PSILOCIN DERIVATIVES AS SEROTONERGIC PSYCHEDELIC AGENTS FOR THE TREATMENT OF CNS DISORDERS

1 . A compound of Formula (I) or a pharmaceutically acceptable salt, solvate and/or prodrug thereof:

wherein R 1 is selected from hydrogen, C 1 -C 3 alkyl, C 1 -C 6 alkyleneP(O)(OR 12 ) 2 , C(O)R 12 , CO 2 R 12 , C(O)N(R 12 ) 2 , S(O)R 12 and SO 2 R 12 ;

R 2 to R 6 are independently selected from hydrogen and C 1 -C 6 alkyl;

R 7 and R 8 are independently selected from hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl, substituted or unsubstituted C 3 -C 7 heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl, or

R 7 and R 8 are taken together with the nitrogen atom therebetween to form a 3- to 7-membered heterocyclic ring optionally including 1 to 2 additional ring heteromoieties selected from O, S, S(O), SO 2 , N and NR 13 ,

wherein said C 3 -C 7 cycloalkyl and 3- to 7-membered heterocyclic ring are each further optionally substituted with a substituent selected from halogen, CO 2 R 13 , C(O)N(R 13 ) 2 , SO 2 R 13 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 3 -C 6 cycloalkyl and a 3- to 6-membered heterocyclic ring including 1 to 2 ring heteromoieties selected from O, S, N, S(O), SO 2 and NR 13 ;

R 9 , R 10 and R 11 are independently selected from hydrogen, halogen, CN, OR 13 , N(R 13 ) 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, CO 2 R 13 , C(O)N(R 13 ) 2 , SOR 13 , SO 2 R 13 , C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 3 -C 7 cycloalkyl and a 3- to 7-membered heterocyclic ring including 1 to 2 ring heteromoieties selected from O, S, S(O), SO 2 , N and NR 13 , wherein said C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 3 -C 7 cycloalkyl and 3- to 7-membered heterocyclic ring groups are optionally substituted by one or more substituents independently selected from CN, OR 13 , N(R 13 ) 2 and SR 13 , and wherein said C 3 -C 7 cycloalkyl and 3- to 7-membered heterocyclic ring are each further optionally substituted with a substituent selected from halogen, CO 2 R 13 , C(O)N(R 13 ) 2 , SO 2 R 13 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 3 -C 6 cycloalkyl and a 3- to 6-membered heterocyclic ring including 1 to 2 ring heteromoieties selected from O, S, S(O), SO 2 , N and NR 13 ;

Y is selected from halogen and X-A;

X is selected from O, NR 13 , S, S(O) and SO 2 ;

A is selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, C 4 -C 6 cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, P(O)(OR 12 ) 2 , C 1 -C 6 alkyleneP(O)(OR 12 ) 2 , C 1 -C 6 alkyleneC 3 -C 7 cycloalkyl, C 1 -C 6 alkyleneC 4 -C 6 cycloalkenyl, C 1 -C 6 alkyleneheterocycloalkyl, C 1 -C 3 alkylenearyl, C 1 -C 6 alkyleneheteroaryl, C(O)Q′, CO 2 Q′, C(O)N(Q′) 2 , S(O)Q′) and SO 2 Q′,

wherein Q′ is selected from C 1 -C 20 alkyl, C 1 -C 20 haloalkyl, C 2 -C 20 alkenyl, C 2 -C 20 haloalkenyl, C 2 -C 20 alkynyl, C 2 -C 20 haloalkynyl, C 3 -C 7 cycloalkyl, C 4 -C 7 cycloalkenyl and a 3- to 7-membered heterocyclic ring including 1 to 2 ring heteromoieties selected from O, S, S(O), SO 2 , N and NR 13 , wherein said C 1 -C 20 alkyl, C 2 -C 20 haloalkyl, C 2 -C 20 alkenyl, C 2 -C 20 haloalkenyl, C 3 -C 7 cycloalkyl, C 4 -C 7 cycloalkenyl and 3- to 7-membered heterocyclic ring groups are optionally substituted by one or more substituents independently selected from CN, OR 13 , N(R 13 ) 2 , CO 2 R 13 , SR 13 , C 3 -C 7 cycloalkyl, C 4 -C 7 cycloalkenyl and a 3- to 7-membered heterocyclic ring, and/or are disubstituted on the same carbon atom with C 1-6 alkyl, or with C 2-6 alkylene to form a C 3 -C 7 cycloalkyl ring, and wherein each of said C 3 -C 7 cycloalkyl, C 4 -C 7 cycloalkenyl, and 3- to 7-membered heterocyclic ring are each further optionally substituted with a substituent selected from of C 1 -C 3 alkyl and C 1 -C 3 haloalkyl;

each R 12 is independently selected from hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl, substituted or unsubstituted C 3 -C 7 heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl, substituted or unsubstituted C 1 -C 6 alkyleneC 3 -C 7 cycloalkyl, substituted or unsubstituted C 1 -C 6 alkyleneC 3 -C 7 heterocycloalkyl, substituted or unsubstituted C 1 -C 6 alkylenearyl and substituted or unsubstituted C 1 -C 6 alkyleneheteroaryl;

