substituted γ-amino acid butyric acid derivatives, β-substituted GAB A derivatives), similarly substituted 3-aminopropylphosphinic acid, 3- aminopropylsulfmic acids, or 3-aminopropyl substituted carboxylic acid (bio)isosteres from commercial or known starting materials are also well known in the art.

[0184] In certain embodiments, starting materials may be used in their fully protected form wherein the amino group or a synthetic equivalent or a precursor thereof and the carboxylic acid, phosphinic acid, sulfuric acid, carboxylic acid (bio)isosteres or synthetic equivalents or precursors of any of the foregoing are appropriately protected. [0185] In certain embodiments, starting materials may be used in their hemi-protected form wherein the amino group or a synthetic equivalent or a precursor thereof is protected and the carboxylic acid group, phosphinic acid, sulfmic acid, or a carboxylic acid

(bio)isostere functional group or synthetic equivalents or precursors of any of the foregoing are unprotected or free.

[0186] In certain embodiments, starting materials may be used in their hemi-protected form wherein the amino group is unprotected or free and the carboxylic acid, phosphinic acid, sulfmic acid, or a carboxylic acid (bio)isostere or synthetic equivalents or precursors of any of the foregoing are appropriately protected.

[0187] In certain embodiments, starting materials may be used in their fully unprotected form wherein the amino group and the carboxylic acid, phosphinic acid, sulfmic acid, or the carboxylic acid (bio)isostere or synthetic equivalents or precursors of any of the foregoing are unprotected.

[0188] Methods for converting 4-aryl-, 4-alkylaryl-, 4-heteroalkylaryl, 4-aryloxy substituted pyrrolidin-2-ones pyrrolidin-2-ones to their corresponding ring-opened

derivatives such as 3-aryl-, 3-alkylaryl-, 3-heteroalkylaryl, 3-aryloxy substituted 4- aminobutyric acid derivatives are known in the art (Ordnez and Cativiela, Tetrahedron:

Asymmetry, 2007, 18, 3-99; M. Ordnez, et al, Tetrahedron: Asymmetry, 2010, 21, 129-147; and Xu, et al, U.S. Patent No. 8,344,028). Such ring-opened derivatives may be prepared either (a) in their fully unprotected form (e.g., with a free amino group and a free carboxylic acid group, zwitterions thereof, any salts thereof, or any pharmaceutically acceptable salts thereof), (b)(i) in their amino-protected form with a free carboxylic acid group, any salts thereof, or any pharmaceutically acceptable salts thereof), (b)(ii) in their carboxyl-protected form and a free amino group, any salts thereof including pharmaceutically acceptable salts, or synthetic equivalents or precursors thereof), or (c) in their fully amino- and carboxylic acid- protected form or synthetic equivalents or precursors thereof. Alternatively, methods of converting any of the ring-opened fully protected, hemi-protected, or unprotected 3-aryl-, 3- alkylaryl-, 3-heteroalkylaryl, 3-aryloxy substituted 4-aminobutyric acid derivatives, to the corresponding 4-aryl-, 4-alkylaryl-, 4-heteroalkylaryl, 4-aryloxy substituted pyrrolidin-2-ones are also well known in the art.

[0189] Many other methods for the preparation of appropriately functionalized or substituted 3-aryl-, 3-alkylaryl-, 3-heteroalkylaryl, 3-aryloxy substituted (β-aryl-, β-alkylaryl- , β-heteroalkylaryl, β-aryloxy substituted) 4-aminobutyric acid analogs, carboxylic acid (bio)isosteres, derivatives, or precursors thereof using commercial or known starting materials described herein are either described in the art or will be readily apparent to one skilled in the art in view of the references provided herein. Accordingly, the methods presented in the schemes provided by the present disclosure are illustrative rather than comprehensive.

[0190] Referring to Scheme 1, selected and representative starting materials for the preparation N-mustard functionalized 4-aryl-, 4-alkylaryl-, 4-heteroalkylaryl, 4-aryloxy substituted pyrrolidin-2-ones, or 3-aryl-, 3-alkylaryl-, 3-heteroalkylaryl, 3-aryloxy substituted (β-aryl-, β-alkylaryl-, β-heteroalkylaryl, β-aryloxy substituted) γ-amino acid analogs or carboxylic acid (bio)isosteres are compounds of Formula (A) and Formula (B).

[0191] Referring to Scheme 1, in certain embodiments R ¹ and/or R ⁵ , and the linker L are as defined herein; one of R ² , R ³ , and R ⁴ in compounds of Formula (A) and Formula (B) is - E-MH, wherein E is a bond ("-"), an oxygen atom ( ^~ 0-), a methylene group (-CH ₂ -), a methyleneoxy group (-CH ₂ -0-), a carbonyl group (-CO-), or a methylenecarbonyl group (- CH ₂ -CO-), and wherein -MH is an amino group (-NH ₂ ), a hydroxyl group (-OH), or a sulfhydryl group (-SH). Each of the other remaining R ² , R ³ , and R ⁴ is hydrogen; each R ⁷ ; and each R ⁸ is hydrogen.

[0192] Referring to Scheme 1, for example (a) -E-MH is equivalent to a primary aromatic amino group (-NH ₂ , aniline) when E is a bond (" ^_ ") and MH is an amino group (- NH ₂ ), (b) -E-MH is equivalent to a primary O-aryl hydroxylamino group (-0-NH ₂ ) when E is an oxygen atom ( ^_ 0-) and MH is an amino group (-NH ₂ ), (c) -E-MH is equivalent to a primary aminomethyl group (-CH ₂ -NH ₂ , primary benzylic amine) when E is a methylene group ( ^~ CH ₂ -) and MH is an amino group (-NH ₂ ), (d) -E-MH is equivalent to an aromatic hydroxyl group (-OH, phenol) when E is a bond ("-") and MH is a hydroxyl group (-OH), (e) -E-MH is equivalent to a hydroxymethyl group (-CH ₂ -OH, benzylic alcohol) when E is a methylene group ( ^~ CH ₂ -) and MH is a hydroxyl group (-OH), (f) -E-MH is equivalent to a primary O-benzylic hydroxylamino group (-CH ₂ -0-NH ₂ ) when E is a methyleneoxy group (-CH ₂ -0-) and MH is an amino group (-NH ₂ ), (g) -E-MH is equivalent to an aromatic sulhydryl group (-SH, thiophenol derivative) when E is a bond ("-") and MH is a hydroxyl group (-OH), (h) -E-MH is equivalent to a methylenesulhydryl group (-CH ₂ -SH, benzylic thiol) when E is a methylene group ( ^~ CH ₂ -) and MH is a sulfhydryl group (-SH), (i) -E-MH is equivalent to an aromatic carboxylic acid group (-CO-OH, benzoic acid) when E is a carbonyl group (-C(=0)-) and MH is a hydroxyl group (-OH), (j) -E-MH is equivalent to a carboxylic acid group (-CO-OH, benzoic acid) when E is a methylenecarbonyl group (- CH ₂ -C(=0)-) and MH is a hydroxyl group (-OH).

[0193] It will be obvious to the one skilled in the art that in some embodiments of the disclosure the group "-E-" in functional groups -E-MH presented in the following schemes is equivalent to the group -A- in the definition of the composition of a chemotherapeutic moiety as described herein.

[0194] The linker L is as defined herein.

[0195] Referring to Scheme 1, in certain embodiments R ²⁰ in compounds of Formula (B) is a protected carboxyl group such as a lower alkyl ester of a carboxyl group, e.g., a methyl, ethyl, or tert-bvXy\ ester, or a benzyl ester derivative, e.g., benzyl, pentamethylbenzyl or (4- methoxy)benzyl. In certain embodiments, R ²⁰ in compounds of Formula (B) is a tert-butyl ester group (C0 ₂ tBu). In certain embodiments, R ²⁰ in compounds of Formula (B) is a methyl ester group (C0 ₂ Me).

[0196] Referring to Scheme 1, in certain embodiments R ²⁰ in compounds Formula (B) is a protected phosphinic acid derivative, e.g., 1,1-diethyloxyethylethoxyphosphino-l-one (-P(=0)(OEt)[C(OEt) ₂ Me] (U.S. Patent No. 8,344,028; Baylis, Tetrahedron Letter, 1995, 36(51), 9385-9388; and Burgos-Lepley, et al, Bioorg. Med. Chem. Lett., 2006, 16, 2333- 2336).

[0197] Referring to Scheme 1, in certain embodiments R ²⁰ in compounds Formula (B) is a protected sulfuric acid precursor derivative, e.g., a 2-mercaptobenzothiazole (Carruthers, et al, Bioorg. Med. Chem. Lett, 1995, 5, 237-240; Carruthers, et al, Bioorg. Med. Chem. Lett, 1998, 5, 3059-3064; Okawara, et al, Chem. Lett., 1984, 2015; and Burgos-Lepley, et al, Bioorg. Med. Chem. Lett., 2006, 16, 2333-2336).

[0198] Referring to Scheme 1, in certain embodiments R ²⁰ in compounds Formula (B) is a unprotected or protected carboxylic acid (bio)isostere including a protected or unprotected lH-tetrazole (Ballatore, et al, ChemMedChem, 2013, 8(3), 385-395; Bryans, et al, U.S. Patent No. 6,518,289; Burgos-Lepley, et al, Bioorg. Med. Chem. Lett., 2006, 16, 2333- 2336).

[0199] Referring to Scheme 1, in certain embodiments of compounds of Formula (A) Q is ΝΗ or N-PG where PG is a suitable nitrogen protecting group, e.g., tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz, Z), (i?AS)-l -phenyl-ethoxycarbonyl, (i?)-l-phenyl- ethoxycarbonyl, (S)- 1 -phenyl-ethoxycarbonyl, 1 -methyl- 1 -phenyl-ethoxycarbonyl, triphenylmethyl (trityl), or the like. In certain embodiments of compounds of Formula (A) Q is NH (non-protected lactam). In certain embodiments of compounds of Formula (A) and of Formula (C), Q is N-Boc (NC0 ₂ tBu) (N-protected lactam).

[0200] Referring to Scheme 1, in certain embodiments of compounds of Formula (B) Q is N(H)-PG where PG is a suitable nitrogen protecting group, e.g., tert-butoxycarbonyl (Boc), allyloxycarbonyl (alloc), benzyloxycarbonyl (Cbz, Z), ethoxycarbonyl, methoxycarbonyl, (R/S)- 1 -phenyl-ethoxycarbonyl, (R)- 1 -phenyl-ethoxycarbonyl, (S)- 1 -phenyl-ethoxycarbonyl, 1 -methyl- 1-phenyl-ethoxycarbonyl, formyl, acetyl, trifluoroacetyl, benzoyl, triphenylmethyl (trityl), 4-methoxyphenyl-diphenylmethyl, di-(4-methoxyphenyl)-phenylmethyl, or the like. In certain embodiments, PG in compounds of Formula (B) is tert-butoxycarbonyl (Boc) and Q is N(H)Boc (N(H)C0 ₂ tBu). In certain embodiments of compounds of Formula (B) PG is acetyl and Q is N(H)-Ac (N(H)COMe). In certain embodiments of compounds of Formula (B) and of Formula (D), PG is benzoyl and Q is N(H)-Bz (N(H)COPh).

[0201] Referring to Scheme 1, in certain embodiments Q is N(PG) ₂ , where PG is a nitrogen protecting group such as an imide-type protecting group, e.g., phthalyl or tert- butoxycarbonyl (Boc). In certain embodiments of compounds of Formula (B) PG is phthalyl and Q is N(phthalyl). In certain embodiments of compounds of Formula (B) PG is tert- butoxycarbonyl and Q is N(Boc) ₂ .

[0202] Referring to Scheme 1 , in certain embodiments the protected amine functionality

30 31 30 31

is an imine where Q is N=CR R and each of R and R is independently selected from branched Ci_ ₄ alkyl, non-branched Ci_ ₄ alkyl, substituted aryl, non-substituted aryl, substituted heteroaryl, and non-substituted heteroaryl.

[0203] The structures presented in the schemes provided by the present disclosure are illustrative rather than comprehensive.

Scheme 1

[0204] Referring to Scheme 2, in certain embodiments R ¹ and/or R ⁵ , R ²⁰ , E, the linker L, and the protecting groups PG and Q are as defined herein; one of R ² , R ³ , and R ⁴ m compounds of Formula (C) and Formula (D) is -E-NH ₂ , wherein E is a bond ("-"), an oxygen atom ( ^~ 0-), a methylene group (-CH ₂ -), or methylenoxy group (-CH ₂ -0-), and MH is an amino group (-NH ₂ ) so that -E-NH ₂ is equivalent to (a) a primary aromatic amino group (-NH ₂ , aniline), (b) a primary O-aryl hydroxylamino group (-0-NH ₂ ), (c) a primary aminomethyl group (-CH ₂ -NH ₂ ), or (d) a primary O-benzyl hydroxylamino group (-CH ₂ -0- NH ₂ ). Each of the other remaining R ² , R ³ , and R ⁴ is hydrogen; and each R ⁷ and each R ⁸ is hydrogen. X is a suitable leaving group e.g., chloro (-C1) or bromo (-Br).

Scheme 2

[0205] Referring to Scheme 2, conversion of the primary amino group as in compounds of Formula (C) and of Formula (D) to the N,N-bis-(2-hydroxyethyl) amino group (N,N-bis-(2- hydroxyethylation)) as in compounds of Formula (E) or of Formula (F) may be accomplished by reacting compounds of Formula (C) and of Formula (D) in suitable solvents such as about 25-75 vol.-% aqueous acetic acid (HO Ac), glacial acetic acid, water, tetrahydrofuran (THF), ethanol (EtOH), 1,4-dioxane, or mixtures of any of the foregoing with an excess of ethylene oxide (oxirane) (about 4-20 equivalents) at a temperature of about -20 °C to about room temperature for about 12-48 hours. Alternatively, the reaction mixture may be heated in a sealed reaction vessel from about 80-140 °C for comparable times (Palmer, et al., J. Med. Chem. 1990, 33(1), 112-121; Jordan, et al, Bioorg. Med. Chem., 2002, 10(8), 2625-2633; Abela Medici, et al, J. Chem. Soc, Perkin Trans. 1, 1997, (20), 2258-2263; Feau, et al, Org. Biomolecular Chem., 2009, 7(24), 5259-5270; Springer, et al, J. Med. Chem., 1990, 33(2), 677-681; Taylor, et al, Chem. Biol. Drug Des., 2007, 70(3), 216-226; Buss, et al, J.

