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  • C07C233/35—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
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  • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
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  • C07C237/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
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  • C07C237/30—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to hydrogen atoms or to acyclic carbon atoms
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  • C07C271/46—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by halogen atoms or by nitro or nitroso groups
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  • C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
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  • C07F9/28—Phosphorus compounds with one or more P—C bonds
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  • C07F9/32—Esters thereof
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  • C07F9/4816—Acyclic saturated acids or derivatices which can have further substituents on alkyl

Definitions

• ⁇ -substituted ⁇ -amino acids ⁇ -substituted ⁇ -amino acid derivatives
• ⁇ -substituted ⁇ -amino acid analogs and their use as therapeutic agents.
• the ⁇ -substituted ⁇ -amino acid derivatives and ⁇ -substituted ⁇ -amino acid analogs are selective substrates for LATl/4F2hc and exhibit rapid uptake and retention in tissue such as tumors expressing the LATl/4F2hc transporter.
• Pharmaceutical compositions comprising the ⁇ - substituted ⁇ -amino acid derivatives and ⁇ -substituted ⁇ -amino acid analogs and uses thereof are also disclosed.
• 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.
• 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.
• 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).
• BCH 2-amino-bicyclo[2,2,l]heptane-2-carboxylic acid
• 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).
• LATl/4F2hc 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).
• LATl/4F2hc has been used as an independent factor to predict poor prognoses in patients with astrocytic brain tumors, lung cancer, and prostate cancer
• NaOKAI 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
• Sakata et al, Pathol Int, 2009, 59(1), 7-18.
• melphalan is an effective chemotherapy drug used in treating multiple myeloma, ovarian cancer, retinoblastoma, and other hematopoietic tumors.
• melphalan is an alkylating agent linked to the essential amino acid phenylalanine.
• 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).
• BCH 2-amino-bicyclo[2,2,l]heptane-2-carboxylic acid
• 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).
• 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).
• 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 ⁇ -substituted ⁇ -amino acid derivatives and ⁇ -substituted ⁇ -amino acid analogs 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.
• Embodiments provided by the present disclosure provide novel ⁇ -substituted ⁇ - amino acid derivatives and ⁇ -substituted ⁇ -amino acid analogs, and methods of using such derivatives, for example, as chemotherapeutic agents. Certain embodiments further relate to methods of synthesizing ⁇ -substituted ⁇ -amino acid derivatives and ⁇ -substituted ⁇ -amino acid analogs and to pharmaceutical compositions comprising such derivatives.
• the ⁇ - substituted ⁇ -amino acid derivatives and ⁇ -substituted ⁇ -amino acid analogs 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 expressing the
• LATl/4F2hc transporter and further serve as chemotherapeutic agents.
• cycloalkyloxy substituted C3-6 cycloalkyloxy, C 4-12 cycloalkylalkyl, substituted C 4-12 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 C3-6 heterocycloalkyl, C 4-12 heterocycloalkylalkyl, substituted C 4-12 heterocycloalkylalkyl, C 5-10 heteroaryl, substituted C 5-10 heteroaryl, C 6-1 6 heteroarylalkyl, and substituted C 6-1 6 heteroarylalkyl;
• 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, C3-6 cycloalkyl, substituted C3-6 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 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
• Ci_ 6 heteroalkoxy substituted Ci_ 6 heteroalkoxy, C3-6 cycloalkyl, substituted C3-6 cycloalkyl, C3-6 cycloalkyloxy, substituted C3-6 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;
• a is selected from 0, 1, 2, 3, and 4.
• chemotherapeutic moieties are provide wherein the
• chemotherapeutic moiety may be any suitable 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 ⁇ -amino acid derivative, ⁇ -amino acid analog, or ⁇ - 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 ⁇ -amino acid derivative, ⁇ -amino acid analog, or ⁇ -amino acid carboxylic acid (bio)isostere is simultaneous a selective substrate for the LATl/4F2hc transporter.
• chemotherapeutic moieties of Formula (2) are provided:
• 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 + (-O (-C(R 11 ) 2 -C(R 11 ) 2 -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 (-OSO 2 R 40 , wherein R 40 is selected from Ci_ 4 alkyl), Ci_ 4 (per)fluoroalklyl sulfonate (-OSO 2 R 40 , wherein R 40 is selected from Ci_ 4 (per)fluoroalkyl), and (substituted) aryl sulfonate (-OSO 2 R 40 , wherein R 40 is selected from C 6-1 o aryl).
• compositions comprising the compound of claim
• 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.
• 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.
• 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.
• an alkyl group is Ci_ 6 alkyl, Ci_ 5 alkyl, Ci_ 4 alkyl, Ci_ 3 alkyl, and in certain embodiments, ethyl or methyl.
• alkylsulfanyl also referred to as “alkylthio”, refers to a radical -SR where R is alkyl or cycloalkyl as defined herein.
• alkylsulfanyl groups include
• Alkylsulfinyl refers to a radical -S(0)R where R is alkyl or cycloalkyl as defined herein.
• alkylsulfinyl groups include methylsulfinyl, ethylsulfinyl, propylsulfmyl, isopropylsulfmyl, butylsulfmyl, and cyclohexylsulfmyl.
• an alkylsulfinyl group is Ci_ 6 alkylsulfinyl, in certain embodiments, Ci_ 5 alkylsulfinyl, in certain embodiments, Ci_ 4 alkylsulfinyl, in certain embodiments, Ci_ 3 alkylsulfinyl, in certain embodiments, ethylsulfmyl, and in certain embodiments,
• Alkylsulfonyl refers to a radical -S(0) 2 R where R is alkyl or cycloalkyl as defined herein.
• alkylsulfonyl groups include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, and cyclohexylsulfonyl.
• 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.
• 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.
• 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.
• 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.
• the radical carbon atom may be at the carbocyclic aromatic ring or at the heterocycloalkyl ring.
• 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.
• an arylalkyl group is C 7 _9 arylalkyl, wherein the alkyl moiety is Ci_ 3 alkyl and the aryl moiety is phenyl.
• 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.
• 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).
• 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
• 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.
• Compounds of Formula (1) and moieties of Formula (2) 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.
• 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.
• Compounds of Formula (1) and moieties of Formula (2) include optical isomers of compounds of Formula (1) and moieties of Formula (2), racemates thereof, and other mixtures thereof.
• 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
• compounds of Formula (1) include (Z)- and (E)-forms (or cis- and trans-forms) of compounds with double bonds either as single geometric isomers or mixtures thereof.
• Compounds of Formula (1) and moieties of Formula (2) 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
• Compounds of Formula (1) are also referred to herein as ⁇ -substituted ⁇ -amino acid derivatives and/or as ⁇ -substituted ⁇ -amino acid analogs.
• chemotherapeutic moiety refers to a moiety effective in treating cancer including, any of those disclosed herein.
• a chemotherapeutic moiety may be any suitable chemotherapeutic moiety of achemotherapeutic drugs known in the art that retains cytotoxic activity when bonded either directly or indirectly through a suitable spacing moiety to a ⁇ -amino acid derivative, ⁇ -amino acid analog, or ⁇ -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 ⁇ -amino acid derivative, ⁇ -amino acid analog, or ⁇ -amino acid carboxylic acid (bio)isostere is simultaneous a selective substrate for the LATl/4F2hc transporter.
