US2023322846A9PendingUtilityA9
Neuroactive steroids and their methods of use
Est. expiryDec 5, 2038(~12.4 yrs left)· nominal 20-yr term from priority
A61P 25/08A61P 25/24C07J 43/003C07J 41/0044C07J 41/0094C07J 41/005C07J 41/0055A61K 31/58A61P 25/00
70
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Claims
Abstract
Provided herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein R 19 , R 5 , R 3a , R 1a , R 1b , R 2a , R 2b , R 4a , R 4b , R 6a , R 6b , R 7a , R 7b , R 11a , R 11b , R 12a , R 12b , R 18 , R D , and q are defined herein. L is selected from the group consisting of: wherein A indicates the point of attachment at C17 and wherein X is selected from the group consisting of —C(0)N(R 55a )(R 55b ), —N(R 55a )(R 55b ), —N(R 55b )C(O)(R 55a ), and R 55C wherein R 55c is carbon-bound substituted or unsubstituted heteroaryl or substituted or unsubstituted aryl. Also provided herein are pharmaceutical compositions comprising a compound of Formula (I) and methods of using the compounds, e.g., in the treatment of CNS-related disorders.
Claims
exact text as granted — not AI-modifiedWhat is claimed:
1 . A compound of Formula I:
or a pharmaceutically acceptable salt thereof;
wherein:
represents a single or double bond, provided if a double bond is present, then one of R 6a or R 6b is absent and R 5 is absent;
L is selected from the group consisting of:
wherein A indicates the point of attachment at C17;
X is selected from the group consisting of —C(O)N(R 55a )(R 55b ), —N(R 55a )(R 55b ), —N(R 55b )C(O)(R 55a ), and R 55c ;
R Y is each independently hydrogen, cyano, haloalkyl, or unsubstituted alkyl;
R 55c is carbon-bound substituted or unsubstituted heteroaryl or substituted or unsubstituted aryl;
R 55a and R 55b is each 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, —OR A1 , —N(R A1 ) 2 —SR A1 , —C(═O)R A1 , —C(═O)OR A1 , —C(═O)SR A1 , —C(═O)N(R A1 ) 2 , —OC(═O)R A1 , —OC(═O)OR A1 , —OC(═O)N(R A1 ) 2 , —OC(═O)SR A1 , —OS(═O) 2 R A1 , —OS(═O) 2 OR A1 , —OS(═O) 2 N(R A1 ) 2 , —N(R A1 )C(═O)R A1 , —N(R A1 )C(═NR A1 )R A1 , —N(R A1 )C(═O)OR A1 , —N(R A1 )C(═O)N(R A1 ) 2 , —N(R A1 )C(═NR A1 ) N(R A1 ) 2 , —N(R A1 )S(═O) 2 R A1 , —N(R A1 )S(═O) 2 OR A1 , —N(R A1 )S(═O) 2 N(R A1 ) 2 , —SC(═O)R A1 , —SC(═O)OR A1 , —SC(═O)SR A1 , —SC(═O)N(R A1 ) 2 , —S(═O) 2 R A1 , —S(═O) 2 OR A1 , or —S(═O) 2 N(R A1 ) 2 , wherein each instance of R A1 is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, a sulfur protecting group when attached to sulfur, or two R A1 groups are taken with the intervening atoms to form a substituted or unsubstituted heterocyclic ring;
or R 55a and R 55b may join together with the intervening atoms to form a substituted or unsubstituted heterocyclyl or a substituted or unsubstituted heteroaryl;