Fluorine Chem., 1986, 34(1), 83-114; Larden and Cheung, Tetrahedron Lett., 1996, 37(42), 7581-7582; Spreitzer and Puschmann, Monatshefte fur Chemie, 2007, 138(5), 517-522; Niculesscu-Duvaz, et al, J. Med. Chem., 2004, 47(10), 2651-2658; Weisz, et al, Bioorg. Med. Chem. Lett, 1995, 5(24), 2985-2988; Thorn, et al, J. Org. Chem, 1975, 40(11), 1556- 1558; Baraldini, et al, J. Med., Chem., 2000, 53(14), 2675-2684; Zheng, et al, Bioorg., Med., Chem., 2010, 18(2), 880-886; Gourdi, et al, J., Med., Chem., 1990, 33(4), 1177-1186; Haines, et al, J. Med. Chem., 1987, 30, 542-547; Matharu, et al, Bioorg. Med. Chem. Lett., 2010, 20, 3688-3691; and Kupczyk-Subotkowska, et al, J. Drug Targeting, 1997, 4(6), 359- 370).

[0206] Referring to Scheme 2, conversion of the primary amino group as in compounds of Formula (C) and of Formula (D) to the N,N-bis-(2-hydroxyethyl) amino group (N,N-bis-(2- hydroxyethylation)) as in compounds of Formula (E) or of Formula (F) may be accomplished by reacting compounds of Formula (C) and of Formula (D) in suitable solvents such water with an excess of about 2-5 equivalents of a suitable 2-halogeno ethanol derivative, e.g., 2- chloroethanol (CICH ₂ CH ₂ OH) or 2-bromoethanol (BrCFLCFLOH), and about 2.0 equivalents of a suitable inorganic base such as sodium bicarbonate (NaHC0 ₃ ), sodium carbonate (Na ₂ C0 ₃ ), or calcium carbonate (CaC0 ₃ ) at about reflux temperature for about 8-24 hours. Optionally, the reaction may be carried out in the presence of a catalytic amount (about 10 mol-%) of potassium iodide (KI) (Palmer, et al, J. Med. Chem. 1990, 33(1), 112-121;

Coggiola, et al, Bioorg. Med. Chem. Lett., 2005, 15(15), 3551-3554; Verny and Nicolas, J. Label. Cmpds Radiopharm., 1988, 25(9), 949-955; and Lin, Bioorg. Med. Chem. Lett., 2011, 21(3), 940-943).

[0207] Referring to Scheme 3, in certain embodiments electron-deficient aryl halides of Formula (G) or Formula (H), activated with strongly electron withdrawing substituents for nucleophilic aromatic substitution reactions (SNAr) at the aryl ring, may be useful starting materials for incorporating N,N-bis-(2-functionalized) ethyl amino groups as in compounds of Formula (I) and Formula (J) where the corresponding N,N-bis-(2-functionalized)ethyl amino groups are N,N-bis-(2-hydroxyethyl) amino groups. Commonly used leaving groups (- X) for SNAr-reactions include halogeno, e.g., fluoro (-F), chloro (-C1), bromo (-Br), with accessory activating groups at the 2- or 4-position relative to the leaving group (ortho- or para-positions). Such groups decrease the electron density in the arene ring and increase the susceptibility to nucleophilic attack and displacement of the leaving group (-X). Examples of activating, strongly electron-withdrawing groups (EWG), include trifluoromethyl (-CF ₃ ), cyano (-CN), nitro (-N0 ₂ ), amide (-CON(R ¹⁰ ) ₂ ), and formyl (-CHO).

[0208] Useful secondary amines for the introduction of the N,N-bis-(2-hydroxyethyl) amino functionality include diethanolamine (ΕΓΝ^Ε^Η ₂ ΟΗ) ₂ ), protected diethanolamine derivatives, e.g., O-benzylether protected diethanolamine (FiN(CH ₂ CH ₂ OBn) ₂ ), or precursors of the putative N,N-bis-(2-hydroxyethyl)amino group, e.g., 3-pyrroline. Employing O- benzylether protected diethanolamine (FfN(CH ₂ CH ₂ OBn) ₂ ) or 3-pyrroline necessitates conversion of the corresponding intermediate substitution products to compounds of Formula (I) and of Formula (J) bearing the target N,N-bis-(2-hydroxyethyl)amino groups using methods well known in the art.

[0209] Referring to Scheme 3, in certain embodiments R ¹ and/or R ⁵ , R ¹⁰ , R ²⁰ , the linker L, the protecting group PG, and Q, the electron withdrawing group (EWG), the leaving group (-X), and the secondary amine FfNR ₂ are defined as described herein; R ¹ and/or R ⁵ may also represent an electron withdrawing group (EWG); one or more of R ² , R ³ , and R ⁴ m

compounds of Formula (G) or of Formula (H) is a suitable leaving group ( ^~ X)), one or more of R ² , R ³ , and R ⁴ is a electron withdrawing group (EWG) preferably in 2- or 4-postion relative to the leaving group X; each of the other remaining R ² , R ³ , and R ⁴ is hydrogen; and each of R ⁷ and R ⁸ is hydrogen.

Solvent, Temperature, Time

Scheme 3

[0210] Referring to Scheme 3, N,N-bis(2-hydroxyethyl)amino derivatives as in compounds of Formula (I) or of Formula (J) may be prepared through nucleophilic aromatic substitution reactions (S Ar) of aromatic halides of Formula (G) and of Formula (H), activated by electron withdrawing groups (EWGs), by reaction with an excess of about 1.5-5 equivalents of the neat amine, e.g., FiN(CH ₂ CH ₂ OH) ₂ , FiN(CH ₂ CH ₂ OBn) ₂ , or 3-pyrroline, (weakly basic reaction conditions) or solutions of the secondary amine in polar aprotic anhydrous solvents, e.g., anhydrous dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), acetonitrile (MeCN), 1,4-dioxane, tetrahydrofuran (THF), or mixtures of the foregoing at a temperature from about 80-200 °C (sealed tube), for about 1-12 hours to provide N,N-bis(2-hydroxyethyl)amino-functionalized compounds of Formula (I) or of Formula (J). The reaction may also be carried out in the presence of a catalyst, e.g., copper powder (about 10 mol-%) (Atwell, et al, J. Med. Chem., 2007, 50(6), 1197-1212; Palmer, et al, J. Med. Chem., 1994, 37, 2175-2184; Palmer, et al, J. Med. Chem., 1992, 35(17), 3214-3222; Palmer, et al, J. Med. Chem, 1990, 33(1), 112-121;

Davies, et al, J. Med. Chem. 2005, 48(16), 5321-5328; Jordan, et al, Bioorg. Med. Chem., 2002, 10(8), 2625-2633; Dheyongera, et al, Bioorg. Med. Chem., 2005, 13(3), 689-698; Lin, et al, Bioorg. Med. Chem. Lett., 2011, 21(3), 940-943; and Ferlin, et al, Bioorg. Med.

Chem., 2004, 12(4), 771-777).

[0211] Referring to Scheme 3, methods to convert the N,N-bis-(2-benzyloxyethyl)amino group to a N,N-bis-(2-hydroxyethyl)amino group include, for example, catalytic

hydrogenolysis of the benzyl ether groups using heterogeneous catalysts, e.g., 5-10% Pd on carbon (Pd/C) or Raney ^® -Nickel under standard hydrogenation reaction conditions known in the art (Vincent and Prunet, Tetrahedron Lett, 2006, 47(24), 4075-4077).

[0212] Referring to Scheme 3, conversion the 3-pyrroline ring of the N-aryl-3-pyrroline moiety to a N,N-bis-(2-hydroxyethyl)amino group as in compounds of Formula (G) or of Formula (H) include oxidative cleavage of the C=C-double with the Lemieux- Johnson reagent (osmium tetroxide/sodium periodate, Os0 ₄ /NaI0 ₄ ) or by ozonolysis with an 0 ₃ /0 ₂ - gas mixture. Reductive work-up, e.g., with borane-dimethylsulfide complex (BH ₃ Me ₂ S), triphenylphosphine (Ph ₃ P), thiourea (C(=S)(NH ₂ ) ₂ ), or zinc dust, may yield intermediate N,N- bis(2-oxoethyl)amino groups which may subsequently be reduced to the desired N,N-bis-(2- hydroxyethyl)amino group as in compounds of Formula (G) or of Formula (H) with suitable reducing reagents, e.g., borane-THF complex (BH ₃ THF), or sodium borohydride (NaBH ₄ ), under standard reaction conditions (Palmer and Denny, Synth. Commun., 1987, 17(5), 601- 610).

[0213] In general, the biological activity of nitrogen mustards is based upon the presence of a N,N-bis(2-chloroethyl) functionality. The chemotherapeutic and cytotoxic effects are directly associated with the alkylation of DNA due to the strong electrophilic character of the N,N-bis(2-chloroethyl) functionality. Formation of covalent linkages including interstrand crosslinks (ICLs) is highly cytotoxic and involves the disruption of fundamental cellular processes including DNA replication leading to cellular death.

[0214] Many methods and reagents for converting primary alcohols to primary alkyl chlorides including conversion of N,N-bis(2-hydroxyethyl)amino groups to NN-bis(2- chloroethyl)amino groups are known in the art. The most common methods include the use of concentrated hydrochloric acid (HC1) and various inorganic chlorides of sulfur or phosphorus which are used either in neat form or as solutions in inert solvents such as chlorinated hydrocarbons, aromatic hydrocarbons, or polar non-protic solvents, at room temperature or at elevated temperatures. Other useful chlorination methods and reagents include, for example, combinations of triphenyl phosphine and trichloroacetonitrile (PI1 ₃ P/CI ₃ CCN),

triphenylphosphine dichloride (PI13PCI ₂ ) (prepared from Ph ₃ P and Cl ₂ ), trimethylsilylchloride and bismuth(III) trichloride (Me ₃ SiCl/BiCl ₃ ), mixtures of Ph ₃ P and carbon tetrachloride (CCI ₄ ), or methanesulfonyl chloride (MeS0 ₂ Cl) in pyridine at elevated temperatures.

[0215] Referring to Scheme 4, it will be appreciated by one skilled in the art that the presence of particular functional or protecting groups in compounds of Formula (K-N) determines the choice a particular reagent, method, or reaction condition for the chloro-de- hydroxylation reaction.

[0216] Referring to Scheme 4, in certain embodiments R ¹ and/or R ⁵ , R ²⁰ , the linker L, E, the protecting groups PG and Q are defined as described herein; one of R ² , R ³ , and R ⁴ m compounds of Formula (K) and of Formula (L) is a -E-N,N-bis(2-hydroxyethyl)amino group (-E-N(CH ₂ -CH ₂ -OH) ₂ ); each of the other remaining R ² , R ³ , and R ⁴ is hydrogen; and each R ⁷ and each R ⁸ is hydrogen. κ Temperature, Time

Scheme 4

[0217] Referring to Scheme 4, in some embodiments N,N-bis(2-hydroxyethyl) compounds of Formula (K) or of Formula (L) may be reacted with an excess of about 2-15 equivalents of thionyl chloride (SOCl ₂ ) either in neat form or as a solution in an anhydrous organic solvent, e.g., dichloromethane (DCM), chloroform (CHCI ₃ ), 1 ,2-dichloroethane (DCE), benzene, or mixtures of any of the foregoing at temperatures from about 0 °C (ice bath) -40 °C or heated at reflux for about 0.5-3 hours to provide compounds of Formula (M) or of Formula (N) (Palmer, et al, J. Med. Chem. 1990, 33(1), 112-121; Jordan, et al, Bioorg. Med. Chem., 2002, 10(8), 2625-2633; Abela Medici, et al, J. Chem. Soc, Perkin Trans. 1, 1997, (20), 2258-2263; Taylor, et al, Chem. Biol. Drug Des., 2007, 70(3), 216-226;

Dheyongera, Bioorg. Med. Chem. 2005, 13(3), 689-698; Zheng, Bioorg. Med. Chem. 2010, 18(2), 880-886; Gourdi, J. Med. Chem., 1990, 33(4), 1177-1186; and Lin, et al, Bioorg. Med. Chem. Lett., 2011, 21(3), 940-943). The reaction may optionally be carried out in the presence of a catalytic amount of zinc chloride (ZnCl ₂ ) (10 mol-% to 40 mol-%) or in the presence of a catalytic amount of N,N-dimethylformamide (DMF) to facilitate the reaction (Squires, et al, J. Org. Chem., 1975, 40(1), 134-136; and Abela Medici, et al, J. Chem. Soc, Perkin Trans. 1, 1997, (20), 2258-2263).

[0218] Referring to Scheme 4, in some embodiments N,N-bis(2-hydroxyethyl) compounds of Formula (K) or of Formula (L) may also be reacted with an excess of about 2- 10 equivalents of phosphorus(V)oxychloride (phosphoryl chloride, POCI3) either in neat form or as a solution in an anhydrous organic solvent, e.g., benzene, acetonitrile, pyridine, or mixtures of any of the foregoing at a temperature from about 0 °C (ice bath) to about room temperature. The reaction mixture may also be heated from about 80 °C to about reflux temperature for about 0.5-6 hours to provide compounds of Formula (M) or of Formula (N) (Palmer, et al, J. Med. Chem. 1990, 33(1), 112-121; Feau, et al, Org. Biomolecular Chem., 2009, 7(24), 5259-5270; Valu, et al., J. Med. Chem., 1990, 33(11), 3014-3019; Baraldini, et al, J. Med., Chem., 2000, 53(14), 2675-2684; Gourdi, et al, J., Med., Chem., 1990, 33(4), 1177-1186; Haines, et al, J. Med. Chem., 1987, 30, 542-547; and Matharu, et al, Bioorg. Med. Chem. Lett, 2010, 20, 3688-3691).

[0219] Referring to Scheme 4, in some embodiments N,N-bis(2-hydroxyethyl) compounds of Formula (K) or of Formula (L) may also be reacted with an excess of carbon tetrachloride (CC1 ₄ ), optionally in an inert solvent, e.g., dichloromethane (DCM), in the presence of an excess of triphenylphosphine (Ph ₃ P) for about 8-24 hours at about room temperature or at reflux temperature for about 2-6 hours to provide compounds of Formula (M) or of Formula (N) (Buss, et al, J. Fluorine Chem., 1986, 34(1), 83-114; and Kupczyk- Subotkowska, et al, J. Drug Targeting, 1997, 4(6), 359-370).

