IP Library › Patent Application 18771262

Patent Application

App. No. 18/771,262

COMPOSITIONS AND METHODS FOR TREATING CNS DISORDERS

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App. No.: 18/771,262

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Abstract

Provided herein is a compound of Formula (I-I) or a pharmaceutically acceptable salt thereof, wherein t, R 7 , R 3 , R 9 , R 6a , R 6b , R 11a , R 11b , R 15a , R 15b , R 16a , R 16b , R 17a , R 17b , R 18a , R 18b , R 19a , R 19b , R 5a , R 5b , R 8 and R 13 are defined herein. Also provided herein are pharmaceutical compositions comprising a compound of Formula (I-I) and methods of using the compounds, e.g., in the treatment of CNS-related disorders.

Claims (137)

1 - 513 . (canceled)

514 . A compound of Formula (I-I):

or a pharmaceutically acceptable salt thereof,

wherein:

t is 1 or 2;

R 7 is hydrogen or methyl, or when is a double bond, R 7 is absent;

R 3 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R 9 is hydrogen or substituted or unsubstituted alkyl;

each of R 6a and R 6b is independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, or R 6a and R 6b are joined to form an oxo (═O) group;

each of R 11a , R 11b , R 15a , R 15b , R 16a , R 16b , R 17a , R 17b , R 18a , R 18b , R 19a , or R 19b is independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted alkynyl, —OR D1 , —OC(═O)R D1 , —NH 2 , —N(R D1 ) 2 , or —NR D1 C(═O)R D1 , wherein each instance of R D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or two R D1 groups are joined to form an substituted or unsubstituted heterocyclic ring; or any one of R 11a and R 11b , R 15a and R 15b , R 16a and R 16b , R 17a and R 17b , and R 18a and R 18b are joined to form an oxo (═O) group;

each of R 5a , R 5b , R 8 and R 13 is independently hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR A1 , —SR A1 , N(R A1 ) 2 , —N(R A1 ), —CN(R A1 ) 2 , —C(O)R A1 , —C(═O)N(R A1 ) 2 , —OC(═O)R A1 , —OC(═O)OR A1 , —OC(═O)SR A1 , —OC(═O)N(R A1 ) 2 , —SC(═O)R A2 , —SC(═O)OR A1 , —SC(═O)SR A1 , —SC(═O)N(R A1 ) 2 , —NHC(═O)R A1 , —NHC(═O)OR A1 , —NHC(═O)SR A1 , —NHC(═O)N(R A1 ) 2 , —OS(═O) 2 R A2 , —OS(═O) 2 OR A1 , —S—S(═O) 2 R A2 , —S—S(═O) 2 OR A1 , —S(═O)R A2 , —SO 2 R A2 , or —S(═O) 2 OR A1 , wherein each instance of R A1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, —SO 2 R A2 , —C(O)R A2 , or two R A1 groups are joined to form an substituted or unsubstituted heterocyclic or heteroaryl ring; and R A2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

or R 8 and R 13 are joined to form an oxo (═O) group, wherein when R 8 and R 13 are joined to form an oxo (═O) group, R 3 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and

wherein at least one of R 5a , R 5b , R 8 and R 13 must be ethyl, substituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR A1 , —SR A1 , —N(R A1 ) 2 , —N(R A1 ), —CN(R A1 ) 2 , —C(O)R A1 , —C(═O)N(R A1 ) 2 , —OC(═O)R A1 , —OC(═O)OR A1 , —OC(═O)SR A1 , —OC(═O)N(R A1 ) 2 , —SC(═O)R A2 , —SC(═O)OR A1 , —SC(═O)SR A1 , —SC(═O)N(R A1 ) 2 , —NHC(═O)R A1 , —NHC(═O)OR A1 , —NHC(═O)SR A1 , —NHC(═O)N(R A1 ) 2 , —OS(═O) 2 R A2 , —OS(═O) 2 OR A1 , —S—S(═O) 2 R A2 , —S—S(═O) 2 OR A1 , —S(═O)R A2 , —SO 2 R A2 , or —S(═O) 2 OR A1 ;

wherein R 8 and R 13 cannot both be unsubstituted methyl; and

wherein represents a single or double bond, provided if a double bond is present in Ring B, then one of R 6a or R 6b and R 7 is absent.

