Compositions and methods for reducing tactile dysfunction, anxiety, and social impairment

1. A method of reducing tactile dysfunction, anxiety, or social impairment in a human subject diagnosed with Autism Spectrum Disorder (ASD), Rett Syndrome (RTT), or Fragile X Syndrome, by administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt thereof:

wherein

A is optionally substituted C 6-10 aryl or optionally substituted heteroaryl;

Y is hydrogen, deuterium, halogen, or optionally substituted C 1-4 alkyl;

Z is oxygen, NR 3 , or CR 3 R 4 ;

R 1 is optionally substituted alkylcarboxylic acid, optionally substituted alkylcarboxylic acid ester, optionally substituted alkylcarboxylic acid amide, optionally substituted heteroalkyl, optionally substituted C 1-6 alkylamino, or C 1-6 alkyl substituted with at least one C 3-7 heterocycle comprising 1-3 nitrogen atoms, 1-2 oxygen atoms, or combinations thereof;

R 2 is optionally substituted C 1-6 alkyl and

each of R 3 and R 4 is, independently, hydrogen, deuterium, or optionally substituted C 1-6 alkyl;

in an amount and for a duration sufficient to reduce the tactile dysfunction, anxiety, or social impairment.

2. The method of claim 1 , wherein A is optionally substituted C 6-10 aryl.

3. The method of claim 1 , wherein Y is halogen.

4. The method of claim 1 , wherein Z is CH 2 .

5. The method of claim 1 , wherein R 1 is optionally substituted alkylcarboxylic acid.

6. The method of claim 1 , wherein the compound has the structure of Formula (III), or a pharmaceutically acceptable salt thereof:

wherein

each of X 1 and X 2 is, independently, hydrogen, deuterium, halogen, C 1-4 alkoxy, C 1-6 alkyl, CF 3 , CH 3 S, CH 3 SO 2 , NR 5 R 6 , or NO 2 ; and

each of R 5 and R 6 is, independently, hydrogen, deuterium, optionally substituted C 1-6 alkyl, optionally substituted C 3-6 cycloalkyl, acyl, carbamate, sulfonamide, or urea.

7. The method of claim 6 , wherein the compound has the structure of Formula (VII), or a pharmaceutically acceptable salt thereof:

wherein

X 1 is hydrogen, deuterium, halogen, C 1-4 alkoxy, C 1-6 alkyl, CF 3 , CH 3 S, CH 3 SO 2 , or NO 2 ;

Y is hydrogen, deuterium, halogen, or C 1-4 alkyl;

Z is oxygen, NH, or CH 2 ; and

R 1 is optionally substituted alkylcarboxylic acid.

8. The method of claim 7 , wherein X 1 is halogen.

9. The method of claim 7 , wherein Y is halogen.

10. The method of claim 7 , wherein Z is CH 2 .

11. The method of claim 7 , wherein X 1 is halogen, Y is halogen, and Z is CH 2 .

12. The method of claim 1 , wherein the compound has the structure:

or a pharmaceutically acceptable salt thereof.

13. The method of claim 1 , having the structure:

or a pharmaceutically acceptable salt thereof.

14. The method of claim 1 , for reducing tactile dysfunction in the subject.

15. The method of claim 1 , for reducing anxiety in the subject.

16. The method of claim 1 , for reducing social impairment in the subject.

17. The method of claim 1 , wherein the subject is a child.

18. A method of treating touch over-reactivity, pain, or mechanical allodynia in a human subject in need thereof, comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt thereof:

wherein

A is optionally substituted C 6-10 aryl or optionally substituted heteroaryl;

Y is hydrogen, deuterium, halogen, or optionally substituted C 1-4 alkyl;

Z is oxygen, NR 3 , or CR 3 R 4 ;

R 1 is optionally substituted alkylcarboxylic acid, optionally substituted alkylcarboxylic acid ester, optionally substituted alkylcarboxylic acid amide, optionally substituted heteroalkyl, optionally substituted C 1-6 alkylamino, or C 1-6 alkyl substituted with at least one C 3-7 heterocycle comprising 1-3 nitrogen atoms, 1-2 oxygen atoms, or combinations thereof;

R 2 is optionally substituted C 1-6 alkyl and

each of R 3 and R 4 is, independently, hydrogen, deuterium, or optionally substituted C 1-6 alkyl;

in an amount and for a duration sufficient to reduce the touch over-reactivity, pain, or mechanical allodynia.

19. The method of claim 18 , wherein the touch over-reactivity or pain is associated with Sensory Processing Disorder (SPD) or fibromyalgia.

20. The method of claim 18 , wherein the mechanical allodynia is associated with nerve injury, shingles, diabetic neuropathy, chemotherapy-induced neuropathy, or a neuropathic pain state.