each R 13 is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 3 -C 7 cycloalkyl, and a 3- to 7-membered heterocyclic ring including 1 to 2 ring heteromoieties selected from O, S, S(O), SO 2 , N and NR 14 , wherein said C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 3 -C 7 cycloalkyl and 3- to 7-membered heterocyclic ring groups are optionally substituted by one or more substituents independently selected from CN, OR 14 , N(R 14 ) 2 and SR 14 , and wherein said C 3 -C 7 cycloalkyl and 3- to 7-membered heterocyclic ring are each further optionally substituted with a substituent selected from halogen, CO 2 R 14 , C(O)N(R 14 ) 2 , SO 2 R 14 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 3 -C 6 cycloalkyl and a 3- to 6-membered heterocyclic ring including 1 to 2 ring heteromoieties selected from O, S, S(O), SO 2 , N and NR 14 ,

R 14 is selected from hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; and

wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof,

provided either R 1 is C 1 -C 6 P(O)(OR 12 ) 2 and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 , Q′, X, Y and A are as defined above for Formula (I); or

Y is X-A wherein A is selected from C 1 -C 6 alkyleneP(O)(OR 12 ) 2 , C 1 -C 6 alkyleneC 3 -C 7 cycloalkyl, C 1 -C 6 alkyleneC 4 -C 6 cycloalkenyl, C 1 -C 6 alkyleneheterocycloalkyl, C 1 -C 3 alkylenearyl, C 1 -C 6 alkyleneheteroaryl, C(O)Q′, CO 2 Q′, C(O)N(Q′) 2 , S(O)Q′ and SO 2 Q′ and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 , Q′ and X are as defined above for Formula (I).

2 . The compound of claim 1 , wherein R 1 is selected from hydrogen, C 1 -C 3 alkyl, C 3 alkyleneP(O)(OR 12 ) 2 , C(O)R 12 , CO 2 R 12 , C(O)N(R 12 ) 2 , S(O)R 12 and SO 2 R 12 ; wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.

3 . The compound of claim 2 , wherein R 1 is selected from S(O)R 12 and SO 2 R 12 , wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.

4 . The compound of claim 2 , wherein R 1 is selected from hydrogen, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 P(O)(OR 12 ) 2 and CH(CH 3 )P(O)(OR 12 ) 2 , wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.

5 . The compound of claim 1 , wherein R 2 is selected from hydrogen and C 1 -C 4 alkyl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.

6 . The compound of claim 1 , wherein R 3 , R 4 , R 5 and R 6 are independently selected from hydrogen and C 1 -C 4 alkyl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.

7 . The compound of claim 1 , wherein R 3 , R 4 , R 5 and R 6 are independently selected from hydrogen, deuterium, Br, F, CH 3 , CD 2 H, CDH 2 and CD 3 .

8 . The compound of claim 1 , wherein at least one of R 3 , R 4 , R 5 and R 6 is deuterium or at least one of R 3 , R 4 , R 5 and R 6 comprises deuterium, or wherein R 3 , R 4 , R 5 and R 6 are all hydrogen or R 3 , R 4 , R 5 and R 6 are all deuterium.

9 . The compound of claim 1 , wherein R 7 and R 8 are independently selected from hydrogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 4 haloalkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.

10 . The compound of claim 9 , wherein R 7 and R 8 are independently selected from hydrogen and C 1 -C 4 alkyl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.

11 . The compound of claim 1 , wherein R 7 and R 8 are taken together with the nitrogen atom therebetween to form a 4- to 7-membered heterocyclic ring optionally including 1 to 2 additional ring heteromoieties selected from O, S, S(O), SO 2 , N and NR 13 , wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.

12 . The compound of claim 1 , wherein R 9 , R 10 and R 11 are independently selected from hydrogen, F, CI, Br, CN, OR 13 , N(R 13 ) 2 , SR 13 , CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , C 1 -C 4 haloalkyl, C 2 -C 6 haloalkenyl, CO 2 R 13 , S(O)R 13 , SO 2 R 13 and C 2 -C 6 alkenyl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.

13 . The compound of claim 1 , wherein Y is halogen, and the halogen in Y is selected from F, CI and Br.

14 . The compound of claim 1 , wherein Y is X-A and X is selected from O, NR 13 and S, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.

15 . The compound of claim 14 , wherein X is O.

16 . The compound of claim 15 , wherein A is selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, C 4 -C 7 cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, P(O)(OR 11 ) 2 , C 1 -C 3 alkyleneP(O)(OR 11 ) 2 , C 1 -C 3 alkyleneC 3 -C 7 cycloalkyl, C 1 -C 3 alkyleneC 4 -C 6 cycloalkenyl, C 1 -C 3 alkyleneheterocycloalkyl, C 1 -C 3 alkylenearyl, C 1 -C 3 alkyleneheteroaryl, C(O)Q′, CO 2 Q′, C(O)N(Q′) 2 , S(O)Q′ and SO 2 Q′, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.

