Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
  • A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
  • A61K47/543—Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
  • C07J31/006—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring not covered by C07J31/003
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
  • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
  • C07J41/005—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of only two carbon atoms, e.g. pregnane derivatives
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
  • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
  • C07J41/0055—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00

Definitions

• NMD A receptors are highly expressed in the CNS and are involved in excitatory synaptic transmission. Activating these receptors contributes to synaptic plasticity in some circumstances and exci totoxi city in others. These receptors are ligand-gated ion channels that admit Ca 2+ after binding of the neurotransmitters glutamate and glycine, and are fundamental to excitatory neurotransmission and normal CNS function.
• NMDA receptors are heteromeric complexes comprised ofNRl, NR2, and/or NR3 subunits and possess distinct recognition sites for exogenous and endogenous ligands. These recognition sites include binding sites for glycine, and glutamate agonists and modulators.
• Positive modulators may be useful as therapeutic agents with potential clinical uses as cognitive enhancers and in the treatment of psychiatric disorders in which glutamatergic transmission is reduced or defective (see, e.g., Horak et al., J. Neuroscience, 2004, 24(46), 10318-10325).
• negative modulators may be useful as therapeutic agents with potential clinical uses in the treatment of psychiatric disorders in which glutamatergic transmission is pathologically increased (e.g., treatment resistant depression).
• the lymphatic system is a network of vessels, organs (e.g., bone marrow, thymus, lymph nodes and spleen) and tissues distributed throughout the body that work together to move lymphatic fluid back into the circulatory system.
• the lymphatic system has several key functions including transporting immune cells, collecting excess fluid from the body’s tissues and returning it to the bloodstream, filtering out waste products and abnormal cells, absorbing dietary lipids, and tumor metastasis. These features of the lymphatic system have made it a desirable approach for improving drug delivery to target organs.
• drug delivery via the lymphatic system has several major advantages, including circumventing first-pass metabolism in the liver and targeting drugs to tissues via the lymphatic system (e.g., certain types of cancer and human immunodeficiency virus).
• Lipid-based therapeutics have unique characteristics that make them promising candidates for enhanced lymphatic delivery.
• Described herein are compounds of Formula (I), pharmaceutical compositions comprising them and methods of use thereof. Also described herein is the use of pharmaceutical compositions comprising the compounds of Formula (I) for the manufacture of a medicament for the treatment of diseases or conditions associated with NMDA receptor modulation. Further described herein are pharmaceutical compositions comprising compounds of Formula (I) for use in treating diseases or conditions associated with NMDA receptor modulation.
• the disclosure provides a compound of Formula (I): or a pharmaceutically acceptable salt thereof.
• the present disclosure provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier thereof.
• the present disclosure provides a method of modulating an NMDA receptor in a subject, comprising administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
• the present disclosure provides a method of treating a disease, disorder, or condition requiring allosteric NMDA receptor modulation in a subject, comprising administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.
• the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in modulating an NMDA receptor in a subject.
• the present disclosure provides a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in modulating an NMDA receptor in a subject.
• the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in treating a disease, disorder, or condition requiring allosteric NMDA receptor modulation.
• the present disclosure provides a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in treating a disease, disorder, or condition requiring allosteric NMDA receptor modulation.
• the present disclosure provides the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for allosterically modulating an NMDA receptor.
• the present disclosure provides the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a disease, disorder, or condition requiring allosteric NMDA receptor modulation.
• compositions are described as having, including, or comprising (or variations thereof), specific components, it is contemplated that compositions also may consist essentially of, or consist of, the recited components.
• Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and/or diastereomers.
• the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
• Isomers e.g., stereoisomers
• HPLC high-performance liquid chromatography
• preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques el al.. Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen etal., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN 1972).
• the disclosure additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.
• isomers Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers.” Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers.” When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible.
• An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively).
• a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture.”
• a pure enantiomeric compounds substantially free from other enantiomers or stereoisomers of the compound i.e., in enantiomeric excess.
• enantiomerically pure or “pure enantiomer” denotes that the compound comprises more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or more than 99.9% by weight, of the enantiomer.
• the weights are based upon total weight of all enantiomers or stereoisomers of the compound.
• the term “diastereomeric purity” refers to the amount of a compound having the depicted absolute stereochemistry, expressed as a percentage of the total amount of the depicted compound and its diastereomers.
• diastereomerically pure denotes that the compound comprises more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or more than 99.9% by weight, of the diastereomer.
• Diastereomeric purity can be determined by any analytical method capable of quantitatively distinguishing between a compound and its diastereomers, such as high- performance liquid chromatography (HPLC) or supercritical fluid chromatograph (SFC).
• HPLC high- performance liquid chromatography
• SFC supercritical fluid chromatograph
• an enantiomerically pure compound can be present with other active or inactive ingredients.
• a pharmaceutical composition comprising enantiomerically pure (R)-position/center/carbon compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure (R)-compound.
• the enantiomerically pure (R)-compound in such compositions can, for example, comprise, at least about 95% by weight (A)-compound and at most about 5% by weight (S)-compound, by total weight of the compound.
• a pharmaceutical composition comprising enantiomerically pure (S)-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure (S)-compound.
• the enantiomerically pure (S)-compound in such compositions can, for example, comprise, at least about 95% by weight (S)-compound and at most about 5% by weight (R)-compound, by total weight of the compound.
• the active ingredient can be formulated with little or no excipient or carrier.
• H may be in any isotopic form, including 1 H, 2 H (D or deuterium), and 3 H (T or tritium); C may be in any isotopic form, including 12 C, 13 C, and 14 C; O may be in any isotopic form, including 16 O and 18 O; and the like.
• C 1-6 alkyl is intended to encompass, C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 alkyl.
• a “Aliphatic” refers to an alkyl, alkenyl, alkynyl, or carbocyclyl group, as defined herein.
• a “bivalent aliphatic” refers to a bivalent radical of an alkyl (i.e., alkylene), alkenyl (i.e., alkenylene), alkynyl (i.e., alkynylene), or carbocyclyl group.
• Alkyl refers to a radical of a straight-chain or branched saturated hydrocarbon group comprising from 1 to 50 carbon atoms (“C 1-50 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C 1 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“ C 1-2 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“ C 1-3 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“ C 1-4 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“ C 1-5 alkyl”).
• an alkyl group has 1 to 6 carbon atoms (“C 1-6 alkyl”), and so on.
• C 1-6 alkyl groups include methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-butyl (C 4 ), tert-butyl (C 4 ), sec-butyl (C 4 ), iso-butyl (C 4 ), n-pentyl (C 5 ), 3-pentanyl (C 5 ), amyl (C 5 ), neopentyl (C 5 ), 3-methyl-2-butanyl (C 5 ), tertiary amyl (C 5 ), and n-hexyl (C 6 ).
• each instance of an alkyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents; e.g., for instance from 1 to 4 substituents, 1 to 3 substituents, or 1 substituent.
• substituents e.g., for instance from 1 to 4 substituents, 1 to 3 substituents, or 1 substituent.
• Common alkyl abbreviations include Me (-CH 3 ), Et (-CH 2 CH 3 ), iPr (- CH(CH 3 ) 2 ), nPr (-CH 2 CH 2 CH 3 ), n-Bu (-CH 2 CH 2 CH 2 CH 3 ), or i-Bu (-CH 2 CH(CH 3 ) 2 ).
• alkylene As used herein, “alkylene,” “alkenylene,” “alkynylene,” “heteroalkylene,” “heteroalkenylene,” and “heteroalkynylene,” refer to a bivalent radical of an alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl group, respectively.
• a range or number of carbons is provided for a particular “alkylene,” “alkenylene,” “alkynylene,” “heteroalkylene,” “heteroalkenylene,” or “heteroalkynylene,” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon bivalent chain.
• Alkylene, “alkenylene,” “alkynylene,” “heteroalkylene,” “heteroalkenylene,” and “heteroalkynylene” groups may be substituted or unsubstituted with one or more substituents as described herein.
• Alkylene or “alkylene group” refers to an alkyl group wherein two hydrogens are removed to provide a bivalent radical, and which may be substituted or unsubstituted.
• Unsubstituted alkylene groups include, but are not limited to, methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene (-CH 2 CH 2 CH 2 -), butylene (-CH 2 CH 2 CH 2 CH 2 -), pentylene (-CH 2 CH 2 CH 2 CH 2 CH 2 -), hexylene (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -), and the like.
• substituted alkylene groups e.g., substituted with one or more halo, -NO 2 , -OH, C 1 -C 6 alkoxy, C 1 -C 6 alkyl (e.g., methyl) groups, including but not limited to, substituted methylene (-CH(CH 3 )-, (-C(CH 3 ) 2 -), substituted ethylene (-CH(CH 3 )CH 2 -,-CH 2 CH(CH 3 )-, -C(CH 3 ) 2 CH 2 -, -CH 2 C(CH 3 ) 2 -), substituted propylene (-CH(CH 3 )CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 -, -CH 2 CH 2 CH(CH 3 )-, -C(CH 3 ) 2 CH 2 CH 2 -, -CH 2 C(CH 3 ) 2 CH 2 -, -CH 2 CH 2 C(CH 3 ) 2 -), or C 1 methylene
• Alkylene abbreviations include, but are not limited to, -(CH(CH 3 ))-, -(CH(CH 2 CH 3 ))-, -(CH(CH 2 CH 2 CH 3 ))-, -(CH(CH 2 CH 2 CH 2 CH 3 ))-, -(CH(CH 2 CH(CH 2 CH 2 CH 3 ))-, -(CH 2 CH(CH 2 CH 2 CH 2 CH 3 ))-, -(CH 2 CH 2 CH(CH 2 CH 2 CH 3 ))-, -(CH(CH 3 )CH 2 )-, -(CH(CH 3 )CH 2 CH 2 CH 2 )-, -(CH 2 CH(CH 3 )CH 2 )-, -(CH 2 CH(CH 3 )CH 2 CH 2 )-, and -(CH 2 CH 2 CH(CH 3 )CH 2 CH 2 )-.
• alkenyl refers to a radical of a straight-chain or branched hydrocarbon group comprising from 2 to 50 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and optionally one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) (“C 2-50 alkenyl”). In certain embodiments, alkenyl does not contain any triple bonds. In some embodiments, an alkenyl group has 2 carbon atoms (“C 2 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C 2-3 alkenyl”).
• an alkenyl group has 2 to 4 carbon atoms (“C 2-4 alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“ C 2-5 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“ C 2-6 alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C 2-7 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C 2-8 alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C 2-9 alkenyl”).
• an alkenyl group has 2 to 10 carbon atoms (“C 2-10 alkenyl”), and so on.
• the one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl).
• Examples of C 2-4 alkenyl groups include ethenyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ), and the like.
• C 2-6 alkenyl groups include the aforementioned C 2-4 alkenyl groups as well as pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 ), and the like. Additional examples of alkenyl include heptenyl (C 7 ), octenyl (C 8 ), octatrienyl (C 8 ), and the like.
• alkenyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
• alkenylene refers to an alkenyl group wherein two hydrogens are removed to provide a bivalent radical, and which may be substituted or unsubstituted.
• substituted alkenylene groups e.g., substituted with one or more alkyl (methyl) groups
• Alkynyl refers to a radical of a straight-chain or branched hydrocarbon group comprising from 2 to 50 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and optionally one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) (“C 2-50 alkynyl”).
• an alkynyl group has 2 carbon atoms (“C 2 alkynyl”).
• an alkynyl group has 2 to 3 carbon atoms (“C 2-3 alkynyl”).
• an alkynyl group has 2 to 4 carbon atoms (“C 2-4 alkynyl”).
• an alkynyl group has 2 to 5 carbon atoms (“C 2-5 alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C 2-6 alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C 2-7 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C 2-8 alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C 2-9 alkynyl”). In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C2-10 alkynyl”), and so on.
• alkynyl does not contain any double bonds.
• the one or more carbon- carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl).
• Examples of C 2-4 alkynyl groups include, without limitation, ethynyl (C 2 ), 1-propynyl (C 3 ), 2-propynyl (C 3 ), 1-butynyl (C 4 ), 2-butynyl (C 4 ), and the like.
• Examples of C 2-6 alkenyl groups include the aforementioned C 2-4 alkynyl groups as well as pentynyl (C 5 ), hexynyl (C 6 ), and the like.
• alkynyl examples include heptynyl (C 7 ), octyny (C 8 ) , and the like.
• each instance of an alkynyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
• the alkynyl group is unsubstituted C 2-10 alkynyl.
• the alkynyl group is substituted C 2-10 alkynyl.
• Alkynylene refers to a linear alkynyl group wherein two hydrogens are removed to provide a bivalent radical, and which may be substituted or unsubstituted.
• exemplary bivalent alkynylene groups include, but are not limited to, substituted or unsubstituted ethynylene, substituted or unsubstituted propynylene, and the like.
• heteroalkyl refers to an alkyl group, as defined herein, which further comprises 1 or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) within the parent chain, wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and/or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment.
• a heteroalkyl group refers to a saturated group comprising from 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC 1-10 alkyl”).
• a heteroalkyl group is a saturated group comprising 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC 1-9 alkyl”). In some embodiments, a heteroalkyl group is a saturated group comprising 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC 1-8 alkyl”). In some embodiments, a heteroalkyl group is a saturated group comprising 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC 1-7 alkyl”). In some embodiments, a heteroalkyl group is a group comprising 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms (“heteroC 1-6 alkyl”).
• a heteroalkyl group is a saturated group comprising 1 to 5 carbon atoms and 1 or 2 heteroatoms (“heteroC 1- 5 alkyl”). In some embodiments, a heteroalkyl group is a saturated group comprising 1 to 4 carbon atoms and lor 2 heteroatoms (“heteroC 1-4 alkyl”). In some embodiments, a heteroalkyl group is a saturated group comprising 1 to 3 carbon atoms and 1 heteroatom (“heteroC 1-3 alkyl”). In some embodiments, a heteroalkyl group is a saturated group comprising 1 to 2 carbon atoms and 1 heteroatom (“heteroC 1-2 alkyl”).
• a heteroalkyl group is a saturated group comprising 1 carbon atom and 1 heteroatom (“heteroC 1 alkyl”). In some embodiments, a heteroalkyl group is a saturated group comprising 2 to 6 carbon atoms and 1 or 2 heteroatoms (“heteroC 2-6 alkyl”). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted heteroC 1-10 alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC 1-10 alkyl.
• heteroalkenyl refers to an alkenyl group, as defined herein, which further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and/or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment.
• one or more heteroatoms e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus
• a heteroalkenyl group refers to a group comprising from 2 to 10 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC 2-10 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC 2-9 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC 2-8 alkenyl”).
• a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-7 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1, 2, or 3 heteroatoms (“heteroC 2-6 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroC 2-5 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and lor 2 heteroatoms (“heteroC 2-4 alkenyl”).
• a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom (“heteroC 2-3 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroC 2-6 alkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents. In certain embodiments, the heteroalkenyl group is an unsubstituted heteroC 2-10 alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC 2-10 alkenyl.
• heteroalkynyl refers to an alkynyl group, as defined herein, which further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and/or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment.
• one or more heteroatoms e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus
• a heteroalkynyl group refers to a group comprising from 2 to 10 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC 2-10 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC 2-9 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC 2-8 alkynyl”).