• 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 + (-O (-C(R 11 ) 2 -C(R 11 ) 2 -R 9 ) 2 );
• each R 11 is independently selected from hydrogen, deuterio, and Ci_ 3 alkyl
• each R 9 is independently selected from fluoro (-F), chloro (-C1), bromo (-Br), iodo (-1), alkyl sulfonate (-OS0 2 R 4 °, wherein R 40 is selected from Ci_ 4 alkyl), Ci_ 4 (per)fluoroalklyl sulfonate (-OSO 2 R 40 , wherein R 40 is selected from Ci_ 4 (per)fluoroalkyl), and (substituted) aryl sulfonate (-OSO 2 R 40 , wherein R 40 is selected from C 6-1 o aryl).
• Cycloalkyl refers to a saturated or partially unsaturated cyclic alkyl radical.
• 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.
• a cycloalkylalkyl group is C 4 _ 30 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 _2o, and in certain embodiments, an cycloalkylalkyl group is C 4 _2o cycloalkylalkyl, e.g., the alkanyl, alkenyl, or alkynyl moiety of the cycloalkylalkyl group is Ci_g and the cycloalkyl moiety of the cycloalkylalkyl group is C 3 _i 2 . In certain embodiments, cycloalkylalkyl is C 4 _9
• 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.
• specific alkyl moieties are intended, the nomenclature cycloalkylheteroalkanyl, cycloalkylheteroalkenyl, and cycloalkylheteroalkynyl is used.
• Cycloalkyloxy refers to a radical -OR where R is cycloalkyl as defined herein.
• Examples of cycloalkyloxy groups include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy.
• 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.
• Disease refers to a disease, disorder, condition, or symptom of any of the foregoing.
• Fluoroalkyl refers to an alkyl group as defined herein in which one or more of the hydrogen atoms is replaced with a fluoro.
• a fluoroalkyl group is Ci_6 fluoroalkyl, Ci_ 5 fluoroalkyl, Ci_ 4 fluoroalkyl, and Ci_ 3 fluoroalkyl.
• the fluoroalkyl group is pentafluoroethyl (-CF 2 CF 3 ), and in certain
• trifluoromethyl (-CF 3 ).
• Fluoroalkoxy refers to an alkoxy group as defined herein in which one or more of the hydrogen atoms is replaced with a fluoro.
• a fluoroalkoxy group is Ci_6 fluoroalkoxy, Ci_ 5 fluoroalkoxy, Ci_ 4 fluoroalkoxy C 1-3 , or fluoroalkoxy, and in certain embodiments, -OCF 2 CF 3 or -OCF 3 .
• ⁇ -Substituted ⁇ -amino acid analog refers to ⁇ -substituted ⁇ -amino acid derivatives in which the carboxyl group is replaced with a phosphinic acid group, a sulfuric acid group, or others, e.g., 3-aminopropylphosphinic acids, 3-aminopropylsulfmic acids, and others.
• Halogen refers to a fluoro, chloro, bromo, or iodo group.
• Heteroalkoxy refers to an alkoxy group in which one or more of the carbon atoms are replaced with a heteroatom.
• 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.
• 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-.
• a heteroalkoxy group is Ci_ 6 heteroalkoxy, Ci_ 5 heteroalkoxy, Ci_ 4 heteroalkoxy, and in certain embodiments Ci_ 3 heteroalkoxy.
• 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.
• 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.
• Ci_ 6 heteroalkyl includes groups having five carbon atoms and one heteroatom, groups having four carbon atoms and two heteroatoms, etc.
• the heteroatomic group is selected from -0-, -S-, -NH-, -N(-CH 3 )-, -SO-,and -S0 2 -, in certain
• the heteroatomic group is selected from -O- and -NH-, and in certain embodiments, the heteroatomic group is -O- or -NH-.
• a heteroalkyl group is Ci_6 heteroalkyl, Ci_ 5 heteroalkyl, or Ci_ 4 heteroalkyl, and in certain embodiments, Ci_ 3 heteroalkyl.
• 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.
• heteroaryl encompasses bicyclic rings in which one ring is heteroaromatic and the second ring is a heterocycloalkyl ring.
• the radical carbon may be at the aromatic ring or at the heterocycloalkyl ring.
• the heteroatoms 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-.
• 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 and C 6 heteroaryl.
• 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,
• heteroaryl groups are those derived from thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole, oxazole, or pyrazine.
• heteroaryl is C 5 heteroaryl and is selected from furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, or isoxazolyl.
• heteroaryl is C 6 heteroaryl, and is selected from pyridinyl, pyrazinyl, pyrimidinyl, and pyridazinyl.
• Heteroarylalkyl refers to an arylalkyl group in which one of the carbon atoms (and certain associated hydrogen atoms) is replaced with a heteroatom.
• 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.
• heteroatoms to replace the carbon atom(s) include N, P, O, S, and Si.
• 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.
• heterocycloalkyl is C 6 heterocycloalkyl and is selected from piperidinyl, tetrahydropyranyl, piperizinyl, oxazinyl, dithianyl, and dioxanyl.
• a heterocycloalkyl group is C3-6 heterocycloalkyl, C3-5 heterocycloalkyl, C5-6 heterocycloalkyl, and in certain embodiments, C 5 heterocycloalkyl or C 6 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-.
• Heterocycloalkylalkyl refers to a cycloalkylalkyl group in which one or more carbon atoms (and certain associated hydrogen atoms) of the cycloalkyl ring are
• the heterocycloalkylalkyl is C 4 _i 2 heterocycloalkylalkyl, C 4 _io heterocycloalkylalkyl, C 4 _8 heterocycloalkylalkyl, C 4 _ 6 heterocycloalkylalkyl, or C 6 _ 7 heterocycloalkylalkyl, and in certain embodiments, C 6 heterocycloalkylalkyl or C 7 heterocycloalkylalkyl.
• Mesyl refers to the group -OS(0) 2 Me or -OMs.
• Parent aromatic ring system refers to an unsaturated cyclic or polycyclic ring system having a cyclic conjugated ⁇ (pi) electron system with 4n+2 electrons (Huckel 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.
• 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.
• 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 ⁇ -electron system characteristic of aromatic systems and a number of ⁇ -electrons corresponding to the Huckel rule (4n +2).
• heteroatoms to replace the carbon atoms include N, P, O, S, and Si, etc.
• 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.
• 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;
• L is -(X) a -, wherein,
• R 5 comprises a chemotherapeutic moiety.
• the conjugate or fusion product of the chemotherapeutic moiety with the ⁇ -amino acid derivative, ⁇ -amino acid analog, or ⁇ -amino acid carboxylic acid (bio)isostere is simultaneous a selective substrate for the LATl/4F2hc transporter.
• the chemotherapeutic moiety is a moiety Formula (2):
• each R 11 is independently selected from hydrogen and deuterio
• 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
• each R 11 is independently selected from hydrogen and deuterio
• each R 9 is independently selected from chloro (-C1), bromo (-Br), iodo (-1), alkyl sulfonate (-OS0 2 R 4 °, 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
• 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 (-OS0 2 R 40 , wherein R 40 is selected from Ci_ 4 alkyl), and Ci_ 4
• 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
• 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 and 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.