[0220] Referring to Scheme 4, in some embodiments N,N-bis(2-hydroxyethyl) compounds of Formula (K) or of Formula (L) may also be reacted with methanesulfonyl chloride (MeS0 ₂ Cl, MsCl) in anhydrous pyridine at about room temperature or at about 70- 100 °C for about 1-3 hours to provide compounds of Formula (M) or of Formula (N) (Jordan, et al, Bioorg. Med. Chem., 2002, 10(8), 2625-2633; Abela Medici, et al, J. Chem. Soc, Perkin Trans. 1, 1997, (20), 2258-2263; Springer, et al, J. Med. Chem., 1990, 33(2), 677- 681; and Larden and H. T. A. Cheung, Tetrahedron Lett., 1996, 37(42), 7581-7582).

[0221] Referring to Scheme 5, although halides are common leaving groups in nucleophilic substitution reactions for synthetic purposes, it is often more convenient to use the corresponding alcohols such as the ones found in N,N-bis(2-hydroxyethyl)amino groups of compounds of Formula (O). Since OH is usually considered a poor leaving group, unless protonated, conversion of a hydroxy group such as in N,N-bis(2-hydroxyethyl)amino groups of compounds of Formula (O) into reactive ester groups, most commonly sulfonic ester groups, converts the hydroxyl group into a functional group with a higher susceptibility to be displaced by an incoming nucleophile including halogenide ions. The N,N-bis(2-aryl- or (polyfluoro)alkylsulfonyloxy)amino groups of aryl- or (polyfluoro)alkylsulfonates of Formula (P) and similar sulfonic esters are most frequently prepared from N,N-bis(2- hydroxy)amino groups of diols of Formula (O) through reaction with an appropriate aryl- or (polyfluoro)alkyl-sulfonyl chloride or anhydride in the presence of a suitable base, e.g., pyridine (nucleophilic catalyst). Besides aromatic (R ⁴⁰ is (substituted) aryl) sulfonic ester groups, aliphatic (R ⁴⁰ is alkyl) sulfonic ester groups, and, in particular, (poly)fluorinated (R ⁴⁰ is poly-F-alkyl) sulfonic ester groups as still more powerful leaving groups are frequently used for activation.

[0222] Referring to Scheme 5, in certain embodiments the R ⁴⁰ -group in compounds of Formula (P) or Formula (R) is for example phenyl and the leaving group is

phenylsulfonyloxy (PhS0 ₂ 0), 4-methylphenyl (para-methylphenyl) and the leaving group is tosylate (4-methylphenylsulfonyloxy, TsO), 4-bromophenyl (para-bromophenyl) and the leaving group is brosylate (4-bromophenylsulfonyloxy, BsO), or 4-nitrophenyl (para- nitrophenyl) and the leaving group is nosylate (4-nitrophenylsulfonyloxy, NsO), methyl and the leaving group is mesylate (methanesulfonyloxy, MsO), trifluomethyl and the leaving group is triflate (trifluoromethanesulfonyloxy, TfO), nonafluoro-n-butyl and the leaving group is nonaflate (nonafluorobutanesulfonyloxy), or 2,2,2-trifluoroethyl and the leaving group is tresylate (2,2,2-trifluoroethanesulfonyloxy). In some embodiments, the R ⁴⁰ -group of compounds of Formula (P) and Formula (R) is methyl and the leaving group is mesylate (methansulfonyloxy, MsO). In some embodiments, the R ⁴⁰ -group of compounds of Formula (P) and of Formula (R) is trifluoromethyl and the leaving group is triflate

(trifluoromethansulfonyloxy, TfO).

[0223] Referring to Scheme 5, N-mustard-type halides of Formula (Q), Formula (R), and Formula (S) containing either (a) a N,N-bis(2-halogenoethyl)amino group (compounds of Formula (Q)), (b) a N-(2-halogenoethyl)amino-, N-(2-halogeno'ethyl)amino- group

(compounds of Formula (S) or mixed halogeno N-mustards), or (c) a N-(2- halogenoethyl)amino, N-(2-aryl- or (polyfluoro)alkylsulfonyloxyethyl)amino groups (compounds of Formula (R) or hybrid halogeno sulfonate N-mustards), may be prepared from the corresponding esters of sulfonic acid esters of Formula (P) through reaction with an excess or a near stoichiometric amount of an alkali metal halide (MX, MX') in suitable protic or non-protic organic solvent at elevated temperature (halo-de-sulfonyloxy substitution) [0224] Referring to Scheme 5, in certain embodiments M in MX or MX' is an alkali metal cation, e.g., lithium (Li ⁺ ) and sodium (Na ⁺ ), X and X' in MX or MX' are halide anions, e.g., chloride (CP), bromide (Br ), and iodide (Γ). MX or MX' are alkali metal halides, e.g., lithium chloride (LiCl), lithium bromide (LiBr), sodium chloride (NaCl), sodium bromide (NaBr), or sodium iodide (Nal). In compounds of Formula (Q), Formula (R), and Formula (S), X is a halogeno, e.g., chloro (-C1), bromo (-Br), and iodo (-1) (Palmer, et al, J. Med. Chem. 1990, 33(1), 112-121; Palmer, et al, J. Med. Chem., 1994, 37, 2175-2184; Palmer, et al, J. Med. Chem., 1996, 39(13), 2518-2528; Davies, et al, J. Med. Chem. 2005, 48(16), 5321-5328; Niculesscu-Duvaz, et al, J. Med. Chem., 2004, 47(10), 2651-2658; Weisz, et al, Bioorg. Med. Chem. Lett., 1995, 5(24), 2985-2988; Thorn, J. Org. Chem, 1975, 40(11), 1556-1558; Lin, et al, Bioorg. Med. Chem. Lett., 2011, 21(3), 940-943; Gourdi, et al, J. Med. Chem. 1990, 33(4), 1177-1186; Yang, et al, Tetrahedron, 2007, 63(25), 5470-5476; Ferlin, et al, Bioorg. Med. Chem., 2004, 12(4), 771-777; and Coggiola, et al, Bioorg. Med. Chem. Lett., 2005, 15(15), 3551-3554).

[0225] Referring to Scheme 5, N-(2-halogenoethyl)amino, N-(2-aryl- or

alkylsulfonyloxyethyl)amino groups of Formula (R) (hybrid halogeno sulfonate N-mustards) may also be prepared from primary alkyl halides of Formula (Q) containing N,N-bis(2- halogenoethyl)amino groups through a) a halo-de-halogenation (halide exchange reaction) or b) a metathetical sulfonyloxy de-halogeno substitution reaction with solubilized silver sulfonates AgOS0 ₂ R ⁴⁰ wherein R ⁴⁰ is defined as described herein under mild conditions in aprotic organic solvents (Emmons and Ferris, J Am. Chem. Soc, 1953, 75(9), 2257).

[0226] Referring to Scheme 5, it will be obvious to those skilled in the art that comparable reagents and reaction conditions may be used to introduce a) the N,N-bis(2-aryl- or (polyfluoro)alkyl-sulfonyloxyethyl) functionality, b) the N,N-bis(2-halogenoethyl) functionality, c) the N-(2-halogenoethyl) N-bis(2-halogeno'ethyl) functionality, d) the N-(2- aryl- or (polyfluoro)alkyl-sulfonyloxyethyl) N-(2-halogenoethyl), or derivatives of any of the foregoing, using the corresponding internally protected β-substituted γ-amino acid precursors (γ-lactams) described in Schemes 2-4.

[0227] Referring to Scheme 5, for example in certain embodiments R ¹ and/or R ⁵ , R ²⁰ , R ⁴⁰ , X, X', E, the linker L, the protecting groups PG and Q are defined as herein; one of R ² , R ³ , and R ⁴ in compounds of Formula (O) is -E-N(CH ₂ -CH ₂ -OH) ₂ each of the other remaining R ² , R ³ , and R ⁴ is hydrogen; and each of R ⁷ and R ⁸ is hydrogen.

Scheme 5

[0228] Referring to Scheme 5, in certain embodiments, the N,N-bis(2- hydroxyethyl)amino group of compounds of Formula (O) may be converted to N,N-bis(2- (polyfluoro)alkyl- or arylsulfonyloxyethyl)amino groups of compounds of Formula (P) (S- alkoxy-de-chlorination) by reacting diols of Formula (O) with an excess of a suitable (perfiuoro)alkyl- or aryl-sulfonyl anhydride (R ⁴⁰ SO ₂ ) ₂ O) (about 2.5-5 equivalents), e.g., methanesulfonyl anhydride (R ⁴⁰ = methyl (Me), (MeSC^O)), in an inert solvent such anhydrous dichloromethane (DCM) or tetrahydrofuran (THF) or a mixture of any of the foregoing in the presence of an excess (about 2-10 equivalents) of a suitable base, e.g., anhydrous triethylamine (Et ₃ N, TEA) or anhydrous pyridine, at a temperature from about 0 °C to about room temperature for about 0.5-24 hours to afford bis-sulfonic acid esters of Formula (P). The reaction may optionally be carried out in the presence of a catalytic amount (about 20 mol-%) of 4-NN-(dimethylamino)pyridine (DMAP) .

[0229] Referring to Scheme 5, in certain embodiments, using comparable reaction conditions with respect to solvents, bases, stoichiometry of reagents, temperature, catalysts, and duration as described for the reaction of diols of Formula (O) with (ployfluoro)alkyl- or aryl-sulfonyl anhydrides, diols of Formula (O) may also be reacted with a suitable alkyl- or aryl-sulfonyl halides, e.g., methanesulfonyl chloride (mesyl chloride, MsCl) (R ⁴⁰ = Me), MeS0 ₂ Cl), to provide the desired bis-sulfonic acid esters of Formula (P).

[0230] Referring to Scheme 5, in certain embodiments N,N-bis(2-(polyfluoro)alkyl- or aryl-sulfonyloxyethyl)amino groups as in compounds of Formula (P) may be converted (halo-de-sulfonyloxy substitution) to N,N-bis(halogenoethyl)amino groups of compounds of Formula (Q) by reacting bis-sulfonyl esters of Formula (P) with an excess of a suitable alkali metal halide salt MX, e.g., lithium chloride (LiCl), lithium bromide (LiBr), sodium chloride (NaCl), sodium bromide (NaBr), or sodium iodide (Nal) (4-16 equivalents) in a suitable organic solvent, e.g., N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), acetone, 2-butanone (methyl ethyl ketone, MEK), 3-methyl-2-butanone (isopropyl methyl ketone, MIPK), acetonitrile (MeCN), methanol (MeOH), tetrahydrofuran (THF), ethyl acetate (EtOAc), or a mixture of any of the foregoing, at room temperature or heated to about 50-150 °C for about 0.5-6 hours to provide compounds of Formula (Q).

[0231] Referring to Scheme 5, in certain embodiments using comparable reaction conditions with respect to solvents, temperature, and duration as described for the preparation of compounds of Formula (Q), the reaction of bis-sulfonyl esters of Formula (P) may also be carried out in the presence of about one molar equivalent of a suitable alkali metal halide salt MX, as defined herein, to provide compounds of Formula (R) bearing N-(2-halogenoethyl)-, N-(2-methylsulfonyloxy ethyl) amino groups (mixed halogeno/sulfonylato N-mustards).

[0232] Referring to Scheme 5, in some embodiments compounds of Formula (Q) may be converted to mixed halogeno/sulfonylato N-mustards of Formula (R) by reacting N-mustard derivatives of Formula (Q) where X is bromo (-Br) with about 1.0 equivalent or slightly less of a suitable soluble silver sulfonate salt, e.g., silver mesylate (AgOS0 ₂ Me, AgOMs) in a polar solvent such as acetonitrile (MeCN) at about reflux temperature to provide the mixed halogeno/mesylate N-mustard of Formula (S) (methathetical reaction).

[0233] Referring to Scheme 5, in certain embodiments, using comparable reaction conditions with respect to solvents, temperature, and duration as described for the preparation of compounds of Formula (Q) and of Formula (R), the reaction of bis-halogeno N-mustards of Formula (Q) or of mixed halogeno/mesylate N-mustards of Formula (R) may also be carried out in the presence of about one molar equivalent of a suitable alkali metal halide salt MX', as defined herein, to provide compounds of Formula (S) bearing N-(2-halogenoethyl)-, N-(2-halogeno'ethyl) amino groups (mixed halogeno N-mustards).

[0234] Reductive N-alkylation is a form of amination/alkylation that involves the reaction of an amino group with a carbonyl group to an amine in the presence of a suitable reducing agent via an intermediate imine or protonated imine. The carbonyl group component is most commonly an aldehyde or ketone functionality, the amino group is most commonly ammonia, a primary or secondary aliphatic amino group, or a primary or secondary aromatic amino group (aniline). For indirect reductive aminations, the intermediate imine may be isolated and reduced with a suitable reducing agent. For direct reductive aminations, the reaction may be carried out simultaneously, with the imine formation and reduction occurring concurrently, typically using reducing agents that are more reactive toward protonated imines than ketones, and that are stable under moderately acidic conditions, e.g., sodium cyanoborohydride (Na(CN)BH ₃ ) or sodium triacetoxyborohydride (NaB(OAc) ₃ H.

[0235] Referring to Scheme 6, the primary amino group of compounds of Formula (T) or of Formula (U), either in a suitable salt form, e.g., a hydrochloride (HC1) salt (Ar-E- ΝΗ ₂ ΉΟ) or as a free base (Ar-E-NH ₂ ) may be subjected to a reductive N-alkylation reaction using a suitable halocarbonyl compounds (X = F, CI or, Br) or derivatives thereof, e.g., a dimethyl acetal, and reducing agents as they are well known in the art (Palani, et al., J. Med. Chem., 2005, 48(15), 4746-4749; Van Oeveren, Bioorg. Med. Chem. Lett., 2007, 17(6), 1527-1531; Delfourne, et al, Bioorg. Med. Chem., 2004, 12(15), 3987-3994;

Delfourne, et al, J. Med. Chem., 2002, 47(17), 3765-3771; and Jordan, et al, Bioorg. Med. Chem., 2002, 10(8), 2625-2633).

[0236] Suitable halocarbonyl compounds include, for example, 2-chloroacetic acid (CICH ₂ CO ₂ H, X is CI)), 2-chloroacetaldehyde (ClCH ₂ CHO, X is CI)), or 2- bromoacetaldehyde dimethylacetal (MeO) ₂ CHCH ₂ Br, X is Br), optionally provided as solutions in suitable solvents, e.g., a 50-wt-% solution of 2-chloroacetaldehyde (ClCH ₂ CHO, X is CI)) in water.

[0237] Referring to Scheme 6, suitable reducing agents for reductive N-alkylations of primary amino groups such as in compounds of Formula (T) and of Formula (U) using 2- chloroacetic acid include boranes, preferably borane-tetrahydrofuran complex (H ₃ B HF), and ceratin alkalimetal borohydrides, e.g., lithium borohydride (LiBH ₄ ) or sodium borohydride (NaBH ₄ ).