515 . The compound or pharmaceutically acceptable salt of claim 514 , wherein the compound of Formula (I-I) is a compound of Formula (I-Ia)

or a pharmaceutically acceptable salt thereof, wherein

n is 0 or 1;

represents a single bond;

R 1 is

(i) methyl optionally substituted with

wherein each instance of R 20 is independently methyl or —CN, and e is 0 or 1, or

(ii) —N(R A1 ) 2 , wherein one instance of R A1 is —H and the other is unsubstituted phenyl or methyl substituted with pyridine or phenyl;

each of R 5a , R 5b , R 6a , R 6b , R 11a , and R 11b are —H;

R 3 is C 1-3 alkyl optionally substituted with C 1-3 alkoxy; and

R 9 is methyl or hydrogen.

516 . The compound or pharmaceutically acceptable salt of claim 515 , wherein R 3 is methyl, methoxymethyl, or ethoxymethyl.

517 . The compound or pharmaceutically acceptable salt of claim 515 , wherein R 9 is methyl or hydrogen.

518 . The compound or pharmaceutically acceptable salt of claim 515 , wherein R 1 is unsubstituted methyl or methyl substituted with substituted with

wherein each instance of R 20 is independently methyl or —CN, and e is 1.

519 . The compound or pharmaceutically acceptable salt of claim 518 , wherein:

(A) R 1 is unsubstituted methyl or methyl substituted with substituted with

wherein R 20 is —CN, and e is 1; or

(B) R 1 is unsubstituted methyl or methyl substituted with substituted with

wherein R 20 is methyl, and e is 1.

520 . The compound or pharmaceutically acceptable salt of claim 515 , wherein the compound of Formula (I-Ia) is:

(A) a compound of Formula (I-Ib)

or a pharmaceutically acceptable salt thereof; or

(B) a compound of Formula (I-Id) or Formula (I-If)

or a pharmaceutically acceptable salt of either of these compounds, wherein each R 10 is independently methyl or —CN; or

or a pharmaceutically acceptable salt thereof, wherein R 5 is methyl or —CN, and e is 0 or 1.

521 . The compound or pharmaceutically acceptable salt of claim 514 , wherein R 8 is hydrogen, and R 13 is —N(R A1 ) 2 , wherein each instance of R A1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, —SO 2 R A2 , —C(O)R A2 , or two R A1 groups are joined to form an substituted or unsubstituted heterocyclic or heteroaryl ring, wherein the heterocycle or heteroaryl have at least one nitrogen atom; and R A2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

522 . The compound of claim 514 , wherein the compound is selected from

523 . The compound of claim 514 , wherein the compound is selected from

524 . The compound of claim 514 , wherein the compound is selected from

525 . The compound of claim 514 , wherein the compound is selected from

526 . The compound of claim 514 , wherein the compound is selected from

527 . A pharmaceutically acceptable salt of a compound of claim 524 .

528 . A pharmaceutically acceptable salt of a compound of claim 526 .

529 . A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt of claim 514 , and a pharmaceutically acceptable excipient.