• 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
• 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.
• 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(-
• 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), andCi_ 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.
• 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 ).
• 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 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
• the chemotherapeutic moiety comprises -CH 2 -N + (-0 )(-CH 2 _ JD 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
• the chemotherapeutic moiety comprises -0-N(-CH 2 -mDm-CH 2 -nD 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
• 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
• 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
• each R 9 is independently selected from chloro (-C1), bromo ( ⁇ Br), iodo (-1), methylsulfonyloxy (-OS0 2 CH 3 ), and
• 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 CH3), and trifluoromethylsulfonyloxy
• 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 (-OSO 2 CH3), and
• 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 CH3), and
• the chemotherapeutic moiety comprises -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 CH3), and trifluoromethylsulfonyloxy (-OSO 2 CF3).
• 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 trifluoromethylsulfonyloxy (-OSO 2 CF 3 ).
• 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 CH 3 ), and
• the chemotherapeutic moiety comprises -CH 2 -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 CH 3 ), and
• 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 (-OSO 2 CH 3 ), and
• 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 (-OSO 2 CH 3 ), and trifluoromethylsulfonyloxy (-OSO 2 CF 3 ).
• 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 ), and phosphonic acid or derivatives thereof (-PO(OH)(OR 12 )), sulfuric acid (-SOOH), sulfonic acid (-S0 2 OH), sulfonamide (- S0 2 NHR 12 or -NHSO 2 R 12 ), sulfonimide or acyl sulfonimide (-SO 2 NHCOR 12 or - CONHSO 2 R 12 ), sulfonylureas (-S0 2 NHCONHR 12 or -NHCONHS0 2 R 12 ), amide (- CONHR 12 or -NHCOR 12 ), acylcyanamide (-CONHCN), 2,2,2-trifiuoroethan-l-o
• the acidic heterocycle and annular tautomers is selected from lH-tetrazole, 5-oxo-l,2,4-oxadiazole, 5-oxo-l,2,4- thiadiazole, 5-thioxo-l,2,4-oxadiazole, thiazolidinedione, oxazolidinedione,
• 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 lH
• R 6 is selected from - COOH, -S(0)OH, -SO 2 OH, -P(0)(OH)R 12 , -P(0)(OH)(OR 12 ), -S0 2 NHR 12 , -NHS0 2 R 12 , - SO 2 NHCOR 12 , -CONHSO 2 R 12 , -SO 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;
• 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 , - SO 2 NHCOCF 3 , -NHSO 2 CH 3 , -NHSO 2 CF 3 , lH-tetrazol-yl, 5-oxo-l ,2,4-oxadiazole-yl, 5- oxo-l ,2,4-thiadiazole-yl, 5-thioxo-l ,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.
• 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.
• R 6 is selected from - COOH, -S(0)OH, -P(0)(OH)H, and lH-tetrazol-yl.
• R 6 is -COOH.
• 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.
• 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.
• each R 7 is independently selected from hydrogen and deuterio.
• each R 7 is hydrogen.
• R 8 is selected from hydrogen, deuterio, halogen, hydroxyl, Ci_ 4 alkyl, Ci_ 4 alkoxy, Ci_ 4 fluoroalkyl, Ci_ 4 fluoroalkoxy, and cyclopropyl.
• R 8 is selected from hydrogen, deuterio, halogen, hydroxyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert- butyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, and cyclopropyl.
• R 8 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, tert-butyl, hydroxyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, and trifluoromethoxy.
• R 8 is methyl
• R 8 is hydrogen.
• each R 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.
• L is (-X-) a wherein a is selected from 0, 1 , 2, 3, and 4, and X is selected from oxygen (-0-), sulfur (-S-), sulfmyl (- SO-), sulfonyl (-S0 2 -), carbonyl (-CO-), -C(R 16 ) 2 - wherein R 16 is independently selected from hydrogen, deuterio, halogen, hydroxyl, and Ci_ 4 alkyl, and amino (-NR 17 -), wherein R 17 is selected from hydrogen, methyl, and ethyl.
• a compound of Formula (1) comprises is selected from a bond ("-"), methylene (-CH 2 -), fluoromethylene (-CFH-), difluoromethylene (-CF 2 -), hydroxymethylene (-C(OH)H-), ethane- 1 ,1-diyl (-CHCH 3 -), 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, andethyl.
• a compound of Formula (1) comprises is selected from a bond ("-"), methylene (-CH 2 -), fluoromethylene (-CFH-), difluoromethylene (-CF 2 -), hydroxymethylene (-C(OH)H-), ethane- 1 ,1-diyl (-CHCH 3 -), propane-2,2-diyl (-C(CH 3 ) 2 -), oxygen (-0-), sulfonyl (-S0 2 -), carbonyl (-CO-), and amino (-NR 17 -), wherein R 17 is selected from hydrogen and methyl.
• a is 2 and 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 (-CHCH 3 -) 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 hydroxym
• 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 -CO-); one X is methylene (-CH 2 -) and one X is amino (-NR -) and L is methyleneamino (-CH 2 -NR 17 -); one X is amino (-NR 17 -) and one X is methylene (-CH 2
• 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-), oxymethylen (-O-CH 2 -), methylenethiyl (-CH 2 -S-), thiylmethylene (-S-CH 2 -), methylenesulfonyl (-CH 2 -S0 2 -), sulfonylmethylene (
• 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;
• 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
• 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;
• 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 ), -CH 2 -N(-0-CH 2 -CH 2
• 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 ), -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 gem
• 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
• 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 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
• 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
• 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
• 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
• L is selected from a bond -CH 2 - -C(OH)H- -CHCH 3 - -C(CH 3 ) 2 -, -CF 2 - - 0-, , -SO 2 -, -NR 17 -, -CO-, -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-, -SO2-CH2-, -CH2-CO-, and -CO-CH 2 -, wherein R 17 is selected from
• 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 10 together with the nitrogen to which they are bonded form a 3- to 5-membered heterocyclic ring;
• 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 )(- CH2-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 , -CH 2 -CO-N
• R 6 is -COOH
• L is selected from a bond -CH 2 - -C(OH)H- -CHCH 3 - -C(CH 3 ) 2 - -CF 2 - - 0-, , -NR 17 -, -CO-, -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-, -CH2-CO-, and -CO-CH 2 - wherein R 17 is selected from hydrogen and methyl.
• 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
• R 6 is -COOH
• each R 7 is 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;
• 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
• 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
• 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 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 -, -CO-, -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- CH 2 - -CH2-O-, -O-CH2-, -CH2-S-, -S-CH2-, -CH 2 -S0 2 -, -S0 2 -CH 2 -, -CH2-CO-, and -CO-
• 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, C 3 _ 5 cycloalkyl, and C 3 _ 5 cycloalkyloxy; wherein each R 10 is independently selected from hydrogen or Ci_ 3 alkyl; or two R 10 together with the nitrogen to which they are bonded form a 3- to 5-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 -
• each of R 2 , R 3 , and R 5 is hydrogen
• R 6 is -COOH
• each R 7 is 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 - -C(CH 3 ) 2 -, -CF 2 -, - 0-, , -NR 17 -, -CO-, -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 CH 2 -, -CH 2 -0-, -0-CH 2 -, -CH 2 -S- -S-CH 2 -, -CH 2 -S0 2 -, -CH 2 -CO-, and -CO-CH 2 - wherein R 17 is selected from hydrogen and
• R 8 is selected from hydrogen, deuterio, Ci_ 4 alkyl, Ci_ 4 fluoroalkyl, and cyclopropyl.