[0238] Referring to Scheme 6, the reaction is generally carried out in the presence of organic solvents such as protic solvents, e.g., methanol (MeOH), acetic acid, (HOAc), trifluoroacetic acid (TFA), 85 wt-% phosphoric acid (H ₃ PO ₄ ), glacial acetic acid (HOAC), 98 wt-% formic acid, or water, or inert organic solvents, e.g., acetonitrile (MeCN),

dichloromethane (DCM), tetrahydrofuran (THF), benzene, or equivalent mixtures of any of the foregoing at a temperature from about 0 °C to about reflux temperature and for about 05- 18 hours. In embodiments where 2-chloroacetaldehyde is used, suitable reducing agents may include, for example, sodium cyanoborohydride (Na(CN)BH ₃ ), sodium

triacetoxyborohydride (NaB(OAc) ₃ H, and sodium borohydride (NaBH ₄ ).

[0239] Reduction via hydrogenation is can also be employed. Preferred hydrogenation conditions include catalytic hydrogenation, for example, using palladium on carbon (Pd/C) as the catalyst. As the hydrogen source, gaseous hydrogen (H ₂ -gas) at pressures ranging from about atmospheric pressure to about 150 psi, or suitable ammonium salts, e.g., ammonium hydrogencarbonate (H ₄ NHC0 ₃ ), may be employed. The hydrogenation may be carried out at ambient temperature.

[0240] Referring to Scheme 6, in certain embodiments, R ¹ and/or R ⁵ , R ²⁰ , E, the linker L, the halogeno group X, and the protecting group PG and Q are defined as herein; one of R ² , R ³ , and R ⁴ in compounds of Formula (T) and Formula (U) is -E-NH ₂ , wherein E is a bond ("-"), an oxygen atom ( ^~ 0-), a methylene group (-CH ₂ ^~ ), or methylenoxy group (-CH ₂ -0- ), and wherein MH is an amino group (-NH ₂ ) so that -E-NH ₂ is equivalent to a) a primary aromatic amino group (-NH ₂ , aniline), b) a primary O-aryl hydroxylamino group (-0-NH ₂ ), c) a primary aminomethyl group (-CH ₂ -NH ₂ ), or a primary O-benzyl hydroxylamino group (-CH ₂ -0-NH ₂ ); each of the other remaining R ² , R ³ , and R ⁴ is hydrogen; each of R ⁷ and R ⁸ is hydrogen.

Scheme 6

[0241] Referring to Scheme 6, in certain embodiments, the primary amino group of compounds of Formula (T) or of Formula (U) may be converted to N,N-bis(2- halogenoethyl)amino groups as in compounds of Formula (V) or of Formula (W) by reacting compounds of Formula (T) or of Formula (U) with an excess of about 4-10 equivalents of a 2-halogenocarbonyl compound, e.g., a 50 wt-% solution of 2-chloroacetaldehyde in water, and an excess of about 3-8 equivalents of a suitable reducing agent, e.g., sodium

cyanoborohydride (NaB(CN)H ₃ ). In certain embodiments, the reaction may be carried out in mixtures of methanol (MeOH) with trifluoroacetic acid (TFA), glacial acetic acid (HO Ac), 98 wt-% formic acid (FA), or 85 wt-% phosphoric acid (H ₃ PO ₄ ). For example, in certain embodiments, 1 : 1 (v/v), 2: 1 (v/v), or 1 :2 (v/v) mixtures MeOH/acid and reaction

temperatures from about 0-40 °C and reaction times of about 0.5-18 hours are employed to provide protected N-mustards of Formula (V) or of Formula (W).

[0242] Estramustine (Emcyt ^® , Estracit ^® ) is an antimicrotubule chemotherapy agent indicated in the United States for the palliative treatment of metastatic and/or progressive prostate cancer. It is derivative of estrogen (specifically, estradiol) with a N-mustard- carbamate ester moiety.

[0243] Referring to Scheme 7, methods to functionalize alcohols or phenols with carbamoyl derivatives of secondary amines yielding carbamates as in, for example, compounds of Formula (Z) wherein M is oxygen (-0-) and G is oxygen (=0) include carbamoyl chlorides or p-nitrophenyl carbamates, and are well known in the art. Likewise, it is well known in the art that carbamates as in, for example, compounds of Formula (Z) wherein M is oxygen (-0-) and G is oxygen (=0) are also accessible through activation of alcohols or phenols with suitable formic ester derivatives including phosgene (C0C1 ₂ ), triphosgene (bis(trichloromethyl) carbonate (BTC)), or Ι,Γ-carbonyldiimidazole (CDI) followed by reaction with an appropriately functionalized amine such as HN(CH ₂ -CH ₂ -R ⁹ ) ₂ wherein R ⁹ is chloro (-C1), bromo (-Br), iodo (-1), or (polyfluoro)alkyl- or aryl sulfonyloxy (-OS0 ₂ R ⁴⁰ ) or combinations thereof and R ⁴⁰ is defined as described herein.

[0244] Likewise and referring to Scheme 7, many methods are known in the literature and to those skilled in the art to prepare compounds of Formula (Z) related to carbamates including a) S-thiocarbamates wherein M is sulfur (-S-) and G is oxygen (=0), b) O- thiocarbamates wherein M is oxygen (-0-) and G is sulfur (=S), c) dithiocarbamates wherein M is sulfur (-S-) and G is sulfur (=S), d) ureas wherein M is nitrogen (-NR ¹⁰ -), and where R ¹⁰ is defined as described herein, and G is oxygen (=0), or thioureas wherein M is nitrogen (-NR ¹⁰ -) and G is sulfur (=S).

[0245] Referring to Scheme 7, in certain embodiments a compound of Formula (X) is, for example, a) a phenol wherein E is a bond ("-") and MH is a hydroxyl group (-OH), b) an aniline wherein E is a bond ("-") and MH is an amino group (-NR ¹⁰ H), c) a thiophenol wherein E is a bond ("-") and MH is a sulfhydryl group (-SH), d) an O-aryl hydroxylamine wherein E is oxygen (-0-) and MH is an amino group (-NR ¹⁰ H), e) a benzylic alcohol wherein E is methylene (-CH ₂ -) and MH is a hydroxyl group (-OH), f) a benzylic amine wherein E is methylene (-CH ₂ -) and MH is an amino group (-NR ¹⁰ H), g) a benzylic thiol wherein E is methylene (-CH ₂ -) and MH is sulfhydryl (-SH), h) an O-benzylic

hydroxylamine wherein E is methyleneoxy (-CH ₂ -0-) and MH is an amino group (-NR ¹⁰ H).

[0246] Referring to Scheme 7, in certain embodiments, R ¹ and/or R ⁵ , R ¹⁰ , R ²⁰ , E, M, Z, the linker L, and the protecting group PG and Q are as defined herein; one of R ² , R ³ , and R ⁴ in compounds of Formula (X) is -E-MH as described herein; each of the other remaining R ² , R ³ , and R ⁴ is hydrogen; each R ⁷ and each R ⁸ is hydrogen; LG is a suitable leaving group such as to chloro ( ^~ C1), 4-nitrophenyloxy (N0 ₂ CeH ₄ 0-), or imidazole; and R ⁹ is chloro (-C1), bromo (-Br), iodo (-1), or (polyfluoro)alkyl- or aryl sulfonyloxy (-OS0 ₂ R ⁴⁰ ) or combinations thereof, and R ⁴⁰ is defined as described herein.

Scheme 7

[0247] Referring to Scheme 7, in certain embodiments the alcohol, the thiol group, or the amino group of compounds of Formula (X) may be converted to the N,N-bis(2-halogeno- or 2-sulfonyloxyethyl)carbamoyl or N,N-bis(2-halogeno- or 2-sulfonyloxyethyl)thiocarbamoyl group of compounds of Formula (Z) by reacting a compound of Formula (X) with, for example, commercial N,N-bis(2-chloroethyl)carbamoyl chloride (U.S. Patent No. 3,299,104), wherein LG is chloro ( ^~ C1), R ⁹ is chloro ( ^~ C1), and G is oxygen (=0) or known (4- nitrophenyl) N,N-bis(2-chloroethyl)carbamate where LG is 4-nitrophenol (4-N0 ₂ -Ph-0-), R ⁹ is chloro ( ^~ C1), and G is oxygen (=0) in suitable solvents such as pyridine, or

triethylamine in 1 ,4-dioxane/benzene mixtures and the like at temperatures of about 0-60 °C to provide carbamate, thiocarbamate, or urea derivatives of Formula (Z).

[0248] Referring to Scheme 7, in certain embodiments the MH-group of compounds of Formula (X) may be activated to their corresponding chloroformates, thiochloroformates, or carbonyl imidazoles of Formula (Y) with, for example, phosgene, thiosphosgene,

triphosgene, carbonyldiimidazole (CDI), thiocarbonyldiimidazole (TCDI) ,or the like, in the presence of a suitable base such as inorganic metal-carbonate, e.g., potassium carbonate (K ₂ C0 ₃ ) and bicarbonates, e.g., sodium hydrogencarbonate (NaHC0 ₃ ), in suitable inert solvents known in the art. The chloroformates or thiochloroformates of Formula (Y) are subsequently converted to the corresponding carbamates of Formula (Z) through reaction with an appropriately functionalized amine such as FfN(CH ₂ -CH ₂ -R ⁹ ) ₂ wherein R ⁹ is chloro (-C1), bromo (-Br), iodo (-1), or (polyfluoro)alkyl- or aryl sulfonyloxy (-OS0 ₂ R ⁴ °) or combinations thereof, and R ⁴⁰ is defined as described herein, e.g., commercial bis(2- chloroethyl)amine hydrochloride wherein R ⁹ is chloro ( ^_ C1) or 2-bromo-N-(2- bromoethyl)ethanamine wherein R ⁹ is bromo ( ^~ Br), and in the presence of a base such as inorganic metal-carbonate, e.g., potassium carbonate (K ₂ CO ₃ ) and bicarbonate, e.g., sodium hydrogencarbonate (NaHC0 ₃ ), ethyl acetate (EtOAc), water, or mixtures of any of the foregoing to yield carbamates of Formula (Z).

[0249] In general, the biological activity of nitrogen mustards is based upon the presence of an alkylating N,N-bis(2-chloroethyl) functionality. The chemotherapeutic and cytotoxic effects are directly associated with the alkylation of DNA due to the strong electrophilic character of the N,N-bis(2-chloroethyl) functionality. Formation of covalent linkages including interstrand crosslinks (ICLs) is highly cytotoxic and involves the disruption of fundamental cellular processes including DNA replication leading to cellular death.

[0250] Because of this property, the nitrogen mustards have been used for a number of years in laboratory investigations and in the clinical treat for malignat growth. Unfortunately, the effective dose of nitrogen mustards is in many cases close to the toxic dose and it is therefore desirable to find a nitrogen mustard or a class of nitrogen mustard type compounds possessing the high carcinolytic activity of the parent compound but having modulated toxicity.

[0251] The amide linkage masks the alkylating and toxic properties of the nitrogen mustard moiety so that the total host is not subjected to undesirable toxic effects sometime encountered with nitrogen mustard therapy: the amino acid moiety of the molecule facilitates the selective delivery of the "masked" nitrogen mustard via the amino acid transport mechanism into the tumor cells, where the higher amidase activity of the tumor cell liberates the reactivated nitrogen mustard within itself. Thus, in effect it will be possible to obtain maximum effect of the nitrogen mustard on the tumor and minimum toxic effect on the host (U.S. Patent No. 3,235,594).

[0252] Referring to Scheme 8, the amide nitrogen mustards of the present disclosure are prepared by condensing carboxylic acids of Formula (AA) wherein E is a carbonyl group (- C(=0)-) or a methylenecarbonyl group (-CH ₂ -C(=0)-) with an appropriately functionalized amine such as FfN(CH ₂ -CH ₂ -R ⁹ ) ₂ wherein X is chloro (-C1), bromo (-Br), iodo (-1), or (polyfluoro)alkyl- or aryl sulfonyloxy (-OS0 ₂ R ⁴ °) or combinations thereof, and R ⁴⁰ is defined as described herein, to provide amides of nitrogen mustards of Formula (AB). [0253] Referring to Scheme 8, a myriad of coupling methods is known in the art to facilitate the formation of amide bonds as in compounds of Formula (AB) from carboxylic acids of Formula (AA) (Montalbetti and Falque, Tetrahedron, 2005, 61, 10827-10852; and Valeur and Bradley, Chem. Soc. Rev., 2009, 38, 606-631).

[0254] Refering to Scheme 8, in certain embodiments, R ¹ and/or R ⁵ , R ²⁰ , E, the linker L, and the protecting group PG and Q are defined as described herein; one of R ² , R ³ , and R ⁴ m compounds of Formula (AA) is -E-OH as described herein; each of the other remaining R ² , R ³ , and R ⁴ is hydrogen; each R ⁷ and each R ⁸ is hydrogen; R ⁹ is a suitable functionalization providing the alkylation properties of the nitrogen mustard.

Scheme 8

[0255] Referring to Scheme 8, in certain embodiments the (thio)carboxyl group of compounds of Formula (AA) may be activated as acyl halides, acyl azides, symmetrical or unsymmetrical carboxylic, carbonic, or boronic anhydrides, acyl imidazoles, activated esters, phosphonium salts, uranium salts, or ammonium salts followed by ammonolysis of the activated intermediate either after prior isolation or in situ with an appropriately

functionalized amine such as FiN(CH ₂ -CH ₂ -R ⁹ ) ₂ to provide nitrogen mustard amides of Formula (AB).

[0256] Referring to Scheme 9, protected N-mustard functionalized β-substituted γ-amino acid precursors or protected N-mustard functionalized β-substituted γ-amino acid analog precursors or carboxylic acid (bio)isosteres of Formula (AC) or of Formula (AD) are converted to the corresponding unprotected N-mustard functionalized β-substituted γ-amino acid derivatives or unprotected N-mustard functionalized β-substituted γ-amino acid analogs or carboxylic acid (bio)isosteres of Formula (AE) by removing the external protecting groups and/or by opening the lactam ring (internal protection).

