STEROL ANALOGS AND USES THEREOF
The invention relates to compositions and methods for the preparation, manufacture, and therapeutic use of compositions comprising mRNA and a lipid nanoparticle comprising a compound of the invention and an ionizable lipid.
1 . A compound having the structure of Formula I:
wherein
R 1a is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, or optionally substituted C 2 -C 6 alkynyl;
X is O or S;
R 1b is H, optionally substituted C 1 -C 6 alkyl, or
each of R b1 , R b2 , and R b3 is, independently, optionally substituted C 1 -C 6 alkyl or optionally substituted C 6 -C 10 aryl;
R 2 is H or OR A , wherein R A is H or optionally substituted C 1 -C 6 alkyl;
R 3 is H or
each independently represents a single bond or a double bond;
W is CR 4a or CR 4a R 4b , wherein if a double bond is present between W and the adjacent carbon, then W is CR 4a ; and if a single bond is present between W and the adjacent carbon, then W is CR 4a R 4b ;
each of R 4a and R 4b is, independently, H, halo, or optionally substituted C 1 -C 6 alkyl;
each of R 5a and R 5b is, independently, H or OR A , or R 5a and R 5b , together with the atom to which each is attached, combine to form
L 1a is absent,
L 1b is absent, e
m is 1, 2, or 3;
L 1c is absent,
and
R 6 is optionally substituted C 3 -C 20 cycloalkyl, optionally substituted C 3 -C 20 cycloalkenyl, optionally substituted C 6 -C 20 aryl, optionally substituted C 2 -C 19 heterocyclyl, or optionally substituted C 2 -C 19 heteroaryl,
or a pharmaceutically acceptable salt thereof.
2 . The compound of claim 1 , wherein the compound has the structure of Formula Ia:
or a pharmaceutically acceptable salt thereof.
3 . The compound of claim 1 , wherein the compound has the structure of Formula Ib:
or a pharmaceutically acceptable salt thereof.
4 . The compound of claim 1 , wherein the compound has the structure of Formula Ic:
or a pharmaceutically acceptable salt thereof.
5 . The compound of claim 1 , wherein the compound has the structure of Formula Id:
or a pharmaceutically acceptable salt thereof.
6 . The compound of any one of claims 1 to 5 , wherein L 1a is absent.
7 . The compound of any one of claims 1 to 5 , wherein L 1a is
8 . The compound of any one of claims 1 to 5 , wherein L 1a is
9 . The compound of any one of claims 1 to 8 , wherein L 1b is absent.
10 . The compound of any one of claims 1 to 8 , wherein L 1b is
11 . The compound of claim 10 , wherein m is 1 or 2.
12 . The compound of any one of claims 1 to 8 , wherein L 1b is
13 . The compound of any one of claims 1 to 8 , wherein L 1b is
14 . The compound of any one of claims 1 to 13 , wherein L 1c is absent.
15 . The compound of any one of claims 1 to 13 , wherein L 1c is
16 . The compound of any one of claims 1 to 13 , wherein L 1c is
17 . The compound of any one of claims 1 to 16 , wherein R 6 is optionally substituted C 6 -C 20 aryl.
18 . The compound of claim 17 , wherein R 6 is optionally substituted C 6 -C 12 aryl.
19 . The compound of claim 18 , wherein R 6 is optionally substituted C 6 -C 10 aryl.
20 . The compound of claim 19 , wherein R 6 is
wherein
n1 is 0, 1, 2, 3, 4, or 5; and
each R 7 is, independently, halo or optionally substituted C 1 -C 6 alkyl.
21 . The compound of claim 20 , wherein each R 7 is, independently,
22 . The compound of claim 21 , wherein n1 is 0, 1, or 2.
23 . The compound of claim 22 , wherein R 6 is
24 . The compound of any one of claims 1 to 16 , wherein R 6 is optionally substituted C 3 -C 20 cycloalkyl.
25 . The compound of claim 24 , wherein R 6 is optionally substituted C 3 -C 12 cycloalkyl.
26 . The compound of claim 25 , wherein R 6 is, wherein
n0 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23; and
each R 8 is, independently, halo or optionally substituted C 1 -C 6 alkyl.
27 . The compound of claim 26 , wherein each R 8 is, independently,
28 . The compound of claim 27 , wherein n0 is 0, 1, 2, 3, 4, 5, or 6.