each of R 1a , R 1b , R 2a , R 2b , R 4a , R 4b , R 7a , R 7b , R 11a , R 11b , R 12a , and R 12b is independently hydrogen, halogen, cyano, —NO 2 , 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 , —N(R A1 ) 2 , —SR A1 , —C(═O)R A1 , —C(═O)OR A1 , —C(═O)SR A1 , —C(═O)N(R A1 ) 2 , —OC(═O)R A1 , —OC(═O)OR A1 , —OC(═O)N(R A1 ) 2 , —OC(═O)SR A1 , —OS(═O) 2 R A1 , —OS(═O) 2 OR A1 , —OS(═O) 2 N(R A1 ) 2 , —N(R A1 )C(═O)R A1 , —N(R A1 )C(═NR A1 )R A1 , —N(R A1 )C(═O)OR A1 , —N(R A1 )C(═O)N(R A1 ) 2 , —N(R A1 )C(═NR A1 ) N(R A1 ) 2 , —N(R A1 )S(═O) 2 R A1 , —N(R A1 )S(═O) 2 OR A1 , —N(R A1 )S(═O) 2 N(R A1 ) 2 , —SC(═O)R A1 , —SC(═O)OR A1 , —SC(═O)SR A1 , —SC(═O)N(R A1 ) 2 , —S(═O) 2 R A1 , —S(═O) 2 OR A1 , or —S(═O) 2 N(R A1 ) 2 , wherein each instance of R A1 is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, or a sulfur protecting group when attached to sulfur; or R 11a and R 11b are joined to form an oxo (═O) group; or R 12a and R 12b are joined to form an oxo (═O) group; or R 4a and R 4b are joined to form an oxo (═O) group; or R 7a and R 7b are joined to form an oxo (═O) group; or R 2a and R 2b are joined to form an oxo (═O) group; or R 1a and R 1b are joined to form an oxo (═O) group;
R 3a 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 5 is hydrogen or substituted or unsubstituted alkyl;
each of R 6a and R 6b is independently hydrogen, halogen, cyano, —NO 2 , —OH, 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;
R D is independently hydrogen, halogen, —CN, —NO 2 , oxo, 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 C3 , —N(R C3 ) 2 , —SR C3 , —C(═O)R C3 , —C(═O)OR C3 , —C(═O)SR C3 , —C(═O)N(R C3 ) 2 , —OC(═O)R C3 , —OC(═O)OR C3 , —OC(═O)N(R C3 ) 2 , —OC(═O)SR C3 , —OS(═O) 2 R C3 , —OS(═O) 2 OR C3 , —OS(═O) 2 N(R C3 ) 2 , —N(R C3 )C(═O)R C3 , —N(R C3 )C(═NR C3 )R C3 , —N(R C3 )C(═O)OR C3 , —N(R C3 )C(═O)N(R C3 ) 2 , —N(R C3 )C(═NR C3 ) N(R C3 ) 2 , —N(R C3 )S(═O) 2 R C3 , —N(R C3 )S(═O) 2 OR C3 , —N(R C3 )S(═O) 2 N(R C3 ) 2 , —SC(═O)R C3 , —SC(═O)OR C3 , —SC(═O)SR C3 , —SC(═O)N(R C3 ) 2 , —S(═O) 2 R C3 , —S(═O) 2 OR C3 , or —S(═O) 2 N(R C3 ) 2 , wherein each instance of R C3 is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, or a sulfur protecting group when attached to sulfur;
R 18 is substituted or unsubstituted alkyl;
R 19 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; and
q is an integer from 0 to 5;
provided that the compound is not:
or a pharmaceutically acceptable salt thereof.
2 . The compound of claim 1 , wherein the compound is a compound of Formula (I-I):
or a pharmaceutically acceptable salt thereof, wherein
each of R 15a , R 15b , R 16a , and R 16b is independently hydrogen, halogen, —CN, —NO 2 , 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 C3 , —N(R C3 ) 2 , —SR C3 , —C(═O)R C3 , —C(═O)OR C3 , —C(═O)SR C3 , —C(═O)N(R C3 ) 2 , —OC(═O)R C3 , —OC(═O)OR C3 , —OC(═O)N(R C3 ) 2 , —OC(═O)SR C3 , —OS(═O) 2 R C3 , —OS(═O) 2 OR C3 , —OS(═O) 2 N(R C3 ) 2 , —N(R C3 )C(═O)R C3 , —N(R C3 )C(═NR C3 )R C3 , —N(R C3 )C(═O)OR C3 , —N(R C3 )C(═O)N(R C3 ) 2 , —N(R C3 )C(═NR C3 ) N(R C3 ) 2 , —N(R C3 )S(═O) 2 R C3 , —N(R C3 )S(═O) 2 OR C3 , —N(R C3 )S(═O) 2 N(R C3 ) 2 , —SC(═O)R C3 , —SC(═O)OR C3 , —SC(═O)SR C3 , —SC(═O)N(R C3 ) 2 , —S(═O) 2 R C3 , —S(═O) 2 OR C3 , or —S(═O) 2 N(R C3 ) 2 , wherein each instance of R C3 is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, a sulfur protecting group when attached to sulfur; or R 15a and R 15b are joined to form an oxo (═O) group; or R 16a and R 16b are joined to form an oxo (═O) group.