[0257] Referring to Scheme 9, in certain embodiments the connector group "A" of the moiety -A-N(CH ₂ -CH ₂ -R ⁹ ) ₂ is a bond ("-"), oxygen (-0-), sulfur (-S-), methylene (-CH ₂ - ), methyleneoxy (-CH ₂ -0-), oxycarbonyl (-0-C(=0)-), thiocarbonyl (-S-C(=0)-), aminocarbonyl (-NR ¹⁰ -C(=O)-), oxythiocarbonyl (-0-C(=S)-), thiothiocarbonyl (-S- C(=S)-), aminothiocarbonyl (-NR ¹⁰ -C(=S)-), methyleneoxycarbonyl (-CH ₂ -0-C(=0)-), methylenethiocarbonyl (-CH ₂ -S-C(=0)-), methyleneaminocarbonyl (-CH ₂ -NR ¹⁰ -C(=O)-), methyleneoxythiocarbonyl (-CH ₂ -0-C(=S)-), methylenethiothiocarbonyl (-CH ₂ -S-C(=S)- ), methyleneaminothiocarbonyl (-CH ₂ -NR ¹⁰ -C(=S)-), carbonyl (-C(=0)-),

methylencarbonyl (-CH ₂ -C(=0)-), thiocarbonyl (-C(=S)-), methylenthiocarbonyl (-CH ₂ - C(=S)-).

[0258] Referring to Scheme 9, in certain embodiments liberation of unprotected N- mustard functionalized β-substituted γ-amino acid derivatives or unprotected N-mustard functionalized β-substituted γ-amino acid analogs or carboxylic acid (bio)isosteres of Formula (AE) from their corresponding precursors of Formula (AC) or of Formula (AD) may be conducted under aqueous acidic conditions (hydrolysis) (Taylor, et al, Chem. Biol. Drug Des., 2007, 70(3), 216-226; Buss, et al, J. Fluorine Chem., 1986, 34(1), 83-114; Abela, et al, J. Chem. Soc, Perkin Trans. 1, 1997, (20), 2258-2263; Weisz, et al, Bioorg. Med. Chem. Lett., 1995, 5(24), 2985-2988; Zheng, Bioorg., Med., Chem., 2010, 18(2), 880-886; Haines, et al, J. Med. Chem., 1987, 30, 542-547; and Matharu, et al, Bioorg., Med., Chem., Lett., 2010, 20, 3688-3691).

[0259] Referring to Scheme 9, in certain embodiments liberation of unprotected N- mustard functionalized β-substituted γ-amino acid derivatives or unprotected N-mustard functionalized β-substituted γ-amino acid analogs or carboxylic acid (bio)isosteres of Formula (AE) from their corresponding precursors of Formula (AD) may also be conducted under anhydrous acidic conditions (Springer, et al, J. Med. Chem., 1990, 33(2), 677-681; Davies, et al, J. Med. Chem. 2005, 48(16), 5321-5328; Niculesscu-Duvaz, et al, J. Med. Chem., 2004, 47(10), 2651-2658; Verny and Nicolas, J. Label. Cmpds, Radiopharm., 1988, 25(9), 949-955; Thorn, et al, J. Org. Chem, 1975, 40(11), 1556-1558; Baraldini, et al, J. Med. Chem., 2000, 53(14), 2675-2684; Gourdi, et al, J. Med. Chem., 1990, 33(4), 1177- 1186; and Kupczyk-Subotkowska, et al, J. Drug Targeting, 1997, 4(6), 359-370).

[0260] Referring to Scheme 9, it will be obvious to those skilled in the art that protected N-mustard functionalized β-substituted γ-amino acid precursors of Formula (AA) or protected N-mustard β-substituted γ-amino acid analog or carboxylic acid (bio)isosteres precursors of Formula (AD) bearing different combinations of suitable protecting groups may also be prepared. Different combinations of protecting groups may require specific reactants and reaction conditions for effective removal of specific set of different protection groups to provide unprotected N-mustard β-substituted γ-amino acid derivatives or unprotected N- mustard funtionalized β-substituted γ-amino acid derivatives, analogs, or carboxylic acid (bio)isosteres of Formula (AE).

[0261] Referring to Scheme 9, in certain embodiments of compounds of Formula (AC), Formula (AD), and of Formula (AE) R ¹ and/or R ⁵ , R ⁹ , the connector group A, the protecting groups PG and Q, and the linker L are defined as described herein; R ⁶ is an unprotected carboxylic acid, a carboxylic acid analog or a carboxylic acid (bio)isostere as defined herein; R ²⁰ is a protected carboxylic acid, a carboxylic acid analog or a carboxylic acid (bio)isostere as defined herein; one of R ² , R ³ , and R ⁴ is a N,N-bis-(2-functionalized)ethylamino group (nitrogen mustard group) linked to a connector A (-A-N(CH ₂ -CH ₂ -R ⁹ )2); each of the remaining R ² , R ³ , and R ⁴ is hydrogen; each of R ⁷ and R ⁸ is hydrogen.

Scheme 9

[0262] Referring to Scheme 9, hydrolytic acidic ring-opening and simultaneous internal N-deprotection of compounds of Formula (AC) or hydrolytic acidic global deprotection of compounds of Formula (AD) to provide N-mustard functionalized β-substituted γ-amino acid derivatives or N-mustard functionalized β-substituted γ-amino acid analogs or carboxylic acid (bio)isosteres of Formula (AE) may be accomplished by treating protected precursors of Formula (AC) or of Formula (AD) at elevated temperatures from about 40-150 °C with aqueous mineral acids, e.g., 2 M to -12 M hydrochloric acid (HC1) for about 6-24 hours. In certain embodiments, mixtures of the mineral acid with organic solvents may be used. A useful aqueous mineral acid reaction mixture to facilitate lactam ring opening or global deprotection is, e.g., a 1 : 1 (v/v) mixture of concentrated hydrochloric acid (~12M or -37 wt- % HCl) with 1,4-dioxane.

[0263] Referring to Scheme 9, other aqueous mineral acids with a non-nucleophilic anion known in the art can be used to facilitate simultaneous hydrolytic acidic ring-opening and simultaneous internal N-deprotection of compounds of Formula (AC) or hydrolytic acidic global deprotection of acid-labile or hydrolysis sensitive protecting groups of the protected carboxylic moiety, of the protected carboxylic acid (bio)isostere, or of the amino

functionality of compounds of Formula (AD) to provide N-mustard functionalized β- substituted γ-amino acid derivatives or N-mustard functionalized β-substituted γ-amino acid analogs or carboxylic acid (bio)isosteres of Formula (AE).

[0264] Referring to Scheme 9, suitable mineral acids may include, for example, diluted or concentrated aqueous solutions of hydrobromic acid (HBr), hydroiodic acid (HI), sulfuric acid (H2SO4), perchloric acid (HCIO4), and phosphoric acid (H3PO4), mixtures of any of the foregoing or mixtures with suitable organic solvents, e.g., 1,4-dioxane, with any of the foregoing.

[0265] It is within the ability of one skilled in the art to select specific and suitable aqueous mineral acids and reaction conditions for hydrolytic acidic ring-opening and simultaneous internal N-deprotection of compounds of Formula (AC) or hydrolytic acidic global deprotection of compounds of Formula (AD) to provide N-mustard functionalized β- substituted γ-amino acid derivatives or N-mustard functionalized β-substituted γ-amino acid analogs or carboxylic acid (bio)isosteres of Formula (AE).

[0266] Referring to Scheme 9, simultaneous global deprotection of compounds of Formula (AD) where R ²⁰ is an acid labile moiety derived from a carboxylic acid, e.g., C0 ₂ tBu, C0 ₂ -pentamethylbenzyl, C0 ₂ -(4-methoxy)benzyl, or C0 ₂ -trityl, and Q is a protected amino group derived from an acid-labile N-protecting group, e.g., N(H)Boc, N(H)trityl, N(H)(4-methoxy)phenyl-diphenylmethyl, or N(H)di-((4-methoxy)phenyl)- phenylmethyl, may also be accomplished by reaction with strong organic acids under anhydrous conditions to liberate free (unprotected) N-mustard functionalized β-substituted γ- amino acid derivatives or N-mustard functionalized β-substituted γ-amino acid analogs or carboxylic acid (bio)isosteres of Formula (AE).

[0267] In certain embodiments, strong (organic) acids useful for global deprotection under anhydrous conditions include trifluoro acetic acid (TFA), 98 wt-% formic acid (FA), methanesulfonic acid (MeS0 ₃ H), 85 wt-% phosphoric acid (H ₃ PO ₄ ), 2 M hydrogen chloride (HC1) in diethyl ether (Et ₂ 0), 4 M hydrogen chloride (HC1) in 1,4-dioxane, or a saturated solution of HC1 in ethyl acetate (EtOAc) (Li, et al, J. Org. Chem., 2006, 71, 9045-9050).

[0268] Depending of the overall sensitivity to strong (organic acids), compounds of Formula (AD) may be reacted with neat either neat strong (organic) acid or with solutions of the strong organic acid in suitable inert solvents such asdichloromethane (DCM),

dichloroethane (DCE), 1,4 -dioxane, diethylether (Et ₂ 0), tetrahydrofuran (THF), or toluene typically in ratios ranging from neat (organic) acid to about 10 vol-% (organic) acid in said inert solvent, and reaction temperatures ranging from about 0-50 °C for about 1-24 hours to provide unprotected N-mustard functionalized β-substituted γ-amino acid derivatives or unprotected N-mustard functionalized β-substituted γ-amino acid analogs or carboxylic acid (bio)isosteres of Formula (AE).

[0269] Optionally, 2-5 equivalents of a suitable scavenging agent such as triethysilane (Et ₃ SiH) (TES), triisopropylsilane (z ^' Pr ₃ SiH), thioanisole, or 1 ,2-dithioethane (HSCH ₂ CH ₂ HS) may be added to the reaction mixture to suppress formation of unwanted side reactions and by-products originating, for example, from alkylation of electron-rich aromatic scaffolds or sulfide groups under global deprotection conditions disclosed herein to provide unprotected N-mustard functionalized β-substituted γ-amino acid derivatives or unprotected N-mustard functionalized β-substituted γ-amino acid analogs or carboxylic acid (bio)isosteres of Formula (AE).

[0270] Separation of unprotected N-mustard functionalized β-substituted γ-amino acid derivatives or unprotected N-mustard functionalized β-substituted γ-amino acid analogs or carboxylic acid (bio)isosteres of Formula (AE) from unreacted starting materials, unwanted byproducts, and impurities may be accomplished using, for example, solid-phase extraction (SPE) techniques, e.g., with QMA ^® cartridges (Waters, USA), LiChrolut ^® cartridges (EMD Chemicals, USA), or Whatman SAX cartridges (Whatman, USA), preparative normal or reverse phase TLC, reverse phase (RP) semi-preparative or preparative HPLC,

crystallization, precipitation, or any other suitable method known in the art.

[0271 ] Purified unprotected N-mustard functionalized β-substituted γ-amino acid derivatives or unprotected N-mustard functionalized β-substituted γ-amino acid analogs or carboxylic acid (bio)isosteres of Formula (AE) may be isolated using any of the methods known in the art. For example, such methods include removal of HPLC solvents (mobile phase) of the combined fractions containing the N-mustard functionalized β-substituted γ- amino acid derivatives or N-mustard functionalized β-substituted γ-amino acid analogs or carboxylic acid (bioisosteres) of Formula (AE) under reduced pressure with a rotary evaporator, or removal of (aqueous) solvent mixtures by primary lyophilization.

[0272] Any suitable method known in the art may be used to produce acid adition salts or salts including pharmaceutically acceptable acid adition salts or salts of compounds of Formula (AE).

[0273] The lyophilization may optionally be conducted in the presence of one or more equivalents of a mineral acid, optionally with a pharmaceutically acceptable counterion, to form (pharmaceutically acceptable) acid addition salts of compounds of Formula (AE). For example, one or more equivalents of hydrochloric acid (HC1) may be added prior to lyophiliation to form mono-, di-, or polyhydrochloride salts of compounds of Formula (AE) or mixtures thereof.

[0274] The lyophilization may optionally be conducted in the presence of one or more equivalents of a base, optionally with a pharmaceutically acceptable counterion, to form (pharmaceutically acceptable) salts of compounds of Formula (AE). For example, one or more equivalents of sodium hydrogen carbonate (NaHCOs) may be added prior to lyophiliation to form mono-, di-, or poly sodium salts of compounds of Formula (AE) or mixtures thereof.

[0275] A characteristic feature of solid tumors is the presence of cells at very low oxygen concentrations (hypoxia; partial pressure of oxygen in tumorous tissue of 0.05-5.0%) often surrounding areas of necrosis. There are clear links between hypoxia and the lack of response to radiotherapy and intrinsic resistance to cytotoxic therapy. It has also been demonstrated that hypoxia in tumours tends to select for a more malignant phenotype (Wilson and Hay, Nat. Rev. Cane, 2011, 11, 393-410; and Brown and Wilson, Nat. Rev. Cane, 2004, 4, 437- 447).

[0276] Reductive metabolic processes are more prevalent in the hypoxic environment of solid tumors. Reductive enzyme systems have the ability to reduce certain functional groups. For example, aromatic and aliphatic N-oxides (-N ⁺ (0 ^~ )R ₂ ) are known to be reducible to the corresponding amines (-NR ₂ ), and nitro groups (-N0 ₂ ) can be either reduced to the corresponding amines (-NH ₂ ) or to hydroxylamines (-NH(OH) depending on the oxygen saturation of the tissue (Denny, et al, Br. J. Cane, 1996, 74, Suppl. XXVII, S32-S38; and Nagasawa, et al, Biol. Pharm. Bull, 2006, 29(12), 2335-2342).

[0277] One promising approach for the design of cancer-cell-selective mustards exploits selective enzymatic reduction of nitroaryl compounds in the oxygen-starved (hypoxic) cells found in solid tumors. N-Oxide derivatives of nitrogen mustards including N-oxides of melphalan (PX-478; U.S. Patent No. 7,399,785; Koh, et al, Mol. Cane. Ther., 2008, 7(1), 90-100; www.medkoo.com) and chlorambucil (Kirkatrick, et al, Anti-Cancer Drugs, 1994, 5, 467-472; Tercel, et al, J. Med. Chem., 1995, 38, 1247-1252; and U.S. Patent No. 5,602,273) have been investigated as bioreductive prodrugs with reduced systemic toxicity in

comparison to the parent drugs. Those drugs take advantage of a) the hypoxic nature, and b) the reductive nature, of certain tumorous cells. The N-oxide functional group deactivates the extremely reactive alkylating agent through capture of the lone electron pair of the parent nitrogen mustard moiety thus diminishing the alkylating properties and the off-target toxicityies associated with that. Bioreductive activation within the hypoxic tumor

environment or milieu by hypoxic cells and their reductive enzyme systems is believed to restore the cytotoxicity of the free nitrogen mustards. The overall effect is an enhanced therapeutic index of the N-oxides of nitrogen mustards relative to their parent nitrogen mustards.