• R 8 is selected from hydrogen, deuterio, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, trifluoromethyl, and cyclopropyl.
• 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; and a is selected from 0, 1, 2, 3, and 4;
• 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 -),sulfonyl (-S0 2 -), and carbonyl (- CO-).
• 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- 1,2-diyl (-CH 2 - CHOH- or -CHOH- CH 2 -), fluoroethane- 1,2-diyl (-CH 2 -CHF- or -CHF-CH 2 -), difluoroethane- 1,2-diyl (-CH 2 -CF 2 - or -CF 2 -CH 2 -), carbonyl amino (-CO-NR 17 - ),methyleneamino (-CH 2 -NR 17 -), methyleneoxy (-CH 2 -0-),methylenethiyl (-CH 2 -S- ),methylenesulfmyl (-CH 2 -SO-), sulfinylmethylene (-SO-CH 2 -CH 2
• stereochemistry of the ⁇ carbon atom is of the (R) configuration
• the absolute axial stereochemistry (atropisomerism) is R a
• the absolute stereochemistry of a compound of Formula (1) is (R,R a ).
• stereochemistry of the ⁇ -carbon atom is of the (R) configuration
• the absolute axial stereochemistry (atropisomerism) is S a
• the absolute stereochemistry of a compound of Formula (1) is (R,S a ).
• stereochemistry of the ⁇ -carbon atom is of the (S) configuration
• the absolute axial stereochemistry (atropisomerism) is R a
• the absolute stereochemistry of a compound of Formula (1) is (S,Ra).
• stereochemistry of the ⁇ -carbon atom is of the (S) configuration
• the absolute axial stereochemistry (atropisomerism) is S a
• the absolute stereochemistry of a compound of Formula (1) is (S,S a ).
• a compound of Formula (1) is selected from: 3-Amino-3-[5-[bis(2-chloroethyl)amino]-2-methyl-phenyl]propanoic acid (1);
• 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.
• 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.
• compounds provided by the present disclosure exhibit a LATl/4F2hc-dependent uptake of at least 10% that of gabapentin measured at an
• 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).
• compounds provided by the present disclosure exhibit a LATl/4F2hc- dependent uptake of at least 10% that of gabapentin measured at an extracellular
• 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).
• compounds provided by the present disclosure exhibit a LATl/4F2hc-dependent uptake of at least 10% that of gabapentin measured at an extracellular
• 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).
• compounds provided by the present disclosure exhibit a LATl/4F2hc- dependent uptake of at least 10% that of gabapentin measured at an extracellular
• Compounds of Formula (1) may be adapted as prodrugs to achieve desirable pharmacokinetic properties.
• suitable prodrugs of ⁇ -substituted ⁇ -amino acid derivatives and ⁇ -substituted ⁇ -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.
• reaction temperatures e.g., reaction temperatures, reaction times, molar ratios of reactants, solvents, pressures, etc.
• 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.
• ⁇ -amino acids are categorized as (a) ⁇ 2 - (mono-a-substituted), (b) ⁇ 3 - (mono ⁇ -substituted),
• such derivatives may be used as convenient starting materials for the preparation of the target compounds provided by the present disclosure.
• suitably functionalized protected and unprotected may be used as convenient starting materials for the preparation of the target compounds provided by the present disclosure.
• racemic or optically active ⁇ -amino acids, ⁇ -amino acids analogs, or ⁇ -amino acid carboxylic acid (bio)isosters may be used as starting materials for the preparation of the target compounds provided by the present disclosure.
• 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.
• 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 carboxylic acid (bio)isostere functional group or synthetic equivalents or precursors of any of the foregoing are
• 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 carboxylic acid (bio)isostere or synthetic equivalents or precursors of any of the foregoing are appropriately protected.
• starting materials may be used in their full unprotected form wherein the amino group and the carboxylic acid, free phosphinic acid, free sulfmic acid, or free carboxylic acid (bio)isostere or synthetic equivalents or precursors of any of the foregoing are unprotected.
• protected and unprotected p 3 -substituted racemic or optically active ⁇ -amino acids, ⁇ -amino acids analogs, or ⁇ -amino acid carboxylic acid (bio)isosters bear a chemical functional group linking the p 3 -carbon atom to an aromatic ring system.
• the aromatic ring system is functionalized with an anchoring group in order to install a chemotherapeutic moiety.
• auxiliary molecular functionalities may, for example, be incorporated to modulate interaction with LAT1 transporter proteins, e.g., efficacy of translocation through biological membranes (binding to the LAT1 -transporter protein and capacity of LAT1 -mediated transport), aid the modulation of physiochemical parameter, or to modulate the activity of the physiologically active N- mustard moiety, e.g., cytotoxicity.
• the underlying aryl-ring may be modified to allow for regioselective incorporation of functional groups that can be converted to chemotherapeutic moieties by using reagents, methods, and protocols well known in the art.
• the underlying aryl-ring may 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 LAT1 transporter proteins, e.g., efficacy of translocation through biological membranes (binding to the LAT1 -transporter protein and capacity of LAT1- mediated transport), or to modulate the activity of the physiologically active
• chemotherapeutic moiety e.g., cytotoxicity.
• -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 -
• R 20 in compounds of Formula (A) 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.
• R 20 in compounds of Formula (A) is a tert-butyl ester group (C0 2 tBu).
• R 20 in compounds of Formula (A) is a methyl ester group (C0 2 Me).
• R 20 in compounds of Formula (A) has alternatively protected phosphonates and phosphinates as described in the art (Palacios, et al, Chem. Rev., 2005, 105,899-931; and Lejzak, et al, J. Enzyme Inhibit., 1993, 7(2), 97-103).
• R 20 in compounds of Formula (A) 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; and Okawara, et al, Chem. Lett., 1984, 2015; C. E. Burgos- Lepley, et al, Bioorg. Med. Chem. Lett., 2006, 16, 2333-2336).
• a protected sulfuric acid precursor derivative e.g., a 2-mercaptobenzothiazole
• 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).
• PG is a nitrogen protecting group such as an imide-type protecting group, e.g., phthalyl or tert-butoxycarbonyl (Boc).
• Q is N(phthalyl).
• compounds of Formula (A) PG is tert-butoxycarbonyl and Q is N(Boc) 2 .
• 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.
• 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 (-NO 2 ), amide (-CON(R 10 ) 2 ), and formyl (-CHO).
• Useful secondary amines for the introduction of the N,N-bis-(2-hydroxyethyl) amino functionality include diethanolamine (FIN(CH 2 CH 2 OH) 2 ), protected diethanolamine derivatives, e.g., O-benzylether protected diethanolamine (HN(CH 2 CH 2 OBn) 2 ), or precursors of the putative N,N-bis-(2-hydroxyethyl)amino group, e.g., 3-pyrroline.