3 . The compound of claim 1 , wherein the compound is a compound of Formula (I-a):
or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 1 .
4 . The compound of any one of claims 1 - 3 , wherein the compound is a compound of Formula (I-Ia):
or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 1 or 2 .
5 . The compound of any one of claims 1 - 4 , wherein L is
6 . The compound of any one of claims 1 - 5 , wherein L is
7 . The compound of any one of claims 1 - 5 , wherein L is
8 . The compound of any one of claims 1 - 5 , wherein L is
9 . The compound of any one of claims 1 - 4 , wherein L is
10 . The compound of any one of claims 1 - 4 , wherein L is
11 . The compound of any one of claims 1 - 4 , wherein L is
12 . The compound of any one of claims 1 - 11 , wherein X is —N(R 55b )C(O)(R 55a ).
13 . The compound of any one of claims 1 - 11 , wherein X is —N(R 55a )(R 55b ).
14 . The compound of any one of claims 1 - 11 , wherein X is —C(O)N(R 55a )(R 55b ).
15 . The compound of any one of claims 1 - 14 , wherein R 55a is hydrogen or methyl and R 55b 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.
16 . The compound of any one of claims 1 - 14 , wherein R 55a and R 55b is each 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.
17 . The compound of any one of claims 1 - 14 , wherein R 55a and R 55b is each independently hydrogen, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
18 . The compound of any one of claims 1 - 14 , wherein R 55a and R 55b is each independently substituted carbocyclyl, substituted heterocyclyl, substituted aryl, or substituted heteroaryl.
19 . The compound of any one of claims 1 - 14 , wherein at least R 55a or R 55b is other than hydrogen.
20 . The compound of any one of claims 1 - 14 , wherein R 55a and R 55b is each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl,
wherein:
each instance of R a is independently hydrogen, halogen, —NO 2 , —CN, —OR D4 , —N(R D4 ) 2 , —C(═O)R D4 , —C(═O)OR D4 , —C(═O)N(R D4 ) 2 , —OC(═O)R D4 , —OC(═O)OR D4 , —N(R D4 )C(═O)R D4 , —OC(═O)N(R D4 ) 2 , —N(R D4 )C(═O)OR D4 , S(═O) 2 R D4 , —S(═O) 2 OR D4 , —OS(═O) 2 R D4 , —S(═O) 2 N(R D4 ) 2 , or —N(R D4 )S(═O) 2 R D4 , substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted C 5-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl;
each instance of R D4 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted C 5-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, or two R D4 groups are taken with the intervening atoms to form a substituted or unsubstituted heterocyclic ring; and
p is an integer selected from 0 to 11.
21 . The compound of any one of claims 1 - 14 , wherein R 55a and R 55b is each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl,
wherein:
each instance of R a is independently hydrogen, halogen, —NO 2 , —CN, —OR D4 , —N(R D4 ) 2 , —C(═O)R D4 , —C(═O)OR D4 , —C(═O)N(R D4 ) 2 , —OC(═O)R D4 , —OC(═O)OR D4 , —N(R D4 )C(═O)R D4 , —OC(═O)N(R D4 ) 2 , —N(R D4 )C(═O)OR D4 , —S(═O) 2 R D4 , —S(═O) 2 OR D4 , —OS(═O) 2 R D4 , —S(═O) 2 N(R D4 ) 2 , or —N(R D4 )S(═O) 2 R D4 , substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted C 5-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl;
each instance of R D4 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted C 5-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, or two R D4 groups are taken with the intervening atoms to form a substituted or unsubstituted heterocyclic ring; and
p is an integer selected from 0 to 3.
22 . The compound of any one of claims 1 - 14 , wherein R 55a and R 55b is each independently hydrogen, substituted or unsubstituted alkyl,
wherein:
each instance of R a is independently hydrogen, halogen, —NO 2 , —CN, —OR D4 , —N(R D4 ) 2 , —C(═O)R D4 , —C(═O)OR D4 , —C(═O)N(R D4 ) 2 , —OC(═O)R D4 , —OC(═O)OR D4 , —N(R D4 )C(═O)R D4 , —OC(═O)N(R D4 ) 2 , —N(R D4 )C(═O)OR D4 , —S(═O) 2 R D4 , —S(═O) 2 OR D4 , —OS(═O) 2 R D4 , —S(═O) 2 N(R D4 ) 2 , or —N(R D4 )S(═O) 2 R D4 , substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted C 5-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl;
each instance of R D4 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted C 5-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, or two R D4 groups are taken with the intervening atoms to form a substituted or unsubstituted heterocyclic ring; and
p is an integer selected from 0 to 5.