[0278] Depending on the pH and the nature of the solvent, particularly aprotic organic solvents, N-oxides of nitrogen mustards are known to intramolecularly rearrange to the corresponding more stable hydroxylamines with markedly less intrinsic cytotoxic potential (Tercel, et al, J. Med. Chem., 1995, 38, 1247-1252; and U.S. Patent No. 5,602,273).

However, it is also known that the hydroxylamines are able to convert back to the parent N- oxides in vivo where the latter can be reduced in the hypoxic and reductive environment of tumerous cells where the underlying nitrogen mustards exerts their cytoxicity.

[0279] Referring to Scheme 10, in certain embodiments of compounds of Formula (AF), Formula (AG), and of Formula (AH) R ¹ and/or R ⁵ , R ⁶ , R ⁹ , and the linker L are defined as described herein; one of R ² , R ³ , and R ⁴ is a N,N-bis-(2-functionalized)ethylamino group (nitrogen mustard group) linked to a connector group "A" (-A-N(CH ₂ -CH ₂ -R ⁹ ) ₂ ) wherein the connector group "A" is a bond ("-") or a methylene group (-CH ₂ -); each of the remaining R ² , R ³ , and R ⁴ is hydrogen; and each of R ⁷ and R ⁸ is hydrogen.

Scheme 10

[0280] Referring to Scheme 10, N-oxidation of the N-mustard group of compounds of Formula (AF) with a slight excess of 3-chloroperbezoic acid (meta-chloroperbenzoic acid, mCPBA) in a solvent such as dichloromethane (DCM) at about room temperature followed by work-up with aqueous sodium hydrogencarbonate furnishes the more stable

hydroxylamine (through putative re-arrangement via a cyclic oxazetidinium species) of Formula (AG).

[0281] Referring to Scheme 10, N-oxidation of the N-mustard group of compounds of Formula (AF) with 3-5 equivalents of peracetic acid (MeCO(02H)), prepared from 35 wt-% aqueous hydrogen peroxide (H ₂ 0 ₂ ) in glacial acetic acid (HO Ac), in a solvent such as dichloromethane (DCM) at about room temperature followed by acid extraction furnishes the corresponding N-oxide of Formula (AH).

Characterization

[0282] To determine the extent to which compounds provided by the present disclosure enter cells via the LATl/4F2hc transporter, amino acid uptake assays into cells that are transfected with DNA encoding the LATl and 4F2hc subunits may be performed using, for example, HEK (human embryonic kidney) or CHO (Chinese hamster ovary) cells. Oocytes may also be injected with cRNA LATl and 4F2hc to express LATl/4F2hc transporter. Compounds may be screened either for specificity for the LATl/4F2hc transporter or for transport into cells endogenously expressing a plurality of transporters. The results of a screening method (e.g., a competition uptake, exchange or direct uptake assay) using a cell expressing the LATl/4F2hc transporter may be compared with the results of a control cell(s) lacking the LATl/4F2hc transporter or in the presence of a specific inhibitor of the

LATl/4F2hc transporter.

[0283] In competition experiments, the ability of a compound to specifically bind to the LATl/4F2hc transporter is determined. A known substrate (reference substrate) for the LATl/4F2hc transporter and a test compound are added to cells expressing the LATl/4F2hc transporter. For example, gabapentin may be used as a reference because it demonstrates high selectivity for LATl/4F2hc. Gabapentin is not a substrate for the intestinal amino acid transporters B°' ⁺ , ATB ⁰⁺ , and LAT2, whereas gabapentin may be a substrate for the organic cation transporter OCTN2 (Cundy, et al, J Pharm Exp Ther, 2004, 311(1), 315-323; and Grigat, et al, Drug Metabol Disp, 2009, 37(2), 330-337). The amount or rate of transport of the reference substrate in the presence of the test compound is compared to the amount or rate of transport of the reference substrate in the absence of the test compound. If the amount or rate of transport of the reference substrate is decreased by the presence of the test compound, the test compound binds to the LATl/4F2hc transporter.

[0284] Compounds that bind the LATl/4F2hc transporter can be further analyzed to determine if they are transported by the LATl/4F2hc transporter or only compete for binding to the transporter. Transport of a compound into a cell can be determined by detecting a signal from within a cell from any of a variety of reporters. The reporter can be as simple as a label such as a fluorophore, a chromophore, a radionuclide, or a reporter can be an agent that is detected utilizing liquid chromatography-mass spectroscopy (LC/MS/MS). The same methods of detection can be used to determine if a reporter is transported from the intracellular space to the medium by administering the test compound to the outside of the cell and sampling the media for the presence of the intracellular reporter after a

predetermined period of time (exchange assays).

[0285] Having determined that a compound is a substrate for LATl/4F2hc, a further screen may be performed to determine the selectivity of the compound toward other membrane transporters. Selectivity refers to the affinities with which a compound is transported by different transporters. In order to demonstrate selectivity for LATl/4F2hc, a compound may be tested in uptake and/or competition assays for other transporters.

Transporters that could potentially transport LATl/4F2hc substrates include SLC1A4 (ASCT1; NP 003029), SLC1A5 (ASCT2; NP 005619), SLC6A1 (GAT1; NP 003033), SLC6A5 (GlyT2; NP 004202), SLC6A6 (TauT; NP 003034), SLC6A8 (CTl; NP 005620), SLC6A9 (GlyTl; NM 008865), SLC6A11 (GAT3; NP 55044), SLC6A12 (BGT1; NP 003035), SLC6A13 (GAT2; NP 057699), SLC6A14 (ATB ^{0 +} ; NP 009162), SLC6A15 (B°AT2; NP 001139807), SLC6A17 (XT1; NP 001010898), SLC6A18 (B°AT3;

NP_872438), SLC6A19 (B°AT1; NP 001003841), SLC7A6 (y ⁺ LAT2; NP OO 1070253), SLC7A7 (y ⁺ LATl; NP_001119577), SLC7A8 (LAT2; NP_036376), SLC7A9 (b°' ⁺ AT;

NP_055085), SCL7A10 (ASC-1; NP_062823), SLC15Al(PepTl; NP_005064), SLC15A2 (PepT2; NP 066568), SLC16A1 (MCT1; NP 003042), SLC16A2 (MCT8; NP 006508), SLC16A10 (TAT1; NP 061063), SLC01B1 (OATP1B1; NP 006437), SLC01B3

(OATP1B3; NP 062818), SLC22A1 (OCT1; NP 003048), SLC22A2 (OCT2; NP 003049), SLC22A4 (OCTN1; NP 003050), SLC22A5 (OCTN2; NP 003051), SLC22A8 (OAT3; NP 004245), SLC36A1 (PAT 1 ; NP 510968), SLC36A1 (PAT 1 ; NP 510968), SLC36A2 (PAT2; NP_861441), SLC38A1 (SNAT1; NP 109599), SLC38A2 (SNAT2; NP_061849), SLC38A3 (SNAT3; NP_006832), SLC38A4 (SNAT4; NP_060488), SLC38A5 (SNAT5; NP_0277053), SLC43A1 (LAT3; NP_003618), and SLC43A2 (LAT4; NP_689559).

[0286] Human genes required for functional expression of a transporter of interest may be cloned using PCR, fully sequenced, and subcloned into plasmids that can be used for expression in mammalian cells or Xenopus laevis oocytes. Unless otherwise noted, all subunits of a transporter of interest are co-expressed in each heterologous system described in the examples. Because many mammalian cell lines exhibit high levels of amino acid transport activity, expression in Xenopus laevis oocytes can be advantageous due to the low levels of endogenous amino acid transport. To assess transport function of a specific transporter protein, it can be desirable to clone the cDNA and express the protein in cells that have low endogenous transport activity. Competition assays may be performed with labeled

compounds that are optimal substrates (reference substrates) for the transporter of interest. Typically, uptake levels of a test compound are compared to uptake of a reference substrate for the transporter of interest.

[0287] Compounds of Formula (1) are substrates for LATl/4F2hc and have a V _max of at least 10%, 20%, and in certain embodiments, at least 50% that of gabapentin. Concomitantly, the compounds have a low affinity toward amino acid transporters of system A, system N, system ASC, and the system L transporter LAT2/4F2hc.

[0288] Biodistribution studies with normal and tumor-bearing rats may be used to determine the disposition of actively transported compounds and the selectivity of substrate accumulation in tissue that expresses the LATl/4F2hc transporter compared with other tissue. Imaging techniques can qualitatively and quantitatively elucidate the role of transport proteins in drug disposition, for example, whole body autoradiography (WBA). WBA allows both the visualization and the quantification of radionuclide-labeled compound levels in a thin section of the whole animal. Information obtained using WBA is analogous to data obtained from diagnostic imaging, albeit at a single point in time.

Pharmaceutical Compositions

[0289] Compounds of Formula (1) or pharmaceutically acceptable salts thereof may be incorporated into pharmaceutical compositions to be administered to a patient by any appropriate route of administration including intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, peroral, sublingual, intracerebral, intravaginal, transdermal, rectal, inhalation, or topical. In certain embodiments,

pharmaceutical compositions provided by the present disclosure are injectable formulations. In certain embodiments, pharmaceutical compositions provided by the present disclosure are injectable intravenous formulations. In certain embodiments, pharmaceutical compositions provided by the present disclosure are oral formulations. Oral formulations may be oral dosage forms.

[0290] Pharmaceutical compositions provided by the present disclosure may comprise a therapeutically-effective amount of a compound of Formula (1) or a pharmaceutically acceptable salt thereof together with a suitable amount of one or more pharmaceutically acceptable vehicles so as to provide a composition for proper administration to a patient. Suitable pharmaceutical vehicles and methods of preparing pharmaceutical compositions are described in the art.

[0291] In certain embodiments, a compound of Formula (1) or a pharmaceutically acceptable salt thereof may be administered by intravenous injection. Suitable forms for injection include sterile aqueous solutions or dispersions of a compound of Formula (1). In certain embodiments, a compound may be formulated in a physiological buffer solution. Prior to administration, a compound of Formula (1) or a pharmaceutically acceptable salt thereof may be sterilized by any art recognized the technique, including addition of antibacterial or antifungal agents, for example, paraben, chlorobutanol, phenol, sorbic acid, thimersol, and the like. In certain embodiments, a compound of Formula (1) or a pharmaceutically acceptable salt thereof may be sterilized by filtration before administration to a subject thereby minimizing or eliminating the need for additional sterilization agents. An injectable dosage of a compound of Formula (1) may include from about 0.01 mL to about 10 mL, from about 0.1 mL to about 10 mL, from about 0.1 mL to about 5 mL, and in certain embodiments, from about 1 mL to about 5 mL. [0292] Pharmaceutical compositions may comprise a therapeutically effective amount of one or more compounds of Formula (1), preferably in purified form, together with a suitable amount of a pharmaceutically acceptable vehicle, so as to provide a form for proper administration to a patient. When administered to a patient, the compounds and

pharmaceutically acceptable vehicles are preferably sterile. Water is a preferred vehicle when the compound is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions may also be employed as liquid vehicles, particularly for injectable solutions. Suitable pharmaceutical vehicles also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. Pharmaceutical compositions may also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. In addition, auxiliary, stabilizing, thickening, lubricating and coloring agents may be used.

[0293] Pharmaceutical compositions comprising a compound may be manufactured by means of conventional mixing, dissolving, granulating, levitating, emulsifying, encapsulating, entrapping or lyophilizing processes. Pharmaceutical compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers, diluents;

excipients or auxiliaries, which facilitate processing of compounds into preparations, which can be used pharmaceutically. Proper formulation is dependent upon the route of

administration chosen.

[0294] Pharmaceutical compositions provided by the present disclosure may take the form of solutions, suspensions, emulsion, or any other form suitable for use. Examples of suitable pharmaceutical vehicles are described in the art.

[0295] For parenteral administration, compounds of Formula (1) may be incorporated into a solution or suspension. Parenteral administration refers to the administration by injection, for instance by intravenous, intracapsular, intrathecal, intrapleural, intratumoral, or intraperitoneal injection or intravesically. In certain embodiments, a compound of Formula (1) is administered intravenously.

[0296] A solution or suspension may also comprise at least one of the following adjuvants: sterile diluents such as water for injection, saline, fixed oils, polyethylene glycols, glycerol, propylene glycol or other synthetic solvents, antioxidants such as ascorbic acid or sodium bisulfite, buffers such as acetates, citrates or phosphates, and agents for adjustment of the tonicity such as sodium chloride or dextrose. A parenteral preparation may be enclosed into ampoules, disposable syringes or multiple dosage vessels made of glass or plastic. [0297] For topical administration, a compound of Formula (1) may be formulated as a solution, gel, ointment, cream, suspension, etc. For transmucosal administration, penetrants appropriate to the barrier to be permeated may be used in the formulation. Such penetrants are generally known in the art. Systemic formulations include those designed for

administration by injection, e.g., subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as those designed for transdermal, transmucosal, oral or pulmonary administration. Systemic formulations may be made in combination with a further active agent that improves mucociliary clearance of airway mucus or reduces mucous viscosity. These active agents include, for example, sodium channel blockers, antibiotics, N- acetyl cysteine, homocysteine, sodium 2-mercaptoethane sulfonate (MESNA), and phospholipids.

[0298] When a compound is acidic or basic it may be included in any of the above- described formulations as the free acid or free base, a pharmaceutically acceptable salt, a solvate of any of the foregoing, or a hydrate of any of the foregoing. Pharmaceutically acceptable salts substantially retain the activity of the free acid or base, may be prepared by reaction with bases or acids, and tend to be more soluble in aqueous and other protic solvents than the corresponding free acid or base form.

[0299] Assessing single patient response to therapy and qualifying a patient for optimal therapy are among the greatest challenges of modern healthcare and relate to trends in personalized medicine. The novel β-substituted γ-amino acid derivatives and β-substituted γ- amino acid analogs provided by the present disclosure have a high selectivity for

LATl/4F2hc. Radio-labeled compounds for positron emission tomography (PET) or Single Photon Emission Computed Tomography (SPECT) with the same selectivity toward

LATl/4F2hc may be used to predict the efficacy of the treatment based on a single-study, case-by-case patient analysis thus excluding subjects that are expected not to benefit from treatment. PET/SPECT scans using radiolabeled LATl/4F2hc selective substrates, once correlated to the concentration β-substituted γ-amino acid derivatives or β-substituted γ- amino acid analogs of Formula (1) can provide a three-dimensional distribution map, which can then be used for macroscopic dose calculations.

[0300] Accordingly, it is within the capability of those of skill in the art to assay and use the compounds of Formula (1) and/or pharmaceutical compositions thereof for therapy.