• a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC 2-7 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1, 2, or 3 heteroatoms (“heteroC 2-6 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“heteroC 2-5 alkynyl”).
• a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and lor 2 heteroatoms (“heteroC 2-4 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom (“heteroC 2-3 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“heteroC 2-6 alkynyl”).
• each instance of a heteroalkynyl group is independently unsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a “substituted heteroalkynyl”) with one or more substituents.
• the heteroalkynyl group is an unsubstituted heteroC 2-10 alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC 2-10 alkynyl.
• Aryl refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 % electrons shared in a cyclic array) comprising 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C 6-14 aryl”).
• an aryl group has six ring carbon atoms (“C 6 aryl”; e.g., phenyl).
• Aryl also includes ring systems wherein the aryl ring, as defined herein, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.
• Typical aryl groups include, but are not limited to, 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, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene.
• aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl.
• each instance of an aryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents.
• the aryl group is unsubstituted C 6-14 aryl.
• the aryl group is substituted C 6-14 aryl.
• R 56 and R 57 may be hydrogen and at least one of R 56 and R 57 is each independently selected from C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, 4-10 membered heterocyclyl, alkanoyl, C 1 -C 8 alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR 58 COR 59 , NR 58 SOR 59 NR 58 SO 2 R 59 , COOalkyl, COOaryl, CONR 58 R 59 , CONR 58 OR 59 , NR 58 R 59 , SO 2 NR 58 R 59 , S-alkyl, SOalkyl, SO 2 alkyl, Saryl, SOaryl, SO 2 aryl; or R 56 and R 57 may be joined to form a cyclic ring (saturated or unsaturated) from
• R 60 and R 61 are independently hydrogen, C 1 -C 8 alkyl, C 1 -C 4 haloalkyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocyclyl, C 6 -C 10 aryl, substituted C 6 -C 10 aryl, 5-10 membered heteroaryl, or substituted 5- 10 membered heteroaryl.
• fused aryl refers to an aryl having two of its ring carbon in common with a second aryl or heteroaryl ring or with a carbocyclyl or heterocyclyl ring.
• Alkyl is a subset of alkyl and aryl, as defined herein, and refers to an optionally substituted alkyl group substituted by an optionally substituted aryl group.
• Heteroaryl refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 71 electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5-10 membered heteroaryl”).
• the point of attachment can be a carbon or nitrogen atom, as valency permits.
• Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings.
• Heteroaryl includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system.
• Heteroaryl also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl/heteroaryl) ring system.
• Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom e.g., indolyl, quinolinyl, carbazolyl, and the like
• the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5- indolyl).
• a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”).
• a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”).
• a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”).
• the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
• the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
• the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
• each instance of a heteroaryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents.
• the heteroaryl group is unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is substituted 5-14 membered heteroaryl.
• Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl.
• Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
• Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.
• Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl.
• Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl.
• Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.
• Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively.
• heteroaryls include the following: wherein each Z is selected from carbonyl, N, NR 65 , O, and S; and R 65 is independently hydrogen, C 1 -C 8 alkyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocyclyl, C 6 -C 10 aryl, and 5-10 membered heteroaryl.
• Heteroaralkyl is a subset of alkyl and heteroaryl, as defined herein, and refers to an optionally substituted alkyl group substituted by an optionally substituted heteroaryl group.
• Carbocyclyl refers to a radical of a non-aromatic cyclic hydrocarbon group comprising from 3 to 10 ring carbon atoms (“C 3 - 10 carbocyclyl”) and zero heteroatoms in the non-aromatic ring system.
• a carbocyclyl group has 3 to 8 ring carbon atoms (“C 3-8 carbocyclyl”).
• a carbocyclyl group has 3 to 6 ring carbon atoms (“C 3-6 carbocyclyl”).
• a carbocyclyl group has 3 to 6 ring carbon atoms (“C 3-6 carbocyclyl”).
• a carbocyclyl group has 5 to 10 ring carbon atoms (“C 5-10 carbocyclyl”).
• Exemplary C 3-6 carbocyclyl groups include, without limitation, cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), and the like.
• Exemplary C 3-8 carbocyclyl groups include, without limitation, the aforementioned C 3-6 carbocyclyl groups as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), bicyclo[2.2.1]heptanyl (C 7 ), bicyclo[2.2.2]octanyl (C 8 ,) and the like.
• Exemplary C 3-10 carbocyclyl groups include, without limitation, the aforementioned C 3-8 carbocyclyl groups as well as cyclononyl (C 9 ), cyclononenyl (C 9 ), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro- 1 H -in denyl (C 9 ), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ), and the like.
• the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) and can be saturated or can be partially unsaturated.
• “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system.
• each instance of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents.
• the carbocyclyl group is unsubstituted C 3-10 carbocyclyl.
• the carbocyclyl group is a substituted C 3-10 carbocyclyl.
• “carbocyclyl,” “carbocycle” or “carbocyclic” refers to a monocyclic, saturated carbocyclyl group comprising from 3 to 10 ring carbon atoms (“C 3-10 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C 3-8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C 3-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C 5-6 cycloalkyl”).
• a cycloalkyl group has 5 to 10 ring carbon atoms (“C 5-10 cycloalkyl”).
• C 5-6 cycloalkyl groups include cyclopentyl (C 5 ) and cyclohexyl (C 5 ).
• Examples of C 3-6 cycloalkyl groups include the aforementioned C 5-6 cycloalkyl groups as well as cyclopropyl (C 3 ) and cyclobutyl (C 4 ).
• C 3-8 cycloalkyl groups include the aforementioned C 3-6 cycloalkyl groups as well as cycloheptyl (C 7 ) and cyclooctyl (C 8 .)
• each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents.
• the cycloalkyl group is unsubstituted C 3-10 cycloalkyl.
• the cycloalkyl group is substituted C 3-10 cycloalkyl.
• Heterocyclyl refers to a radical of a 3- to 10- membered non-aromatic ring system comprising ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-10 membered heterocyclyl”).
• the point of attachment can be a carbon or nitrogen atom, as valency permits.
• a heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated.
• Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings.
• Heterocyclyl also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system.
• each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents.
• the heterocyclyl group is unsubstituted 3-10 membered heterocyclyl. In certain embodiments, the heterocyclyl group is substituted 3-10 membered heterocyclyl.
• a heterocyclyl group is a 5-10 membered non-aromatic ring system comprising ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 membered heterocyclyl”).
• a heterocyclyl group is a 5-8 membered non-aromatic ring system comprising ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”).
• a heterocyclyl group is a 5-6 membered non-aromatic ring system comprising ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”).
• the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
• the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
• the 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.
• Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl.
• Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl.
• Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2, 5-dione.
• Exemplary 5- membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one.
• Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
• Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.
• Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6- membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl.
• Exemplary 5-membered heterocyclyl groups fused to a Ce aryl ring include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like.
• Exemplary 6-membered heterocyclyl groups fused to an aryl ring include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.
• Hetero when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g, heteroalkyl, cycloalkyl, e.g., heterocyclyl, aryl, e.g., heteroaryl, cycloalkenyl, e.g, cycloheteroalkenyl, and the like comprising from 1 to 5, and particularly from 1 to 3 heteroatoms.
• alkyl e.g, heteroalkyl, cycloalkyl, e.g., heterocyclyl, aryl, e.g., heteroaryl, cycloalkenyl, e.g, cycloheteroalkenyl, and the like comprising from 1 to 5, and particularly from 1 to 3 heteroatoms.
• “Acyl” refers to a radical -C(O)R 20 , where R 20 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, as defined herein.
• “Alkanoyl” is an acyl group wherein R 20 is a group other than hydrogen.
• R 20 is C 1 -C 8 alkyl, substituted with halo or hydroxy; or C 3 -C 10 cycloalkyl, 4-10 membered heterocyclyl, C 6 -C 10 aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C 1 -C 4 alkyl, halo, unsubstituted C 1 -C 4 alkoxy, unsubstituted C 1 -C 4 haloalkyl, unsubstituted C 1 -C 4 hydroxyalkyl, or unsubstituted C 1 -C 4 haloalkoxy or hydroxy.
• Alkoxy refers to the group -OR 29 where R 29 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
• Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n- hexoxy, and 1,2-dimethylbutoxy.
• Particular alkoxy groups are lower alkoxy, i.e., with between 1 and 6 carbon atoms. Further particular alkoxy groups have between 1 and 4 carbon atoms.
• R 29 is a group that has 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, in particular 1 substituent, selected from the group consisting of amino, substituted amino, C 6 -C 10 aryl, aryloxy, carboxyl, cyano, C 3 -C 10 cycloalkyl, 4-10 membered heterocyclyl, halogen, 5-10 membered heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl- S(O) 2 - and aryl-S(O) 2 -.
• substituents for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, in particular 1 substituent, selected from the group consisting of amino, substituted amino, C 6 -C 10 aryl, aryloxy, carboxyl, cyano, C 3 -
• Exemplary ‘substituted alkoxy’ groups include, but are not limited to, -O-(CH 2 ) t (C 6 -C 10 aryl), -O-(CH 2 ) t (5-10 membered heteroaryl), -O-(CH 2 ) t ( C 3 -C 10 cycloalkyl), and -O-(CH 2 ) t (4-10 membered heterocyclyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocyclyl groups present, may themselves be substituted by unsubstituted C 1 -C 4 alkyl, halo, unsubstituted C 1 -C 4 alkoxy, unsubstituted Ci- C 4 haloalkyl, unsubstituted C 1 -C 4 hydroxyalkyl, or unsubstituted C 1 -C 4 haloalkoxy or hydroxy.
• Particular exemplary ‘substituted alkoxy’ groups are -OCF 3 , -OCH 2 CF 3 , -OCH 2 Ph, -OCH 2 -cyclopropyl, -OCH 2 CH 2 OH, and -OCH 2 CH 2 NMe 2 .
• Amino refers to the radical -NH 2 .
• Substituted amino refers to an amino group of the formula -N(R 38 ) 2 wherein R 38 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or an amino protecting group, wherein at least one of R 38 is not a hydrogen.
• each R 38 is independently selected from hydrogen, C 1 -C 8 alkyl, C 3 -C 8 alkenyl, C 3 -C 8 alkynyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, or C 3 - C 10 cycloalkyl; or C 1 -C 8 alkyl, substituted with halo or hydroxy; C 3 -C 8 alkenyl, substituted with halo or hydroxy; C 3 -C 8 alkynyl, substituted with halo or hydroxy, or -(CH 2 XC 6 -C 10 aryl), -(CH 2 )t(5-10 membered heteroaryl), -(CH 2 )t(C 3 -C 10 cycloalkyl), or -(CH 2 )t(4-10 membered heterocyclyl), wherein t is an integer between 0 and 8, each of which is substituted by unsubstit
• Exemplary “substituted amino” groups include, but are not limited to, -NR 39 -C 1 -C 8 alkyl, -NR 39 -(CH 2 )t(C 6 -C 10 aryl), -NR 39 -(CH2)t(5-10 membered heteroaryl), -NR 39 - (CH 2 XC 3 -C 10 cycloalkyl), and -NR 39 -(CH 2 X4-10 membered heterocyclyl), wherein t is an integer from 0 to 4, for instance 1 or 2, each R 39 independently represents H or C 1 -C 8 alkyl; and any alkyl groups present, may themselves be substituted by halo, substituted or unsubstituted amino, or hydroxy; and any aryl, heteroaryl, cycloalkyl, or heterocyclyl groups present, may themselves be substituted by unsubstituted C 1 -C 4 alkyl, halo, unsubstituted C 1 -C 4
• substituted amino includes the groups alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylamino, and substituted dialkylamino as defined below.
• Substituted amino encompasses both monosubstituted amino and disubstituted amino groups.
• Carboxy refers to the radical -C(O)OH.
• Halo refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I).
• the halo group is either fluoro or chloro.
• Haldroxy refers to the radical -OH.
• Niro refers to the radical -NO2.
• Cycloalkylalkyl refers to an alkyl radical in which the alkyl group is substituted with a cycloalkyl group.
• Typical cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl, and cyclooctylethyl, and the like.
• Heterocyclylalkyl refers to an alkyl radical in which the alkyl group is substituted with a heterocyclyl group.
• Typical heterocyclylalkyl groups include, but are not limited to, pyrrolidinylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyrrolidinylethyl, piperidinylethyl, piperazinylethyl, morpholinylethyl, and the like.
• Nonrogen-containing heterocyclyl means a 4- to 7- membered non-aromatic cyclic group containing at least one nitrogen atom, for example, but without limitation, morpholine, piperidine (e.g., 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g., 2-pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline, imidazolidinone, 2- pyrazoline, pyrazolidine, piperazine, and N-alkyl piperazines such as N-methyl piperazine. Particular examples include azetidine, piperidone and piperazone.
• a “wavy bond” or in the structures depicted herein refers to the point of attachment of the group.
• Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, as defined herein, are optionally substituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” carbocyclyl, “substituted” or “unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or “unsubstituted” heteroaryl group).
• substituted means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
• a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position.
• substituted is contemplated to include substitution with all permissible substituents of organic compounds, any of the substituents described herein that results in the formation of a stable compound.
• the present disclosure contemplates any and all such combinations in order to arrive at a stable compound.
• heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.
• a “counterion” or “anionic counterion” is a negatively charged group associated with a cationic quaternary amino group in order to maintain electronic neutrality.
• exemplary counterions include halide ions (e.g., F , Cl", Br , I"), NO 3 , CIO 4 , OH", H 2 PO 4 , HSO 4 -, SO 4 - 2 sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate, naphthal ene-2-sulfonate, naphthal ene-l-sulfonic acid-5-sulfonate, ethan-l-sulfonic acid-2-sulfonate, and the like), and carboxylate ions (e.g., acetate, ethanoate, propano
• Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms.
• Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, -OH, -OR aa , -N(R cc ) 2 , -CN, perhaloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5-14 membered heteroaryl, or two R cc groups attached to a nitrogen atom are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups, and wherein R
• “Pharmaceutically acceptable” means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.
• “Pharmaceutically acceptable salt” refers to a salt of a compound disclosed herein that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
• such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts.
• such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2- naphthalenesulfonic acid, 4-toluenesulf
• Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
• pharmaceutically acceptable cation refers to an acceptable cationic counter- ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like. See, e.g., Berge, et al., J. Pharm. Sci. (1977) 66(1): 1-79.
• “Pharmaceutically acceptable carrier” refers to compositions, carriers, diluents, and reagents which are pharmaceutically acceptable materials that are capable of administration to or upon a subject.
• a pharmaceutically acceptable carrier can be involved with carrying or transporting the subject agents from one organ, or portion of the body, to another organ, or portion of the body.
• the carrier can be in the form of a solid, semi-solid or liquid diluent, cream or a capsule.
• the active ingredient can be mixed with excipients which are pharmaceutically acceptable and compatible with the active ingredient and in amounts suitable for use in the therapeutic methods described herein. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol or the like and combinations thereof.
• isotopic variant refers to a compound disclosed herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof), wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
• isotopes that can be incorporated into compounds of the present application include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 32 P, 33 P, 33 S, 34 S, 35 S, 18 F, and 37 C1.
• Isotopic variants of compounds and pharmaceutically acceptable salts thereof disclosed herein can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples, by substituting a readily available isotopically-labeled reagent for a non-isotopically-labeled reagent.