23 . The compound of any one of claims 1 - 14 , wherein R 55a and R 55b is independently hydrogen, substituted or unsubstituted alkyl,
wherein:
each instance of R a is independently hydrogen, halogen, —CN, —OR D4 , —N(R D4 ) 2 , -substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted 5- to 10-membered heteroaryl;
each instance of R D4 is independently hydrogen or substituted or unsubstituted C 1-6 alkyl; and
p is an integer selected from 0 to 2.
24 . The compound of any one of claims 1 - 14 , wherein R 55a and R 55b join together with the intervening atoms to form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl.
25 . The compound of any one of claims 1 - 14 , wherein R 55a and R 55b join together with the intervening atoms to form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl selected from the group consisting of:
wherein:
each instance of R a is independently hydrogen, oxo, halogen, —NO 2 , —CN, —OR D4 , —N(R D4 ) 2 , —C(═O)R D4 , —C(═O)OR D4 , —C(═O)N(R D4 ) 2 , —OC(═O)R D4 , —OC(═O)OR D4 , —N(R D4 )C(═O)R D4 , —OC(═O)N(R D4 ) 2 , —N(R D4 )C(═O)OR D4 , —S(═O) 2 R D4 , —S(═O) 2 OR D4 , —OS(═O) 2 R D4 , —S(═O) 2 N(R D4 ) 2 , or —N(R D4 )S(═O) 2 R D4 , substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted C 5-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl;
each instance of R D4 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted C 5-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, or two R D4 groups are taken with the intervening atoms to form a substituted or unsubstituted heterocyclic ring; and
p is an integer selected from 0 to 10.
26 . The compound of any one of claims 1 - 14 , wherein R 55a and R 55b join together with the intervening atoms to form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl selected from the group consisting of:
wherein:
each instance of R a is independently hydrogen, oxo, halogen, —NO 2 , —CN, —OR D4 , —N(R D4 ) 2 , —C(═O)R D4 , —C(═O)OR D4 , —C(═O)N(R D4 ) 2 , —OC(═O)R D4 , —OC(═O)OR D4 , —N(R D4 )C(═O)R D4 , —OC(═O)N(R D4 ) 2 , —N(R D4 )C(═O)OR D4 , —S(═O) 2 R D4 , —S(═O) 2 OR D4 , —OS(═O) 2 R D4 , —S(═O) 2 N(R D4 ) 2 , or —N(R D4 )S(═O) 2 R D4 , substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted C 5-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl;
each instance of R D4 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted C 5-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, or two R D4 groups are taken with the intervening atoms to form a substituted or unsubstituted heterocyclic ring; and
p is an integer selected from 0 to 10.
27 . The compound of any one of claims 1 - 14 , wherein R 55a and R 55b join together with the intervening atoms to form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl selected from the group consisting of:
wherein:
each instance of R a is independently hydrogen, oxo, halogen, —CN, —OR D4 , —N(R D4 ) 2 , or substituted or unsubstituted C 1-6 alkyl;
each instance of R D4 is independently hydrogen or substituted or unsubstituted C 1-6 alkyl; and
p is an integer selected from 0 to 2.
28 . The compound of any one of claims 1 - 11 , wherein X is R 55c .
29 . The compound of any one of claims 1 - 11 and 28 , wherein R 55c is substituted or unsubstituted phenyl or carbon-bound substituted or unsubstituted heteroaryl containing at least one nitrogen in the heteroaryl ring.
30 . The compound of any one of claims 1 - 11 and 28 - 29 , wherein R 55c is substituted or unsubstituted phenyl or carbon-bound substituted or unsubstituted heteroaryl selected from the group consisting of pyridyl, isothiazolyl, thiazolyl, pyrimidyl, pyrazinyl, and oxazolyl.
31 . The compound of any one of claims 1 - 11 and 28 - 30 , wherein R 55c is selected from the group consisting of:
wherein:
each instance of R a is independently hydrogen, halogen, —CN, —OR D4 , —N(R D4 ) 2 , —C(═O)R D4 , —C(═O)OR D4 , or substituted or unsubstituted C 1-6 alkyl;
each instance of R D4 is independently hydrogen or substituted or unsubstituted C 1-6 alkyl; and
p is an integer selected from 0 to 2.