29 . The compound of claim 28 , wherein R 6 is
30 . The compound of claims 1 to 16 , wherein R 6 is optionally substituted C 3 -C 10 cycloalkyl.
31 . The compound of claim 30 , wherein R 6 is optionally substituted C 3 -C 10 monocycloalkyl.
32 . The compound of claim 31 , wherein R 6 is
wherein
n2 is 0, 1, 2, 3, 4, or 5;
n3 is 0, 1, 2, 3, 4, 5, 6, or 7;
n4 is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9;
n5 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11;
n6 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13; and
each R 8 is, independently, halo or optionally substituted C 1 -C 6 alkyl.
33 . The compound of claim 32 , wherein each R 8 is, independently,
34 . The compound of claim 33 , wherein n2 is 0 or 1.
35 . The compound of claim 34 , wherein R 6 is
36 . The compound of claim 33 , wherein n3 is 0 or 1.
37 . The compound of claim 36 , wherein R 6 is
38 . The compound of claim 33 , wherein n4 is 0, 1, or 2.
39 . The compound of claim 38 , wherein R 6 is
40 . The compound of claim 33 , wherein n5 is 0, 1, 2, or 3.
41 . The compound of claim 40 , wherein R 6 is
42 . The compound of claim 33 , wherein n6 is 0, 1, 2, 3, or 4.
43 . The compound of claim 42 , wherein R 6 is
44 . The compound of claim 30 , wherein R 6 is optionally substituted C 3 -C 10 polycycloalkyl.
45 . The compound of claim 44 , wherein R 6 is
46 . The compound of any one of claims 1 to 16 , wherein R 6 is optionally substituted C 3 -C 20 cycloalkenyl.
47 . The compound of claim 46 , wherein R 6 is optionally substituted C 3 -C 12 cycloalkenyl.
48 . The compound of claim 47 , wherein R 6 is optionally substituted C 3 -C 10 cycloalkenyl.
49 . The compound of claim 48 , wherein R 6 is
wherein
n7 is 0,1, 2, 3, 4, 5, 6, or 7;
n8 is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9;
n9 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11; and
each R 9 is, independently, halo or optionally substituted C 1 -C 6 alkyl.
50 . The compound of claim 49 , wherein R 6 is
51 . The compound of claim 49 or 50 , wherein each R 9 is, independently,
52 . The compound of claim 51 , wherein n7 is 0, 1, or 2.
53 . The compound of claim 52 , wherein R 6 is
54 . The compound of claim 51 , wherein n8 is 0, 1, 2, or 3.
55 . The compound of claim 54 , wherein R 6 is
56 . The compound of claim 51 , wherein n9 is 0, 1, 2, 3, or 4.
57 . The compound of claim 56 , wherein R 6 is
58 . The compound of any one of claims 1 to 16 , wherein R 6 is optionally substituted C 2 -C 19 heterocyclyl.
59 . The compound of claim 58 , wherein R 6 is optionally substituted C 2 -C 1 heterocyclyl.
60 . The compound of claim 59 , wherein R 6 is optionally substituted C 2 -C 9 heterocyclyl.
61 . The compound of claim 60 , wherein R 6 is
wherein
n10 is 0, 1, 2, 3, 4, or 5;
n11 is 0, 1, 2, 3, 4, 5, 6, or 7;
n12 is 0, 1, 2, 3, 4, 5, 6, 7, or 8;
n13 is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9;
each R 10 is, independently, halo or optionally substituted C 1 -C 6 alkyl; and
each of Y 1 and Y 2 is, independently, O, S, NR B , or CR 11a R 11b ,
wherein R B is H or optionally substituted C 1 -C 6 alkyl;
each of R 11a and R 11b is, independently, H, halo, or optionally substituted C 1 -C 6 alkyl; and
if Y 2 is CR 11a R 11b , then Y 1 is O, S, or NR B .
62 . The compound of claim 61 , wherein Y 1 is O.
63 . The compound of claim 61 or 62 , wherein Y 2 is O.
64 . The compound of claim 61 or 62 , wherein Y 2 is CR 11a R 11b .
65 . The compound of any one of claims 61 to 64 , wherein each R 10 is, independently,
66 . The compound of claim 65 , wherein n10 is 0 or 1.
67 . The compound of claim 66 , wherein R 6 is
68 . The compound of claim 65 , wherein n11 is 0, 1, 2, 3, 4, or 5.
