WO2023137446A1 - Promédicaments de 3,4-méthylènedioxy-n-éthyl-amphétamine (mdea) et leurs utilisations - Google Patents

Promédicaments de 3,4-méthylènedioxy-n-éthyl-amphétamine (mdea) et leurs utilisations Download PDF

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WO2023137446A1
WO2023137446A1 PCT/US2023/060662 US2023060662W WO2023137446A1 WO 2023137446 A1 WO2023137446 A1 WO 2023137446A1 US 2023060662 W US2023060662 W US 2023060662W WO 2023137446 A1 WO2023137446 A1 WO 2023137446A1
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alkyl
cycloalkyl
heteroaryl
compound
heterocycloalkyl
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Matthew Duncton
Samuel CLARK
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Terran Biosciences Inc.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/58—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • MDEA 4,4-methylenedioxy-N-ethyl-amphetamine, or MDE
  • MDE is a synthetic analog of the psychedelic phenethylamine class of compounds.
  • R 1 is -C(O)OR 3 , -C(O)R 4 , -CH(R 5 )OR 6 , -C(O)OCH(R 5 )OC(O)R 4 , - C(O)OCH(R 5 )OC(O)OR 4 , -C(O)OCH(R 5 )OC(O)NHR 4 , -CH(R 5 )NHC(O)R 6 , - CH(R 5 )C(O)R 6 , -S(O) 2 R 7 , -S(O) 2 OR 7 , -P(O)OR 8 [N(R 9 )R 10 ], -C(O)N(R 9 )R 10 , - P(O)OR 11 (OR 12 ), -CH(R 4 )OP(O)
  • Figure 1-A shows mean concentration-time profiles of S-MDE following IV dosing of S-MDE (1 mg/kg) to male Sprague Dawley (SD) rats.
  • Figure 1-B shows mean concentration-time profiles of S-MDE following oral dosing of S-MDE (10 mg/Kg) to male Sprague Dawley (SD) rats.
  • Figure 2 shows mean concentration-time profiles of MDE following oral dosing of MDE trimethyllock prodrug (10 mg/kg) to male SD rats.
  • Figure 3 shows mean concentration-time profiles of MDE following oral dosing of MDE THP methyl ester prodrug (10 mg/kg) to male SD rats.
  • Figure 4 shows mean concentration-time profiles of MDE following oral dosing of MDE THP 1-ethyl ester prodrug (10 mg/kg) to male SD rats.
  • Figure 5 shows mean concentration-time profiles of MDE following oral dosing of MDE oxetane methyl ester prodrug (10 mg/kg) to male SD rats.
  • Figure 6 shows mean concentration-time profiles of MDE following oral dosing of MDE t-butyl methyl succinate prodrug (10 mg/kg) to male SD rats.
  • Figure 7 shows mean concentration-time profiles of MDE following oral dosing of MDE t-butyl methyl glutarate prodrug (10 mg/kg) to male SD rats.
  • Figure 8 shows mean concentration-time profiles of MDE following oral dosing of MDE t-butyl methyl adipate prodrug (10 mg/kg) to male SD rats.
  • Figure 9 shows mean concentration-time profiles of MDE following oral dosing of MDE methyl hemi-succinate prodrug (10 mg/kg) to male SD rats.
  • Figure 10 shows mean concentration-time profiles of MDE following oral dosing of MDE methyl hemi-glutarate prodrug (10 mg/kg) to male SD rats.
  • Figure 11 shows mean concentration-time profiles of MDE following oral dosing of MDE methyl hemi-adipate prodrug (10 mg/kg) to male SD rats.
  • Figure 12 shows mean concentration-time profiles of MDE following oral dosing of MDE methyl Boc-valine prodrug (10 mg/kg) to male SD rats.
  • Figure 13 shows mean concentration-time profiles of MDE following oral dosing of MDE acetamide prodrug (10 mg/kg) to male SD rats.
  • Figure 14 shows mean concentration-time profiles of MDE following oral dosing of (S)-MDE methyl pivolate prodrug (10 mg/kg) to male SD rats.
  • Figure 15 illustrates the percentage of time spent in the open arms after racemic MDE compared to vehicle and chlordiazepoxide control on the elevated zero maze.
  • Figure 16 illustrates the percentage of time spent in the open arms after R-MDE compared to vehicle and chlordiazepoxide control on the elevated zero maze.
  • Figure 17 illustrates the percentage of time spent in the open arms after S-MDE compared to vehicle and chlordiazepoxide control on the elevated zero maze.
  • Figure 18 illustrates the frequency of SAPs after racemic MDE compared to vehicle and chlordiazepoxide control on the elevated zero maze.
  • Figure 19 illustrates the frequency of SAPs after R-MDE compared to vehicle and chlordiazepoxide control on the elevated zero maze.
  • Figure 20 illustrates the frequency of SAPs after S-MDE compared to vehicle and chlordiazepoxide control on the elevated zero maze.
  • DETAILED DESCRIPTION [00030] Described herein, in certain embodiments, are compositions and methods relating to synthesis of analogs of 3,4-Methylenedioxy-N-ethyl-amphetamine (MDEA, or MDE).
  • the analogs described herein are prodrugs, that is, compounds that are converted to MDEA under physiologic conditions.
  • MDEA contains a chiral center and two enantiomers of MDEA are known (R)- and (S)-enantiomers (R-MDE or R-MDEA and S-MDE or S-MDEA, respectively). It is also possible that a prodrug of an individual enantiomer of MDEA may have advantages over the other enantiomer or the racemic mixture.
  • the present disclosure provides a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: R 1 is -C(O)OR 3 , -C(O)R 4 , -CH(R 5 )OR 6 , -C(O)OCH(R 5 )OC(O)R 4 , - C(O)OCH(R 5 )OC(O)OR 4 , -C(O)OCH(R 5 )OC(O)NHR 4 , -CH(R 5 )NHC(O)R 6 , - CH(R 5 )C(O)R 6 , -S(O) 2 R 7 , -S(O) 2 OR 7 , -P(O)OR 8 [N(R 9 )R 10 ], -C(O)N(R 9 )R 10 , - P(O)OR 11 (OR 12 ), -CH(R 4 )OP(O)OR 8
  • each of R 3 , R 4 , R 6 , R 7 , and R 8 is independently C 1 -C 10 alkyl, C 2 - C 10 alkenyl, C 1 -C 6 haloalkyl, C 3 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or monocyclic heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl is unsubstituted or substituted with one to five R A .
  • each of R 3 , R 4 , R 6 , R 7 , and R 8 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 haloalkyl, C 3 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, 5-membered monocyclic heteroaryl, or 6-membered monocyclic heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl is unsubstituted or substituted with one to three R A .
  • R 5 is hydrogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 1 -C 6 haloalkyl, C 3 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or monocyclic heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl is unsubstituted or substituted with one to five R A .
  • R 5 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 haloalkyl, C 3 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, 5-membered monocyclic heteroaryl, or 6-membered monocyclic heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl is unsubstituted or substituted with one to three R A .
  • R 3 is , wherein each of R A1 , R A2 , R A3 , and R A4 is independently hydrogen or C 1 -C 10 alkyl; and R A5 is C 3 -C 6 heteroalkyl, 3- to 6-membered heterocycloalkyl, monocyclic heteroaryl, or -C(O)OR 13 , -N(R 13 )C(O)OR 14 , -N(R 13 )C(O)R 14 , - C(O)R 14 , -OC(O)R 15 , or -OC(O)OR 16 .
  • R 4 is A1 A2 , wherein each of R and R is independently hydrogen, C 1 -C 10 alkyl, C 3 -C 6 cycloalkyl, phenyl, or monocyclic heteroaryl, or R A1 and R A2 together with the atom to which they are attached form a C 3 -C 6 cycloalkyl ring; each of R A3 and R A4 is independently hydrogen, C 1 -C 10 alkyl, C 3 -C 6 cycloalkyl, phenyl, or monocyclic heteroaryl, or R A3 and R A4 together with the atom to which they are attached form a C 3 -C 6 cycloalkyl ring; and R 6 is hydrogen, C 1 -C 10 alkyl, C 3 -C 6 cycloalkyl, phenyl, or monocyclic heteroaryl.
  • R 4 is A1 A2 wherein each of R and R is independently hydrogen, C 1 -C 10 alkyl, C 3 -C 6 cycloalkyl, phenyl, or monocyclic heteroaryl, or R A1 and R A2 together with the atom to which they are attached form a C 3 -C 6 cycloalkyl ring; each of R A3 and R A4 is independently hydrogen, C 1 -C 10 alkyl, C 3 -C 6 cycloalkyl, phenyl, or monocyclic heteroaryl, or R A3 and R A4 together with the atom to which they are attached form a C 3 -C 6 cycloalkyl ring; R f is hydrogen or C 1 -C 10 alkyl; and R 6 is hydrogen, C 1 -C 10 alkyl, C 3 -C 6 cycloalkyl, phenyl, or monocyclic heteroaryl.
  • each of R 9 and R 10 is independently hydrogen, C 1 -C 10 alkyl, C 3 - C 6 heteroalkyl, C 3 -C 8 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or monocyclic heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl is unsubstituted or substituted with one to five R A , or R 9 and R 10 together with the atom to which they are attached form a 3- to 6-membered heterocycloalkyl ring or a heteroaryl ring that is unsubstituted or substituted with one to five R A .
  • each of R 9 and R 10 is independently hydrogen, C 1 -C 6 alkyl, C 3 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, 5-membered monocyclic heteroaryl, or 6-membered monocyclic heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl is unsubstituted or substituted with one to three R A , or R 9 and R 10 together with the atom to which they are attached form a 3- to 6-membered heterocycloalkyl ring or a heteroaryl ring that is unsubstituted or substituted with one to three R A .
  • each of R 11 and R 12 is independently hydrogen, C 1 -C 10 alkyl, C 3 - C 6 heteroalkyl, C 3 -C 8 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or monocyclic heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl is unsubstituted or substituted with one to five R A , or R 11 and R 12 together with the atoms to which they are attached form a 3- to 6-membered heterocycloalkyl ring that is unsubstituted or substituted with one to five R A .
  • each of R 11 and R 12 is independently hydrogen, C 1 -C 6 alkyl, C 3 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, 5-membered monocyclic heteroaryl, or 6-membered monocyclic heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl is unsubstituted or substituted with one to three R A , or R 11 and R 12 together with the atoms to which they are attached form a 3- to 6-membered heterocycloalkyl ring that is unsubstituted or substituted with one to three R A .
  • each R A is independently C 1 -C 10 alkyl, C 3 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, monocyclic heteroaryl, an amino acid side chain, -OR 13 , -N(R 18 )R 19 , -C(O)OR 13 , -N(R 13 )C(O)OR 14 , -N(R 13 )C(O)R 14 , -C(O)R 14 , - OC(O)R 15 , -OC(O)OR 16 , -OP(O)OR 17 [N(R 18 )R 19 ], -C(O)N(R 18 )R 19 , -OC(O)N(R 18 )R 19 , or - OP(O)OR 20 (OR 21 ), wherein alkyl, heteroalkyl, cycloalkyl, hetero
  • each R A is independently C 1 -C 6 alkyl, C 3 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, 5-membered monocyclic heteroaryl, 6-membered monocyclic heteroaryl, an amino acid side chain, -OR 13 , -N(R 18 )R 19 , -C(O)OR 13 , - N(R 13 )C(O)OR 14 , -N(R 13 )C(O)R 14 , -C(O)R 14 , -OC(O)R 15 , -OC(O)OR 16 , - OP(O)OR 17 [N(R 18 )R 19 ], -C(O)N(R 18 )R 19 , -OC(O)N(R 18 )R 19 , or -OP(O)OR 20 (OR 21 ), wherein alkyl, heteroalkyl
  • each of R 13 , R 14 , R 15 , R 16 , or R 17 is independently hydrogen, C 1 - C 10 alkyl, C 3 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or monocyclic heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl is unsubstituted or substituted with one to five R B .
  • each of R 13 , R 14 , R 15 , R 16 , or R 17 is independently hydrogen, C 1 -C 6 alkyl, C 3 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, 5-membered monocyclic heteroaryl, or 6-membered monocyclic heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl is unsubstituted or substituted with one to three R B .
  • each of R 18 and R 19 is independently hydrogen, C 1 -C 10 alkyl, C 3 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or monocyclic heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl is unsubstituted or substituted with one to five R B ; or R 18 and R 19 together with the atom to which they are attached form a 3- to 6-membered heterocycloalkyl ring or heteroaryl ring, each of which is unsubstituted or substituted with one to five R B .
  • each of R 18 and R 19 is independently hydrogen, C 1 -C 6 alkyl, C 3 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, 3- to 6- membered heterocycloalkyl, phenyl, 5-membered monocyclic heteroaryl, or 6-membered monocyclic heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl is unsubstituted or substituted with one to three R B ; or R 18 and R 19 together with the atom to which they are attached form a 3- to 6-membered heterocycloalkyl ring or heteroaryl ring, each of which is unsubstituted or substituted with one to three R B .
  • each of R 20 and R 21 is independently hydrogen, C 1 -C 10 alkyl, C 3 - C 6 heteroalkyl, C 3 -C 8 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or monocyclic heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl is unsubstituted or substituted with one to five R B , or R 20 and R 21 together with the atoms to which they are attached form a 3- to 6-membered heterocycloalkyl ring that is unsubstituted or substituted with one to five R B .
  • each of R 20 and R 21 is independently hydrogen, C 1 -C 6 alkyl, C 3 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, 5-membered monocyclic heteroaryl, or 6-membered monocyclic heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl is unsubstituted or substituted with one to three R B , or R 20 and R 21 together with the atoms to which they are attached form a 3- to 6-membered heterocycloalkyl ring that is unsubstituted or substituted with one to three R B .
  • each R B is independently halogen, amino, cyano, hydroxyl, C 1 - C 10 alkyl, C 3 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, monocyclic heteroaryl, benzyl, -C(O)CH 3 , -C(O)Ph, or (monocyclic heteroaryl)-C 1 -C 4 alkyl wherein cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl is unsubstituted or substituted with one to five halogen, amino, cyano, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 acetyl, or benzoyl.
  • each R B is independently halogen, amino, cyano, hydroxyl, C 1 -C 6 alkyl, C 3 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, 5-membered monocyclic heteroaryl, 6-membered monocyclic heteroaryl, benzyl, -C(O)CH 3 , -C(O)Ph, or (5- or 6-membered monocyclic heteroaryl)-CH 2 -, wherein cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl is unsubstituted or substituted with one to three halogen, amino, cyano, hydroxyl, C 1 - C 6 alkyl, C 1 -C 6 acetyl, or benzoyl.
  • compounds of Formula (I) have Formula (Ia), or a pharmaceutically acceptable salt thereof, wherein R 3 is alkyl, alkenyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is substituted or unsubstituted.
  • R 3 is alkyl that is substituted.
  • R 3 is alkyl substituted with heteroalkyl, heterocycloalkyl, or heteroaryl, wherein each of heteroalkyl, heterocycloalkyl, and heteroaryl is unsubstituted or substituted.
  • R 3 is alkyl that is unsubstituted.
  • R 3 is heteroalkyl.
  • R 3 is heteroalkyl that is unsubstituted.
  • R 3 is ethyl.
  • R 1 is -C(O)OR 3 , wherein R 3 is alkyl. In some embodiments of Formula (I), R 1 is -C(O)OR 3 , wherein R 3 is alkyl substituted with heterocycloalkyl. In some embodiments of Formula (I), R 1 is -C(O)OR 3 , wherein R 3 is alkyl substituted with -N(R 13 )C(O)OR 14 . In some embodiments of Formula (I), R 13 is hydrogen or alkyl. In some embodiments of Formula (I), R 14 is alkyl, aryl, or heteroaryl.
  • R 3 is methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl, iso-amyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -CH 2 CF 3 , -CH 2 cPr, vinyl, phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, or 6-pyrimidyl.
  • R 3 is methyl, ethyl, n-propyl, isopropyl, n-pentyl, iso-amyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -CH 2 CF 3 , -CH 2 cPr, vinyl, phenyl, 2-pyridyl, 3-pyridyl, 4- pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, or 6-pyrimidyl.
  • [00048] in some embodiments is a compound of Formulas (I) and (Ia), wherein the compound is: or a pharmaceutically acceptable salt thereof. [00049] In some embodiments is a compound of Formulas (I) and (Ia), wherein the compound is: , or a pharmaceutically acceptable salt thereof. [00050] In some embodiments is a compound of Formulas (I) and (Ia), the compound is: , or a pharmaceutically acceptable salt thereof. [00051] In some embodiments is a compound of Formulas (I) and (Ia), R 3 is cycloalkyl that is substituted or unsubstituted. In some embodiments is a compound of Formula (I), wherein R 3 is cycloalkyl that is substituted.
  • R 1 is cycloalkyl that is substituted with amino, aminoalkyl, or a nitrogen-containing heterocycle.
  • compounds have the structure of Formula (Ia-1), or a pharmaceutically acceptable salt thereof: [00053] In some embodiments of Formulas (I),(Ia) and (Ia-1), wherein the compound is: , or a pharmaceutically acceptable salt thereof.
  • [00054] in some embodiments is a compound of Formulas (I), (Ia) and (Ia-1), the compound is: , or a pharmaceutically acceptable salt thereof.
  • compounds having the structure of Formula (Ia-2), or a pharmaceutically acceptable salt thereof are provided herein:
  • a compound of Formulas (I), (Ia) and (Ia-2) wherein the compound is: , or a pharmaceutically acceptable salt thereof.
  • a compound of Formulas (I), (Ia) and (Ia-2) wherein the compound is: , or a pharmaceutically acceptable salt thereof.
  • R 3 is unsubstituted alkyl, then R 3 is not tert-butyl.
  • R 3 is a compound of Formula (I) and (Ia) having the structure of Formula (Ia1): or a pharmaceutically acceptable salt thereof, wherein is cycloalkyl or heterocycloalkyl, and each of R 18 and R 19 is independently hydrogen, alkyl, cycloalkyl, or heteroalkyl; or R 18 and R 19 together with the atom to which they are attached form a heterocycloalkyl ring.
  • a compound of Formula (I), (Ia) and (Ia1) having the structure of Formula (Ia1-1): or a pharmaceutically acceptable salt thereof, wherein is cycloalkyl or heterocycloalkyl, and each of R 18 and R 19 is independently hydrogen, alkyl, cycloalkyl, or heteroalkyl; or R 18 and R 19 together with the atom to which they are attached form a heterocycloalkyl ring.
  • each of R 18 and R 19 is independently hydrogen, alkyl, cycloalkyl, or heteroalkyl; or R 18 and R 19 together with the atom to which they are attached form a heterocycloalkyl ring.
  • each of R 18 and R 19 is independently hydrogen, alkyl, cycloalkyl, or heteroalkyl; or R 18 and R 19 together with the atom to which they are attached form a heterocycloalkyl ring.
  • R 18 and R 19 is independently hydrogen, alkyl, cycloalkyl, or heteroalkyl; or R 18 and R 19 together with the atom to which they are attached form a heterocycloalkyl ring.
  • a compound of Formulas (I), (Ia), (Ia1) and (Ia2) wherein the compound is: , or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a compound of Formula (Ia3): or a pharmaceutically acceptable salt thereof, wherein: each of R A1 , R A2 , R A3 , and R A4 is independently hydrogen or alkyl, and R A5 is heteroalkyl, heterocycloalkyl, heteroaryl, or -C(O)OR 13 , -N(R 13 )C(O)OR 14 , - N(R 13 )C(O)R 14 , -C(O)R 14 , -OC(O)R 15 , or -OC(O)OR 16 .
  • one of R A1 , R A2 , R A3 , and R A4 is alkyl, and each of R A1 , R A2 , R A3 , and R A4 that is not alkyl is hydrogen.
  • two of R A1 , R A2 , R A3 , and R A4 are alkyl, and each of R A1 , R A2 , R A3 , and R A4 that is not alkyl is hydrogen.
  • each of R A1 , R A2 , R A3 , and R A4 is hydrogen.
  • R A3 , and R A4 together with the atom to which they are attached form a cycloalkyl ring, and R A1 and R A2 are each hydrogen.
  • R A5 is C(O)OR 13 , and R 13 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, iso-amyl, phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, and 6-pyrimidyl.
  • a compound of Formula (Ia3) wherein each of R A1 , R A2 , R A3 , and R A4 is hydrogen.
  • a compound of Formula (Ia3) wherein the compound is: or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (Ia3) wherein the compound is: , or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (Ia3) wherein the compound is: , or a pharmaceutically acceptable salt thereof.
  • R 4 is alkyl. In some embodiments of a compound of Formula (Ib), R 4 is CH 2 CF 3 . In some embodiments of a compound of Formula (Ib), R 4 is unsubstituted alkyl. In some embodiments of Formula (Ib), R 4 is methyl, ethyl, n- propyl, isopropyl, n-butyl, tert-butyl, 3-methyl-1-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, or n- nonyl.
  • a compound of Formula (Ib) is one wherein R 4 is cycloalkyl. In some embodiments of compound of Formula (Ib), R 4 is unsubstituted cycloalkyl. In some embodiments of compounds of Formula (Ib), R 4 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments of a compound of Formula (Ib), the compound is one wherein R 4 is aryl. In some embodiments of Formula (Ib), wherein R 4 is substituted or unsubstituted phenyl.
  • R 4 is heteroaryl and in certain such some embodiments of Formula (Ib), R 4 is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2- pyrimidyl, 3-pyrimidyl, or 6-pyrimidyl.
  • R 4 is R A substituted with -OR 13 , -N(R 18 )R 19 ,or - C(O)OR 13 , such as wherein R 4 is alkyl, substituted with -OR 13 , -N(R 18 )R 19 ,or -C(O)OR 13 .
  • R 4 is alkyl substituted with -N(R 18 )R 19
  • R 4 is alkyl substituted with -N(R 18 )R 19
  • each of R 18 and R 19 is independently alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or hydrogen, wherein alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is unsubstituted or substituted with one or more R B ; or R 18 and R 19 together with the atom to which they are attached form a heterocycloalkyl ring or heteroaryl ring, each of which is unsubstituted or substituted with one or more R B .
  • R 4 is alkyl substituted with -N(R 18 )R 19 , wherein R 18 and R 19 together with the atom to which they are attached form a heterocycloalkyl ring, for example a heterocycloalkyl ring substituted with substituted with one or more R B , such as wherein R B is selected from alkyl, arylalkyl and -C(O)CH 3 .
  • R 4 is alkyl substituted with -N(R 18 )R 19 , wherein R 18 and R 19 together with the atom to which they are attached form a heterocycloalkyl ring, such as an azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl or piperidinyl ring.
  • R 4 is heteroalkyl.
  • R 4 is CH 2 CH 2 OMe or CH 2 CH 2 SO 2 Me.
