NOVEL PRODRUGS AND CONJUGATES OF DIMETHYLTRYPTAMINE

1 . A compound of Formula (I):

or a pharmaceutically acceptable salt thereof;

wherein,

R 1 and R 2 are independently hydrogen, alkyl, cycloalkyl, or R 1 and R 2 together with the atoms to which they are attached form a heterocycle;

X, Y and Z are independently hydrogen, halogen, —O—, —S—, —NR A —, or —(P═O)—OR A (—OR′), wherein R A is hydrogen or alkyl;

R′, R 3 , R 4 , R 5 and R 6 are independently absent, hydrogen, alkyl, —(C═O)-alkyl, —(C═O)CHR 7 , —(C═O)(CH 2 ) n (NH 2 ), —(C)CH(NH 2 )(CH 3 ), —(C═O)CH(NH 2 ), (CH 2 ) n (NH)(C═NH), or —(C═O)(CH 2 ) n (NH)(C═NH)—NH 2 ;

R 7 and R 8 are independently hydrogen or alkyl;

R 9 is hydrogen, alkyl, or halogen;

L and M are independently alkyl or aryl;

W is oxygen, sulfur or NR 6 ;

n is an integer from 2-7; and

m is an integer from 1-4,

wherein at least one of R′, R 3 , R 4 , and R 5 and R 6 is —(C═O)-alkyl, —(C═O)CHR 7 (NH 2 ), —(C═O)(CH 2 ) n (NH 2 ), —(C═O)CH(NH 2 )(CH 2 ) n (NH 2 ), —(C═O)(CH 2 ) n (NH)(C═NH)—NH 2 or

2 . The compound of claim 1 , wherein R 1 and R 2 are independently C 1 -C 6 alkyl.

3 . The compound of claim 1 or 2 , wherein R 1 and R 2 are independently methyl, ethyl, propyl, and isopropyl.

4 . The compound of any one of claims 1 - 3 , wherein R 1 and R 2 are methyl.

5 . The compound of any one of claims 1 - 4 , wherein X, Y and Z are H.

6 . The compound of any one of claims 1 - 5 , wherein R 8 is hydrogen.

7 . The compound of any one of claims 1 - 6 , wherein R 8 is alkyl.

8 . The compound of any one of claims 1 - 7 , wherein R 8 is C 1 -C 6 alkyl.

9 . The compound of any one of claims 1 - 8 , wherein R 9 is a halogen.

10 . The compound of any one of claims 1 - 9 , wherein R 9 is Br.

11 . The compound of any one of claims 1 - 8 , wherein R 9 is alkyl.

12 . The compound of any one of claims 1 - 8 or 11 , wherein R 9 is C 1 -C 6 alkyl.

13 . The compound of any one of claims 1 - 8 , wherein R 7 and R 8 are independently hydrogen or C 1 -C 8 alkyl and R 9 is hydrogen, halogen, or C 1 -C 8 alkyl.

14 . The compound of claim 13 , wherein the halogen is bromine.

15 . The compound of claim 13 , wherein said C 1 -C 8 alkyl is substituted with at least one of hydroxyl, thiol and halogen.

16 . The compound of any one of claims 1 - 15 , wherein m is 1.

17 . The compound of any one of claims 1 - 15 , wherein m is 2.

18 . The compound of claim 1 , wherein X, Y and Z are hydrogen; W is NR 6 ; and R 6 is —(C═O)— alkyl or —(C═O)(CH 2 ) n (NH 2 ).

19 . The compound of claim 1 , wherein two of X, Y and Z are hydrogen.

20 . The compound of claim 19 , wherein the non-hydrogen X, Y or Z is —O—, —S—, —NR A —, or —(P═O)—OR A (—OR′), wherein R A is hydrogen or alkyl.

21 . The compound of claim 1 , wherein X and Y are hydrogen; Z is —O—, —S—, —NR A —, or —(P═O)—OR A (—OR′), wherein R A is hydrogen or alkyl.