• a “subject” to which administration is contemplated includes, but is not limited to, a human subject (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and/or dogs.
• the subject is a human.
• the subject is a non-human animal.
• the terms “human,” “patient,” and “subject” are used interchangeably herein.
• the term “treat,” “treating,” or “treatment” includes reversing, reducing, or arresting the symptoms, clinical signs, and underlying pathology of a condition in a manner to improve or stabilize a subject’s condition.
• treatment is an approach for obtaining beneficial or desired results, including clinical results.
• Beneficial or desired clinical results can include, but are not limited to, alleviation, amelioration, reduction of the severity, or slowing the progression of one or more symptoms or conditions associated with a condition, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment.
• prophylactic contemplates an action that occurs before a subject begins to suffer from the specified disease, disorder, or condition.
• the “effective amount” of a compound refers to an amount sufficient to elicit the desired biological response.
• the effective amount of a compound of the disclosure may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health, and condition of the subject.
• An effective amount encompasses therapeutic and prophylactic treatment.
• a therapeutically effective amount refers to an amount sufficient to treat a disease in a patient, e.g., effecting a beneficial and/or desirable alteration in the health of a patient suffering from a disease, treatment, healing, inhibition or amelioration of a physiological response or condition, delaying or minimizing one or more symptoms associated with the disease, disorder, or condition etc.
• the full therapeutic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses.
• a therapeutically effective amount may be administered in one or more administrations.
• the precise effective amount needed for a subject will depend upon, for example, the subject’s size, health and age, the nature and extent of disease, the therapeutics or combination of therapeutics selected for administration, and the mode of administration. The skilled worker can readily determine the effective amount for a given situation by routine experimentation.
• pharmaceutically effective amount also refer to the amount required to improve the clinical symptoms of a patient.
• a therapeutically effective amount of a compound also refers to an amount of the therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder, or condition.
• therapeutically effective amount can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.
• a “prophylactically effective amount” of a compound is an amount sufficient to prevent a disease, disorder, or condition, or one or more symptoms associated with the disease, disorder, or condition, or prevent its recurrence.
• a prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the disease, disorder, or condition.
• the term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.
• “pharmacokinetics” can be defined as the study of bodily absorption, distribution, metabolism, and excretion of drugs. “Pharmacokinetics” can also be defined as the characteristic interactions of a drug and a body in terms of its absorption, distribution, metabolism, and excretion; or a branch of pharmacology concerned with the way drugs are taken into, move around, and are eliminated from, a body.
• administering or “administration of’ a substance, a compound or an agent to a subject can be carried out using one of a variety of methods known to those skilled in the art.
• a compound or an agent can be administered, intravenously, arterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, ocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (by absorption, e.g., through a skin duct).
• a compound or agent can also appropriately be introduced by rechargeable or biodegradable polymeric devices or other devices, e.g., patches and pumps, or formulations, which provide for the extended, slow or controlled release of the compound or agent.
• Administering can also be performed, for example, once, a plurality of times, and/or over one or more extended periods.
• the administration includes both direct administration, including selfadministration, and indirect administration, including the act of prescribing a drug.
• a physician who instructs a patient to self-administer a drug, or to have the drug administered by another, and/or who provides a patient with a prescription for a drug is administering the drug to the patient.
• the disclosure contemplates that the agents may be administered at the same or differing times and via the same or differing routes of administration.
• Appropriate methods of administering a substance, a compound or an agent to a subject will also depend, for example, on the age of the subject, whether the subject is active or inactive at the time of administering, whether the subject is cognitively impaired at the time of administering, the extent of the impairment, and the chemical and biological properties of the compound or agent (e.g., solubility, digestibility, bioavailability, stability, and toxicity).
• lipid refers to natural and non-natural hydrophobic and/or lipophilic fats, oils, polymers, hydrocarbons, and other such materials.
• suitable lipids when incorporated into a compound, are processed or metabolized similarly to triglycerides in the gastrointestinal tract or mimic such processing or metabolism.
• glyceride refers to an ester of glycerol (1,2,3-propanetriol) with acyl radicals of fatty acids or other lipids and is also known as an acylglycerol.
• a “monoglyceride” is a glycerol molecule wherein only one position of the molecule is esterified with a fatty acid.
• a “diglyceride” is a glycerol molecule wherein two positions of the molecule are esterified with fatty acids.
• a “diglyceride” is a glycerol molecule wherein three positions of the molecule are esterified with fatty acids.
• a “simple glyceride” is one where all esterified positions contain the same fatty acid.
• a “mixed glyceride” is one where different fatty acids are present at the esterified positions.
• the carbons of the glycerol backbone are designated sn-1, sn-2 and sn-3, with sn-2 being in the middle and sn-1 and sn-3 being the ends of the glycerol.
• cleavable moiety refers to a chemical moiety that may be cleaved via hydrolysis, reduction, or enzymatic reaction.
• Cleavable moieties include, but are not limited to acid-labile moieties, hydrolysis-labile moieties, enzymatically cleavable moieties, reduction labile moieties, and self-immolative moieties.
• self-immolative moiety refers to a bivalent chemical moiety that comprises a covalent, scissile bond as one of its bivalent bonds and a stable, covalent bond with a therapeutic agent as its other bivalent bond, wherein the bond with the therapeutic agent becomes labile upon cleavage of the scissile bond.
• the self-immolative group can be any such group known to those of skill in the art.
• self-immolative moieties include, but are not limited to, disulfide groups, hydrazones, acetal self-immolative moieties, carboxyacetal self-immolative moieties, carboxy(methylacetal) self-immolative moieties, para-hydroxybenzyl carbonyl self-immolative moieties, flipped ester self- immolative moieties, and trimethyl lock, or 2-hydroxyphenyl carbamate (2-HPC) self- immolative moieties.
• Other suitable self-immolative moieties are known in the art as described, for example, in C. Blencowe et al., Polym. Chem. 2011, 2, 773-790 and Kratz et al., ChemMedChem.
• acid labile refers to a molecule or compound that is sensitive to acids and can be cleaved or undergo significant changes in its structure or properties when exposed to acidic conditions.
• the disclosure provides compounds useful for preventing and/or treating a broad range of disorders, including, but not limited to, NMDA- mediated disorders. These compounds are expected to show, inter alia, improved in vivo potency, pharmacokinetic (PK) properties, oral bioavailability, formulatability, stability, and/or safety.
• PK pharmacokinetic
• the disclosure provides a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein:
• Q is -C 1-8 alkylene-; each of R 1 and R 2 is independently hydrogen, an acid-labile group, a lipid, or - C(O)R 3 ; each R 3 is independently an optionally substituted C 1-40 aliphatic;
• X is -O-, -NR-, -S-, -O(C 1-6 aliphatic)-O-, -O(C 1-6 aliphatic)-S-,
• each R is independently hydrogen, or an optionally substituted group selected from the group consisting of C 1-6 aliphatic, 3-8 membered carbocycle, C 6-10 aryl, 4-8 membered heterocycle comprising 1-2 hetero
• Y is absent, -C(O)-, -C(NR)-, or -C(S)-;
• Z is absent or an optionally substituted bivalent C 1-30 aliphatic, wherein 0-8 methylene units of Z are independently replaced by -R 8 -, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O) 2 -, -C(S)-, -OS(O) 2 -, -S(O) 2 O-, -NRS(O) 2 -, -S(O) 2 NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-, or an amino acid; and wherein one methylene unit of Z is optionally replaced with -M-; or
• Z is selected from the group consisting of -C(R 4a )(R 4b )C(O)-M-, C(R 4a )(R 4b )-M-, -C(R 4a )(R 4b )C(R 5a )(R 5b )(CH 2 ) n C(O)-M-, -C(R 4a )(R 4b )C(R 5a )(R 5b )(CH 2 ) n -M-, -(CH 2 ) m C(R 4a )(R 4b )(CH 2 ) n C(R 5a )(R 5b )(CH 2 ) m C(O)-M-, and -(CH 2 ) m C(R 4a )(R 4b )(CH 2 ) n C(R 5a )(R 5b )(CH 2 ) m -M-; wherein either side of Z may be attached to
• R 4a and R 4b or R 5a and R 5b together with the carbon atom to which they are attached, form a C 3-6 carbocycle or a 3-6 membered heterocycle comprising 1-2 heteroatoms independently selected from the group consisting of N, O and S; each R 9 is independently selected from the group consisting of 3-8 membered carbocycle, C 6-10 aryl, 4-8 membered heterocycle comprising 1-2 heteroatoms independently selected from the group consisting of N, O, and S, and 5-10 membered heteroaryl comprising 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; each R 10 is independently selected from the group consisting of C 1-6 aliphatic optionally substituted with 1 to 6 -CN, -OR, -NR 2 , -SR, -R 9 , deuterium or halogen;
• -M- is a cleavable moiety; each n is independently 0-18; each m is independently 0-6; p is 1 or 2; and
• Agent is selected from the group consisting of:
• the disclosure provides a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: each of R 1 and R 2 is independently hydrogen, an acid-labile group, a lipid, or -C(O)R 3 ; each R 3 is independently an optionally substituted C 1-40 aliphatic;
• X is -O-, -NR-, -S-, -O(C 1-6 aliphatic)-O-, -O(C 1-6 aliphatic)-S-,
• each R is independently hydrogen, or an optionally substituted group selected from the group consisting of C 1-6 aliphatic, 3-8 membered carbocycle, C 6-10 aryl, 4-8 membered heterocycle comprising 1-2 hetero
• Y is absent, -C(O)-, -C(NR)-, or -C(S)-;
• Z is absent or an optionally substituted bivalent C1-30 aliphatic, wherein 0-8 methylene units of Z are independently replaced by -R 8 -, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O) 2 -, -C(S)-, -OS(O) 2 -, -S(O) 2 O-, -NRS(O) 2 -, -S(O) 2 NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-, or an amino acid; and wherein one methylene unit of Z is optionally replaced with -M-; or
• Z is selected from the group consisting of -C(R 4a )(R 4b )C(O)-M-, C(R 4a )(R 4b )-M-, -C(R 4a )(R 4b )C(R 5a )(R 5b )(CH 2 ) n C(O)-M-, -C(R 4a )(R 4b )C(R 5a )(R 5b )(CH 2 ) n -M-, -(CH 2 ) m C(R 4a )(R 4b )(CH 2 ) n C(R 5a )(R 5b )(CH 2 ) m C(O)-M-, and -(CH 2 ) m C(R 4a )(R 4b )(CH 2 ) n C(R 5a )(R 5b )(CH 2 ) m -M-; wherein either side of Z may be attached to
• R 4a and R 4b or R 5a and R 5b together with the carbon atom to which they are attached, form a C 3-6 carbocycle or a 3-6 membered heterocycle comprising 1-2 heteroatoms independently selected from the group consisting of N, O and S; each R 9 is independently selected from the group consisting of 3-8 membered carbocycle, C 6-10 aryl, 4-8 membered heterocycle comprising 1-2 heteroatoms independently selected from the group consisting of N, O, and S, and 5-10 membered heteroaryl comprising 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; each R 10 is independently selected from the group consisting of C 1-6 aliphatic optionally substituted with 1 to 6 -CN, -OR, -NR2, -SR, -R 9 , deuterium or halogen;
• -M- is a cleavable moiety; each n is independently 0-18; each m is independently 0-6; p is 1 or 2; and
• Agent is selected from the group consisting of:
• W is In some embodiments, W is In some embodiments, W is In some embodiments, W is . In some embodiments, W is -C(O)N-(R 3 )2.
• Q is -C 1-8 alkylene-. In some embodiments, Q is -C 1-6 alkylene-. In some embodiments, Q is -C 1 alkylene-. In some embodiments, Q is -C 2 alkylene-. In some embodiments, Q is -C 3 alkylene-. In some embodiments, Q is -C 4 alkylene-. In some embodiments, Q is -C 5 alkylene-. In some embodiments, Q is -C 6 alkylene-. In some embodiments, Q is -C 7 alkylene-. In some embodiments, Q is -C 8 alkylene-.
• R 1 is hydrogen. In some embodiments, R 1 is an acid-labile group. In some embodiments, R 1 is a lipid. In some embodiments, R 1 is a fatty acid. In some embodiments, R 1 is -C(O)R 3 .
• R 2 is hydrogen. In some embodiments, R 2 is an acid-labile group. In some embodiments, R 2 is a lipid. In some embodiments, R 2 is a fatty acid. In some embodiments, R 2 is -C(O)R 3 .
• R 1 is a lipid.
• R 2 is a lipid.
• lipids include fatty acids. Exemplary fatty acids may be saturated or unsaturated medium- chain or long-chain fatty acids.
• the fatty acid comprises a C 2-40 aliphatic group. In some embodiments, the fatty acid comprises a C 2 aliphatic group. In some embodiments, the fatty acid comprises a C 3 aliphatic group. In some embodiments, the fatty acid comprises a C 4 aliphatic group. In some embodiments, the fatty acid comprises a C 5 aliphatic group. In some embodiments, the fatty acid comprises a C 6 aliphatic group.
• the fatty acid comprises a C 7 aliphatic group. In some embodiments, the fatty acid comprises a C 8 aliphatic group. In some embodiments, the fatty acid comprises a C 9 aliphatic group. In some embodiments, the fatty acid comprises a C 10 aliphatic group. In some embodiments, the fatty acid comprises a C 11 aliphatic group. In some embodiments, the fatty acid comprises a C 12 aliphatic group. In some embodiments, the fatty acid comprises a C 13 aliphatic group. In some embodiments, the fatty acid comprises a C 14 aliphatic group. In some embodiments, the fatty acid comprises a C 15 aliphatic group.
• the fatty acid comprises a C 16 aliphatic group. In some embodiments, the fatty acid comprises a C 17 aliphatic group. In some embodiments, the fatty acid comprises a C 18 aliphatic group. In some embodiments, the fatty acid comprises a C 19 aliphatic group. In some embodiments, the fatty acid comprises a C 20 aliphatic group. In some embodiments, the fatty acid comprises a C 21 aliphatic group. In some embodiments, the fatty acid comprises a C 22 aliphatic group. In some embodiments, the fatty acid comprises a C 23 aliphatic group. In some embodiments, the fatty acid comprises a C 24 aliphatic group.
• the fatty acid comprises a C 25 aliphatic group. In some embodiments, the fatty acid comprises a C 26 aliphatic group. In some embodiments, the fatty acid comprises a C 27 aliphatic group. In some embodiments, the fatty acid comprises a C 28 aliphatic group. In some embodiments, the fatty acid comprises a C 29 aliphatic group. In some embodiments, the fatty acid comprises a C 30 aliphatic group. In some embodiments, the fatty acid comprises a C 31 aliphatic group. In some embodiments, the fatty acid comprises a C 32 aliphatic group. In some embodiments, the fatty acid comprises a C 33 aliphatic group.
• the fatty acid comprises a C 34 aliphatic group. In some embodiments, the fatty acid comprises a C 35 aliphatic group. In some embodiments, the fatty acid comprises a C 36 aliphatic group. In some embodiments, the fatty acid comprises a C 37 aliphatic group. In some embodiments, the fatty acid comprises a C 38 aliphatic group. In some embodiments, the fatty acid comprises a C 39 aliphatic group. In some embodiments, the fatty acid comprises a C 40 aliphatic group.
• R 1 is an acid labile group.