32 . The compound of any one of claims 1 - 31 , wherein R 5 is hydrogen in the cis position, relative to R 19 .
33 . The compound of any one of claims 1 - 31 , wherein R 5 is hydrogen in the trans position, relative to R 19 .
34 . The compound of any one of claims 1 - 31 , wherein R 5 is methyl in the cis position, relative to R 19 .
35 . The compound of any one of claims 1 - 31 , wherein R 5 is methyl in the trans position, relative to R 19 .
36 . The compound of claim 1 , wherein the compound is a compound of Formula (I-b), (I-c), (I-d), (I-e), (I-l), (I-m), (I-n), or (I-p):
or a pharmaceutically acceptable salt thereof.
37 . The compound of claim 1 , wherein the compound is a compound of Formula (I-f), (I-g), or (I-h):
or a pharmaceutically acceptable salt thereof.
38 . The compound of claim 1 , wherein the compound is a compound of Formula (I-i), (I-j), or (I-k):
or a pharmaceutically acceptable salt thereof.
39 . The compound of claim 1 , wherein the compound is a compound of Formula (I-o):
or a pharmaceutically acceptable salt thereof.
40 . The compound of claim 1 , wherein the compound is a compound of Formula (I-qq), (I-q), (I-s), (I-t), or (I-u):
or a pharmaceutically acceptable salt thereof, wherein
Q, Q′, and Q″ are each independently CR w or N;
R w is hydrogen, cyano, —NH 2 , or substituted or unsubstituted alkyl; and
at least one of Q, Q′, and Q″ is CR w .
41 . The compound of claim 1 , wherein the compound is a compound of Formula (I-r):
or a pharmaceutically acceptable salt thereof, wherein
k is an integer 1 or 2;
R z is substituted or unsubstituted alkyl or substituted or unsubstituted aryl; or two R z s on adjacent carbons combine with the intervening atoms to form a substituted or unsubstituted aryl; and
j is an integer 0-6.
42 . The compound of claim 1 , wherein the compound is a compound of Formula (I-v), (I-w), or (I-x):
or a pharmaceutically acceptable salt thereof.
43 . The compound of claim 42 , wherein R 55c is substituted or unsubstituted phenyl or carbon-bound substituted or unsubstituted heteroaryl containing at least one nitrogen in the heteroaryl ring.
44 . The compound of claim 42 or 43 , wherein R 55c is substituted or unsubstituted phenyl or carbon-bound substituted or unsubstituted heteroaryl selected from the group consisting of: pyridyl, isothiazolyl, thiazolyl, pyrimidyl, pyrazinyl, and oxazolyl.
45 . The compound of any one of claims 1 - 44 , wherein R 19 is hydrogen or substituted or unsubstituted alkyl.
46 . The compound of any one of claims 1 - 45 , wherein R 19 is hydrogen or substituted C 1-6 alkyl.
47 . The compound of any one of claims 1 - 46 , wherein R 19 is —CH 2 OCH 3 .
48 . The compound of any one of claims 1 - 45 , wherein R 19 is hydrogen or unsubstituted C 1-6 alkyl.
49 . The compound of any one of claims 1 - 45 and 48 , wherein R 19 is unsubstituted C 1-6 alkyl.
50 . The compound of any one of claims 1 - 45 and 48 - 49 , wherein R 19 is methyl.
51 . The compound of any one of claims 1 - 45 and 48 - 49 , wherein R 19 is ethyl.
52 . The compound of any one of claims 1 - 51 , wherein R 18 is unsubstituted alkyl.
53 . The compound of any one of claims 1 - 52 , wherein R 18 is unsubstituted C 1-6 alkyl.
54 . The compound of any one of claims 1 - 53 , wherein R 18 is methyl.
55 . The compound of any one of claims 1 - 53 , wherein R 18 is ethyl.
56 . The compound of any one of claims 1 - 51 , wherein R 18 is substituted alkyl.
57 . The compound of any one of claims 1 - 56 , wherein R D is each independently hydrogen, halogen, —CN, —NO 2 , oxo, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted carbocyclyl.