  • R 4 is –(CH 2 ) n CO 2 H, wherein n is 1, 2, 3, 4, 5, or 6. In some embodiments of Formulas (I) and (Ib), R 4 is –(CH 2 ) n CO 2 R 13 , wherein n is 1, 2, 3, 4, 5, or 6. In some embodiments of Formulas (I) and (Ib), R 4 is –(CH 2 ) n CO 2 R 13 , wherein R 13 is alkyl. In some embodiments of Formulas (I) and (Ib), R 4 is –(CH 2 ) n CO 2 R 13 , wherein R 13 is unsubstituted alkyl.
  • R 4 is –(CH 2 ) s CO 2 R 13 , wherein R 13 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or -CH(Et) 2 .
  • R 4 is –(CH 2 ) n OR 13 , wherein n is 1, 2, 3, 4, 5, 6 or 7.
  • R 4 is –(CH 2 ) n OR 13 , wherein R 13 is alkyl.
  • R 4 is –(CH 2 ) n OR 13 , wherein R 13 is unsubstituted alkyl.
  • R 4 is –(CH 2 ) s OR 13 , wherein R 13 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or -CH(Et) 2 .
  • R 13 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or -CH(Et) 2 .
  • the compound is:
  • R 4 is , , .
  • R 4 is , and in certain such embodiments of a compound of Formula (Ib), wherein R 4 is 14 , R is alkyl, cycloalkyl, or aryl, such as compounds wherein R 14 is methyl, ethyl, n-propyl, isopropyl, or CH 2 CH 2 OMe. In some embodiments of Formula (Ib), wherein R 4 is 14 R is phenyl.
  • R 4 is wherein R A7 is hydrogen or alkyl. In some embodiments of such compounds of Formula (Ib), R 4 is , wherein R A7 is hydrogen.
  • R 4 is , wherein R A7 is alkyl. In some embodiments of Formula (Ib), R 4 is A7 , wherein R is unsubstituted alkyl. In some embodiments of Formula (Ib), R 4 is A7 , and R is methyl, ethyl, n-propyl, isopropyl, or n-butyl. [00083] In some embodiments of Formulas (I) and (Ib), R 4 is –(CH 2 ) n N(R 18 )R 19 , wherein n is 1, 2, 3, 4, 5, 6 or 7.
  • R 4 is [00084] –(CH 2 ) n -N(R 18 )R 19 , wherein R 18 and R 19 together with the atom to which they are attached form a heterocycloalkyl ring, such as an azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl or piperidinyl ring, and in certain such embodiments the heterocycloalkyl ring is substituted with one or more R B , such as wherein R B is selected from alkyl, heteroalkyl, - C(O)CH 3 and -C(O)Ph.
  • the present disclosure provides a compound of Formula (Ib), wherein the compound is: or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a compound of Formula (Ib), wherein the compound is:
  • each n is independently 1, 2, 3, 4, 5, or 6; and each X is independently -O-, -S-, -S(O)-, -S(O) 2 -, -NH-, or NR B , wherein R B is selected from alkyl, heteroalkyl, -C(O)CH 3 and -C(O)Ph, each of which is substituted or unsubstituted.
  • R 4 is -CH(R A1 )NH 2 , wherein R A1 is hydrogen, alkyl, heteroalkyl, or an amino acid side chain.
  • R 4 is -CH(R A1 )NH 2
  • R A1 is an amino acid side chain
  • the amino acid side chain is formed from an ⁇ -amino acid side chain, such as one of the naturally occurring amino acid side chains, such as an amino acid selected from alanine, serine, tryptophan, aspartic acid, glutamic acid and the like.
  • R 4 when R 4 is formed from alanine, R A1 is methyl.
  • R 4 is -CH(R A1 )NH 2 , wherein R A1 is an amino acid side chain.
  • R 4 is -CH(R A1 )NH 2 , wherein R A1 is methyl, ethyl, n-propyl, isopropyl, tert-butyl, CH(Me)Et, CH 2 CH(Me) 2 , or CH 2 CH 2 SMe.
  • R 4 is -CH(R A1 )NH 2 , wherein R A1 is benzyl.
  • R 2 is an amino acid residue, for example, in some embodiments of Formula (Ib), R 4 , together with the carbonyl to which it is attached, is an amino acid residue.
  • R 2 is an amino acid residue
  • Examples of compounds according to Formulas (I) and (Ib), wherein R 2 is an amino acid residue can be represented by Formula (Ib1) [00093] wherein the amino acid moiety Formula (Ib1) may be the (R) or the (S) configuration at the ⁇ -carbon as illustrated below: .
  • compounds of Formula (Ib1) have two stereocenters, each of which can be in the (R) or the (S) configuration.
  • the present disclosure provides compounds of Formulas (I) and (Ib) having Formula (Ib2), or a pharmaceutically acceptable salt thereof: or a pharmaceutically acceptable salt thereof, wherein: each of R A1 and R A2 is independently hydrogen, alkyl, cycloalkyl, aryl or heteroaryl, or R A1 and R A2 together with the atom to which they are attached form a cycloalkyl ring; each of R A3 and R A4 is independently hydrogen, alkyl, cycloalkyl, aryl or heteroaryl, or R A3 and R A4 together with the atom to which they are attached form a cycloalkyl ring; and R 6 is hydrogen, alkyl, cycloalkyl, aryl, or heteroaryl.
  • each of R A1 , R A2 , R A3 , and R A4 is hydrogen. In some embodiments of a compound of Formulas (Ib) and (Ib2), each of R A1 , R A2 , R A3 , and R A4 is hydrogen or unsubstituted alkyl. In some embodiments of Formulas (Ib) and (Ib2), each of R A1 , R A2 , R A3 , and R A4 is hydrogen. In some embodiments of Formulas (Ib) and (Ib2), R 6 is alkyl.
  • R 6 is unsubstituted alkyl. In some embodiments of Formulas (Ib) and (Ib2), R 6 is cycloalkyl. In some embodiments of Formulas (Ib) and (Ib2), R 6 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, 3-methyl- 1-butyl, isopentyl, n-pentyl, n-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.
  • R 6 is phenyl. In some embodiments of Formulas (Ib) and (Ib2), R 6 is 4-nitrophenyl. In some embodiments of Formulas (Ib) and (Ib2), R 6 is benzyl. In some embodiments of Formulas (Ib) and (Ib2), R 6 is heteroaryl. In some embodiments of Formulas (Ib) and (Ib2), R 6 is heteroaryl, such as 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, or 4-pyrimidyl.
  • a compound of Formula (Ib2) wherein the compound is: , or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a compound of Formula (Ib) having Formula (Ib3): or a pharmaceutically acceptable salt thereof, wherein: each of R A1 and R A2 is independently hydrogen, alkyl, cycloalkyl, aryl or heteroaryl, or R A1 and R A2 together with the atom to which they are attached form a cycloalkyl ring; each of R A3 and R A4 is independently hydrogen, alkyl, cycloalkyl, aryl or heteroaryl
  • each of R A1 , R A2 , R A3 , and R A4 is hydrogen. In some embodiments of a compound of Formulas (Ib) and (Ib3), each of R A1 , R A2 , R A3 , and R A4 is hydrogen or unsubstituted alkyl. In some embodiments of Formulas (Ib) and (Ib3), each of R A1 , R A2 , R A3 , and R A4 is hydrogen. In some embodiments of Formulas (Ib) and (Ib3), R 6 is alkyl.
  • R 6 is unsubstituted alkyl. In some embodiments of Formulas (Ib) and (Ib3), R 6 is cycloalkyl. In some embodiments of Formulas (Ib) and (Ib3), R 6 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert- butyl, 3-methyl-1-butyl, isopentyl, n-pentyl, n-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.
  • R 6 is phenyl. In some embodiments of Formulas (Ib) and (Ib3), R 6 is 4-nitrophenyl. In some embodiments of Formulas (Ib) and (Ib3), R 6 is benzyl. In some embodiments of Formulas (Ib) and (Ib3), R 6 is heteroaryl. In some embodiments of Formulas (Ib) and (Ib3), R 6 is heteroaryl, such as 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, or 4-pyrimidyl. In some embodiments of Formulas (Ib) and (Ib3), R f is hydrogen.
  • R f is alkyl, such as methyl.
  • R f is alkyl, such as methyl.
  • R f is alkyl, such as methyl.
  • R f is alkyl, such as methyl.
  • R f is alkyl, such as methyl.
  • R f is alkyl, such as methyl.
  • R f is alkyl, such as methyl.
  • R f is alkyl, such as methyl.
  • R f is alkyl, such as methyl.
  • R 4 is alkyl, alkenyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroalkyl.
  • Such compounds of Formula (Ic) may be referred to as N-acyloxyalkoxy prodrugs.
  • R 5 is hydrogen, alkyl, or cycloalkyl; and R 4 is alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, or heteroaryl.
  • R 5 is hydrogen or alkyl.
  • R 5 is hydrogen or unsubstituted alkyl.
  • R 5 is hydrogen.
  • R 4 is alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In some embodiments of Formulas (I) and (Ic), R 4 is alkyl. In some embodiments of Formulas (I) and (Ic), R 4 is heteroalkyl. In some embodiments of Formulas (I) and (Ic), R 4 is unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. In some embodiments of Formulas (I) and (Ic), R 4 is alkyl.
  • R 4 is heteroalkyl. In some embodiments of Formulas (I) and (Ic), R 4 is heterocycloalkyl substituted with arylalkyl. In some embodiments of Formulas (I) and (Ic), R 5 is methyl, isopropyl, tert-butyl, or -CH(Et) 2 . [000105] In some embodiments of compounds of Formula (Ic), R 4 is heteroalkyl. In some embodiments of Formula (Ic), R 4 is heterocycloalkyl. In some embodiments of Formula (Ic), R 4 is heteroalkyl or R 4 is heterocycloalkyl.
  • R 4 is alkyl. In some embodiments of a compound of Formula (Ic), R 4 is CH 2 CF 3 . In some embodiments of a compound of Formula (Ic), R 4 is unsubstituted alkyl. In some embodiments of Formula (Ic), R 4 is methyl, ethyl, n- propyl, isopropyl, n-butyl, tert-butyl, 3-methyl-1-butyl,. In some embodiments a compound of Formula (Ic) is one wherein R 4 is cycloalkyl. In some embodiments of compound of Formula (Ic), R 4 is unsubstituted cycloalkyl.
  • R 4 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.
  • the compound is one wherein R 4 is aryl.
  • R 4 is substituted or unsubstituted phenyl.
  • R 4 is heteroaryl and in certain such some embodiments of Formula (Ic), R 4 is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2- pyrimidyl, 3-pyrimidyl, or 6-pyrimidyl.
  • R 4 is A7 and R is benzyl.
  • R 4 is R A substituted with -OR 13 , -N(R 18 )R 19 ,or -C(O)OR 13 , such as wherein R 4 is alkyl, substituted with -OR 13 , -N(R 18 )R 19 ,or -C(O)OR 13 .
  • R 4 is alkyl substituted with -N(R 18 )R 19
  • R 4 is alkyl substituted with -N(R 18 )R 19
  • each of R 18 and R 19 is independently alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or hydrogen, wherein alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is unsubstituted or substituted with one or more R B ; or R 18 and R 19 together with the atom to which they are attached form a heterocycloalkyl ring or heteroaryl ring, each of which is unsubstituted or substituted with one or more R B .
  • R 4 is alkyl substituted with -N(R 18 )R 19 , wherein R 18 and R 19 together with the atom to which they are attached form a heterocycloalkyl ring, for example a heterocycloalkyl ring substituted with substituted with one or more R B , such as wherein R B is selected from alkyl, arylalkyl and -C(O)CH 3 .
  • R 4 is alkyl substituted with -N(R 18 )R 19 , wherein R 18 and R 19 together with the atom to which they are attached form a heterocycloalkyl ring, such as an azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl or piperidinyl ring. [000110] In some embodiments of Formulas (I) and (Ic), R 4 is heteroalkyl. In some embodiments of Formulas (I) and (Ic), R 4 is CH 2 CH 2 OMe or CH 2 CH 2 SO 2 Me.
  • R 4 is –(CH 2 ) n CO 2 H, wherein n is 1, 2, 3, 4, 5, or 6. In some embodiments of Formulas (I) and (Ic), R 4 is –(CH 2 ) n CO 2 R 13 , wherein n is 1, 2, 3, 4, 5, or 6. In some embodiments of Formulas (I) and (Ic), R 4 is –(CH 2 ) n CO 2 R 13 , wherein R 13 is alkyl. In some embodiments of Formulas (I) and (Ic), R 4 is –(CH 2 ) n CO 2 R 13 , wherein R 13 is unsubstituted alkyl.
  • R 4 is –(CH 2 ) s CO 2 R 13 , wherein R 13 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or -CH(Et) 2 .
  • R 4 is –(CH 2 ) n OR 13 , wherein n is 1, 2, 3, 4, 5, 6 or 7.
  • R 4 is –(CH 2 ) n OR 13 , wherein R 13 is alkyl.
  • R 4 is –(CH 2 ) n OR 13 , wherein R 13 is unsubstituted alkyl. In some embodiments of Formulas (I) and (Ic), R 4 is –(CH 2 ) s OR 13 , wherein R 13 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or -CH(Et) 2 . [000112] In some embodiments of Formulas (I) and (Ic), R 4 is -CH(R A1 )NH 2 , wherein R A1 is hydrogen, alkyl, heteroalkyl, or an amino acid side chain.
  • R 2 is an amino acid residue, for example, with reference to Formula (Ic), R 4 , together with the carbonyl to which it is attached, in some embodiments, is an amino acid residue, that is R 4 is -CH(R A1 )NH 2 .
  • R 4 is - CH(R A1 )NH 2
  • R A1 is an amino acid side chain
  • the amino acid side chain is formed from an ⁇ -amino acid side chain, such as one of the naturally occurring amino acid side chains, such as an amino acid selected from alanine, serine, tryptophan, aspartic acid, glutamic acid and the like.
  • R A1 when R A1 is formed from alanine, R A1 is methyl.
  • R 4 is -CH(R A1 )NH 2 , wherein R A1 is an amino acid side chain.
  • R 4 is -CH(R A1 )NH 2 , wherein R A1 is methyl, ethyl, n- propyl, isopropyl, tert-butyl, CH(Me)Et, CH 2 CH(Me) 2 , or CH 2 CH 2 SMe.
  • R 4 is –(CH 2 ) n OR 13 , wherein n is 1, 2, 3, 4, 5, 6 or 7. In some embodiments of Formulas (I) and (Ic), R 4 is –(CH 2 ) n OR 13 , wherein R 13 is alkyl. In some embodiments of Formulas (I) and (Ic), R 4 is –(CH 2 ) n OR 13 , wherein R 13 is unsubstituted alkyl.
  • R 4 is –(CH 2 ) s OR 13 , wherein R 13 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or -CH(Et) 2 .
  • the compounds have the Formula(Ic2), or a pharmaceutically acceptable salt thereof: [000117]
  • R13 is alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl, each of which is substituted or unsubstituted;
  • R 2 is alkyl that is substituted or unsubstituted, or hydrogen; and
  • n is 1, 2, 3, 4, 5, or 6.
  • R 13 is methyl, ethyl, isopropyl, n-propyl, tert-butyl, n-butyl, n-pentyl, iso-amyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R 13 is methyl.
  • R 4 is –(CH 2 ) n N(R 18 )R 19 , wherein n is 1, 2, 3, 4, 5, 6 or 7.
  • R 4 is –(CH 2 ) n -N(R 18 )R 19 , wherein R 18 and R 19 independently are selected from hydrogen and alkyl, or together with the atom to which they are attached form a heterocycloalkyl ring, such as an azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl or piperidinyl ring.
  • each of R 18 and R 19 is independently alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or hydrogen, wherein alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is unsubstituted or substituted with one or more R B ; or R 18 and R 19 together with the atom to which they are attached form a heterocycloalkyl ring that is substituted or unsubstituted; R 5 is alkyl that is substituted or unsubstituted, or hydrogen; and n is 1, 2, 3, 4, 5,
  • each of R 18 and R 19 independently is hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl, iso-amyl, n- hexyl, n-heptyl, n-octyl, n-nonyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -CH 2 CF 3 , or -CH 2 cPr.
  • R X and R Y together with the atom to which they are attached form an azetidine ring, a piperidine ring, piperazine ring, a morpholine ring, or a pyrrolidine ring, each of which is substituted or unsubstituted.
  • a compound of Formula (Ic5) wherein R B is methyl, ethyl, n- propyl, isopropyl, or -CH(Et) 2 .
  • a compound of Formula (Ic5) wherein X is -NH-.
  • compounds having the structure of Formula (Ic-1), or a pharmaceutically acceptable salt thereof are provided: [000128] In some embodiments of compounds of Formulas (Ic), (Ic2) and (Ic-1), the compounds have the structure of Formula (Ic2-1), or a pharmaceutically acceptable salt thereof: [000129] In some embodiments of compounds of Formula (Ic), (Ic3), and (Ic-1), the compounds have the structure of Formula (Ic3-1), or a pharmaceutically acceptable salt thereof: [000130] In some embodiments of compounds of Formulas (Ic), (Ic3), (Ic-1), and (Ic3-1) have the structure of Formula (Ic4-1), or a pharmaceutically acceptable salt thereof: [000131] In some embodiments is a compound of Formulas (Ic), (Ic3, (Ic-1), and (Ic3-1) having the structure of Formula (Ic5-1): or a pharmaceutically acceptable salt thereof wh B erein R is selected from hydrogen,
  • [000132] in some embodiments is a compound of Formulas (I), (Ic), and (Ic1) having the structure of Formula (Ic1-1), or a pharmaceutically acceptable salt thereof: [000133] In some embodiments is a compound of Formula (Ic) having the structure of Formula (Ic-2), or a pharmaceutically acceptable salt thereof: [000134] In some embodiments is a compound of Formula (Ic) and (Ic-2) having the structure of Formula (Ic2-2), or a pharmaceutically acceptable salt thereof: [000135] In some embodiments is a compound of Formula (Ic), (Ic3), and (Ic-2), having the structure of Formula (Ic2-2), or a pharmaceutically acceptable salt thereof: [000136] In some embodiments is a compound of Formula (Ic), (Ic3), (Ic-2), and (Ic4) having the structure of Formula (Ic4-2), or a pharmaceutically acceptable salt thereof: [000137] In some embodiments is a compound of Formula (Ic), (Ic3), (I
  • [000138] is a compound of Formulas (I), (Ic), and (Ic1) having the structure of Formula (Ic1-2), or a pharmaceutically acceptable salt thereof: [000139] In some embodiments is a compound of Formulas (Ic), (Ic1), (Ic2), (Ic3), (Ic4), (Ic5), (Ic-1), (Ic1-1), (Ic2-1), (Ic3-1), (Ic4-1), (Ic5-1), (Ic-2), (Ic1-2), (Ic2-2), (Ic3-2), (Ic4-2), and/or (Ic5-2), wherein R 5 is hydrogen.
  • In some embodiments is a compound of Formulas (Ic), (Ic1), (Ic2), (Ic3), (Ic4), (Ic5), (Ic-1), (Ic1-1), (Ic2-1), (Ic3-1), (Ic4-1), (Ic5-1), (Ic-2), (Ic1-2), (Ic2-2), (Ic3-2), (Ic4-2), and/or (Ic5-2), wherein R 5 is methyl, ethyl, n-propyl, isopropyl, or -CH(Et) 2 .
  • n is 1.
  • the present disclosure provides a compound of Formula (Id), or a pharmaceutically acceptable salt thereof: or a pharmaceutically acceptable salt thereof, wherein R 6 is alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is substituted or unsubstituted.
  • R 6 and the carbonyl to which R 6 is attached form an amino acid residue; and each of R f and R 5 independently is alkyl that is substituted or unsubstituted, or hydrogen.
  • each of R f and R 5 independently is alkyl that is substituted or unsubstituted, or hydrogen.
  • R 6 is a compound of Formula (Id), wherein R 6 together which the carbonyl to which R 6 is attached form an amino acid residue.
  • R 6 is alkyl or heteroalkyl that is substituted or unsubstituted.
  • R 6 is alkyl that is substituted.
  • R 6 is alkyl that is substituted with heterocycloalkyl that is substituted or unsubstituted.
  • compounds have Formula (Id), wherein R 5 is unsubstituted alkyl.
  • R 5 is hydrogen, methyl, ethyl, or isopropyl.
  • R 6 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, or benzyl.
  • R 5 is hydrogen, and R 6 is alkyl. In some embodiments of Formulas (I) and (Id), R 5 is alkyl, and R 6 is alkyl. In some embodiments of Formulas (I) and (Id), R 5 is hydrogen, and R 6 is unsubstituted alkyl. In some embodiments of Formulas (I) and (Id), R 5 is unsubstituted alkyl, and R 6 is unsubstituted alkyl. In some embodiments of Formulas (I) and (Id), R 6 is methyl, ethyl, isopropyl, tert-butyl, or cyclopropyl.
  • R 5 is hydrogen, and R 6 is methyl, ethyl, isopropyl, tert-butyl, or cyclopropyl. In some embodiments of Formulas (I) and (Id), R 5 is hydrogen, and R 6 is tert-butyl. In some embodiments of Formulas (I) and (Id), R 1 is C 1-6 alkyl, such as methyl, R 5 is hydrogen, and R 4 is tert-butyl. In some embodiments of Formulas (I) and (Id), R 1 is C 1-6 alkyl, R 5 is hydrogen, and R 4 is tert-butyl.
  • R 6 is alkyl. In some embodiments of Formulas (I) and (Id), R 6 is unsubstituted alkyl. In some embodiments of Formulas (I) and (Id), R 6 is cycloalkyl. In some embodiments of Formulas (I) and (Id), R 6 is methyl, ethyl, n-propyl, tert-butyl, 3-methyl-1-butyl, n-pentyl, n-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.
  • R 6 is phenyl. In some embodiments of Formulas (I) and (Id), R 6 is 4-nitrophenyl. In some embodiments of Formulas (I) and (Id), R 6 is benzyl. In some embodiments of Formulas (I) and (Id), R 6 is heteroaryl. In some embodiments of Formulas (I) and (Id), R 6 is heteroaryl, such as 2-pyridyl, 3-pyridyl, 4- pyridyl, 2-pyrimidyl, or 4-pyrimidyl. [000147] In some embodiments of Formulas (I) and (Id), R 6 is heteroalkyl.
  • R 6 is CH 2 CH 2 OMe or CH 2 CH 2 SO 2 Me. In some embodiments of Formulas (I) and (Id), R 6 is –(CH 2 ) n CO 2 H, wherein n is 1, 2, 3, 4, 5, or 6. In some embodiments of Formulas (I) and (Id), R 6 is –(CH 2 ) n CO 2 R 13 , wherein n is 1, 2, 3, 4, 5, or 6. In some embodiments of Formulas (I) and (Id), R 6 is –(CH 2 ) n CO 2 R 13 , wherein R 13 is alkyl.