530 . A compound of Formula (I-II):

or a pharmaceutically acceptable salt thereof,

wherein:

R 77 is hydrogen or methyl, or when is a double bond, R 7 is absent;

R 23 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R 29 is hydrogen or substituted or unsubstituted alkyl;

each of R 26a and R 26b is independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, or R 26a and R 26b are joined to form an oxo (═O) group;

each of R 21a , R 21b , R 25a , R 25b , R 36a , R 36b , R 27a , R 27b , R 29a , or R 29b is independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted alkynyl, —OR D1 , —OC(═O)R D1 , —NH 2 , —N(R D1 ) 2 , or —NR D1 C(═O)R D1 , wherein each instance of R D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or two R D1 groups are joined to form an substituted or unsubstituted heterocyclic ring; or any one of R 21a and R 21b , R 25a and R 25b , R 36a and R 36b , R 27a and R 27b , and R 29a and R 29b are joined to form an oxo (═O) group;

each of R 55a , R 55b , R 33a , and R 33b is each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR A1 , —SR A1 , N(R A1 ) 2 , —N(R A1 ), —CN(R A1 ) 2 , —C(O)R A1 , —C(═O)N(R A1 ) 2 , —OC(═O)R A1 , —OC(═O)OR A1 , —OC(═O)SR A1 , —OC(═O)N(R A1 ) 2 , —SC(═O)R A2 , —SC(═O)OR A1 , —SC(═O)SR A1 , —SC(═O)N(R A1 ) 2 , —NHC(═O)R A1 , —NHC(═O)OR A1 , —NHC(═O)SR A1 , —NHC(═O)N(R A1 ) 2 , —OS(═O) 2 R A2 , —OS(═O) 2 OR A1 , —S—S(═O) 2 R A2 , —S—S(═O) 2 OR A1 , —S(═O)R A2 , —SO 2 R A2 , or —S(═O) 2 OR A1 wherein each instance of R A1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, —SO 2 R A2 , —C(O)R A2 , or two R A1 groups are joined to form an substituted or unsubstituted heterocyclic or heteroaryl ring; and R A2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

wherein represents a single or double bond, provided if a double bond is present in Ring B, then one of R 26a or R 26b is absent, and provided if a single bond is present in Ring B, then the hydrogen at C5 is in the alpha or beta position.

531 . A compound of Formula (II-I):

or a pharmaceutically acceptable salt thereof,

wherein:

t is 1;

n is 0, 1 or 2;

R 19 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted C 2 -C 6 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl;

R 5 is hydrogen or methyl, or when is a double bond, R 5 is absent;

R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR A1 , —SR A1 , —N(R A1 ) 2 , —N(R A1 ), —OC(═O)R A1 , —OC(═O)OR A1 , —OC(═O)SR A1 , —OC(═O)N(R A1 ) 2 , —SC(═O)R A2 , —SC(═O)OR A1 , —SC(═O)SR A1 , —SC(═O)N(R A1 ) 2 , —NHC(═O)R A1 , —NHC(═O)OR A1 , —NHC(═O)SR A1 , —NHC(═O)N(R A1 ) 2 , —OS(═O) 2 R A2 , —OS(═O) 2 OR A1 , —S—S(═O) 2 R A2 , —S—S(═O) 2 OR A1 , —S(═O)R A2 , —SO 2 R A2 , or —S(═O) 2 OR A1 , wherein each instance of R A1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R A1 groups are joined to form an substituted or unsubstituted heterocyclic or heteroaryl ring; and R A2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

each of R 1a , R 1b , R 2a , R 2b , R 2aa , R 2ab , R 3a , R 3b , R 4a , R 4b , R 7a , R 7b , R 11a , R 11b , R 12a , or R 12b , is independently hydrogen, halogen, cyano, nitro, azido, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted alkynyl, —OR D1 , —OC(═O)R D1 , —NH 2 , —N(R D1 ) 2 , or —NR D1 C(═O)R D1 , wherein each instance of R D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or two R D1 groups are joined to form a substituted or unsubstituted heterocyclic ring; or any one of R 2a and R 2b , R 3a and R 3b , R 4a and R 4b , R 7a and R 7b , R 11a and R 11b , and R 12a and R 12b are joined to form an oxo (═O) group;