• 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 HNR 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-position relative to the leaving group X; each of the other remaining R 2 , R 3 , and R 4 is hydrogen; each of R 7 and R 8 is hydrogen.
• EWG electron withdrawing group
• N,N-bis(2-hydroxyethyl)amino derivatives as in compounds of Formula (E) may be prepared through nucleophilic aromatic substitution reactions (SNAr) of aromatic halides of Formula (D) activated by electron withdrawing groups (EWGs), by reaction with an excess of about 1.5-5 equivalents of the neat amine, e.g., FrN(CH 2 CH 2 OH)2, FrN(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 (s
• SNAr nucleophil
• suitable reducing reagents e.g., borane-THF complex (BH 3 THF), or sodium borohydride (NaBH 4 )
• chlorination methods and reagents include, for example, combinations of triphenyl phosphine and trichloroacetonitrile (Ph 3 P/Cl 3 CCN), triphenylphosphine dichloride (PI1 3 PCI 2 ) (prepared from PI1 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.
• PI1 3 PCI 2 triphenylphosphine dichloride
• CCI 4 mixtures of Ph 3 P and carbon tetrachloride
• MeS0 2 Cl methanesulfonyl chloride
• N,N-bis(2-hydroxyethyl) compounds of Formula (F) 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 (CHC1 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)
• DCM dichloromethane
• CHC1 3 chloroform
• DCE 1 ,2-dichloroethane
• 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)
• N,N-bis(2-hydroxyethyl) compounds of Formula (F) 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 (G) (Palmer, et al, J. Med. Chem.
• N,N-bis(2-hydroxyethyl) compounds of Formula (F) 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 (G) (Buss, et al, J.
• CC1 4 carbon tetrachloride
• DCM dichloromethane
• N,N-bis(2-hydroxyethyl) compounds of Formula (F) 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 (G) (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 Cheung, Tetrahedron Lett., 1996, 37(42), 7581-7582).
• MeS0 2 Cl, MsCl methanesulfonyl chloride
• 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 (H). 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 (H) 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.
• N,N-bis(2-aryl- or (polyfluoro)alkylsulfonyloxy)amino groups of aryl- or (polyfluoro)alkylsulfonates of Formula (I) and similar sulfonic esters are most frequently prepared from NN-bis(2- hydroxy)amino groups of diols of Formula (H) 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).
• a suitable base e.g., pyridine (nucleophilic catalyst).
• 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.
• R 40 -group of compounds of Formula (I) and Formula (K) is methyl and the leaving group is mesylate
• R 40 -group of compounds of Formula (I) and of Formula (K) is trifluoromethyl and the leaving group is triflate
• 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 ( ⁇ ).
• MX or M are alkali metal halides, e.g., lithium chloride (LiCl), lithium bromide (LiBr), sodium chloride (NaCl), sodium bromide (NaBr), or sodium iodide (Nal).
• X is a halogeno, e.g., chloro (-C1), bromo (-Br), or iodo (-1)
• halogeno e.g., chloro (-C1), bromo (-Br), or iodo (-1)
• alkylsulfonyloxyethyl)amino groups of Formula (K) may also be prepared from primary alkyl halides of Formula (J) 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).
• diols of Formula (H) may also be reacted with a suitable alkyl- or aryl-sulfonyl halides, e.g., methanesulfonyl chloride (mesyl chloride, MsCl) (R 40 is Me), MeS0 2 Cl), to provide the desired bis-sulfonic acid esters of Formula (I).
• a suitable alkyl- or aryl-sulfonyl halides e.g., methanesulfonyl chloride (mesyl chloride, MsCl) (R 40 is Me), MeS0 2 Cl
• N,N-bis(2-(polyfluoro)alkyl- or aryl-sulfonyloxyethyl)amino groups as in compounds of Formula (I) may be converted (halo- de-sulfonyloxy substitution) to N,N-bis(halogenoethyl)amino groups of compounds of Formula (J) by reacting bis-sulfonyl esters of Formula (I) 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 ethy
• reaction of bis-sulfonyl esters of Formula (I) 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 (K) bearing N-(2-halogenoethyl)-, N-(2-methylsulfonyloxyethyl) amino groups (mixed halogeno/sulfonylato N-mustards).
• compounds of Formula (J) may be converted to mixed halogeno/sulfonylato N-mustards of Formula (K) by reacting N-mustard derivatives of Formula (J) 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 (K) (methathetical reaction).
• a suitable soluble silver sulfonate salt e.g., silver mesylate (AgOS0 2 Me, AgOMs
• MeCN acetonitrile
• reaction of bis-halogeno N-mustards of Formula (J) 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 (L) bearing N-(2-halogenoethyl)-, N-(2- halogeno'ethyl) amino groups (mixed halogeno N-mustards).
• 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).
• the intermediate imine may be isolated and reduced with a suitable reducing agent.
• 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.
• 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.
• 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 P0 4 ), glacial acetic acid (HOAC), 98 wt-% formic acid, or water, or inert organic solvents, e.g., acetonitrile (MeCN),
• protic solvents e.g., methanol (MeOH), acetic acid, (HOAc), trifluoroacetic acid (TFA), 85 wt-% phosphoric acid (H 3 P0 4 ), glacial acetic acid (HOAC), 98 wt-% formic acid, or water
• organic solvents such as protic solvents, e.g., methanol (MeOH), acetic acid, (HOAc), trifluoroacetic acid (TFA), 85 w
• Estramustine (Emcyt ® , Estracit ® ) is an antimicrotubule chemotherapy agent indicated in the US 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.
• suitable formic ester derivatives including phosgene (COCl 2 ), triphosgene (bis(trichloromethyl) carbonate (BTC)), or ⁇ , ⁇
• a compound of Formula (O) 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 (--) and MH is an amino group (-NR
• R 1 and/or R 5 , R 10 , R 20 , E, M, Z, the linker L, and the protecting group PG and Q are defined as described herein; one of R 2 , R 3 , and R 4 in compounds of Formula (O) is -E-MH as described herein; each of the other remaining R 2 , R 3 , and R 4 is hydrogen; each of R 7 and R 8 is hydrogen; LG is a suitable leaving group such as chloro ( ⁇ C1), 4-nitrophenyloxy (NO 2 C 6 H 4 O-), or imidazole; and R 9 is chloro (-C1), bromo (-Br), iodo (-1), or (polyfluoro)alkyl- or aryl sulfonyloxy (-OSO 2 R 40 ) or combinations thereof, and R 40 is defined as described herein.
• LG is chloro ( ⁇ C1)
• R 9 is chloro ( ⁇ C1)
• R 9 is chloro ( ⁇ C1)
• the MH-group of compounds of Formula (O) may be activated to their corresponding chloroformates, thiochloroformates, or carbonyl imidazoles of Formula (P) 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 CO3) and bicarbonates, e.g., sodium hydrogencarbonate (NaHC0 3 ), in suitable inert solvents known in the art.
• a suitable base such as inorganic metal-carbonate, e.g., potassium carbonate (K 2 CO3) and bicarbonates, e.g., sodium hydrogencarbonate (NaHC0 3 ), in suitable inert solvents known in the art.