22 . The compound of claim 1 , wherein X and Z are hydrogen; Y is —O—, —S—, —NR A —, or —(P═O)—OR A (—OR′), wherein R A is hydrogen or alkyl.

23 . The compound of claim 1 , wherein Y and Z are hydrogen; X is —O—, —S—, —NR A —, or —(P═O)—OR A (—OR′), wherein R A is hydrogen or alkyl.

24 . The compound of any one of claims 1 - 23 , wherein R 5 is —(C═O)-alkyl or —(C═O)(CH 2 ) n (NH 2 ).

25 . The compound of any one of claims 1 - 24 , wherein R 4 is —(C═O)-alkyl or —(C═O)(CH 2 ) n (NH 2 ).

26 . The compound of any one of claims 1 - 25 , wherein R 3 is —(C═O)-alkyl or —(C═O)(CH 2 ) n (NH 2 ).

27 . The compound of any one of claims 1 - 26 , wherein R 6 is —(C═O)-alkyl or —(C═O)(CH 2 ) n (NH 2 ).

28 . The compound of any one of claims 1 - 23 , wherein at least one of R′, R 3 , R 4 , R 5 and R 6 is —(C═O)(CH 2 ) n (NH 2 ) and n is 3.

29 . The compound of any one of claims 1 - 23 , wherein at least one of R′, R 3 , R 4 , R 5 and R 6 is —(C═O)CH(NH 2 )(CH 2 ) n (NH 2 ), and n is 4.

30 . The compound of any one of claims 1 - 23 , wherein at least one of R′, R 3 , R 4 , R 5 and R 6 is —(C═O)(CH 2 ) n (NH)(C═NH)—NH 2 and n is 3.

31 . The compound of any one of claims 1 - 23 , wherein at least one of R′, R 3 , R 4 , R 5 and R 6 is —(C═O)CH(NH)(CH 2 ) n (C═NH)—NH 2 and n is 2.

32 . The compound of any one of claims 1 - 31 , wherein L is methyl or isopropyl and M is alkyl or aryl.

33 . The compound of any one of claims 1 - 32 , wherein W is NR 6 and R 6 is hydrogen or alkyl.

34 . A compound of claim 1 , which is a salt of the Formula (IV):

wherein R 10 is —(C═O)-alkyl, —(C═O)CHR 7 (NH 2 ), —(C═O)(CH 2 ) n (NH 2 ), —(C═O)CH(NH 2 )(CH 2 ) n (NH 2 ), —(C═O)(CH 2 ) n (NH)(C═NH)—NH 2 or

A is a pharmaceutically acceptable anion.

35 . The compound of any one of claims 1 - 34 , wherein the compound is a compound shown in Table 1, Table 2, Table 3, or Table 4.

36 . A compound of Formula (III):

or a pharmaceutically acceptable salt thereof;

wherein,

R 1 and R 2 are independently hydrogen, alkyl, cycloalkyl, or R 1 and R 2 together with the atoms to which they are attached form a heterocycle;

X, Y and Z are independently hydrogen, halogen, —O—, —S—, —NR A —, or —(P═O)—OR A (—OR′), wherein R A is hydrogen or alkyl,

R′, R 3 , R 4 , and R 5 are independently absent, hydrogen, alkyl, —(C═O)-alkyl, —(C═O)CHR 7 (NH 2 ), —(C═O)(CH 2 ) n (NH 2 ), —(C═O)CH(NH 2 )(CH 2 ) n (NH 2 ), —(C═O)CH(NH 2 ) (CH 2 ) n (NH)(C═NH)—NH 2 , —(C═O)(CH 2 ) n (NH)(C═NH)—NH 2 or

R 7 and R 8 are independently hydrogen or alkyl;

R 9 is hydrogen, alkyl or halogen;

L and M are independently alkyl or aryl;

n is an integer from 2-7; and

m is an integer from 1-4,

wherein at least one of R′, R 3 , R 4 , and R 5 is —(C═O)-alkyl, —(C═O)CHR 7 (NH 2 ), —(C═O)(CH 2 ) n (NH 2 ), —(C═O)CH(NH 2 )(CH 2 ) n (NH 2 ), —(C═O)(CH 2 ) n (NH)(C═NH)—NH 2 or

37 . The compound of claim 36 , wherein R 1 and R 2 are independently C 1 -C 6 alkyl.