wherein at least one of R 1a , R 1b , R 2a , R 2b , R 2aa , R 2ab , R 3a , R 3b , R 4a or R 4b is hydroxyl;

each of R 15a , R 15b , R 16a and R 16b is each independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR A1 , —SR A1 , —N(R A1 ) 2 , —N(R A1 ), —CN(R A1 ) 2 , —C(O)R A1 , —OC(═O)R A1 , —OC(═O)OR A1 , —OC(═O)SR A1 , —OC(═O)N(R A1 ) 2 , —SC(═O)R A2 , —SC(═O)OR A1 , —SC(═O)SR A1 , —SC(═O)N(R A1 ) 2 , —NHC(═O)R A1 , —NHC(═O)OR A1 , —NHC(═O)SR A1 , —NHC(═O)N(R A1 ) 2 , —OS(═O) 2 R A2 , —OS(═O) 2 OR A1 , —S—S(═O) 2 R A2 , —S—S(═O) 2 OR A1 , —S(═O)R A2 , —SO 2 R A2 , or —S(═O) 2 OR A1 , wherein each instance of R A1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, —SO 2 R A2 , —C(O)R A2 , or two R A1 groups are joined to form an substituted or unsubstituted heterocyclic or heteroaryl ring; and R A2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and

wherein when n is 0, t is 1, R 19 is methyl, R 5 is hydrogen, R 3a is hydroxyl, ring B has a double bond, and R 6a , R 6b , R 1a , R 1b , R 2a , R 2b , R 2aa , R 2ab , R 3b , R 4a , R 4b , R 7a , R 7b , R 11a , R 11b , R 12a , R 12b , R 15a , R 15b , R 16a and R 16b are each hydrogen, then R 1 is not methyl;

wherein represents a single or double bond, provided if a double bond is present in ring B, then one of R 6a or R 6b and R 5 is absent.

532 . A compound of Formula (II-II):

or a pharmaceutically acceptable salt thereof, wherein

t is 1;

n is 0, 1 or 2;

R 19 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted C 2 -C 6 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl;

R 5 is hydrogen or methyl, or when is a double bond, R 5 is absent;

wherein at least one of R 1a , R 1b , R 2a , R 2b , R 2aa , R 2ab , R 3a , R 3b , R 4a or R 4b is hydroxyl;

wherein represents a single or double bond, provided if a double bond is present in ring B, then one of R 6a or R 6b and R 5 is absent; and

wherein at least one of R 1a , R 1b , R 2a , R 2b , R 3a , or R 3b , is hydroxyl.

533 . A compound of Formula (III-I):

or a pharmaceutically acceptable salt thereof, wherein

R 5 is hydrogen or substituted or unsubstituted methyl, or when is a double bond, R 5 is absent;

R 19 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;

each of R 1a , R 1b , R 12a , R 12b , R 2a , R 2b , R 4a , R 4b , R 11a , R 11b , R 18a , and R 18b , is independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted alkynyl, —OR D1 , —OC(═O)R D1 , —NH 2 , —N(R D1 ) 2 , or —NR D1 C(═O)R D1 , wherein each instance of R D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or two R D1 groups are joined to form an substituted or unsubstituted heterocyclic ring; or any one of R 1a and R 1b , R 12a and R 12b , R 2a and R 2b , R 4a and R 4b , R 11a and R 11b , and R 18a and R 18b are joined to form an oxo (═O) group;

each of R 7a , R 7b , R 7aa , and R 7bb is independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted alkynyl, —OR D1 , —OC(═O)R D1 , —NH 2 , —N(R D1 ) 2 , or —NR D1 C(═O)R D1 , wherein each instance of R D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or two R D1 groups are joined to form an substituted or unsubstituted heterocyclic ring; or any one of R 7a and R 7b and R 7aa and R 7bb are joined to form an oxo (═O) group;

