PRODRUGS OF MDMA, MDA, AND DERIVATIVES THEREOF

Abstract

The present disclosure provides prodrug compounds of MDMA, MDA, and derivatives thereof having an improved pharmacokinetic profile suitable for the treatment of various neurological diseases.

Claims

1. A compound of Formula (I): ##STR00205## or a pharmaceutically acceptable salt thereof; wherein, R.sub.1 is H or alkyl; R.sub.2 and R.sub.2′ are each independently H, halogen, alkyl, —OH, or —O-alkyl, or R.sub.2 and R.sub.2′ together with the atom to which they are attached form a cycloalkyl ring; R.sub.3 and R.sub.3′ are each independently H, alkyl, —OH, —O-alkyl, or —O-cycloalkyl, or R.sub.3 and R.sub.3′ together with the atom to which they are attached form an oxo; R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are each independently H, halogen, —OH, —O-alkyl, —O— cycloalkyl, alkylene-OR.sub.8, —SH, —S-alkyl, —S-cycloalkyl, or alkylene-SR.sub.8, or R.sub.5 and R.sub.6 together with the atoms to which they are attached form a 5- to 8-membered heterocyclyl ring; R.sub.8 is H, alkyl, cycloalkyl, or alkylenecycloalkyl; and X is ##STR00206## wherein: R.sub.9 is alkyl or phenyl, and R.sub.10 is phenyl or C.sub.1-6 alkyl.

2. The compound of claim 1, wherein at least one of R.sub.4, R.sub.5, R.sub.6 and R.sub.7 is not H.

3. The compound of claim 1, wherein R.sub.1 is H or C.sub.1-C.sub.6 alkyl.

4. The compound of claim 1, wherein R.sub.1 is H.

5. The compound of claim 1, wherein R.sub.1 is CH.sub.3.

6. The compound of claim 1, wherein R.sub.2 and R.sub.2′ are each independently H, alkyl, or —OH.

7. The compound of claim 1, wherein R.sub.2 is alkyl and R.sub.2′ is H.

8. The compound of claim 1, wherein R.sub.2 and R.sub.2′ are each alkyl.

9. The compound of claim 6, wherein R.sub.2 and R.sub.2 are each independently methyl or isopropyl.

10. The compound of claim 1, wherein R.sub.3 and R.sub.3′ are each independently H, —OH, or —O-alkyl, or R.sub.3 and R.sub.3′ together with the atom to which they are attached form an oxo.

11. The compound of claim 1, wherein R.sub.4 is H.

12. The compound of claim 1, wherein R.sub.7 is H.

13. The compound of claim 1, wherein R.sub.5 and R.sub.6 are each independently halogen, —OH, —O-alkyl, —O-cycloalkyl, alkylene-OR.sub.8, —SH, —S-alkyl, —S-cycloalkyl, or alkylene-SR.sub.8.

14. The compound of claim 1, wherein R.sub.5 and R.sub.6 together with the atoms to which they are attached form a 5- to 8-membered heterocyclyl ring.

15. The compound of claim 1, wherein R.sub.8 is alkyl.

16. The compound of claim 1, wherein R.sub.9 is C.sub.1-5 alkyl.

17. The compound of claim 1, wherein R.sub.9 is methyl or isopropyl.

18. The compound of claim 1, wherein R.sub.10 is C.sub.1-5 alkyl.

19. The compound of claim 18, wherein R.sub.10 is methyl or isopropyl.

20. The compound of claim 1, having the structure of Formula (Ib): ##STR00207## wherein n is 1 or 2.

21. The compound of claim 1, wherein the compound is: ##STR00208##

22. The compound of claim 1, wherein X is cleavable at a pH of from about 1 to about 5.

23. The compound of claim 1, wherein X is cleavable at a pH of from about 2 to about 4.

24. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.

25. The pharmaceutical composition of claim 24, wherein the composition provides an in vivo plasma level characterized by a C.sub.max of free amine of about 100 ng/mL to about 500 ng/mL, after oral administration of from about 80 mg to about 125 mg of a compound of Formula (I).

26. The pharmaceutical composition of claim 24, wherein the composition provides an in vivo plasma level characterized by an AUC.sub.(0-24) of free amine of about 1000 h*ng/mL to about 6000 h*ng/mL, after oral administration of from about 80 mg to about 125 mg of a compound of Formula (I).

27. The pharmaceutical composition of claim 24, wherein the composition provides an in vivo T.sub.1/2 of free amine of about 5 h to about 15 h, after oral administration of from about 80 mg to about 125 mg of a compound of Formula (I).

28. The pharmaceutical composition of claim 24, wherein when R.sub.1 is H, the composition provides a C.sub.max of free amine within a range of about 60-90% of about 12 ng/mL to about 15 ng/mL achieved following oral administration of a 125 mg dose of MDA to a human subject.

29. The pharmaceutical composition of claim 24, wherein when R.sub.1 is H, the composition provides a C.sub.max of free amine within a range of about 60-90% of about 7 ng/mL to about 8.5 ng/mL achieved following oral administration of a 75 mg dose of MDA to a human subject.

30. The pharmaceutical composition of claim 22, wherein when R.sub.1 is methyl, the composition provides a C.sub.max of free amine within a range of about 60-90% of about 220 ng/mL to about 250 ng/mL achieved following oral administration of a 125 mg dose of MDMA to a human subject.

31. The pharmaceutical composition of claim 24, wherein R.sub.1 is methyl, the composition provides a T.sub.1/2 of free amine within a range of about 105-150% of about 8 h to about 9 h achieved following oral administration of a 125 mg dose of MDMA to a human subject.

32. The pharmaceutical composition of claim 24, wherein when R.sub.1 is methyl, the composition provides a C.sub.max of free amine within a range of about 60-90% of about 120 ng/mL to about 140 ng/mL achieved following oral administration of a 75 mg dose of MDMA to a human subject.

33. The pharmaceutical composition of claim 24, wherein when R.sub.1 is methyl, the composition provides a T.sub.1/2 of free amine within a range of 105-150% of about 7 h to about 9 h achieved following oral administration of a 75 mg dose of MDMA to a human subject.

34-68. (canceled)

69. A compound of Formula (IIIa) ##STR00209## or a pharmaceutically acceptable salt thereof; wherein, R.sub.1 is H or alkyl; R.sub.2 is H, halogen, alkyl, —OH, or —O-alkyl; R.sub.3 is H alkyl, —OH, —O-alkyl, or —O-cycloalkyl; R.sub.4 and R.sub.7 are each independently H, halogen, —OH, —O-alkyl, —O— cycloalkyl, alkylene-OR.sub.8, —SH, —S-alkyl, —S-cycloalkyl, or alkylene-SR.sub.8; R.sub.8 is H, alkyl, cycloalkyl, or alkylenecycloalkyl; and B is ##STR00210## wherein R.sub.B is H or alkyl R.sub.11 and R.sub.12 are each independently H, alkyl, cycloalkyl, or R.sub.11 and R.sub.12 together with the atoms to which they are attached form a 5- to 8-membered heterocyclyl ring.

70. The compound of claim 69, wherein at least one of R.sub.4 and R.sub.7 is not H.

71. The compound of claim 69, wherein R.sub.1 is H or C.sub.1-C.sub.6 alkyl.

72. The compound of claim 69, wherein R.sub.1 is H.

73. The compound of claim 69, wherein R.sub.1 is CH.sub.3.

74. The compound of claim 69, wherein R.sub.2 is H, alkyl, or —OH.

75. The compound of claim 69, wherein R.sub.2 is alkyl.

76. The compound of claim 69, wherein R.sub.2 is alkyl.

77. The compound of claim 74, wherein R.sub.2 is methyl or isopropyl.

78. The compound of claim 69, wherein R.sub.3 is H, —OH, or —O-alkyl.

79. The compound of claim 69, wherein R.sub.4 is H.

80. The compound of claim 69, wherein R.sub.7 is H.

81-84. (canceled)

85. The compound of claim 69, having the structure of Formula (IIIb): ##STR00211## or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2.

86. The compound of claim 85, having the structure: ##STR00212## or a pharmaceutically acceptable salt thereof.

87. The compound of claim 86, having the structure: ##STR00213##

88. The compound of claim 86, having the structure: ##STR00214##

89. A pharmaceutical composition comprising a compound of claim 69 and a pharmaceutically acceptable excipient.

90. The pharmaceutical composition of claim 89, wherein the composition provides an in vivo plasma level characterized by a C.sub.max of free amine of about 100 ng/mL to about 500 ng/mL, after oral administration of from about 80 mg to about 125 mg of a compound of Formula (III).

91. The pharmaceutical composition of claim 89, wherein the composition provides an in vivo plasma level characterized by an AUC.sub.(0-24) of free amine of about 1000 h*ng/mL to about 6000 h*ng/mL, after oral administration of from about 80 mg to about 125 mg of a compound of Formula (III).

92. The pharmaceutical composition of claim 89, wherein the composition provides an in vivo T.sub.1/2 of free amine of about 5 h to about 15 h, after oral administration of from about 80 mg to about 125 mg of a compound of Formula (III) and release of promoiety B.

93. A method of treating post-traumatic stress disorder (PTSD) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition of claim 89.

94. A method of treating an eating disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition of claim 89.

95. A method of treating depression in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition of claim 89.

96. The method of claim 95, wherein the depression is major depressive disorder (MDD) or treatment-resistant depression (TRD).

97. A method of treating an anxiety disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition of claim 89.

98. The method of claim 97, wherein the anxiety disorder is generalized anxiety disorder.

99. (canceled)

100. (canceled)

Description

DETAILED DESCRIPTION

Compounds of the Disclosure

[0081] The present disclosure provides compounds that are prodrugs of MDMA, MDA, and derivatives thereof, as well as pharmaceutical compositions thereof.

[0082] In some embodiments, the present disclosure provides a compound of Formula (I):

##STR00022## [0083] or a pharmaceutically accept able salt thereof; [0084] wherein: [0085] R.sub.1 is H or alkyl; [0086] R.sub.2 and R.sub.2′ are each independently H, halogen, alkyl, —OH, or —O-alkyl, or R.sub.2 and R.sub.2′ together with the atom to which they are attached form a cycloalkyl ring; [0087] R.sub.3 and R.sub.3′ are each independently hydrogen, alkyl, —OH, —O-alkyl, or —O-cycloalkyl, or [0088] R.sub.3 and R.sub.3′ together with the atom to which they are attached form an oxo; [0089] R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are each independently hydrogen, halogen, —OH, —O-alkyl, —O-cycloalkyl, alkylene-OR.sub.8, —SH, —S-alkyl, —S-cycloalkyl, or alkylene-SR.sub.8, or R.sub.5 and R.sub.6 together with the atoms to which they are attached form a 5- to 8-membered heterocyclyl ring; [0090] R.sub.8 is H, alkyl, cycloalkyl, or alkylenecycloalkyl; [0091] X is a cleavable promoiety having the structure

##STR00023##

wherein: [0092] R.sub.9 and R.sub.10 are each independently alkyl or aryl.

[0093] In some embodiments of Formula (I), R.sub.1 is H, alkyl, or cycloalkyl. In some embodiments, R.sub.1 is H, C.sub.1-C.sub.6 alkyl, or C.sub.3-C.sub.6 cycloalkyl. In some embodiments, R.sub.1 is H or C.sub.1-C.sub.6 alkyl. In some embodiments, R.sub.1 is H. In some embodiments, R.sub.1 is C.sub.1-C.sub.6 alkyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is methyl, ethyl, or isopropyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is methyl or ethyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is methyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is ethyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is isopropyl. In some embodiments, R.sub.1 is methyl, ethyl, or isopropyl. In some embodiments, R.sub.1 is methyl or ethyl. In some embodiments R.sub.1 is methyl. In some embodiments, R.sub.1 is ethyl. In some embodiments, R.sub.1 is isopropyl. In some embodiments, R.sub.1 is cyclopropyl.

[0094] In some embodiments of Formula (I), R.sub.2 and R.sub.2′ are each independently H, halogen, alkyl, —OH, or —O-alkyl. In some embodiments, R.sub.2 and R.sub.2′ are each independently H, halogen, C.sub.1-C.sub.6 alkyl, —OH, or —O—C.sub.1-C.sub.6 alkyl. In some embodiments, R.sub.2 and R.sub.2′ are each independently H or alkyl. In some embodiments, R.sub.2 and R.sub.2′ are each independently H or C.sub.1-C.sub.6 alkyl. In some embodiments, the halogen is F. In some embodiments, the alkyl is C.sub.1-C.sub.6 alkyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is methyl, ethyl, or isopropyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is methyl or ethyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is methyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is ethyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is isopropyl.

[0095] In some embodiments, R.sub.2 and R.sub.2′ together with the atom to which they are attached form an oxo or a cycloalkyl ring. In some embodiments, R.sub.2 and R.sub.2′ together with the atom to which they are attached form an oxo. In some embodiments, R.sub.2 and R.sub.2′ together with the atom to which they are attached form a cycloalkyl ring. In some embodiments, the cycloalkyl ring is a C.sub.3-6 cycloalkyl ring. In some embodiments, the cycloalkyl ring is a cyclopropyl. In some embodiments, R.sub.2 is alkyl and R.sub.2′ is H. In some embodiments, R.sub.2 is alkyl and R.sub.2′ is absent. In some embodiments, R.sub.2 is H and R.sub.2′ is alkyl. In some embodiments, R.sub.2 is H and R.sub.2′ is F. In some embodiments, R.sub.2 is H and R.sub.2′ is —OH. In some embodiments, R.sub.2 is H and R.sub.2′ is —OCH.sub.3. In some embodiments, R.sub.2 is F and R.sub.2′ is F. In some embodiments, R.sub.2 is alkyl and R.sub.2′ is alkyl. In some embodiments, the alkyl is methyl.

[0096] In some embodiments of Formula (I), R.sub.3 and R.sub.3′ are each independently H, halogen, alkyl, —OH, —O-alkyl or —O-cycloalkyl. In some embodiments, R.sub.3 and R.sub.3′ are each independently H, halogen, C.sub.1-C.sub.6 alkyl, —OH, —O—C.sub.1-C.sub.6 alkyl, or —O—C.sub.3-6 cycloalkyl. In some embodiments, R.sub.3 and R.sub.3′ are each independently H or alkyl. In some embodiments, R.sub.3 and R.sub.3′ are each H. In some embodiments, R.sub.3 and R.sub.3′ are each independently H or C.sub.1-C.sub.6 alkyl. In some embodiments, the halogen is F. In some embodiments, the alkyl is C.sub.1-C.sub.6 alkyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is methyl, ethyl, or isopropyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is methyl or ethyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is methyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is ethyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is isopropyl.

[0097] In some embodiments, R.sub.3 and R.sub.3′ together with the atom to which they are attached form an oxo or a cycloalkyl ring. In some embodiments, R.sub.3 and R.sub.3′ together with the atom to which they are attached form an oxo. In some embodiments, R.sub.3 and R.sub.3′ together with the atom to which they are attached form a cycloalkyl ring. In some embodiments, the cycloalkyl ring is a C.sub.3-6 cycloalkyl ring. In some embodiments, the cycloalkyl ring is a cyclopropyl. In some embodiments, R.sub.3 is H and R.sub.3′ is alkyl. In some embodiments, R.sub.3 is H and R.sub.3′ is F. In some embodiments, R.sub.3 is H and R.sub.3′ is —OH. In some embodiments, R.sub.3 is H and R.sub.3′ is —OCH.sub.3. In some embodiments, R.sub.3 is F and R.sub.3′ is F. In some embodiments, R.sub.3 is alkyl and R.sub.3′ is alkyl. In some embodiments, the alkyl is methyl. In some embodiments, R.sub.3 is H and R.sub.3′ is absent.

[0098] In some embodiments of Formula (I), R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are each independently hydrogen, halogen, alkyl, —OH, —O-alkyl, —O-cycloalkyl, alkylene-OR.sub.8, —SH, —S-alkyl, —S-cycloalkyl, or alkylene-SR.sub.8. In some embodiments, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are each independently hydrogen, halogen, —OH, —O-alkyl, —O-cycloalkyl, alkylene-OR.sub.8, —SH, —S-alkyl, —S-cycloalkyl, or alkylene-SR.sub.8. In some embodiments, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are each independently hydrogen, halogen, —OH, —O—C.sub.1-C.sub.6 alkyl, —O—C.sub.3-C.sub.6 cycloalkyl, alkylene-OR.sub.8, —SH, —S—C.sub.1-C.sub.6 alkyl, —S—C.sub.3-C.sub.6 cycloalkyl, or alkylene-SR.sub.8. In some embodiments, R.sub.4, R.sub.8, R.sub.6 and R.sub.7 are each independently hydrogen, halogen, —OH, —O-alkyl, —O-cycloalkyl, or alkylene-OR.sub.8. In some embodiments, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are each independently hydrogen, halogen, —OH, —O—C.sub.1-C.sub.6 alkyl, —O—C.sub.3-C.sub.6 cycloalkyl, or alkylene-OR.sub.8. In some embodiments, R.sub.4, R.sub.8, R.sub.6 and R.sub.7 are each independently H, halogen, alkyl, —OH, —O-alkyl or —O-cycloalkyl. In some embodiments, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are each independently H, halogen, C.sub.1-C.sub.6 alkyl, —OH, —O—C.sub.1-C.sub.6 alkyl, or —O—C.sub.3-6 cycloalkyl. In some embodiments, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are each independently hydrogen, halogen, —OH, or —O-alkyl. In some embodiments, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are each independently alkylene-OR.sub.8, —SH, —S-alkyl, —S-cycloalkyl, or alkylene-SR.sub.8. In some embodiments, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are each independently H or —O-alkyl. In some embodiments, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are each independently H or —O—C.sub.1-C.sub.6 alkyl. In some embodiments, the halogen is F. In some embodiments, the alkyl is C.sub.1-C.sub.6 alkyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is methyl, ethyl, or isopropyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is methyl or ethyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is methyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is ethyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is isopropyl. In some embodiments, the alkyl is —O—C.sub.1-C.sub.6 alkyl. In some embodiments, the —O—C.sub.1-C.sub.6 alkyl is —O-methyl, —O-ethyl, or —O-isopropyl. In some embodiments, the —O—C.sub.1-C.sub.6 alkyl is —O— methyl or —O-ethyl. In some embodiments, the —O—C.sub.1-C.sub.6 alkyl is —O-methyl. In some embodiments, the —O—C.sub.1-C.sub.6 alkyl is ethyl. In some embodiments, the —O—C.sub.1-C.sub.6 alkyl is —O— isopropyl. In some embodiments, alkylene is a C.sub.1-6 alkylene. In some embodiments, alkylene is a C.sub.1-3 alkylene. In some embodiments, alkylene is a methylene or ethylene. In some embodiments, alkylene is methylene.

[0099] In some embodiments of Formula (I), R.sub.8 is H, alkyl, cycloalkyl, or alkylenecycloalkyl. In some embodiments, R.sub.8 is H, alkyl, or alkylenecycloalkyl. In some embodiments, R.sub.8 is H or alkyl. In some embodiments, the alkyl is a C.sub.1-6 alkyl. In some embodiments, the alkylenecycloalkyl is a C.sub.1-3alkylene-C.sub.3-6cycloalkyl.

[0100] In some embodiments of Formula (I), at least one of R.sub.4, R.sub.5, R.sub.6 and R.sub.7 is not H. In some embodiments, at least two of R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are not H. In some embodiments, two of R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are not H. In some embodiments, R.sub.5 and R.sub.6 are not H.