58 . The compound of any one of claims 1 - 57 , wherein R D is each independently hydrogen, oxo, substituted or unsubstituted alkyl, hydroxy, or substituted or unsubstituted carbocyclyl.
59 . The compound of any one of claims 1 - 58 , wherein R D is independently hydrogen, oxo, methyl, ethyl, hydroxy, or cyclopropyl.
60 . The compound of claim 1 , wherein the compound is a compound of Formula (I-Ib), (I-Ic), (I-Id), (I-Ie), (I-Il), (I-Im), (I-In), (I-Ip1), or (I-Ip2):
or a pharmaceutically acceptable salt thereof.
61 . The compound of claim 1 , wherein the compound is a compound of Formula (I-If), (I-Ig), or (I-Ih):
or a pharmaceutically acceptable salt thereof.
62 . The compound of claim 1 , wherein the compound is a compound of Formula (I-Ii), (I-Ij), or (I-Ik):
or a pharmaceutically acceptable salt thereof.
63 . The compound of claim 1 , wherein the compound is a compound of Formula (I-Io1) or (I-Io2):
or a pharmaceutically acceptable salt thereof.
64 . The compound of claim 1 , wherein the compound is a compound of Formula (I-Iqq), (I-Iq1), (I-Iq2), (I-It1), (I-It2), (I-Iu1), or (I-Iu2):
or a pharmaceutically acceptable salt thereof, wherein
Q, Q′, and Q″ are each independently CR w or N;
R w is hydrogen, cyano, —NH 2 , or substituted or unsubstituted alkyl; and
at least one of Q, Q′, and Q″ is CR w .
65 . The compound of claim 64 , wherein R 19 is hydrogen, methyl, ethyl, or methoxymethyl.
66 . The compound of claim 1 , wherein the compound is a compound of Formula (I-Irr), (I-Ir1) or (I-Ir2):
or a pharmaceutically acceptable salt thereof, wherein
k is an integer 1 or 2;
R z is substituted or unsubstituted alkyl or substituted or unsubstituted aryl; or two R z s on adjacent carbons combine with the intervening atoms to form a substituted or unsubstituted aryl; and
j an integer 0-6.
67 . The compound of claim 66 , wherein the compound is a compound of Formula (I-Ir3) or (I-Ir4):
or a pharmaceutically acceptable salt thereof, wherein
k is an integer 1 or 2;
R z′ is substituted or unsubstituted alkyl or cyano; and
j′ an integer 0-4.
68 . The compound of claim 1 , wherein the compound is a compound of Formula (I-Iw1), (I-Iw2), (I-Ix1), or (I-Ix2):
or a pharmaceutically acceptable salt thereof.
69 . The compound of any one of claims 1 - 68 , wherein R 3a is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl.
70 . The compound of any one of claims 1 - 69 , wherein R 3a is substituted or unsubstituted C 1-6 alkyl.
71 . The compound of any one of claims 1 - 70 , wherein R 3a is substituted C 1-6 alkyl.
72 . The compound of any one of claims 1 - 70 , wherein R 3a is unsubstituted C 1-6 alkyl.
73 . The compound of any one of claims 1 - 70 and 72 , wherein R 3a is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl.
74 . The compound of any one of claims 1 - 70 and 72 - 73 , wherein R 3a is methyl.
75 . The compound of any one of claims 1 - 71 , wherein R 3a is —CH 2 OCH 3 or CH 2 OCH 2 CH 3 .
76 . The compound of any one of claims 1 - 71 , wherein R 3a is —CH 2 C 3 H 5 .
77 . The compound of any one of claims 1 - 68 , wherein R 3a is substituted or unsubstituted alkyl or substituted or unsubstituted carbocyclyl.
78 . The compound of any one of claims 1 - 68 , wherein R 3a is substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
79 . The compound of any one of claims 1 - 68 and 77 - 78 , wherein R 3a is substituted or unsubstituted carbocyclyl.
80 . The compound of any one of claims 1 - 68 and 77 - 79 , wherein R 3a is cyclopropyl.
81 . The compound of any one of claims 1 - 80 , wherein R 4a and R 4b is each independently hydrogen, halogen, —CN, —NO 2 , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, —OR E5 , —OC(═O)R E5 , —OS(═O) 2 OR E5 , —N(R E5 ) 2 , or —N(R E5 )C(═O)R E5 , —N(R E5 )S(═O) 2 R E5 , —N(R E5 )S(═O) 2 OR E5 ; wherein each instance of R E5 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, or two R E5 groups are taken with the intervening atoms to form a substituted or unsubstituted heterocyclic ring.