69 . The compound of claim 68 , wherein R 6 is
70 . The compound of claim 65 , wherein n12 is 0, 1, 2, 3, 4, 5, or 6.
71 . The compound of claim 70 , wherein R 6 is CH 3 , CH 3 , or CH 3
72 . The compound of any one of claims 1 to 16 , wherein R 6 is optionally substituted C 2 -C 19 heteroaryl.
73 . The compound of claim 72 , wherein R 6 is optionally substituted C 2 -C 11 heteroaryl.
74 . The compound of claim 73 , wherein R 6 is optionally substituted C 2 -C 9 heteroaryl.
75 . The compound of claim 74 , wherein R 6 is
wherein
Y 3 is NR C , O, or S;
n14 is 0, 1, 2, 3, or 4;
R C is H or optionally substituted C 1 -C 6 alkyl; and
each R 12 is, independently, halo or optionally substituted C 1 -C 6 alkyl.
76 . The compound of claim 75 , wherein each R 12 is, independently,
77 . The compound of claim 76 , wherein n14 is 0, 1, or 2.
78 . The compound of any one of claims 75 to 77 , wherein Y 3 is S.
79 . The compound of claim 78 , wherein R 6 is
80 . The compound of claim any one of claims 75 to 77 , wherein Y 3 is NR C .
81 . The compound of claim 80 , wherein R C is H or
82 . The compound of claim 81 , wherein R 6 is
83 . A compound having the structure of Formula II:
wherein
R 1a is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, or optionally substituted C 2 -C 6 alkynyl;
X is O or S;
R 1b is H or optionally substituted C 1 -C 6 alkyl;
R 2 is H or OR A , where R A is H or optionally substituted C 1 -C 6 alkyl;
R 3 is H or
represents a single bond or a double bond;
W is CR 4a or CR 4a R 4b , where if a double bond is present between W and the adjacent carbon, then W is CR 4a ; and if a single bond is present between W and the adjacent carbon, then W is CR 4a R 4b ;
each of R 4a and R 4b is, independently, H, halo, or optionally substituted C 1 -C 6 alkyl;
each of R 5a and R 5b is, independently, H or OR A , or R 5a and R 5b , together with the atom to which each is attached, combine to form
L 1 is optionally substituted C 1 -C 6 alkylene; and
each of R 13a , R 13b , and R 13c is, independently, optionally substituted C 1 -C 6 alkyl or optionally substituted C 6 -C 10 aryl,
or a pharmaceutically acceptable salt thereof.
84 . The compound of 83, wherein the compound has the structure of Formula IIa:
or a pharmaceutically acceptable salt thereof.
85 . The compound of 83 , wherein the compound has the structure of Formula IIb:
or a pharmaceutically acceptable salt thereof.
86 . The compound of any one of claims 83 to 85 , wherein each of R 13a , R 13b , and R 13c is, independently,
87 . A compound having the structure of Formula III:
wherein
R 1a is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, or optionally substituted C 2 -C 6 alkynyl;
X is O or S;
R 1b is H or optionally substituted C 1 -C 6 alkyl;
R 2 is H or OR A , where R A is H or optionally substituted C 1 -C 6 alkyl;
R 3 is H or
each independently represents a single bond or a double bond;
W is CR 4a or CR 4a R 4b , where if a double bond is present between W and the adjacent carbon, then W is CR 4a ; and if a single bond is present between W and the adjacent carbon, then W is CR 4a R 4b ;
each of R 4a and R 4b is, independently, H, halo, hydroxyl, optionally substituted C 1 -C 6 alkyl, —OS(O) 2 R 4c , where R 4c is optionally substituted C 1 -C 6 alkyl or optionally substituted C 6 -C 10 aryl;
each of R 5a and R 5b is, independently, H or OR A , or R 5a and R 5b , together with the atom to which each is attached, combine to form
R 14 is H or C 1 -C 6 alkyl; and
R 15 is
where
R 16 is H or optionally substituted C 1 -C 6 alkyl;
R 17a is H, optionally substituted C 6 -C 10 aryl, or optionally substituted C 1 -C 6 alkyl;
R 17b is H, OR 17c , optionally substituted C 6 -C 10 aryl, or optionally substituted C 1 -C 6 alkyl;
R 17c is H or optionally substituted C 1 -C 6 alkyl;
o1 is 0, 1, 2, 3, 4, 5, 6, 7, or 8;
p1 is 0, 1, or 2;
p2 is 0, 1, or 2;
Z is CH 2 , O, S, or NR D , where R D is H or optionally substituted C 1 -C 6 alkyl; and
each R 18 is, independently, halo or optionally substituted C 1 -C 6 alkyl,
or a pharmaceutically acceptable salt thereof.