  • R 4 is –(CH 2 ) n CO 2 R 13 , wherein R 13 is unsubstituted alkyl. In some embodiments of Formulas (I) and (Id), R 4 is –(CH 2 ) s CO 2 R 13 , wherein R 13 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or -CH(Et) 2 . [000148] In some embodiments is a compound of Formulas (I) and (Id), wherein the compound is: or a pharmaceutically acceptable salt thereof. [000149] In some embodiments is a compound of Formulas (I) and (Id), wherein the compound is:
  • a compound of Formulas (I) and (Id) having the structure of Formula (Idl), or a pharmaceutically acceptable salt thereof: or a pharmaceutically acceptable salt thereof, wherein R 13 is alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl, each of which is substituted or unsubstituted; R 5 is hydrogen or alkyl that is substituted or unsubstituted; and n is 1, 2, 3, 4, 5, or 6.
  • a compound of Formulas (Id) and (Id1) wherein R 13 is methyl, ethyl, isopropyl, n-propyl, tert-butyl, n-butyl, n-pentyl, iso-amyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R 13 is methyl, ethyl, isopropyl, n-propyl, tert-butyl, n-butyl, n-pentyl, iso-amyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R 13 is methyl, ethyl, isopropyl, n-propyl, tert-butyl, n-butyl, n-pentyl, iso-amyl, cyclopropyl,
  • each of R 18 and R 19 is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl are substituted or unsubstituted; or R 18 and R 19 together with the atom to which they are attached form a heterocycloalkyl ring that is substituted or unsubstituted; R 5 is alkyl that is substituted or unsubstituted, or hydrogen; and n is 1, 2, 3, 4, 5, or 6.
  • each of R 18 and R 19 is independently hydrogen methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl, iso-amyl, n- hexyl, n-heptyl, n-octyl, n-nonyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -CH 2 CF 3 , or -CH 2 cPr.
  • R B is methyl, ethyl, n- propyl, isopropyl, or -CH(Et) 2 .
  • R B is hydrogen.
  • the carbon to which R A1 is attached is chiral (unless R A1 is hydrogen, as in glycine), and this carbon atom can have either the (R) or (S) configuration.
  • R A1 when R A1 is formed from alanine, R A1 is methyl.
  • R A1 is a compound of Formula (Id5), wherein R A1 is methyl, isopropyl, - CH(Me)Et, -CH 2 CH(Me) 2 , or -CH 2 Ph.
  • R A1 is methyl, isopropyl, - CH(Me)Et, -CH 2 CH(Me) 2 , or -CH 2 Ph.
  • a compound of Formula (Id) and (Id5) wherein the compound is: , , , or a pharmaceutically acceptable salt thereof.
  • [000160] is a compound of Formula (Id) having the structure of Formula (Id-1), or a pharmaceutically acceptable salt thereof: [000161] In some embodiments is a compound of Formula (Id) and (Id-1) having the structure of Formula (Id1-1), or a pharmaceutically acceptable salt thereof: [000162] In some embodiments is a compound of Formula (Id) and (Id-1)having the structure of Formula (Id2-1), or a pharmaceutically acceptable salt thereof: [000163] In some embodiments is a compound of Formula (Id), (Id2), (Id-1), and (Id2-1) having the structure of Formula (Id3-1), or a pharmaceutically acceptable salt thereof: [000164] In some embodiments is a compound of Formula (Id), (Id2), (Id2-1), and (Id4) having the structure of Formula (Id4-1), or a pharmaceutically acceptable salt thereof: [000165] In some embodiments is a compound of Formula (Id), (Id), (
  • In some embodiments is a compound of Formulas (Id), (Id1), (Id2), (Id3), (Id4), (Id5), (Id-1), (Id1-1), (Id2-1), (Id3-1), (Id4-1), (Id5-1) (Id-2), (Id1-2), (Id2-2), (Id3-2), (Id4-2), and/or (Id5-2), wherein R 5 is methyl, ethyl, n-propyl, isopropyl, or -CH(Et) 2 .
  • n is 1.
  • the present disclosure provides a compound of Formula (Ie), or a pharmaceutically acceptable salt thereof: or a pharmaceutically acceptable salt thereof, wherein R 15 is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is substituted or unsubstituted.
  • R 15 and the carbonyl to which R 15 is attached form an amino acid residue.
  • R15 is alkyl or heteroalkyl that is substituted or unsubstituted.
  • R 15 is alkyl that is substituted.
  • R 15 is alkyl that is substituted with heterocycloalkyl that is substituted or unsubstituted.
  • R 15 is alkyl, such as methyl.
  • R 15 is heteroalkyl that is substituted with cycloalkyl or heterocycloalkyl, wherein cycloalkyl or heterocycloalkyl are substituted or unsubstituted.
  • R 15 is heterocycloalkyl that is substituted or unsubstituted.
  • R 15 is heterocycloalkyl that is substituted with alkyl.
  • R 15 is methyl, ethyl, n- propyl, isopropyl, tert-butyl, n-pentyl, iso-amyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -CH 2 CF 3 , -CH 2 cPr, -CH 2 CH 2 OMe, vinyl, phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidy
  • the present disclosure provides a compound of Formula (If), or a pharmaceutically acceptable salt thereof: or a pharmaceutically acceptable salt thereof, wherein R 4 is alkyl, alkenyl, heteroalkyl, cycloalkyl, haloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is substituted or unsubstituted; and R 5 is alkyl that is substituted or unsubstituted, or hydrogen.
  • compounds of Formula (If) may be referred to as N-acyloxymethylene carbonate prodrug compounds.
  • R 4 is heteroalkyl.
  • R 4 is heterocycloalkyl.
  • R 5 is hydrogen and R 4 is heteroalkyl.
  • R 4 is heterocycloalkyl.
  • R 5 is hydrogen or C 1-6 alkyl and R 4 is heteroalkyl.
  • R 4 is heterocycloalkyl.
  • R 4 is alkyl. In some embodiments of a compound of Formula (If), R 4 is CH 2 CF 3 . In some embodiments of a compound of Formula (If), R 4 is unsubstituted alkyl. In some embodiments of Formula (If), R 4 is methyl, ethyl, n- propyl, isopropyl, n-butyl, tert-butyl, 3-methyl-1-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, or n- nonyl.
  • a compound of Formula (If) is one wherein R 4 is cycloalkyl. In some embodiments of compound of Formula (If), R 4 is unsubstituted cycloalkyl. In some embodiments of compounds of Formula (If), R 4 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments of a compound of Formula (If), the compound is one wherein R 4 is aryl. In some embodiments of Formula (If), wherein R 4 is substituted or unsubstituted phenyl.
  • R 4 is heteroaryl and in certain such some embodiments of Formula (If), R 4 is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2- pyrimidyl, 3-pyrimidyl, or 6-pyrimidyl.
  • R 4 is R A substituted with -OR 13 , - N(R 18 )R 19 ,or -C(O)OR 13 , such as wherein R 4 is alkyl, substituted with -OR 13 , -N(R 18 )R 19 ,or - C(O)OR 13 .
  • R 4 is alkyl substituted with -N(R 18 )R 19
  • R 4 is alkyl substituted with -N(R 18 )R 19
  • each of R 18 and R 19 is independently alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or hydrogen, wherein alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is unsubstituted or substituted with one or more R B ; or R 18 and R 19 together with the atom to which they are attached form a heterocycloalkyl ring or heteroaryl ring, each of which is unsubstituted or substituted with one or more R B .
  • R 4 is alkyl substituted with -N(R 18 )R 19 , wherein R 18 and R 19 together with the atom to which they are attached form a heterocycloalkyl ring, for example a heterocycloalkyl ring substituted with substituted with one or more R B , such as wherein R B is selected from alkyl, arylalkyl and -C(O)CH 3 .
  • R 4 is alkyl substituted with -N(R 18 )R 19 , wherein R 18 and R 19 together with the atom to which they are attached form a heterocycloalkyl ring, such as an azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl or piperidinyl ring.
  • R 4 is heteroalkyl.
  • R 4 is CH 2 CH 2 OMe or CH 2 CH 2 SO 2 Me.
  • R 4 is –(CH 2 ) n CO 2 H, wherein n is 1, 2, 3, 4, 5, or 6. In some embodiments of Formulas (I) and (If), R 4 is –(CH 2 ) n CO 2 R 13 , wherein n is 1, 2, 3, 4, 5, or 6. In some embodiments of Formulas (I) and (If), R 4 is –(CH 2 ) n CO 2 R 13 , wherein R 13 is alkyl. In some embodiments of Formulas (I) and (If), R 4 is –(CH 2 ) n CO 2 R 13 , wherein R 13 is unsubstituted alkyl.
  • R 4 is –(CH 2 ) s CO 2 R 13 , wherein R 13 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or -CH(Et) 2 .
  • R 4 is –(CH 2 ) n OR 13 , wherein n is 1, 2, 3, 4, 5, 6 or 7.
  • R 4 is –(CH 2 ) n OR 13 , wherein R 13 is alkyl.
  • R 4 is –(CH 2 ) n OR 13 , wherein R 13 is unsubstituted alkyl. In some embodiments of Formulas (I) and (If), R 4 is –(CH 2 ) s OR 13 , wherein R 13 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or -CH(Et) 2 . [000188] In some embodiments of Formulas (I) and (If), R 4 is –(CH 2 ) n N(R 18 )R 19 , wherein n is 1, 2, 3, 4, 5, 6 or 7.
  • R 4 is [000189] –(CH 2 ) n -N(R 18 )R 19 , wherein R 18 and R 19 together with the atom to which they are attached form a heterocycloalkyl ring, such as an azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl or piperidinyl ring.
  • R 5 is unsubstituted alkyl.
  • a compound of Formula (If) wherein R 5 is methyl, ethyl, n- propyl, isopropyl, tert-butyl, or hydrogen.
  • R 5 is a compound of Formula (If) or a pharmaceutically acceptable salt thereof, wherein R 5 is methyl or hydrogen.
  • R 5 is a compound of Formula (If), wherein R 5 is methyl.
  • R 5 is hydrogen. [000191]
  • R 4 is methyl, ethyl, n- propyl, isopropyl, tert-butyl, n-pentyl, iso-amyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -CH 2 CF 3 , -CH 2 cPr, -CH 2 CH 2 OMe, vinyl, phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, or 6- pyrimidyl.
  • a compound of Formula (If) wherein R 5 is hydrogen. In some embodiments is a compound of Formula (If), wherein R 5 is methyl, ethyl, n-propyl, isopropyl, or -CH(Et) 2 .
  • a compound of Formula (If) having the structure of Formula (If-1), or a pharmaceutically acceptable salt thereof [000195] In some embodiments is a compound of Formula (If) having the structure of Formula (If-2), or a pharmaceutically acceptable salt thereof: Certain Terminology [000196] Compounds herein can include all stereoisomers, enantiomers, diastereomers, mixtures, racemates, atropisomers, and tautomers thereof.
  • Non-limiting examples of optional substituents include hydroxyl groups, sulfhydryl groups, halogens, amino groups, nitro groups, nitroso groups, cyano groups, azido groups, sulfoxide groups, sulfone groups, sulfonamide groups, carboxyl groups, carboxaldehyde groups, imine groups, alkyl groups, halo-alkyl groups, alkenyl groups, halo-alkenyl groups, alkynyl groups, halo-alkynyl groups, alkoxy groups, aryl groups, aryloxy groups, aralkyl groups, arylalkoxy groups, heterocycloalkyl groups, heteroaryl groups, cycloalkyl groups, acyl groups, acyloxy groups, carbamate groups, amide groups, ureido groups, epoxy groups, and ester groups.
  • alkyl groups include straight, branched, and cyclic alkyl and alkylene groups.
  • An alkyl group can be, for example, a C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , C 22 , C 23 , C 24 , C 25 , C 26 , C 27 , C 28 , C 29 , C 30 , C 31 , C 32 , C 33 , C 34 , C 35 , C 36 , C 37 , C 38 , C 39 , C 40 , C 41 , C 42 , C 43 , C 44 , C 45 , C 46 , C 47 , C 48 , C 49 , or C 50 group that is substituted or unsubstit
  • Alkyl groups can include branched and unbranched alkyl groups.
  • straight alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl.
  • Branched alkyl groups include any straight alkyl group substituted with any number of alkyl groups.
  • Non-limiting examples of branched alkyl groups include isopropyl, isobutyl, sec- butyl, and t-butyl.
  • Non-limiting examples of substituted alkyl groups includes hydroxymethyl, chloromethyl, trifluoromethyl, aminomethyl, 1-chloroethyl, 2-hydroxyethyl, 1,2-difluoroethyl, and 3-carboxypropyl.
  • Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. Cycloalkyl groups also include fused-, bridged-, and spiro-bicycles and higher fused-, bridged-, and spiro-systems.
  • a cycloalkyl group can be substituted with any number of straight, branched, or cyclic alkyl groups.
  • Non-limiting examples of cyclic alkyl groups include cyclopropyl, 2-methyl-cycloprop- 1-yl, cycloprop-2-en-1-yl, cyclobutyl, 2,3-dihydroxycyclobut-1-yl, cyclobut-2-en-1-yl, cyclopentyl, cyclopent-2-en-1-yl, cyclopenta-2,4-dien-1-yl, cyclohexyl, cyclohex-2-en-1-yl, cycloheptyl, cyclooctanyl, 2,5-dimethylcyclopent-1-yl, 3,5-dichlorocyclohex-1-yl, 4- hydroxycyclohex-1-yl, 3,3,5-trimethylcyclohex-1-yl, octahydropentalenyl, oct
  • Non-limiting examples of alkenyl groups include straight, branched, and cyclic alkenyl groups.
  • the olefin or olefins of an alkenyl group can be, for example, E, Z, cis, trans, terminal, or exo-methylene.
  • An alkenyl group can be, for example, a C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , C 22 , C 23 , C 24 , C 25 , C 26 , C 27 , C 28 , C 29 , C 30 , C 31 , C 32 , C 33 , C 34 , C 35 , C 36 , C 37 , C 38 , C 39 , C 40 , C 41 , C 42 , C 43 , C 44 , C 45 , C 46 , C 47 , C 48 , C 49 , or C 50 group that is substituted or unsubstituted.
  • Non-limiting examples of alkenyl and alkenylene groups include ethenyl, prop-1-en-1-yl, isopropenyl, but-1-en-4-yl; 2-chloroethenyl, 4- hydroxybuten-1-yl, 7-hydroxy-7-methyloct-4-en-2-yl, and 7-hydroxy-7-methyloct-3,5-dien-2-yl.
  • alkynyl groups include straight, branched, and cyclic alkynyl groups. The triple bond of an alkynyl group can be internal or terminal.
  • An alkynyl or alkynylene group can be, for example, a C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , C 22 , C 23 , C 24 , C 25 , C 26 , C 27 , C 28 , C 29 , C 30 , C 31 , C 32 , C 33 , C 34 , C 35 , C 36 , C 37 , C 38 , C 39 , C 40 , C 41 , C 42 , C 43 , C 44 , C 45 , C 46 , C 47 , C 48 , C 49 , or C 50 group that is substituted or unsubstituted.
  • Non-limiting examples of alkynyl groups include ethynyl, prop-2-yn-1-yl, prop-1-yn-1-yl, and 2-methyl-hex-4-yn-1-yl; 5-hydroxy-5-methylhex-3-yn-1-yl, 6-hydroxy-6- methylhept-3-yn-2-yl, and 5-hydroxy-5-ethylhept-3-yn-1-yl.
  • a halo-alkyl group can be any alkyl group substituted with any number of halogen atoms, for example, fluorine, chlorine, bromine, and iodine atoms.
  • a halo-alkenyl group can be any alkenyl group substituted with any number of halogen atoms.
  • a halo-alkynyl group can be any alkynyl group substituted with any number of halogen atoms.
  • An alkoxy group can be, for example, an oxygen atom substituted with any alkyl, alkenyl, or alkynyl group.
  • An ether or an ether group comprises an alkoxy group. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, and isobutoxy.
  • a heterocycle can be any ring containing a ring atom that is not carbon, for example, N, O, S, P, Si, B, or any other heteroatom.
  • a heterocycle can be substituted with any number of substituents, for example, alkyl groups and halogen atoms.
  • a heterocycle can be aromatic (heteroaryl) or non-aromatic.
  • Non-limiting examples of heterocycles include pyrrole, pyrrolidine, pyridine, piperidine, succinimide, maleimide, morpholine, imidazole, thiophene, furan, tetrahydrofuran, pyran, and tetrahydropyran.
  • Non-limiting examples of heterocycles include: heterocyclic units having a single ring containing one or more heteroatoms, non-limiting examples of which include, diazirinyl, aziridinyl, azetidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, isothiazolinyl, oxathiazolidinonyl, oxazolidinonyl, hydantoinyl, tetrahydrofuranyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, piperidin-2-onyl, 2,3,4,5-tetrahydro-1H-azepinyl, 2,3-dihydro-1H-indole, and 1,2,3,4-tetrahydroquinoline;
  • heteroaryl include: i) heteroaryl rings containing a single ring, non-limiting examples of which include, 1,2,3,4-tetrazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl, triazinyl, thiazolyl, 1H-imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, furanyl, thiophenyl, pyrimidinyl, 2-phenylpyrimidinyl, pyridinyl, 3-methylpyridinyl, and 4-dimethylaminopyridinyl; and ii) heteroaryl rings containing 2 or more fused rings one of which is a heteroaryl ring, non- limiting examples of which include: 7H-purinyl, 9H-purinyl, 6-amino-9H-purinyl, 5H- pyrrolo[3,2-d]pyrimidinyl, 7H
  • Alkyl refers to an optionally substituted straight-chain, or optionally substituted branched-chain saturated hydrocarbon having from one to about ten carbon atoms, or from one to six carbon atoms, wherein an sp 3 -hybridized carbon of the alkyl residue is attached to the rest of the molecule by a single bond.
  • Examples include, but are not limited to, methyl, ethyl, n- propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2- methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1- pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3- dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl, and hexyl, and longer alkyl groups, such as heptyl, octyl
  • C 1 -C 6 alkyl means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated.
  • the alkyl is a C 1 -C 10 alkyl, a C 1 - C 9 alkyl, a C 1 -C 8 alkyl, a C 1 -C 7 alkyl, a C 1 -C 6 alkyl, a C 1 -C 5 alkyl, a C 1 -C 4 alkyl, a C 1 -C 3 alkyl, a C 1 -C 2 alkyl, or a C1 alkyl.
  • an alkyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkyl is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, - OMe, -NH 2 , or -NO 2 .
  • the alkyl is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, or -OMe.
  • alkyl is optionally substituted with halogen.
  • Alkenyl refers to an optionally substituted straight-chain, or optionally substituted branched-chain hydrocarbon having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms, wherein an sp 2 - hybridized carbon of the alkenyl residue is attached to the rest of the molecule by a single bond.
  • the group may be in either the cis or trans conformation about the double bond(s), and should be understood to include both isomers.
  • a numerical range such as “C 2 -C 6 alkenyl” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated.
  • the alkenyl is a C 2 - C 10 alkenyl, a C 2 -C 9 alkenyl, a C 2 -C 8 alkenyl, a C 2 -C 7 alkenyl, a C 2 -C 6 alkenyl, a C 2 -C 5 alkenyl, a C 2 -C 4 alkenyl, a C 2 -C 3 alkenyl, or a C 2 alkenyl.
  • an alkenyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • an alkenyl is optionally substituted with oxo, halogen, -CN, - CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • an alkenyl is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, or -OMe.
  • alkenyl is optionally substituted with halogen.
  • Alkynyl refers to an optionally substituted straight-chain or optionally substituted branched-chain hydrocarbon having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and the like.
  • C 2 -C 6 alkynyl means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated.
  • the alkynyl is a C 2 -C 10 alkynyl, a C 2 -C 9 alkynyl, a C 2 -C 8 alkynyl, a C 2 -C 7 alkynyl, a C 2 -C 6 alkynyl, a C 2 -C 5 alkynyl, a C 2 -C 4 alkynyl, a C 2 -C 3 alkynyl, or a C 2 alkynyl.
  • an alkynyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • an alkynyl is optionally substituted with oxo, halogen, -CN, - CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • an alkynyl is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, or -OMe.
  • alkynyl is optionally substituted with halogen.
  • Alkoxy refers to a radical of the formula -ORa where Ra is an alkyl radical as defined.
  • Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, and isobutoxy.
  • alkoxy is C 1 -C 6 alkoxy.
  • an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • an alkoxy is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • an alkoxy is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, or -OMe.
  • the alkoxy is optionally substituted with halogen.
  • “Aminoalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Hydroxyalkyl include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the hydroxyalkyl is aminomethyl.
  • “Aryl” refers to a radical derived from a hydrocarbon ring system comprising hydrogen, 6 to 30 carbon atoms, and at least one aromatic ring.
  • the aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems.
  • the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl.
  • Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene.
  • the aryl is phenyl.
  • an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • an aryl is optionally substituted with halogen, methyl, ethyl, -CN, - CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.
  • Cycloalkyl refers to a stable, partially or fully saturated, monocyclic or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom), bridged, or spiro ring systems.
  • Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C 3 -C 15 cycloalkyl), from three to ten carbon atoms (C 3 -C 10 cycloalkyl), from three to eight carbon atoms (C 3 -C 8 cycloalkyl), from three to six carbon atoms (C 3 -C 6 cycloalkyl), from three to five carbon atoms (C 3 -C 5 cycloalkyl), or three to four carbon atoms (C 3 -C 4 cycloalkyl).
  • the cycloalkyl is a 3- to 6-membered cycloalkyl.
  • the cycloalkyl is a 5- to 6-membered cycloalkyl.
  • Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic cycloalkyls or carbocycles include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl.
  • Partially saturated cycloalkyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, - OMe, -NH 2 , or -NO 2 .
  • a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe.
  • the cycloalkyl is optionally substituted with halogen.
  • “Deuteroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more deuteriums.
  • the alkyl is substituted with one deuterium. In some embodiments, the alkyl is substituted with one, two, or three deuteriums. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six deuteriums.
  • Deuteroalkyl include, for example, CD 3 , CH 2 D, CHD 2 , CH 2 CD 3 , CD 2 CD 3 , CHDCD 3 , CH 2 CH 2 D, or CH 2 CHD 2 . In some embodiments, the deuteroalkyl is CD 3 . [000218] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halogens.
  • the alkyl is substituted with one, two, or three halogens. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six halogens.
  • Haloalkyl include, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.
  • the haloalkyl is trifluoromethyl. In some embodiments, haloalkyl is C 1 - C 6 haloalkyl.
  • Halo or “halogen” refers to bromo, chloro, fluoro, or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.
  • Heteroalkyl refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • a heteroalkyl is a C 1 -C 6 heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, -N(alkyl)-), sulfur, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • heteroalkyl are, for example, -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 OCH 2 CH 2 OCH 3 , or - CH(CH 3 )OCH 3 .