[0101] In some embodiments of Formula (I), R.sub.5 and R.sub.6 together with the atoms to which they are attached form a 5- to 8-membered heterocyclyl ring. In some embodiments of Formula (I), R.sub.5 and R.sub.6 together with the atoms to which they are attached form a 5- or 6-membered heterocyclyl ring. In some embodiments of Formula (I), R.sub.5 and R.sub.6 together with the atoms to which they are attached form a 5-membered heterocyclyl ring. In some embodiments of Formula (I), R.sub.5 and R.sub.6 together with the atoms to which they are attached form a 5-membered heterocyclyl ring. In some embodiments, the heterocyclyl ring has one or two oxygen atoms. In some embodiments, the heterocyclyl ring has two oxygen atoms. In some embodiments, the heterocyclic ring is

##STR00024##

In some embodiments, the heterocyclic ring is

##STR00025##

[0102] In some embodiments of Formula (I), R.sub.4 and R.sub.7 are each independently H, halogen (e.g., F, Cl, or Br), or alkyl (e.g., methyl or ethyl) and R.sub.5 and R.sub.6 are each independently —OH, —O-alkyl, —O-cycloalkyl, alkylene-OR.sub.8, —SH, —S-alkyl, —S-cycloalkyl, or alkylene-SR.sub.8. In some embodiments, R.sub.4 and R.sub.7 are each independently H, halogen (e.g., F, Cl, or Br), or alkyl (e.g., methyl or ethyl) and R.sub.5 and R.sub.6 are each independently —OH, —O-alkyl, —O-cycloalkyl, or alkylene-OR.sub.8. In some embodiments, R.sub.4 and R.sub.7 are each independently H, halogen (e.g., F, Cl, or Br), or alkyl (e.g., methyl or ethyl) and R.sub.5 and R.sub.6 are each independently —OH, —O—C.sub.1-C.sub.6 alkyl, —O—C.sub.3-C.sub.6 cycloalkyl, or alkylene-OR.sub.8. In some embodiments, R.sub.4 and R.sub.7 are each H.

[0103] In some embodiments of Formula (I), R.sub.4 and R.sub.7 are each independently H, halogen (e.g., F, Cl, or Br), or alkyl (e.g., methyl or ethyl) and R.sub.5 and R.sub.6 together with the atoms to which they are attached form heterocyclyl ring. In some embodiments of Formula (I), R.sub.4 and R.sub.7 are each independently H, halogen (e.g., F, Cl, or Br), or alkyl (e.g., methyl or ethyl) and R.sub.5 and R.sub.6 together with the atoms to which they are attached form a 5- or 6-membered heterocyclyl ring. In some embodiments, the heterocyclyl ring has one or two oxygen atoms. In some embodiments, the heterocyclyl ring has two oxygen atoms. In some embodiments, the heterocyclic ring is or

##STR00026##

In some embodiments, the heterocyclic ring is

##STR00027##

In some embodiments, R.sub.4 and R.sub.7 are each H.

[0104] In some embodiments, X is a cleavable promoiety that is cleaved at a pH of from about 1 to about 5. In some embodiments, X is a cleavable promoiety that is cleaved at a pH of from about 2 to about 4. In some embodiments, X is a cleaved at pH 2. In some embodiments, X is a cleaved at pH 3. In some embodiments, X is a cleaved at pH 4.

[0105] In some embodiments of Formula (I), X is a cleavable promoiety having the structure

##STR00028##

wherein R.sub.9 and R.sub.10 are each independently alkyl or phenyl. In some embodiments of Formula (I), X is a cleavable promoiety having the structure

##STR00029##

wherein R.sub.9 and R.sub.10 are each independently alkyl. In some embodiments, the alkyl is C.sub.1-C.sub.6 alkyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is methyl, ethyl, or isopropyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is methyl or ethyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is methyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is ethyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is isopropyl. In some embodiments, R.sub.9 and R.sub.10 are each independently methyl or isopropyl. In some embodiments, R.sub.9 and R.sub.10 are each methyl. In some embodiments, R.sub.9 and R.sub.10 are each ethyl. In some embodiments, R.sub.9 and R.sub.10 are each isopropyl.

[0106] In some embodiments, the present disclosure provides a compound of Formula (Ia):

##STR00030##

wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.7, and X are as defined above in Formula (I); and
R.sub.11 and R.sub.12 are each independently H, alkyl, cycloalkyl, or R.sub.11 and R.sub.12 together with the atoms to which they are attached form a 5- to 8-membered heterocyclyl ring.

[0107] In some embodiments of Formula (Ia), R.sub.11 and R.sub.12 are each independently H, alkyl, alkylenecycloalkyl, or cycloalkyl. In some embodiments, R.sub.11 and R.sub.12 are each independently H, C.sub.1-5 alkyl, C.sub.1-3alkylene-C.sub.3-6cycloalkyl, or C.sub.3-6 cycloalkyl. In some embodiments, R.sub.11 and R.sub.12 are each independently H or C.sub.1-5 alkyl.

[0108] In some embodiments of Formula (Ia), R.sub.11 and R.sub.12 together with the atoms to which they are attached form a 5- to 8-membered heterocyclyl ring. In some embodiments, R.sub.11 and R.sub.12 together with the atoms to which they are attached form a 5- or 6-membered heterocyclyl ring. In some embodiments, R.sub.11 and R.sub.12 together with the atoms to which they are attached form a 5-membered heterocyclyl ring. In some embodiments, the heterocyclic ring is

##STR00031##

In some embodiments, the heterocyclic ring is

##STR00032##

[0109] In some embodiments, the compound of the present disclosure is a compound of Formula (Ib):

##STR00033##

wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.7, and X are as defined above in Formula (I); and n is 1 or 2.

[0110] In some embodiments of Formula (I), n is 1. In some embodiments, n is 2.

[0111] In some embodiments, the compound of the present disclosure is a compound of Formula (Ic):

##STR00034##

wherein R.sub.1, R.sub.2, R.sub.9 and R.sub.10 are as defined above in Formula (I). In some embodiments, R.sub.1 is H or alkyl; and R.sub.2, R.sub.9, and R.sub.10 are each independently Me or iPr.

[0112] In some embodiments, the compound of the present disclosure is:

##STR00035##

[0113] In some embodiments, the present disclosure provides a compound of Formula (II):

##STR00036## [0114] or a pharmaceutically acceptable salt thereof; [0115] wherein: [0116] R.sub.1 is H or alkyl; [0117] R.sub.2 and R.sub.2′ are each independently H, halogen, alkyl, —OH, or —O-alkyl, or R.sub.2 and R.sub.2′ together with the atom to which they are attached form a cycloalkyl ring; [0118] R.sub.3 and R.sub.3′ are each independently hydrogen, alkyl, —OH, —O-alkyl, or —O-cycloalkyl, or [0119] R.sub.3 and R.sub.3′ together with the atom to which they are attached form an oxo; [0120] R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are each independently hydrogen, halogen, —OH, —O-alkyl, —O-cycloalkyl, alkylene-OR.sub.8, —SH, —S-alkyl, —S-cycloalkyl, or alkylene-SR.sub.8, or R.sub.5 and R.sub.6 together with the atoms to which they are attached form a 5- to 8-membered heterocyclyl ring; [0121] R.sub.8 is H, alkyl, cycloalkyl, or alkylenecycloalkyl; and [0122] A is a cleavable promoiety having the structure

##STR00037##

wherein: [0123] R.sub.9 is H, alkyl or acyl; and [0124] R.sub.10 is H, aryl, or —(CH.sub.2).sub.m—R.sub.11, wherein: [0125] m is an integer from 1-5; and [0126] R.sub.11 is amino, guanidino, thioalkyl, or aryl.

[0127] In some embodiments of Formula (II), R.sub.1 is H, alkyl, or cycloalkyl. In some embodiments, R.sub.1 is H, C.sub.1-C.sub.6 alkyl, or C.sub.3-C.sub.6 cycloalkyl. In some embodiments, R.sub.1 is H or C.sub.1-C.sub.6 alkyl. In some embodiments, R.sub.1 is H. In some embodiments, R.sub.1 is C.sub.1-C.sub.6 alkyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is methyl, ethyl, or isopropyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is methyl or ethyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is methyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is ethyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is isopropyl. In some embodiments, R.sub.1 is methyl, ethyl, or isopropyl. In some embodiments, R.sub.1 is methyl or ethyl. In some embodiments R.sub.1 is methyl. In some embodiments, R.sub.1 is ethyl. In some embodiments, R.sub.1 is isopropyl. In some embodiments, R.sub.1 is cyclopropyl.

[0128] In some embodiments of Formula (II), R.sub.2 and R.sub.2′ are each independently H, halogen, alkyl, —OH, or —O-alkyl. In some embodiments, R.sub.2 and R.sub.2′ are each independently H, halogen, C.sub.1-C.sub.6 alkyl, —OH, or —O—C.sub.1-C.sub.6 alkyl. In some embodiments, R.sub.2 and R.sub.2′ are each independently H or alkyl. In some embodiments, R.sub.2 and R.sub.2′ are each independently H or C.sub.1-C.sub.6 alkyl. In some embodiments, the halogen is F. In some embodiments, the alkyl is C.sub.1-C.sub.6 alkyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is methyl, ethyl, or isopropyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is methyl or ethyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is methyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is ethyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is isopropyl.

[0129] In some embodiments, R.sub.2 and R.sub.2′ together with the atom to which they are attached form an oxo or a cycloalkyl ring. In some embodiments, R.sub.2 and R.sub.2′ together with the atom to which they are attached form an oxo. In some embodiments, R.sub.2 and R.sub.2′ together with the atom to which they are attached form a cycloalkyl ring. In some embodiments, the cycloalkyl ring is a C.sub.3-6 cycloalkyl ring. In some embodiments, the cycloalkyl ring is a cyclopropyl. In some embodiments, R.sub.2 is alkyl and R.sub.2′ is H. In some embodiments, R.sub.2 is alkyl and R.sub.2′ is absent. In some embodiments, R.sub.2 is H and R.sub.2′ is alkyl. In some embodiments, R.sub.2 is H and R.sub.2′ is F. In some embodiments, R.sub.2 is H and R.sub.2′ is —OH. In some embodiments, R.sub.2 is H and R.sub.2′ is —OCH.sub.3. In some embodiments, R.sub.2 is F and R.sub.2′ is F. In some embodiments, R.sub.2 is alkyl and R.sub.2′ is alkyl. In some embodiments, the alkyl is methyl.

[0130] In some embodiments of Formula (II), R.sub.3 and R.sub.3′ are each independently H, halogen, alkyl, —OH, —O-alkyl or —O-cycloalkyl. In some embodiments, R.sub.3 and R.sub.3′ are each independently H, halogen, C.sub.1-C.sub.6 alkyl, —OH, —O—C.sub.1-C.sub.6 alkyl, or —O—C.sub.3-6 cycloalkyl. In some embodiments, R.sub.3 and R.sub.3′ are each independently H or alkyl. In some embodiments, R.sub.3 and R.sub.3′ are each H. In some embodiments, R.sub.3 and R.sub.3′ are each independently H or C.sub.1-C.sub.6 alkyl. In some embodiments, the halogen is F. In some embodiments, the alkyl is C.sub.1-C.sub.6 alkyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is methyl, ethyl, or isopropyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is methyl or ethyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is methyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is ethyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is isopropyl.

[0131] In some embodiments, R.sub.3 and R.sub.3′ together with the atom to which they are attached form an oxo or a cycloalkyl ring. In some embodiments, R.sub.3 and R.sub.3′ together with the atom to which they are attached form an oxo. In some embodiments, R.sub.3 and R.sub.3′ together with the atom to which they are attached form a cycloalkyl ring. In some embodiments, the cycloalkyl ring is a C.sub.3-6 cycloalkyl ring. In some embodiments, the cycloalkyl ring is a cyclopropyl. In some embodiments, R.sub.3 is H and R.sub.3′ is alkyl. In some embodiments, R.sub.3 is H and R.sub.3′ is F. In some embodiments, R.sub.3 is H and R.sub.3′ is —OH. In some embodiments, R.sub.3 is H and R.sub.3′ is —OCH.sub.3. In some embodiments, R.sub.3 is F and R.sub.3′ is F. In some embodiments, R.sub.3 is alkyl and R.sub.3′ is alkyl. In some embodiments, the alkyl is methyl. In some embodiments, R.sub.3 is H and R.sub.3′ is absent.

[0132] In some embodiments of Formula (II), R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are each independently hydrogen, halogen, alkyl, —OH, —O-alkyl, —O-cycloalkyl, alkylene-OR.sub.8, —SH, —S-alkyl, —S-cycloalkyl, or alkylene-SR.sub.8. In some embodiments, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are each independently hydrogen, halogen, —OH, —O-alkyl, —O-cycloalkyl, alkylene-OR.sub.8, —SH, —S-alkyl, —S-cycloalkyl, or alkylene-SR.sub.8. In some embodiments, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are each independently hydrogen, halogen, —OH, —O—C.sub.1-C.sub.6 alkyl, —O—C.sub.3-C.sub.6 cycloalkyl, alkylene-OR.sub.8, —SH, —S—C.sub.1-C.sub.6 alkyl, —S—C.sub.3-C.sub.6 cycloalkyl, or alkylene-SR.sub.8. In some embodiments, R.sub.4, R.sub.8, R.sub.6 and R.sub.7 are each independently hydrogen, halogen, —OH, —O-alkyl, —O-cycloalkyl, or alkylene-OR.sub.8. In some embodiments, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are each independently hydrogen, halogen, —OH, —O—C.sub.1-C.sub.6 alkyl, —O—C.sub.3-C.sub.6 cycloalkyl, or alkylene-OR.sub.8. In some embodiments, R.sub.4, R.sub.8, R.sub.6 and R.sub.7 are each independently H, halogen, alkyl, —OH, —O-alkyl or —O-cycloalkyl. In some embodiments, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are each independently H, halogen, C.sub.1-C.sub.6 alkyl, —OH, —O—C.sub.1-C.sub.6 alkyl, or —O—C.sub.3-6 cycloalkyl. In some embodiments, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are each independently hydrogen, halogen, —OH, or —O-alkyl. In some embodiments, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are each independently alkylene-OR.sub.8, —SH, —S-alkyl, —S-cycloalkyl, or alkylene-SR.sub.8. In some embodiments, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are each independently H or —O-alkyl. In some embodiments, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are each independently H or —O—C.sub.1-C.sub.6 alkyl. In some embodiments, the halogen is F. In some embodiments, the alkyl is C.sub.1-C.sub.6 alkyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is methyl, ethyl, or isopropyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is methyl or ethyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is methyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is ethyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is isopropyl. In some embodiments, the alkyl is —O—C.sub.1-C.sub.6 alkyl. In some embodiments, the —O—C.sub.1-C.sub.6 alkyl is —O-methyl, —O-ethyl, or —O-isopropyl. In some embodiments, the —O—C.sub.1-C.sub.6 alkyl is —O— methyl or —O-ethyl. In some embodiments, the —O—C.sub.1-C.sub.6 alkyl is —O-methyl. In some embodiments, the —O—C.sub.1-C.sub.6 alkyl is ethyl. In some embodiments, the —O—C.sub.1-C.sub.6 alkyl is —O— isopropyl. In some embodiments, alkylene is a C.sub.1-6 alkylene. In some embodiments, alkylene is a C.sub.1-3 alkylene. In some embodiments, alkylene is a methylene or ethylene. In some embodiments, alkylene is methylene.

[0133] In some embodiments of Formula (II), R.sub.8 is H, alkyl, cycloalkyl, or alkylenecycloalkyl. In some embodiments, R.sub.8 is H, alkyl, or alkylenecycloalkyl. In some embodiments, R.sub.8 is H or alkyl. In some embodiments, the alkyl is a C.sub.1-6 alkyl. In some embodiments, the alkylenecycloalkyl is a C.sub.1-3alkylene-C.sub.3-6cycloalkyl.

[0134] In some embodiments of Formula (II), at least one of R.sub.4, R.sub.5, R.sub.6 and R.sub.7 is not H. In some embodiments, at least two of R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are not H. In some embodiments, two of R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are not H. In some embodiments, R.sub.5 and R.sub.6 are not H.

[0135] In some embodiments of Formula (II), R.sub.5 and R.sub.6 together with the atoms to which they are attached form a 5- to 8-membered heterocyclyl ring. In some embodiments of Formula (II), R.sub.5 and R.sub.6 together with the atoms to which they are attached form a 5- or 6-membered heterocyclyl ring. In some embodiments of Formula (II), R.sub.5 and R.sub.6 together with the atoms to which they are attached form a 5-membered heterocyclyl ring. In some embodiments of Formula (II), R.sub.5 and R.sub.6 together with the atoms to which they are attached form a 5-membered heterocyclyl ring. In some embodiments, the heterocyclyl ring has one or two oxygen atoms. In some embodiments, the heterocyclyl ring has two oxygen atoms. In some embodiments, the heterocyclic ring is

##STR00038##

In some embodiments, the heterocyclic ring is

##STR00039##

[0136] In some embodiments of Formula (II), R.sub.4 and R.sub.7 are each independently H, halogen (e.g., F, Cl, or Br), or alkyl (e.g., methyl or ethyl) and R.sub.5 and R.sub.6 are each independently —OH, —O-alkyl, —O-cycloalkyl, alkylene-OR.sub.8, —SH, —S-alkyl, —S-cycloalkyl, or alkylene-SR.sub.8. In some embodiments, R.sub.4 and R.sub.7 are each independently H, halogen (e.g., F, Cl, or Br), or alkyl (e.g., methyl or ethyl) and R.sub.5 and R.sub.6 are each independently —OH, —O-alkyl, —O-cycloalkyl, or alkylene-OR.sub.8. In some embodiments, R.sub.4 and R.sub.7 are each independently H, halogen (e.g., F, Cl, or Br), or alkyl (e.g., methyl or ethyl) and R.sub.5 and R.sub.6 are each independently —OH, —O—C.sub.1-C.sub.6 alkyl, —O—C.sub.3-C.sub.6 cycloalkyl, or alkylene-OR.sub.8. In some embodiments, R.sub.4 and R.sub.7 are each H.

[0137] In some embodiments of Formula (II), R.sub.4 and R.sub.7 are each independently H, halogen (e.g., F, Cl, or Br), or alkyl (e.g., methyl or ethyl) and R.sub.5 and R.sub.6 together with the atoms to which they are attached form heterocyclyl ring. In some embodiments of Formula (II), R.sub.4 and R.sub.7 are each independently H, halogen (e.g., F, Cl, or Br), or alkyl (e.g., methyl or ethyl) and R.sub.5 and R.sub.6 together with the atoms to which they are attached form a 5- or 6-membered heterocyclyl ring. In some embodiments, the heterocyclyl ring has one or two oxygen atoms. In some embodiments, the heterocyclyl ring has two oxygen atoms. In some embodiments, the heterocyclic ring is

##STR00040##

In some embodiments, the heterocyclic ring is

##STR00041##

In some embodiments, R.sub.4 and R.sub.7 are each H.

[0138] In some embodiments, A is a cleavable promoiety that is cleaved at a pH of from about 7 to about 11. In some embodiments, A is a cleavable promoiety that is cleaved at a pH of from about 8 to about 10. In some embodiments, A is a cleavable promoiety that is cleaved at a pH of from about 8 to about 9. In some embodiments, A is a cleaved at pH 8. In some embodiments, A is a cleaved at pH 9.