each of R 16a , R 16b , R 17a and R 17b is each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR A1 , —SR A1 , N(R A1 ) 2 , —N(R A1 ), —CN(R A1 ) 2 , —C(O)R A1 , —OC(═O)R A1 , —OC(═O)OR A1 , —OC(═O)SR A1 , —OC(═O)N(R A1 ) 2 , —SC(═O)R A2 , —SC(═O)OR A1 , —SC(═O)SR A1 , —SC(═O)N(R A1 ) 2 , —NHC(═O)R A1 , —NHC(═O)OR A1 , —NHC(═O)SR A1 , —NHC(═O)N(R A1 ) 2 , —OS(═O) 2 R A2 , —OS(═O) 2 OR A1 , —S—S(═O) 2 R A2 , —S—S(═O) 2 OR A1 , —S(═O)R A2 , —SO 2 R A2 , or —S(═O) 2 OR A1 , wherein each instance of R A1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, —SO 2 R A2 , —C(O)R A2 , or two R A1 groups are joined to form an substituted or unsubstituted heterocyclic or heteroaryl ring; and R A2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R 17a and R 17b are joined to form an oxo group; and

wherein represents a single or double bond, provided if a double bond is present, then R 5 and one of R 6a or R 6b are absent.

534 . A compound of Formula (IV-I):

or a pharmaceutically acceptable salt thereof, wherein

R 5 is hydrogen or substituted or unsubstituted methyl, or when is a double bond, R 5 is absent;

R 19 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;

each of R 1a , R 1b , R 12a , R 12b , R 2a , R 2b , R 4a , R 4b , R 11a , R 11b , R 18a , and R 18b is independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted alkynyl, —OR D1 , —OC(═O)R D1 , —NH 2 , —N(R D1 ) 2 , or —NR D1 C(═O)R D1 , wherein each instance of R D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or two R D1 groups are joined to form an substituted or unsubstituted heterocyclic ring; or any one of R 1a and R 1b , R 12a and R 12b , R 2a and R 2b , R 4a and R 4b , R 11a and R 11b , and R 18a and R 18b are joined to form an oxo (═O) group;

each of R 16a , R 16b , R 17a , and R 17b is each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR A1 , —SR A1 , —N(R A1 ) 2 , —N(R A1 ), —CN(R A1 ) 2 , —C(O)R A1 , —OC(═O)R A1 , —OC(═O)OR A1 , —OC(═O)SR A1 , —OC(═O)N(R A1 ) 2 , —SC(═O)R A2 , —SC(═O)OR A1 , —SC(═O)SR A1 , —SC(═O)N(R A1 ) 2 , —NHC(═O)R A1 , —NHC(═O)OR A1 , —NHC(═O)SR A1 , —NHC(═O)N(R A1 ) 2 , —OS(═O) 2 R A2 , —OS(═O) 2 OR A1 , —S—S(═O) 2 R A2 , —S—S(═O) 2 OR A1 , —S(═O)R A2 , —SO 2 R A2 , or —S(═O) 2 OR A1 , wherein each instance of R A1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, —SO 2 R A2 , —C(O)R A2 , or two R A1 groups are joined to form an substituted or unsubstituted heterocyclic or heteroaryl ring; and R A2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and

wherein represents a single or double bond, provided if a double bond is present, then R 5 and one of R 6a or R 6b are absent.

535 . A compound of Formula (V-I):

or a pharmaceutically acceptable salt thereof, wherein

R 5 is hydrogen or substituted or unsubstituted methyl, or when is a double bond, R 5 is absent;