Therapeutic Dose

[0301] A compound of Formula (1) and/or pharmaceutical composition thereof will generally be used in an amount effective to achieve the intended purpose. For use to treat a disease such as cancer, a compound of Formula (1) and/or pharmaceutical compositions thereof, may be administered or applied in a therapeutically effective amount.

[0302] The amount of a compound of Formula (1) and/or pharmaceutical composition thereof that will be effective in the treatment of a particular disorder or condition disclosed herein will depend in part on the nature of the disorder or condition, and can be determined by standard clinical techniques known in the art. In addition, in vitro or in vivo assays may optionally be employed to help identify optimal dosage ranges. The amount of a compound of Formula (1) and/or pharmaceutical composition thereof administered will depend on, among other factors, the subject being treated, the weight of the subject, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.

[0303] A compound of Formula (1) may be assayed in vitro and in vivo, for the desired therapeutic activity, prior to use in humans. For example, in vitro assays may be used to determine whether administration of a specific compound or a combination of compounds is preferred. The compounds may also be demonstrated to be effective and safe using animal model systems.

[0304] In certain embodiments, a therapeutically effective dose of a compound of Formula (1) and/or pharmaceutical composition thereof will provide therapeutic benefit without causing substantial toxicity. Toxicity of compounds of Formula (1) and/or pharmaceutical compositions thereof may be determined using standard pharmaceutical procedures and may be readily ascertained by the skilled artisan. The dose ratio between toxic and therapeutic effect is the therapeutic index. In certain embodiments, a compound of Formula (1) and/or pharmaceutical composition thereof exhibits a particularly high therapeutic index in treating disease and disorders. In certain embodiments, a dose of a compound of Formula (1) and/or pharmaceutical composition thereof will be within a range of circulating concentrations that include an effective dose with minimal toxicity.

Kits

[0305] A compound of Formula (1), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any of the foregoing may be included in a kit that may be used to administer the compound to a patient for therapeutic purposes. A kit may include a pharmaceutical composition comprising a compound of Formula (1) suitable for

administration to a patient and instructions for administering the pharmaceutical composition to the patient. In certain embodiments, a kit for use in treating cancer in a patient comprises a compound of Formula (1) or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable vehicle for administering the compound, and instructions for administering the compound to a patient.

[0306] Instructions supplied with a kit may be printed and/or supplied, for example, as an electronic-readable medium, a video cassette, an audiotape, a flash memory device, or may be published on an internet web site or distributed to a patient and/or health care provider as an electronic communication.

Therapeutic Uses

[0307] Compounds of Formula (1) may be used for treating cancer in a patient, wherein the cancerous tissue expresses the LATl/4F2hc. In certain embodiments, the cancerous tissue expressing the LATl/4F2hc transporter is in the brain of the patient.

[0308] Compounds of Formula (1) may be used in the treatment of a wide variety of neoplasms where elevated LATl/4F2hc mediated uptake occurs. Compounds of Formula (1) are particularly useful for treating brain tumors, including metastases of other solid tumors, such as lung or breast cancer, in the brain.

[0309] In certain embodiments, a compound of Formula (1) or a pharmaceutical composition comprising a compound of Formula (1) may be administered to treat a cancer known to be treated by an alkylating agent, such as, for example, melphalan.

[0310] In certain embodiments, a compound of Formula (1) or a pharmaceutical composition comprising a compound of Formula (1) may be used to treat, for example, one or more of the following cancers: adult and childhood acute lymphoblastic leukemia (ALL), adult and childhood acute myeloid leukemia (AML), childhood adrenocortical carcinoma, a IDs-related cancers, a IDs-related lymphoma, anal cancer, appendix cancer, astrocytoma, childhood atypical teratoid/rhabdoid tumor, basal cell carcinoma (nonmelanoma), extrahepatic bile duct cancer, childhood bladder cancer, bone cancer, osteosarcoma, malignant fibrous histiocytoma, childhood craniopharyngioma, childhood brain stem glioma, adult and child brain tumor, childhood central nervous system embryonal tumors, childhood cerebellar astrocytoma, brain tumor, cerebral astrocytoma/malignant glioma, ductal carcinoma in situ, childhood ependymoblastoma, childhood ependymoma, childhood esthesioneuroblastoma, childhood medulloblastoma, childhood medulloepithelioma, childhood pineal parenchymal tumors of intermediate differentiation, supratentorial primitive neuroectodermal tumors and pineoblastoma, childhood visual pathway and hypothalamic glioma, childhood brain and spinal cord tumors, adult and childhood breast cancer, male breast cancer, childhood bronchial tumors, hematopoetic tumors of the lymphoid lineage, hematopoetic tumors of the myeloid lineage, burkitt lymphoma, childhood carcinoid tumor, gastrointestinal carcinoid tumor, carcinoma of head and neck, childhood central nervous system embryonal tumors, primary central nervous system lymphoma, childhood cerebellar astrocytoma, cerebral astrocytoma/malignant glioma, childhood cervical cancer, childhood cancers, childhood chordoma, chronic lymphocytic leukemia (CLL), chronic

myeloproliferative disorders, colorectal cancer, cutaneous t-cell lymphoma, childhood central nervous system embryonal tumors, desmoplastic small round cell tumor, endometrial cancer, childhood ependymoblastoma, childhood ependymoma, esophageal cancer, childhood esophageal cancer, ewing family of tumors, childhood extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, dye cancer, Intraocular melanoma, retinoblastoma, gallbladder cancer, gastric (stomach) cancer, childhood gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (gist), childhood gastrointestinal stromal cell tumor, childhood extracranial germ cell tumor, extragonadal germ cell tumor, ovarian germ cell tumor, gestational trophoblastic

tumor/disease, adult glioma, glioblastoma, childhood brain stem, childhood cerebral astrocytoma, childhood visual pathway and hypothalamic glioma, hairy cell leukemia, childhood heart cancer, head and neck cancer, childhood head and neck cancer, adult (primary) hepatocellular (liver) cancer, childhood (primary) hepatocellular (liver) cancer, adult Hodgkin lymphoma, childhood Hodgkin lymphoma, hypopharyngeal cancer, childhood hypothalamic and visual pathway glioma, intraocular melanoma, pancreatic neuroendocrine tumors (islet cell tumors), endocrine pancreas tumors (islet cell tumors), Kaposi sarcoma, kidney (renal cell) cancer, kidney cancer, laryngeal cancer, childhood laryngeal cancer, adult acute lymphoblastic leukemia, childhood acute lymphoblastic leukemia, adult acute myeloid leukemia, childhood acute myeloid leukemia, chronic myelogenous leukemia (cml), hairy cell leukemia, lip and oral cavity cancer, adult primary liver cancer, childhood primary liver cancer, non-small cell lung cancer, small cell lung cancer, a IDs-related lymphoma, Burkitt lymphoma, t-cell lymphoma, b-cell lymphoma, cutaneous t-cell lymphoma, adult Hodgkin lymphoma, childhood Hodgkin lymphoma, adult non-Hodgkin lymphoma, childhood non- Hodgkin lymphoma, primary central nervous system lymphoma, langerhans cell

histiocytosis, Waldenstrom macroglobulinemia, malignant fibrous histiocytoma of bone and osteosarcoma, childhood medulloblastoma, childhood medulloepithelioma, melanoma, intraocular (dye) melanoma, Merkel cell carcinoma, adult malignant mesothelioma, childhood mesothelioma, primary metastatic squamous neck cancer with occult, mouth cancer, myelodysplastic/ myeloproliferative neoplasms, midline tract carcinoma involving nUt gene, childhood multiple endocrine neoplasia syndrome, multiple myeloma/plasma cell neoplasm, mycosis fungoides, myelodysplasia syndromes myelodysplasia/

myeloproliferative diseases, chronic myelogenous leukemia, adult acute myeloid leukemia, childhood acute myeloid leukemia, multiple myeloma, chronic myeloproliferative disorders, malignant germ cell tumors, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, childhood nasopharyngeal cancer, neuroblastoma, adult non-Hodgkin lymphoma, childhood non-Hodgkin lymphoma, non-small cell lung cancer, childhood oral cancer, lip and oral cavity cancer, oropharyngeal cancer, osteosarcoma and malignant fibrous histiocytoma of bone, childhood ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential tumor, pancreatic cancer, childhood pancreatic cancer, islet cell tumors, childhood papillomatosis, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, childhood pineal parenchymal tumors of intermediate differentiation, childhood pineoblastoma and supratentorial primitive neuroectodermal tumors, pituitary tumor, paraganglioma, plasma cell neoplasm/multiple myeloma, pleuropulmonary blastoma, childhood pleuropulmonary blastoma, primary central nervous system (ens) lymphoma, pregnancy and breast cancer, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell (kidney) cancer, childhood renal cell (kidney) cancer, renal pelvis and ureter, transitional cell cancer, respiratory tract carcinoma involving the nUt gene on chromosome 15, retinoblastoma, childhood

rhabdomyosarcoma, salivary gland cancer, childhood salivary gland cancer, sarcoma (dwing family of tumors), Kaposi sarcoma, adult soft tissue sarcoma, childhood soft tissue sarcoma, uterine sarcoma, sezary syndrome, skin cancer (nonmelanoma), childhood skin cancer, melanoma, Merkel cell skin carcinoma, small cell lung cancer, small intestine cancer, adult soft tissue sarcoma, childhood soft tissue sarcoma, squamous cell carcinoma (nonmelanoma), primary and metastatic squamous neck cancer with occult, stomach (gastric) cancer, childhood stomach (gastric) cancer, childhood supratentorial primitive neuroectodermal tumors, cutaneous t-cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, childhood thymoma and thymic carcinoma, thyroid cancer, childhood thyroid cancer, gestational trophoblastic tumor, adult unknown primary site, carcinoma of, childhood cancer of unknown primary site, unusual cancers of childhood, transitional cell cancer of ureter and renal pelvis, urethral cancer, endometrial uterine cancer, uterine sarcoma, vaginal cancer, childhood vaginal cancer, childhood visual pathway and hypothalamic glioma, vulvar cancer, Waldenstrom macroglobulinemia, Wilms tumor, and women's cancers.

[0311] In certain embodiments, a compound of Formula (1) or a pharmaceutical composition comprising a compound of Formula (1) may be used to treat, for example, one or more of the following cancers wherein the cancer is selected from any of the primary adult and childhood brain and CNS cancers including glioblastoma (GBM) and astrocystoma, skin cancers including melanoma, lung cancers including small cell lung cancers, non-small cell lung cancers (NSCLC), and large cell lung cancers, breasts cancers including triple negative breast cancer (TNBC), blood cancers including myelodysplasia syndrome (MDS), multiple myeloma (MM), and acute myeloid leukemia (AML), prostate cancer including castrate resistant prostate cancer (CRPC), liver cancers including hepatocellular carcinoma (HCC), esophageal and gastric cancers, and any systemic and central metastases of any of the foregoing.

[0312] Compounds of Formula (1) maybe used to treat a cancer in which there is differential LATl/4F2hc transport activity relative to surrounding tissue and/or tissue in other body organs. Patients having a tumor exhibiting a greater LATl/4F2hc transport activity than non-diseased tissue are expected to respond more favorably to treatment with a therapeutic agent that is a substrate for the LATl/4F2hc transporter and to experience fewer adverse effects associated with the effects of the therapeutic agent on non-diseased tissue.

Compounds of Formula (1) are therapeutic agents, are substrates for the LATl/4F2hc transporter, and exhibit cytotoxicity.

[0313] The amount of a compound of Formula (1) that will be effective in the treatment of a cancer will depend, at least in part, on the nature of the disease, and may be determined by standard clinical techniques known in the art. In addition, in vitro or in vivo assays may be employed to help identify optimal dosing ranges. Dosing regimens and dosing intervals may also be determined by methods known to those skilled in the art. The amount of compound of Formula (1) administered may depend on, among other factors, the subject being treated, the weight of the subject, the severity of the disease, the route of administration, and the judgment of the prescribing physician.

[0314] For systemic administration, a therapeutically effective dose may be estimated initially from in vitro assays. Initial doses may also be estimated from in vivo data, e.g., animal models, using techniques that are known in the art. Such information may be used to more accurately determine useful doses in humans. One having ordinary skill in the art may optimize administration to humans based on animal data.

[0315] A dose of compound of Formula (1) and appropriate dosing intervals may be selected to maintain a sustained therapeutically effective concentration of the compound of Formula (1) in the blood of a patient, and in certain embodiments, without exceeding a minimum adverse concentration. [0316] In certain embodiments, pharmaceutical compositions comprising a compound of Formula (1) may be administered once per day, twice per day, and in certain embodiments at intervals of more than once per day. Dosing may be provided alone or in combination with other drugs and may continue as long as required for effective treatment of the disease. Dosing may also be undertaken using continuous or semi-continuous administration over a period of time. Dosing includes administering a pharmaceutical composition to a mammal, such as a human, in a fed or fasted state.

[0317] A pharmaceutical composition may be administered in a single dosage form or in multiple dosage forms or as a continuous or an accumulated dose over a period of time.

When multiple dosage forms are used the amount of compound of Formula (1) contained within each of the multiple dosage forms may be the same or different.

[0318] Suitable daily dosage ranges for administration may range from about 2 mg to about 50 mg of a compound of Formula (1) per kilogram body weight.

[0319] Suitable daily dosage ranges for administration may range from about 1 mg to about 100 mg of a compound of Formula (1) per square meter (m ² ) of body surface.

[0320] In certain embodiments, a compound of Formula (1) may be administered to treat cancer in a subject in an amount from about 50 mg to about 2,000 mg per day, from about

100 mg to about 1,500 mg per day, from about 200 mg to about 1,000 mg per day, or in any other appropriate daily dose.

[0321] In certain embodiments, pharmaceutical compositions comprising a compound of Formula (1) may be administered to treat cancer in a subject so as to provide a therapeutically effective concentration of a compound of Formula (1) in the blood or plasma of the subject. In certain embodiments, a therapeutically effective concentration of a compound of Formula (1) in the blood or plasma of a subject is from about 1 μg/mL to about 60 μg/mL, from about 2 μg/mL to about 50 μg/mL, from about 5 μg/mL to about 40 μg/mL, from about 5 μg/mL to about 20 μg/mL, and in certain embodiments, from about 5 μg/mL to about 10 μg/mL. In certain embodiments, a therapeutically effective concentration of a compound of Formula (1) in the blood or plasma of a subject is at least about 2 μg/mL, at least about 5 μg/mL, at least about 10 μg/mL, at least about 15 μg/mL, at least about 25 μg/mL, and in certain

embodiments, at least about 30 μg/mL. In certain embodiments, a therapeutically effective concentration of a compound of Formula (1) in the blood or plasma of a subject is less than an amount that causes unacceptable adverse effects including adverse effects to homeostasis. In certain embodiments, a therapeutically effective concentration of a compound of Formula (1) in the blood or plasma of a subject is an amount sufficient to restore and/or maintain homeostasis in the subject.