• R 2 is an acid labile group.
• Exemplary acid labile groups include, but are not limited to, -C(O)OR, -C(O)NR 2 , -CH 2 OR, -C(NR)R, -P(O) 2 OR, an amino acid or a PEG group.
• R 1 and R 2 are the same. In some embodiments, R 1 and R 2 are different.
• each R 3 is independently a substituted C 1-40 aliphatic. In some embodiments, each R 3 is independently a substituted C 1 aliphatic. In some embodiments, each R 3 is independently a substituted C 2 aliphatic. In some embodiments, each R 3 is independently a substituted C 3 aliphatic. In some embodiments, each R 3 is independently a substituted C 4 aliphatic. In some embodiments, each R 3 is independently a substituted C 5 aliphatic. In some embodiments, each R 3 is independently a substituted C 6 aliphatic. In some embodiments, each R 3 is independently a substituted C 7 aliphatic.
• each R 3 is independently a substituted C 8 aliphatic. In some embodiments, each R 3 is independently a substituted C 9 aliphatic. In some embodiments, each R 3 is independently a substituted C 10 aliphatic. In some embodiments, each R 3 is independently a substituted C 11 aliphatic. In some embodiments, each R 3 is independently a substituted C 12 aliphatic. In some embodiments, each R 3 is independently a substituted C 13 aliphatic. In some embodiments, each R 3 is independently a substituted C 14 aliphatic. In some embodiments, each R 3 is independently a substituted C 15 aliphatic. In some embodiments, each R 3 is independently a substituted C 16 aliphatic.
• each R 3 is independently a substituted C 17 aliphatic. In some embodiments, each R 3 is independently a substituted C 18 aliphatic. In some embodiments, each R 3 is independently a substituted C 19 aliphatic. In some embodiments, each R 3 is independently a substituted C 20 aliphatic. In some embodiments, each R 3 is independently a substituted C 21 aliphatic. In some embodiments, each R 3 is independently a substituted C 22 aliphatic. In some embodiments, each R 3 is independently a substituted C 23 aliphatic. In some embodiments, each R 3 is independently a substituted C 24 aliphatic. In some embodiments, each R 3 is independently a substituted C 25 aliphatic.
• each R 3 is independently a substituted C 26 aliphatic. In some embodiments, each R 3 is independently a substituted C 27 aliphatic. In some embodiments, each R 3 is independently a substituted C 28 aliphatic. In some embodiments, each R 3 is independently a substituted C 29 aliphatic. In some embodiments, each R 3 is independently a substituted C 30 aliphatic. In some embodiments, each R 3 is independently a substituted C 31 aliphatic. In some embodiments, each R 3 is independently a substituted C 32 aliphatic. In some embodiments, each R 3 is independently a substituted C 33 aliphatic. In some embodiments, each R 3 is independently a substituted C 34 aliphatic.
• each R 3 is independently a substituted C 35 aliphatic. In some embodiments, each R 3 is independently a substituted C 36 aliphatic. In some embodiments, each R 3 is independently a substituted C 37 aliphatic. In some embodiments, each R 3 is independently a substituted C 38 aliphatic. In some embodiments, each R 3 is independently a substituted C 39 aliphatic. In some embodiments, each R 3 is independently a substituted C 40 aliphatic.
• each R 3 is independently an optionally substituted C 1-40 aliphatic. In some embodiments, each R 3 is independently an optionally substituted C 1 aliphatic. In some embodiments, each R 3 is independently an optionally substituted C 2 aliphatic. In some embodiments, each R 3 is independently an optionally substituted C 3 aliphatic. In some embodiments, each R 3 is independently an optionally substituted C 4 aliphatic. In some embodiments, each R 3 is independently an optionally substituted C 5 aliphatic. In some embodiments, each R 3 is independently an optionally substituted C 6 aliphatic. In some embodiments, each R 3 is independently an optionally substituted C 7 aliphatic.
• each R 3 is independently an optionally substituted C 8 aliphatic. In some embodiments, each R 3 is independently an optionally substituted C 9 aliphatic. In some embodiments, each R 3 is independently an optionally substituted C 10 aliphatic. In some embodiments, each R 3 is independently an optionally substituted C 11 aliphatic. In some embodiments, each R 3 is independently an optionally substituted C 12 aliphatic. In some embodiments, each R 3 is independently an optionally substituted C 13 aliphatic. In some embodiments, each R 3 is independently an optionally substituted C 14 aliphatic. In some embodiments, each R 3 is independently an optionally substituted C 15 aliphatic.
• each R 3 is independently an optionally substituted C 16 aliphatic. In some embodiments, each R 3 is independently an optionally substituted C 17 aliphatic. In some embodiments, each R 3 is independently an optionally substituted C 18 aliphatic. In some embodiments, each R 3 is independently an optionally substituted C 19 aliphatic. In some embodiments, each R 3 is independently an optionally substituted C 20 aliphatic. In some embodiments, each R 3 is independently an optionally substituted C 21 aliphatic. In some embodiments, each R 3 is independently an optionally substituted C 22 aliphatic. In some embodiments, each R 3 is independently an optionally substituted C 23 aliphatic.
• each R 3 is independently an optionally substituted C 24 aliphatic. In some embodiments, each R 3 is independently an optionally substituted C 25 aliphatic. In some embodiments, each R 3 is independently an optionally substituted C 26 aliphatic. In some embodiments, each R 3 is independently an optionally substituted C 27 aliphatic. In some embodiments, each R 3 is independently an optionally substituted C 28 aliphatic. In some embodiments, each R 3 is independently an optionally substituted C 29 aliphatic. In some embodiments, each R 3 is independently an optionally substituted C 30 aliphatic. In some embodiments, each R 3 is independently an optionally substituted C 31 aliphatic.
• each R 3 is independently an optionally substituted C 32 aliphatic. In some embodiments, each R 3 is independently an optionally substituted C 33 aliphatic. In some embodiments, each R 3 is independently an optionally substituted C 34 aliphatic. In some embodiments, each R 3 is independently an optionally substituted C 35 aliphatic. In some embodiments, each R 3 is independently an optionally substituted C 36 aliphatic. In some embodiments, each R 3 is independently an optionally substituted C 37 aliphatic. In some embodiments, each R 3 is independently an optionally substituted C 38 aliphatic. In some embodiments, each R 3 is independently an optionally substituted C 39 aliphatic. In some embodiments, each R 3 is independently an optionally substituted C 40 aliphatic.
• each R 3 is independently C 1-40 aliphatic. In some embodiments, each R 3 is independently C 1 aliphatic. In some embodiments, each R 3 is independently C 2 aliphatic. In some embodiments, each R 3 is independently C3 aliphatic. In some embodiments, each R 3 is independently C4 aliphatic. In some embodiments, each R 3 is independently C 5 aliphatic. In some embodiments, each R 3 is independently C 6 aliphatic. In some embodiments, each R 3 is independently C 7 aliphatic. In some embodiments, each R 3 is independently C 8 aliphatic. In some embodiments, each R 3 is independently C 9 aliphatic. In some embodiments, each R 3 is independently C 10 aliphatic.
• each R 3 is independently C 11 aliphatic. In some embodiments, each R 3 is independently C 12 aliphatic. In some embodiments, each R 3 is independently C 13 aliphatic. In some embodiments, each R 3 is independently C 14 aliphatic. In some embodiments, each R 3 is independently C 15 aliphatic. In some embodiments, each R 3 is independently C 16 aliphatic. In some embodiments, each R 3 is independently C 17 aliphatic. In some embodiments, each R 3 is independently C 18 aliphatic. In some embodiments, each R 3 is independently C 19 aliphatic. In some embodiments, each R 3 is independently C 20 aliphatic. In some embodiments, each R 3 is independently C 21 aliphatic.
• each R 3 is independently C 22 aliphatic. In some embodiments, each R 3 is independently C 23 aliphatic. In some embodiments, each R 3 is independently C 24 aliphatic. In some embodiments, each R 3 is independently C 25 aliphatic. In some embodiments, each R 3 is independently C 26 aliphatic. In some embodiments, each R 3 is independently C 27 aliphatic. In some embodiments, each R 3 is independently C 28 aliphatic. In some embodiments, each R 3 is independently C 29 aliphatic. In some embodiments, each R 3 is independently C 30 aliphatic. In some embodiments, each R 3 is independently C 31 aliphatic. In some embodiments, each R 3 is independently C 32 aliphatic.
• each R 3 is independently C 33 aliphatic. In some embodiments, each R 3 is independently C 34 aliphatic. In some embodiments, each R 3 is independently C 35 aliphatic. In some embodiments, each R 3 is independently C 36 aliphatic. In some embodiments, each R 3 is independently C 37 aliphatic. In some embodiments, each R 3 is independently C 38 aliphatic. In some embodiments, each R 3 is independently C 39 aliphatic. In some embodiments, each R 3 is independently C 40 aliphatic.
• X is -O-. In some embodiments, X is -NR-. In some embodiments, X is -S-. In some embodiments, X is -O(C 1-6 aliphatic)-O-, wherein 0-2 methylene units of the C 1-6 aliphatic group are independently and optionally replaced with -O-, -NR-, or -S-, and wherein each instance of C 1-6 aliphatic is independently and optionally substituted with 1-3 deuterium or halogen.
• X is -O(C 1-6 aliphatic)-S-, wherein 0-2 methylene units of the C 1-6 aliphatic group are independently and optionally replaced with -O-, -NR-, or -S-, and wherein each instance of C 1-6 aliphatic is independently and optionally substituted with 1-3 deuterium or halogen.
• X is -O(C 1-6 aliphatic)-NR-, wherein 0-2 methylene units of the C 1-6 aliphatic group are independently and optionally replaced with -O-, -NR-, or -S-, and wherein each instance of C 1-6 aliphatic is independently and optionally substituted with 1-3 deuterium or halogen.
• X is -S(C 1-6 aliphatic)-O-, wherein 0-2 methylene units of the C 1-6 aliphatic group are independently and optionally replaced with -O-, -NR-, or -S-, and wherein each instance of C 1-6 aliphatic is independently and optionally substituted with 1-3 deuterium or halogen.
• X is -S(C 1-6 aliphatic)-S-, wherein 0-2 methylene units of the C 1-6 aliphatic group are independently and optionally replaced with -0-, -NR-, or -S-, and wherein each instance of C 1-6 aliphatic is independently and optionally substituted with 1-3 deuterium or halogen.
• X is
• X is -NR(C 1-6 aliphatic)-O-, wherein 0-2 methylene units of the C 1-6 aliphatic group are independently and optionally replaced with -O-, -NR-, or -S-, and wherein each instance of C 1-6 aliphatic is independently and optionally substituted with 1-3 deuterium or halogen.
• X is -NR(C 1-6 aliphatic)-O-, wherein 0-2 methylene units of the C 1-6 aliphatic group are independently and optionally replaced with -O-, -NR-, or -S-, and wherein each instance of C 1-6 aliphatic is independently and optionally substituted with 1-3 deuterium or halogen.
• X is -NR(C 1-6 aliphatic)-S-, wherein 0-2 methylene units of the C 1-6 aliphatic group are independently and optionally replaced with -O-, -NR-, or -S-, and wherein each instance of C 1-6 aliphatic is independently and optionally substituted with 1-3 deuterium or halogen.
• X is
• X is -(C 1-6 aliphatic)-. In some embodiments, X is -O(C 1-6 aliphatic)-O-. In some embodiments, X is -O(C 1-6 aliphatic)-S-. In some embodiments, X is -O(C 1-6 aliphatic)-NR-.
• X is -S(C 1-6 aliphatic)-O-. In some embodiments, X is -S(C 1-6 aliphatic)-S-. In some embodiments, X is -S(C 1-6 aliphatic)-NR-. In some embodiments, X is -NR(C 1-6 aliphatic)-O-. In some embodiments, X is
• X is -NR(C 1-6 aliphatic)-NR-. In some embodiments, X is -(C 1-6 aliphatic)-.
• R is hydrogen
• R is an optionally substituted -6 aliphatic. In some embodiments, R is an optionally substituted 3-8 membered carbocycle. In some embodiments, R is an optionally substituted C 6-10 aryl. In some embodiments, R is an optionally substituted 4-8 membered heterocycle comprising 1-2 heteroatoms independently selected from the group consisting of N, O and S. In some embodiments, R is an optionally substituted 5-10 membered heteroaryl comprising 1-4 heteroatoms independently selected from the group consisting of N, O, and S.
• R is selected from the group consisting of hydrogen, C 1-6 aliphatic, 3-8 membered carbocycle, C 6-10 aryl, 4-8 membered heterocycle comprising 1- 2 heteroatoms independently selected from the group consisting of N, O and S, and 5-10 membered heteroaryl comprising 1-4 heteroatoms.
• R is a Ci16 aliphatic.
• R is a 3-8 membered carbocycle.
• R is a 4-8 membered heterocycle comprising 1-2 heteroatoms independently selected from the group consisting of N, O and S.
• R is a 5-10 membered heteroaryl comprising 1-4 heteroatoms independently selected from the group consisting of N, O and S.
• R is a substituted -6 aliphatic. In some embodiments, R is a substituted 3-8 membered carbocycle. In some embodiments, R is a substituted C 6-10 aryl. In some embodiments, R is a substituted 4-8 membered heterocycle comprising 1-2 heteroatoms independently selected from the group consisting of N, O and S. In some embodiments, R is a substituted 5-10 membered heteroaryl comprising 1-4 heteroatoms independently selected from the group consisting of N, O and S.
• Y is absent. In some embodiments, Y is -C(O)-. In some embodiments, Y is -C(NR)-. In some embodiments, Y is -C(S)-.
• Z is absent.
• Z is an optionally substituted bivalent C1-30 aliphatic, wherein 0-8 methylene units of Z are independently replaced by -R 8 -, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O) 2 -, -C(S)-, -N(R)S(O) 2 -, -S(O) 2 NR-, -N(R)C(O)-, -C(O)NR-, -OC(O)NR-, - N(R)C(O)O-, or an amino acid; and wherein 1 methylene unit of Z is optionally replaced with -M-.