38 . The compound of claim 36 or 37 , wherein R 1 and R 2 are independently methyl, ethyl, propyl, and isopropyl.

39 . The compound of any one of claims 36 - 38 , wherein R 1 and R 2 are methyl.

40 . The compound of any one of claims 36 - 39 , wherein X, Y and Z are H.

41 . The compound of any one of claims 36 - 40 , wherein R 8 is hydrogen.

42 . The compound of any one of claims 36 - 41 , wherein R 8 is alkyl.

43 . The compound of any one of claims 36 - 42 , wherein R 8 is C 1 -C 6 alkyl.

44 . The compound of any one of claims 36 - 43 , wherein R 9 is hydrogen.

45 . The compound of any one of claims 36 - 43 , wherein R 9 is alkyl.

46 . The compound of claim 45 , R 9 is C 1 -C 6 alkyl.

47 . The compound of any one of claims 36 - 46 , wherein R 7 and R 8 are independently hydrogen or C 1 -C 8 alkyl and R 9 is hydrogen, halogen or C 1 -C 8 alkyl.

48 . The compound of claim 47 , wherein the C 1 -C 8 alkyl is substituted with at 1-3 groups including hydroxyl, thiol or halogen.

49 . The compound of any one of claims 36 - 48 , wherein m is 1.

50 . The compound of any one of claims 36 - 48 , wherein m is 2.

51 . The compound of any one of claims 1 - 39 or 41 - 50 , wherein two of X, Y and Z are hydrogen.

52 . The compound of claim 51 , wherein the non-hydrogen X, Y or Z is —O—, —S—, —NR A —, or —(P═O)—OR A (—OR′), wherein R A is hydrogen or alkyl.

53 . The compound of claim 36 , wherein X and Y are hydrogen; Z is —O—, —S—, —NR A —, or —(P═O)—OR A (—OR′), wherein R A is hydrogen or alkyl.

54 . The compound of claim 36 , wherein X and Z are hydrogen; Y is —O—, —S—, —NR A —, or —(P═O)—OR A (—OR′), wherein R A is hydrogen or alkyl.

55 . The compound of claim 36 , wherein Y and Z are hydrogen; X is —O—, —S—, —NR A —, or —(P═O)—OR A (—OR′), wherein R A is hydrogen or alkyl.

56 . The compound of any one of claims 36 - 55 , wherein R 4 is —(C═O)-alkyl, or —(C═O)(CH 2 ) n (NH 2 ).

57 . The compound of any one of claims 36 - 56 , wherein R 5 is —(C═O)-alkyl or —(C═O)(CH 2 ) n (NH 2 ).

58 . The compound of any one of claims 36 - 57 , wherein R 3 is —(C═O)-alkyl, or —(C═O)(CH 2 ) n (NH 2 ).

59 . The compound of any one of claims 36 - 55 , wherein at least one of R′, R 3 , R 4 , and R 5 is —(C═O)(CH 2 ) n (NH 2 ) and n is 3.

60 . The compound of any one of claims 36 - 55 , wherein at least one of R′, R 3 , R 4 , and R 5 is —(C═O)CH(NH 2 )(CH 2 ) n (NH 2 ) and n is 4.

61 . The compound of any one of claims 36 - 55 , wherein at least one of R′, R 3 , R 4 , and R 5 is —(C═O)(CH 2 ) n (NH)(C═NH)—NH 2 and n is 3.

62 . The compound of any one of claims 36 - 55 , wherein at least one of R′, R 3 , R 4 , and R 5 is —(C═O)CH(NH 2 )(CH 2 ) n (NH)(C═NH)—NH 2 and n is 2.