[0322] In certain embodiments, pharmaceutical compositions comprising a compound of Formula (1) may be administered to treat cancer in a subject so as to provide a therapeutically effective concentration of a compound of Formula (1) in the blood or plasma of a subject for an extended period of time such as, for example, for at least about 4 hours, for at least about 6 hours, for at least about 8 hours, for at least about 10 hours, and in certain embodiments, for at least about 12 hours.

[0323] The amount of a compound of Formula (1) administered may vary during a treatment regimen.

[0324] Pharmaceutical compositions provided by the present disclosure may further comprise one or more pharmaceutically active compounds in addition to a compound of Formula (1). Such compounds may be provided to treat the cancer being treated with the compound of Formula (1) or to treat a disease, disorder, or condition other than the cancer being treated with the compound of Formula (1).

[0325] In certain embodiments, a compound of Formula (1) may be used in combination with at least one other therapeutic agent. In certain embodiments, a compound of Formula (1) may be administered to a patient together with another compound for treating cancer in the subject. In certain embodiments, the at least one other therapeutic agent may be a different compound of Formula (1). A compound of Formula (1) and the at least one other therapeutic agent may act additively or, and in certain embodiments, synergistically. The at least one additional therapeutic agent may be included in the same pharmaceutical composition or vehicle comprising the compound of Formula (1) or may be in a separate pharmaceutical composition or vehicle. Accordingly, methods provided by the present disclosure further include, in addition to administering a compound of Formula (1), administering one or more therapeutic agents effective for treating cancer or a different disease, disorder or condition than cancer. Methods provided by the present disclosure include administration of a compound of Formula (1) and one or more other therapeutic agents provided that the combined administration does not inhibit the therapeutic efficacy of a compound of Formula (1) and/or does not produce adverse combination effects.

[0326] In certain embodiments, pharmaceutical compositions comprising a compound of Formula (1) may be administered concurrently with the administration of another therapeutic agent, which may be part of the same pharmaceutical composition as, or in a different pharmaceutical composition than that comprising a compound of Formula (1). A compound of Formula (1) may be administered prior or subsequent to administration of another therapeutic agent. In certain embodiments of combination therapy, the combination therapy may comprise alternating between administering a compound of Formula (1) and a composition comprising another therapeutic agent, e.g., to minimize adverse drug effects associated with a particular drug. When a compound of Formula (1) is administered concurrently with another therapeutic agent that potentially may produce an adverse drug effect including, for example, toxicity, the other therapeutic agent may be administered at a dose that falls below the threshold at which the adverse drug reaction is elicited.

[0327] In certain embodiments, pharmaceutical compositions comprising a compound of Formula (1) may be administered with one or more substances to enhance, modulate and/or control release, bioavailability, therapeutic efficacy, therapeutic potency, stability, and the like of a compound of Formula (1). For example, to enhance the therapeutic efficacy of a compound of Formula (1), a compound of Formula (1) or a pharmaceutical composition comprising a compound of Formula (1) may be co-administered with one or more active agents to increase the absorption or diffusion of the compound of Formula (1) from the gastrointestinal tract to the systemic circulation, or to inhibit degradation of the compound of Formula (1) in the blood of a subject. In certain embodiments, a pharmaceutical composition comprising a compound of Formula (1) may be co-administered with an active agent having pharmacological effects that enhance the therapeutic efficacy of the compound of Formula (1).

[0328] In certain embodiments, a compound of Formula (1) or a pharmaceutical composition comprising a compound of Formula (1) may be administered in conjunction with an agent known or believed to be effective in treating cancer in a patient.

[0329] For example, in certain embodiments, a compound of Formula (1) or a

pharmaceutical composition comprising a compound of Formula (1) may be administered in conjunction with another chemotherapeutic agents, such as, for example, N-acetyl cysteine (NAC), adriamycin, alemtuzumab, amifostine, arsenic trioxide, ascorbic acid, bendamustine, bevacizumab, bortezomib, busulfan, buthionine sulfoxime, carfilzomib, carmustine, clofarabine, cyclophosphamide, cyclosporine, cytarabine, dasatinib, datinomycin, defibrotide, dexamethasone, docetaxel, doxorubicin, etoposide, filgrastim, floxuridine, fludarabine, gemcitabine, interferon alpha, ipilimumab, lenalidomide, leucovorin, melphalan,

mycofenolate mofetil, paclitaxel, palifermin, panobinostat, pegfilrastim, prednisolone, prednisone, revlimid, rituximab, sirolimus, sodium 2-mercaptoethane sulfonate (MESNA), sodium thiosulfate, tacrolimus, temozolomide, thalidomide, thioguanine, thiotepa, topotecan, velcade, or a combination of any of the foregoing. In certain embodiments, a compound of Formula (1) and/or pharmaceutical compositions thereof can be used in combination therapy with other chemotherapeutic agents including one or more antimetabolites such as folic acid analogs; pyrimidine analogs such as fluorouracil, floxuridine, and cytosine arabinoside;

purine analogs such as mercaptopurine, thiogunaine, and pentostatin; natural products such as vinblastine, vincristine, etoposide, tertiposide, dactinomycin, daunorubicin, doxurubicin, bleomycin, mithamycin, mitomycin C, L-asparaginase, and interferon alpha; platinum coordination complexes such as cis-platinum, and carboplatin; mitoxantrone; hydroxyurea; procarbazine; hormones and antagonists such as prednisone, hydroxyprogesterone caproate, medroxyprogesterone acetate, megestrol acetate, diethylstilbestrol, ethinyl estradiol, tamoxifen, testosterone propionate, fluoxymesterone, flutamide, and leuprolide, anti- angiogenesis agents or inhibitors such as angiostatin, retinoic acids, paclitaxel, estradiol derivatives, and thiazolopyrimidine derivatives; apoptosis prevention agents; and radiation therapy.

[0330] In certain embodiments, a compound of Formula (1) may be coadministered with a compound that inhibits DNA repair such as, for example, 06-benzylguanine (06-BG).In certain embodiments, a compound of Formula (1) may be coadministred with a compound that blocks and/or inhibits transporters other than LAT1 such as, for example, amino acids. In certain embodiments, compounds of Formula (1) may be administered to a patient together with one or more amino acids such as, for example, arginine (Arg), serine (Ser), lysine (Lys), asparagine (Asn), glutamine (Gin), threonine (Thr), or mixtures of any of the foregoing. In certain embodiments, co-aministration of amino acids is intended to saturate amino acid transporters that interact with compounds of Formula (1) and thereby increase the selectivity for L ATI .

[0331] The efficacy of administering a compound of Formula (1) for treating cancer may be assessed using in vitro and animal studies and in clinical trials.

[0332] The suitability of compounds of Formula (1) and/or pharmaceutical compositions thereof in treating cancers listed above may be determined by methods described in the art. For example, screens developed to demonstrate the anti-tumor activity of oncolytic agents are known (Miller, et al, J Med Chem, 1977, 20(3), 409-413; Sweeney, et al, Cancer Res, 1978, 38(9), 2886-2891; and Weiss and Von Hoff, Semin Oncol, 1985, 12(3 Suppl 4), 69-74). Accordingly, it is well with the capability of those of skill in the art to assay and use the compounds and/or pharmaceutical compositions thereof to treat the above diseases or disorders. [0333] Methods provided by the present disclosure have use in animals, including mammals, such as in humans.

General Experimental Protocols

[0334] All reagents and solvents were purchased from commercial suppliers and used without further purification or manipulation.

[0335] Proton NMR spectra were recorded on a Varian Mercury Plus300 MHz

Spectrometer equipped with an Oxford magnet, a Sun Sunblade 150 host computer, a Solaris operating system, VNMR data processing software, and a HP LaserJet printer. CDC1 ₃ (99.8% D), MeOH-d ⁴ (CD ₃ OD, 99.8+% D), deuteroxide (D ₂ 0) (99.8+% D) were used as recording solvents unless otherwise noted. The CHCI ₃ , MeOH-d ³ , HDO solvent signals or

tetramethylsilane (TMS) were used for calibration of the individual spectra.

[0336] Analytical thin layer chromatography (TLC) was performed using EMD Millipore aluminum-backed TLC sheets (EMD5554-7) pre-coated with silica gel 60 F254 (200 μιη thickness, 60 A pore size) where F254 is a fluorescent indicator with a 254 nm excitation wavelength. An ENF-240C Spectroline ^® UV-lamp (Spectronics Corporation, USA) was used for TLC detection and visualization. Dyeing or staining reagents for TLC detection and visualization, e.g., an ethanolic ninhydrin solution or a 0.2 wt-% aqueous potassium permanganate (KMn0 ₄ ) solution, were prepared according methods known in the art.

[0337] Analytical LC/MS was performed on a Shimadzu LC/MS-2020 Prominence Series system equipped with CBM-20A communication bus module (Shimadzu 228-45012- 32), a SPD-20AV UV/VIS detector (Shimadzu 228-45004-32), a SIL-20AC autosampler (Shimadzu 228-45136-32), DGU-20A5 degasser (Shimadzu 228-45019-32), two LC-20AD XP HPLC pumps (Shimadzu 228-45137-32), an Agilent Zorbax 5 μιη XDB-C18 2.1 50 mm column (Agilent 960 967-902), and a commercial desktop computer and printer for data computation. Gradients of water (solvent A) (Arrowhead, Nestle North America, Inc.) and acetonitrile (MeCN; solvent B) (EMD AX0145-1 or Aldrich CHROMASOLV ^® 439134) containing 0.075 vol-% of formic acid (EMD FX0440-7) were used in analytical LC/MS analyses.

[0338] Analytical LC/UV was performed on an Agilent 1100 Series system equipped with an Agilent 1100 Series degasser (Agilent G1379A), an Agilent 1100 Series quad pump (Agilent G1311A), an Agilent 1100 Series autosampler (ALS) (Agilent G1329A), an Agilent 1100 Series COLCOM (Agilent G1316A), a Phenomenex Gemini C18 5 μιη 110 A pore size 150 x 4.6 mm HPLC column (Phenomenex 00F-4435-E0), a Compaq Presario personal computer, and a HP LaserJet P2015 printer for data computation. Gradients of water (solvent A) (Arrowhead, Nestle North America, Inc.) and acetonitrile (MeCN; solvent B) (EMD AX0145-1 or Aldrich CHROMASOLV ^® 439134) containing 0.075 vol-% of formic acid (EMD FX0440-7) were used in analytical LC/UV analyses.

[0339] Preparative HPLC was conducted with a Varian ProStar Series system equipped with a Model 340 UV-C UV-VIS detector, a Model 210 solvent delivery module, a Hamilton PRP-112-20 μιη 100 A 21.2 x 250 mm preparative HPLC column (Hamilton 79428), and a commercial desktop personal computer for data computation. Gradients of water (solvent A) (Arrowhead, Nestle North America, Inc.) and acetonitrile (MeCN; solvent B) (EMD

AX0145-1 or Aldrich CHROMASOLV ^® 439134) containing 0.1 vol-% of formic acid (EMD FX0440-7) were used for preparative HPLC purifications.

[0340] Compound isolation from aqueous solvent mixtures, e.g., acetonitrile/water/0.1 vol-% formic acid, was accomplished by primary lyophilization of pooled and frozen (after freeze drying) fractions under reduced pressure at room temperature using manifold freeze dryers such as Heto Drywinner DW 6-85-1, Heto FD4, or VIRTIS Freezemobile 25 ES equipped with a high vacuum pump. Optionally, and if the isolated compound had ionizable functional groups such as an amino group or a carboxylic acid, the lyophilization process was conducted in the presence of an excess (about 1.1 to 5.0 equivalents) of 1.0 M hydrochloric acid (HC1) to yield the purified compound(s) as the corresponding hydrochloride salt (HC1- salt), dihydrochloride salts, and/or the corresponding protonated free carboxylic acid. Melting points were determined in duplicate with a SRS OptiMelt MPA-100 automated melting point system with digital imaging processing technology and are uncorrected (Stanford Research Systems, USA).

[0341] Filtrations were conducted using commercial Celite ^® 545 (EMD CX0574-1) which was compressed in to glass Buchner-funnels to create a plug of 2-5 cm thickness. Reaction mixtures containing precipitated reaction side products or heterogenous catalyst residues were filtered off using standard techniques. Care must be taken filtering off activated catalysts or finely dispersed metals (ignition!).

[0342] Unless otherwise noted, aqueous work-up typically constitutes dilution of a crude reaction product, with or without residual reaction solvent, with 1.0 M hydrochloric acid (HC1) or a saturated aqueous solution of ammonium chloride (NH ₄ C1), multiple extraction with an organic solvent, e.g., ethyl acetate (EtOAc), diethyl ether (Et ₂ 0), or dichloromethane (DCM), washing with water, a saturated aqueous solution of sodium hydrogencarbonate (NaHC0 ₃ ), and brine (saturated aqueous solution of sodium chloride (NaCl)), drying of the organic phase (combined organic extracts) over anhydrous magnesium sulfate (MgS0 ₄ ) (EMD MX0075-1) or sodium sulfate (Na ₂ S0 ₄ ) (EMD SX0760E-3), filtration, washing of the filter residue, and evaporation of the combined filtrates under reduced pressure using a rotary evaporator at room or elevated temperature followed by compound purification e.g., silica gel column chromatography, crystallization or titruation.

[0343] Silica gel column chromatography was conducted with silica gel (about 100-200 mL silica gel per gram of compound) 600.04-0.063 mm (40-63 μιη, 230-400 mesh) (EMD Millipore EMI .09385.9026/ EM1.09385.1033/EM1.09385.2503) using single solvents or mixtures of suitable solvents, e.g., ethyl acetate (EtOAc) and hexane or dichloromethane (DCM) and methanol (MeOH), as determined by TLC. Samples/fractions containing desired product detected by analytical TLC and/or analytical LC/MS, or LC/UV were pooled and the solvents were removed under reduced pressure using a Heidolph Laborota 4001 Efficient rotary evaporator (Heidolph, Germany) (Heidolph 519-10000-01-5) equipped with a HB digit heating bath (Heidolph 517-01002-01-4), and a Rotavac valve control vacuum pump

(Heidolph 591-00130-01-0).

[0344] Chemical names were generated using the ChemDraw Ultra 12.0 (CambridgeSoft, Cambridge, MA, USA) nomenclature program.

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