[0139] In some embodiments of Formula (II), A is a cleavable promoiety having the structure

##STR00042##

wherein R.sub.9 is H or acyl and R.sub.10 is as defined herein. In some embodiments of Formula (II), A is a cleavable promoiety having the structure

##STR00043##

wherein R.sub.9 is H or

##STR00044##

and R.sub.10 is as defined herein. In some embodiments, R.sub.10 is H, Ph or —(CH.sub.2).sub.m—R.sub.11, wherein R.sub.11 is —NH.sub.2,

##STR00045##

or —SCH.sub.3 and m is an integer from 1-5. In some embodiments, m is an integer from 2-4.

[0140] In some embodiments, the promoiety A is a group capable of internal release. A specific example of an internally released protecting group utilizes ornithine. The prodrug in such a case can be stabilized to prevent cyclization and release by dosing a salt of the amine or by utilizing a slow release of a secondary protecting group such as a carbamate. Accordingly, in some embodiments, a promoiety A capable of internal release is:

##STR00046##

or a pharmaceutically acceptable salt or carbamate thereof.

[0141] In some embodiments of Formula (II), promoiety A is:

##STR00047##

In some embodiments, promoiety A is

##STR00048##

In some embodiments, promoiety A is

##STR00049##

[0142] In some embodiments, the present disclosure provides a compound of Formula (IIa):

##STR00050## [0143] wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.7, and A are as defined above in Formula (II); and [0144] R.sub.11 and R.sub.12 are each independently H, alkyl, cycloalkyl, or R.sub.11 and R.sub.12 together with the atoms to which they are attached form a 5- to 8-membered heterocyclyl ring.

[0145] In some embodiments of Formula (IIa), R.sub.11 and R.sub.12 are each independently H, alkyl, alkylenecycloalkyl, or cycloalkyl. In some embodiments, R.sub.11 and R.sub.12 are each independently H, C.sub.1-5 alkyl, C.sub.1-3alkylene-C.sub.3-6cycloalkyl, or C.sub.3-6 cycloalkyl. In some embodiments, Rn and R.sub.12 are each independently H or C.sub.1-5 alkyl.

[0146] In some embodiments of Formula (IIa), R.sub.11 and R.sub.12 together with the atoms to which they are attached form a 5- to 8-membered heterocyclyl ring. In some embodiments, R.sub.11 and R.sub.12 together with the atoms to which they are attached form a 5- or 6-membered heterocyclyl ring. In some embodiments, R.sub.11 and R.sub.12 together with the atoms to which they are attached form a 5-membered heterocyclyl ring. In some embodiments, the heterocyclic ring is

##STR00051##

In some embodiments, the heterocyclic ring is

##STR00052##

[0147] In some embodiments, the compound of the present disclosure is a compound of Formula (IIb):

##STR00053##

wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.7, and A are as defined above in Formula (II); and n is 1 or 2.

[0148] In some embodiments of Formula (II), n is 1. In some embodiments, n is 2.

[0149] In some embodiments, the compound of the present disclosure is a compound of Formula (IIc):

##STR00054##

wherein R.sub.1, R.sub.2, R.sub.9 and R.sub.10 are as defined above in Formula (II). In some embodiments, R.sub.1 is H or alkyl (e.g., Me, Et or iPr); R.sub.2 is alkyl (e.g., Me, Et, or iPr); R.sub.9 is H or —C(O)CH.sub.3; and R.sub.10 is H, Ph or —(CH.sub.2).sub.m—R.sub.11, wherein R.sub.11 is —NH.sub.2,

##STR00055##

or —SCH.sub.3 and m is an integer from 2-4.

[0150] In some embodiments, the compound of the present disclosure is:

##STR00056##

[0151] In some embodiments, the compound of the present disclosure is

##STR00057##

[0152] In some embodiments, the present disclosure provides a compound of Formula (III):

##STR00058## [0153] or a pharmaceutically acceptable salt thereof; [0154] wherein: [0155] R.sub.1 is H or alkyl; [0156] R.sub.2 and R.sub.2′ are each independently H, halogen, alkyl, —OH, or —O-alkyl, or R.sub.2 and R.sub.2′ together with the atom to which they are attached form a cycloalkyl ring; [0157] R.sub.3 and R.sub.3′ are each independently hydrogen, alkyl, —OH, —O-alkyl, or —O-cycloalkyl, or [0158] R.sub.3 and R.sub.3′ together with the atom to which they are attached form an oxo; [0159] R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are each independently hydrogen, halogen, —OH, —O-alkyl, —O— cycloalkyl, alkylene-OR.sub.8, —SH, —S-alkyl, —S-cycloalkyl, or alkylene-SR.sub.8, or R.sub.5 and R.sub.6 together with the atoms to which they are attached form a 5- to 8-membered heterocyclyl ring; [0160] R.sub.8 is H, alkyl, cycloalkyl, or alkylenecycloalkyl; and [0161] B is

##STR00059##

wherein R.sub.B is H or alkyl.

[0162] In some embodiments of Formula (III), R.sub.1 is H, alkyl, or cycloalkyl. In some embodiments, R.sub.1 is H, C.sub.1-C.sub.6 alkyl, or C.sub.3-C.sub.6 cycloalkyl. In some embodiments, R.sub.1 is H or C.sub.1-C.sub.6 alkyl. In some embodiments, R.sub.1 is H. In some embodiments, R.sub.1 is C.sub.1-C.sub.6 alkyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is methyl, ethyl, or isopropyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is methyl or ethyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is methyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is ethyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is isopropyl. In some embodiments, R.sub.1 is methyl, ethyl, or isopropyl. In some embodiments, R.sub.1 is methyl or ethyl. In some embodiments R.sub.1 is methyl. In some embodiments, R.sub.1 is ethyl. In some embodiments, R.sub.1 is isopropyl. In some embodiments, R.sub.1 is cyclopropyl.

[0163] In some embodiments of Formula (III), R.sub.2 and R.sub.2′ are each independently H, halogen, alkyl, —OH, or —O-alkyl. In some embodiments, R.sub.2 and R.sub.2′ are each independently H, halogen, C.sub.1-C.sub.6 alkyl, —OH, or —O—C.sub.1-C.sub.6 alkyl. In some embodiments, R.sub.2 and R.sub.2′ are each independently H or alkyl. In some embodiments, R.sub.2 and R.sub.2′ are each independently H or C.sub.1-C.sub.6 alkyl. In some embodiments, the halogen is F. In some embodiments, the alkyl is C.sub.1-C.sub.6 alkyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is methyl, ethyl, or isopropyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is methyl or ethyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is methyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is ethyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is isopropyl.

[0164] In some embodiments, R.sub.2 and R.sub.2′ together with the atom to which they are attached form an oxo or a cycloalkyl ring. In some embodiments, R.sub.2 and R.sub.2′ together with the atom to which they are attached form an oxo. In some embodiments, R.sub.2 and R.sub.2′ together with the atom to which they are attached form a cycloalkyl ring. In some embodiments, the cycloalkyl ring is a C.sub.3-6 cycloalkyl ring. In some embodiments, the cycloalkyl ring is a cyclopropyl. In some embodiments, R.sub.2 is alkyl and R.sub.2′ is H. In some embodiments, R.sub.2 is alkyl and R.sub.2′ is absent. In some embodiments, R.sub.2 is H and R.sub.2′ is alkyl. In some embodiments, R.sub.2 is H and R.sub.2′ is F. In some embodiments, R.sub.2 is H and R.sub.2′ is —OH. In some embodiments, R.sub.2 is H and R.sub.2′ is —OCH.sub.3. In some embodiments, R.sub.2 is F and R.sub.2′ is F. In some embodiments, R.sub.2 is alkyl and R.sub.2′ is alkyl. In some embodiments, the alkyl is methyl.

[0165] In some embodiments of Formula (III), R.sub.3 and R.sub.3′ are each independently H, halogen, alkyl, —OH, —O-alkyl or —O-cycloalkyl. In some embodiments, R.sub.3 and R.sub.3′ are each independently H, halogen, C.sub.1-C.sub.6 alkyl, —OH, —O—C.sub.1-C.sub.6 alkyl, or —O—C.sub.3-6 cycloalkyl. In some embodiments, R.sub.3 and R.sub.3′ are each independently H or alkyl. In some embodiments, R.sub.3 and R.sub.3′ are each H. In some embodiments, R.sub.3 and R.sub.3′ are each independently H or C.sub.1-C.sub.6 alkyl. In some embodiments, the halogen is F. In some embodiments, the alkyl is C.sub.1-C.sub.6 alkyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is selected from the group consisting of methyl, ethyl, or isopropyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is methyl or ethyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is methyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is ethyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is isopropyl.

[0166] In some embodiments, R.sub.3 and R.sub.3′ together with the atom to which they are attached form an oxo or a cycloalkyl ring. In some embodiments, R.sub.3 and R.sub.3′ together with the atom to which they are attached form an oxo. In some embodiments, R.sub.3 and R.sub.3′ together with the atom to which they are attached form a cycloalkyl ring. In some embodiments, the cycloalkyl ring is a C.sub.3-6 cycloalkyl ring. In some embodiments, the cycloalkyl ring is a cyclopropyl. In some embodiments, R.sub.3 is H and R.sub.3′ is alkyl. In some embodiments, R.sub.3 is H and R.sub.3′ is F. In some embodiments, R.sub.3 is H and R.sub.3′ is —OH. In some embodiments, R.sub.3 is H and R.sub.3′ is —OCH.sub.3. In some embodiments, R.sub.3 is F and R.sub.3′ is F. In some embodiments, R.sub.3 is alkyl and R.sub.3′ is alkyl. In some embodiments, the alkyl is methyl. In some embodiments, R.sub.3 is H and R.sub.3′ is absent.

[0167] In some embodiments of Formula (III), R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are each independently hydrogen, halogen, alkyl, —OH, —O-alkyl, —O-cycloalkyl, alkylene-OR.sub.8, —SH, —S-alkyl, —S-cycloalkyl, or alkylene-SR.sub.8. In some embodiments, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are each independently hydrogen, halogen, —OH, —O-alkyl, —O-cycloalkyl, alkylene-OR.sub.8, —SH, —S-alkyl, —S-cycloalkyl, or alkylene-SR.sub.8. In some embodiments, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are each independently hydrogen, halogen, —OH, —O—C.sub.1-C.sub.6 alkyl, —O—C.sub.3-C.sub.6 cycloalkyl, alkylene-OR.sub.8, —SH, —S—C.sub.1-C.sub.6 alkyl, —S—C.sub.3-C.sub.6 cycloalkyl, or alkylene-SR.sub.8. In some embodiments, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are each independently hydrogen, halogen, —OH, —O-alkyl, —O-cycloalkyl, or alkylene-OR.sub.8. In some embodiments, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are each independently hydrogen, halogen, —OH, —O—C.sub.1-C.sub.6 alkyl, —O—C.sub.3-C.sub.6 cycloalkyl, or alkylene-OR.sub.8. In some embodiments, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are each independently H, halogen, alkyl, —OH, —O-alkyl or —O-cycloalkyl. In some embodiments, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are each independently H, halogen, C.sub.1-C.sub.6 alkyl, —OH, —O—C.sub.1-C.sub.6 alkyl, or —O—C.sub.3-6 cycloalkyl. In some embodiments, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are each independently hydrogen, halogen, —OH, or —O-alkyl. In some embodiments, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are each independently alkylene-OR.sub.8, —SH, —S-alkyl, —S-cycloalkyl, or alkylene-SR.sub.8. In some embodiments, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are each independently H or —O-alkyl. In some embodiments, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are each independently H or —O—C.sub.1-C.sub.6 alkyl. In some embodiments, the halogen is F. In some embodiments, the alkyl is C.sub.1-C.sub.6 alkyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is selected from the group consisting of methyl, ethyl, or isopropyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is methyl or ethyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is methyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is ethyl. In some embodiments, the C.sub.1-C.sub.6 alkyl is isopropyl. In some embodiments, the alkyl is —O—C.sub.1-C.sub.6 alkyl. In some embodiments, the —O—C.sub.1-C.sub.6 alkyl is —O-methyl, —O-ethyl, or —O-isopropyl. In some embodiments, the —O—C.sub.1-C.sub.6 alkyl is —O-methyl or —O-ethyl. In some embodiments, the —O—C.sub.1-C.sub.6 alkyl is —O-methyl. In some embodiments, the —O—C.sub.1-C.sub.6 alkyl is ethyl. In some embodiments, the —O—C.sub.1-C.sub.6 alkyl is —O-isopropyl. In some embodiments, alkylene is a C.sub.1-6 alkylene. In some embodiments, alkylene is a C.sub.1-3 alkylene. In some embodiments, alkylene is a methylene or ethylene. In some embodiments, alkylene is methylene.

[0168] In some embodiments of Formula (III), R.sub.8 is H, alkyl, cycloalkyl, or alkylenecycloalkyl. In some embodiments, R.sub.8 is H, alkyl, or alkylenecycloalkyl. In some embodiments, R.sub.8 is H or alkyl. In some embodiments, the alkyl is a C.sub.1-6 alkyl. In some embodiments, the alkylenecycloalkyl is a C.sub.1-3alkylene-C.sub.3-6cycloalkyl.

[0169] In some embodiments of Formula (III), at least one of R.sub.4, R.sub.5, R.sub.6 and R.sub.7 is not H. In some embodiments, at least two of R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are not H. In some embodiments, two of R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are not H. In some embodiments, R.sub.5 and R.sub.6 are not H.

[0170] In some embodiments of Formula (III), R.sub.5 and R.sub.6 together with the atoms to which they are attached form a 5- to 8-membered heterocyclyl ring. In some embodiments of Formula (III), R.sub.5 and R.sub.6 together with the atoms to which they are attached form a 5- or 6-membered heterocyclyl ring. In some embodiments of Formula (III), R.sub.5 and R.sub.6 together with the atoms to which they are attached form a 5-membered heterocyclyl ring. In some embodiments of Formula (III), R.sub.5 and R.sub.6 together with the atoms to which they are attached form a 5-membered heterocyclyl ring. In some embodiments, the heterocyclyl ring has one or two oxygen atoms. In some embodiments, the heterocyclyl ring has two oxygen atoms. In some embodiments, the heterocyclic ring is

##STR00060##

In some embodiments, the heterocyclic ring is

##STR00061##

[0171] In some embodiments of Formula (III), R.sub.4 and R.sub.7 are each independently H, halogen (e.g., F, Cl, or Br), or alkyl (e.g., methyl or ethyl) and R.sub.5 and R.sub.6 are each independently —OH, —O-alkyl, —O-cycloalkyl, alkylene-OR.sub.8, —SH, —S-alkyl, —S-cycloalkyl, or alkylene-SR.sub.8. In some embodiments, R.sub.4 and R.sub.7 are each independently H, halogen (e.g., F, Cl, or Br), or alkyl (e.g., methyl or ethyl) and R.sub.5 and R.sub.6 are each independently —OH, —O-alkyl, —O-cycloalkyl, or alkylene-OR.sub.8. In some embodiments, R.sub.4 and R.sub.7 are each independently H, halogen (e.g., F, Cl, or Br), or alkyl (e.g., methyl or ethyl) and R.sub.5 and R.sub.6 are each independently —OH, —O—C.sub.1-C.sub.6 alkyl, —O—C.sub.3-C.sub.6 cycloalkyl, or alkylene-OR.sub.8. In some embodiments, R.sub.4 and R.sub.7 are each H.

[0172] In some embodiments of Formula (III), R.sub.4 and R.sub.7 are each independently H, halogen (e.g., F, Cl, or Br), or alkyl (e.g., methyl or ethyl) and R.sub.5 and R.sub.6 together with the atoms to which they are attached form heterocyclyl ring. In some embodiments of Formula (III), R.sub.4 and R.sub.7 are each independently H, halogen (e.g., F, Cl, or Br), or alkyl (e.g., methyl or ethyl) and R.sub.5 and R.sub.6 together with the atoms to which they are attached form a 5- or 6-membered heterocyclyl ring. In some embodiments, the heterocyclyl ring has one or two oxygen atoms. In some embodiments, the heterocyclyl ring has two oxygen atoms. In some embodiments, the heterocyclic ring is

##STR00062##

In some embodiments, the heterocyclic ring is

##STR00063##

In some embodiments, R.sub.4 and R.sub.7 are each H.

[0173] In some embodiments, B is a cleavable promoiety that is cleaved at a pH of from about 7 to about 11. In some embodiments, B is a cleavable promoiety that is cleaved at a pH of from about 8 to about 10. In some embodiments, B is a cleavable promoiety that is cleaved at a pH of from about 8 to about 9. In some embodiments, B is a cleaved at pH 8. In some embodiments, A is a cleaved at pH 9.

[0174] In some embodiments of Formula (III), B is a cleavable promoiety having the structure

##STR00064##

In some embodiments of Formula (III), B is a cleavable promoiety having the structure

##STR00065##

In some embodiments of Formula (III), B is a cleavable promoiety having the structure.

##STR00066##

[0175] In some embodiments of Formula (III), B is a cleavable promoiety having the structure

##STR00067##

In some embodiments, B is a cleavable promoiety having the structure

##STR00068##

In some embodiments, B is a cleavable promoiety having the structure

##STR00069##

[0176] In some embodiments, the present disclosure provides a compound of Formula (IIIa):

##STR00070## [0177] wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.7, and B are as defined above in Formula (III); and [0178] R.sub.11 and R.sub.12 are each independently H, alkyl, cycloalkyl, or R.sub.1 and R.sub.12 together with the atoms to which they are attached form a 5- to 8-membered heterocyclyl ring.

[0179] In some embodiments, the present disclosure provides a compound of Formula (IIIa1):

##STR00071## [0180] wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.7, and B are as defined above in Formula (III); and [0181] R.sub.11 and R.sub.12 are each independently H, alkyl, cycloalkyl, or R.sub.11 and R.sub.12 together with the atoms to which they are attached form a 5- to 8-membered heterocyclyl ring.

[0182] In some embodiments, the present disclosure provides a compound of Formula (IIIa2):

##STR00072## [0183] wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.7, and B are as defined above in Formula (III); and [0184] R.sub.11 and R.sub.12 are each independently H, alkyl, cycloalkyl, or R.sub.11 and R.sub.12 together with the atoms to which they are attached form a 5- to 8-membered heterocyclyl ring.

[0185] In some embodiments of Formula (IIIa), R.sub.11 and R.sub.12 are each independently H, alkyl, alkylenecycloalkyl, or cycloalkyl. In some embodiments, R.sub.11 and R.sub.12 are each independently H, C.sub.1-5 alkyl, C.sub.1-3alkylene-C.sub.3-6cycloalkyl, or C.sub.3-6 cycloalkyl. In some embodiments, Rn and R.sub.12 are each independently H or C.sub.1-5 alkyl.

[0186] In some embodiments of Formula (IIIa), R.sub.11 and R.sub.12 together with the atoms to which they are attached form a 5- to 8-membered heterocyclyl ring. In some embodiments, Rn and R.sub.12 together with the atoms to which they are attached form a 5- or 6-membered heterocyclyl ring. In some embodiments, R.sub.11 and R.sub.12 together with the atoms to which they are attached form a 5-membered heterocyclyl ring. In some embodiments, the heterocyclic ring is

##STR00073##

In some embodiments, the heterocyclic ring is

##STR00074##

[0187] In some embodiments, the compound of the present disclosure is a compound of Formula (IIIb):

##STR00075##

wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.7, and B are as defined above in Formula (III); and n is 1 or 2.

[0188] In some embodiments, the compound of the present disclosure is a compound of Formula (IIIb1):

##STR00076##

wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.7, an B are as defined above in Formula (III); and n is 1 or 2.

[0189] In some embodiments, the compound of the present disclosure is a compound of Formula (IIIb2):

##STR00077##

wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.7, and B are as defined above in Formula (III); and n is 1 or 2.

[0190] In some embodiments of Formula (III), n is 1. In some embodiments, n is 2.