• Z is an optionally substituted C 1-30 alkylene (i.e., Cialkylene, C 2 alkylene, C 3 alkylene, C 4 alkylene, C 5 alkylene, C 6 alkylene, C 7 alkylene, C 8 alkylene, C 9 alkylene, C 10 alkylene, C 11 alkylene, C 12 alkylene, C 13 alkylene, C 14 alkylene, C 15 alkylene, C 16 alkylene, C 17 alkylene, C 18 alkylene, C19 alkylene, C 20 alkylene, C 21 alkylene, C 22 alkylene, C 23 alkylene, C 24 alkylene, C 25 alkylene, C 26 alkylene, C 27 alkylene, C 28 alkylene, C 29 alkylene or C 30 alkylene), wherein 0-8 (i.e., 0, 1, 2, 3, 4, 5, 6, 7, or 8) methylene units of Z are independently replaced by -R 8 -, -O-, -NR-, -S
• Z is an optionally substituted C 2 -3oalkenylene (i.e., C 2 alkenylene, C 3 alkenylene, C 4 alkenylene, C 5 alkenylene, C 6 alkenylene, C 7 alkenylene, C 8 alkenylene, C 9 alkenylene, C 10 alkenylene, C 11 alkenylene, C 12 alkenylene, C 13 alkenylene, C 14 alkenylene, C 15 alkenylene, C 16 alkenylene, C 17 alkenylene, C 18 alkenylene, C 19 alkenylene, C 20 alkenylene, C 21 alkenylene, C 22 alkenylene, C 23 alkenylene, C 24 alkenylene, C 25 alkenylene, C 26 alkenylene, C 27 alkenylene, C 28 alkenylene, C 29 alkenylene or C 30 alkenylene), wherein 0-8 methylene units of Z are independently replaced by -R 8 -
• Z is an optionally substituted C 2-30 alkynylene (i.e., C 2 alkynylene, C 3 alkynylene, C 4 alkynylene, C 5 alkynylene, C 6 alkynylene, C 7 alkynylene, C 8 alkynylene, C 9 alkynylene, C 10 alkynylene, C 11 alkynylene, C 12 alkynylene, C 13 alkynylene, C 14 alkynylene, C 15 alkynylene, C 16 alkynylene, C 17 alkynylene, C 18 alkynylene, C 19 alkynylene, C 20 alkynylene, C 21 alkynylene, C 22 alkynylene, C 23 alkynylene, C 24 alkynylene, C 25 alkynylene, C 26 alkynylene, C 27 alkynylene, C 28 alkynylene, C 29 alkynylene or C
• Z is a bivalent C1-30 aliphatic, wherein 0-8 methylene units of Z are independently replaced by -R 8 -, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O) 2 -, -C(S)-, -N(R)S(O) 2 -, -S(O) 2 NR-, -N(R)C(O)-, -C(O)NR-, -OC(O)NR-, -N(R)C(O)O-, or an amino acid; and wherein 1 methylene unit of Z is optionally replaced with -M-.
• Z is C 1-30 alkylene (ie., Cialkylene, C 2 alkylene, C 3 alkylene, C 4 alkylene, C 5 alkylene, C 6 alkylene, C 7 alkylene, C 8 alkylene, C 9 alkylene, C 10 alkylene, C 11 alkylene, C 12 alkylene, C 13 alkylene, C 14 alkylene, C 15 alkylene, C 16 alkylene, C 17 alkylene, C 18 alkylene, C 19 alkylene, C 20 alkylene, C 21 alkylene, C 22 alkylene, C 23 alkylene, C 24 alkylene, C 25 alkylene, C 26 alkylene, C 27 alkylene, C 28 alkylene, C 29 alkylene or C 30 alkylene), wherein 0-8 methylene units of Z are independently replaced by -R 8 -, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(C(O)
• Z is C 2-30 alkenylene (i.e., C 2 alkenylene, C 3 alkenylene, C 4 alkenylene, C 5 alkenylene, C 6 alkenylene, C 7 alkenylene, C 8 alkenylene, C 9 alkenylene, C 10 alkenylene, C 11 alkenylene, C 12 alkenylene, C 13 alkenylene, C 14 alkenylene, C 15 alkenylene, C 16 alkenylene, C 17 alkenylene, C 18 alkenylene, C 19 alkenylene, C 20 alkenylene, C 21 alkenylene, C 22 alkenylene, C 23 alkenylene, C 24 alkenylene, C 25 alkenylene, C 26 alkenylene, C 27 alkenylene, C 28 alkenylene, C 29 alkenylene or C 30 alkenylene), wherein 0-8 methylene units of Z are independently replaced by -R 8 -, -O-,
• Z is C 2-30 alkynylene (i.e., C 2 alkynylene, C 3 alkynylene, C 4 alkynylene, C 5 alkynylene, C 6 alkynylene, C 7 alkynylene, C 8 alkynylene, C 9 alkynylene, C 10 alkynylene, C 11 alkynylene, C 12 alkynylene, C 13 alkynylene, C 14 alkynylene, C 15 alkynylene, C 16 alkynylene, C 17 alkynylene, C 18 alkynylene, C 19 alkynylene, C 20 alkynylene, C 21 alkynylene, C 22 alkynylene, C 23 alkynylene, C 24 alkynylene, C 25 alkynylene, C 26 alkynylene, C 27 alkynylene, C 28 alkynylene, C 29 alkynylene or C 30 alkynylene
• Z is selected from the group consisting of -C(R 4a )(R 4b )C(O)-M-, -C(R 4a )(R 4b )-M-, -C(R 4a )(R 4b )C(R 5a )(R 5b )(CH 2 ) n C(O)-M-, -C(R 4a )(R 4b )C(R 5a )(R 5b )(CH 2 ) n -M-, -(CH 2 ) m C(R 4a )(R 4b )(CH 2 ) n C(R 5a )(R 5b )(CH 2 ) m C(O)-M-, and -(CH 2 ) m C(R 4a )(R 4b )(CH 2 ) n C(R 5a )(R 5b )(CH 2 ) m -M-,
• Z is selected from the group consisting of -CH(R 4a )C(O)-M-, -CH(R 4a )-M-, -CH(R 4a )CH(R 5a )C(O)-M-, -CH(R 4a )CH(R 5a )(CH 2 ) n C(O)-M-, -CH(R 4a )CH(R 5a )(CH 2 ) n -M-, and -C(R 4a )(R 4b )(CH 2 ) n C(R 5a )(R 5b )C(O)-M-, wherein either side of Z may be attached to Agent.
• 0-8 methylene units of Z are independently replaced by -R 8 -. In some embodiments, 0-8 methylene units of Z are independently replaced by -O-. In some embodiments, 0-8 methylene units of Z are independently replaced by -NR-. In some embodiments, 0-8 methylene units of Z are independently replaced by -S-. In some embodiments, 0-8 methylene units of Z are independently replaced by -OC(O)-. In some embodiments, 0-8 methylene units of Z are independently replaced by -C(O)O-. In some embodiments, 0-8 methylene units of Z are independently replaced by -C(O)-. In some embodiments, 0-8 methylene units of Z are independently replaced by -C(O)-.
• 0-8 methylene units of Z are independently replaced by -S(O)-. In some embodiments, 0-8 methylene units of Z are independently replaced by -S(O) 2 -. In some embodiments, 0-8 methylene units of Z are independently replaced by -C(S)-. In some embodiments, 0-8 methylene units of Z are independently replaced by -OS(O) 2 -. In some embodiments, 0-8 methylene units of Z are independently replaced by -S(O) 2 O-. In some embodiments, 0-8 methylene units of Z are independently replaced by -N(R)S(O) 2 -.
• 0-8 methylene units of Z are independently replaced by -S(O) 2 NR-. In some embodiments, 0-8 methylene units of Z are independently replaced by -N(R)C(O)-. In some embodiments, 0-8 methylene units of Z are independently replaced by -C(O)NR-. In some embodiments, 0-8 methylene units of Z are independently replaced by -OC(O)NR-. In some embodiments, 0-8 methylene units of Z are independently replaced by -N(R)C(O)O-. In some embodiments, 0-8 methylene units of Z are independently replaced by an amino acid. [0128] In some embodiments, the amino acid may be naturally-occurring or non-naturally occurring.
• the amino acid is an L-amino acid. In some embodiments, the amino acid is a D-amino acid.
• Amino acids include, but are not limited to glycine, alanine, leucine, isoleucine, valine, tyrosine, lysine, serine, threonine, methionine, proline, phenylalanine, tryptophan, asparagine, glutamine, aspartic acid, glutamic acid, arginine, histidine, cysteine, and selenocysteine.
• the amino acid is selected
• Z is a bivalent C 1-25 , C 5-25 , C 7-25 , or C 1-20 aliphatic optionally substituted with 1, 2, 3, or 4 groups selected from deuterium, halogen, -CN, a 3-8 membered carbocycle, C 6-10 aryl, a 4-8 membered heterocycle comprising 1-2 heteroatoms independently selected from the group consisting of N, O and S, a 5-10 membered heteroaryl comprising 1-4 heteroatoms independently selected from the group consisting of N, O, and S, or a C 1-6 aliphatic group optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; wherein 0-4 methylene units of Z are independently replaced by -O-, -OC(O)-, -C(O)O-, or -C(O)-; and 1 methylene unit of Z is optionally replaced with -M-.
• each -R 8 - is independently an optionally substituted bivalent C 3-6 carbocycle. In some embodiments, each -R 8 - is independently an optionally substituted bivalent C 6-10 aryl. In some embodiments, each -R 8 - is independently an optionally substituted bivalent 3-6 membered heterocycle comprising 1-4 heteroatoms independently selected from the group consisting of N, O, and S. In some embodiments, each -R 8 - is independently an optionally substituted bivalent 5-10 membered heteroaryl comprising 1-4 heteroatoms independently selected from the group consisting of N, O, and S.
• each -R 8 - is independently a bivalent group selected from the group consisting of a C 3-6 carbocycle, a C 6-10 aryl, a 3-6 membered heterocycle comprising 1- 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; and 5-10 membered heteroaryl comprising 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.
• each -R 8 - is independently a bivalent C 3-6 carbocycle.
• each -R 8 - is independently a bivalent C 6-10 aryl.
• each -R 8 - is independently a bivalent substituted 3-6 membered heterocycle comprising 1-4 heteroatoms independently selected from the group consisting of N, O, and S. In some embodiments, each -R 8 - is independently a bivalent substituted 5-10 membered heteroaryl comprising 1-4 heteroatoms independently selected from the group consisting of N, O, and S.
• R 4a is selected from the group consisting of hydrogen, deuterium, halogen, -CN, -OR, -NR2, -SR, -R 9 , and -R 10 .
• R 4a is hydrogen.
• R 4a is deuterium.
• R 4a is halogen.
• R 4a is -CN.
• R 4a is -OR.
• R 4a is -NR 2 .
• R 4a is -SR.
• R 4a is -R 9 .
• R 4a is -R 10 .
• R 4b is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, -OR, -NR 2 , -SR, -R 9 , and -R 10 .
• R 4b is hydrogen.
• R 4b is deuterium.
• R 4b is halogen.
• R 4b is -CN.
• R 4b is -OR.
• R 4b is -NR2.
• R 4b is -SR.
• R 4b is -R 9 .
• R 4b is -R 10 .
• each of R 4a and R 4b is independently hydrogen, deuterium, halogen, -CN, or C 1-4 aliphatic optionally substituted with 1- 6 deuterium or halogen atoms; or R 4a and R 4b together with the carbon atom to which they are attached, form a C 3-6 carbocycle or a 3-6 membered heterocycle comprising 1-2 heteroatoms independently selected from the group consisting of N, O and S.
• R 5a is selected from the group consisting of hydrogen, deuterium, halogen, -CN, -OR, -NR 2 , -SR, -R 9 , and -R 10 .
• R 5a is hydrogen.
• R 5a is deuterium.
• R 5a is halogen.
• R 5a is -CN. In some embodiments, R 5a is -OR. In some embodiments, R 5a is -NR 2 . In some embodiments, R 5a is -SR. In some embodiments, R 5a is -R 9 . In some embodiments, R 5a is -R 10 .
• R 5b is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, -OR, -NR 2 , -SR, -R 9 , and -R 10 .
• R 5b is hydrogen.
• R 5b is deuterium.
• R 5b is halogen.
• R 5b is -CN.
• R 5b is -OR.
• R 5b is -NR2.
• R 5b is -SR.
• R 5b is -R 9 .
• R 5b is -R 10 .
• each of R 5a and R 5b is independently hydrogen, deuterium, halogen, -CN, or C 1-4 aliphatic optionally substituted with 1-6 deuterium or halogen atoms; or R 5a and R 5b together with the carbon atom to which they are attached, form a C 3-6 carbocycle or a 3-6 membered heterocycle comprising 1-2 heteroatoms independently selected from the group consisting of N, O and S.
• each of R 4a , R 4b , R 5a and R 5b is independently hydrogen or C 1-4 alkyl optionally substituted with 1-6 deuterium or halogen atoms.
• At least one instance of R 4a and R 4b is not hydrogen.
• R 4a and R 4b together with the carbon atom to which they are attached form a C 3-6 carbocycle or a 3-6 membered heterocycle comprising 1-2 heteroatoms independently selected from the group consisting of N, O and S.
• R 4a and R 4b together with the carbon atom to which they are attached form a C 3-6 carbocycle.
• R 4a and R 4b together with the carbon atom to which they are attached form a 3-6 membered heterocycle comprising 1-2 heteroatoms independently selected from the group consisting of N, O and S.
• R 5a and R 5b together with the carbon atom to which they are attached form a C 3-6 carbocycle or a 3-6 membered heterocycle comprising 1-2 heteroatoms independently selected from the group consisting of N, O and S.
• R 5a and R 5b together with the carbon atom to which they are attached form a C 3-6 carbocycle.
• R 5a and R 5b together with the carbon atom to which they are attached form a 3-6 membered heterocycle comprising 1-2 heteroatoms independently selected from the group consisting of N, O and S.
• R 9 is a 3-8 membered carbocycle. In some embodiments, R 9 is a C 6-10 aryl. In some embodiments, R 9 is a 4-8 membered heterocycle comprising 1-2 heteroatoms independently selected from the group consisting of N, O, and S. In some embodiments, R 9 is a 5-10 membered heterocycle comprising 1-4 heteroatoms independently selected from the group consisting of N, O, and S.
• each of R 10 is independently selected from the group consisting of C 1-6 aliphatic optionally substituted with -CN, -OR, -NR2, -SR, or -R 9 , wherein said C 1-6 aliphatic is optionally and additionally substituted with 1-6 deuterium or halogen atoms.
• R 10 is an unsubstituted C 1-6 aliphatic.
• R 10 is C 1-6 aliphatic substituted with 1 to 6 -CN.
• R 10 is C 1-6 aliphatic substituted with 1 to 6
• R 10 is C 1-6 aliphatic substituted with 1 to 6 -NR 2 . In some embodiments, R 10 is C 1-6 aliphatic substituted with 1 to 6 -SR. In some embodiments, R 10 is C 1-6 aliphatic substituted with 1 to 6 -R 9 . In some embodiments, R 10 is C 1-6 aliphatic substituted with 1 to 6 deuterium. In some embodiments, R 10 is C 1-6 aliphatic substituted with 1 to 6 halogen.
• -M- is a cleavable moiety.
• the cleavable moiety is a self-immolative moiety.
• -M- is selected from the group consisting of an acetal, an o- benzyl alcohol, a p-benzylalcohol, a styryl group, a coumarin, and a group that self-immolates via a cyclization reaction.
• -M- is selected from the group consisting of a disulfide, hydrazone, acetal self-immolative group, carboxyacetal self-immolative moiety, carboxy(methylacetal) self-immolative moiety, para-hydroxybenzyl carbonyl self- immolative moieties, flipped ester self-immolative moiety, trimethyl lock, or 2- hydroxyphenyl carbamate (2-HPC) self-immolative moiety.
• -M- is selected from the group consisting of :
• each R 6a and R 6b is independently selected from the group consisting of hydrogen, deuterium, Ci-io aliphatic, halogen, or -CN; each R 7 is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, -OR, -NR 2 , -NO 2 , -SR, -R 9 , or -R 10 ; each Z 1 is independently selected from the group consisting -O-, -NR-, or -S-; each Z 2 is independently selected from the group consisting -O-, -NR-, -S-, -OC(O)-,
• each Z 3 is independently selected from -O-, -NR-, -S-, -C(R 6a )(R 6b )-, or a covalent bond.