  • a heteroalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, - CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.
  • “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls.
  • Hydroxyalkyl include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.
  • “Heterocycle” refers to heteroaryl and heterocycloalkyl ring systems.
  • a heterocycle can be any ring containing a ring atom that is not carbon, for example, N, O, S, P, Si, B, or any other heteroatom.
  • a heterocycle can be substituted with any number of substituents, for example, alkyl groups and halogen atoms.
  • a heterocycle can be aromatic (heteroaryl) or non- aromatic.
  • heterocycles include pyrrole, pyrrolidine, pyridine, piperidine, succinimide, maleimide, morpholine, imidazole, thiophene, furan, tetrahydrofuran, pyran, and tetrahydropyran.
  • Non-limiting examples of heterocycles include: heterocyclic units having a single ring containing one or more heteroatoms, non-limiting examples of which include, diazirinyl, aziridinyl, azetidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, isothiazolinyl, oxathiazolidinonyl, oxazolidinonyl, hydantoinyl, tetrahydrofuranyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, piperidin-2-onyl, 2,3,4,5-tetrahydro-1H-azepinyl, 2,3-dihydro-1H-indole, and 1,2,3,4-tetrahydroquinoline
  • Heterocycloalkyl refers to a stable 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur.
  • the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
  • heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (C 2 -C 15 heterocycloalkyl), from two to ten carbon atoms (C 2 -C 10 heterocycloalkyl), from two to eight carbon atoms (C 2 -C 8 heterocycloalkyl), from two to six carbon atoms (C 2 -C 6 heterocycloalkyl), from two to five carbon atoms (C 2 -C 5 heterocycloalkyl), or two to four carbon atoms (C 2 -C 4 heterocycloalkyl).
  • the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl.
  • the cycloalkyl is a 5- to 6-membered heterocycloalkyl.
  • heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, t
  • heterocycloalkyl is aziridinyl, azetidinyl, morpholinyl, piperidinyl, piperazinyl, oxetanyl, tetrahydrofuryl, tetrahydropyranyl, or thiomorpholinyl.
  • heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to, the monosaccharides, the disaccharides, and the oligosaccharides.
  • a heterocycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or - OMe.
  • the heterocycloalkyl is optionally substituted with halogen.
  • Heteroaryl refers to a 5- to 14-membered ring system radical comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring.
  • the heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
  • the heteroaryl is a 5- to 10-membered heteroaryl.
  • the heteroaryl is a 5- to 6-membered heteroaryl.
  • Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furany
  • heteroaryl is imidazolyl, indazolyl, indolyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazolyl, or tetrazolyl.
  • a heteroaryl is optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 . In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.
  • heteroaryl include: i) heteroaryl rings containing a single ring, non-limiting examples of which include, 1,2,3,4-tetrazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl, triazinyl, thiazolyl, 1H-imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, furanyl, thiophenyl, pyrimidinyl, 2-phenylpyrimidinyl, pyridinyl, 3-methylpyridinyl, and 4-dimethylaminopyridinyl; and ii) heteroaryl rings containing 2 or more fused rings one of which is a heteroaryl ring, non- limiting examples of which include: 7H-purinyl, 9H-purinyl, 6-amino-9H-purinyl, 5H- pyrrolo[3,2-d]pyrimidinyl, 7H
  • Certain compounds according to Formula (I) disclosed herein are isotopically enriched, meaning that they have an isotope present in greater than its natural abundance at one or more position.
  • isotopic enrichment factor means the ratio between the isotopic abundance and the natural abundance of a specified isotope.
  • a particular position is designated as having a particular isotope, such as deuterium, it is understood that the abundance of deuterium at that position is substantially greater than the natural abundance of deuterium, which is about 0.015% (on a mol/mol basis).
  • a position designated as a particular isotope will have a minimum isotopic enrichment factor of at least 3000 (45% incorporation of the indicated isotope).
  • isotopically enriched compounds disclosed herein having deuterium will have a minimum isotopic enrichment factor of at least 3000 (45% deuterium incorporation) at each atom designated as deuterium in the compound.
  • Such compounds may be referred to herein as “deuterated” compounds.
  • deuterated compounds disclosed herein have an isotopic enrichment factor for each designated atom of at least 3500 (52.5%), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). [000229] In some embodiments, the present disclosure provides a deuterated analogue of any compound disclosed herein.
  • a deuterated analogue can include a compound herein where one or more 1 H atoms is replaced with a deuterium atom.
  • isotopically enriched compounds of the present disclosure according to Formula I include, without limitation, those having deuterium on the methylene dioxole moiety, for example wherein Formula (I) has the structure: [000230]
  • a deuterated analogue of Compound 1: can be, for example, [000231] Any compound herein can be purified.
  • a compound herein can be least 1% pure, at least 2% pure, at least 3% pure, at least 4% pure, at least 5% pure, at least 6% pure, at least 7% pure, at least 8% pure, at least 9% pure, at least 10% pure, at least 11% pure, at least 12% pure, at least 13% pure, at least 14% pure, at least 15% pure, at least 16% pure, at least 17% pure, at least 18% pure, at least 19% pure, at least 20% pure, at least 21% pure, at least 22% pure, at least 23% pure, at least 24% pure, at least 25% pure, at least 26% pure, at least 27% pure, at least 28% pure, at least 29% pure, at least 30% pure, at least 31% pure, at least 32% pure, at least 33% pure, at least 34% pure, at least 35% pure, at least 36% pure, at least 37% pure, at least 38% pure, at least 39% pure, at least 40% pure, at least 41% pure, at least 42% pure, at least 4
  • compositions provide for pharmaceutically-acceptable salts of any compound described herein as well as the use of such salts.
  • any compound with an ionizable group such as an acidic hydrogen, or a basic nitrogen
  • Pharmaceutically-acceptable salts include, for example, acid-addition salts and base-addition salts.
  • the acid that is added to the compound to form an acid-addition salt can be an organic acid or an inorganic acid.
  • a base that is added to the compound to form a base-addition salt can be an organic base or an inorganic base.
  • a pharmaceutically-acceptable salt is a metal salt. In some embodiments, a pharmaceutically-acceptable salt is an ammonium salt.
  • Metal salts can arise from the addition of an inorganic base to a compound of the present disclosure.
  • the inorganic base consists of a metal cation paired with a basic counterion, such as, for example, hydroxide, carbonate, bicarbonate, or phosphate.
  • the metal can be an alkali metal, alkaline earth metal, transition metal, or main group metal. In some embodiments, the metal is lithium, sodium, potassium, cesium, cerium, magnesium, manganese, iron, calcium, strontium, cobalt, titanium, aluminum, copper, cadmium, or zinc.
  • a metal salt is a lithium salt, a sodium salt, a potassium salt, a cesium salt, a cerium salt, a magnesium salt, a manganese salt, an iron salt, a calcium salt, a strontium salt, a cobalt salt, a titanium salt, an aluminum salt, a copper salt, a cadmium salt, or a zinc salt.
  • Ammonium salts can arise from the addition of ammonia or an organic amine to a compound of the present disclosure.
  • the organic amine is trimethyl amine, triethyl amine, diisopropyl amine, ethanol amine, diethanol amine, triethanol amine, morpholine, N-methylmorpholine, piperidine, N-methylpiperidine, N-ethylpiperidine, dibenzylamine, piperazine, pyridine, pyrazole, pyrazolidine, pyrazoline, pyridazine, pyrimidine, imidazole, or pyrazine.
  • an ammonium salt is a triethyl amine salt, trimethyl amine salt, a diisopropyl amine salt, an ethanol amine salt, a diethanol amine salt, a triethanol amine salt, a morpholine salt, an N-methylmorpholine salt, a piperidine salt, an N-methylpiperidine salt, an N- ethylpiperidine salt, a dibenzylamine salt, a piperazine salt, a pyridine salt, a pyrazole salt, a pyridazine salt, a pyrimidine salt, an imidazole salt, or a pyrazine salt.
  • Acid addition salts can arise from the addition of an acid to a compound of the present disclosure.
  • the acid is organic.
  • the acid is inorganic.
  • the acid is hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, nitrous acid, sulfuric acid, sulfurous acid, a phosphoric acid, isonicotinic acid, lactic acid, salicylic acid, tartaric acid, ascorbic acid, gentisic acid, gluconic acid, glucuronic acid, saccharic acid, formic acid, benzoic acid, glutamic acid, pantothenic acid, acetic acid, propionic acid, butyric acid, fumaric acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, oxalic acid, xinafoic
  • the salt is a hydrochloride salt, a hydrobromide salt, a hydroiodide salt, a nitrate salt, a nitrite salt, a sulfate salt, a sulfite salt, a phosphate salt, isonicotinate salt, a lactate salt, a salicylate salt, a tartrate salt, an ascorbate salt, a gentisate salt, a gluconate salt, a glucuronate salt, a saccharate salt, a formate salt, a benzoate salt, a glutamate salt, a pantothenate salt, an acetate salt, a propionate salt, a butyrate salt, a fumarate salt, a succinate salt, a methanesulfonate salt, an ethanesulfonate salt, a benzenesulfonate salt, a p- toluenesul
  • compositions comprising a compound of the present disclosure and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • the amount of compound in the composition is an amount effective to treat the relevant disease, disorder, or condition in a patient in need thereof (an “effective amount”).
  • a composition of the present disclosure is formulated for oral administration to a patient.
  • pharmaceutically acceptable carrier, adjuvant, or vehicle refers to a non- toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the agent with which it is formulated.
  • compositions include, but are not limited to, ion exchangers, alumina, stearates such as aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose- based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, polyethylene glycol and wool fat.
  • ion exchangers alumina, stearates such as aluminum stearate, lecithin
  • serum proteins such as human serum albumin
  • buffer substances such as phosphates, glycine,
  • compositions of the present disclosure may be administered orally, parenterally, enterally, intracistemally, intraperitoneally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the composition is administered orally, intraperitoneally, or intravenously.
  • the composition is a transmucosal formulation.
  • Sterile injectable forms of the compositions of this disclosure may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in l,3-butanediol.
  • a non-toxic parenterally acceptable diluent or solvent for example as a solution in l,3-butanediol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer’s solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or di -glycerides.
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically -acceptable oils, such as olive oil or castor oil, especially in their poly oxy ethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • compositions may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
  • carriers commonly used include lactose and com starch.
  • Lubricating agents such as magnesium stearate, may also be added.
  • useful diluents include lactose and dried corn starch.
  • compositions may be administered in the form of suppositories for rectal administration.
  • suppositories for rectal administration.
  • suppositories can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, beeswax and polyethylene glycols.
  • the pharmaceutically acceptable composition is formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, the pharmaceutically acceptable composition is administered without food. In other embodiments, the pharmaceutically acceptable composition is administered with food. [000246] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 -butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvent
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in l,3-butanediol.
  • Injectable formulations can be sterilized, for example, by filtration through a bacterial- retaining filter, 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.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this disclosure with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f ) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetylene glycol, g,
  • the dosage form may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • embedding compositions examples include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
  • Therapeutic agents can also be in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g ., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • Dosage forms for topical or transdermal administration of a compound of this disclosure include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this disclosure.
  • the present disclosure contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin.
  • the rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • the present disclosure provides a pharmaceutically acceptable composition
  • a pharmaceutically acceptable composition comprising a compound according to any of Table 1, Formula (I), (Ia), (Ia-1), (Ia- 2), (Ia1), (Ia1-1), (Ia1-2), (Ia2), (Ia2-1), (Ia2-2), (Ia3), (Ia3-1), (Ia3-2), (Ib), (Ib-1), (Ib-2), (Ib1), (Ib2), (Ib2-1), (Ib2-2), (Ib3), (Ib3-1), (Ib3-2), (Ic), (Ic-1), (Ic-2), (Ic1), (Ic1-1), (Ic1-2), (Ic2), (Ic2-1), (Ic2-2), (Ic3), (Ic3-1), (Ic3-2), (Ic4), (Ic4-1), (Ic4-2), (Ic5), (Ic5-1), (Ic5-2), (Id), (Id-1), (Id-2), (
  • compositions of the present disclosure can comprise racemic, scalemic, or diasteromerically enriched mixtures of any compound described herein.
  • the present disclosure provides a pharmaceutical composition comprising a mixture of diastereomers of a compound of Table 1, Formula (I), (Ia), (Ia-1), (Ia- 2), (Ia1), (Ia1-1), (Ia1-2), (Ia2), (Ia2-1), (Ia2-2), (Ia3), (Ia3-1), (Ia3-2), (Ib), (Ib-1), (Ib-2), (Ib1), (Ib2), (Ib2-1), (Ib2-2), (Ib3), (Ib3-1), (Ib3-2), (Ic), (Ic-1), (Ic-2), (Ic1), (Ic1-1), (Ic1-2), (Ic2), (Ic2-1), (Ic2-2), (Ic3), (Ic3-1), (Ic3-2), (Ic4),
  • the present disclosure provides a pharmaceutical composition comprising a mixture of diastereomers of a compound of Table 1, Formula (I), (Ia), (Ia-1), (Ia- 2), (Ia1), (Ia1-1), (Ia1-2), (Ia2), (Ia2-1), (Ia2-2), (Ia3), (Ia3-1), (Ia3-2), (Ib), (Ib-1), (Ib-2), (Ib1), (Ib2), (Ib2-1), (Ib2-2), (Ib3), (Ib3-1), (Ib3-2), (Ic), (Ic-1), (Ic-2), (Ic1), (Ic1-1), (Ic1-2), (Ic2), (Ic2-1), (Ic2-2), (Ic3), (Ic3-1), (Ic3-2), (Ic4), (Ic4-1), (Ic4-2), (Ic5), (Ic5-1), (Ic5-2), (Id), (Id-1), (
  • the present disclosure provides a pharmaceutical composition comprising a mixture of diastereomers of a compound of Table 1, Formula (I), (Ia), (Ia-1), (Ia- 2), (Ia1), (Ia1-1), (Ia1-2), (Ia2), (Ia2-1), (Ia2-2), (Ia3), (Ia3-1), (Ia3-2), (Ib), (Ib-1), (Ib-2), (Ib1), (Ib2), (Ib2-1), (Ib2-2), (Ib3), (Ib3-1), (Ib3-2), (Ic), (Ic-1), (Ic-2), (Ic1), (Ic1-1), (Ic1-2), (Ic2), (Ic2-1), (Ic2-2), (Ic3), (Ic3-1), (Ic3-2), (Ic4), (Ic4-1), (Ic4-2), (Ic5), (Ic5-1), (Ic5-2), (Id), (Id-1),
  • the present disclosure provides a pharmaceutical composition comprising a mixture of diastereomers of a compound of Table 1, Formula (I), (Ia), (Ia-1), (Ia- 2), (Ia1), (Ia1-1), (Ia1-2), (Ia2), (Ia2-1), (Ia2-2), (Ia3), (Ia3-1), (Ia3-2), (Ib), (Ib-1), (Ib-2), (Ib1), (Ib2), (Ib2-1), (Ib2-2), (Ib3), (Ib3-1), (Ib3-2), (Ic), (Ic-1), (Ic-2), (Ic1), (Ic1-1), (Ic1-2), (Ic2), (Ic2-1), (Ic2-2), (Ic3), (Ic3-1), (Ic3-2), (Ic4), (Ic4-1), (Ic4-2), (Ic5), (Ic5-1), (Ic5-2), (Id), (Id-1),
  • the present disclosure provides a pharmaceutical composition comprising a mixture of diastereomers of a compound of Table 1, Formula (I), (Ia), (Ia-1), (Ia- 2), (Ia1), (Ia1-1), (Ia1-2), (Ia2), (Ia2-1), (Ia2-2), (Ia3), (Ia3-1), (Ia3-2), (Ib), (Ib-1), (Ib-2), (Ib1), (Ib2), (Ib2-1), (Ib2-2), (Ib3), (Ib3-1), (Ib3-2), (Ic), (Ic-1), (Ic-2), (Ic1), (Ic1-1), (Ic1-2), (Ic2), (Ic2-1), (Ic2-2), (Ic3), (Ic3-1), (Ic3-2), (Ic4), (Ic4-1), (Ic4-2), (Ic5), (Ic5-1), (Ic5-2), (Id), (Id-1),
  • the present disclosure provides a pharmaceutical composition comprising a mixture of diastereomers of a compound of Table 1, Formula (I), (Ia), (Ia-1), (Ia- 2), (Ia1), (Ia1-1), (Ia1-2), (Ia2), (Ia2-1), (Ia2-2), (Ia3), (Ia3-1), (Ia3-2), (Ib), (Ib-1), (Ib-2), (Ib1), (Ib2), (Ib2-1), (Ib2-2), (Ib3), (Ib3-1), (Ib3-2), (Ic), (Ic-1), (Ic-2), (Ic1), (Ic1-1), (Ic1-2), (Ic2), (Ic2-1), (Ic2-2), (Ic3), (Ic3-1), (Ic3-2), (Ic4), (Ic4-1), (Ic4-2), (Ic5), (Ic5-1), (Ic5-2), (Id), (Id-1), (
  • the present disclosure provides a method of treating or preventing a disease, disorder, or condition in which an increased level of a phenethylamine psychedelic such as MDEA is beneficial, comprising administering to a subject in need thereof an effective amount of a compound of Table 1, Formula (I), (Ia), (Ia-1), (Ia-2), (Ia1), (Ia1-1), (Ia1-2), (Ia2), (Ia2-1), (Ia2-2), (Ia3), (Ia3-1), (Ia3-2), (Ib), (Ib-1), (Ib-2), (Ib1), (Ib2), (Ib2-1), (Ib2-2), (Ib3), (Ib3-1), (Ib3-2), (Ic), (Ic-1), (Ic-2), (Ic1), (Ic1-1), (Ic1-2), (Ic2), (Ic2-1), (Ic2-2), (Ic3), (Ic3-1), (Ic3-1), (Ic3-2), (Ic), (
  • the condition comprises post-traumatic stress disorder, major depression, schizophrenia, Alzheimer’s disease, frontotemporal dementia, Parkinson’s disease, Parkinson’s dementia, dementia, Lewy body dementia, multiple system atrophy, or substance abuse.
  • the condition comprises musculoskeletal pain disorder including fibromyalgia, muscle pain, joint stiffness, osteoarthritis, rheumatoid arthritis, muscle cramps.
  • the present disclosure provides a method of treating a disease of women’s reproductive health including premenstrual dysphoric disorder (PMDD), premenstrual syndrome (PMS), post-partum depression, and menopause.
  • the compounds of the present invention can also be used to treat any brain disease.
  • a compound disclosed herein has activity as a 5-HT 2A modulator.
  • a compound disclosed herein elicits a biological response by activating the 5-HT 2A receptor (e.g., allosteric modulation or modulation of a biological target that activates the 5-HT 2A receptor).
  • 5-HT 2A agonism has been correlated with the promotion of neural plasticity.
  • 5-HT 2A antagonists abrogate the neuritogenesis and spinogenesis effects of hallucinogenic compounds with 5-HT 2A agonist activity, for example, DMT, LSD, and DOI.
  • a compound disclosed herein is a 5-HT 2A modulator and promotes neural plasticity (e.g., cortical structural plasticity).
  • a compound disclosed herein is a selective 5-HT 2A modulator and promotes neural plasticity (e.g., cortical structural plasticity).
  • Promotion of neural plasticity can include, for example, increased dendritic spine growth, increased synthesis of synaptic proteins, strengthened synaptic responses, increased dendritic arbor complexity, increased dendritic branch content, increased spinogenesis, increased neuritogenesis, or any combination thereof.
  • increased neural plasticity includes increased cortical structural plasticity in the anterior parts of the brain.
  • the 5-HT 2A modulators e.g., 5-HT 2A agonists
  • non-hallucinogenic 5-HT 2A modulators e.g., 5-HT 2A agonists
  • the hallucinogenic potential of the compounds described herein is assessed in vitro.
  • the hallucinogenic potential assessed in vitro of the compounds described herein is compared to the hallucinogenic potential assessed in vitro of hallucinogenic homologs.
  • the compounds described herein elicit less hallucinogenic potential in vitro than the hallucinogenic homologs.
  • serotonin receptor modulators such as modulators of serotonin receptor 2A (5-HT 2A modulators, e.g., 5-HT 2A agonists), are used to treat a brain disorder.
  • a compound of the present disclosure functions as a 5-HT 2A agonist alone, or in combination with a second therapeutic agent that also is a 5-HT 2A modulator.
  • the second therapeutic agent can be an agonist or an antagonist.
  • Serotonin receptor modulators useful as second therapeutic agents for combination therapy as described herein are known to those of skill in the art and include, without limitation, ketanserin, volinanserin (MDL-100907), eplivanserin (SR-46349), pimavanserin (ACP-103), glemanserin (MDL-11939), ritanserin, flibanserin, nelotanserin, blonanserin, mianserin, mirtazapine, roluperiodone (CYR-101, MIN-101), quetiapine, olanzapine, altanserin, acepromazine, nefazodone, risperidone, pruvanserin, AC-90179, AC-279, adatanserin, fananserin, HY10275, benanserin, butanserin, manserin, iferanserin, lidanserin, pelanserin, seganserin, tropanserin, lorcaserin,
  • the serotonin receptor modulator used as a second therapeutic is pimavanserin or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof.
  • the serotonin receptor modulator is administered prior to administration of a compound disclosed herein, such as about three or about one hours prior to administration of the compound.
  • the serotonin receptor modulator is administered at most about one hour prior to the compound.
  • the second therapeutic agent is a serotonin receptor modulator.
  • the serotonin receptor modulator is provided at a dose of from about 10 mg to about 350 mg.
  • the serotonin receptor modulator is provided at a dose of from about 20 mg to about 200 mg. In some embodiments, the serotonin receptor modulator is provided at a dose of from about 10 mg to about 100 mg. In certain such embodiments, a compound of the present disclosure is provided at a dose of from about 10 mg to about 100 mg, or from about 20 to about 200 mg, or from about 15 to about 300 mg, and the serotonin receptor modulator is provided at a dose of about 10 mg to about 100 mg. [000269] In some embodiments, non-hallucinogenic 5-HT2 A modulators (e.g., 5-HT2 A agonists) are used to treat neurological diseases.
  • 5-HT2 A modulators e.g., 5-HT2 A agonists
  • the neurological diseases comprise decreased neural plasticity, decreased cortical structural plasticity, decreased 5-HT 2A receptor content, decreased dendritic arbor complexity, loss of dendritic spines, decreased dendritic branch content, decreased spinogenesis, decreased neuritogenesis, retraction of neurites, or any combination thereof.
  • non-hallucinogenic 5-HT 2A modulators e.g., 5-HT 2A agonists
  • non-hallucinogenic 5-HT 2A modulators are used for increasing neuronal plasticity.
  • non-hallucinogenic 5-HT 2A modulators are used for treating a brain disorder.