[0191] In some embodiments, the compound of the present disclosure is a compound of Formula (IIIc):

##STR00078##

wherein R.sub.1 and R.sub.2 are as defined above in Formula (III). In some embodiments, R.sub.1 is H or alkyl (e.g., Me or iPr); and R.sub.2 is alkyl (e.g., Me or iPr). In some embodiments, R.sub.1 is H or Me; and R.sub.2 is Me or iPr.

[0192] In some embodiments, the compound of the present disclosure is:

##STR00079##

[0193] In some embodiments, the compound of the present disclosure is a compound of Formula (IIId):

##STR00080##

wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.7 are as defined above in Formula (III); and R.sub.B is H or alkyl. In some embodiments, R.sub.1 is H or alkyl (e.g., Me or iPr); and R.sub.2 is alkyl (e.g., Me or iPr). In some embodiments, R.sub.1 is H or Me; and R.sub.2 is Me or iPr.

[0194] In some embodiments, the compound of the present disclosure is a compound of Formula (IIId1):

##STR00081##

[0195] In some embodiments, the compound of the present disclosure is a compound of Formula (IIId1a):

##STR00082##

wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.7 are as defined above in Formula (III). In some embodiments, R.sub.1 is H or alkyl (e.g., Me or iPr); and R.sub.2 is alkyl (e.g., Me or iPr). In some embodiments, R.sub.1 is H or Me; and R.sub.2 is Me or iPr.

[0196] In some embodiments, the compound of the present disclosure is a compound of Formula (IIId1b):

##STR00083##

wherein R.sub.1, R.sub.2, R.sub.4, and R.sub.7 are as defined above in Formula (III). In some embodiments, R.sub.1 is H or alkyl (e.g., Me or iPr); and R.sub.2 is alkyl (e.g., Me or iPr). In some embodiments, R.sub.1 is H or Me; and R.sub.2 is Me or iPr.

[0197] In some embodiments, the compound of the present disclosure is a compound of Formula (IIId2):

##STR00084##

[0198] In some embodiments, the compound of the present disclosure is a compound of Formula (IIId2a):

##STR00085##

[0199] In some embodiments, the compound of the present disclosure is a compound of Formula (IIId2b):

##STR00086##

[0200] In some embodiments, the compound of Formula (III) is:

##STR00087##

wherein R.sub.2 is as defined above in Formula (III); and R.sub.B is H or alkyl.

[0201] In some embodiments, the compound of Formula (III) is:

##STR00088##

wherein R.sub.B is H or alkyl.

[0202] In some embodiments, the compound of Formula (III) is:

##STR00089##

[0203] In some embodiments, the compound of Formula (III) is:

##STR00090##

[0204] In some embodiments, R.sub.B is H or C.sub.1-5alkyl. In some embodiments, R.sub.B is H or Me. In some embodiments, R.sub.B is H. In some embodiments, R.sub.B is methyl.

[0205] It is contemplated that each of the therapeutic agents may be administered per se as well as in various forms including pharmaceutically acceptable esters, prodrugs, salts, solvates, enantiomers, stereoisomers, active metabolites, co-crystals, and other physiologically functional derivatives thereof. In some embodiments, the prodrugs disclosed herein comprise a mixture of enantiomers, including a racemic mixture thereof. In some embodiments, the prodrugs disclosed herein are enantiomerically pure. In some embodiments, the enantiomeric excess is from 0% (racemic) to 100% (enantiomerically pure), e.g., 0%, 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100%, including all ranges and values therebetween. In some embodiments, the enantiomeric excess is greater than 90%. In some embodiments, the enantiomeric excess is greater than 95%. In some embodiments, the enantiomeric excess is greater than 90%. In some embodiments, the enantiomeric excess is greater than 99%.

Pharmaceutical Compositions of the Present Disclosure

[0206] In various embodiments, the present disclosure provides a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (II), Formula (IIa), Formula (IIb), Formula (IIc), Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), or Formula (IIId)) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0207] In some embodiments, the pharmaceutically acceptable salt is a salt of 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid (L), aspartic acid (L), benzenesulfonic acid, benzoic acid, camphoric acid (+), camphor-10-sulfonic acid (+), capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid (D), gluconic acid (D), glucuronic acid (D), glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid (DL), lactobionic acid, lauric acid, maleic acid, malic acid, (−L) malonic acid, mandelic acid (DL), methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, pyroglutamic acid (−L), salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid (+L), thiocyanic acid, toluenesulfonic acid (p), and undecylenic acid.

[0208] The pharmaceutically acceptable excipients and adjuvants are added to the composition or formulation for a variety of purposes. In some embodiments, a pharmaceutical composition comprising one or more compounds disclosed herein, or a pharmaceutically acceptable salt thereof, further comprises a pharmaceutically acceptable carrier. In some embodiments, a pharmaceutically acceptable carrier includes a pharmaceutically acceptable excipient, binder, and/or diluent. In some embodiments, suitable pharmaceutically acceptable carriers include, but are not limited to, inert solid fillers or diluents and sterile aqueous or organic solutions. In some embodiments, suitable pharmaceutically acceptable excipients include, but are not limited to, water, salt solutions, alcohol, polyethylene glycols, gelatin, lactose, amylase, magnesium stearate, talc, silicic acid, viscous paraffin, and the like. General considerations in the formulation and/or manufacture of pharmaceutical compositions agents can be found, for example, in Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The Science and Practice of Pharmacy, 21.sup.th Edition (Lippincott Williams & Wilkins, 2005).

[0209] For the purposes of this disclosure, the compounds disclosed herein can be formulated for administration by a variety of means including orally, parenterally, by inhalation spray, topically, or rectally in formulations containing pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used here includes subcutaneous, intravenous, intramuscular, and intraarterial injections with a variety of infusion techniques. Intraarterial and intravenous injection as used herein includes administration through catheters.

Pharmacokinetics

[0210] The administration of pharmaceutical compositions comprising prodrugs of MDMA, MDA, and/or derivatives thereof disclosed herein can result in a measurable modification of the pharmacokinetic profile (e.g., circulating drug concentration) of free MDMA, MDA and/or derivative thereof relative to the administration of each as a free amine drug.

Formula (I)

[0211] Accordingly, in some embodiments of Formula (I), a pharmaceutical composition of the present disclosure provides an in vivo plasma level characterized by a Cmax of free amine of about 100 ng/mL to about 500 ng/mL, e.g., 100 ng/mL to about 500 ng/mL, about 100 ng/mL to about 450 ng/mL, 100 ng/mL to about 400 ng/mL, 100 ng/mL to about 350 ng/mL, 100 ng/mL to about 300 ng/mL or 100 ng/mL to about 250 ng/mL, after oral administration of from about 80 mg to about 125 mg of a compound of Formula (I) and release of promoiety X.

[0212] In some embodiments of Formula (I), the pharmaceutical composition of the present disclosure provides an in vivo plasma level characterized by an AUC.sub.(0-24) of free amine of about 1000 h*ng/mL to about 6000 h*ng/mL, e.g., 1000 h*ng/mL to about 6000 h*ng/mL, 1000 h*ng/mL to about 5500 h*ng/mL, 1000 h*ng/mL to about 5000 h*ng/mL, 1000 h*ng/mL to about 4500 h*ng/mL, 1000 h*ng/mL to about 4000 h*ng/mL, 1000 h*ng/mL to about 3500 h*ng/mL, or 1000 h*ng/mL to about 3000 h*ng/mL, after oral administration of from about 80 mg to about 125 mg of a compound of Formula (I) and release of promoiety X.

[0213] In some embodiments of Formula (I), the pharmaceutical composition of the present disclosure provides an in vivo T.sub.1/2 of free amine of about 5 h to about 15 h, e.g., about 5 h to about 13 h, about 5 h to about 12 h, about 5 h to about 11 h, about 5 h to about 10 h, about 6 h to about 13 h, about 6 h to about 12 h, about 6 h to about 11 h, or about 6 h to about 10 h, after oral administration of from about 80 mg to about 125 mg of a compound of Formula (I) and release of promoiety X.

[0214] In some embodiments of Formula (I), a pharmaceutical composition of the present disclosure provides an in vivo plasma level characterized by a Cmax of free amine that is about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95% of the Cmax achieved upon administration of a 125 mg dose of MDA to a human subject.

[0215] In some embodiments of Formula (I), when R.sub.1 is H, the composition provides a Cmax of free amine within a range of about 50-90% of about 12 ng/mL to about 15 ng/mL, e.g., about 5.5 ng/mL, about 6 ng/mL, about 6.5 ng/mL, about 7 ng/mL, about 7.5 ng/mL, about 8 ng/mL, about 8.5 ng/mL, about 9 ng/mL, about 9.5 ng/mL, about 10 ng/mL, about 10.5 ng/mL, about 11 ng/mL, about 11.5 ng/mL, about 12 ng/mL, about 12.5 ng/mL, about 13 ng/mL, or about 13.5 ng/mL, achieved following oral administration of about a 125 mg dose of MDA to a human subject.

[0216] In some embodiments of Formula (I), a pharmaceutical composition of the present disclosure provides an in vivo plasma level characterized by a Cmax of free amine that is about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95% of the Cmax achieved upon administration of a 75 mg dose of MDA to a human subject.

[0217] In some embodiments of Formula (I), when R.sub.1 is H, the composition provides a Cmax of free amine within a range of about 50-90% of about 7 ng/mL to about 8.5 ng/mL, e.g., about 3.2 ng/mL, about 3.5 ng/mL, about 3.8 ng/mL, about 4.1 ng/mL, about 4.4 ng/mL, about 4.7 ng/mL, about 5.0 ng/mL, about 5.3 ng/mL, about 5.6 ng/mL, about 5.9 ng/mL, about 6.2 ng/mL, about 6.5 ng/mL, about 6.8 ng/mL, about 7.1 ng/mL, about 7.4 ng/mL, or about 7.7 ng/mL, achieved following oral administration of about a 75 mg dose of MDA to a human subject.

[0218] In some embodiments of Formula (I), when R.sub.1 is methyl, the composition provides a Cmax of free amine within a range of about 50-90% of about 220 ng/mL to about 250 ng/mL, e.g., about 100 ng/mL, about 110 ng/mL, about 120 ng/mL, about 130 ng/mL, about 140 ng/mL, about 150 ng/mL, about 160 ng/mL, about 170 ng/mL, about 180 ng/mL, about 190 ng/mL, about 200 ng/mL, about 210 ng/mL, about 220 ng/mL, or about 230 ng/mL, achieved following oral administration of a 125 mg dose of MDMA to a human subject.

[0219] In some embodiments of Formula (I), when R.sub.1 is methyl, the composition provides a Cmax of free amine within a range of about 50-90% of about 120 ng/mL to about 140 ng/mL, e.g., about 50 ng/mL, about 60 ng/mL, about 70 ng/mL, about 80 ng/mL, about 90 ng/mL, about 100 ng/mL, about 110 ng/mL, about 120 ng/mL, or about 130 ng/mL, achieved following oral administration of a 75 mg dose of MDMA to a human subject.

[0220] In some embodiments of Formula (I), when R.sub.1 is methyl, the composition provides a T.sub.1/2 of free amine within a range of about 105-150% of about 8 h to about 9 h, e.g., about 8.4 h, about 8.8 h, about 9.2 h, about 9.6 h, about 10 h, about 10.4 h, about 10.8 h, about 11.2 h, about 11.6 h, about 12 h, about 12.4 h, about 12.8 h, about 13.2 h, or about 13.6 h, achieved following oral administration of a 125 mg dose of MDMA to a human subject.

[0221] In some embodiments of Formula (I), when R.sub.1 is methyl, the composition provides a T.sub.1/2 of free amine within a range of about 105-150% of about 7 h to about 9 h, e.g., about 7.4 h, about 7.6 h, about 8 h, about 8.4 h, about 8.8 h, about 9.2 h, about 9.6 h, about 10 h, about 10.4 h, about 10.8 h, about 11.2 h, about 11.6 h, about 12 h, about 12.4 h, about 12.8 h, about 13.2 h, or about 13.6 h, achieved following oral administration of a 75 mg dose of MDMA to a human subject.

Formula (II)

[0222] In some embodiments of Formula (II), a pharmaceutical composition of the present disclosure provides an in vivo plasma level characterized by a Cmax of free amine of about 100 ng/mL to about 500 ng/mL, e.g., 100 ng/mL to about 500 ng/mL, about 100 ng/mL to about 450 ng/mL, 100 ng/mL to about 400 ng/mL, 100 ng/mL to about 350 ng/mL, 100 ng/mL to about 300 ng/mL or 100 ng/mL to about 250 ng/mL, after oral administration of from about 80 mg to about 125 mg of a compound of Formula (II) and release of promoiety A.

[0223] In some embodiments of Formula (II), the pharmaceutical composition of the present disclosure provides an in vivo plasma level characterized by an AUC.sub.(0-24) of free amine of about 1000 h*ng/mL to about 6000 h*ng/mL, e.g., 1000 h*ng/mL to about 6000 h*ng/mL, 1000 h*ng/mL to about 5500 h*ng/mL, 1000 h*ng/mL to about 5000 h*ng/mL, 1000 h*ng/mL to about 4500 h*ng/mL, 1000 h*ng/mL to about 4000 h*ng/mL, 1000 h*ng/mL to about 3500 h*ng/mL, or 1000 h*ng/mL to about 3000 h*ng/mL, after oral administration of from about 80 mg to about 125 mg of a compound of Formula (II) and release of promoiety A.

[0224] In some embodiments of Formula (II), the pharmaceutical composition of the present disclosure provides an in vivo T.sub.1/2 of free amine of about 5 h to about 15 h, e.g., about 5 h to about 13 h, about 5 h to about 12 h, about 5 h to about 11 h, about 5 h to about 10 h, about 6 h to about 13 h, about 6 h to about 12 h, about 6 h to about 11 h, or about 6 h to about 10 h, after oral administration of from about 80 mg to about 125 mg of a compound of Formula (II) and release of promoiety A.

[0225] In some embodiments of Formula (II), a pharmaceutical composition of the present disclosure provides an in vivo plasma level characterized by a Cmax of free amine that is about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95% of the Cmax achieved upon administration of a 75-125 mg dose of MDA to a human subject.

[0226] In some embodiments of Formula (II), when R.sub.1 is H, the composition provides a Cmax of free amine within a range of about 50-90% of about 12 ng/mL to about 15 ng/mL, e.g., about 5.5 ng/mL, about 6 ng/mL, about 6.5 ng/mL, about 7 ng/mL, about 7.5 ng/mL, about 8 ng/mL, about 8.5 ng/mL, about 9 ng/mL, about 9.5 ng/mL, about 10 ng/mL, about 10.5 ng/mL, about 11 ng/mL, about 11.5 ng/mL, about 12 ng/mL, about 12.5 ng/mL, about 13 ng/mL, or about 13.5 ng/mL, achieved following oral administration of about a 125 mg dose of MDA to a human subject.

[0227] In some embodiments of Formula (II), when R.sub.1 is H, the composition provides a Cmax of free amine within a range of about 50-90% of about 7 ng/mL to about 8.5 ng/mL, e.g., about 3.2 ng/mL, about 3.5 ng/mL, about 3.8 ng/mL, about 4.1 ng/mL, about 4.4 ng/mL, about 4.7 ng/mL, about 5.0 ng/mL, about 5.3 ng/mL, about 5.6 ng/mL, about 5.9 ng/mL, about 6.2 ng/mL, about 6.5 ng/mL, about 6.8 ng/mL, about 7.1 ng/mL, about 7.4 ng/mL, or about 7.7 ng/mL, achieved following oral administration of about a 75 mg dose of MDA to a human subject.

[0228] In some embodiments of Formula (II), a pharmaceutical composition of the present disclosure provides an in vivo plasma level characterized by a Cmax of free amine that is about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95% of the Cmax achieved upon administration of a 75-125 mg dose of MDMA to a human subject.

[0229] In some embodiments of Formula (II), when R.sub.1 is methyl, the composition provides a Cmax of free amine within a range of about 50-90% of about 220 ng/mL to about 250 ng/mL, e.g., about 100 ng/mL, about 110 ng/mL, about 120 ng/mL, about 130 ng/mL, about 140 ng/mL, about 150 ng/mL, about 160 ng/mL, about 170 ng/mL, about 180 ng/mL, about 190 ng/mL, about 200 ng/mL, about 210 ng/mL, about 220 ng/mL, or about 230 ng/mL, achieved following oral administration of a 125 mg dose of MDMA to a human subject.

[0230] In some embodiments of Formula (II), when R.sub.1 is methyl, the composition provides a Cmax of free amine within a range of about 50-90% of about 120 ng/mL to about 140 ng/mL, e.g., about 50 ng/mL, about 60 ng/mL, about 70 ng/mL, about 80 ng/mL, about 90 ng/mL, about 100 ng/mL, about 110 ng/mL, about 120 ng/mL, or about 130 ng/mL, achieved following oral administration of a 75 mg dose of MDMA to a human subject.

[0231] In some embodiments of Formula (II), when R.sub.1 is methyl, the composition provides a T.sub.1/2 of free amine within a range of about 105-150% of about 8 h to about 9 h, e.g., about 8.4 h, about 8.8 h, about 9.2 h, about 9.6 h, about 10 h, about 10.4 h, about 10.8 h, about 11.2 h, about 11.6 h, about 12 h, about 12.4 h, about 12.8 h, about 13.2 h, or about 13.6 h, achieved following oral administration of a 125 mg dose of MDMA to a human subject.

[0232] In some embodiments of Formula (II), when R.sub.1 is methyl, the composition provides a T.sub.1/2 of free amine within a range of about 105-150% of about 7 h to about 9 h, e.g., about 7.4 h, about 7.6 h, about 8 h, about 8.4 h, about 8.8 h, about 9.2 h, about 9.6 h, about 10 h, about 10.4 h, about 10.8 h, about 11.2 h, about 11.6 h, about 12 h, about 12.4 h, about 12.8 h, about 13.2 h, or about 13.6 h, achieved following oral administration of a 75 mg dose of MDMA to a human subject.

Formula (III)

[0233] In some embodiments of Formula (III), a pharmaceutical composition of the present disclosure provides an in vivo plasma level characterized by a Cmax of free amine of about 100 ng/mL to about 500 ng/mL, e.g., 100 ng/mL to about 500 ng/mL, about 100 ng/mL to about 450 ng/mL, 100 ng/mL to about 400 ng/mL, 100 ng/mL to about 350 ng/mL, 100 ng/mL to about 300 ng/mL or 100 ng/mL to about 250 ng/mL, after oral administration of from about 80 mg to about 125 mg of a compound of Formula (III) and release of promoiety B.

[0234] In some embodiments of Formula (III), the pharmaceutical composition of the present disclosure provides an in vivo plasma level characterized by an AUC.sub.(0-24) of free amine of about 1000 h*ng/mL to about 6000 h*ng/mL, e.g., 1000 h*ng/mL to about 6000 h*ng/mL, 1000 h*ng/mL to about 5500 h*ng/mL, 1000 h*ng/mL to about 5000 h*ng/mL, 1000 h*ng/mL to about 4500 h*ng/mL, 1000 h*ng/mL to about 4000 h*ng/mL, 1000 h*ng/mL to about 3500 h*ng/mL, or 1000 h*ng/mL to about 3000 h*ng/mL, after oral administration of from about 80 mg to about 125 mg of a compound of Formula (III) and release of promoiety B.