88 . The compound of claim 87 , wherein the compound has the structure of Formula IIIa:
or a pharmaceutically acceptable salt thereof.
89 . The compound of claim 87 , wherein the compound has the structure of Formula IIIb:
or a pharmaceutically acceptable salt thereof.
90 . The compound of any one of claims 87 to 89 , wherein R 14 is
91 . The compound of any one of claims 87 to 90 , wherein R 14 is
92 . The compound of any one of claims 87 to 91 , wherein R 15 is
93 . The compound of claim 92 , wherein R 16 is
94 . The compound of any one of claims 87 to 93 , wherein R 15 is
95 . The compound of claim 94 , wherein R 17a is H or optionally substituted C 1 -C 6 alkyl.
96 . The compound of claim 94 or 95 , wherein R 17b is H or optionally substituted C 1 -C 6 alkyl.
97 . The compound of claim 94 or 95 , wherein R 17b is optionally substituted C 6 -C 10 aryl.
98 . The compound of claim 94 or 95 , wherein R 17b is OR 17c .
99 . The compound of any one of claims 87 to 93 , wherein R 15 is
100 . The compound of claim 99 , wherein each R 18 is, independently,
101 . The compound of claim 99 or 100 , wherein Z is CH 2 .
102 . The compound of claim 99 or 100 , wherein Z is O or NR D .
103 . The compound of any one of claims 99 to 102 , wherein p1 is 0 or 1.
104 . The compound of any one of claims 99 to 103 , wherein p2 is 0 or 1.
105 . A compound having the structure of Formula IV:
wherein
R 1a is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, or optionally substituted C 2 -C 6 alkynyl;
X is O or S;
R 1b is H or optionally substituted C 1 -C 6 alkyl;
R 2 is H or OR A , where R A is H or optionally substituted C 1 -C 6 alkyl;
R 3 is H or
represents a single bond or a double bond;
W is CR 4a or CR 4a R 4b , where if a double bond is present between W and the adjacent carbon, then W is CR 4a ; and if a single bond is present between W and the adjacent carbon, then W is CR 4a R 4b ;
each of R 4a and R 4b is, independently, H, halo, or optionally substituted C 1 -C 6 alkyl;
each of R 5a and R 5b is, independently, H or OR A , or R 5a and R 5b , together with the atom to which each is attached, combine to form
s is 0 or 1;
R 19 is H or C 1 -C 6 alkyl;
R 20 is C 1 -C 6 alkyl; and
R 21 is H or C 1 -C 6 alkyl,
or a pharmaceutically acceptable salt thereof.
106 . The compound of claim 105 , wherein the compound has the structure of Formula IVa:
or a pharmaceutically acceptable salt thereof.
107 . The compound of claim 105 , wherein the compound has the structure of Formula IVb:
or a pharmaceutically acceptable salt thereof.
108 . The compound of any one of claims 105 to 107 , wherein each of R 19 , R 20 , and R 21 is, independently,
109 . A compound having the structure of Formula V:
wherein
R 1a is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, or optionally substituted C 2 -C 6 alkynyl;
X is O or S;
R 1b is H or optionally substituted C 1 -C 6 alkyl;
R 2 is H or OR A , wherein R A is H or optionally substituted C 1 -C 6 alkyl;
R 3 is H or
represents a single bond or a double bond;
W is CR 4a or CR 4a R 4b , wherein if a double bond is present between W and the adjacent carbon, then W is CR 4a ; and if a single bond is present between W and the adjacent carbon, then W is CR 4a R 4b ;
each of R 4a and R 4b is, independently, H, halo, or optionally substituted C 1 -C 6 alkyl;
each of R 5a and R 5b is, independently, H or OR A , or R 5a and R 5b , together with the atom to which each is attached, combine to form
R 22 is H or C 1 -C 6 alkyl; and
R 23 is halo, hydroxyl, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 1 -C 6 heteroalkyl,
or a pharmaceutically acceptable salt thereof.
110 . The compound of claim 109 , wherein the compound has the structure of Formula Va:
or a pharmaceutically acceptable salt thereof.