• R 6a is hydrogen. In some embodiments, R 6a is deuterium. In some embodiments, R 6a is C 1-6 aliphatic. In some embodiments, R 6a is C 1-6 alkyl. In some embodiments, R 6a is methyl, ethyl, propyl or isopropyl. In some embodiments, R 6a is methyl. In some embodiments, R 6a is ethyl. In some embodiments, R 6a is propyl. In some embodiments, R 6a is isopropyl. In some embodiments, R 6a is halogen. In some embodiments, R 6a is -CN.
• each R 7 is hydrogen. In some embodiments, each R 7 is deuterium. In some embodiments, each R 7 is halogen. In some embodiments, each R 7 is -CN. In some embodiments, each R 7 is -OR. In some embodiments, each R 7 is -NR2. In some embodiments, each R 7 is -NO2. In some embodiments, each R 7 is - SR. In some embodiments, each R 7 is -R 9 . In some embodiments, each R 7 is -R 10 .
• Z 1 is -O-. In some embodiments, Z 1 is -NR-. In some embodiments, Z 1 is -S-. In some embodiments, Z 1 is -NH- or -NMe-.
• Z 2 is -O-. In some embodiments, Z 2 is -NR-. In some embodiments, Z 2 is -S-. In some embodiments, Z 2 is -OC(O)-. In some embodiments, Z 2 is -N(R)C(O)O-. In some embodiments, Z 2 is -OC(O)NR-. In some embodiments, Z 2 is -NH-. In some embodiments, Z 2 is -NMe-. In some embodiments, Z 2 is -NHC(O)O-. In some embodiments, Z 2 is -NMeC(O)O-. In some embodiments, Z 2 is -OC(O)NH-. In some embodiments, Z 2 is -OC(O)NMe-. In some embodiments, Z 2 is covalently bound to A.
• -M- is selected from the group consisiting of: either side of M may be attached to Agent.
• -M- is selected from the group constisting of:
• m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6. In some embodiments, each m is independently 0, 1, or 2. In some embodiments, each m is independently 1, 2, 3, or 4.
• Formula (I) means that either one or two moieties may be covalently attached to the Agent.
• the attachment of to the Agent may be at any available modifiable nitrogen, oxygen, or sulfur atom in the Agent.
• the disclosure provides a compound of Formula (II): or a pharmaceutically acceptable salt thereof, wherein each of Z, p, and Agent are as defined herein.
• the disclosure provides a compound of Formula (III): or a pharmaceutically acceptable salt thereof, wherein each of R 1 , X, Z, p, and Agent are as defined herein.
• the disclosure provides a compound of Formula (VI): or a pharmaceutically acceptable salt thereof, wherein each of X, Z, p, and Agent are as defined herein.
• the disclosure provides a compound of Formula (VII): or a pharmaceutically acceptable salt thereof, wherein each of R 1 , X, p, and Agent are as defined herein.
• the disclosure provides a compound of Formula (VIII): or a pharmaceutically acceptable salt thereof, wherein each of R 3 , p, and Agent are as defined herein.
• the disclosure provides a compound of of Formula (X): or a pharmaceutically acceptable salt thereof, wherein each of R 1 , R 2 , R 4a , R 5a , M, X, p, and Agent are as defined herein.
• the disclosure provides a compound of Formula (XI): or a pharmaceutically acceptable salt thereof, wherein each of R 1 , R 2 , R 4a , R 5a , X, n, p, and Agent are as defined herein.
• the disclosure provides a compound of Formula (XII): or a pharmaceutically acceptable salt thereof, wherein each of R 1 , R 2 , X, M, p and Agent are as defined herein.
• the disclosure provides a compound of Formula (XIV): or a pharmaceutically acceptable salt thereof, wherein each of R 1 , R 2 , R 4a , R 4b , R 5a , R 5b , M, p and Agent are as defined herein.
• the disclosure provides a compound of Formula (XV): or a pharmaceutically acceptable salt thereof, wherein each of R 1 , R 2 , R 4a , R 5a , M, p and Agent are as defined herein.
• the disclosure provides a compound of Formula (XVI): or a pharmaceutically acceptable salt thereof, wherein each of R 1 , R 2 , R 4a , R 5a , M, p and Agent are as defined herein.
• the disclosure provides a compound of Formula (XVII): or a pharmaceutically acceptable salt thereof, wherein each of R 1 , R 2 , R 4a , R 4b , R 5a , R 5b , M, p and Agent are as defined herein.
• the disclosure provides a compound of Formula (XX): or a pharmaceutically acceptable salt thereof, wherein each of R 1 , R 2 , R 4a , R 4b , R 5a , R 5b , p, and Agent are as defined herein.
• the disclosure provides a compound of Formula (XXI): or a pharmaceutically acceptable salt thereof, wherein each of R 1 , R 2 , R 4a , R 4b , R 5a , R 5b , M, p, and Agent are as defined herein.
• the disclosure provides a compound of Formula (XXIV): or a pharmaceutically acceptable salt thereof, wherein each of R 1 , R 2 , R 4a , R 4b , R 5a , R 5b , p, and Agent are as defined herein.
• the disclosure provides a compound of Formula (XXVI): or a pharmaceutically acceptable salt thereof, wherein each of p and Agent are as defined herein.
• the disclosure provides a compound of Formula (XXVII): or a pharmaceutically acceptable salt thereof, wherein each of p and Agent are as defined herein.
• a range of 0-1 includes 0 and 1.
• the range of 0-4 includes 0, 1, 2, 3, and 4.
• the range 1-18 includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, and 18. Where more than one range is disclosed in a formula, each range is independently and optionally selected from the disclosed range.
• the disclosure provides any one of Compounds 1-2201 shown in any one of Table 2, Table 3, Table 4, Table 5, Table 6, Table 7, Table 8, Table 9, Table 10, Table 10, Table 11, Table 12, Table 13, Table 14, Table 15, Table 16, Table 17, Table 18, Table 19, Table 20, Table 21, Table 22, Table 23, Table 24, Table 25, Table 26, Table 27, Table 28, Table 29, Table 30, Table 31, or Table 32, pharmaceutically acceptable salts thereof, deuterated variants thereof or combinations thereof.
• the compound is selected from any one of Compounds 1-2201, or a pharmaceutically acceptable salt thereof.
• the compound is selected from any one of Compounds 1-2201.
• the compound is selected from a pharmaceutically acceptable salt of any one of Compounds 1-2201.
• the compound is selected from a deuterated variant of any one of Compounds 1-2201.
• the compound is selected from a deuterated variant of a pharmaceutically acceptable salt of any one of Compounds 1-2201.
• the compound is selected from any of the compounds depicted in in Table 2, pharmaceutically acceptable salts thereof, deuterated variants thereof or combinations thereof.
• the compound is selected from any of the compounds depicted in in Table 3, pharmaceutically acceptable salts thereof, deuterated variants thereof or combinations thereof.
• the compound is selected from any of the compounds depicted in in Table 4, pharmaceutically acceptable salts thereof, deuterated variants thereof or combinations thereof.
• the compound is selected from any of the compounds depicted in in Table 5, pharmaceutically acceptable salts thereof, deuterated variants thereof or combinations thereof. Table 5
• the compound is selected from any of the compounds depicted in in Table 6, pharmaceutically acceptable salts thereof, deuterated variants thereof or combinations thereof.
• the compound is selected from any of the compounds depicted in in Table 7, pharmaceutically acceptable salts thereof, deuterated variants thereof or combinations thereof.
• the compound is selected from any of the compounds depicted in in Table 8, pharmaceutically acceptable salts thereof, deuterated variants thereof or combinations thereof. Table 8
• the compound is selected from any of the compounds depicted in in Table 9, pharmaceutically acceptable salts thereof, deuterated variants thereof or combinations thereof.
• the compound is selected from any of the compounds depicted in in Table 10, pharmaceutically acceptable salts thereof, deuterated variants thereof or combinations thereof.
• the compound is selected from any of the compounds depicted in in Table 11, pharmaceutically acceptable salts thereof, deuterated variants thereof or combinations thereof. Table 11
• the compound is selected from any of the compounds depicted in in Table 12, pharmaceutically acceptable salts thereof, deuterated variants thereof or combinations thereof.
• the compound is selected from any of the compounds depicted in in Table 13, pharmaceutically acceptable salts thereof, deuterated variants thereof or combinations thereof.
• the compound is selected from any of the compounds depicted in in Table 14, pharmaceutically acceptable salts thereof, deuterated variants thereof or combinations thereof. Table 14
• the compound is selected from any of the compounds depicted in in Table 15, pharmaceutically acceptable salts thereof, deuterated variants thereof or combinations thereof.
• the compound is selected from any of the compounds depicted in in Table 16, pharmaceutically acceptable salts thereof, deuterated variants thereof or combinations thereof.
• the compound is selected from any of the compounds depicted in in Table 17, pharmaceutically acceptable salts thereof, deuterated variants thereof or combinations thereof. Table 17
• the compound is selected from any of the compounds depicted in in Table 18, pharmaceutically acceptable salts thereof, deuterated variants thereof or combinations thereof.
• the compound is selected from any of the compounds depicted in in Table 19, pharmaceutically acceptable salts thereof, deuterated variants thereof or combinations thereof.
• the compound is selected from any of the compounds depicted in in Table 20, pharmaceutically acceptable salts thereof, deuterated variants thereof or combinations thereof. Table 20
• the compound is selected from any of the compounds depicted in in Table 21, pharmaceutically acceptable salts thereof, deuterated variants thereof or combinations thereof. Table 21
• the compound is selected from any of the compounds depicted in in Table 22, pharmaceutically acceptable salts thereof, deuterated variants thereof or combinations thereof.
• the compound is selected from any of the compounds depicted in in Table 23, pharmaceutically acceptable salts thereof, deuterated variants thereof or combinations thereof. Table 23
• the compound is selected from any of the compounds depicted in in Table 24, pharmaceutically acceptable salts thereof, deuterated variants thereof or combinations thereof.
• the compound is selected from any of the compounds depicted in in Table 25, pharmaceutically acceptable salts thereof, deuterated variants thereof or combinations thereof.
• the compound is selected from any of the compounds depicted in in Table 26, pharmaceutically acceptable salts thereof, deuterated variants thereof or combinations thereof. Table 26
• the compound is selected from any of the compounds depicted in in Table 27, pharmaceutically acceptable salts thereof, deuterated variants thereof or combinations thereof.
• the compound is selected from any of the compounds depicted in in Table 28, pharmaceutically acceptable salts thereof, deuterated variants thereof or combinations thereof.
• the compound is selected from any of the compounds depicted in in Table 29, pharmaceutically acceptable salts thereof, deuterated variants thereof or combinations thereof.
• the compound is selected from any of the compounds depicted in in Table 30, pharmaceutically acceptable salts thereof, deuterated variants thereof or combinations thereof.
• the compound is selected from any of the compounds depicted in in Table 31, pharmaceutically acceptable salts thereof, deuterated variants thereof or combinations thereof.
• the compound is selected from any of the compounds depicted in in Table 32, pharmaceutically acceptable salts thereof, deuterated variants thereof or combinations thereof. Table 32
• the disclosure provides a pharmaceutical composition
• a pharmaceutical composition comprising the compounds (e.g., compounds of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XVII), (XXVIII), (XXIX), (XXX), (XXXI), (XXII), (XXXIII), (XXIV), (XXXV), (XXXVI), (XXVII), (XXVII), (XXVIII), (XXXIX), (XXX), (XXI), (XXII), (XXIII), (XXIV), (XXXV), (XXVI),
• the compound or pharmaceutically acceptable salt thereof of the present disclosure is provided in an effective amount in the pharmaceutical composition. In some embodiments, the compound or pharmaceutically acceptable salt thereof of the present disclosure is provided in a therapeutically effective amount. In some embodiments, the pharmaceutical composition comprises an effective amount of the compound or pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof.
• compositions provided herein can be administered by a variety of routes including oral, parenteral, rectal, transdermal, intradermal, intrathecal, subcutaneous, intravenous, intramuscular, and intranasal.
• the amount of the compound administered to the subject is typically determined by a physician, in the light of relevant circumstances, including the condition to be treated, the route of administration, the actual compound to be administered, the age, weight, and response of the individual subject, the severity of the subject’s symptoms, and the like.
• the compounds provided herein are administered to a subject at risk for developing the disease, condition or disorder, typically on the advice and under the supervision of a physician, and at the dosages described herein.
• Subjects at risk for developing a particular condition include, but are not limited to, those having a family history of the condition, or those who have been identified by a screening or evaluation method to be particularly susceptible to developing the condition.
• compositions provided herein may also be administered chronically (“chronic administration”).
• Chronic administration refers to administration of a compound or pharmaceutical composition thereof over an extended period of time, e.g., for example, over 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or indefinitely (e.g., for the rest of the subject’s life).
• the pharmaceutical composition of the present disclosure is formulated for oral administration to a subject.
• the compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing.
• unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
• Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions.
• the compound is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.
• each dose typically, one to five doses (e.g., 1, 2, 3, 4, 5 doses) per day are representative regimens. Using these dosing patterns, each dose provides from about 0.01 to about 20 mg/kg of the compound provided herein.
• Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like.
• Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
• a binder such as microcrystalline cellulose, gum tragacanth or gelatin
• an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
• the pharmaceutical composition of the present disclosure is formulated for oral administration to a subject as a lipid-based formulation.
• Lipid-based formulations for oral administration are known in the art and typically include one or more lipid components which may be classified according to the Lipid Formulation Classification System (LFCS).
• LFCS Lipid Formulation Classification System
• Examples of lipid formulations that may be used in the lipid formulations disclosed herein include the Type I, Type II, Type, III and Type IV formulations per the LFCS classification system. (Pouton, Eur. J. Pharm. Sci. 11 (Supp 2), S93-S98, 2000; Pouton, Eur. J. Pharm. Sci. 29 278-287, 2006).
• the lipid-based pharmaceutical compositions may contain any one or more of oils or lipids, surfactants, co-surfactants, co-emulsifiers, cosolvents, antioxidants and/or solidifying agents.
• the lipid-based pharmaceutical compositions may be chosen formulated to provide for sustained release of the active in the gastrointestinal tract in order to control the rate of absorption. These methodologies and formulations are known in the art. See, e.g., Mishra, Handbook of Encapsulation and Controlled Release, CRC Press, Boca Raton, (2016); Wilson and Crowley Controlled Release in Oral Drug Delivery, Springer, NY (2011); Wise, Handbook of Pharmaceutical Controlled Release Technology, Marcel Dekker, NY, (2000). [0236] Injectable compositions are typically based upon injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art.
• the active compound in such compositions is typically a minor component, often being from about 0.05 to 10% by weight with the remainder being the injectable carrier and the like.
• injectable compositions can be sterilized, e.g., by filtration, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
• Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses.
• Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s), generally in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight.
• the active ingredients When formulated as an ointment, the active ingredients will typically be combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in-water cream base.
• Such transdermal formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration of stability of the active ingredients or the formulation.
• transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.
• the present disclosure also relates to the pharmaceutically acceptable acid addition salt of a compound or Agent as disclosed herein.
• the acid which may be used to prepare the pharmaceutically acceptable salt is that which forms a non-toxic acid addition salt, i.e., a salt containing pharmacologically acceptable anions such as the hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, para-toluenesulfonate, and the like.