[0235] In some embodiments of Formula (III), the pharmaceutical composition of the present disclosure provides an in vivo T.sub.1/2 of free amine of about 5 h to about 15 h, e.g., about 5 h to about 13 h, about 5 h to about 12 h, about 5 h to about 11 h, about 5 h to about 10 h, about 6 h to about 13 h, about 6 h to about 12 h, about 6 h to about 11 h, or about 6 h to about 10 h, after oral administration of from about 80 mg to about 125 mg of a compound of Formula (III) and release of promoiety B.

[0236] In some embodiments of Formula (III), a pharmaceutical composition of the present disclosure provides an in vivo plasma level characterized by a Cmax of free amine that is about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95% of the Cmax achieved upon administration of a 75-125 mg dose of MDA to a human subject.

[0237] In some embodiments of Formula (III), when R.sub.1 is H, the composition provides a Cmax of free amine within a range of about 50-90% of about 12 ng/mL to about 15 ng/mL, e.g., about 5.5 ng/mL, about 6 ng/mL, about 6.5 ng/mL, about 7 ng/mL, about 7.5 ng/mL, about 8 ng/mL, about 8.5 ng/mL, about 9 ng/mL, about 9.5 ng/mL, about 10 ng/mL, about 10.5 ng/mL, about 11 ng/mL, about 11.5 ng/mL, about 12 ng/mL, about 12.5 ng/mL, about 13 ng/mL, or about 13.5 ng/mL, achieved following oral administration of about a 125 mg dose of MDA to a human subject.

[0238] In some embodiments of Formula (III), when R.sub.1 is H, the composition provides a Cmax of free amine within a range of about 50-90% of about 7 ng/mL to about 8.5 ng/mL, e.g., about 3.2 ng/mL, about 3.5 ng/mL, about 3.8 ng/mL, about 4.1 ng/mL, about 4.4 ng/mL, about 4.7 ng/mL, about 5.0 ng/mL, about 5.3 ng/mL, about 5.6 ng/mL, about 5.9 ng/mL, about 6.2 ng/mL, about 6.5 ng/mL, about 6.8 ng/mL, about 7.1 ng/mL, about 7.4 ng/mL, or about 7.7 ng/mL, achieved following oral administration of about a 75 mg dose of MDA to a human subject.

[0239] In some embodiments of Formula (III), a pharmaceutical composition of the present disclosure provides an in vivo plasma level characterized by a Cmax of free amine that is about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95% of the Cmax achieved upon administration of a 75-125 mg dose of MDMA to a human subject.

[0240] In some embodiments of Formula (III), when R.sub.1 is methyl, the composition provides a Cmax of free amine within a range of about 50-90% of about 220 ng/mL to about 250 ng/mL, e.g., about 100 ng/mL, about 110 ng/mL, about 120 ng/mL, about 130 ng/mL, about 140 ng/mL, about 150 ng/mL, about 160 ng/mL, about 170 ng/mL, about 180 ng/mL, about 190 ng/mL, about 200 ng/mL, about 210 ng/mL, about 220 ng/mL, or about 230 ng/mL, achieved following oral administration of a 125 mg dose of MDMA to a human subject.

[0241] In some embodiments of Formula (III), when R.sub.1 is methyl, the composition provides a Cmax of free amine within a range of about 50-90% of about 120 ng/mL to about 140 ng/mL, e.g., about 50 ng/mL, about 60 ng/mL, about 70 ng/mL, about 80 ng/mL, about 90 ng/mL, about 100 ng/mL, about 110 ng/mL, about 120 ng/mL, or about 130 ng/mL, achieved following oral administration of a 75 mg dose of MDMA to a human subject.

[0242] In some embodiments of Formula (III), when R.sub.1 is methyl, the composition provides a T.sub.1/2 of free amine within a range of about 105-150% of about 8 h to about 9 h, e.g., about 8.4 h, about 8.8 h, about 9.2 h, about 9.6 h, about 10 h, about 10.4 h, about 10.8 h, about 11.2 h, about 11.6 h, about 12 h, about 12.4 h, about 12.8 h, about 13.2 h, or about 13.6 h, achieved following oral administration of a 125 mg dose of MDMA to a human subject.

[0243] In some embodiments of Formula (III), when R.sub.1 is methyl, the composition provides a T.sub.1/2 of free amine within a range of about 105-150% of about 7 h to about 9 h, e.g., about 7.4 h, about 7.6 h, about 8 h, about 8.4 h, about 8.8 h, about 9.2 h, about 9.6 h, about 10 h, about 10.4 h, about 10.8 h, about 11.2 h, about 11.6 h, about 12 h, about 12.4 h, about 12.8 h, about 13.2 h, or about 13.6 h, achieved following oral administration of a 75 mg dose of MDMA to a human subject.

Methods of Treatment

[0244] In some embodiments, the present disclosure provides a method of treating or preventing neurological disorders in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, e.g., a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (II), Formula (IIa), Formula (IIB), Formula (IIc), Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), or Formula (IIId), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0245] In some embodiments, the neurological disorder is a mood disorder. In some embodiments, the mood disorder is clinical depression, postnatal depression or postpartum depression, perinatal depression, atypical depression, melancholic depression, psychotic major depression, cationic depression, seasonal affective disorder, dysthymia, double depression, depressive personality disorder, recurrent brief depression, major depressive disorder, minor depressive disorder, bipolar disorder or manic depressive disorder, depression caused by chronic medical conditions, treatment-resistant depression, refractory depression, suicidality, suicidal ideation, or suicidal behavior. In some embodiments, the method described herein provides therapeutic effect to a subject suffering from depression (e.g., moderate or severe depression). In some embodiments, the mood disorder is associated with neuroendocrine diseases and disorders, neurodegenerative diseases and disorders (e.g., epilepsy), movement disorders, tremor (e.g., Parkinson's Disease), or women's health disorders or conditions. In certain embodiments the mood disorder is depression. In some embodiments, the mood disorder is treatment-resistant depression or major depressive disorder. In some embodiments, the mood disorder is major depressive disorder. In some embodiments, the mood disorder is treatment-resistant depression.

[0246] In some embodiments, the present disclosure provides a method of treating or preventing PTSD, mood disorders, general anxiety disorder, addictive disorders, and/or drug dependence in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, e.g., a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (II), Formula (IIa), Formula (IIB), Formula (IIc), Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), or Formula (IIId), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0247] In one embodiment, the prodrug of the present disclosure is used to treat PTSD. In one embodiment, the prodrug of the present disclosure is used for induction and maintenance therapy to treat PTSD. In one embodiment, the prodrug of the present disclosure is used to treat PTSD with an improved safety profile when compared to treatment with the entactogenic, oneirophrenic or psychedelic compound (e.g. MDMA or related compound, psilocybin or dimethyltryptamine) alone. In one embodiment, the prodrug of the present disclosure is used for induction and maintenance therapy to treat PTSD with an improved safety profile when compared to treatment with the entactogenic, oneirophrenic or psychedelic compound (e.g. MDMA or related compound, psilocybin or dimethyltryptamine) alone.

[0248] In one embodiment, the prodrug of the present disclosure is used to treat behavioral or mood disorders. Examples of behavioral or mood disorders include anxiety, such as social anxiety in autistic subjects (e.g. autistic adults) and anxiety related to life-threatening illnesses, stress (where moderation thereof is measured, for example, by effects on amygdala responses). In some embodiments, the anxiety disorder is panic disorder, obsessive-compulsive disorder, or general anxiety disorder. Other examples include lack of motivation, attention, accuracy, speed of response, perseveration, and/or cognitive engagement. Further examples include depression (e.g., MDD or TRD), attention disorders, disorders of executive function and/or cognitive engagement, obsessive compulsive disorder, bipolar disorder, panic disorder, phobia, schizophrenia, psychopathy, antisocial personality disorder and/or neurocognitive disorders.

[0249] In one embodiment, the prodrug of the present disclosure is used to treat an addictive disorder. In some embodiments, the addictive disorder is alcohol abuse, substance abuse, smoking, or obesity. In some embodiments, the disorder is an eating disorder (anorexia nervosa, bulimia, nervosa, binge eating disorder, etc.) or an auditory disorder.

[0250] In some embodiments, the disorder is an impulsive disorder. In some embodiments, the impulsive disorder is attention deficit hyperactivity disorder (ADHD), attention deficit disorder (ADD), Tourette's syndrome or autism.

[0251] In some embodiments, the disorder is a compulsive disorder. In some embodiments, the compulsive disorder is obsessive compulsive disorder (OCD), gambling, or aberrant sexual behavior.

[0252] In some embodiments, the disorder is a personality disorder. In some embodiments, the personality disorder is conduct disorder, antisocial personality, or aggressive behavior.

NUMBERED EMBODIMENTS OF THE DISCLOSURE

[0253] 1. A compound of Formula (I).

##STR00091## [0254] or a pharmaceutically acceptable salt or enantiomer thereof, [0255] wherein, [0256] R.sub.1 is H or alkyl; [0257] R.sub.2 and R.sub.2′ are each independently H, halogen, alkyl, —OH, or —O-alkyl, or R.sub.2 and R.sub.2′ together with the atom to which they are attached form a cycloalkyl ring; [0258] R.sub.3 and R.sub.3′ are each independently hydrogen, alkyl, —OH, —O-alkyl, or —O-cycloalkyl, or [0259] R.sub.3 and R.sub.3′ together with the atom to which they are attached form an oxo; [0260] R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are each independently hydrogen, halogen, —OH, —O-alkyl, —O— cycloalkyl, alkylene-OR.sub.8, —SH, —S-alkyl, —S-cycloalkyl, or alkylene-SR.sub.8, or R.sub.5 and R.sub.6 together with the atoms to which they are attached form a 5- to 8-membered heterocyclyl ring; [0261] R.sub.8 is H, alkyl, cycloalkyl, or alkylenecycloalkyl; [0262] X is a cleavable promoiety having the structure

##STR00092##

wherein: [0263] R.sub.9 and R.sub.10 are each independently alkyl.
1a. The compound of embodiment 1, having the structure:

##STR00093##

or a pharmaceutically acceptable salt thereof.
1b. The compound of embodiment 1, having the structure:

##STR00094##

or a pharmaceutically acceptable salt thereof.
2. The compound of embodiment 1, wherein at least one of R.sub.4, R.sub.5, R.sub.6 and R.sub.7 is not H.
3. The compound of embodiment 1 or 2, wherein R.sub.1 is H or C.sub.1-C.sub.6 alkyl.
4. The compound of embodiment 1 or 2, wherein R.sub.1 is H.
5. The compound of embodiment 1 or 2, wherein R.sub.1 is CH.sub.3.
6. The compound of any one of embodiments 1-5, wherein R.sub.2 and R.sub.2′ are each independently H, alkyl, or —OH.
7. The compound of any one of embodiments 1-5, wherein R.sub.2 is alkyl and R.sub.2′ is H.
8. The compound of any one of embodiments 1-5, wherein R.sub.2 and R.sub.2′ are each alkyl.
9. The compound of any one of embodiments 6-8, wherein the alkyl is methyl or isopropyl.
10. The compound of any one of embodiments 1-9, wherein R.sub.3 and R.sub.3′ are each independently H, —OH, or —O-alkyl, or R.sub.3 and R.sub.3′ together with the atom to which they are attached form an oxo.
10a. The compound of any one of embodiments 1-9, wherein R.sub.3 and R.sub.3′ are each H.
11. The compound of any one of embodiments 1-10, wherein R.sub.4 is H.
12. The compound of any one of embodiments 1-11, wherein R.sub.7 is H.
13. The compound of any one of embodiments 1-12, wherein R.sub.5 and R.sub.6 are each independently halogen, —OH, —O-alkyl, —O-cycloalkyl, alkylene-OR.sub.8, —SH, —S-alkyl, —S-cycloalkyl, or alkylene-SR.sub.8.
14. The compound of any one of embodiments 1-12, wherein R.sub.5 and R.sub.6 together with the atoms to which they are attached form a 5- to 8-membered heterocyclyl ring.
15. The compound of any one of embodiments 1-14, wherein R.sub.8 is alkyl.
16. The compound of any one of embodiments 1-15, wherein R.sub.9 is C.sub.1-5 alkyl.
17. The compound of any one of embodiments 1-16, wherein R.sub.9 is methyl or isopropyl.
18. The compound of any one of embodiments 1-17, wherein R.sub.10 is C.sub.1-5 alkyl.
19. The compound of embodiment 18, wherein R.sub.10 is methyl or isopropyl.
19a. The compound of embodiment 18, wherein R.sub.10 is methyl, isopropyl, or tert-butyl.
20. The compound of any one of embodiments 1-12 and 14-19a, having the structure of Formula (Ib):

##STR00095## [0264] wherein n is 1 or 2.
20a. The compound of embodiment 20, having the structure:

##STR00096##

or a pharmaceutically acceptable salt thereof.
20b. The compound of embodiment 20, having the structure:

##STR00097##

or a pharmaceutically acceptable salt thereof.
20c. The compound of any one of embodiments 20-20b, wherein R.sub.3 is H.
21. The compound of any one of embodiments 1-12 and 14-20, wherein the compound is:

##STR00098##

21a. The compound of embodiment 21, wherein the compound is:

##STR00099##

21b. The compound of embodiment 21, wherein the compound is:

##STR00100##

22. The compound of any one of embodiments 1-21b, wherein X is cleavable at a pH of from about 1 to about 5.
23. The compound of any one of embodiments 1-21b, wherein X is cleavable at a pH of from about 2 to about 4.
24. A pharmaceutical composition comprising the compound of any one of embodiments 1-23 and a pharmaceutically acceptable excipient.
25. The pharmaceutical composition of embodiment 24, capable of providing an in vivo plasma level characterized by a Cmax of free amine of about 100 ng/mL to about 500 ng/mL, after oral administration of from about 80 mg to about 125 mg of a compound of Formula (I) and release of promoiety X.
26. The pharmaceutical composition of embodiment 24 or 25, capable of providing an in vivo plasma level characterized by an AUC.sub.(0-24) of free amine of about 1000 h*ng/mL to about 6000 h*ng/mL, after oral administration of from about 80 mg to about 125 mg of a compound of Formula (I) and release of promoiety X.
27. The pharmaceutical composition of any one of embodiments 24-26, capable of providing an in vivo T.sub.1/2 of free amine of about 5 h to about 15 h, after oral administration of from about 80 mg to about 125 mg of a compound of Formula (I) and release of promoiety X.
28. The pharmaceutical composition of embodiment 24, wherein when R.sub.1 is H, the composition is capable of providing a Cmax of free amine within a range of about 60-90% of about 12 ng/mL to about 15 ng/mL achieved following oral administration of a 125 mg dose of MDA to a human subject.
29. The pharmaceutical composition of embodiment 24, wherein when R.sub.1 is H, the composition is capable of providing a Cmax of free amine within a range of about 60-90% of about 7 ng/mL to about 8.5 ng/mL achieved following oral administration of a 75 mg dose of MDA to a human subject.
30. The pharmaceutical composition of embodiment 22, wherein when R.sub.1 is methyl, the composition is capable of providing a Cmax of free amine within a range of about 60-90% of about 220 ng/mL to about 250 ng/mL achieved following oral administration of a 125 mg dose of MDMA to a human subject.
31. The pharmaceutical composition of embodiment 24, wherein R.sub.1 is methyl, the composition is capable of providing a T.sub.1/2 of free amine within a range of about 105-150% of about 8 h to about 9 h achieved following oral administration of a 125 mg dose of MDMA to a human subject.
32. The pharmaceutical composition of embodiment 24, wherein when R.sub.1 is methyl, the composition is capable of providing a Cmax of free amine within a range of about 60-90% of about 120 ng/mL to about 140 ng/mL achieved following oral administration of a 75 mg dose of MDMA to a human subject.
33. The pharmaceutical composition of embodiment 24, wherein when R.sub.1 is methyl, the composition is capable of providing a T.sub.1/2 of free amine within a range of 105-150% of about 7 h to about 9 h achieved following oral administration of a 75 mg dose of MDMA to a human subject.
34. A compound of Formula (II):

##STR00101## [0265] or a pharmaceutically acceptable salt thereof; [0266] wherein, [0267] R.sub.1 is H or alkyl; [0268] R.sub.2 and R.sub.2′ are each independently H, halogen, alkyl, —OH, or —O-alkyl, or R.sub.2 and R.sub.2′ together with the atom to which they are attached form a cycloalkyl ring; [0269] R.sub.3 and R.sub.3′ are each independently hydrogen, alkyl, —OH, —O-alkyl, or —O-cycloalkyl, or [0270] R.sub.3 and R.sub.3′ together with the atom to which they are attached form an oxo; [0271] R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are each independently hydrogen, halogen, —OH, —O-alkyl, —O— cycloalkyl, alkylene-OR.sub.8, —SH, —S-alkyl, —S-cycloalkyl, or alkylene-SR.sub.8, or R.sub.5 and R.sub.6 together with the atoms to which they are attached form a 5- to 8-membered heterocyclyl ring; [0272] R.sub.8 is H, alkyl, cycloalkyl, or alkylenecycloalkyl; and [0273] A is a cleavable promoiety having the structure

##STR00102## wherein: [0274] R.sub.9 is H, alkyl or acyl; and [0275] R.sub.10 is H, aryl, or —(CH.sub.2).sub.m—R.sub.11, wherein: [0276] m is an integer from 1-5; and [0277] R.sub.11 is amino, guanidino, thioalkyl, or aryl.
34a. The compound of embodiment 34, having the structure:

##STR00103##

or a pharmaceutically acceptable salt thereof.
34b. The compound of embodiment 34, having the structure:

##STR00104##

or a pharmaceutically acceptable salt thereof.
35. The compound of any one of embodiments 34-34b, wherein at least one of R.sub.4, R.sub.5, R.sub.6 and R.sub.7 is not H.
36. The compound of any one of embodiments 34-35, wherein R.sub.1 is H or C.sub.1-C.sub.6 alkyl.
37. The compound of any one of embodiments 34-35, wherein R.sub.1 is H.
38. The compound of any one of embodiments 34-35, wherein R.sub.1 is CH.sub.3.
39. The compound of any one of embodiments 34-38, wherein R.sub.2 and R.sub.2′ are each independently H, alkyl, or —OH.
40. The compound of any one of embodiments 34-38, wherein R.sub.2 is alkyl and R.sub.2′ is H.
41. The compound of any one of embodiments 34-38, wherein R.sub.2 and R.sub.2′ are each alkyl.
42. The compound of any one of embodiments 39-41, wherein the alkyl is methyl or isopropyl.
43. The compound of any one of embodiments 34-42, wherein R.sub.3 and R.sub.3′ are each independently H, —OH, or —O-alkyl or R.sub.3 and R.sub.3′ together with the atom to which they are attached form an oxo.
43a. The compound of any one of embodiments 34-42, wherein R.sub.3 and R.sub.3′ are each H.
44. The compound of any one of embodiments 34-43, wherein R.sub.4 is H.
45. The compound of any one of embodiments 34-44, wherein R.sub.7 is H.
46. The compound of any one of embodiments 34-45, wherein R.sub.5 and R.sub.6 are each independently halogen, —OH, —O-alkyl, —O-cycloalkyl, alkylene-OR.sub.8, —SH, —S-alkyl, —S-cycloalkyl, or alkylene-SR.sub.8.
47. The compound of any one of embodiments 34-45, wherein R.sub.5 and R.sub.6 together with the atoms to which they are attached form a 5- or 6-membered heterocyclyl ring.
48. The compound of any one of embodiments 34-47, wherein R.sub.8 is alkyl.
49. The compound of any one of embodiments 34-48, wherein R.sub.9 is H or.