111 . The compound of claim 109 , wherein the compound has the structure of Formula Vb:
or a pharmaceutically acceptable salt thereof.
112 . The compound of any one of claims 109 to 111 , wherein each of R 22 and R 23 is, independently,
113 . A compound having the structure of Formula VI:
wherein
R 1a is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, or optionally substituted C 2 -C 6 alkynyl;
X is O or S;
R 1b is H or optionally substituted C 1 -C 6 alkyl;
R 2 is H or OR A , wherein R A is H or optionally substituted C 1 -C 6 alkyl;
R 3 is H or
represents a single bond or a double bond;
W is CR 4a or CR 4a R 4b , wherein if a double bond is present between W and the adjacent carbon, then W is CR 4a ; and if a single bond is present between W and the adjacent carbon, then W is CR 4a R 4b ;
each of R 4a and R 4b is, independently, H, halo, or optionally substituted C 1 -C 6 alkyl;
each of R 5a and R 5b is, independently, H or OR A , or R 5a and R 5b , together with the atom to which each is attached, combine to form
R 24 is H or C 1 -C 6 alkyl; and
each of R 25a and R 25b is C 1 -C 6 alkyl,
or a pharmaceutically acceptable salt thereof.
114 . The compound of claim 113 , wherein the compound has the structure of Formula Via:
or a pharmaceutically acceptable salt thereof.
115 . The compound of claim 113 , wherein the compound has the structure of Formula VIb:
or a pharmaceutically acceptable salt thereof.
116 . The compound of any one of claims 113 to 115 , wherein each of R 24 , R 25a , and R 25b is, independently,
117 . A compound having the structure of Formula VII:
wherein
R 1a is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, or
wherein each of R 1c , R 1c , and R 1e is, independently, optionally substituted C 1 -C 6 alkyl or optionally substituted C 6 -C 10 aryl;
X is O or S;
R 1b is H or optionally substituted C 1 -C 6 alkyl;
R 2 is H or OR A , wherein R A is H or optionally substituted C 1 -C 6 alkyl;
R 3 is H or
represents a single bond or a double bond;
W is CR 4a or CR 4a R 4b , wherein if a double bond is present between W and the adjacent carbon, then W is CR 4a ; and if a single bond is present between W and the adjacent carbon, then W is CR 4a R 4b ;
each of R 4a and R 4b is, independently, H, halo, or optionally substituted C 1 -C 6 alkyl;
each of R 5a and R 5b is, independently, H or OR A , or R 5a and R 5b , together with the atom to which each is attached, combine to form
q is 0 or 1;
each of R 26a and R 26b is, independently, H or optionally substituted C 1 -C 6 alkyl, or R 26a and R 26b , together with the atom to which each is attached, combine to form
wherein each of R 26c and R 26 is, independently, H or optionally substituted C 1 -C 6 alkyl; and
each of R 27a and R 27b is H, hydroxyl, or optionally substituted C 1 -C 6 alkyl,
or a pharmaceutically acceptable salt thereof.
118 . The compound of claim 117 , wherein the compound has the structure of Formula VIIa:
or a pharmaceutically acceptable salt thereof.
119 . The compound of claim 117 , wherein the compound has the structure of Formula VIIb:
or a pharmaceutically acceptable salt thereof.
120 . The compound of any one of claims 117 to 119 , wherein each of R 26 , R 27a , and R 27b is, independently,
121 . A compound having the structure of Formula VIII:
wherein
R 1a is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, or optionally substituted C 2 -C 6 alkynyl;
X is O or S;
R 1b is H or optionally substituted C 1 -C 6 alkyl;
R 2 is H or OR A , where R A is H or optionally substituted C 1 -C 6 alkyl;
R 3 is H or
represents a single bond or a double bond;
W is CR 4a or CR 4a R 4b , where if a double bond is present between W and the adjacent carbon, then W is CR 4a ; and if a single bond is present between W and the adjacent carbon, then W is CR 4a R 4b ;
each of R 4a and R 4b is, independently, H, halo, or optionally substituted C 1 -C 6 alkyl;
each of R 5a and R 5b is, independently, H or OR A , or R 5a and R 5b , together with the atom to which each is attached, combine to form
R 28 is H or optionally substituted C 1 -C 6 alkyl;
r is 1, 2, or 3;
each R 29 is, independently, H or optionally substituted C 1 -C 6 alkyl; and
each of R 30a , R 30b , and R 30c is C 1 -C 6 alkyl,
or a pharmaceutically acceptable salt thereof.