17 . The compound of claim 16 , wherein A is selected from hydrogen, P(O)(OR 11 ) 2 , CH 2 P(O)(OR 11 ) 2 , CH(CH 3 )P(O)(OR 11 ) 2 , C(O)N(Q′) 2 and C(O)Q′.

18 . The compound of claim 17 , wherein A is C(O)N(Q′) 2 or C(O)Q′ wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.

19 . The compound of claim 16 , wherein A is selected from hydrogen and C 1 -C 4 alkyl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.

20 . The compound of claim 16 , wherein A is selected from CH 2 C 3 -C 7 cycloalkyl, CH 2 C 4 -C 6 cycloalkenyl, CH 2 heterocycloalkyl, CH 2 aryl and CH 2 heteroaryl, or A is selected from C 3 -C 7 cycloalkyl, C 4 -C 7 cycloalkenyl, heterocycloalkyl, aryl and heteroaryl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.

21 . The compound of claim 16 , wherein Q′ is selected from C 1 -C 20 alkyl, C 2 -C 20 alkenyl and C 2 -C 20 alkynyl optionally substituted with one or two substituents independently selected from N(R 13 ) 2 and CO 2 R 13 , and/or disubstituted on the same carbon atom with C 1-6 alkyl, or with C 2-6 alkylene to form a C 3 -C 7 cycloalkyl ring, wherein said C 3 -C 7 cycloalkyl ring is further optionally substituted with a substituent selected from C 1 -C 3 alkyl and C 1 -C 3 haloalkyl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.

22 . The compound of claim 16 , wherein Q′ is C 1 -C 20 alkyl or C 2 -C 20 alkenyl substituted by N(R 13 ) 2 or Q′ is C 1 -C 20 alkyl or C 2 -C 20 alkenyl substituted by N(R 13 ) 2 and disubstituted on the same carbon atom with C 2-6 alkylene to form a C 3 -C 7 cycloalkyl ring, wherein said C 3 -C 7 cycloalkyl ring is further optionally substituted with a substituent selected from C 1 -C 3 alkyl and C 1 -C 3 haloalkyl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.

23 . The compound of claim 16 , wherein Q′ is C 1 -C 20 alkyl or C 2 -C 20 alkenyl substituted by CO 2 R 13 , or Q′ is C 1 -C 20 alkyl or C 2 -C 20 alkenyl, wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.

24 . The compound of claim 16 , wherein Q′ is selected from C 3 -C 7 cycloalkyl, C 4 -C 7 cycloalkenyl and a 3- to 7-membered heterocyclic ring including 1 to 2 ring heteromoieties selected from O, S, S(O), SO 2 , N and NR 13 , wherein said C 3 -C 7 cycloalkyl, C 4 -C 7 cycloalkenyl and 3- to 7-membered heterocyclic ring groups are optionally substituted by one to three substituents independently selected from CN, OR 13 , N(R 13 ) 2 , CO 2 R 13 , SR 13 , C 3 -C 7 cycloalkyl, C 4 -C 7 cycloalkenyl and a 3- to 7-membered heterocyclic ring and wherein each of said C 3 -C 7 cycloalkyl, C 4 -C 7 cycloalkenyl and 3- to 7-membered heterocyclic rings are each further optionally substituted with a substituent selected from C 1 -C 3 alkyl; wherein all available hydrogen atoms are optionally substituted with a halogen atom and/or all available atoms are optionally substituted with an alternate isotope thereof.

25 . The compound of claim 16 , wherein Q′ is selected from the groups listed below:

wherein:

indicates a point of covalent attachment.

26 . The compound of claim 1 , wherein the compound of Formula (I) is selected from the compounds listed below:

Compound

ID #

Chemical Structure

I-16

I-17

I-18

I-19

I-20

I-21

I-22

I-23

I-24

I-25

I-26

I-27

I-28

I-29

I-30

I-31

I-32

I-33

I-34

I-35

I-36

I-37

I-38

I-39

I-40

I-41

I-42

I-46

I-47

I-48

or a pharmaceutically acceptable salt, solvate and/or prodrug thereof.

27 . A pharmaceutical composition comprising one or more compounds of claim 1 and pharmaceutically acceptable carrier.

28 . The pharmaceutical composition of claim 27 , wherein the composition comprises 0.5 mg to about 500 mg of one or more compounds of claim 1 .

29 . A method for activating a serotonin receptor in a cell, either in a biological sample or in a patient, or a method of treating a disease, disorder or condition by activation of a serotonin receptor comprising administering a therapeutically effective amount of one or more compounds of claim 1 to the cell or to a subject in need thereof, respectively.

30 . A method of treating a mental illness, psychosis, psychotic symptoms, a central nervous system (CNS) disease, disorder or condition and/or a neurological disease, disorder or condition comprising administering a therapeutically effective amount of one or more compounds of claim 1 to a subject in need thereof.