##STR00105##

50. The compound of any one of embodiments 34-49, wherein R.sub.9 is H.
51. The compound of any one of embodiments 34-50, wherein R.sub.10 is H, Ph or —(CH.sub.2).sub.m—R.sub.11, and wherein R.sub.11 is —NH.sub.2,

##STR00106##

or —SCH.SUB.3..

[0278] 52. The compound of embodiment 50 or 51, wherein m is an integer from 2-4.
53. The compound of any one of embodiments 34-52, wherein promoiety A is:

##STR00107##

53a. The compound of any one of embodiments 34-52, wherein promoiety A is:

##STR00108##

54. The compound of any one of embodiments 34-53, wherein promoiety A is

##STR00109##

54a. The compound of any one of embodiments 34-53, wherein promoiety A is

##STR00110##

55. The compound of any one of embodiments 34-45 and 47-54a, having the structure of Formula (IIa):

##STR00111## [0279] wherein n is 1 or 2.
55a. The compound of embodiment 55, having the structure:

##STR00112##

or a pharmaceutically acceptable salt thereof.
55b. The compound of embodiment 55, having the structure:

##STR00113##

or a pharmaceutically acceptable salt thereof.
55c. The compound of any one of embodiments 55-55b, wherein R.sub.3 is H.
56. The compound of any one of embodiments 34-45 and 47-54, wherein the compound is:

##STR00114##

56a. The compound of embodiment 56, wherein the compound is:

##STR00115##

56b. The compound of embodiment 56, wherein the compound is:

##STR00116##

57. The compound of any one of embodiments 34-56b, wherein the promoiety A is cleavable at a pH of from about 8 to about 10.
58. The compound of any one of embodiments 34-56b, wherein the promoiety A is cleavable at a pH of from about 8 or 9.
59. A pharmaceutical composition comprising a compound of any one of embodiments 34-58 and a pharmaceutically acceptable excipient.
60. The pharmaceutical composition of embodiment 59, wherein when R.sub.1 is H, the composition is capable of providing a Cmax of free amine within a range of about 60-90% of about 12 ng/mL to about 15 ng/mL achieved following oral administration of a 125 mg dose of MDA to a human subject.
61. The pharmaceutical composition of embodiment 59, wherein when R.sub.1 is H, the composition is capable of providing a Cmax of free amine within a range of about 60-90% of about 7 ng/mL to about 8.5 ng/mL achieved following oral administration of a 75 mg dose of MDA to a human subject.
62. The pharmaceutical composition of embodiment 59, wherein when R.sub.1 is methyl, the composition is capable of providing a Cmax of free amine within a range of about 60-90% of about 220 ng/mL to about 250 ng/mL achieved following oral administration of a 125 mg dose of MDMA to a human subject.
63. The pharmaceutical composition of embodiment 59, wherein R.sub.1 is methyl, the composition is capable of providing a T.sub.1/2 of free amine within a range of about 105-150% of about 8 h to about 9 h achieved following oral administration of a 125 mg dose of MDMA to a human subject.
64. The pharmaceutical composition of embodiment 59, wherein when R.sub.1 is methyl, the composition is capable of providing a Cmax of free amine within a range of about 60-90% of about 120 ng/mL to about 140 ng/mL achieved following oral administration of a 75 mg dose of MDMA to a human subject.
65. The pharmaceutical composition of embodiment 59, wherein when R.sub.1 is methyl, the composition is capable of providing a T.sub.1/2 of free amine within a range of 105-150% of about 7 h to about 9 h achieved following oral administration of a 75 mg dose of MDMA to a human subject.
66. The pharmaceutical composition of embodiment 59, capable of providing an in vivo plasma level characterized by a Cmax of free amine of about 100 ng/mL to about 500 ng/mL, after oral administration of from about 80 mg to about 125 mg of a compound of Formula (II) and release of promoiety A.
67. The pharmaceutical composition of embodiment 59 or 66, capable of providing an in vivo plasma level characterized by an AUC.sub.(0-24) of free amine of about 1000 h*ng/mL to about 6000 h*ng/mL, after oral administration of from about 80 mg to about 125 mg of a compound of Formula (II) and release of promoiety A.
68. The pharmaceutical composition of any one of embodiments 59 and 66-67, capable of providing an in vivo T.sub.1/2 of free amine of about 5 h to about 15 h, after oral administration of from about 80 mg to about 125 mg of a compound of Formula (II) and release of promoiety A.
69. A compound of Formula (III):

##STR00117## [0280] or a pharmaceutically acceptable salt thereof; [0281] wherein, [0282] R.sub.1 is H or alkyl; [0283] R.sub.2 and R.sub.2′ are each independently H, halogen, alkyl, —OH, or —O-alkyl, or R.sub.2 and R.sub.2′ together with the atom to which they are attached form a cycloalkyl ring; [0284] R.sub.3 and R.sub.3′ are each independently hydrogen, alkyl, —OH, —O-alkyl, or —O-cycloalkyl, or [0285] R.sub.3 and R.sub.3′ together with the atom to which they are attached form an oxo; [0286] R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are each independently hydrogen, halogen, —OH, —O-alkyl, —O-cycloalkyl, alkylene-OR.sub.8, —SH, —S-alkyl, —S-cycloalkyl, or alkylene-SR.sub.8, or R.sub.5 and R.sub.6 together with the atoms to which they are attached form a 5- to 8-membered heterocyclyl ring; [0287] R.sub.8 is H, alkyl, cycloalkyl, or alkylenecycloalkyl; and [0288] B is

##STR00118##

wherein R.sub.B is H or alkyl; and R.sub.C and R.sub.D are each independently H or alkyl.
69a. The compound of embodiment 69, having the structure:

##STR00119##

or a pharmaceutically acceptable salt thereof.
69b. The compound of embodiment 69, having the structure:

##STR00120##

or a pharmaceutically acceptable salt thereof.
70. The compound of any one of embodiments 69-69b, wherein at least one of R.sub.4, R.sub.5, R.sub.6 and R.sub.7 is not H.
71. The compound of any one of embodiments 69-70, wherein R.sub.1 is H or C.sub.1-C.sub.6 alkyl.
72. The compound of any one of embodiments 69-70, wherein R.sub.1 is H.
73. The compound of any one of embodiments 69-70, wherein R.sub.1 is CH.sub.3.
74. The compound of any one of embodiments 69-73, wherein R.sub.2 and R.sub.2′ are each independently H, alkyl, or —OH.
75. The compound of any one of embodiments 69-73, wherein R.sub.2 is alkyl and R.sub.2′ is H.
76. The compound of any one of embodiments 69-73, wherein R.sub.2 and R.sub.2′ are each alkyl.
77. The compound of any one of embodiments 74-76, wherein the alkyl is methyl or isopropyl.
78. The compound of any one of embodiments 69-77, wherein R.sub.3 and R.sub.3′ are each independently H, —OH, or —O-alkyl or R.sub.3 and R.sub.3′ together with the atom to which they are attached form an oxo.
78a. The compound of any one of embodiments 69-77, wherein R.sub.3 and R.sub.3′ are each H.
79. The compound of any one of embodiments 69-78, wherein R.sub.4 is H.
80. The compound of any one of embodiments 69-79, wherein R.sub.7 is H.
81. The compound of any one of embodiments 69-80, wherein R.sub.5 and R.sub.6 are each independently halogen, —OH, —O-alkyl, —O-cycloalkyl, alkylene-OR.sub.8, —SH, —S-alkyl, —S-cycloalkyl, or alkylene-SR.sub.8.
82. The compound of any one of embodiments 69-80, wherein R.sub.5 and R.sub.6 together with the atoms to which they are attached form a 5- to 8-membered heterocyclyl ring.
83. The compound of any one of embodiments 69-82, wherein R.sub.8 is alkyl.
84. The compound of any one of embodiments 69-83, wherein B is

##STR00121##

84a. The compound of any one of embodiments 69-83, wherein B is

##STR00122##

wherein R.sub.B is H or alkyl.
84b. The compound of any one of embodiments, 69-83, wherein B is

##STR00123##

wherein R.sub.B is H or alkyl.
84c. The compound of embodiment 84a or 84b, wherein R.sub.B is H or Me.
84d. The compound of embodiment 84a or 84b, wherein R.sub.B is H.
84e. The compound of any one of embodiments 69-83, wherein B is

##STR00124##

84f. The compound of embodiment 84e, wherein alkyl is methyl, ethyl, or isopropyl.
84g. The compound of embodiment 84e or 84f, wherein alkyl is methyl.
84h. The compound of any one of embodiments 69-83, wherein B is

##STR00125##

84i. The compound of embodiment 84h, wherein aryl is optionally substituted phenyl.
84j. The compound of embodiment 84h, wherein optionally substituted phenyl is

##STR00126##

84k. The compound of any one of embodiments 69-83, wherein B is

##STR00127##

84l. The compound of embodiment 84k, wherein R.sub.C and R.sub.D are each independently H, Me, Et, or i-Pr.
84m. The compound of embodiment 84k or 84l, wherein R.sub.C and R.sub.D are each H.
85. The compound of any one of embodiments 69-80 and 82-84m, having the structure of Formula (IIIb):

##STR00128## [0289] wherein n is 1 or 2.
85a. The compound of embodiment 85, having the structure:

##STR00129##

or a pharmaceutically acceptable salt thereof.
85b. The compound of embodiment 85, having the structure:

##STR00130##

or a pharmaceutically acceptable salt thereof.
85c. The compound of any one of embodiments 85-85b, wherein R.sub.3 is H.
85d. The compound of any one of embodiments 69-83 and 84a-85, having the structure:

##STR00131##

85e. The compound of any one of embodiments 69-83 and 84a-85, having the structure:

##STR00132##

85f. The compound of any one of embodiments 69-83 and 84a-85, having the structure:

##STR00133##

85g. The compound of any one of embodiments 69-83 and 84a-85c, having the structure:

##STR00134##

85h. The compound of embodiment 85g having the structure:

##STR00135##

85i. The compound of embodiment 85g or 85h having the structure:

##STR00136##

85j. The compound of embodiment 85h or 85i, having the structure:

##STR00137##

86. A pharmaceutical composition comprising a compound of any one of embodiments 69-85j and a pharmaceutically acceptable excipient.
87. The pharmaceutical composition of embodiment 86, capable of providing an in vivo plasma level characterized by a Cmax of free amine of about 100 ng/mL to about 500 ng/mL, after oral administration of from about 80 mg to about 125 mg of a compound of Formula (III) and release of promoiety B.
88. The pharmaceutical composition of embodiment 86 or 87, capable of providing an in vivo plasma level characterized by an AUC.sub.(0-24) of free amine of about 1000 h*ng/mL to about 6000 h*ng/mL, after oral administration of from about 80 mg to about 125 mg of a compound of Formula (III) and release of promoiety B.
89. The pharmaceutical composition of any one of embodiments 86-88, capable of providing an in vivo T.sub.1/2 of free amine of about 5 h to about 15 h, after oral administration of from about 80 mg to about 125 mg of a compound of Formula (III) and release of promoiety B.
90. A method of treating post-traumatic stress disorder (PTSD) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition of any one of embodiments 24-33, 59-68, and 86-89.
91. A method of treating an eating disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition of any one of embodiments 24-33, 59-68, and 86-89.
92. A method of treating depression in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition of any one of embodiments 24-33, 59-68, and 86-89.
93. The method of embodiment 92, wherein the depression is major depressive disorder (MDD) or treatment-resistant depression (TRD).
94. A method of treating an anxiety disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition of any one of embodiments 24-33, 59-68, and 86-89.
95. The method of embodiment 94, wherein the anxiety disorder is generalized anxiety disorder.
96. A compound selected from compounds 1-11 of Table 6.
97. A compound selected from compounds 1-45 of Table 1.

EXAMPLES

Example 1. Preparation of Prodrug Compounds of the Present Disclosure

[0290] Compounds of the present disclosure are prepared from MDA, MDMA or derivative thereof in a one or two-step synthetic route that relies on standard amide and ester bond-forming reactions between commercially available reagents.

[0291] Specific enantiomers (or diastereomers in some cases) are obtained by separation of the mixtures and identification of the desired isomer.

[0292] General reaction conditions are provided, and reaction products can be purified by known methods including silica gel chromatography using various organic solvents such as hexane, dichloromethane, ethyl acetate, methanol and the like or preparative reverse phase high pressure liquid chromatography.

[0293] Preparation of compounds can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in Greene and Wuts, Protective Groups in Organic Synthesis, 44th. Ed., Wiley & Sons, 2006, as well as in Jerry March, Advanced Organic Chemistry, 4.sup.th edition, John Wiley & Sons, publisher, New York, 1992 which are incorporated herein by reference in their entirety.

Example 2. PK Measurements in Healthy Human Subjects Administered MDMA

[0294]

TABLE-US-00001 Dose 75 mg MDMA 125 mg MDMA C.sub.max (ng/mL) 130.9 236.4 AUC.sub.0-24 (ng/ml*h.sup.−1) 1331 2623 T.sub.max (h) 1.8 2.4 T.sub.1/2 (h) 7.7 8.6

Example 3. PK Measurements in Healthy Human Subjects Administered MDA

[0295]

TABLE-US-00002 Dose 75 mg MDA 125 mg MDA C.sub.max (ng/mL) 7.8 13.7 AUC.sub.0-24 (ng/ml*h.sup.−1) 122 215 T.sub.max (h) 5 7

[0296] Prodrugs have been exemplified in the following classes:

[0297] 1. Enacarbil (N-acyloxyalkoxy Carbonyl) Derivatives

##STR00138##

[0298] 2. Simple Amino Acids

##STR00139##

[0299] In some embodiments, amino acids provide a group that can be internally released to provide the MDMA, MDA, or a derivative thereof. A specific example of an internally released protecting group utilizes ornithine. prodrug can be stabilized to prevent cyclization and release by dosing a salt of the amine or by utilizing a slow release of a secondary protecting group such as a carbamate. The α-amino group is an optional substituent.

##STR00140##

[0300] 3. Amides/Amino Acid Variants

[0301] Below is a pro-drug amide derived from docarpamine. Amide groups can be cleaved enzymatically in vivo.

##STR00141##

[0302] 4. Carbamates

[0303] The non-limiting carbamate examples shown below are generally freed via simple hydrolysis.

##STR00142##

[0304] 5. Dialkyl-1,3-dioxol-2-one

##STR00143##

[0305] 6. Methoxymethyl Phosphinyl Amide (Kirby and Dowd, 2022)

##STR00144##

[0306] Syntheses of the prodrugs may be accomplished from MDA or MDMA and commercially available reagents in one or two steps. Isolation of specific enantiomers can be achieved by separation of the mixtures or by enantioselective synthesis methods.

[0307] 7. Methoxymethyl Phosphate

##STR00145##

TABLE-US-00003 TABLE 1 Compounds of the invention ID Structure Chemical name 1 [00146] embedded image ethyl(1-(benzo[d][1,3]dioxol-5-yl)propan-2- yl)(methyl)carbamate 2 [00147] ethyl(1-(benzo[d][1,3]dioxol-5-yl)propan-2-yl)carbamate 3 [00148] 1-(((1-(benzo[d][1,3]dioxol-5-yl)propan-2- yl)(methyl)carbamoyl)oxy)ethyl pivalate 4 [00149] 2-amino-N-(1-(benzo[d][1,3]dioxol-5-yl)propan-2-yl)-N- methylacetamide 5 [00150] embedded image 2-amino-N-(1-(benzo[d][1,3]dioxol-5-yl)propan-2- yl)acetamide 6 [00151] tert-butyl(R)-(1-(benzo[d][1,3]dioxol-5-yl)propan-2- yl)carbamate 7 [00152] tert-butyl(R)-(1-(benzo[d][1,3]dioxol-5-yl)propan-2- yl)(methyl)carbamate 8 [00153] (R)-4-(((1-(benzo[d][1,3]dioxol-5-yl)propan-2- yl)amino)methyl)-5-methyl-1,3-dioxol-2-one 9 [00154] embedded image (R)-4-(((1-(benzo[d][1,3]dioxol-5-yl)propan-2- yl)(methyl)amino)methyl)-5-methyl-1,3-dioxol-2-one 10 [00155] phenyl N-(1-(benzo[d][1,3]dioxol-5-yl)propan-2-yl)-N- (methoxymethyl)phosphonamidate 11 [00156] phenyl N-(1-(benzo[d][1,3]dioxol-5-yl)propan-2-yl)-N- (methoxymethyl)-N-methylphosphonamidate 12 [00157] embedded image 1-(((1-(benzo[d][1,3]dioxol-5-yl)propan-2- yl)(methyl)carbamoyl)oxy)ethyl isobutyrate 13 [00158] 1-(((1-(benzo[d][1,3]dioxol-5-yl)propan-2- yl)carbamoyl)oxy)ethyl isobutyrate 14 [00159] 1-(((1-(benzo[d][1,3]dioxol-5-yl)propan-2- yl)carbamoyl)oxy)ethyl pivalate 15 [00160] 1-(((1-(benzo[d][1,3]dioxol-5-yl)propan-2- yl)(methyl)carbamoyl)oxy)ethyl acetate 16 [00161] embedded image 1-(((1-(benzo[d][1,3]dioxol-5-yl)propan-2- yl)carbamoyl)oxy)ethyl acetate 17 [00162] 2,4-diamino-N-(l-(benzo[d][1,3]dioxol-5-yl)propan-2- yl)butanamide 18 [00163] 2,5-diamino-N-(l-(benzo[d][1,3]dioxol-5-yl)propan-2- yl)pentanamide 19 [00164] 2,5-diamino-N-(1-(benzo[d][1,3]dioxol-5-yl)propan-2-yl)-N- methylpentanamide 21 [00165] embedded image 2,4-diamino-N-(1-(benzo[d][1,3]dioxol-5-yl)propan-2-yl)-N- methylbutanamide 22 [00166] (2S)-2-amino-3-(4-(((1-(benzo[d][1,3]dioxol-5-yl)propan-2- yl)carbamoyl)oxy)phenyl)propanoic acid 23 [00167] methyl(3-amino-4-((1-(benzo[d][1,3]dioxol-5-yl)propan-2- yl)amino)-4-oxobutyl)carbamate 25 [00168] embedded image (2S)-2-amino-3-(4-(((1-(benzo[d][1,3]dioxol-5-yl)propan-2- yl)(methyl)carbamoyl)oxy)phenyl)propanoic acid 26 [00169] methyl(1-(benzo[d][1,3]dioxol-5-yl)propan-2- yl)(methyl)carbamate 29 [00170] tert-butyl(1-(benzo[d][1,3]dioxol-5-yl)propan-2- yl)carbamate 30 [00171] isopropyl(1-(benzo[d][1,3]dioxol-5-yl)propan-2- yl)carbamate 31 [00172] embedded image isopropyl(1-(benzo[d][1,3]dioxol-5-yl)propan-2- yl)(methyl)carbamate 32 [00173] tert-butyl(1-(benzo[d][1,3]dioxol-5-yl)propan-2- yl)(methyl)carbamate 34 [00174] methyl(1-(benzo[d][1,3]dioxol-5-yl)propan-2-yl)carbamate 35 [00175] methyl(3-amino-4-((1-(benzo[d][1,3]dioxol-5-yl)propan-2- yl)(methyl)amino)-4-oxobutyl)carbamate 36 [00176] embedded image 2-amino-N-(1-(benzo[d][1,3]dioxol-5-yl)propan-2-yl)-5- guanidinopentanamide 37 [00177] 2-amino-N-(1-(benzo[d][1,3]dioxol-5-yl)propan-2-yl)-5- guanidino-N-methylpentanamide 38 [00178] (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (R)-(1- (benzo[d][1,3]dioxol-5-yl)propan-2-yl)carbamate 39 [00179] embedded image 1-((((R)-1-(benzo[d][1,3]dioxol-5-yl)propan-2- yl)(methyl)carbamoyl)oxy)ethyl pivalate 40 [00180] 1-(benzo [d][1,3]dioxol-5-yl)propan-2- yl)(methyl)amino)methyl dihydrogen phosphate 41 [00181] (R)-((1-(benzo[d][1,3]dioxol-5-yl)propan-2-yl)amino)methyl dihydrogen phosphate 42 [00182] (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl(R)-(1- (benzo[d][1,3]dioxol-5-yl)propan-2-yl)(methyl)carbamate 43 [00183] embedded image 1-((((R)-1-(benzo[d][1,3]dioxol-5-yl)propan-2- yl)carbamoyl)oxy)ethyl pivalate 44 [00184] phenyl N-((R)-1-(benzo[d][1,3]dioxol-5-yl)propan-2-yl)-P- (methoxymethyl)-N-methylphosphonamidate 45 [00185] phenyl N-((R)-1-(benzo[d][1,3]dioxol-5-yl)propan-2-yl)-P- (methoxymethyl)phosphonamidate

Example 4: Synthesis of Compounds

Synthesis of Prodrug 1.0: Ethyl (1-(benzo[d][1,3]dioxol-5-yl)propan-2-yl)(methyl)carbamate

[0308] Compound 1.0 was synthesized from commercially available compound 1A in six steps (Scheme 1).