• a non-toxic acid addition salt i.e., a salt containing pharmacologically acceptable anions such as the hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, para-tol
• the present disclosure also provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier, e.g., a composition suitable for injection, such as for intravenous (IV) administration, or for oral administration.
• a pharmaceutically acceptable carrier e.g., a composition suitable for injection, such as for intravenous (IV) administration, or for oral administration.
• Pharmaceutically acceptable carriers include any and all diluents or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, preservatives, lubricants and the like, as suited to the particular dosage form desired, e.g., injection, oral, etc.
• General considerations in the formulation and/or manufacture of pharmaceutical compositions agents can be found, for example, in Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The Science and Practice of Pharmacy, 21st Edition (Lippincott Williams & Wilkins, 2005).
• the present disclosure also relates to pharmaceutical compositions comprising a cyclodextrin derivative.
• cyclodextrins are a-, - and y- cyclodextrins consisting of 6, 7 and 8 a-1 ,4-linked glucose units, respectively, optionally comprising one or more substituents on the linked sugar moieties, which include, but are not limited to, methylated, hydroxyalkylated, acylated, and sulfoalkylether substitution.
• the cyclodextrin is a sulfoalkyl ether 0-cyclodextrin, e.g., for example, sulfobutyl ether 0-cyclodextrin, also known as Captisol®. See, e.g., U.S.
• the formulation comprises hexapropyl- 0 -cyclodextrin. In a more particular embodiment, the formulation comprises hexapropyl- 0 -cyclodextrin (10-50% in water).
• the compounds provided herein can be administered as the sole active agent, or they can be administered in combination with other active agents.
• the present invention provides a combination of a compound of the present invention and another pharmacologically active agent. Administration in combination can proceed by any technique apparent to those of skill in the art including, for example, separate, sequential, concurrent, and alternating administration.
• the compounds of this disclosure can also be administered in sustained release forms or from sustained release drug delivery systems.
• sustained release materials can be found in Remington ’s Pharmaceutical Sciences.
• the disclosure provides compounds (e.g., a compound of Formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XVII), (XXVIII), (XXIX), (XXX), (XXXI), (XXII), (XXXIII), (XXIV), (XXXV), (XXXVI), (XXVII), (XXVII), (XXVIII), (XXXIX), (XXXI), (XXI), (XXII), (XXIII), (XXIV), (XXXV), (XXXVI), (XXVII), (X
• a target site e.g., lymph, lymphocytes, lymphoid tissues, tissues with high lipase activity, the liver, the systemic circulation, brain.
• the compounds of Formula (I)-(LVIII), pharmaceutically acceptable salt thereof, and pharmaceutical compositions thereof disclosed herein are useful for transporting and releasing an Agent as disclosed hereinat at a target tissue by avoiding first pass metabolism.
• the compounds of Formula (I)-(LVIII), pharmaceutically acceptable salt thereof, and pharmaceutical compositions thereof disclosed herein are useful for improving the bioavailability and other pharmacokinetic characteristics of an Agent as disclosed herein.
• the compounds of Formula (I)-(LVIII), or pharmaceutically acceptable salts thereof as disclosed herein is delivered to the central nervous system (CNS).
• the compouds of Formula (I)-(LVIII), or pharmaceutically acceptable salts thereof as disclosed herein crosses the blood-brain barrier (BBB) via the lymphatic system.
• the compounds of Formula (I)-(LVIII), or pharmaceutically acceptable salts thereof as disclosed herein are cleaved releasing an Agent as disclosed herein, after the compounds of Formula (I)-(LVIII), or pharmaceutically acceptable salts thereof as disclosed herein reaches the target tissue.
• the Agent is released when the cleavable linker is cleaved.
• the compounds, Agents, pharmaceutically acceptable salts, deuterated variants, or combinations thereof described herein are generally designed to penetrate the blood brain barrier (e.g., designed to be transported across the blood brain barrier).
• the compound, Agent, pharmaceutically acceptable salt, deuterated variant, or combination thereof of the present disclosure is a positive allosteric modulator (PAM) of NMD A receptors and activates NMD A receptor function.
• PAM positive allosteric modulator
• the compound, Agent, pharmaceutically acceptable salt, deuterated variant, or combination thereof of the present disclosure is a negative allosteric modulator (NAM) of an NMDA receptor and inhibits NMDA receptor function.
• the compound, Agent, pharmaceutically acceptable salt, deuterated variant, or combination thereof is a neutral allosteric ligands (NALs) of NMDA receptors, which binds at allosteric sites and block the effects of a PAM and/or NAM of an NMDA receptor.
• NALs neutral allosteric ligands
• the disclosure provides a method for effecting allosteric modulation of an NMDA receptor in a subject, comprising administering to the subject an effective amount of a compound, Agent, pharmaceutically acceptable salt, deuterated variant, or combination thereof or pharmaceutical composition as disclosed herein.
• the method is for effecting positive allosteric modulation of an NMDA receptor in a subject.
• the method is for effecting negative allosteric modulation of an NMDA receptor in a subject.
• the method comprises binding an NMDA receptor at an allosteric site with a compound disclosed herein and blocking the effects of an allosteric NMDA modulator (i.e., PAM and/or NAM) in a subject.
• an allosteric NMDA modulator i.e., PAM and/or NAM
• the disclosure provides a method for treating a disease, disorder, or condition requiring allosteric NMDA receptor modulation in a subject, comprising administering to the subject an effective amount of a compound, Agent, pharmaceutically acceptable salt, deuterated variant, or combination thereof or pharmaceutical composition thereof as disclosed herein.
• treating the disease, disorder, or condition requires positive allosteric NMDA receptor modulation in a subject.
• treating the disease, disorder, or condition requires negative allosteric NMDA receptor modulation in a subject.
• the disclosure provides a method for treating a CNS-related condition in a subject, comprising administering to the subject an effective amount of a compound, Agent, pharmaceutically acceptable salt, deuterated variant, or combination thereof or a pharmaceutical composition thereof as disclosed herein.
• the disclosure provides a method for preventing a disease, disorder or condition requiring allosteric NMDA receptor modulation in a subject, comprising administering to the subject an effective amount of a compound, Agent, pharmaceutically acceptable salt, deuterated variant, or combination thereof or a pharmaceutical composition thereof as disclosed herein.
• preventing the disease, disorder, or condition requires positive allosteric NMDA receptor modulation in a subject.
• preventing the disease, disorder, or condition requires negative allosteric NMDA receptor modulation in a subject.
• the disclosure provides a method for preventing a CNS-related condition in a subject, comprising administering to the subject an effective amount of a compound, Agent, pharmaceutically acceptable salt, deuterated variant, or combination thereof or a pharmaceutical composition thereof as disclosed herein.
• the disclosure provides a method for inducing sedation or anesthesia in a subject, comprising administering to the subject an effective amount of a compound, Agent a pharmaceutically acceptable salt, deuterated variant, or combination thereof or a pharmaceutical composition thereof as disclosed herein.
• the disclosure provides a compound, Agent, pharmaceutically acceptable salt, deuterated variant, or combination thereof or pharmaceutical composition thereof as disclosed herein for use in effecting allosteric modulation of an NMDA receptor in a subject.
• the compound, Agent, pharmaceutically acceptable salt, deuterated variant, or combination thereof or pharmaceutical composition is for use in effecting positive allosteric modulation of an NMDA receptor in a subject.
• the compound, Agent, pharmaceutically acceptable salt, deuterated variant, or combination thereof or pharmaceutical composition is for use in effecting negative allosteric modulation of an NMDA receptor in a subject.
• the disclosure provides a compound, Agent, pharmaceutically acceptable salt, deuterated variant, or combination thereof or pharmaceutical composition as disclosed herein for use in treating a disease, disorder or condition requiring allosteric NMDA receptor modulation in a subject.
• treating the disease, disorder, or condition requires positive allosteric NMDA receptor modulation in a subject.
• treating the disease, disorder, or condition requires negative allosteric NMDA receptor modulation in a subject.
• the disclosure provides a compound, Agent, pharmaceutically acceptable salt, deuterated variant, or combination thereof or pharmaceutical composition as disclosed herein for use in treating a CNS-related condition in a subject.
• the disclosure provides a compound, Agent, pharmaceutically acceptable salt, deuterated variant, or combination thereof or pharmaceutical composition as disclosed herein for use in preventing a disease, disorder or condition requiring allosteric NMDA receptor modulation in a subject. In some embodiments, preventing the disease, disorder, or condition requires positive allosteric NMDA receptor modulation in a subject. In some embodiments, preventing the disease, disorder, or condition requires negative allosteric NMDA receptor modulation in a subject. [0263] In one aspect, the disclosure provides a compound, Agent, pharmaceutically acceptable salt, deuterated variant, or combination thereof or pharmaceutical composition as disclosed herein for use in preventing a CNS-related condition in a subject.
• the disclosure provides a compound, Agent, pharmaceutically acceptable salt, deuterated variant, or combination thereof or pharmaceutical composition as disclosed herein for use in inducing sedation or anesthesia in a subject.
• the disclosure provides the use of a compound, Agent, pharmaceutically acceptable salt, deuterated variant, or combination thereof or pharmaceutical composition as disclosed herein for the manufacture of a medicament for effecting allosteric modulation of an NMDA receptor in a subject.
• the medicament is for effecting positive allosteric modulation of an NMDA receptor in a subject.
• the medicament is for effecting negative allosteric modulation of an NMDA receptor in a subject.
• the disclosure provides the use of a compound, Agent, pharmaceutically acceptable salt, deuterated variant, or combination thereof or pharmaceutical composition as disclosed herein for the manufacture of a medicament for treating a disease, disorder or condition requiring allosteric NMDA receptor modulation in a subject.
• treating the disease, disorder, or condition requires positive allosteric NMDA receptor modulation in a subject.
• treating the disease, disorder, or condition requires negative allosteric NMDA receptor modulation in a subject.
• the disclosure provides the use of a compound, Agent, pharmaceutically acceptable salt, deuterated variant, or combination thereof or pharmaceutical composition as disclosed herein for the manufacture of a medicament for treating a CNS-related condition in a subject.
• the disclosure provides the use of a compound, Agent, pharmaceutically acceptable salt, deuterated variant, or combination thereof or pharmaceutical composition as disclosed herein for the manufacture of a medicament for preventing a disease, disorder or condition requiring allosteric NMDA receptor modulation in a subject.
• the medicament is for preventing a disease, disorder, or condition requiring positive allosteric NMDA receptor modulation in a subject.
• the medicament is for preventing a disease, disorder, or condition requiring negative allosteric NMDA receptor modulation in a subject.
• the disclosure provides the use compound, Agent, pharmaceutically acceptable salt, deuterated variant, or combination thereof or pharmaceutical composition as disclosed herein for the manufacture of a medicament for preventing a CNS-related condition in a subject.
• the disclosure provides the use of compound, Agent, pharmaceutically acceptable salt, deuterated variant, or combination thereof or pharmaceutical composition as disclosed herein for the manufacture of a medicament for inducing sedation or anesthesia in a subject.
• the method of treating a disease, disorder or condition comprises administering a compound, pharmaceutically acceptable salt or pharmaceutical composition of the disclosure in combination with one or more additional therapeutic agents.
• the one or more additional therapeutic agent is administered simultaneously with the compound, pharmaceutically acceptable salt or pharmaceutical composition of the disclosure.
• the one or more additional therapeutic agent and the compound, pharmaceutically acceptable salt or pharmaceutical composition of the disclosure are administered sequentially.
• the one or more additional therapeutic agent is administered prior to the compound, pharmaceutically acceptable salt or pharmaceutical composition of the disclosure.
• the one or more additional therapeutic agent is administered after the compound, pharmaceutically acceptable salt or pharmaceutical composition of the disclosure.
• Exemplary CNS conditions related to positive allosteric modulation of NMD A receptors include, but are not limited to, an adjustment disorder, an anxiety disorder (including obsessive-compulsive disorder, posttraumatic stress disorder, and social phobia), a cognitive disorder (including Alzheimer’s disease and other forms of dementia), a dissociative disorder, an eating disorder, a mood disorder (including depression, bipolar disorder, and dysthymic disorder), schizophrenia or another psychotic disorder (including schizoaffective disorder and post-partum psychosis), a sleep disorder (including insomnia), a substance-related disorder, a personality disorder (including obsessive-compulsive personality disorder), an autism spectrum disorder (including those involving mutations to the Shank group of proteins), multiple sclerosis, a neurodevelopmental disorder (including Rett syndrome, Tuberous Sclerosis complex), attention deficit disorder, attention deficit hyperactivity disorder, pain (including acute and chronic pain), a metabolic encephalopathies (including phenylketoneuria), an encephalopathy secondary to
• Exemplary CNS conditions related to negative allosteric modulation of NMDA receptors include, but are not limited to, adjustment disorders, stress or stress disorders (including post-traumatic stress disorder (PTSD)), anxiety disorders (including obsessive- compulsive disorder, posttraumatic stress disorder, social phobia, social anxiety disorder, and generalized anxiety disorder), cognitive disorders (including Alzheimer’s disease and other forms of dementia (e.g., frontotemporal dementia), as well as attention disorders such as attention deficit hyperactive disorder (ADHD)), eating disorders, mood disorders (including depression (e.g., postpartum depression), bipolar disorder, dysthymic disorder, suicidality), schizophrenia spectrum disorders (e.g., schizophrenia, schizoaffective disorder), psychotic disorders, sleep disorders (including insomnia), substance abuse-related disorders and/or withdrawal syndromes (e.g., addiction to opiates, cocaine, and/or alcohol), personality disorders (including obsessive-compulsive personality disorder (OCD)), autism spectrum disorders (including those involving mutations to the Shank
• Exemplary CNS conditions related to positive allosteric modulation of NMDA receptors include, but are not limited to, an adjustment disorder, an anxiety disorder (including obsessive-compulsive disorder, posttraumatic stress disorder, and social phobia), a cognitive disorder (including Alzheimer’s disease and other forms of dementia), a dissociative disorder, an eating disorder, a mood disorder (including depression, bipolar disorder, and dysthymic disorder), schizophrenia or another psychotic disorder (including schizoaffective disorder and post-partum psychosis), a sleep disorder (including insomnia), a substance-related disorder, a personality disorder (including obsessive-compulsive personality disorder), an autism spectrum disorder (including those involving mutations to the Shank group of proteins), multiple sclerosis, a neurodevelopmental disorder (including Rett syndrome, Tuberous Sclerosis complex), attention deficit disorder, attention deficit hyperactivity disorder, pain (including acute and chronic pain), a metabolic encephalopathies (including phenylketoneuria), an encephalopathy secondary to
• Exemplary CNS conditions related to negative allosteric modulation of NMDA receptors include, but are not limited to, adjustment disorders, stress or stress disorders (including post-traumatic stress disorder (PTSD)), anxiety disorders (including obsessive- compulsive disorder, posttraumatic stress disorder, social phobia, social anxiety disorder, and generalized anxiety disorder), cognitive disorders (including Alzheimer’s disease and other forms of dementia (e.g., frontotemporal dementia), as well as attention disorders such as attention deficit hyperactive disorder (ADHD)), eating disorders, mood disorders (including depression (e.g., postpartum depression), bipolar disorder, dysthymic disorder, suicidality), schizophrenia spectrum disorders (e.g., schizophrenia, schizoaffective disorder), psychotic disorders, sleep disorders (including insomnia), substance abuse-related disorders and/or withdrawal syndromes (e.g., addiction to opiates, cocaine, and/or alcohol), personality disorders (including obsessive-compulsive personality disorder (OCD)), autism spectrum disorders (including those involving mutations to the Shank
• the disclosure provides a dosing regimen lymphatic uptake, metabolism, and release of the Agent.