R 3 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R 19 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;

each of R 1a , R 1b , R 12a , R 12b , R 12aa , R 12bb , R 2a , R 2b , R 4a , R 4b , R 11a , R 11b , R 18a and R 18b is independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted alkynyl, —OR D1 , —OC(═O)R D1 , —NH 2 , —N(R D1 ) 2 , or —NR D1 C(═O)R D1 , wherein each instance of R D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or two R D1 groups are joined to form an substituted or unsubstituted heterocyclic ring; or any one of R 1a and R 1b , R 12a and R 12b , R 12aa and R 12bb , R 2a and R 2b , R 4a and R 4b , R 11a and R 11b , and R 18a and R 18b are joined to form an oxo (═O) group;

each of R 7a and R 7b is independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted alkynyl, —OR D1 , —OC(═O)R D1 , —NH 2 , —N(R D1 ) 2 , or —NR D1 C(═O)R D1 , wherein each instance of R D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or two R D1 groups are joined to form an substituted or unsubstituted heterocyclic ring; or R 7a and R 7b are joined to form an oxo (═O) group;

each of R 16a , R 16b , R 17a and R 17b is each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR A1 , —SR A1 , —N(R A1 ) 2 , —N(R A1 ), —CN(R A1 ) 2 , —C(O)R A1 , —OC(═O)R A1 , —OC(═O)OR A1 , —OC(═O)SR A1 , —OC(═O)N(R A1 ) 2 , —SC(═O)R A2 , —SC(═O)OR A1 , —SC(═O)SR A1 , —SC(═O)N(R A1 ) 2 , —NHC(═O)R A1 , —NHC(═O)OR A1 , —NHC(═O)SR A1 , —NHC(═O)N(R A1 ) 2 , —OS(═O) 2 R A2 , —OS(═O) 2 OR A1 , —S—S(═O) 2 R A2 , —S—S(═O) 2 OR A1 , —S(═O)R A2 , —SO 2 R A2 , or —S(═O) 2 OR A1 , wherein each instance of R A1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, —SO 2 R A2 , —C(O)R A2 , or two R A1 groups are joined to form an substituted or unsubstituted heterocyclic or heteroaryl ring; and R A2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and

wherein represents a single or double bond, provided if a double bond is present, then R 5 and one of R 6a or R 6b are absent.

536 . A method of therapeutically treating a CNS-related disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of claim 514 , or a pharmaceutically acceptable salt thereof.

537 . The method of claim 536 , wherein the CNS-related disorder is a disorder mediated by GABA A receptor activity.

538 . The method of claim 537 , wherein the CNS-related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a convulsive disorder, a disorder of memory and/or cognition, a movement disorder, a personality disorder, autism spectrum disorder, pain, traumatic brain injury, a vascular disease, a substance abuse disorder and/or withdrawal syndrome, tinnitus, or status epilepticus.

539 . A method of synthesizing a compound of Formula (I-D7)

comprising:

(1-1) contacting a compound of Formula (I-D6),

with PCC, in the presence of silica gel and an organic solvent to generate the compound of Formula (I-D7).

540 . A method of synthesizing a compound of Formula (I-C3)

comprising:

(2-1) contacting a compound of Formula (I-C2),

with palladium on carbon in the presence of hydrogen gas and MeOH to generate the compound of Formula (I-C3).

541 . A method of synthesizing a compound of Formula (I-C5)

comprising:

(3-1) contacting a compound of Formula (I-C1),

with CH 3 NH 2 in the presence of NaBH 4 and an organic solvent to generate the compound of Formula (I-C5).

542 . A method of synthesizing a compound of Formula (I-D4)

comprising:

(4-1) contacting a compound of Formula (I-D3),

with a solution comprising KOH and MeOH to generate the compound of Formula (I-D4).

Assignments (2)

CHANGE OF NAME Recorded Apr 23, 2026

From: SAGE THERAPEUTICS, INC.

To: SAGE THERAPEUTICS, LLC

Reel/Frame 075472/0569 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 16, 2025

From: ROBICHAUD, ALBERT JEAN; SALITURO, FRANCESCO G.; BLANCO-PILLADO, MARIA JESUS; LA, DANIEL; HARRISON, BOYD L.

To: SAGE THERAPEUTICS, INC.

Reel/Frame 069891/0671 →