##STR00186##

[0309] Synthesis of 1A

[0310] To a stirred solution of 4-bromocatechol (5.0 g, 26.45 mmol, 1.0 equiv) and potassium carbonate (7.3 g, 52.91 mmol, 2.0 equiv) in acetone (50.0 mL) was added (bromomethyl)benzene (6.8 g, 39.68 mmol, 1.5 equiv) dropwise at 25° C. under nitrogen atmosphere. The mixture was stirred for 16h at 60° C. Added 100 mL of water to the reaction, the aqueous layer was extracted with ethyl acetate (3×300 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, acetonitrile in Water (0.05% NH.sub.4HCO.sub.3), 10% to 100% gradient in 20 min; detector, UV 254 nm. This resulted in 1A (5.0 g, 51%) as a white solid. MS m/z [M+H].sup.+ (ESI): 369.04.

[0311] Synthesis of 1B

[0312] To a stirred solution of 1A (1.0 g, 2.71 mmol, 1.0 equiv) and K.sub.3PO.sub.4 (1.7 g, 8.12 mmol, 3.0 equiv) in acetone (10.0 mL) was added XPhos Pd(crotyl)Cl (182.5 mg, 0.27 mmol, 0.1 equiv) at 25° C. under nitrogen atmosphere. The mixture was stirred for 6h at 50° C. The reaction was diluted with 50 mL of dichloromethane, washed with 2×20 mL saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, acetonitrile in Water (0.05% NH.sub.4HCO.sub.3), 10% to 100% gradient in 20 min; detector, UV 254 nm. This resulted in 1B (480.0 mg, 51%) as a white solid. MS m/z [M+H].sup.+ (ESI): 347.16.

[0313] Synthesis of 1C

[0314] To a solution of methanamine hydrochloride (935.5 mg, 13.86 mmol, 10.0 equiv) in methyl alcohol (5.0 mL) was added sodium cyanoborohydride (435.4 mg, 6.93 mmol, 5.0 equiv) and 1B (480.0 mg, 1.39 mmol, 1.0 equiv) at 0° C. The resulting mixture was stirred for 16h at room temperature. The reaction was diluted with 50 mL of dichloromethane, washed with 2×20 mL saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, acetonitrile in Water (0.1% TFA), 10% to 100% gradient in 20 min; detector, UV 254 nm. to afford 1C (450.0 mg, 90%) as a white solid. MS m/z [M+H].sup.+ (ESI): 362.20.

[0315] Synthesis of 1D

[0316] To a stirred solution of 1C (450.0 mg, 1.25 mmol, 1.0 equiv) and triethylamine (377.9 mg, 3.74 mmol, 3.0 equiv) in dichloromethane (5.0 mL) was added ethyl chloroformate (270.2 mg, 2.49 mmol, 2.0 equiv) dropwise at 0° C. under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature. The reaction was diluted with 50 mL of dichloromethane, washed with 2×20 mL saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, acetonitrile in Water (0.05% NH.sub.4HCO.sub.3), 10% to 100% gradient in 20 min; detector, UV 254 nm. 300 mg of 1D was obtained as a colorless oil. MS m/z [M+H]+(ESI): 434.23.

[0317] Synthesis of 1E and Final Product 1.0

[0318] A mixture of 1D (300.0 mg, 0.69 mmol, 1.0 equiv) and 10% Pd/C (60.0 mg) in tetrahydrofuran (1.0 mL) was stirred for 3 h at room temperature under hydrogen atmosphere. The solid was filtered and washed with tetrahydrofuran. The filtrate was concentrated under reduced pressure. The crude product 1E was used in the next step directly without further purification. To a stirred solution of 1E (100.0 mg, 0.40 mmol, 1.0 equiv) and cesium carbonate (231.5 mg, 0.71 mmol, 1.8 equiv) in DMF (1.0 mL) was added bromo(chloro)methane (91.9 mg, 0.71 mmol, 1.8 equiv) dropwise at 0° C. under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature. The reaction was diluted with 50 mL of dichloromethane, washed with 2×20 mL saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, acetonitrile in Water (0.05% NH.sub.4HCO.sub.3), 10% to 100% gradient in 20 min; detector, UV 254 nm. 28.9 mg (27%) of 1.0, Ethyl (1-(benzo[d][1,3]dioxol-5-yl)propan-2-yl)(methyl)carbamate was obtained as a colorless oil.

[0319] MS m/z [M+H]+ (ESI): 266.10. .sup.1H NMR (300 MHz, DMSO-d6) δ 6.81-6.60 (m, 3H), 5.95 (s, 2H), 4.31-4.25 (m, 1H), 3.96-3.81 (m, 2H), 2.64-2.59 (m, 5H), 1.08-0.99 (m, 6H).

Synthesis of Prodrug 2.0: Ethyl (1-(benzo[d][1,3]dioxol-5-yl)propan-2-yl)carbamate

[0320] Prodrug 2.0 was synthesized from the previous intermediate 1C in 4 steps (Scheme 2).

##STR00187##

[0321] Synthesis of 2A

[0322] To a solution of NH.sub.4OAc (2.22g, 28.83 mmol, 10.0 equiv.) in methyl alcohol (10.0 mL) was added sodium cyanoborohydride (0.91g, 14.44 mmol, 5.0 equiv.), 1C (1 g, 2.89 mmol, 1.0 equiv.) and AcOH (1 mL) at 0° C. The resulting mixture was stirred for 16h at room temperature. The reaction was diluted with 100 mL of dichloromethane, washed with 2×50 mL saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, acetonitrile in Water (0.1% TFA), 10% to 100% gradient in 20 min; detector, UV 254 nm. to afford 2A (840 mg, 84%) as a white solid.

[0323] Synthesis of 2B

[0324] To a solution of 2A (300.0 mg, 0.86 mmol, 1.0 equiv) and triethylamine (262.1 mg, 2.58 mmol, 3.0 equiv) in dichloromethane was added ethyl chloroformate (93.7 mg, 0.86 mmol, 1.0 equiv) dropwise at 0° C. under nitrogen atmosphere. The mixture was stirred at 25° C. for 16h. The reaction was diluted with 50 mL of dichloromethane, washed with 2×20 mL saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water (0.10% NH.sub.3.Math.H.sub.2O), 10% to 100% gradient in 20 min; detector, UV 254 nm. This resulted in 2B (160 mg, 44%) as a yellow solid. MS m/z [M+H].sup.+ (ESI): 420.21.

[0325] Synthesis of 2C and Final Product 2.0

[0326] A mixture of 2B (150.0 mg, 0.36 mmol, 1.0 equiv) and 10% Pd/C (30.0 mg) in tetrahydrofuran (5.0 mL) was stirred for 3 h at room temperature under hydrogen atmosphere. The solid was filtered and washed with tetrahydrofuran. The filtrate was concentrated under reduced pressure to crude material 2C. The crude product (2C) was used in the next step directly without further purification.

[0327] To a solution of 2C (100.0 mg, 0.42 mmol, 1.0 equiv) and cesium carbonate (217.8 mg, 0.67 mmol, 1.6 equiv) in N, N-Dimethylformamide was added bromo(chloro)methane (86.5 mg, 0.67 mmol, 1.6 equiv) dropwise at 0° C. under nitrogen atmosphere. The resulting mixture was stirred for 2h at room temperature under nitrogen atmosphere. The reaction was diluted with 50 mL of dichloromethane, washed with 2×20 mL saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5 μm; Mobile Phase A: Water (0.1% TFA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 27% B to 55% B in 9 min, 55% B; Wavelength: 254 nm) to afford Prodrug 2.0, ethyl (1-(benzo[d][1,3]dioxol-5-yl)propan-2-yl)carbamate (18 mg) as a colorless oil. MS m/z [M+H].sup.+ (ESI): 252.05. .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 6.72-6.62 (m, 3H), 5.88 (s, 2H), 4.04-3.97 (m, 2H), 3.81-3.70 (m, 1H), 2.73-2.52 (m, 2H), 1.21-1.07 (m, 6H).

Synthesis of Prodrug 3.0: 1-(((1-(benzo[d][1,3]dioxol-5-yl)propan-2-yl)(methyl)carbamoyl)oxy)ethyl pivalate

[0328] Compound 3.0 was synthesized from previously synthesized intermediate 1D (scheme 1) in four steps (Scheme 3).

##STR00188##

[0329] Synthesis of 3B

[0330] To a solution of 1D (200.0 mg, 0.55 mmol, 1.0 equiv) and TEA (167.9 mg, 1.65 mmol, 3.0 equiv), DMAP (33.8 mg, 0.27 mmol, 0.5 equiv) in dichloromethane was added 1-chloroethyl carbonochloridate, 3A (237.3 mg, 1.65 mmol, 3.0 equiv) dropwise at 0° C. under nitrogen atmosphere. The resulting mixture was stirred for 16h at room temperature. The reaction was diluted with 50 mL of dichloromethane, washed with 2×20 mL saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude (3B) was used in next step directly without further purification.

[0331] Synthesis of 3D

[0332] To a solution of 3B (150.0 mg, 0.32 mmol, 1.0 equiv) and pivalic acid, 3C (65.4 mg, 0.64 mmol, 2.0 equiv) in DMF was added cesium carbonate (125.32 mg, 0.385 mmol, 1.2 equiv), potassium iodide (10.6 mg, 0.06 mmol, 0.20 equiv) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 4h at 100° C. under nitrogen atmosphere. The reaction was diluted with 30 mL of dichloromethane, washed with 2×20 mL saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water (0.10% NH.sub.3.Math.H.sub.2O), 10% to 100% gradient in 20 min; detector, UV 254 nm. This resulted in 3D (114.0 mg, 66%) as a yellow oil. MS m/z [M+H].sup.+ (ESI): 534.28.

[0333] A mixture of 3D (150.0 mg, 0.28 mmol, 1.0 equiv) and 10% Pd/C (40.0 mg) in tetrahydrofuran (1.0 mL) was stirred for 3 h at room temperature under hydrogen atmosphere. The solid was filtered and washed with tetrahydrofuran. The filtrate was concentrated under reduced pressure to provide 3E. The crude product (3E) was used in the next step directly without further purification.

[0334] Synthesis of 3.0

[0335] To a solution of 3E (90.0 mg, 0.25 mmol, 1.0 equiv) and cesium carbonate (132.7 mg, 0.41 mmol, 1.6 equiv) in DMF was added bromo(chloro)methane (52.7 mg, 0.41 mmol, 1.6 equiv) dropwise at 0° C. under nitrogen atmosphere. The resulting mixture was stirred for 2h at room temperature under nitrogen atmosphere. The reaction was diluted with 50 mL of dichloromethane, washed with 2×20 mL saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5 pm; Mobile Phase A: Water (0.1% TFA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 50% B to 80% B in 9 min, 80% B; Wavelength: 254 nm) to afford

[0336] Prodrug 3.0, 1-(((1-(benzo[d][1,3]dioxol-5-yl)propan-2-yl)(methyl)carbamoyl)oxy)ethyl pivalate (18 mg, 18%) as a colorless oil. MS m/z [M+H]+(ESI): 366.05. 1H NMR (400 MHz, Methanol-d4) δ 6.70-6.32 (m, 4H), 5.94-5.88 (m, 2H), 4.43-4.31 (m, 1H), 2.79-2.66 (m, 5H), 1.48-1.40 (m, 2H), 1.33-1.22 (m, 1H), 1.19-1.13 (m, 12H).

Synthesis of Prodrug 4.0: 2-amino-N-(1-(benzo[d][1,3]dioxol-5-yl)propan-2-yl)-N-methylacetamide

[0337] Compound 4.0 was synthesized from commercially available compound NBoc protected glycine and previously synthesized intermediate 1D (Scheme 1) in four steps (Scheme 4).

##STR00189##

[0338] Synthesis of 4A

[0339] To a stirred solution of 1A (500.0 mg, 1.38 mmol, 1.0 equiv) and HATU (1.1 g, 2.77 mmol, 2.0 equiv) in DMF (5.0 mL) was added [(tert-butoxycarbonyl)amino]acetic acid (290.8 mg, 1.66 mmol, 1.2 equiv) and DIEA (536.3 mg, 4.15 mmol, 3.0 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 16h at room temperature. The reaction was diluted with 50 mL of dichloromethane, washed with 2×20 mL saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, acetonitrile in Water (0.05% NH.sub.4HCO.sub.3), 10% to 100% gradient in 20 min; detector, UV 254 nm. 450 mg of 4A was obtained as a colorless oil. MS m/z [M+H]+ (ESI): 519.28.

[0340] Synthesis of 4B

[0341] A mixture of 4A (450.0 mg, 0.87 mmol, 1.0 equiv) and 10% Pd/C (90.0 mg) in Tetrahydrofuran (5.0 mL) was stirred for 3 h at room temperature under hydrogen atmosphere. The solids were filtered and washed with Tetrahydrofuran. The filtrate was concentrated under reduced pressure and crude product 4B was obtained. The crude product 4B was used in the next step directly without further purification.

[0342] Synthesis of 4C

[0343] To a stirred mixture of 4B (250.0 mg, 0.74 mmol, 1.0 equiv) and cesium carbonate (433.3 mg, 1.33 mmol, 1.8 equiv) in DMF (3.0 mL) was added bromo(chloro)methane (172.1 mg, 1.33 mmol, 1.8 equiv) dropwise at 0° C. under nitrogen atmosphere. The resulting mixture was stirred for 2h at room temperature. The reaction was diluted with 30 mL of dichloromethane, washed with 2×20 mL saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, acetonitrile in Water (0.05% NH.sub.4HCO.sub.3), 10% to 100% gradient in 20 min; detector, UV 254 nm. 200 mg of 4C was obtained as a colorless oil. MS m/z [M+H]+(ESI): 351.18.

[0344] Synthesis of product, Prodrug 4.0

[0345] To a stirred solution of 4C (100.0 mg, 0.29 mmol, 1.0 equiv) in dichloromethane (1.0 mL) was added TFA (0.2 mL, 2.69 mmol) dropwise at room temperature. The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, acetonitrile in Water (0.1% TFA), 10% to 100% gradient in 20 min; detector, UV 254 nm. 35.4 mg of 4.0, 2-amino-N-(1-(benzo[d][1,3]dioxol-5-yl)propan-2-yl)-N-methylacetamide, was obtained as a yellow oil (TFA Salt). MS m/z [M+H].sup.+ (ESI): 251.10. .sup.1H NMR (300 MHz, Methanol-d4) δ 6.77-6.65 (m, 3H), 5.90 (d, J=8.7 Hz, 2H), 4.87-4.76 (m, 1H), 3.92-3.70 (m, 2H), 3.06-2.84 (m, 3H), 2.80-2.70 (m, 2H), 1.32-1.16 (m, 3H).

Synthesis of Prodrug 5.0: 2-amino-N-(1-(benzo[d][1,3]dioxol-5-yl)propan-2-yl)acetamide

[0346] Prodrug 5.0 was synthesized from the previous intermediate 2A in 4 steps (Scheme 5).

##STR00190##

[0347] Synthesis of 5B

[0348] To a solution of 2A (500.0 mg, 1.44 mmol, 1.0 equiv) and [(tert-butoxycarbonyl)amino]acetic acid (378.1 mg, 2.16 mmol, 1.5 equiv), DIEA (557.9 mg, 4.32 mmol, 3.0 equiv) in DMF (5 mL) was added HATU (1367.9 mg, 3.59 mmol, 2.5 equiv) at 25° C. under nitrogen atmosphere. The resulting mixture was stirred for 16h at room temperature under nitrogen atmosphere. The reaction was diluted with 50 mL of dichloromethane, washed with 2×20 mL saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water (0.1% FA), 10% to 100% gradient in 30 min; detector, UV 254 nm. This resulted in 5B (582 mg, 80%) as a white solid. MS m/z [M+H].sup.+ (ESI): 505.26.

[0349] Synthesis of 5C

[0350] A mixture of 5B (500.0 mg, 0.99 mmol, 1.0 equiv) and 10% Pd/C (100.0 mg) in tetrahydrofuran (10.0 mL) was stirred for 3 h at room temperature under hydrogen atmosphere. The solid was filtered and washed with tetrahydrofuran. The filtrate was concentrated under reduced pressure. The crude product (5C) was used in the next step directly without further purification.

[0351] Synthesis of 5D

[0352] To a mixture of 5C (500.0 mg, 1.54 mmol, 1.0 equiv) and cesium carbonate (803.5 mg, 2.46 mmol, 1.6 equiv) in DMF (5 mL) was added bromo(chloro)methane (319.1 mg, 2.46 mmol, 1.6 equiv) dropwise at 0° C. under nitrogen atmosphere. The resulting mixture was stirred for 2h at room temperature. The reaction was diluted with 50 mL of dichloromethane, washed with 2×30 mL saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water (0.1% FA), 10% to 100% gradient in 20 min; detector, UV 254 nm. This resulted in 5D (400.0 mg, 77%) as a white solid. MS m/z [M+H].sup.+ (ESI): 337.17.

[0353] Synthesis of 5.0

[0354] To a solution of 5D (70.0 mg, 0.21 mmol, 1.0 equiv) in dichloromethane (1 mL) was added TFA (0.2 mL) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile Phase A: Water (0.1% TFA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 28% B in 9 min, 28% B; Wavelength: 254 nm) to afford Prodrug 5.0, 2-amino-N-(1-(benzo[d][1,3]dioxol-5-yl)propan-2-yl)acetamide, (42 mg, 82%) as a white solid (TFA Salt). MS m/z [M+H].sup.+ (ESI): 237.10. .sup.1H NMR (300 MHz, Methanol-d4) δ 6.73-6.64 (m, 3H), 5.89 (s, 2H), 4.17-4.05 (m, 1H), 3.64-3.51 (m, 2H), 2.76-2.61 (m, 2H), 1.13 (d, J=6.6 Hz 3H).

Synthesis of Prodrug 6.0: tert-butyl (R)-(1-(benzo[d][1,3]dioxol-5-yl)propan-2-yl)carbamate. Synthesis of Prodrug 7.0: tert-butyl (R)-(1-(benzo[d][1,3]dioxol-5-yl)propan-2-yl)(methyl)carbamate

[0355] Prodrugs 6.0 and 7.0 were synthesized from the previously described chemistry from commercially available intermediate 6A and 6C in a few steps (Scheme 6).