122 . The compound of claim 121 , wherein the compound has the structure of Formula VIIIa:
or a pharmaceutically acceptable salt thereof.
123 . The compound of claim 121 , wherein the compound has the structure of Formula VIIIb:
or a pharmaceutically acceptable salt thereof.
124 . The compound of any one of claims 121 to 123 , wherein each of R 28 , R 30a , R 30b , and R 30c is independently,
125 . The compound of any one of claims 121 to 124 , wherein each R 29 is, independently, H,
126 . A compound having the structure of Formula IX:
wherein
R 1a is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, or optionally substituted C 2 -C 6 alkynyl;
X is O or S;
R 1b is H or optionally substituted C 1 -C 6 alkyl;
R 2 is H or OR A , where R A is H or optionally substituted C 1 -C 6 alkyl;
R 3 is H or
represents a single bond or a double bond;
W is CR 4a or CR 4a R 4b , where if a double bond is present between W and the adjacent carbon, then W is CR 4a ; and if a single bond is present between W and the adjacent carbon, then W is CR 4a R 4b ;
each of R 4a and R 4b is, independently, H, halo, or optionally substituted C 1 -C 6 alkyl;
each of R 5a and R 5b is, independently, H or OR A , or R 5a and R 5b , together with the atom to which each is attached, combine to form
R 31 is H or C 1 -C 6 alkyl; and
each of R 32a and R 32b is C 1 -C 6 alkyl,
or a pharmaceutically acceptable salt thereof.
127 . The compound of claim 126 , wherein the compound has the structure of Formula IXa:
or a pharmaceutically acceptable salt thereof.
128 . The compound of claim 126 , wherein the compound has the structure of Formula IXb:
or a pharmaceutically acceptable salt thereof.
129 . The compound of any one of claims 126 to 128 , wherein each of R 31 , R 32a , and R 32b is, independently,
130 . A compound having the structure of Formula X:
wherein
R 1a is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, or optionally substituted C 2 -C 6 alkynyl;
X is O or S;
R 2 is H or OR A , wherein R A is H or optionally substituted C 1 -C 6 alkyl;
R 3 is H or
represents a single bond or a double bond;
W is CR 4a or CR 4a R 4b , wherein if a double bond is present between W and the adjacent carbon, then W is CR 4a ; and if a single bond is present between W and the adjacent carbon, then W is CR 4a R 4b ;
each of R 4a and R 4b is, independently, H, halo, or optionally substituted C 1 -C 6 alkyl;
each of R 5a and R 5b is, independently, H or OR A , or R 5a and R 5b , together with the atom to which each is attached, combine to form
R 33a is optionally substituted C 1 -C 6 alkyl or
wherein R 35 is optionally substituted C 1 -C 6 alkyl or optionally substituted C 6 -C 10 aryl;
R 33b is H or optionally substituted C 1 -C 6 alkyl; or
R 35 and R 33b , together with the atom to which each is attached, form an optionally substituted C 3 -C 9 heterocyclyl; and
R 34 is optionally substituted C 1 -C 6 alkyl or optionally substituted C 1 -C 6 heteroalkyl,
or a pharmaceutically acceptable salt thereof.
131 . The compound of claim 130 , wherein the compound has the structure of Formula Xa:
or a pharmaceutically acceptable salt thereof.
132 . The compound of claim 130 , wherein the compound has the structure of Formula Xb:
or a pharmaceutically acceptable salt thereof.
133 . The compound of any one of claims 130 to 132 , wherein R 33a is R 35
134 . The compound of any one of claims 130 to 133 , wherein R 35 is
135 . The compound of claim 130 or 134 , wherein R 35 is
wherein
t is 0, 1, 2, 3, 4, or 5; and
each R 36 is, independently, halo, hydroxyl, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 1 -C 6 heteroalkyl.
136 . The compound of any one of claims 130 to 135 , wherein R 34 is
wherein u is 0, 1, 2, 3, or 4.
137 . The compound of claim 136 , wherein u is 3 or 4.