• the dose of the compound may be adjusted so as to provide the desired plasma or lymphatic system concentration of the Agent.
• the dose of the compound, or pharmaceutically acceptable salt thereof of the disclosure is selected such that when said compound, or pharmaceutically acceptable salt thereof is administered to the subject, it provides, upon lymphatic uptake, metabolism, and release of the Agent, a desired, effective concentration or dose of Agent to treat a disease, disorder, or condition disclosed herein.
• a compound or pharmaceutically acceptable salt thereof e.g., compounds 46-48, 117-119, 188-190, 259-261, 330-332, 401-403, 472-474, 543-545, 614- 616, 685-687, 756-768, 827-829, 898-900, 969-971, 1040-1042, 1111-1113, 1182-1184, 1253-1255, 1324-1326, 1395-1397, 1466-1468, 1537-1539, 1608-1610, 1679-1681, 1750- 1752, 1821-1823, 1892-1894, 1963-1965, 2034-2036, 2105-2107 or 2176-2178) of the disclosure is administered to the subject in an amount sufficient to provide a dose of Agent No.
• Agent No e.g., compounds 46-48, 117-119, 188-190, 259-261, 330-332, 401-403, 472-474, 543-545, 614- 616, 685-687, 756-768, 827-829
• a compound or pharmaceutically acceptable salt thereof e.g., compounds 46- 48, 117-119, 188-190, 259-261, 330-332, 401-403, 472-474, 543-545, 614-616, 685-687, 756-768, 827-829, 898-900, 969-971, 1040-1042, 1111-1113, 1182-1184, 1253-1255, 1324- 1326, 1395-1397, 1466-1468, 1537-1539, 1608-1610, 1679-1681, 1750-1752, 1821-1823, 1892-1894, 1963-1965, 2034-2036, 2105-2107 or 2176-2178) of the disclosure is administered to the subject in an amount sufficient to provide a dose of about 0.3 mg of Agent No.
• a compound or pharmaceutically acceptable salt thereof e.g., compounds 46-48, 117-119, 188-190, 259-261, 330-332, 401-403, 472-474, 543-545, 614-616, 685-687, 756-768, 827-829, 898-900, 969-971, 1040-1042, 1111-1113, 1182-1184, 1253-1255, 1324-1326, 1395-1397, 1466-1468, 1537-1539, 1608-1610, 1679- 1681, 1750-1752, 1821-1823, 1892-1894, 1963-1965, 2034-2036, 2105-2107 or 2176-2178) of the disclosure is administered to the subject in an amount sufficient to provide a dose of about 0.6 mg of Agent No.
• a compound or pharmaceutically acceptable salt thereof e.g., compounds 46-48, 117-119, 188-190, 259-261, 330-332, 401- 403, 472-474, 543-545, 614-616, 685-687, 756-768, 827-829, 898-900, 969-971, 1040-1042, 1111-1113, 1182-1184, 1253-1255, 1324-1326, 1395-1397, 1466-1468, 1537-1539, 1608- 1610, 1679-1681, 1750-1752, 1821-1823, 1892-1894, 1963-1965, 2034-2036, 2105-2107 or 2176-2178) of the disclosure is administered to the subject in an amount sufficient to provide a dose of about 0.9 mg of Agent No.
• a compound or pharmaceutically acceptable salt thereof e.g., compounds 46-48, 117-119, 188-190, 259-261, 330-332, 401-403, 472-474, 543-545, 614-616, 685-687, 756-768, 827-829, 898-900, 969- 971, 1040-1042, 1111-1113, 1182-1184, 1253-1255, 1324-1326, 1395-1397, 1466-1468, 1537-1539, 1608-1610, 1679-1681, 1750-1752, 1821-1823, 1892-1894, 1963-1965, 2034- 2036, 2105-2107 or 2176-2178) of the disclosure is administered to the subject in an amount sufficient to provide a dose of about 1.2 mg of Agent No.
• a compound or pharmaceutically acceptable salt thereof e.g., compounds 46-48, 117-119, 188- 190, 259-261, 330-332, 401-403, 472-474, 543-545, 614-616, 685-687, 756-768, 827-829, 898-900, 969-971, 1040-1042, 1111-1113, 1182-1184, 1253-1255, 1324-1326, 1395-1397, 1466-1468, 1537-1539, 1608-1610, 1679-1681, 1750-1752, 1821-1823, 1892-1894, 1963- 1965, 2034-2036, 2105-2107 or 2176-2178) of the disclosure is administered to the subject in an amount sufficient to provide a dose of about 1.5 mg of Agent No.
• a compound or pharmaceutically acceptable salt thereof e.g., compounds 46- 48, 117-119, 188-190, 259-261, 330-332, 401-403, 472-474, 543-545, 614-616, 685-687, 756-768, 827-829, 898-900, 969-971, 1040-1042, 1111-1113, 1182-1184, 1253-1255, 1324- 1326, 1395-1397, 1466-1468, 1537-1539, 1608-1610, 1679-1681, 1750-1752, 1821-1823, 1892-1894, 1963-1965, 2034-2036, 2105-2107 or 2176-2178) of the disclosure is administered to the subject in an amount sufficient to provide a dose of about 1.8 mg of Agent No.
• a compound or pharmaceutically acceptable salt thereof e.g., compounds 46-48, 117-119, 188-190, 259-261, 330-332, 401-403, 472-474, 543-545, 614-616, 685-687, 756-768, 827-829, 898-900, 969-971, 1040-1042, 1111-1113, 1182-1184, 1253-1255, 1324-1326, 1395-1397, 1466-1468, 1537-1539, 1608-1610, 1679- 1681, 1750-1752, 1821-1823, 1892-1894, 1963-1965, 2034-2036, 2105-2107 or 2176-2178) of the disclosure is administered to the subject in an amount sufficient to provide a dose of about 2.1 mg of Agent No. 18.
• a compound or pharmaceutically acceptable salt thereof e.g., compounds 46-48, 117-119, 188-190, 259-261, 330-332, 401-403, 472-474, 543-545, 614-616, 685
• a compound or pharmaceutically acceptable salt thereof e.g., compounds 46-48, 117-119, 188-190, 259-261, 330-332, 401-403, 472-474, 543-545, 614- 616, 685-687, 756-768, 827-829, 898-900, 969-971, 1040-1042, 1111-1113, 1182-1184, 1253-1255, 1324-1326, 1395-1397, 1466-1468, 1537-1539, 1608-1610, 1679-1681, 1750- 1752, 1821-1823, 1892-1894, 1963-1965, 2034-2036, 2105-2107 or 2176-2178) of the disclosure is administered to the subject in an amount sufficient to provide a total daily dose of Agent No.
• a compound or pharmaceutically acceptable salt thereof e.g., compounds 46- 48, 117-119, 188-190, 259-261, 330-332, 401-403, 472-474, 543-545, 614-616, 685-687, 756-768, 827-829, 898-900, 969-971, 1040-1042, 1111-1113, 1182-1184, 1253-1255, 1324- 1326, 1395-1397, 1466-1468, 1537-1539, 1608-1610, 1679-1681, 1750-1752, 1821-1823, 1892-1894, 1963-1965, 2034-2036, 2105-2107 or 2176-2178) of the disclosure is administered to the subject in an amount sufficient to provide a total daily dose of about 0.3 mg of Agent No.
• a compound or pharmaceutically acceptable salt thereof e.g., compounds 46-48, 117-119, 188-190, 259-261, 330-332, 401-403, 472-474, 543-545, 614-616, 685-687, 756-768, 827-829, 898-900, 969-971, 1040-1042, 1111-1113, 1182-1184, 1253-1255, 1324-1326, 1395-1397, 1466-1468, 1537-1539, 1608-1610, 1679- 1681, 1750-1752, 1821-1823, 1892-1894, 1963-1965, 2034-2036, 2105-2107 or 2176-2178) of the disclosure is administered to the subject in an amount sufficient to provide a total daily dose of about 0.6 mg of Agent No.
• a compound or pharmaceutically acceptable salt thereof e.g., compounds 46-48, 117-119, 188-190, 259-261, 330-332, 401-403, 472-474, 543-545, 614-616, 685-687, 756-768, 827-829, 898-900, 969- 971, 1040-1042, 1111-1113, 1182-1184, 1253-1255, 1324-1326, 1395-1397, 1466-1468, 1537-1539, 1608-1610, 1679-1681, 1750-1752, 1821-1823, 1892-1894, 1963-1965, 2034- 2036, 2105-2107 or 2176-2178) of the disclosure is administered to the subject in an amount sufficient to provide a total daily dose of about 0.9 mg of Agent No.
• a compound or pharmaceutically acceptable salt thereof e.g., compounds 46- 48, 117-119, 188-190, 259-261, 330-332, 401-403, 472-474, 543-545, 614-616, 685-687, 756-768, 827-829, 898-900, 969-971, 1040-1042, 1111-1113, 1182-1184, 1253-1255, 1324- 1326, 1395-1397, 1466-1468, 1537-1539, 1608-1610, 1679-1681, 1750-1752, 1821-1823, 1892-1894, 1963-1965, 2034-2036, 2105-2107 or 2176-2178) of the disclosure is administered to the subject in an amount sufficient to provide a total daily dose of about 1.2 mg of Agent No.
• a compound or pharmaceutically acceptable salt thereof e.g., compounds 46-48, 117-119, 188-190, 259-261, 330-332, 401-403, 472-474, 543-545, 614-616, 685-687, 756-768, 827-829, 898-900, 969-971, 1040-1042, 1111-1113, 1182-1184, 1253-1255, 1324-1326, 1395-1397, 1466-1468, 1537-1539, 1608-1610, 1679- 1681, 1750-1752, 1821-1823, 1892-1894, 1963-1965, 2034-2036, 2105-2107 or 2176-2178) of the disclosure is administered to the subject in an amount sufficient to provide a total daily dose of about 1.5 mg of Agent No.
• a compound or pharmaceutically acceptable salt thereof e.g., compounds 46-48, 117-119, 188-190, 259-261, 330-332, 401-403, 472-474, 543-545, 614-616, 685-687, 756-768, 827-829, 898-900, 969- 971, 1040-1042, 1111-1113, 1182-1184, 1253-1255, 1324-1326, 1395-1397, 1466-1468, 1537-1539, 1608-1610, 1679-1681, 1750-1752, 1821-1823, 1892-1894, 1963-1965, 2034- 2036, 2105-2107 or 2176-2178) of the disclosure is administered to the subject in an amount sufficient to provide a total daily dose of about 1.8 mg of Agent No.
• a compound or pharmaceutically acceptable salt thereof e.g., compounds 46- 48, 117-119, 188-190, 259-261, 330-332, 401-403, 472-474, 543-545, 614-616, 685-687, 756-768, 827-829, 898-900, 969-971, 1040-1042, 1111-1113, 1182-1184, 1253-1255, 1324- 1326, 1395-1397, 1466-1468, 1537-1539, 1608-1610, 1679-1681, 1750-1752, 1821-1823, 1892-1894, 1963-1965, 2034-2036, 2105-2107 or 2176-2178) of the disclosure is administered to the subject in an amount sufficient to provide a total daily dose of about 2.1 mg of Agent No. 18.
• a compound or pharmaceutically acceptable salt thereof e.g., compounds 46- 48, 117-119, 188-190, 259-261, 330-332, 401-403, 472-474, 543-545, 614-616,
• the absolute configuration of an asymmetric center elucidated by the X-ray crystal structure of a compound can be used to infer the absolute configuration of a corresponding asymmetric center in another compound obtained from the same or similar synthetic methodologies.
• the absolute configuration of an asymmetric center elucidated by the X-ray crystal structure of a compound can be used to infer the absolute configuration of a corresponding asymmetric center in another compound coupled with a spectroscopic technique, e.g., NMR spectroscopy, e.g., J H NMR spectroscopy or 19 F NMR spectroscopy.
• CSA Camphorsulphonic acid
• DMAP 4-dimethylaminopyridine
• DCM dichloromethane
• DCC Dicyclohexylcarbodiimide
• TBS t-Butyldimethylsilyl
• MeOH Methanol
• EtOAc Ethyl Acetate
• ACN Acetonitrile
• AgOTf Silver trifluoromethanesulfonate
• DCE 1,2-Dichloroethane
• THF Tetrahydrofuran
• TBAF Tetra-n- butylammonium fluoride
• DMP Dess-Martin Periodinane.
• the compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization.
• the compounds provided herein may be isolated and purified by known standard procedures. Such procedures include (but are not limited to) recrystallization, column chromatography, HPLC, or supercritical fluid chromatography (SFC). The following schemes are presented with details as to the preparation of representative compounds that have been disclosed herein.
• the compounds provided herein may be prepared from known or commercially available starting materials and reagents by one skilled in the art of organic synthesis.
• Exemplary chiral columns available for use in the separation/purification of the enantiomers/diastereomers provided herein include, but are not limited to, CHIRALPAK® AD- 10, CHIRALCEL® OB, CHIRALCEL® OB-H, CHIRALCEL® OD, CHIRALCEL® OD-H, CHIRALCEL® OF, CHIRALCEL® OG, CHIRALCEL® OJ and CHIRALCEL® OK.
• 1H-NMR reported herein (e.g., for the region between 5 (ppm) of about 0.5 to about 4 ppm) will be understood to be an exemplary interpretation of the NMR spectrum (e.g., exemplary peak integrations) of a compound.
• Exemplary general method for preparative HPLC Column: Waters RB ridge prep 10 pm Cl 8, 19*250 mm. Mobile phase: acetonitrile, water (NH4HCO3) (30 L water, 24 g NH4HCO3, 30 mL NH 3 .H2O). Flow rate: 25 mL/min.
• Exemplary general method for analytical HPLC Mobile phase: A: water (10 mM NH4HCO3, B: acetonitrile Gradient: 5%-95% B in 1.6 or 2 min Flow rate: 1.8 or 2 mL/min; Column: XBridge Cl 8, 4.6*50mm, 3.5 pm at 45 C.
• AD_3_EtOH_DEA_5_40_25ML would indicate: “Column: Chiralpak AD-3
• Example 1 Exemplary general method for the synthesis of a compound of the disclosure:
• PG protecting group.
• Carboxylic acids of formula (i) which can be prepared according to procedures know in the art, are dissolved in dichloromethane, treated with di-methylaminopyridine followed by addition of the Agent. If the Agent comprises two hydroxyl groups, one of the hydroxyl groups is protected and only the free hydroxyl group will react with the carboxylic acid of formula (ii) to form a compound of formula (iii). See Panel A. If neither of the hydroxyl groups of the Agent are protected, both can react with two equivalents of the carboxylic acid of formula (i), to form a compound of formula (iv). See Panel B.
• Step 2 Synthesis of Compound 293 [0325] To a solution of Compound G-3 (700 mg, 665 pmol) in THF (30.0 mL) was added
• Step 1 Synthesis of Compound 1-3
• Step 2 Synthesis of Compound 222

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