82 . The compound of any one of claims 1 - 80 , wherein R 4a and R 4b is each independently hydrogen, halogen, —CN, —NO 2 , —OR F6 , —OC(═O)R F6 , —N(R F6 ) 2 , or —N(R F6 )C(═O)R F6 ; wherein each instance of R F6 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, or two R F6 groups are taken with the intervening atoms to form a substituted or unsubstituted heterocyclic ring.
83 . The compound of any one of claims 1 - 80 , wherein R 4a and R 4b are independently hydrogen, —OH, or substituted or unsubstituted C 1-6 alkyl.
84 . The compound of any one of claims 1 - 80 , wherein each of R 4a and R 4b are independently hydrogen, —OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 alkoxyhalo.
85 . The compound of any one of claims 1 - 80 , wherein R 4a and R 4b are independently —CH 3 , —CH 2 CH 3 , —OH, —OCH 3 , or —CH(CH 3 ) 2 .
86 . The compound of any one of claims 1 - 80 , wherein R 4a and R 4b are both hydrogen.
87 . The compound of any one of claims 1 - 80 , wherein R 4a and R 4b are joined to form an oxo (═O) group.
88 . The compound of any one of claims 1 - 87 , wherein R 6a and R 6b is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl.
89 . The compound of any one of claims 1 - 87 , wherein R 6a and R 6b is independently hydrogen or substituted alkyl.
90 . The compound of any one of claims 1 - 87 , wherein R 6a and R 6b is independently hydrogen or unsubstituted alkyl.
91 . The compound of any one of claims 1 - 87 , wherein both R 6a and R 6b are hydrogen.
92 . The compound of any one of claims 1 - 87 , wherein R 6a is halogen or alkyl and R 6b is hydrogen.
93 . The compound of any one of claims 1 - 87 , wherein R 6a and R 6b are both halogen.
94 . The compound of any one of claims 1 - 87 , wherein R 6a and R 6b are both alkyl.
95 . The compound of any one of claims 1 - 94 , wherein R 7a and R 7b is each independently hydrogen, halogen, —CN, —NO 2 , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, —OR E5 , —OC(═O)R E5 , —OS(═O) 2 OR E5 , —N(R E5 ) 2 , or —N(R E5 )C(═O)R E5 , —N(R E5 )S(═O) 2 R E5 , —N(R E5 )S(═O) 2 OR E5 ; wherein each instance of R E5 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, or two R E5 groups are taken with the intervening atoms to form a substituted or unsubstituted heterocyclic ring.
96 . The compound of any one of claims 1 - 94 , wherein R 7a and R 7b is each independently hydrogen, halogen, —CN, —NO 2 , —OR F6 , —OC(═O)R F6 , —N(R F6 ) 2 , or —N(R F6 )C(═O)R F6 ; wherein each instance of R F6 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, or two R F6 groups are taken with the intervening atoms to form a substituted or unsubstituted heterocyclic ring.
97 . The compound of any one of claims 1 - 94 , wherein R 7a and R 7b are independently hydrogen, —OH, or substituted or unsubstituted C 1-6 alkyl.
98 . The compound of any one of claims 1 - 94 , wherein each of R 7a and R 7b are independently hydrogen, —OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 alkoxyhalo.
99 . The compound of any one of claims 1 - 94 , wherein R 7a and R 7b are independently —CH 3 , —CH 2 CH 3 , —OH, —OCH 3 , or —CH(CH 3 ) 2 .
100 . The compound of any one of claims 1 - 94 , wherein R 7a and R 7b are both hydrogen.
101 . The compound of any one of claims 1 - 94 , wherein R 7a and R 7b are joined to form an oxo (═O) group.
102 . The compound of any one of claims 1 - 101 , wherein R 11a and R 11b is each independently hydrogen, halogen, —CN, —NO 2 , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, —OR E5 , —OC(═O)R E5 , —OS(═O) 2 OR E5 , —N(R E5 ) 2 , or —N(R E5 )C(═O)R E5 , —N(R E5 )S(═O) 2 R E5 , —N(R E5 )S(═O) 2 OR E5 ; wherein each instance of R E5 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, or two R E5 groups are taken with the intervening atoms to form a substituted or unsubstituted heterocyclic ring.