  • non-hallucinogenic 5-HT 2A modulators e.g., 5-FIT 2A agonists
  • a compound herein is given to patients in a low dose that is lower than would produce noticeable psychedelic effects but high enough to provide a therapeutic benefit. This dose range is predicted to be between 200 ⁇ g (micrograms) and 2 mg.
  • a compound described herein is used to treat a neurological disease.
  • a compound provided herein can exhibit, anti-addictive properties, antidepressant properties, anxiolytic properties, or a combination thereof.
  • the neurological disease is a neuropsychiatric disease.
  • the neuropsychiatric disease is a mood or anxiety disorder.
  • the neurological disease is a migraine, headaches (e.g., cluster headache), post -traumatic stress disorder (PTSD), anxiety, depression, neurodegenerative disorder, Alzheimer’s disease, Parkinson’s disease, psychological disorder, treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, and addiction (e.g., substance use disorder).
  • the neurological disease is a migraine or cluster headache.
  • the neurological disease is a neurodegenerative disorder, Alzheimer’s disease, or Parkinson’s disease.
  • the neurological disease is a psychological disorder, treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, post-traumatic stress disorder (PTSD), addiction (e.g., substance use disorder), depression, or anxiety.
  • the neuropsychiatric disease is a psychological disorder, treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, post -traumatic stress disorder (PTSD), addiction (e.g., substance use disorder), depression, or anxiety.
  • the neuropsychiatric disease or neurological disease is post-traumatic stress disorder (PTSD), addiction (e.g., substance use disorder), schizophrenia, depression, or anxiety.
  • the neuropsychiatric disease or neurological disease is addiction (e.g., substance use disorder). In some embodiments, the neuropsychiatric disease or neurological disease is depression. In some embodiments, the neuropsychiatric disease or neurological disease is anxiety. In some embodiments, the neuropsychiatric disease or neurological disease is post- traumatic stress disorder (PTSD). In some embodiments, the neurological disease is stroke or traumatic brain injury. In some embodiments, the neuropsychiatric disease or neurological disease is schizophrenia.
  • addiction e.g., substance use disorder
  • the neuropsychiatric disease or neurological disease is depression. In some embodiments, the neuropsychiatric disease or neurological disease is anxiety. In some embodiments, the neuropsychiatric disease or neurological disease is post- traumatic stress disorder (PTSD). In some embodiments, the neurological disease is stroke or traumatic brain injury. In some embodiments, the neuropsychiatric disease or neurological disease is schizophrenia.
  • a compound of the present disclosure is used for increasing neuronal plasticity. In some embodiments, a compound described herein is used for treating a brain disorder. In some embodiments, a compound described herein is used for increasing translation, transcription, or secretion of neurotrophic factors.
  • a compound disclosed herein can also be useful for increasing neuronal plasticity in a subject.
  • neuronal plasticity can refer to the ability of the brain to change structure and/or function throughout a subject’s life. New neurons can be produced and integrated into the central nervous system throughout the subject’s life. Increasing neuronal plasticity can include, but is not limited to, promoting neuronal growth, promoting neuritogenesis, promoting synaptogenesis, promoting dendritogenesis, increasing dendritic arbor complexity, increasing dendritic spine density, and increasing excitatory synapsis in the brain.
  • increasing neuronal plasticity comprises promoting neuronal growth, promoting neuritogenesis, promoting synaptogenesis, promoting dendritogenesis, increasing dendritic arbor complexity, and increasing dendritic spine density.
  • increasing neuronal plasticity by treating a subject with a compound the present disclosure can treat neurodegenerative disorder, Alzheimer’s, Parkinson’s disease, psychological disorder, depression, addiction, anxiety, post-traumatic stress disorder, treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, or substance use disorder.
  • the present disclosure provides a method for increasing neuronal plasticity, comprising contacting a neuronal cell with a compound of the present disclosure.
  • increasing neuronal plasticity improves a brain disorder described herein.
  • a compound disclosed herein is used to increase neuronal plasticity and has, for example, anti-addictive properties, antidepressant properties, anxiolytic properties, or a combination thereof.
  • decreased neuronal plasticity is associated with a neuropsychiatric disease.
  • the neuropsychiatric disease is a mood or anxiety disorder.
  • the neuropsychiatric disease includes, for example, migraine, cluster headache, post-traumatic stress disorder (PTSD), schizophrenia, anxiety, depression, and addiction (e.g., substance abuse disorder).
  • Brain disorders can include, for example, migraines, addiction (e.g., substance use disorder), depression, and anxiety.
  • the experiment or assay to determine increased neuronal plasticity derived from the administration of any compound of the present disclosure is a phenotypic assay, a dendritogenesis assay, a spinogenesis assay, a synaptogenesis assay, a Sholl analysis, a concentration-response experiment, a 5-HT 2A agonist assay, a 5-HT 2A antagonist assay, a 5-HT 2A binding assay, or a 5-HT 2A blocking experiment (e.g., ketanserin blocking experiments).
  • the experiment or assay to determine the hallucinogenic potential of any compound of the present disclosure is a mouse head-twitch response (HTR) assay.
  • HTR mouse head-twitch response
  • the condition is a musculoskeletal pain disorder including fibromyalgia, muscle pain, joint stiffness, osteoarthritis, rheumatoid arthritis, muscle cramps.
  • the present disclosure provides a method of treating a disease of women’s reproductive health including premenstrual dysphoric disorder (PMDD), premenstrual syndrome (PMS), post-partum depression, and menopause.
  • the present disclosure provides a method of treating a brain disorder, including administering to a subject in need thereof, a therapeutically effective amount of a compound of the present disclosure.
  • the present disclosure provides a method of treating a brain disorder with combination therapy, including administering to a subject in need thereof, a therapeutically effective amount of a compound of the present disclosure and at least one additional therapeutic agent.
  • a compound of the present disclosure is used to treat brain disorders.
  • the compound has, for example, anti- addictive properties, antidepressant properties, anxiolytic properties, or a combination thereof.
  • the brain disorder is a neuropsychiatric disease.
  • the neuropsychiatric disease is a mood or anxiety disorder.
  • brain disorders include, for example, migraine, cluster headache, post -traumatic stress disorder (PTSD), anxiety, depression, panic disorder, suicidality, schizophrenia, and addiction (e.g., substance abuse disorder).
  • brain disorders include, for example, migraines, addiction (e.g., substance use disorder), depression, and anxiety.
  • the present disclosure provides a method of treating a brain disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein.
  • the brain disorder is a neurodegenerative disorder, Alzheimer’s disease, Parkinson’s disease, a psychological disorder, depression, addiction, anxiety, post-traumatic stress disorder, treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, or a substance use disorder.
  • the brain disorder is a neurodegenerative disorder, Alzheimer’s disease or Parkinson’s disease.
  • the brain disorder is a psychological disorder, depression, addiction, anxiety, or a post -traumatic stress disorder.
  • the brain disorder is depression.
  • the brain disorder is addiction.
  • the brain disorder is treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury or substance use disorder.
  • the brain disorder is treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, or substance use disorder.
  • the brain disorder is stroke or traumatic brain injury.
  • the brain disorder is treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, or substance use disorder.
  • the brain disorder is schizophrenia.
  • the brain disorder is alcohol use disorder. [000283]
  • the method further comprises administering one or more additional therapeutic agent.
  • Non-limiting examples of additional therapeutics suitable for administration with a compound of the present disclosure can include lithium, olanzapine (Zyprexa), quetiapine (Seroquel), risperidone (Risperdal), aripiprazole (Abilify), ziprasidone (Geodon), clozapine (Clozaril), divalproex sodium (Depakote), lamotrigine (Lamictal), valproic acid (Depakene), carbamazepine (Equetro), topiramate (Topamax), levomilnacipran (Fetzima), duloxetine (Cymbalta, Yentreve), venlafaxine (Effexor), citalopram (Celexa), fluvoxamine (Luvox), escitalopram (Lexapro), fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), clomipramine (A
  • a compound of the present disclosure is used in combination with the standard of care therapy for a neurological disease described herein.
  • the standard of care therapies may include, for example, lithium, olanzapine, quetiapine, risperidone, ariprazole, ziprasidone, clozapine, divalproex sodium, lamotrigine, valproic acid, carbamazepine, topiramate, levomilnacipran, duloxetine, venlafaxine, citalopram, fluvoxamine, escitalopram, fluoxetine, paroxetine, sertraline, clomipramine, amitriptyline, desipramine, imipramine, nortriptyline, phenelzine, tranylcypromine, diazepam, alprazolam, clonazepam, or any combination thereof.
  • Nonlimiting examples of standard of care therapy for depression are sertraline, fluoxetine, escitalopram, venlafaxine, or aripiprazole.
  • Non-limiting examples of standard of care therapy for depression are citralopram, escitalopram, fluoxetine, paroxetine, diazepam, or sertraline. Additional examples of standard of care therapeutics are known to those of ordinary skill in the art.
  • Methods of increasing at least one of translation, transcription, or secretion of neurotrophic factors can refer to a family of soluble peptides or proteins which support the survival, growth, and differentiation of developing and mature neurons.
  • Increasing at least one of translation, transcription, or secretion of neurotrophic factors can be useful for, for example, increasing neuronal plasticity, promoting neuronal growth, promoting neuritogenesis, promoting synaptogenesis, promoting dendritogenesis, increasing dendritic arbor complexity, increasing dendritic spine density, and increasing excitatory synapsis in the brain.
  • increasing at least one of translation, transcription, or secretion of neurotrophic factors increases neuronal plasticity.
  • increasing at least one of translation, transcription, or secretion of neurotrophic factors promotes neuronal growth, promotes neuritogenesis, promotes synaptogenesis, promotes dendritogenesis, increases dendritic arbor complexity, and/or increases dendritic spine density.
  • a 5-HT 2A modulators e.g., 5-HT 2A agonists
  • a compound of the present disclosure is used to increase translation, transcription, or secretion of neurotrophic factors.
  • increasing translation, transcription or secretion of neurotrophic factors is sufficient for the treatment of migraine, headaches (e.g., cluster headache), post-traumatic stress disorder (PTSD), anxiety, depression, neurodegenerative disorder, Alzheimer’s disease, Parkinson’s disease, psychological disorder, treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, or addiction (e.g., substance use disorder).
  • An experiment or assay can be used to detect increased translation of neurotrophic factors, which can include, for example, ELISA, western blot, an immunofluorescence assay, a proteomic experiment, and mass spectrometry.
  • the experiment or assay used to detect increased transcription of neurotrophic factors is a gene expression assay, PCR, or microarray. In some embodiments, the experiment or assay used to detect increased secretion of neurotrophic factors is ELISA, western blot, an immunofluorescence assay, a proteomic experiment, or a mass spectrometry assay.
  • the present disclosure provides a method for increasing translation, transcription, or secretion of neurotrophic factors, wherein the method comprises contacting a neuronal cell with a compound disclosed herein.
  • Combination therapy [000289] In particular embodiments of treating the disorders described above, combination therapy is used as described herein.
  • a compound disclosed herein is administered in combination with a serotonin receptor modulator.
  • the serotonin receptor modulator is selected from the group consisting of altanserin, blonanserin, eplivanserin, glemanserin, volinanserin, ketanserin, ritanserin, pimavanserin, nelotanserin, pruvanserin, and flibanserin.
  • the serotonin receptor modulator is selected from the group consisting of serotonin receptor modulator is selected from the group consisting of eplivanserin, volinanserin, ketanserin, ritanserin, pimavanserin, nelotanserin, pruvanserin, flibanserin, olanzapine, quetiapine, risperidone, and buspirone.
  • the serotonin receptor modulator for use with the compounds disclosed herein, including those described in Table 1 is eplivanserin, wherein the eplivanserin is administered in about 1 mg to about 40 mg, or about 5 mg to about 10 mg, and the compounds disclosed herein, including those described in Table 1, are administered between about 10 mg to about 300 mg, or about 100 mg to about 180 mg, or about 120 mg, or about 150 mg, or about 160 mg.
  • the serotonin receptor modulator for use with the compounds disclosed herein, including those described in Table 1 is volinanserin, wherein the volinanserin is administered in about 1 mg to about 60 mg, or about 5 mg to about 20 mg, and the compounds disclosed herein, including those described in Table 1, are administered between about 10 mg to about 300 mg, or about 100 mg to about 180 mg, or about 120 mg, or about 150 mg, or about 160 mg.
  • the serotonin receptor modulator for use with the compounds disclosed herein, including those described in Table 1 is ketanserin, wherein the ketanserin is administered in about 10 mg to about 80 mg, about 30 mg to about 50 mg, or about 40 mg and the compounds disclosed herein, including those described in Table 1, are administered between about 10 mg to about 300 mg, or about 100 mg to about 180 mg, or about 120 mg, or about 150 mg, or about 160 mg.
  • the serotonin receptor modulator for use with the compounds disclosed herein, including those described in Table 1 is ritanserin, wherein the ritanserin is administered in about 1 mg to about 40 mg, or about 2.5 mg to about 10 mg, and the compounds disclosed herein, including those described in Table 1, are administered between about 10 mg to about 300 mg, or about 100 mg to about 180 mg, or about 120 mg, or about 150 mg, or about 160 mg.
  • the serotonin receptor modulator for use with the compounds disclosed herein, including those described in Table 1 is pimavanserin, wherein the pimavanserin is administered in about 1 mg to about 60 mg, or about 17 mg to about 34 mg, and the compounds disclosed herein, including those described in Table 1, are administered between about 10 mg to about 300 mg, or about 100 mg to about 180 mg, or about 120 mg, or about 150 mg, or about 160 mg.
  • the serotonin receptor modulator for use with the compounds disclosed herein, including those described in Table 1 is nelotanserin, wherein the nelotanserin is administered in about 1 mg to about 80 mg, or about 40 mg to about 80 mg, and the compounds disclosed herein, including those described in Table 1, are administered between about 10 mg to about 300 mg, or about 100 mg to about 180 mg, or about 120 mg, or about 150 mg, or about 160 mg.
  • the serotonin receptor modulator for use with the compounds disclosed herein, including those described in Table 1 is pruvanserin, wherein the pruvanserin is administered in about 1 mg to about 40 mg, or about 3 mg to about 10 mg, and the compounds disclosed herein, including those described in Table 1, are administered between about 10 mg to about 300 mg, or about 100 mg to about 180 mg, or about 120 mg, or about 150 mg, or about 160 mg.
  • the serotonin receptor modulator for use with the compounds disclosed herein, including those described in Table 1 is flibanserin, wherein the flibanserin is administered in about 10 mg to about 200 mg, or about 80 mg to about 120 mg, or about 100 mg and the compounds disclosed herein, including those described in Table 1, are administered between about 10 mg to about 300 mg, or about 100 mg to about 180 mg, or about 120 mg, or about 150 mg, or about 160 mg.
  • the serotonin receptor modulator for use with the compounds disclosed herein, including those described in Table 1 is olanzapine, wherein the olanzapine is administered in about 2.5 mg to about 30 mg, or about 5mg or about 10 mg, or about 20 mg or about 25mg, and the compounds disclosed herein, including those described in Table 1, are administered between about 10 mg to about 300 mg, or about 100 mg to about 180 mg, or about 120 mg, or about 150 mg, or about 160 mg.
  • the serotonin receptor modulator for use with the compounds disclosed herein, including those described in Table 1 is an extended -release of olanzapine such as ZYPREXA RELPREVV, wherein the extended release olanzapine is administered in about 50 mg to about 450 mg, or about 150 mg or about 210 mg, or about 300 mg or about 405 mg, and the compounds disclosed herein, including those described in Table 1, are administered between about 10 mg to about 300 mg, or about 100 mg to about 180 mg, or about 120 mg, or about 150 mg, or about 160 mg.
  • olanzapine such as ZYPREXA RELPREVV
  • the serotonin receptor modulator for use with the compounds disclosed herein, including those described in Table 1 is quetiapine, wherein the quetiapine is administered in about 25 mg to about 800 mg, or about 50 mg to about 100 mg, or about 150mg or about 200mg or about 250mg or about 300mg, and the compounds disclosed herein, including those described in Table 1, are administered between about 10 mg to about 300 mg, or about 100 mg to about 180 mg, or about 120 mg, or about 150 mg, or about 160 mg.
  • the serotonin receptor modulator for use with the compounds disclosed herein, including those described in Table 1 is an extended-release of quetiapine, wherein the extended-release of quetiapine is administered in about 50 mg to about 300 mg, or about 50mg or about 100 mg or about 200 mg, or about 300 mg, and the compounds disclosed herein, including those described in Table 1, are administered between about 10 mg to about 300 mg, or about 100 mg to about 180 mg, or about 120 mg, or about 150 mg, or about 160 mg.
  • the serotonin receptor modulator for use with the compounds disclosed herein, including those described in Table 1 is risperidone, wherein the risperidone is administered in about 0.5mg to about 20mg or about.5mg, or about Img, or about 2mg, or about 3 mg or about 4mg or about 5 mg or about 7.5 mg or about lOmg or about 16mg, and the compounds disclosed herein, including those described in Table 1, are administered between about 10 mg to about 300 mg, or about 100 mg to about 180 mg, or about 120 mg, or about 150 mg, or about 160 mg.
  • the serotonin receptor modulator for use with the compounds disclosed herein, including those described in Table 1 is an extended -release of risperidone including (RISPERDAL CONSTA), wherein the extended-release of risperidone is administered in about 12.5 mg, or about 25 mg, or about 37.5 mg, or about 50 mg, and the compounds disclosed herein, including those described in Table 1, are administered between about 10 mg to about 300 mg, or about 100 mg to about 180 mg, or about 120 mg, or about 150 mg, or about 160 mg.
  • RISPERDAL CONSTA RISPERDAL CONSTA
  • the serotonin receptor modulator for use with the compounds disclosed herein, including those described in Table 1 is buspirone, wherein the buspirone is administered in about 1 mg to about 100 mg, or about 1 mg or about 2 mg, or about 3 mg, or about 4 mg, or about 5 mg, or about 6 mg, or about 7 mg, or about 7.5 mg, or about 10 mg, or about 15 mg, or about 22.5 mg, or about 30 mg, or about 37.5 mg, or about 45 mg, or about 52.5 mg, or about 60 mg, or about 1 mg to about 10 mg, or about 5 mg to about 10 mg, or about 10 mg to about 15 mg, or about 15 mg to about 30 mg, or about 30 mg to about 60 mg, or about 60 mg to about 80 mg, or about 80 mg to about 100 mg, and the compounds disclosed herein, including those described in Table 1, are administered between about 10 mg to about 300 mg, or about 100 mg to about 180 mg, or about 120 mg, or about 150 mg, or about 160 mg.
  • a compound disclosed herein, including those described in Table 1 is co-administered with a serotonin receptor modulator in the same or in separate compositions.
  • the compound disclosed herein, including those described in Table 1 is administered in a modified release formulation such that the subject is effectively pretreated with serotonin receptor modulator prior to release of an effective amount of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is administered or released from a composition provided herein prior to the administration and/or release of the psychedelic. This allows pretreatment to attenuate activation of the serotonin receptor by the psychedelic.
  • the serotonin receptor modulator is administered or released from the composition provided herein to pretreat a subject by at least about at about 5 minutes, 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.25 hours, 1.5 hours, 2 hours, or 3 hours prior to the release of the psychedelic.
  • the serotonin receptor modulator attenuates the activation of the serotonin receptor when the serotonin receptor modulator is used to pretreat at most about 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, or more than 9 hours prior to the release of the psychedelic.
  • the serotonin receptor modulator attenuates the activation of the serotonin receptor when the serotonin receptor modulator is used to pretreat in a range of about 5 minutes to about 3 hours, about 10 minutes to about 3 hours, about 20 minutes to about 3 hours, about 30 minutes to about 3 hours, about 40 minutes to about 3 hours, about 50 minutes to about 3 hours, about 1 hour to about 3 hours, about 5 minutes to about 2 hours, about 10 minutes to about 2 hours, about 20 minutes to about 2 hours, about 30 minutes to about 2 hours, about 40 minutes to about 2 hours, about 50 minutes to about 2 hours, about 1 hour to about 2 hours, about 5 minutes to about 1 hour, about 10 minutes to about 1 hour, about 20 minutes to about 1 hour, about 30 minutes to about 1 hour, about 40 minutes to about 1 hour, or about 50 minutes to about 1 hour prior to the release of the psychedelic.
  • the serotonin receptor modulator is administered at about 1 hour to about 3 hours prior to the administration of the psychedelic.
  • the serotonin receptor modulator is eplivanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the eplivanserin is administered to pretreat at least 15 minutes prior to the administration of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is eplivanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the eplivanserin is administered to pretreat between at least 30 minutes prior and 360 minutes prior to the release or administration of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is eplivanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the eplivanserin is administered to pretreat between at least 60 minutes prior and 360 minutes prior to the release or administration of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is eplivanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the eplivanserin is administered to pretreat between at least 90 minutes and 240 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is eplivanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the eplivanserin is administered to pretreat at least 120 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is eplivanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the eplivanserin is administered to pretreat at least 150 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is eplivanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the eplivanserin is administered to pretreat between about 15 minutes and about 150 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is eplivanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the eplivanserin is administered to pretreat at least 180 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is eplivanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the eplivanserin is administered to pretreat at least 210 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is eplivanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the eplivanserin is administered to pretreat at least 240 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is eplivanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the eplivanserin is administered to pretreat at least 270 minutes prior to MDE.