• the chloroformates or thiochloroformates of Formula (P) are subsequently converted to the corresponding carbamates of Formula (Q) through 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, 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 C0 3 ) and bicarbonate, e.g., sodium
• the nitrogen mustards have been used for a number of years in laboratory investigations and in the clinical treat for malignat growth.
• 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.
• 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.
• 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.
• an appropriately functionalized amine such as HN(CH 2 -CH 2 -R 9 )2 wherein X
• liberation of unprotected N- mustard functionalized ⁇ -substituted ⁇ -amino acid derivatives or unprotected N-mustard functionalized ⁇ -substituted ⁇ -amino acid analogs or carboxylic acid (bio)isosteres of Formula (U) from their corresponding precursors of Formula (T) 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; A. J. Abela, et al, J. Chem.
• liberation of unprotected N- mustard functionalized ⁇ -substituted ⁇ -amino acid derivatives or unprotected N-mustard functionalized ⁇ -substituted ⁇ -amino acid analogs or carboxylic acid (bio)isosteres of Formula (U) from their corresponding precursors of Formula (T) 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.
• 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 ⁇ -substituted ⁇ -amino acid derivatives or unprotected N- mustard funtionalized ⁇ -substituted ⁇ -amino acid derivatives, analogs, or carboxylic acid (bio)isosteres of Formula (U).
• 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.
• hydrolytic acidic global deprotection of compounds of Formula (T) to provide N-mustard functionalized ⁇ -substituted ⁇ -amino acid derivatives or N- mustard functionalized ⁇ -substituted ⁇ -amino acid analogs or carboxylic acid (bio)isosteres of Formula (U) may be accomplished by treating protected precursors of Formula (T) 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.
• aqueous mineral acids e.g., 2 M to ⁇ 12 M hydrochloric acid (HC1)
• Reductive metabolic processes are more prevalent in the hypoxic environment of solid tumors.
• Reductive enzyme systems have the ability to reduce certain functional groups.
• 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).
• a known substrate (reference substrate) for the LATl/4F2hc transporter and a test compound are added to cells expressing the LATl/4F2hc transporter.
• 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.
• 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
• LC/MS/MS liquid chromatography-mass spectroscopy
• 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.
• 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 OO 1139807), SLC6A17 (XT1; NP 001010898), SLC6A18 (B°AT3;
• NP_8724378 SLC6A19 (B°AT1; NP OO 1003841), 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
• a transporter of interest 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
• test substrates compounds that are optimal substrates (reference substrates) for the transporter of interest.
• uptake levels of a test compound are compared to uptake of a reference substrate for the transporter of interest.
• 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.
• 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.
• compositions provided by the present disclosure are injectable formulations.
• pharmaceutical compositions provided by the present disclosure are injectable intravenous formulations.
• pharmaceutical compositions provided by the present disclosure are oral formulations. Oral formulations may be oral dosage forms.
• 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.
• 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.
• a compound of Formula (1) may be formulated as a solution, gel, ointment, cream, suspension, etc.
• 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
• Radio-labeled compounds for positron emission tomography (PET) or Single Photon Emission Computed Tomography (SPECT) with the same selectivity toward PET positron emission tomography
• SPECT Single Photon Emission Computed Tomography
• a compound of Formula (1) and/or pharmaceutical composition thereof can generally be used in an amount effective to achieve the intended purpose.
• a compound of Formula (1) and/or pharmaceutical compositions thereof may be administered or applied in a therapeutically effective amount.
• 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.
• 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.
• a compound of Formula (1) and/or pharmaceutical composition thereof exhibits a particularly high therapeutic index in treating disease and disorders.
• 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 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.
• kit 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.
• Compounds of Formula (1) may be used for treating cancer in a patient, wherein the cancerous tissue expresses the LATl/4F2hc.
• the cancerous tissue expressing the LATl/4F2hc transporter is in the brain of the patient.
• 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.
• an alkylating agent such as, for example, melphalan.
• 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 acute lymphoblastic leukemia (all), childhood acute lymphoblastic leukemia (all), childhood acute myeloid leukemia (ami), adult acute myeloid leukemia (ami), 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 brain tumor, childhood brain tumor, childhood brain stem glioma, 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, breast cancer, childhood breast cancer, male breast cancer, childhood bronchial tumors, hematopoetic tumors of the lymphoid lineage, hematopoetic tumors of the myeloid lineage, burkitt lymphoma, childhood
• 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, myelodysplastic syndromes myelodysplastic/myeloproliferative diseases, chronic myelogenous leukemia, adult acute myeloid leukemia, childhood acute myeloid leukemia, multiple myeloma, chronic myeloprolif
• 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.
• GBM glioblastoma
• NSCLC non-small cell lung cancers
• TNBC triple negative breast
• Compounds of Formula (1) are therapeutic agents, are substrates for the LATl/4F2hc transporter, and exhibit cytotoxicity.
• 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.
• 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.
• the amount of compound of Formula (1) contained within each of the multiple dosage forms may be the same or different.
• 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.
• 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.
• a therapeutically effective concentration of a compound of Formula (1) in the blood or plasma of a subject is from about 1 ⁇ g/mL to about 60 ⁇ g/mL, from about 2 ⁇ g/mL to about 50 ⁇ g/mL, from about 5 ⁇ g/mL to about 40 ⁇ g/mL, from about 5 ⁇ g/mL to about 20 ⁇ g/mL, and in certain embodiments, from about 5 ⁇ g/mL to about 10 ⁇ g/mL.
• a therapeutically effective concentration of a compound of Formula (1) in the blood or plasma of a subject is at least about 2 ⁇ g/mL, at least about 5 ⁇ g/mL, at least about 10 ⁇ g/mL, at least about 15 ⁇ g/mL, at least about 25 ⁇ g/mL, and in certain
• 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.
• 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).
• a compound of Formula (1) may be used in combination with at least one other therapeutic agent.
• a compound of Formula (1) may be administered to a patient together with another compound for treating cancer in the subject.
• 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.
• 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.
• 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.
• 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.
• the other therapeutic agent may be administered at a dose that falls below the threshold at which the adverse drug reaction is elicited.
• 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.
• 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;
• Methods provided by the present disclosure have use in animals, including mammals, such as in humans.
• TLC thin layer chromatography
• EMD5554-7 EMD Millipore aluminum-backed TLC sheets
• silica gel 60 F254 200 ⁇ thickness, 60 A pore size
• 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.
• 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 ⁇ XDB-C18 2.1 50 mm column (Agilent 960 967-902), and a commercial desktop computer and printer for data computation.
• 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 ⁇ 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.
• Agilent 1100 Series degasser Agilent 1100 Series degasser
• Agilent 1100 Series quad pump Agilent 1100 Series quad pump
• ALS Agilent 1100 Series autosampler
• Agilent 1100 Series COLCOM Agilent 1100 Series COLCOM
• 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 ⁇ 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.
• Compound isolation from aqueous solvent mixtures 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.
• manifold freeze dryers such as Heto Drywinner DW 6-85-1, Heto FD4, or VIRTIS Freezemobile 25 ES equipped with a high vacuum pump.
• 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.
• HC1- salt hydrochloric 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).
• 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
• 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 ⁇ , 230-400 mesh) (EMD Millipore EMI .09385.9026/ EMI .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.