103 . The compound of any one of claims 1 - 101 , wherein R 11a and R 11b is each independently hydrogen, halogen, —CN, —NO 2 , —OR F6 , —OC(═O)R F6 , —N(R F6 ) 2 , or —N(R F6 )C(═O)R F6 ; wherein each instance of R F6 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, or two R F6 groups are taken with the intervening atoms to form a substituted or unsubstituted heterocyclic ring.
104 . The compound of any one of claims 1 - 101 , wherein R 11a and R 11b are independently hydrogen, —OH, or substituted or unsubstituted C 1-6 alkyl.
105 . The compound of any one of claims 1 - 101 , wherein each of R 11a and R 11b are independently hydrogen, —OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 alkoxyhalo.
106 . The compound of any one of claims 1 - 101 , wherein R 11a and R 11b are independently —CH 3 , —CH 2 CH 3 , —OH, —OCH 3 , or —CH(CH 3 ) 2 .
107 . The compound of any one of claims 1 - 101 , wherein R 11a and R 11b are both hydrogen.
108 . The compound of any one of claims 1 - 101 , wherein R 11a and R 11b are joined to form an oxo (═O) group.
109 . The compound of any one of claims 1 - 108 , wherein R 12a and R 12b is each independently hydrogen, halogen, —CN, —NO 2 , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, —OR E5 , —OC(═O)R E5 , —OS(═O) 2 OR E5 , —N(R E5 ) 2 , or —N(R E5 )C(═O)R E5 , —N(R E5 )S(═O) 2 R E5 , —N(R E5 )S(═O) 2 OR E5 ; wherein each instance of R E5 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, or two R E5 groups are taken with the intervening atoms to form a substituted or unsubstituted heterocyclic ring.
110 . The compound of any one of claims 1 - 108 , wherein R 12a and R 12b is each independently hydrogen, halogen, —CN, —NO 2 , —OR F6 , —OC(═O)R F6 , —N(R F6 ) 2 , or —N(R F6 )C(═O)R F6 ; wherein each instance of R F6 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, or two R F6 groups are taken with the intervening atoms to form a substituted or unsubstituted heterocyclic ring.
111 . The compound of any one of claims 1 - 108 , wherein R 12a and R 12b are independently hydrogen, —OH, or substituted or unsubstituted C 1-6 alkyl.
112 . The compound of any one of claims 1 - 108 , wherein each of R 12a and R 12b are independently hydrogen, —OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 alkoxyhalo.
113 . The compound of any one of claims 1 - 108 , wherein R 12a and R 12b are independently —CH 3 , —CH 2 CH 3 , —OH, —OCH 3 , or —CH(CH 3 ) 2 .
114 . The compound of any one of claims 1 - 108 , wherein R 12a and R 12b are both hydrogen.
115 . The compound of any one of claims 1 - 108 , wherein R 12a and R 12b are joined to form an oxo (═O) group.
116 . The compound of any one of claims 1 - 115 , wherein R 1a and R 1b are independently hydrogen, —OH, or substituted or unsubstituted C 1-6 alkyl.
117 . The compound of any one of claims 1 - 115 , wherein each of R 1a and R 1b are independently hydrogen, —OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 alkoxyhalo.
118 . The compound of any one of claims 1 - 117 , wherein R 1a and R 1b are both hydrogen.
119 . The compound of any one of claims 1 - 118 , wherein R 2a and R 2b are independently hydrogen, —OH, or substituted or unsubstituted C 1-6 alkyl.
120 . The compound of any one of claims 1 - 118 , wherein each of R 2a and R 2b are independently hydrogen, —OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 alkoxyhalo.
121 . The compound of any one of claims 1 - 120 , wherein R 2a and R 2b are both hydrogen.
122 . A pharmaceutical composition comprising a compound of any one of claims 1 - 121 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
123 . A method of 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 claims 1 - 121 or a pharmaceutically acceptable salt thereof.
124 . The method of claim 123 , 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.
125 . The method of claim 123 , wherein the CNS-related disorder is depression.
126 . The method of claim 123 , wherein the CNS-related disorder is postpartum depression.
127 . The method of claim 123 , wherein the CNS-related disorder is major depressive disorder.
128 . The method of claim 127 , wherein the major depressive disorder is moderate major depressive disorder.
129 . The method of claim 127 , wherein the major depressive disorder is severe major depressive disorder.Join the waitlist — get patent alerts
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