  • the serotonin receptor modulator is eplivanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the eplivanserin is administered to pretreat at least 300 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is eplivanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the eplivanserin is administered to pretreat at least 330 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is eplivanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the eplivanserin is administered to pretreat at least 360 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is eplivanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein eplivanserin is administered to pretreat between about 60 minutes and about 180 minutes prior to the administration of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is volinanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the volinanserin is administered to pretreat a subject between at least 15 minutes and 360 minutes prior to the administration or release of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is volinanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the volinanserin is administered to pretreat between at least 30 minutes and 360 minutes prior to the administration or release of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is volinanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the volinanserin is administered to pretreat between at least 60 minutes and 240 minutes prior to the administration or release of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is volinanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the volinanserin is administered to pretreat at least 90 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is volinanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the volinanserin is administered to pretreat at least 120 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is volinanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the volinanserin is administered to pretreat at least 150 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is volinanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the volinanserin is administered to pretreat between about 15 minutes and about 150 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is volinanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the volinanserin is administered to pretreat at least 180 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is volinanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the volinanserin is administered to pretreat at least 210 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is volinanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the volinanserin is administered to pretreat at least 240 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is volinanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the volinanserin is administered to pretreat at least 270 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is volinanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the volinanserin is administered to pretreat at least 300 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is volinanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the volinanserin is administered to pretreat at least 330 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is volinanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the volinanserin is administered to pretreat at least 360 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is volinanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein volinanserin is administered to pretreat between about 60 minutes and about 180 minutes prior to the administration of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is ketanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the ketanserin is administered to pretreat at least 15 minutes prior to the administration of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is ketanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the ketanserin is administered to pretreat between at least 30 minutes and 360 minutes prior to the administration or release of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is ketanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the ketanserin is administered to pretreat between at least 60 minutes and 240 minutes prior to the administration or release of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is ketanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the ketanserin is administered to pretreat at least 90 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is ketanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the ketanserin is administered to pretreat at least 120 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is ketanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the ketanserin is administered to pretreat at least 150 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is ketanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the ketanserin is administered to pretreat between about 15 minutes and about 150 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is ketanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the ketanserin is administered to pretreat at least 180 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is ketanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the ketanserin is administered to pretreat at least 210 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is ketanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the ketanserin is administered to pretreat at least 240 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is ketanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the ketanserin is administered to pretreat at least 270 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is ketanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the ketanserin is administered to pretreat at least 300 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is ketanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the ketanserin is administered to pretreat at least 330 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is ketanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the ketanserin is administered to pretreat at least 360 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is ketanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein ketanserin is administered to pretreat between about 60 minutes and about 180 minutes prior to the administration of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is ritanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the ritanserin is administered to pretreat at least 15 minutes prior to the administration of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is ritanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the ritanserin is administered to pretreat at least 30 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is ritanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the ritanserin is administered to pretreat between at least 60 minutes and 240 minutes prior to the administration or release of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is ritanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the ritanserin is administered to pretreat at least 90 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is ritanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the ritanserin is administered to pretreat at least 120 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is ritanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the ritanserin is administered to pretreat at least 150 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is ritanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the ritanserin is administered to pretreat between about 15 minutes and about 150 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is ritanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the ritanserin is administered to pretreat at least 180 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is ritanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the ritanserin is administered to pretreat at least 210 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is ritanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the ritanserin is administered to pretreat at least 240 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is ritanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the ritanserin is administered to pretreat at least 270 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is ritanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the ritanserin is administered to pretreat at least 300 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is ritanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the ritanserin is administered to pretreat at least 330 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is ritanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the ritanserin is administered to pretreat at least 360 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is ritanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein ritanserin is administered to pretreat between about 60 minutes and about 180 minutes prior to the administration of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is pimavanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the pimavanserin is administered to pretreat at least 15 minutes prior to the administration of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is pimavanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the pimavanserin is administered to pretreat at least 30 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is pimavanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the pimavanserin is administered to pretreat between at least 60 minutes and 240 minutes prior to the administration or release of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is pimavanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the pimavanserin is administered to pretreat at least 90 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is pimavanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the pimavanserin is administered to pretreat at least 120 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is pimavanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the pimavanserin is administered to pretreat at least 150 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is pimavanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the pimavanserin is administered to pretreat between about 15 minutes and about 150 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is pimavanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the pimavanserin is administered to pretreat at least 180 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is pimavanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the pimavanserin is administered to pretreat at least 210 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is pimavanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the pimavanserin is administered to pretreat at least 240 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is pimavanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the pimavanserin is administered to pretreat at least 270 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is pimavanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the pimavanserin is administered to pretreat at least 300 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is pimavanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the pimavanserin is administered to pretreat at least 330 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is pimavanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the pimavanserin is administered to pretreat at least 360 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is pimavanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein pimavanserin is administered to pretreat between about 60 minutes and about 180 minutes prior to the administration of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is nelotanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the nelotanserin is administered to pretreat at least 15 minutes prior to the administration of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is nelotanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the nelotanserin is administered to pretreat at least 30 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is nelotanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the nelotanserin is administered to pretreat between at least 60 minutes and 240 minutes prior to the administration or release of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is nelotanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the nelotanserin is administered to pretreat at least 90 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is nelotanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the nelotanserin is administered to pretreat at least 120 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is nelotanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the nelotanserin is administered to pretreat at least 150 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is nelotanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the nelotanserin is administered to pretreat between about 15 minutes and about 150 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is nelotanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the nelotanserin is administered to pretreat at least 180 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is nelotanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the nelotanserin is administered to pretreat at least 210 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is nelotanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the nelotanserin is administered to pretreat at least 240 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is nelotanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the nelotanserin is administered to pretreat at least 270 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is nelotanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the nelotanserin is administered to pretreat at least 300 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is nelotanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the nelotanserin is administered to pretreat at least 330 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is nelotanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the nelotanserin is administered to pretreat at least 360 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is nelotanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein nelotanserin is administered to pretreat between about 60 minutes and about 180 minutes prior to the administration of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is pruvanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the pruvanserin is administered to pretreat at least 15 minutes prior to the administration of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is pruvanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the pruvanserin is administered to pretreat at least 30 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is pruvanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the pruvanserin is administered to pretreat between at least 60 minutes and 240 minutes prior to the administration or release of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is pruvanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the pruvanserin is administered to pretreat at least 90 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is pruvanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the pruvanserin is administered to pretreat at least 120 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is pruvanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the pruvanserin is administered to pretreat at least 150 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is pruvanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the pruvanserin is administered to pretreat between about 15 minutes and about 150 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is pruvanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the pruvanserin is administered to pretreat at least 180 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is pruvanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the pruvanserin is administered to pretreat at least 210 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is pruvanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the pruvanserin is administered to pretreat at least 240 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is pruvanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the pruvanserin is administered to pretreat at least 270 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is pruvanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the pruvanserin is administered to pretreat at least 300 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is pruvanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the pruvanserin is administered to pretreat at least 330 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is pruvanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the pruvanserin is administered to pretreat at least 360 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is pruvanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein pruvanserin is administered to pretreat between about 60 minutes and about 180 minutes prior to the administration of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is flibanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the flibanserin is administered to pretreat at least 15 minutes prior to the administration of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is flibanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the flibanserin is administered to pretreat at least 30 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is flibanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the flibanserin is administered to pretreat between at least 60 minutes and 240 minutes prior to the administration or release of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is flibanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the flibanserin is administered to pretreat at least 90 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is flibanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the flibanserin is administered to pretreat at least 120 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is flibanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the flibanserin is administered to pretreat at least 150 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is flibanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the flibanserin is administered to pretreat between about 15 minutes and about 150 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is flibanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the flibanserin is administered to pretreat at least 180 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is flibanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the flibanserin is administered to pretreat at least 210 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is flibanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the flibanserin is administered to pretreat at least 240 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is flibanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the flibanserin is administered to pretreat at least 270 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is flibanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the flibanserin is administered to pretreat at least 300 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is flibanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the flibanserin is administered to pretreat at least 330 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is flibanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the flibanserin is administered to pretreat at least 360 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is flibanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein flibanserin is administered to pretreat between about 60 minutes and about 180 minutes prior to the administration of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is olanzapine and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the olanzapine is administered to pretreat at least 15 minutes prior to the administration of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is olanzapine and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the olanzapine is administered to pretreat at least 30 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is olanzapine and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the olanzapine is administered to pretreat between at least 60 minutes and 240 minutes prior to the administration or release of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is olanzapine and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the olanzapine is administered to pretreat at least 90 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is olanzapine and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the olanzapine is administered to pretreat at least 120 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is olanzapine and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the olanzapine is administered to pretreat at least 150 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is olanzapine and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the olanzapine is administered to pretreat between about 15 minutes and about 150 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is olanzapine and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the olanzapine is administered to pretreat at least 180 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is olanzapine and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the olanzapine is administered to pretreat at least 210 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is olanzapine and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the olanzapine is administered to pretreat at least 240 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is olanzapine and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the olanzapine is administered to pretreat at least 270 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is olanzapine and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the olanzapine is administered to pretreat at least 300 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is olanzapine and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the olanzapine is administered to pretreat at least 330 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is olanzapine and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the olanzapine is administered to pretreat at least 360 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is olanzapine and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein olanzapine is administered to pretreat between about 60 minutes and about 180 minutes prior to the administration of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is risperidone and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the risperidone is administered to pretreat at least 15 minutes prior to the administration of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is risperidone and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the risperidone is administered to pretreat at least 30 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is risperidone and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the risperidone is administered to pretreat between at least 60 minutes and 240 minutes prior to the administration or release of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is risperidone and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the risperidone is administered to pretreat at least 90 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is risperidone and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the risperidone is administered to pretreat at least 120 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is risperidone and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the risperidone is administered to pretreat at least 150 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is risperidone and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the risperidone is administered to pretreat between about 15 minutes and about 150 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is risperidone and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the risperidone is administered to pretreat at least 180 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is risperidone and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the risperidone is administered to pretreat at least 210 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is risperidone and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the risperidone is administered to pretreat at least 240 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is risperidone and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the risperidone is administered to pretreat at least 270 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is risperidone and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the risperidone is administered to pretreat at least 300 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is risperidone and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the risperidone is administered to pretreat at least 330 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is risperidone and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the risperidone is administered to pretreat at least 360 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is risperidone and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein risperidone is administered to pretreat between about 60 minutes and about 180 minutes prior to the administration of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is quetiapine and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the quetiapine is administered to pretreat at least 15 minutes prior to the administration of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is quetiapine and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the quetiapine is administered to pretreat at least 30 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is quetiapine and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the quetiapine is administered to pretreat between at least 60 minutes and 240 minutes prior to the administration or release of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is quetiapine and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the quetiapine is administered to pretreat at least 90 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is quetiapine and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the quetiapine is administered to pretreat at least 120 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is quetiapine and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the quetiapine is administered to pretreat at least 150 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is quetiapine and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the quetiapine is administered to pretreat between about 15 minutes and about 150 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is quetiapine and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the quetiapine is administered to pretreat at least 180 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is quetiapine and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the quetiapine is administered to pretreat at least 210 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is quetiapine and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the quetiapine is administered to pretreat at least 240 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is quetiapine and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the quetiapine is administered to pretreat at least 270 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is quetiapine and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the quetiapine is administered to pretreat at least 300 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is quetiapine and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the quetiapine is administered to pretreat at least 330 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is quetiapine and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the quetiapine is administered to pretreat at least 360 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is quetiapine and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein quetiapine is administered to pretreat between about 60 minutes and about 180 minutes prior to the administration of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is buspirone and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the buspirone is administered to pretreat at least 15 minutes prior to the administration of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is buspirone and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the buspirone is administered to pretreat at least 30 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is buspirone and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the buspirone is administered to pretreat between at least 60 minutes and 240 minutes prior to the administration or release of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is buspirone and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the buspirone is administered to pretreat at least 90 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is buspirone and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the buspirone is administered to pretreat at least 120 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is buspirone and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the buspirone is administered to pretreat at least 150 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is buspirone and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the buspirone is administered to pretreat between about 15 minutes and about 150 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is buspirone and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the buspirone is administered to pretreat at least 180 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is buspirone and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the buspirone is administered to pretreat at least 210 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is buspirone and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the buspirone is administered to pretreat at least 240 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is buspirone and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the buspirone is administered to pretreat at least 270 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is buspirone and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the buspirone is administered to pretreat at least 300 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is buspirone and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the buspirone is administered to pretreat at least 330 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is buspirone and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the buspirone is administered to pretreat at least 360 minutes prior to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is buspirone and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein buspirone is administered to pretreat between about 60 minutes and about 180 minutes prior to the administration of the prodrug of MDE disclosed herein, including those described in Table 1.
  • a compound disclosed herein, including those described in Table 1 is co-administered with a serotonin receptor modulator in the same or in separate compositions.
  • the serotonin receptor modulator is administered after the compound disclosed herein, including those described in Table 1.
  • the compound disclosed herein, including those described in Table 1 is administered in a modified release formulation such that the subject is effectively post-treated with serotonin receptor modulator post to release of an effective amount of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is part of a single fixed dose formulation that releases the prodrug of MDE disclosed herein, including those described in Table 1, first followed by serotonin receptor modulator on two different release profiles.
  • the compound disclosed herein, including those described in Table 1 is administered first as a single dosage and, after a length of time, serotonin receptor modulator is administered as a second dosage separate from the first dosage.
  • the serotonin receptor modulator is administered or released from a composition provided herein after the administration and/or release of the psychedelic. This allows post-treatment to attenuate activation of the serotonin receptor by the psychedelic.
  • the serotonin receptor modulator is administered or released from the composition provided herein to post-treat a subject by at least about at about 5 minutes, 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.25 hours, 1.5 hours, 2 hours, or 3 hours after the release of the psychedelic.
  • the serotonin receptor modulator attenuates the activation of the serotonin receptor when the serotonin receptor modulator is used to post-treat at most about 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, or more than 9 hours after the release of the psychedelic.
  • the serotonin receptor modulator attenuates the activation of the serotonin receptor when the serotonin receptor modulator is used to post -treat in a range of about 5 minutes to about 3 hours, about 10 minutes to about 3 hours, about 20 minutes to about 3 hours, about 30 minutes to about 3 hours, about 40 minutes to about 3 hours, about 50 minutes to about 3 hours, about 1 hour to about 3 hours, about 5 minutes to about 2 hours, about 10 minutes to about 2 hours, about 20 minutes to about 2 hours, about 30 minutes to about 2 hours, about 40 minutes to about 2 hours, about 50 minutes to about 2 hours, about 1 hour to about 2 hours, about 5 minutes to about 1 hour, about 10 minutes to about 1 hour, about 20 minutes to about 1 hour, about 30 minutes to about 1 hour, about 40 minutes to about 1 hour, or about 50 minutes to about 1 hour after the release of the psychedelic.
  • the serotonin receptor modulator is administered at about 1 hour to about 3 hours after the administration of the psychedelic.
  • the serotonin receptor modulator is eplivanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the eplivanserin is administered to post-treat at least 15 minutes after the administration of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is eplivanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the eplivanserin is administered to post-treat between at least 30 minutes after and 360 minutes after the release or administration of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is eplivanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the eplivanserin is administered to post-treat between at least 60 minutes after and 360 minutes after the release or administration of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is eplivanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the eplivanserin is administered to post-treat between at least 90 minutes and 240 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is eplivanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the eplivanserin is administered to post- treat at least 120 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is eplivanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the eplivanserin is administered to post-treat at least 150 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is eplivanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the eplivanserin is administered to post-treat between about 15 minutes and about 150 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is eplivanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the eplivanserin is administered to post-treat at least 180 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is eplivanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the eplivanserin is administered to post-treat at least 210 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is eplivanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the eplivanserin is administered to post-treat at least 240 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is eplivanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the eplivanserin is administered to post-treat at least 270 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is eplivanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the eplivanserin is administered to post-treat at least 300 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is eplivanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the eplivanserin is administered to post-treat at least 330 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is eplivanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the eplivanserin is administered to post-treat at least 360 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is eplivanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein eplivanserin is administered to post-treat between about 60 minutes and about 180 minutes after the administration of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is volinanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the volinanserin is administered to post-treat a subject between at least 15 minutes and 360 minutes after the administration or release of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is volinanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the volinanserin is administered to post-treat between at least 30 minutes and 360 minutes after the administration or release of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is volinanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the volinanserin is administered to post-treat between at least 60 minutes and 240 minutes after the administration or release of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is volinanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the volinanserin is administered to post-treat at least 90 minutes after MDE.