• suitable solvents e.g., ethyl acetate (EtOAc) and hexane or dichloromethane (DCM) and methanol (MeOH
• Variant B Adapting literature known protocol (Aoyama, et al, Synlett, 1998, 35- 36), commercial activated manganese(IV) oxide (Mn0 2 ) (250-275 mmol) is added at room temperature to a solution of the benzylic alcohol (25 mmol) in dichloromethane (DCM) (100 mL). The reaction mixture is stirred for 12-24 h. The reaction is monitored by TLC and/or LCMS to completion. The reaction mixture is filtered over a short path of Celite® 545 and the filtrate is concentrated under reduced pressure. The material is often of sufficient purity to be used directly in the next step without further isolation and purification. If needed, the crude material is purified by silica gel column chromatography or is re-crystallized.
• Variant C Adapting a literature known protocol (Corey and Suggs, Tetrahedron Lett., 1975, 16(31), 2647-2650; and Fujikawa, et al, J. Am. Chem. Soc, 2008, 130, 14533- 14543), to a solution of the benzylic alcohol (20 mmol) in dichloromethane (DCM) (100 mL) is added commercial pyridinium chlorochromate (Pyr + Cr0 3 O , PCC) (28-40 mmol). The reaction mixture is heated to reflux (55 °C oil bath temperature) for 1-4 hours. The reaction is monitored by TLC and/or LCMS to completion. The reaction is cooled to room temperature. Work-up and product isolation and purification are conducted as described for Variant B.
• DCM dichloromethane
• PCC commercial pyridinium chlorochromate
• the reaction mixture is cooled to room temperature upon the target compound precipitates generally out.
• the precipitate is filtered off using a Buchner-funnel and the filter residue is washed with additional EtOH (2x).
• EtOH (2x) additional EtOH
• the collected product is dried under reduced pressure to afford of the target compound generally as a colorless solids which are often of sufficient purity to be used directly in the next step without further purification and isolation procedures.
• Neat diisopropylethylamine (DIPEA, Hunigs-base) (20-50 mmol) is added followed by the appropriate alkyl chloro formate (15 mmol), e.g., benzylchloro formate (ZC1 or CbzCl) or ethylchloroformate, is added dropwise and the reaction mixture is stirred with gradual warming to room temperature for overnight. The reaction is monitored by TLC and/or LC/MS to completion. The solvents are removed under reduced pressure using a rotary evaporator. The residue is diluted with 1.0 molar hydrochloric acid (HC1) and the aqueous phase is extracted with ethyl acetate (EtOAc) (3 X ).
• DIPEA Hunigs-base
• Variant A Adapting a literature known protocol (Chandrappa, et al., Synlett, 2010, (20), 3019-3022), to a suspension of the nitro aromatic derivative (10 mmol) in a mixture of ethanol (EtOH) or methanol (MeOH) with water (10-20 mL alcohol:0.5-3 mL water), iron powder (Fe) (30-100 mmol), and calcium chloride dihydrate (CaCl 2 '2H 2 0) (5-10 mmol) are added. The resulting reaction mixture is heated from about 50 °C to about reflux (oil bath) for about 0.5-3 h. The reaction is followed by TLC (nihydrin stain) and/or analytical LC/MS to completion.
• the reaction mixture is stirred at about room temperature to about 40 °C or heated to reflux for about 10 minutes to about 3 h.
• the reaction is carried out using neat SOCl 2 directly as the solvent.
• the reaction is carried out in the presence of a catalytic amount of zinc chloride (ZnCl 2 ) (10 mol-% to 40 mol-%) or N,N-dimethylformamide (about 1 to 3 drops) 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).
• ZnCl 2 zinc chloride
• N,N-dimethylformamide about 1 to 3 drops
• Variant C Chlorination with Methanesulfonyl Chloride/Pyridine
• Methanesulfonyl anhydride (Ms 2 0) (20.0 mmol) is added portion- wise or as a solution in DCM (5-10 mL). The reaction mixture is stirred with gradual warming to room temperature for about 8-24 h. The reaction is be followed by TLC and/or LC/MS. Solvents are removed under reduced pressure using a rotary evaporator. The residue is diluted with 1.0 M hydrochloric acid (HC1), and the aqueous phase is extracted with ethyl acetate (EtOAc) (3x).
• HC1 hydrochloric acid
• EtOAc ethyl acetate
• Variant B Adapting literature known protocols (Palmer, et al., J. Med. Chem. 1990, 33(1), 112-121; B. D. Palmer, et al, J. Med. Chem., 1994, 37, 2175-2184; Palmer, et al, J. Med. Chem, 1996, 39(13), 2518-2528; Spreitzer and Puschmann, Monatshefte fur Chemie, 2007, 138(5), 517-522; Lin, et al, Bioorg. Med. Chem. Lett., 2011, 21(3), 940-943; Gourdi, et al, J. Med. Chem., 1990, 33(4), 1177-1186; Ferlin, et al, Bioorg. Med.
• Methanesulfonyl chloride (12.5 mmol) is added drop-wise to the reaction mixture. The reaction mixture is stirred for about 1-2 h at this temperature. The reaction may be followed by TLC and/or LC/MS. Aqueous work-up and purification by silica gel chromatography are performed as described for Variant A.
• N,N-bis(2-methylsulfonyloxyethyl) derivative 5.0 mmol
• an alkali metal halide e.g., lithium chloride (LiCl), lithium bromide (LiBr), sodium chloride (NaCl), sodium bromide (NaBr), or sodium iodide (NaT) (20-80 mmol) in an anhydrous 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)
• LiCl lithium bromide
• NaCl sodium chloride
• NaBr sodium bromid
• the crude residue may be further purified by silica gel column chromatography using EtOAc, methanol (MeOH), dichloromethane (DCM), and hexanes, or mixtures of any of the foregoing to furnish the purified target compound.
• the crude target compound may be further purified by re-crystallization.
• 2-methyl-5-nitro- phenyl)methanol (la) was prepared from commercial 2-methyl-5-nitro benzoic acid (50.0 g, 276 mmol) with borane dimethylsulfide complex (2.0 M BH 3 SMe 2 in THF) (166 mL, 332 mmol) in anhydrous tetrahydrofuran (400 mL) to yield 44.0 g (-quantitative yield) of the target compound (la) as a pale yellow solid which was of sufficient purity to be used directly in the next step without further isolation and purification.
• 3-amino-3-(2-methyl-5-nitro- phenyl)propanoic acid (lc) was prepared from 2-methyl-5-nitro-benzaldehyde (lb) (5.0 g, 30.3 mmol), malonic acid (3.2 g, 30.3 mmol), and ammonium acetate (NH 4 OAc) (4.7 g, 60.7 mmol) in ethanol (EtOH) (70 mL) at reflux for 48 hours (oil bath). The reaction was followed by LC/MS to completion.
• Step D Methyl 3-amino-3-(2-methyl-4-nitro-phenyl)propanoate Hydrochloride (Id) [0388] Following the General Procedure of Description 4, methyl 3-amino-3-(2-methyl- 4-nitro-phenyl)propanoate hydrochloride (Id) was prepared in a suspension in anhydrous methanol (MeOH) (40 mL) from 3-amino-3-(2-methyl-5-nitro-phenyl)propanoic acid (lc) (2.2 g, 9.81 mmol) with neat thionyl chloride (SOCl 2 ) (3.54 mL, 5.8 g, 49.1 mmol).