##STR00191##

[0356] Synthesis of 6B

[0357] To a 100 mL flask was charged magnesium (60.4 mg, 2.487 mmol, 2.00 equiv.), iodine (one crystal) and tetrahydrofuran (1.5 mL) at room temperature under nitrogen. 5-Bromo-2H-1,3-benzodioxole (50 mg) was added to the mixture and heated to 50° C. at which time the iodine color disappeared, and the internal temperature rose to 56° C. 5-Bromo-2H-1,3-benzodioxole (450 mg, total added 500 mg, 2.487 mmol, 2.0 equiv.) was added, via syringe, to the mixture dropwise maintaining an internal temperature of 45-55° over 10 minutes. After addition was complete the syringe was rinsed with THF (0.1 mL) and the rinse charged to the reaction at 49° C. After stirring for 1.5 hours the batch was a clear amber color with an internal temperature of 19.6° C. THF (1 mL) was added. This crude material 6B was used directly for the next steps.

[0358] 2. Synthesis of 6.0

[0359] The flask was cooled to 0.8° C. using an ice/water bath then solid CuBr.Math.SMe2 (52.3 mg, 0.254 mmol, 0.2 equiv) was charged in one portion. An exotherm to 6° C. was observed. After cooling to 0.5° C. a solution of tert-butyl (2R)-2-methylaziridine-1-carboxylate (200 mg, 1.272 mmol, 1.0 equiv.) in tetrahydrofuran (0.5 mL) was added over 20 minutes, while maintaining an internal temperature<6° C. After stirring for 4 hours TLC analysis (5:1 heptane/EA) of the brown slurry showed complete reaction. After a further 20 minutes the reaction was quenched with dropwise addition sat. ammonium chloride (5.0 mL), while maintaining an internal temperature<18° C. (3 minutes). After stirring for 12 minutes at room temperature the biphasic mixture was diluted with Ethyl acetate (1.5 mL). The layers were separated, and the aqueous layer was extracted with Ethyl acetate (2×1.5 mL). The combined organic layers dried over sodium sulfate (1.3 g), filtered, and concentrated under reduced pressure. Chromatographic purification in silica, eluting with 0-15% Ethyl acetate/heptane afforded 6.0, tert-butyl (R)-(1-(benzo[d][1,3]dioxol-5-yl)propan-2-yl)carbamate, (130 mg, 36% yield) as a white solid. 50 mg purified by reversed Flash with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile Phase A: 10 mmol NH.sub.4HCO.sub.3+0.05% NH.sub.3H.sub.2O, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 23% B to 53% B in 8 min, 53% B; Wavelength: 254 nm. The fractions of desired product were lyophilized. This resulted in 28.0 mg as a white solid. MS m/z [M−H].sup.− (ESI):278.15. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 6.81-6.61 (m, 4H), 5.95-5.94 (m, 2H), 3.61-3.53 (m, 1H), 2.63-2.58 (m, 1H), 2.49-2.44 (m, 1H), 1.34 (s, 9H), 0.98 (d, J=6.8 Hz, 3H).

[0360] Synthesis of Prodrug 7.0

[0361] A solution of prodrug 6.0 (100 mg, 0.358 mmol, 1 equiv) in DMF (2 mL) was treated with sodium hydride (12.89 mg, 0.537 mmol, 1.5 equiv) for 30 min at 0° C. under nitrogen atmosphere followed by the addition of methyl iodide (101.63 mg, 0.716 mmol, 2 equiv) dropwise at 0° C. The resulting mixture was stirred for 16 hours at room temperature. The crude product was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150 mm 5 μm, n; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 25% B to 55% B in 8 min, 55% B; Wavelength: 254 nm) to afford 7.0, tert-butyl (R)-(1-(benzo[d][1,3]dioxol-5-yl)propan-2-yl)(methyl)carbamate, (34.5 mg, 32% yield) as a light-yellow oil. MS m/z [M+H].sup.+ (ESI): 294.05. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 6.81-6.59 (m, 3H), 5.93 (s, 2H), 4.33-4.10 (m, 1H), 2.61-2.55 (m, 5H), 1.30-1.08 (m, 12H). ee purity: 99.29%, [α].sub.D.sup.28.6=−118° (c=1 mg/mL, ACN)

Synthesis of Prodrug 8.0: (R)-4-(((1-(benzo[d][1,3]dioxol-5-yl)propan-2-yl)amino)methyl)-5-methyl-1,3-dioxol-2-one

[0362] ##STR00192##

[0363] Synthesis of 8B

[0364] To a solution of 6.0 (4 g, 14.320 mmol, 1 equiv) in DMF (40 mL) was added sodium hydride (60% in oil, 859.1 mg, 1.5 equiv) at 0° C. The mixture was stirred for 15 minutes. 4-methoxybenzyl chloride 8A (4.49 g, 28.640 mmol, 2 equiv) was added by dropwise and the mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was quenched by saturated ammonium chloride aqueous solution and extracted with dichloromethane (2×200 mL). The combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether/ethyl acetate (9:1) to afford 8B (4.2 g, 73% yield) as a yellow oil. MS m/z [M+Na].sup.+ (ESI):422.15.

[0365] Synthesis 8C

[0366] To a stirred solution of 8B (4.2 g, 10.513 mmol, 1 equiv) in dichloromethane (56 mL) was added trifluoroacetic acid (28 mL) by dropwise at 0° C. The resulting mixture was stirred for 10 minutes at 0° C. The value of pH was adjusted to ˜8 with saturated sodium bicarbonate aqueous solution at 0° C. The resulting mixture was extracted with ethyl acetate (2×200 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with dichloromethane/methanol (20:1) to afford 8C (2 g, 63% yield) as a yellow oil. MS m/z [M+H]+(ESI):300.20.

[0367] Synthesis 8E

[0368] To a solution of 8C (300 mg, 1.002 mmol, 1 equiv) in DMF (3 mL), Na.sub.2CO.sub.3 (214.4 mg, 2.004 mmol, 2 equiv), sodium iodide (30.0 mg, 0.200 mmol, 0.2 equiv) and 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one 8D (297.7 mg, 2.004 mmol, 2 equiv) was added. The mixture was stirred for 4 hours. Then, the solid was filtered. The filtrate was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water (0.05% ammonium bicarbonate), 20% to 100% gradient in 15 min; detector, UV 220 nm. The fractions of desired product were concentrated under reduced pressure. This resulted in 8E (300 mg, 73% yield) as a yellow oil. MS m/z [M+H]+(ESI):412.20.

Synthesis of 8.0: (R)-4-(((1-(benzo[d][1,3]dioxol-5-yl)propan-2-yl)amino)methyl)-5-methyl-1,3-dioxol-2-one

[0369] A solution of 8E (300 mg, 0.729 mmol, 1 equiv) in TFA (3 mL) was stirred for 2 days at 80° C. Then, it was cooled to room temperature and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water (0.05% TFA), 10% to 50% gradient in 15 min; detector, UV 220 nm. The fractions of desired product were concentrated under reduced pressure. This resulted in crude product. It was purified by Column: XSelect CSH Prep C18 OBD Column, 19*250 mm, 5 μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 13% B to 23% B in 8 min, 23% B; Wavelength: 254 nm. The fractions of desired product were lyophilized. This resulted in 8.0, (R)-4-(((1-(benzo[d][1,3]dioxol-5-yl)propan-2-yl)amino)methyl)-5-methyl-1,3-dioxol-2-one, (15.7 mg) as a grey semi-solid (FA salt). MS m/z [M+H].sup.+ (ESI):292.05. .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 6.82-6.71 (m, 3H), 5.94 (s, 2H), 4.21 (s, 2H), 3.58-3.49 (m, 1H), 3.15-3.09 (m, 1H), 2.70-2.63 (m, 1H), 2.20 (s, 3H), 1.27 (d, J=6.6 Hz, 3H). ee purity: 100%, [α].sub.D.sup.28.6=−168° (c=1 mg/mL, ACN)

Synthesis of Prodrug 9.0: (R)-4-(((1-(benzo[d][1,3]dioxol-5-yl)propan-2-yl)(methyl)amino)methyl)-5-methyl-1,3-dioxol-2-one

[0370] To a solution of 8.0 (290 mg, 0.996 mmol, 1 equiv) in methanol (4.35 mL), sodium cyanoborohydride (125.12 mg, 1.992 mmol, 2 equiv) and formaldehyde (161.58 mg, 1.992 mmol, 2 equiv, 37% in water) was added at 0° C. It was stirred for 2 hours at room temperature. Then, it was quenched with saturated ammonium chloride aqueous solution. The resulting mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. It was purified by Column: Xselect CSH C18 OBD Column 30*150 mm 5 μm, n; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 10% B to 40% B in 8 min, 40% B; Wavelength: 254 nm. The fractions of desired product were lyophilized. This resulted in 9.0, (R)-4-(((1-(benzo[d][1,3]dioxol-5-yl)propan-2-yl)(methyl)amino)methyl)-5-methyl-1,3-dioxol-2-one, (44.8 mg) as a light grey oil (FA salt). MS m/z [M+H].sup.+ (ESI):306.10. .sup.1H NMR (400 MHz, Acetonitrile-d.sub.3) δ 6.80-6.72 (m, 2H), 6.70-6.64 (m, 1H), 5.93 (s, 2H), 3.45-3.35 (m, 2H), 3.00-2.91 (m, 1H), 2.81-2.76 (m, 1H), 2.49-2.41 (m, 1H), 2.25 (s, 3H), 2.04 (s, 3H), 0.96 (d, J=6.4 Hz, 3H). ee purity: 100%, [α].sub.D.sup.28.6=−95° (c=1 mg/mL, ACN).

[0371] It will be appreciated that the prodrugs of the invention afford increased exposure and bioavailability relative to parent drug itself. Prodrugs generated across different sites of the MDMA/MDA scaffold have specific pharmacokinetic profiles and afford distinct advantages to fine tune exposure, duration of exposure and overall intensity of entactogenic effects. Underlying these advantages are increased metabolic stability, increased absorption and decreased maximal plasma concentrations of parent drug over time. Prodrugs of the invention which limit maximal plasma concentrations of parent drug over time also limit amphetaminergic-like side effects of MDMA including hypertension. Limiting these side effects expands the suitability of MDMA for its intended PTSD population, of which many are obese and diagnosed with chronic hypertension.

Synthesis of Prodrug 11: phenyl N-(1-(benzo[d][1,3]dioxol-5-yl)propan-2-yl)-P-(methoxymethyl)-N-methylphosphonamidate

[0372] Prodrug 11 was synthesis in 6 steps from commercially available intermediate (10A). and described in Scheme 8.

##STR00193##

[0373] Synthesis of Intermediate 11B:

[0374] To a solution of 11A (200 mg, 1.098 mmol, 1 equiv) in acetonitrile (2 mL), bromo-trimethylsilane (504.27 mg, 3.294 mmol, 3 equiv) was added. It was stirred for 2 hours at 50° C. Then, it was cooled to room temperature and concentrated under reduced pressure. The crude was dissolved in dichloromethane (4 mL), one drop of N,N-Dimethylformamide and oxalyl chloride (418.06 mg, 3.294 mmol, 3 equiv) was added at 0° C. under nitrogen atmosphere. It was stirred for 1 hour at room temperature. Then, the solvent was removed under reduced pressure. This resulted in 11B (175 mg, 97% yield) as a yellow oil. The crude was used at next step directly.

[0375] Synthesis of Intermediate 11C:

[0376] To a solution of 11B (175 mg, 1.074 mmol, 1.2 equiv) in dichloromethane (2 mL), a solution phenol (84.24 mg, 0.895 mmol, 1 equiv) and triethylamine (271.72 mg, 2.685 mmol, 3 equiv) in dichloromethane (2 mL) was added by dropwise at −10° C. under nitrogen atmosphere. The mixture was stirred for 1 hour at room temperature. Then, a solution of 1D (258.84 mg, 0.716 mmol, 0.8 equiv) in dichloromethane (2 mL) was added into the system. It was stirred for 1 hour at room temperature. The reaction was diluted with DCM, washed with saturated sodium phosphate monobasic. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water (0.05% TFA), 20% to 100% gradient in 15 min; detector, UV 220 nm. This resulted in 11C (200 mg, 31% yield) as a colorless oil. MS m/z [M+H].sup.+ (ESI): 546.35. This product (11C) was used directly for the next step without further characterization.

[0377] Synthesis of Intermediate 11D:

[0378] To a solution of 11C (200 mg, 0.275 mmol, 1 equiv, 75%) in tetrahydrofuran (4 mL) was added Pd/C (10%, 100 mg) under nitrogen atmosphere. The mixture was hydrogenated at room temperature for 3 hours under hydrogen atmosphere using a hydrogen balloon, filtered through a celite pad and concentrated under reduced pressure. The crude (11D: MS m/z [M+H].sup.+ (ESI):366.20) was used at next step directly.

Synthesis of final Prodrug 11: Phenyl N-(1-(benzo[d][1,3]dioxol-5-yl)propan-2-yl)-P-(methoxymethyl)-N-methylphosphonamidate

[0379] To a mixture of 11D (150 mg, 0.287 mmol, 1 equiv, 70%) in DMF (1.5 mL) was added bromochloromethane (59.49 mg, 0.459 mmol, 1.6 equiv) dropwise at room temperature under nitrogen atmosphere. It was stirred for 2 hours at room temperature. Then, the resulting mixture was filtered. The filtrate was purified by Column: XBridge Shield RP18 OBD Column 19*250 mm, 5 μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 0% B to 25% B in 10 min; Wavelength: 254 nm nm; RT1 (min): 9.0. The fractions of desired product were lyophilized. This resulted in prodrug 11, phenyl N-(1-(benzo[d][1,3]dioxol-5-yl)propan-2-yl)-P-(methoxymethyl)-N-methylphosphonamidate (33.1 mg, 30% yield) as a yellow oil. MS m/z [M+H].sup.+ (ESI): 378.10. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.40-7.24 (m, 2H), 7.20-6.99 (m, 3H), 6.85-6.69 (m, 2H), 6.67-6.56 (m, 1H), 5.98-5.92 (m, 2H), 4.03-3.63 (m, 2H), 3.37-3.35 (m, 2H), 3.32-3.26 (m, 1H), 3.25-3.22 (m, 2H), 2.60-2.51 (m, 4H), 0.99-0.84 (m, 3H). .sup.31P NMR (400 MHz, DMSO-d.sub.6) δ 24.51, 24.23.

Example 2: Evaluation of Compound Stability

[0380]

TABLE-US-00004 TABLE 2 Compound Chemical stability PBS (pH 6.5) % Remaining at 0, 30, 60, 120 and 240 ID minutes Prodrug-class 1 100.00, 90.48, 90.36, 89.59, 90.28 carbamate 2 100.00, 89.05, 87.87, 91.21, 88.66 carbamate 3 100.00, 103.45, 107.91, 105.56, 96.60 N-acyloxy alkoxy carbonyl 4 100.00, 88.84, 92.54, 92.04, 92.48 Amide/amino Acids 5 100.00, 95.53, 97.09, 98.67, 105.87 Amide/amino Acids 6 100.00, 84.81, 93.60, 103.65, 91.66 carbamate 7 100.00, 94.54, 105.49, 105.72, 102.75 carbamate 8 100, 96, 93, 75, 72 Dialkyl-1,3-dioxol-2-one 9 100, 83, 75, 55, 32 Dialkyl-1,3-dioxol-2-one

TABLE-US-00005 TABLE 3 Compound Chemical stability SGF with pepsin % Remaining at 0, 30, 60, 120 and 240 ID minutes Prodrug-class 1 100.00, 101.86, 98.61, 103.31, 100.50 carbamate 2 100.00, 100.95, 97.74, 98.18, 99.08 carbamate 3 100.00, 106.44, 108.51, 103.98, 106.17 N-acyloxy alkoxy carbonyl 4 100.00, 108.06, 98.50, 106.18, 103.88 Amide/amino Acids 5 100.00, 99.68, 105.84, 94.42, 91.97 Amide/amino Acids 6 100.00, 85.17, 79.89, 56.87, 31.48 carbamate 7 100.00, 74.97, 63.49, 56.42, 28.25 carbamate 8 100, 103, 98, 96, 92 Dialkyl-1,3-dioxol-2-one 9 100, 97, 92, 87, 71 Dialkyl-1,3-dioxol-2-one

TABLE-US-00006 TABLE 4 Compound Chemical stability SGF without pepsin % Remaining at 0, 30, 60, 120 and 240 ID minutes Prodrug-class 1 100.00, 103.81, 101.90, 103.81, 104.29 carbamate 2 100.00, 102.53, 101.64, 90.45, 99.40 carbamate 3 100.00, 97.82, 97.35, 93.65, 94.12 N-acyloxy alkoxy carbonyl 4 100.00, 94.49, 96.72, 96.67, 96.46 Amide/amino acids 5 100.00, 101.17, 91.48, 95.49, 100.41 Amide/amino acids 6 100.00, 87.96, 77.20, 57.49, 28.57 carbamate 7 100.00, 89.90, 73.62, 61.79, 30.52 carbamate 8 100, 97, 94, 90, 86 Dialkyl-1,3-dioxol-2-one 9 1000, 94, 89, 83, 72 Dialkyl-1,3-dioxol-2-one

TABLE-US-00007 TABLE 5 Compound Mouse Plasma stability % Remaining at 0, 15, 30, 60, and 120 ID minutes Prodrug-class 1 100.00, 108.51, 87.67, 98.49, 89.31 carbamate 2 100.00, 101.77, 86.60, 89.02, 84.42 carbamate 3 100, 0.0, 0.0, 0.0, 0.0 N-acyloxy alkoxy carbonyl 4 100.00, 102.99, 83.50, 94.51, 87.42 Amide/amino acids 5 100.00, 103.33, 87.64, 90.78, 83.06 Amide/amino acids 6 100, 102, 106, 92, 95 carbamate 7 100, 101, 92, 83, 92 carbamate 8 100, 72, 54, 25, 6 Dialkyl-1,3-dioxol-2-one 9 100, 70, 22, 4 Dialkyl-1,3-dioxol-2-one

Example 3: Evaluation of Compound Solubility

[0381]

TABLE-US-00008 TABLE 6 Compound Solubility FaSSIF Solubility ID Structure MW Prodrug-class (uM) 1 [00194] embedded image 265.31 carbamate 309.11 2 [00195] 251.28 carbamate 313.43 3 [00196] 365.43 N-acyloxy alkoxy carbonyl 101.28 4 [00197] 250.3 Amide/amino Acids 291.11 5 [00198] 236.27 Amide/amino Acids 304.05 6 [00199] 279.34 carbamate 175.28 7 [00200] 293.36 carbamate 256.53 8 [00201] embedded image 291.3 Dialkyl-1,3- dioxol-2-one 282.91 9 [00202] 305.33 Dialkyl-1,3- dioxol-2-one 223.28 10 [00203] 363.35 Methoxymethyl phosphinyl NA 11 [00204] 377.38 Methoxymethyl phosphinyl NA

PRODRUGS OF MDMA, MDA, AND DERIVATIVES THEREOF

Inventors

Cpc classification

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C07D411/12

CHEMISTRY; METALLURGY

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C07D317/58

CHEMISTRY; METALLURGY

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A61P25/24

HUMAN NECESSITIES

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C07F9/65517

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C07F9/30

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International classification

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C07D317/58

CHEMISTRY; METALLURGY

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C07D411/12

CHEMISTRY; METALLURGY

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C07F9/30

CHEMISTRY; METALLURGY

Abstract

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Description