  • the serotonin receptor modulator is volinanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the volinanserin is administered to post-treat at least 120 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is volinanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the volinanserin is administered to post-treat at least 150 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is volinanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the volinanserin is administered to post-treat between about 15 minutes and about 150 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is volinanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the volinanserin is administered to post-treat at least 180 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is volinanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the volinanserin is administered to post-treat at least 210 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is volinanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the volinanserin is administered to post-treat at least 240 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is volinanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the volinanserin is administered to post-treat at least 270 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is volinanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the volinanserin is administered to post-treat at least 300 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is volinanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the volinanserin is administered to post-treat at least 330 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is volinanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the volinanserin is administered to post-treat at least 360 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is volinanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein volinanserin is administered to post-treat between about 60 minutes and about 180 minutes after the administration of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is ketanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the ketanserin is administered to post-treat at least 15 minutes after the administration of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is ketanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the ketanserin is administered to post-treat between at least 30 minutes and 360 minutes after the administration or release of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is ketanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the ketanserin is administered to post-treat between at least 60 minutes and 240 minutes after the administration or release of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is ketanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the ketanserin is administered to post-treat at least 90 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is ketanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the ketanserin is administered to post-treat at least 120 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is ketanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the ketanserin is administered to post-treat at least 150 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is ketanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the ketanserin is administered to post-treat between about 15 minutes and about 150 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is ketanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the ketanserin is administered to post-treat at least 180 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is ketanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the ketanserin is administered to post-treat at least 210 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is ketanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the ketanserin is administered to post-treat at least 240 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is ketanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the ketanserin is administered to post-treat at least 270 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is ketanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the ketanserin is administered to post-treat at least 300 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is ketanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the ketanserin is administered to post-treat at least 330 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is ketanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the ketanserin is administered to post-treat at least 360 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is ketanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein ketanserin is administered to post-treat between about 60 minutes and about 180 minutes after the administration of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is ritanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the ritanserin is administered to post-treat at least 15 minutes after the administration of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is ritanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the ritanserin is administered to post-treat at least 30 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is ritanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the ritanserin is administered to post-treat between at least 60 minutes and 240 minutes after the administration or release of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is ritanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the ritanserin is administered to post-treat at least 90 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is ritanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the ritanserin is administered to post-treat at least 120 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is ritanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the ritanserin is administered to post-treat at least 150 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is ritanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the ritanserin is administered to post-treat between about 15 minutes and about 150 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is ritanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the ritanserin is administered to post-treat at least 180 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is ritanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the ritanserin is administered to post-treat at least 210 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is ritanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the ritanserin is administered to post-treat at least 240 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is ritanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the ritanserin is administered to post-treat at least 270 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is ritanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the ritanserin is administered to post-treat at least 300 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is ritanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the ritanserin is administered to post-treat at least 330 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is ritanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the ritanserin is administered to post-treat at least 360 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is ritanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein ritanserin is administered to post-treat between about 60 minutes and about 180 minutes after the administration of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is pimavanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the pimavanserin is administered to post-treat at least 15 minutes after the administration of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is pimavanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the pimavanserin is administered to post-treat at least 30 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is pimavanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the pimavanserin is administered to post-treat between at least 60 minutes and 240 minutes after the administration or release of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is pimavanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the pimavanserin is administered to post-treat at least 90 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is pimavanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the pimavanserin is administered to post-treat at least 120 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is pimavanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the pimavanserin is administered to post-treat at least 150 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is pimavanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the pimavanserin is administered to post-treat between about 15 minutes and about 150 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is pimavanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the pimavanserin is administered to post-treat at least 180 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is pimavanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the pimavanserin is administered to post-treat at least 210 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is pimavanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the pimavanserin is administered to post-treat at least 240 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is pimavanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the pimavanserin is administered to post-treat at least 270 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is pimavanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the pimavanserin is administered to post-treat at least 300 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is pimavanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the pimavanserin is administered to post-treat at least 330 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is pimavanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the pimavanserin is administered to post-treat at least 360 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is pimavanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein pimavanserin is administered to post-treat between about 60 minutes and about 180 minutes after the administration of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is nelotanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the nelotanserin is administered to post-treat at least 15 minutes after the administration of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is nelotanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the nelotanserin is administered to post-treat at least 30 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is nelotanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the nelotanserin is administered to post-treat between at least 60 minutes and 240 minutes after the administration or release of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is nelotanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the nelotanserin is administered to post-treat at least 90 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is nelotanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the nelotanserin is administered to post-treat at least 120 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is nelotanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the nelotanserin is administered to post-treat at least 150 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is nelotanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the nelotanserin is administered to post-treat between about 15 minutes and about 150 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is nelotanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the nelotanserin is administered to post-treat at least 180 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is nelotanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the nelotanserin is administered to post-treat at least 210 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is nelotanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the nelotanserin is administered to post-treat at least 240 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is nelotanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the nelotanserin is administered to post-treat at least 270 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is nelotanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the nelotanserin is administered to post-treat at least 300 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is nelotanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the nelotanserin is administered to post-treat at least 330 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is nelotanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the nelotanserin is administered to post-treat at least 360 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is nelotanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein nelotanserin is administered to post-treat between about 60 minutes and about 180 minutes after the administration of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is pruvanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the pruvanserin is administered to post-treat at least 15 minutes after the administration of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is pruvanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the pruvanserin is administered to post-treat at least 30 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is pruvanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the pruvanserin is administered to post-treat between at least 60 minutes and 240 minutes after the administration or release of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is pruvanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the pruvanserin is administered to post-treat at least 90 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is pruvanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the pruvanserin is administered to post-treat at least 120 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is pruvanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the pruvanserin is administered to post-treat at least 150 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is pruvanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the pruvanserin is administered to post-treat between about 15 minutes and about 150 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is pruvanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the pruvanserin is administered to post- treat at least 180 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is pruvanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the pruvanserin is administered to post-treat at least 210 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is pruvanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the pruvanserin is administered to post-treat at least 240 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is pruvanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the pruvanserin is administered to post-treat at least 270 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is pruvanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the pruvanserin is administered to post-treat at least 300 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is pruvanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the pruvanserin is administered to post-treat at least 330 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is pruvanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein the pruvanserin is administered to post-treat at least 360 minutes after the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is pruvanserin and the psychedelic is a prodrug of MDE disclosed herein, including those described in Table 1, wherein pruvanserin is administered to post-treat between about 60 minutes and about 180 minutes after the administration of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is flibanserin, wherein the flibanserin is administered to post-treat at least 15 minutes post to the administration of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is flibanserin, wherein the flibanserin is administered to post- treat at least 30 minutes post to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is flibanserin, wherein the flibanserin is administered to post-treat between at least 60 minutes and 240 minutes post to the administration or release of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is flibanserin, wherein the flibanserin is administered to post-treat at least 90 minutes post to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is flibanserin, wherein the flibanserin is administered to post-treat at least 120 minutes post to the prodrug of MDE disclosed herein, including those described in Table 1. In some embodiments, the serotonin receptor modulator is flibanserin, wherein the flibanserin is administered to post-treat at least 150 minutes post to the prodrug of MDE disclosed herein, including those described in Table 1. In some embodiments, the serotonin receptor modulator is flibanserin, wherein the flibanserin is administered to post-treat between about 15 minutes and about 150 minutes post to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is flibanserin, wherein the flibanserin is administered to post-treat at least 180 minutes post to the prodrug of MDE disclosed herein, including those described in Table 1. In some embodiments, the serotonin receptor modulator is flibanserin, wherein the flibanserin is administered to post-treat at least 210 minutes post to the prodrug of MDE disclosed herein, including those described in Table 1. [000350] In some embodiments, the serotonin receptor modulator is flibanserin, wherein the flibanserin is administered to post-treat at least 240 minutes post to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is flibanserin, wherein the flibanserin is administered to post-treat at least 270 minutes post to the prodrug of MDE disclosed herein, including those described in Table 1. In some embodiments, the serotonin receptor modulator is flibanserin, wherein the flibanserin is administered to post-treat at least 300 minutes post to the prodrug of MDE disclosed herein, including those described in Table 1. In some embodiments, the serotonin receptor modulator is flibanserin, wherein the flibanserin is administered to post-treat at least 330 minutes post to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is flibanserin, wherein the flibanserin is administered to post- treat at least 360 minutes post to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is flibanserin, wherein flibanserin is administered to post-treat between about 60 minutes and about 180 minutes post to the administration of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is olanzapine, wherein the olanzapine is administered to post-treat at least 15 minutes post to the administration of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is olanzapine, wherein the olanzapine is administered to post- treat at least 30 minutes post to the prodrug of MDE disclosed herein, including those described in Table 1. In some embodiments, the serotonin receptor modulator is olanzapine, wherein the olanzapine is administered to post-treat between at least 60 minutes and 240 minutes post to the administration or release of the prodrug of MDE disclosed herein, including those described in Table 1. In some embodiments, the serotonin receptor modulator is olanzapine, wherein the olanzapine is administered to post-treat at least 90 minutes post to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is olanzapine, wherein the olanzapine is administered to post-treat at least 120 minutes post to the prodrug of MDE disclosed herein, including those described in Table 1. In some embodiments, the serotonin receptor modulator is olanzapine, wherein the olanzapine is administered to post-treat at least 150 minutes post to the prodrug of MDE disclosed herein, including those described in Table 1. In some embodiments, the serotonin receptor modulator is olanzapine, wherein the olanzapine is administered to post-treat between about 15 minutes and about 150 minutes post to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is olanzapine, wherein the olanzapine is administered to post-treat at least 180 minutes post to the prodrug of MDE disclosed herein, including those described in Table 1. In some embodiments, the serotonin receptor modulator is olanzapine, wherein the olanzapine is administered to post-treat at least 210 minutes post to the prodrug of MDE disclosed herein, including those described in Table 1. [000352] In some embodiments, the serotonin receptor modulator is olanzapine, wherein the olanzapine is administered to post-treat at least 240 minutes post to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is olanzapine, wherein the olanzapine is administered to post-treat at least 270 minutes post to the prodrug of MDE disclosed herein, including those described in Table 1. In some embodiments, the serotonin receptor modulator is olanzapine, wherein the olanzapine is administered to post-treat at least 300 minutes post to the prodrug of MDE disclosed herein, including those described in Table 1. In some embodiments, the serotonin receptor modulator is olanzapine, wherein the olanzapine is administered to post-treat at least 330 minutes post to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is olanzapine, wherein the olanzapine is administered to post- treat at least 360 minutes post to the prodrug of MDE disclosed herein, including those described in Table 1. In some preferred embodiments, the serotonin receptor modulator is olanzapine, wherein olanzapine is administered to post-treat between about 60 minutes and about 180 minutes post to the administration of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is quetiapine, wherein the quetiapine is administered to post-treat at least 15 minutes post to the administration of the prodrug of MDE disclosed herein, including those described in Table 1. In some embodiments, the serotonin receptor modulator is quetiapine, wherein the quetiapine is administered to post- treat at least 30 minutes post to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is quetiapine, wherein the quetiapine is administered to post-treat between at least 60 minutes and 240 minutes post to the administration or release of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is quetiapine, wherein the quetiapine is administered to post-treat at least 90 minutes post to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is quetiapine, wherein the quetiapine is administered to post-treat at least 120 minutes post to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is quetiapine, wherein the quetiapine is administered to post-treat at least 150 minutes post to the prodrug of MDE disclosed herein, including those described in Table 1. In some embodiments, the serotonin receptor modulator is quetiapine, wherein the quetiapine is administered to post-treat between about 15 minutes and about 150 minutes post to the prodrug of MDE disclosed herein, including those described in Table 1. In some embodiments, the serotonin receptor modulator is quetiapine, wherein the quetiapine is administered to post-treat at least 180 minutes post to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is quetiapine, wherein the quetiapine is administered to post-treat at least 210 minutes post to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is quetiapine, wherein the quetiapine is administered to post-treat at least 240 minutes post to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is quetiapine, wherein the quetiapine is administered to post-treat at least 270 minutes post to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is quetiapine, wherein the quetiapine is administered to post-treat at least 300 minutes post to the prodrug of MDE disclosed herein, including those described in Table 1. In some embodiments, the serotonin receptor modulator is quetiapine, wherein the quetiapine is administered to post-treat at least 330 minutes post to the prodrug of MDE disclosed herein, including those described in Table 1. In some embodiments, the serotonin receptor modulator is quetiapine, wherein the quetiapine is administered to post- treat at least 360 minutes post to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is quetiapine, wherein quetiapine is administered to post-treat between about 60 minutes and about 180 minutes post to the administration of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is risperidone, wherein the risperidone is administered to post-treat at least 15 minutes post to the administration of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is risperidone, wherein the risperidone is administered to post- treat at least 30 minutes post to the prodrug of MDE disclosed herein, including those described in Table 1. In some embodiments, the serotonin receptor modulator is risperidone, wherein the risperidone is administered to post-treat between at least 60 minutes and 240 minutes post to the administration or release of the prodrug of MDE disclosed herein, including those described in Table 1. In some embodiments, the serotonin receptor modulator is risperidone, wherein the risperidone is administered to post-treat at least 90 minutes post to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is risperidone, wherein the risperidone is administered to post-treat at least 120 minutes post to the prodrug of MDE disclosed herein, including those described in Table 1. In some embodiments, the serotonin receptor modulator is risperidone, wherein the risperidone is administered to post-treat at least 150 minutes post to the prodrug of MDE disclosed herein, including those described in Table 1. In some embodiments, the serotonin receptor modulator is risperidone, wherein the risperidone is administered to post-treat between about 15 minutes and about 150 minutes post to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is risperidone, wherein the risperidone is administered to post-treat at least 180 minutes post to the prodrug of MDE disclosed herein, including those described in Table 1. In some embodiments, the serotonin receptor modulator is risperidone, wherein the risperidone is administered to post-treat at least 210 minutes post to the prodrug of MDE disclosed herein, including those described in Table 1. [000356] In some embodiments, the serotonin receptor modulator is risperidone, wherein the risperidone is administered to post-treat at least 240 minutes post to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is risperidone, wherein the risperidone is administered to post-treat at least 270 minutes post to the prodrug of MDE disclosed herein, including those described in Table 1. In some embodiments, the serotonin receptor modulator is risperidone, wherein the risperidone is administered to post-treat at least 300 minutes post to the prodrug of MDE disclosed herein, including those described in Table 1. In some embodiments, the serotonin receptor modulator is risperidone, wherein the risperidone is administered to post-treat at least 330 minutes post to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is risperidone, wherein the risperidone is administered to post- treat at least 360 minutes post to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is risperidone, wherein risperidone is administered to post-treat between about 60 minutes and about 180 minutes post to the administration of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is buspirone, wherein the buspirone is administered to post-treat at least 15 minutes post to the administration of the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is buspirone, wherein the buspirone is administered to post- treat at least 30 minutes post to the prodrug of MDE disclosed herein, including those described in Table 1. In some embodiments, the serotonin receptor modulator is buspirone, wherein the buspirone is administered to post-treat between at least 60 minutes and 240 minutes post to the administration or release of the prodrug of MDE disclosed herein, including those described in Table 1. In some embodiments, the serotonin receptor modulator is buspirone, wherein the buspirone is administered to post-treat at least 90 minutes post to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is buspirone, wherein the buspirone is administered to post-treat at least 120 minutes post to the prodrug of MDE disclosed herein, including those described in Table 1. In some embodiments, the serotonin receptor modulator is buspirone, wherein the buspirone is administered to post-treat at least 150 minutes post to the prodrug of MDE disclosed herein, including those described in Table 1. In some embodiments, the serotonin receptor modulator is buspirone, wherein the buspirone is administered to post-treat between about 15 minutes and about 150 minutes post to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is buspirone, wherein the buspirone is administered to post-treat at least 180 minutes post to the prodrug of MDE disclosed herein, including those described in Table 1. In some embodiments, the serotonin receptor modulator is buspirone, wherein the buspirone is administered to post-treat at least 210 minutes post to the prodrug of MDE disclosed herein, including those described in Table 1. [000358] In some embodiments, the serotonin receptor modulator is buspirone, wherein the buspirone is administered to post-treat at least 240 minutes post to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is buspirone, wherein the buspirone is administered to post-treat at least 270 minutes post to the prodrug of MDE disclosed herein, including those described in Table 1. In some embodiments, the serotonin receptor modulator is buspirone, wherein the buspirone is administered to post-treat at least 300 minutes post to the prodrug of MDE disclosed herein, including those described in Table 1. In some embodiments, the serotonin receptor modulator is buspirone, wherein the buspirone is administered to post-treat at least 330 minutes post to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is buspirone, wherein the buspirone is administered to post- treat at least 360 minutes post to the prodrug of MDE disclosed herein, including those described in Table 1.
  • the serotonin receptor modulator is buspirone, wherein buspirone is administered to post-treat between about 60 minutes and about 180 minutes post to the administration of the prodrug of MDE disclosed herein, including those described in Table 1.
  • Salts may be prepared from compounds by known salt-forming procedures. Unless otherwise stated, all starting materials are obtained from commercial suppliers and used without further purification. More specific compounds required for the syntheses are listed below: [000364] 5-(tert-Butoxy)-5-oxopentanoic acid (cas 63128-51-8) purchased from Sigma Aldrich (catalogue number SY3H3D678586) [000365] 6-(tert-Butoxy)-6-oxohexanoic acid (cas 52221-07-5) purchased from BLDpharm (catalogue number BD00759729) [000366] 3-(2-Acetoxy-4,6-dimethylphenyl)-3-methylbutyric acid (cas 134098-68-3) purchased from Sigma Aldrich (catalogue number 756377) [000367] 2-Methoxyethyl chloroformate (cas 628-12-6) purchased from Enamine (catalogue number EN300-222696) [000368] If not indicated otherwise, the analytical HP
  • Example 1 iso-Propyl N-[(1S)-2-(1,3-benzodioxol-5-yl)-1-methyl-ethyl]-N-ethyl-carbamate (Compound 1A) [000369] A solution of 2M iso-propyl chloroformate in dioxane (0.93 mmol, 467 ⁇ L) was added dropwise over 5 min to a stirred solution of (2S)-1-(1,3-benzodioxol-5-yl)-N-ethyl-propan-2- amine hydrochloride (152 mg, 0.62 mmol) and DIPEA (402 mg, 3.11 mmol, 542 ⁇ L) in DCM (5 mL) at rt under N2.
  • Example 2 tert-Butyl N-[(1S)-2-(1,3-benzodioxol-5-yl)-1-methyl-ethyl]-N-ethyl-carbamate (Compound 2A) [000371] Di-tert-butyl dicarbonate (216 mg, 0.99 mmol) was added in several portion over 10 min to a stirred solution of (2S)-1-(1,3-benzodioxol-5-yl)-N-ethyl-propan-2-amine hydrochloride (200 mg, 0.82 mmol) and DIPEA (212 mg, 1.64 mmol, 286 ⁇ L) in DCM (5 mL) at 0 °C under N2.
  • Example 3 N-[(1S)-2-(1,3-Benzodioxol-5-yl)-1-methyl-ethyl]-2-(dimethylamino)-N-ethyl- acetamide (Compound 3A) [000373] HATU (360 mg, 0.95 mmol) was added in one portion, followed by DIPEA (490 mg, 3.79 mmol, 660 ⁇ L) which was added dropwise over 2 min to a stirred solution of (2S)-1-(1,3- benzodioxol-5-yl)-N-ethyl-propan-2-amine hydrochloride (154 mg, 0.63 mmol) and N,N- dimethylglycine (130 mg, 1.26 mmol) in DMF (5 mL) at rt under N2.
  • Example 4 N-[(1S)-2-(1,3-Benzodioxol-5-yl)-1-methyl-ethyl]-N-ethyl-tetrahydropyran-4- carboxamide (Compound 4A) [000375] DMAP (8 mg, 0.07 mmol), EDC HCl (188 mg, 0.98 mmol) and tetrahydropyran-4- carboxylic acid (170 mg, 1.30 mmol) were added in one portion for each reagent to a stirred solution of (2S)-1-(1,3-benzodioxol-5-yl)-N-ethyl-propan-2-amine hydrochloride (159 mg, 0.65 mmol) and DIPEA (422 mg, 3.26 mmol, 568 ⁇ L) in DCM (5 mL) at rt under N2.
  • Example 6 N-[[[(1S)-2-(1,3-benzodioxol-5-yl)-1-methyl-ethyl]-ethyl- amino]methyl]acetamide (Compound 6A) [000379] Formaldehyde (150 mg, 1.85 mmol, 139 ⁇ L, 37% in water) was added dropwise over 2 min to a stirred solution of (2S)-1-(1,3-benzodioxol-5-yl)-N-ethyl-propan-2-amine hydrochloride (150 mg, 0.62 mmol), acetamide (73 mg, 1.23 mmol) and NaOH (25 mg, 0.62 mmol) in THF (2 mL) and Water (4 mL) at rt under N 2 .
  • (2S)-1-(1,3-benzodioxol-5-yl)-N-ethyl-propan-2-amine hydrochloride 150 mg, 0.62 mmol
  • Example 7 Chloromethyl N-[(1S)-2-(1,3-benzodioxol-5-yl)-1-methyl-ethyl]-N-ethyl- carbamate (Compound 7A) [000380] Triethylamine (1.37 g, 13.6 mmol, 1.89 mL) was added dropwise over 5 min to a stirred suspension of (2S)-1-(1,3-benzodioxol-5-yl)-N-ethyl-propan-2-amine hydrochloride (1.10 g, 4.52 mmol) in DCM (45 mL) at 0 °C under N2.
  • Example 8 ⁇ [(S)-2-(2H-1,3-Benzodioxol-5-yl)-1-methyl-ethyl]-N- ethylaminocarbonyloxy ⁇ methyl tert-butyl adipate (Compound 8A) [000382] A solution of tetrabutylammonium hydroxide in MeOH (0.74 mmol, 741 ⁇ L, 1 M) was added dropwise over 5 min to a stirred solution of 6-tert-butoxy-6-oxo-hexanoic acid (150 mg, 0.74 mmol) in MeOH (3 mL) at rt under N2. The mixture was stirred at rt for 1 h and then concentrated in vacuo.
  • Example 9 4-( ⁇ [(S)-2-(2H-1,3-Benzodioxol-5-yl)-1-methyl-ethyl]-N- ethylaminocarbonyloxy ⁇ methoxycarbonyl)butyric acid (Compound 9A) [000384] A solution of ⁇ [(S)-2-(2H-1,3-benzodioxol-5-yl)-1-methyl-ethyl]-N- ethylaminocarbonyloxy ⁇ methyl tert-butyl glutarate (141 mg, 0.31 mmol) in formic acid (2.93 g, 63.6 mmol, 2.40 mL) was stirred at rt under N2 overnight.
  • Example 10 N-[(1S)-2-(1,3-benzodioxol-5-yl)-1-methyl-ethyl]-N-ethyl-4-(1- piperidyl)piperidine-1-carboxamide hydrochloride (Compound 10A) [000386] 1-Chlorocarbonyl-4-piperidinopiperidine hydrochloride (252 mg, 0.94 mmol) was added in one portion to a stirred solution of (2S)-1-(1,3-benzodioxol-5-yl)-N-ethyl-propan-2- amine hydrochloride (153 mg, 0.63 mmol) and DIPEA (730 mg, 5.65 mmol, 984 ⁇ L) in DCM (5 mL) at rt under N2.
  • the crude compound was re-purified by column chromatography on silica gel, eluting with a gradient of 0-10% MeOH in DCM with ammonia, to leave N-[(1S)-2-(1,3- benzodioxol-5-yl)-1-methyl-ethyl]-N-ethyl-4-(1-piperidyl)piperidine-1-carboxamide hydrochloride (65 mg, 24%) as a gum.
  • Formulation for PO Administration For PO dosing, the prodrug was formulated in 10% DMSO / 20% PEG400 / 70% water to a concentration of 2 mg free metabolite material/mL. This provided a dose of 10 mg free metabolite/kg when the prodrug was administered PO in 5 mL/kg dosing volumes.
  • Formulation for IV administration For IV dosing, S-MDE was formulated as solution in saline to a concentration of 0.5 mg free metabolite material/mL. This provided a dose of 1 mg free metabolite/kg when administered IV in 2 mL/kg dosing volumes.
  • Example A-1 Measurement of Concentration of MDE after IV or oral administration of MDE Prodrugs In Vivo [000393] The pharmacokinetic properties of the synthesized MDE prodrugs after oral administration in a rat model were assessed. The concentration of MDE was measured in each rat at various sampling timepoints after oral administration of the synthesized MDE prodrugs to rats. [000394] Dose formulations were made at equivalent concentrations of active compound (MDE) adjusted for molecular weight of the compounds. The synthesized MDE prodrugs were dosed at 10 mg/kg oral (PO) nominal dose. Nominal doses were used in PK parameter determinations.
  • MDE active compound
  • Example A-1-1 S-MDE Parent Compound (IV & PO) Chemical name: (S)-N-ethyl-3,4-methylenedioxyamphetamine (S-MDE or S-MDEA) Structural class: parent Mechanistic class: n/a – parent compound Table 3.
  • S-MDE (IV & PO) Pharmacokinetic Parameters [000396] Figure 1-A shows mean concentration-time profiles of S-MDE following IV dosing of S-MDE (1 mg/kg) to male Sprague Dawley (SD) rats.
  • Figure 1-B shows mean concentration-time profiles of S-MDE following oral dosing of S-MDE (10 mg/Kg) to male Sprague Dawley (SD) rats.
  • Example A-1-2 MDE Trimethyllock prodrug Chemical name: [2-[3-[[(1S)-2-(1,3-Benzodioxol-5-yl)-1-methyl-ethyl]-ethyl-amino]-1,1- dimethyl-3-oxo-propyl]-3,5-dimethyl-phenyl] acetate (Compound 4C) Structural class: amide Mechanistic class: presumed esterase + intramolecular cyclization Table 4.
  • FIG. 1 shows mean concentration-time profiles of MDE following oral dosing of MDE trimethyllock prodrug (10 mg/kg) to male SD rats.
  • Example A-1-3 MDE THP methyl ester prodrug Chemical name: [[(1S)-2-(1,3-Benzodioxol-5-yl)-1-methyl-ethyl]-ethyl-carbamoyl]oxymethyl tetrahydropyran-4-carboxylate (Compound 8E) Structural class: acyloxymethyl carbamate Mechanistic class: presumed esterase + chemical breakdown Table 5.
  • FIG. 3 shows mean concentration-time profiles of MDE following oral dosing of MDE THP methyl ester prodrug (10 mg/kg) to male SD rats.
  • Example A-1-4 MDE THP 1-ethyl ester prodrug Chemical name: 1-[[(1S)-2-(1,3-Benzodioxol-5-yl)-1-methyl-ethyl]-ethyl-carbamoyl]oxyethyl tetrahydropyran-4-carboxylate (Compound 8F) Structural class: acyloxymethyl carbamate Mechanistic class: presumed esterase + chemical breakdown Table 6.
  • FIG. 4 shows mean concentration-time profiles of MDE following oral dosing of MDE THP 1-ethyl ester prodrug (10 mg/kg) to male SD rats.
  • Example A-1-5 MDE oxetane methyl ester prodrug Chemical name: ⁇ [(S)-2-(2H-1,3-Benzodioxol-5-yl)-1-methyl-ethyl]-N- ethylaminocarbonyloxy ⁇ methyl 3-oxetanecarboxylate (Compound 8G) Structural class: acyloxymethyl carbamate Mechanistic class: presumed esterase + chemical breakdown Table 7.
  • FIG. 5 shows mean concentration-time profiles of MDE following oral dosing of MDE oxetane methyl ester prodrug (10 mg/kg) to male SD rats.
  • Example A-1-6 MDE t-butyl methyl succinate prodrug Chemical name: ⁇ [(S)-2-(2H-1,3-Benzodioxol-5-yl)-1-methyl-ethyl]-N- ethylaminocarbonyloxy ⁇ methyl tert-butyl succinate (Compound 8B) Structural class: acyloxymethyl carbamate Mechanistic class: presumed esterase + chemical breakdown and / or presumed esterase + intramolecular cyclization + chemical breakdown Table 8.
  • Figure 6 shows mean concentration-time profiles of MDE following oral dosing of MDE t-butyl methyl succinate prodrug (10 mg/kg) to male SD rats.
  • Example A-1-7 MDE t-butyl methyl glutarate prodrug
  • Structural class acyloxymethyl carbamate
  • Mechanistic class presumed esterase + chemical breakdown and / or presumed esterase + intramolecular cyclization + chemical breakdown Table 9.
  • Figure 7 shows mean concentration-time profiles of MDE following oral dosing of MDE t-butyl methyl glutarate prodrug (10 mg/kg) to male SD rats.
  • Example A-1-8 MDE t-butyl methyl adipate prodrug
  • Compound 8A Structural class: acyloxymethyl carbamate
  • Mechanistic class presumed esterase + chemical breakdown and / or presumed esterase + intramolecular cyclization + chemical breakdown Table 10.
  • Figure 8 shows mean concentration-time profiles of MDE following oral dosing of MDE t-butyl methyl adipate prodrug (10 mg/kg) to male SD rats.
  • Example A-1-9 MDE methyl hemi-succinate prodrug Chemical name: 3-( ⁇ [(S)-2-(2H-1,3-Benzodioxol-5-yl)-1-methyl-ethyl]-N- ethylaminocarbonyloxy ⁇ methoxycarbonyl)propionic acid (Compound 9B) Structural class: acyloxymethyl carbamate Mechanistic class: presumed pH-dependent cyclization + chemical breakdown and / or esterase + chemical breakdown Table 11.
  • Figure 9 shows mean concentration-time profiles of MDE following oral dosing of MDE methyl hemi-succinate prodrug (10 mg/kg) to male SD rats.
  • Example A-1-10 MDE methyl hemi-glutarate prodrug Chemical name: 4-( ⁇ [(S)-2-(2H-1,3-Benzodioxol-5-yl)-1-methyl-ethyl]-N- ethylaminocarbonyloxy ⁇ methoxycarbonyl)butyric acid (Compound 9A) Structural class: acyloxymethyl carbamate Mechanistic class: presumed pH-dependent cyclization + chemical breakdown and / or esterase + chemical breakdown Table 12.
  • Figure 10 shows mean concentration-time profiles of MDE following oral dosing of MDE methyl hemi-glutarate prodrug (10 mg/kg) to male SD rats.