63 . The compound of any one of claims 36 - 55 , wherein at least one of R′, R 3 , R 4 , and R 5 is

64 . The compound of any one of claims 36 - 63 , in salt form, of the Formula (V):

wherein R 10 is —(C═O)-alkyl, —(C═O)CHR 7 (NH 2 ), —(C═O)(CH 2 ) n (NH 2 ), —(C═O)CH(NH 2 )(CH 2 ) n (NH 2 ), —(C═O)CH(NH 2 )(CH 2 ) n (NH)(C═NH)—NH 2 , —(C═O)(CH 2 ) n (NH)(C═NH)—NH 2 or

and

wherein A is a pharmaceutically acceptable anion.

65 . The compound claim 64 , wherein L is methyl or isopropyl and M is alkyl or aryl.

66 . A pharmaceutical composition comprising the compound of any one of claims 1 - 65 and a pharmaceutically acceptable excipient.

67 . A compound as shown in Table 2, wherein X and Y are hydrogen and R 3 and R 4 are absent.

68 . A compound as shown in Table 2, wherein X is hydrogen, R 3 is absent, Y is O, and R 4 is hydrogen.

69 . A compound as shown in Table 2, wherein X is hydrogen, R 3 is absent, Y is O, and R 4 is Me.

70 . A compound as shown in Table 2, wherein X is hydrogen, R 3 is absent, Y is O, and R 4 is Ac.

71 . A compound as shown in Table 2, wherein X is O, R 3 is hydrogen, Y is hydrogen, and R 4 is absent.

72 . A compound as shown in Table 2, wherein X is O, R 3 is Me, Y is hydrogen, and R 4 is absent.

73 . A compound as shown in Table 2, wherein X is O, R 3 is Ac, Y is hydrogen, and R 4 is absent.

74 . A compound of the formula:

75 . A compound of the formula:

76 . A compound of the formula

77 . A compound of the formula:

78 . A compound of Formula (VI):

R 1 and R 2 are independently hydrogen, alkyl, cycloalkyl, or R 1 and R 2 together with the atoms to which they are attached form a heterocycle;

R 3 , R 4 , R 5 and R 6 are independently absent, hydrogen, alkyl, —(C═O)-alkyl, —(C═O)CHR 7 , —(C═O)(CH 2 ) n (NH 2 ), —(C)CH(NH 2 )(CH 3 ), —(C═O)CH(NH 2 ), (CH 2 ) n (NH)(C═NH), or —(C═O)(CH 2 ) n (NH)(C═NH)—NH 2 ;

X is carbon or nitrogen;

W is carbon, oxygen, or nitrogen; and

Z is hydrogen, deuterium, or oxygen.

79 . The compound of claim 78 , having the following chemical formula:

80 . A compound selected from the formulae:

81 . A phosphonooxymethyl prodrug according to claim 1 of the Formula (VIII):

wherein

Ru and R 12 are pharmaceutically acceptable salt and are independently H, D, Na + , K + , NH 4 + ; or

R 1 and R 12 are independently a pharmaceutically acceptable salt, hydrogen, deuterium, alkyl, substituted alkyl, cycloalkyl, or R 11 and R 12 together with the atoms to which they are attached form an alkyl, cycloalkyl, heterocycles and are ether, hemiaminal ketal and amino acid, wherein the pharmaceutically acceptable salt is Na + , K + , NH 4 + .

82 . A pharmaceutical composition comprising a compound of any one of claims 1 - 65 or 67 - 81 and a pharmaceutically acceptable excipient.

83 . An oral dosage form comprising the pharmaceutical composition of claim 66 or 82 .

84 . A method of treating post-traumatic stress disorder (PTSD) in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of any one of claims 1 - 65 or 67 - 81 or a pharmaceutical composition of claims 66 , 82 or 83 to the subject.

85 . A method of treating depression in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of any one of claims 1 - 65 or 67 - 81 or a pharmaceutical composition of claims 66 , 82 or 83 to the subject.

86 . The method of claim 85 , wherein the depression is major depressive disorder (MDD) or treatment-resistant depression (TRD).

87 . A method of treating an anxiety disorder in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of any one of claims 1 - 65 or 67 - 81 or a pharmaceutical composition of claims 66 , 82 or 83 to the subject.