• DIPEA diisopropylethylamine
• Step F Methyl 3-(5-amino-2-methyl-phenyl)-3-benzyloxycarbonylamino-propanoate
• Step G Methyl 3-benzyloxycarbonylamino-3-[5-[bis(2-chloroethyl)amino]-2-methyl- phenyl] propanoate (lg)
• Step H 3-Amino-3- [5- [bis(2-chloroethyl)amino]-2-methyl-phenyl] propanoic acid (1)
• 3-amino-3-[5-[bis(2- chloroethyl)amino]-2-methyl-phenyl]propanoic acid (1) was prepared through hydrolytic deprotection of methyl 3-benzyloxycarbonylamino-3-[5-[bis(2-chloroethyl)amino]-2-methyl- phenyl]propanoate (lg) (2.9 g, 6.2 mmol) in a mixture of concentrated hydrochloric acid (HC1) (20 mL) and 1,4-dioxane (20 mL) at about 100 °C (oil bath) in 48 hours.
• HC1 concentrated hydrochloric acid
• 1,4-dioxane 20 mL
• hydrochloric acid HC1
• HC1 hydrochloric acid or an excess of 1.0 N or higher concentrated hydrochloric acid
• spectroscopic data correspond to the data provided in the literature.
• the compound is also commercially available.
• 3-amino-3-(2-methyl-4-nitro- phenyl)propanoic acid (2c) was prepared from 2-methyl-4-nitro-benzaldehyde (2b) (800 mg, 5.0 mmol), malonic acid (520 mg, 5.0 mmol), and ammonium acetate (NH 4 OAc) (578 mg, 7.5 mmol) in ethanol (EtOH) (10 mL) at reflux for 48 h (oil bath). The reaction was followed by LC/MS to completion. Filtrative work-up afforded 510 mg (45% yield) of the target compound (lc) as a near colorless solid which was of sufficient purity to be used directly in the next step without further purification and isolation.
• methyl 3-amino-3-(2-methyl- 4-nitro-phenyl)propanoate hydrochloride (2d) was prepared in a suspension in anhydrous methanol (MeOH) (10 mL) from 3-amino-3-(2-methyl-4-nitro-phenyl)propanoic acid (2c) (510 mg, 2.27 mmol) with neat thionyl chloride (SOCl 2 ) (2.0 mL, 3.28 g, 27.5 mmol).
• Step E Methyl 3-(ethoxycarbonylamino)-3-(2-methyl-4-nitro-phenyl)propanoate (2e) [0397] Following the General Procedure of Description 5, methyl 3- (ethoxycarbonylamino)-3-(2-methyl-4-nitro-phenyl)propanoate (2e) was prepared from crude methyl 3-amino-3-(2-methyl-4-nitro-phenyl)propanoate hydrochloride (2e) (624 mg, 2.27 mmol), ethyl chloroformate (EtOCOCl) (327 ⁇ , 371 mg 3.42 mmol), and
• Step F Methyl 3-(4-amino-2-methyl-phenyl)-3-(ethoxycarbonylamino)propanoate (2f)
• methyl 3-(4- amino-2-methyl-phenyl)-3-(ethoxycarbonylamino)propanoate (2f) is prepared from methyl 3- (ethoxycarbonylamino)-3-(2-methyl-4-nitro-phenyl)propanoate (2e) (701 mg, 2.26 mmol) through hydrogenation (about 15 psi; H 2 -filled balloon) in the presence 10 wt-% Pd/C containing 50-wt-% water ( ⁇ 70 mg) and at room temperature for about 12 hours to afford 632 mg (about quantitative yield) of the target compound (2f) as a brownish oil, which was of sufficient purity to be used in the next step without additional purification and isolation.
• Step G Methyl 3-[4-[bis(2-chloroethyl)amino]-2-methyl-phenyl]-3- (ethoxycarbonylamino)-propanoate (2g)
• Step H 3-Amino-3- [4- [bis(2-chloroethyl)amino]-2-methyl-phenyl] propanoic acid (2) [0400] Following the General Procedure of Description 8, 3-amino-3-[4-[bis(2- chloroethyl)amino]-2-methyl-phenyl]propanoic acid (2) was prepared through hydro lytic deprotection of methyl 3 -[4- [bis(2-chloroethyl)amino] -2-methyl-phenyl] -3- (ethoxycarbonylamino)-propanoate (2 ) (150 mg, 0.37 mmol) in concentrated hydrochloric acid (HC1) (5 mL) at about 100 °C (oil bath) in 48 h.
• HC1 concentrated hydrochloric acid
• reaction mixture was heated at about 75 °C (oil bath) for about 30 min before 2- (bromomethyl)-l-methyl-4-nitro-benzene (3a) (8.2 g, 35.6 mmol) was added, and the reaction mixture was heated at reflux (oil bath) for about 10 h. The reaction was followed by LC/MS to completion.
• Step E Benzyl V-[3-diazo-l-[(2-methyl-5-nitro-phenyl)methyl]-2-oxo-propyl]carbamate (3e)
• the mixed anhydride of (3d) is prepared from 2-benzyloxycarbonylamino-3-(2-methyl-5-nitro-phenyl)propanoic acid (3d) (3.0 g, 8.38 mmol), N-methylmorpholine (NMM) (1.20 mL, 1.1 g, 10.9 mmol), neat isobutyl chloroformate (1.34 mL, 1.4 g, 10.1 mmol) at about -20 °C (dry ice/acetone bath) under a nitrogen atmosphere. After the 2 hours -20 °C, an excess of ( ⁇ 6 equivalents) of the freshly prepared ethereal solution of diazomethane was added (-100 mL).
• Step F Methyl 3-benzyloxycarbonylamino-4-(2-methyl-5-nitro-phenyl)butanoate (3f) [0407] Following the general procedure of Description 11 (Part C), methyl 3- benzyloxycarbonylamino-4-(2-methyl-5-nitro-phenyl)butanoate (3f) is prepared from benzyl N- [3 -diazo-l-[(2-methyl-5-nitro-phenyl)methyl]-2-oxo-propyl] carbamate (3e) (2.5 g, 6.55 mmol) and a mixture of silver benzoate (AgBz) (0.75 g, 3.3 mmol) in THF (5 mL) and triethylamine (TEA) (1.93 mL, 1.4 g, 13.1 mmol) in a mixture of degassed anhydrous methanol (MeOH) (2.1 mL) and degassed anhydrous tetrahydrofuran (THF) (15
• methyl 4-(5- amino-2-methyl-phenyl)-3-benzyloxycarbonylamino-butanoate (3g) was prepared from methyl 3-benzyloxycarbonylamino-4-(2-methyl-5-nitro-phenyl)butanoate (3f) (2.1 g, 5.4 mmol), iron powder (Fe) (2.7 g, 48.9 mmol), and calcium chloride dihydrate (CaCi 2 -2H 2 0) (0.35 g, 2.4 mmol) in a mixture of methanol (MeOH)/water (41 mL:7.5 mL, v/v).
• MeOH methanol
• TFA trifluoroacetic acid

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• 2018
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