  • Example A-1-11 MDE methyl hemi-adipate prodrug
  • Chemical name 5-( ⁇ [(S)-2-(2H-1,3-Benzodioxol-5-yl)-1-methyl-ethyl]-N- ethylaminocarbonyloxy ⁇ methoxycarbonyl)valeric acid
  • Compound 9C Structural class: acyloxymethyl carbamate
  • Mechanistic class presumed pH-dependent cyclization + chemical breakdown and / or esterase + chemical breakdown Table 13.
  • Figure 11 shows mean concentration-time profiles of MDE following oral dosing of MDE methyl hemi-adipate prodrug (10 mg/kg) to male SD rats.
  • Example A-1-12 MDE methyl Boc-valine prodrug Chemical name: [[(1S)-2-(1,3-Benzodioxol-5-yl)-1-methyl-ethyl]-ethyl-carbamoyl]oxymethyl (2R)-2-(tert-butoxycarbonylamino)-3-methyl-butanoate (Compound 8I) Structural class: acyloxymethyl carbamate Mechanistic class: presumed esterase + chemical breakdown Table 14.
  • Figure 12 shows mean concentration-time profiles of MDE following oral dosing of MDE methyl Boc-valine prodrug (10 mg/kg) to male SD rats.
  • Example A-1-13 MDE trifluoroacetamide prodrug Chemical name: N-[(1S)-2-(1,3-Benzodioxol-5-yl)-1-methyl-ethyl]-N-ethyl-2,2,2-trifluoro- acetamide (Compound 2B) Structural class: amide Mechanistic class: presumed amidase Table 15.
  • Example A-1-15 MDE t-butyl glutarate prodrug Chemical name: tert-Butyl 4- ⁇ [(S)-2-(2H-1,3-benzodioxol-5-yl)-1-methyl-ethyl]-N- ethylcarbamoyl ⁇ butyrate (Compound 4B) Structural class: amide Mechanistic class: presumed amidase Table 17.
  • MDE lysine prodrug Chemical name: (2S)-2,6-diamino-N-[(1S)-2-(1,3-benzodioxol-5-yl)-1-methyl-ethyl]-N-ethyl- hexanamide dihydrochloride (Compound 5A) Structural class: amide Mechanistic class: presumed amidase Table 19.
  • MDE ethyl carbonate prodrug Chemical name: Ethyl N-[(1S)-2-(1,3-benzodioxol-5-yl)-1-methyl-ethyl]-N-ethyl-carbamate (Compound 1B) Structural class: carbamate Mechanistic class: presumed esterase Table 21.
  • MDE i-butyl carbonate prodrug Chemical name: iso-Butyl N-[(1S)-2-(1,3-benzodioxol-5-yl)-1-methyl-ethyl]-N-ethyl-carbamate (Compound 1D) Structural class: carbamate Mechanistic class: presumed esterase Table 22.
  • Figure 14 shows mean concentration-time profiles of MDE following oral dosing of (S)-MDE methyl pivolate prodrug (10 mg/kg) to male SD rats.
  • Example A-1-22 (S)-MDE methyl glycol prodrug Chemical name: 2-Methoxyethyl N-[(1S)-2-(1,3-benzodioxol-5-yl)-1-methyl-ethyl]-N-ethyl- carbamate (Compound 1E) Structural class: carbamate Mechanistic class: presumed esterase Table 24.
  • rat zero-maze model is a refined alternative to the plus-maze, the most widely used animal model of anxiety, and consists of an elevated annular platform, divided equally into four quadrants. Two opposite quadrants are enclosed by Perspex walls on both the inner and the outer edges of the platform, while the remaining two opposite quadrants are open being enclosed only by a Perspex “lip”.
  • the elevated 0-maze comprises a black Perspex annular platform (105 cm diameter, 10 cm width) elevated to 65 cm above ground level, divided equally into four quadrants.
  • IP Rac-MDE (tosylate salt with 54.6% free base content) was formulated in Vehicle 1 (Saline) for injection to concentrations of 0.5, 1, 2, 3 and 6 mg/mL to provide doses of 2.5, 5, 10, 15 and 30 mg/kg when administered ip in 5 mL/kg dosing volumes.
  • IP R-MDE (tosylate salt with 54.6% free base content) was formulated in Vehicle 1 (Saline) for injection to concentrations of 0.5, 1, 3 and 6 mg/mL to provide doses of 2.5, 5, 10, 15 and 30 mg/kg when administered ip in 5 mL/kg dosing volumes.
  • IP S-MDE (tosylate salt with 54.6% free base content) was formulated in Vehicle 1 (Saline) for injection to concentrations of 0.5, 1, 2, 3 and 6 mg/mL to provide doses of 2.5, 5, 10, 15 and 30 mg/kg when administered ip in 5 mL/kg dosing volumes.
  • Chlordiazepoxide was formulated in Vehicle 1 (saline) to a concentration of 1.2 mg/mL to provide a dose of 6 mg/kg when administered ip in 5 mL/kg dosing volumes.
  • Vehicle 1 saline
  • Rac-MDE chlordiazepoxide
  • Table 27 Synopsis of testing schedule Rac-MDE and chlordiazepoxide in the rat elevated Effect of administration of R-MDE and chlordiazepoxide on behavior in a rat 0-maze study
  • 35 male Sprague-Dawley rats in treatment groups of 5, were intraperitoneally dosed with either Vehicle 1 (saline) or R-MDE at 1 of 5 dose levels (2.5, 5, 10, 15 & 30 mg/kg) or chlordiazepoxide (6 mg/kg) in 5 mL/kg injection volumes. Thirty min later at T 0, rats were individually placed in a closed arm of the zero-maze and behavior was assessed by a “blind” observer using remote video monitoring over the subsequent 5 min.
  • Table 28 Synopsis of testing schedule R-MDE and chlordiazepoxide in the rat elevated zero maze model of anxiety. Effect of administration of S-MDE and chlordiazepoxide on behavior in a rat 0-maze study [000420] 35 male Sprague-Dawley rats in treatment groups of 5, were intraperitoneally dosed with either Vehicle 1 (saline) or S-MDE at 1 of 5 dose levels (2.5, 5, 15 & 30 mg/kg) or chlordiazepoxide (6 mg/kg) in 5 mL/kg injection volumes.
  • racemic MDE has a greater therapeutic index than racemic MDE and a much greater therapeutic index than R MDE. Since racemic MDE is comprised of equal amounts of S-MDE and R-MDE, this indicates that the anxiogenic side effects seen with lower doses of racemic MDE are due to the anxiogenic effects of R-MDE. This surprising result shows that S- MDE does not have the anxiogenic side effects seen with racemic MDE and R-MDE. The data shows that while racemic MDE, S-MDE and R-MDE all have anxiolytic effects as effective as chlordiazepoxide at the high dose level, racemic MDE and R-MDE show anxiogenic effects at lower doses, an effect not seen with S-MDE.
  • racemic MDE or R-MDE must receive a dose high enough to reach the anxiolytic threshold since lower doses may cause anxiety as a side effect and result in worsening of the disorder being treated.
  • a drug-induced increase in anxiety due to improper dosing of racemic MDE or R- MDE could have severe side effects on patients and worsen their underlying disorder.
  • the data presented herein show that patients treated with a racemic MDE or R-MDE must be carefully titrated to avoid the anxiogenic effects and to reach the anxiolytic effect level.
  • the data show that in some embodiments a Risk Evaluation and Mitigation Strategy (REMS) program should be utilized so that patients treated with racemic MDE or R-MDE should undergo an initial dose titration to determine the effective range specific to that patient. This dose titrating protocol would decrease the side effects related to underdosing racemic MDE or R-MDE.
  • the data also inform Phase 2 and Phase 3 clinical trial design. Clinical trials for neurological and psychiatric disorders often include one or more low dose arms to show a dose dependent effect of the full dose on the disease of interest.
  • racemic and R-MDE should only be dosed at the full effective dose and a low dose arm should not be included as a comparator as this may lead to harmful side effects on the patients.
  • studies of racemic and R-MDE should only use inactive matched placebo or a different standard of care therapeutic as a control.
  • MDE should only be dosed at its effective dose range to avoid harmful side effects to the patients. This would be especially critical in clinical studies of anxiety disorders or depression including post-traumatic stress disorder, generalized anxiety disorder, panic disorder, major depressive disorder, or treatment resistant depression where increased anxiety could worsen the underlying disorder and lead to potentially devastating effects on the patients.
  • S-MDE which is anxiolytic without any anxiogenic effects.
  • a clinician treating a patient with S-MDE does not need to utilize a specific dose titration protocol to reduce anxiogenic effects.
  • clinical studies of S-MDE have a greater safety margin and are able to use lower doses in different arms of the study to demonstrate a dose dependent effect on the disease of interest.
  • S-MDE allows greater flexibility in clinical trial design including the safe use of a low dose active comparator to reduce expectancy bias.
  • S-MDE would be preferred to racemic MDE or R-MDE to treat patients with anxiety or depressive disorders including post-traumatic stress disorder, generalized anxiety disorder, panic disorder, major depressive disorder, or treatment resistant depression.
  • S-MDE is a safer alternative to racemic MDE or R-MDE for the treatment of neurological and psychiatric disorders.
  • Prodrugs of MDE are expected to have the same effect post-cleavage of the pro-portion so these results with MDE would be expected to apply to dosing the prodrugs as well.
  • Example C MDE Dose Titration Risk Evaluation and Mitigation Strategy (REMS) Protocol General Information on MDE Treatment Session
  • the MDE doses presented in examples C and D are based on the effective dose of MDE.
  • Prodrugs of MDE are expected to achieve efficacious levels of MDE post-cleavage of the pro-portion once the dose of the prodrug is adjusted to account for the extra weight of the pro- portion and pharmacokinetic or pharmacodynamic advantages of the prodrug.
  • the doses in these sections apply to the active amount of MDE released by the prodrug.
  • Initial MDE dosing and subsequent dosing adjustments must be done under the supervision of a qualified healthcare professional in a clinic or inpatient setting.
  • the patient must remain under supervision of the healthcare professional for at least 6 hours and up to approximately 24 hours after the final MDE dose adjustment.
  • the patient will be assessed periodically during the session for anxiety and other effects of MDE. Dose adjustments within a MDE treatment session will be based on changes from baseline levels of anxiety.
  • Postdose anxiety measurement timing and duration of observation after dosing are based on the following information reported by (https://psychonautwiki.org/wiki/MDEA/Summary): Duration of effects of MDE [000429] MDE dosing is based on the following information reported by the following databases (https://erowid.org/chemicals/mde/mde_dose.shtml) and (https://psychonautwiki.org/wiki/MDEA/Summary): MDE dosages Predose Assessment [000430] The patient’s baseline level of anxiety will be measured and recorded.
  • MDE Dosing [000431] The patient will receive an initial single oral dose of MDE in the range of approximately 120 mg – 180 mg based on oral doses reported as producing moderate effects (https://psychonautwiki.org/wiki/MDEA/Summary). Postdose Assessment [000432] Change from baseline anxiety level will be measured at approximately 1 to 2 hours after dosing based on reported time to achieve peak effects (https://psychonautwiki.org/wiki/MDEA/Summary). MDE Dose Adjustment [000433] MDE effects have been maintained by taking a larger initial dose followed by smaller doses (50 mg to 75 mg p.o.) (PiHKAL 1991).
  • MDE dose adjustment MDE Discontinuation MDE dose adjustment MDE Discontinuation
  • the patient will be observed for at least 6 hours after final MDE dose is administered.
  • the patient may be confined to the inpatient unit for prolonged observation up to approximately 24 hours after last MDE dose if indicated based on persistent effects.
  • Anxiety that appears after the final MDE titration dose is administered can be managed with an appropriate anxiolytic agent. If this is necessary, the patient must remain under observation and undergo periodic reassessment until the supervising healthcare professional determines the patient can be discharged from care.
  • Example D A double-blind, randomized, placebo-controlled clinical trial of MDE-assisted psychotherapy in PTSD
  • a multicenter, randomized, double-blind, placebo-controlled trial is conducted to assess the efficacy and safety of MDE-assisted psychotherapy versus psychotherapy with placebo control in participants diagnosed with at least moderate post-traumatic stress disorder (PTSD).
  • PTSD is a debilitating and often times chronic disorder associated with profound mental, physical, occupational, and functional impairment. PTSD can develop due to exposure to a traumatic event or persistent or recurring threats to an individual. Studies indicate that approximately 10% of individuals exposed to a traumatic event eventually go on to be diagnosed with PTSD (American Psychiatric Association.
  • PTSD is a complex psychiatric disorder characterized by symptom heterogeneity including avoidance of trauma-related material, emotional blunting and distancing, hyper-vigilance, hyper-arousal, persistent negative alterations in mood, persistent alterations in cognition, disturbing thoughts, disruptions in sleep and/or dreams, and physical or mental distress. Symptoms can be severe and long lasting. Although this symptom heterogeneity may suggest a wide spectrum of separate disturbances, emotional dysregulation is considered to be a core component of this disorder.
  • emotional dysregulation in affected individuals is believed to give rise to observable and measurable features such as presence of hypervigilance and attentional biases, enhanced startle response, hyper-arousal, apathetic feeling or emotional numbness, irritability, enhanced memories associated with traumatic events, difficulty in discerning danger versus safety, a generalization of fear, and avoidance of reminders of trauma.
  • Emotional dysregulation may be defined and also measured by elevated emotional reactivity based on abnormal detection or appraisal of emotional triggers involving bottom-up sensory detection and neuronal processing.
  • Biochemical alterations found in individuals diagnosed with PTSD suggest abnormalities in the hypothalamic-pituitary-adrenal (HPA) axis.
  • HPA hypothalamic-pituitary-adrenal
  • the HPA axis is known to regulate reactions to stress and controls significant aspects of the neuroendocrine system impacting many homeostatic systems in the body.
  • catecholamine and cortisol levels detected in urine rise after exposure to a stressor.
  • PTSD many individuals show a low secretion of cortisol and high secretion of catecholamine in response to a stressor indicating a change in catecholamine to cortisol ratio in the urine.
  • More evidence that the HPA axis is impacted in PTSD is found in elevated levels of catecholamines and corticotropin-releasing factor in the brain of many affected individuals.
  • the initiation and/or maintenance of emotional dysregulation in PTSD may be due to abnormalities in top-down control of emotional responses indicating that cognitive influences and higher order representations may impinge on information and emotional processing.
  • abnormalities in neuronal processing in PTSD occur either implicitly (e.g., unconsciously) or explicitly (e.g., consciously) indicating involvement of distinct cognitive processes.
  • Exaggerated responses in the amygdala and insular cortex have been demonstrated in meta-analyses in PTSD pathology, as have decreases in activity in other brain regions including the anterior cingulate cortex and aspects the prefrontal cortex including the ventromedial prefrontal cortex.
  • MDE is a synthetic analog of the psychedelic phenethylamine class of compounds known to act as a mixed reuptake inhibitor/releasing agent of serotonin, norepinephrine, and dopamine and administration of MDE can produce acute modulations of neurotransmission. MDE administration also has indirect effects on neurohormone release.
  • MDE can function as a psychoplastogen promoting neuronal growth, modulating neuronal connectivity, and regulating neuronal plasticity through longer term neuronal changes.
  • the combined neurobiological effects of MDE administration on individuals reduce fear of emotional injury or distress, enhance introspection and communication, and increase empathetic feelings and compassion. Additionally, MDE may serve to enhance fear extinction. These combined effects may yield acute and longer-term productive psychological states to enhance behavioral or cognitive- behavioral therapies.
  • MDE administration may enhance neuronal function at the biochemical and cellular levels to generate or restore favorable neural network pathways and connectivity to increase behavioral or cognitive-behavioral therapy productiveness.
  • An optional Risk Evaluation and Mitigation Strategy (REMS) Protocol may be implemented for the racemic MDE, R-MDE, and placebo-groups.
  • the Treatment Period lasts for approximately 12 weeks.
  • each Experimental Session is followed by three Intervening Sessions of non-drug psychotherapy.
  • Each Experimental Session involves an overnight stay.
  • the Primary Outcome measure the change in Clinician Administered PTSD Scale for DSM-5 (CAPS-5), is determined by a blinded Independent Rater (IR) pool multiple times throughout the study.
  • IR blinded Independent Rater
  • a Preparation Period is undertaken for enrolled participants involving medication tapering and clinical baseline assessments to confirm each participant meets enrollment criteria.
  • a detailed assessment of co-morbidities to PTSD is recorded. Participants may remain on prescribed courses of selective serotonin reuptake inhibitor (SSRI) or serotonin and norepinephrine reuptake inhibitor (SNRI) treatment. Dosages and/or frequency of administration of a prescribed SSRI or SNRI may be adjusted to fit within study parameters. Participants may be required to taper a prescribed course of medication in order to maintain eligibility within the study.
  • the Treatment Period consists of three monthly Experimental Sessions and associated Intervening Sessions of integrative behavioral psychotherapy. The Treatment Period lasts approximately 12 weeks. Following the Treatment Period is a Follow-up Period and Study Conclusion. During the Follow-up Period and Study Conclusion, participants complete 4 weeks with no study visits, followed by a Study Conclusion visit.
  • the Treatment Period schedule follows the Screening Period and the Preparatory Period
  • Randomization occurs prior to the initiation of Experimental Session 1. Each participant is provided the next randomized number in a sequence by a blinded study monitor. Participants are then randomized, according to a computer-generated randomization schedule, 1:1:1:1 to racemic MDE, S-MDE, R-MDE, or placebo. The randomization schedule is prepared and implemented by an independent statistician. Participants, clinicians, and study teams are blinded to treatment allocation. Racemic MDE and R-MDE treatment groups may be subjected to anxiogenic effects due to underdosing of participants.
  • an optional dose titration schedule exists for racemic MDE and R-MDE treatment groups if a participant displays no change or a significant worsening of assessed anxiety symptomatology. Participants are assessed for general well-being and anxiety by a medical practitioner about 0.75 hours after the first dose is administered. Assessments performed may include general assessments of physical and mental well-being, a structured clinical interview for DSM-5 (SCID-5) module A1, and/or a STAI assessment and may continue throughout the period of overnight observation. [000446] Subjects then undergo three Intervening Sessions with the first session the morning after the initial dose administration. S-MDE treatment group or placebo group participants qualifying with a significant worsening of assessed anxiety symptomatology would undergo a placebo dose titration administration.
  • S-MDE treatment group or placebo group participants qualifying with a significant worsening of assessed anxiety symptomatology would undergo a placebo dose titration administration.
  • Subjects would then undergo three Intervening Sessions with the first session the morning after the placebo dose titration administration.
  • the pharmacist is to reveal actual treatment contents to the primary investigator, who is to alert the Sponsor of the emergency. If the participant or study center personnel are unblinded, the subject is to be removed from the study.
  • the primary objective of this study is to evaluate the efficacy and safety of MDE treatment combined with psychotherapy to treat moderate to severe PTSD compared to identical psychotherapy combined with placebo treatment.
  • MDE treatment is further subdivided into three separate treatment groups (racemic MDE, S-MDE, and R-MDE) with each treatment subgroup only receiving administration of the single assigned drug. Treatment outcomes are determined based on a change in CAPS-5 Total Severity.
  • MDE treatment is further subdivided into three separate treatment groups (racemic MDE, S-MDE, and R-MDE) with each treatment subgroup only receiving administration of the single assigned drug. Treatment outcomes are determined based on a change in SDS.
  • Another secondary objective of this study is to evaluate clinician-rated depression of MDE treatment combined with psychotherapy to treat moderate to severe PTSD compared to identical psychotherapy combined with placebo treatment. Identical study parameters are in place as for the clinician-rated functional impairment assessment except that treatment outcomes are determined based on a change in HAM-D.
  • An additional secondary objective of this study is to evaluate sleep assessments of MDE treatment combined with psychotherapy to treat moderate to severe PTSD compared to identical psychotherapy combined with placebo treatment. Identical study parameters are in place as for the clinician-rated functional impairment assessment except that treatment outcomes are determined based on a change in ESS. Co-morbidities present in participants with a strong positive response to MDE treatment are correlated. Co-morbidities present in participants with weak-to-no positive response to MDE treatment are correlated.
  • Participants may be enrolled in the study while remaining on a treatment regimen involving SSRI or SNRI treatment prescribed for PTSD. In some cases, enrolled participants currently taking an SSRI, an SNRI, or another medication are tapered off these medications and stabilized prior to baseline assessments. Participants with a confirmed personality disorder diagnosis are excluded from this study. Participants must be in good general physical health without one or more severe chronic conditions that could affect the safety or tolerability of MDE treatment.
  • Statistical Analysis [000450] The change from baseline in CAPS-5, SDS, HAM-D, and ESS in participants is analyzed using a mixed effects model for repeated measures (MMRM) to obtain covariance parameter estimates.
  • the model includes treatment center, treatment subtype, baseline assessments, assessment time point, and time point-by-treatment as explanatory variables.
  • Treatment center is treated as a random effect; all other explanatory variables are treated as fixed effects.
  • Model-based point estimates e.g., least squares means, 95% confidence intervals, and p- values
  • Treatment center is treated as a random effect; all other explanatory variables are treated as fixed effects.
  • Model-based point estimates e.g., least squares means, 95% confidence intervals, and p- values
  • this study has 90% power to detect a significant treatment effect, using a two-sided test with an alpha value of 0.05.
  • Results [000451] The results may indicate that the primary objective is achieved.
  • racemic MDE-treated, S-MDE-treated, and R-MDE-treated participants may demonstrate a significant mean reduction in CAPS-5 assessment compared to the placebo group.
  • the S-MDE-treated subgroup may achieve a significant mean reduction in CAPS-5 assessment with a lower total dosage of drug compared to the racemic MDE-treated subgroup.
  • the R-MDE- treated subgroup may achieve a significant mean reduction in CAPS-5 assessment with a lower total dosage of drug compared to the racemic MDE-treated subgroup.
  • racemic MDE-treated, S-MDE-treated, and R-MDE-treated participants may demonstrate a significant improvement in clinician-rated functional impairment score as measured by SDS compared to placebo-treated controls.
  • racemic MDE-treated, S-MDE-treated, and R-MDE-treated participants may demonstrate a significant improvement depression as measured by HAM-D compared to placebo-treated controls.
  • racemic MDE-treated, S-MDE- treated, and R-MDE-treated participants may demonstrate a significant improvement in lessening daytime sleepiness as measured by ESS.

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Abstract

La présente divulgation concerne des promédicaments de 3,4-méthylènedioxy-N-éthyl-amphétamine (MDEA), des méthodes de production des promédicaments et des méthodes pour leur utilisation dans le traitement de troubles cérébraux et neurologiques.
PCT/US2023/060662 2022-01-14 2023-01-13 Promédicaments de 3,4-méthylènedioxy-n-éthyl-amphétamine (mdea) et leurs utilisations WO2023137446A1 (fr)

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WO2022053696A1 (fr) * 2020-09-11 2022-03-17 Compass Pathfinder Limited Nouveaux dérivés safrylamine ayant des propriétés de promédicaments

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