138 . A compound having the structure of Formula XI:
wherein
R 1a is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, or optionally substituted C 2 -C 6 alkynyl;
X is O or S;
R 2 is H or OR A , wherein R A is H or optionally substituted C 1 -C 6 alkyl;
R 3 is H or
represents a single bond or a double bond;
W is CR 4a or CR 4a R 4b , wherein if a double bond is present between W and the adjacent carbon, then W is CR 4a ; and if a single bond is present between W and the adjacent carbon, then W is CR 4a R 4b ;
each of R 4a and R 4b is, independently, H, halo, or optionally substituted C 1 -C 6 alkyl;
each of R 5a and R 5b is, independently, H or OR A , or R 5a and R 5b , together with the atom to which each is attached, combine to form
each of R 37a and R 37b is, independently, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, halo, or hydroxyl,
or a pharmaceutically acceptable salt thereof.
139 . The compound of claim 138 , wherein the compound has the structure of Formula XIa:
or a pharmaceutically acceptable salt thereof.
140 . The compound of claim 138 , wherein the compound has the structure of Formula XIb:
or a pharmaceutically acceptable salt thereof.
141 . The compound of any one of claims 138 to 140 , wherein R 37a is hydroxyl.
142 . The compound of any one of claims 138 to 141 , wherein R 37b is
143 . A compound having the structure of Formula XII:
wherein
R 1a is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, or optionally substituted C 2 -C 6 alkynyl;
X is O or S;
R 2 is H or OR A , wherein R A is H or optionally substituted C 1 -C 6 alkyl;
R 3 is H or
represents a single bond or a double bond;
W is CR 4a or CR 4a R 4b , wherein if a double bond is present between W and the adjacent carbon, then W is CR 4a ; and if a single bond is present between W and the adjacent carbon, then W is CR 4a R 4b ;
each of R 4a and R 4b is, independently, H, halo, or optionally substituted C 1 -C 6 alkyl;
each of R 5a and R 5b is, independently, H or OR A , or R 5a and R 5b , together with the atom to which each is attached, combine to form
and
Q is O, S, or NR E , wherein R E is H or optionally substituted C 1 -C 6 alkyl; and
R 38 is optionally substituted C 1 -C 6 alkyl,
or a pharmaceutically acceptable salt thereof.
144 . The compound of claim 143 , wherein the compound has the structure of Formula XIIa:
or a pharmaceutically acceptable salt thereof.
145 . The compound of claim 143 , wherein the compound has the structure of Formula XIIb:
or a pharmaceutically acceptable salt thereof.
146 . The compound of any one of claims 143 to 145 , wherein Q is NR E .
147 . The compound of any one of claims 143 to 146 , wherein R E is H or
148 . The compound of claim 147 , wherein R E is
149 . The compound of any one of claims 144 to 148 , wherein R 38 is
wherein u is 0, 1, 2, 3, or 4.
150 . A compound having the structure of Formula XIII:
wherein
R 1a is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, or optionally substituted C 2 -C 6 alkynyl;
X is O or S;
R 1b is H, optionally substituted C 1 -C 6 alkyl, or
each of R b1 , R b2 , and R b3 is, independently, optionally substituted C 1 -C 6 alkyl or optionally substituted C 6 -C 10 aryl;
R 2 is H or OR A , where R A is H or optionally substituted C 1 -C 6 alkyl;
R 3 is H or
each independently represents a single bond or a double bond;
W is CR 4a or CR 4a R 4b , where if a double bond is present between W and the adjacent carbon, then W is CR 4a ; and if a single bond is present between W and the adjacent carbon, then W is CR 4a R 4b ;
each of R 4a and R 4b is, independently, H, halo, or optionally substituted C 1 -C 6 alkyl;
each of R 5a and R 5b is, independently, H or OR A , or R 5a and R 5b , together with the atom to which each is attached, combine to form
R 39 is H or optionally substituted C 2 -C 20 alkyl;
R 40a is optionally substituted C 3 -C 20 alkyl; and
R 40b is optionally substituted C 3 -C 20 alkyl,
or a pharmaceutically acceptable salt thereof.
151 . The compound of claim 150 , wherein the compound has the structure of Formula XIIa:
or a pharmaceutically acceptable salt thereof.
152 . The compound of claim 150 , wherein the compound has the structure of Formula XIIb:
or a pharmaceutically acceptable salt thereof.
153 . The compound of claim 150 , wherein the compound has the structure of Formula XIIc:
or a pharmaceutically acceptable salt thereof.
154 . The compound of claim 150 , wherein the compound has the structure of Formula XIId:
or a pharmaceutically acceptable salt thereof.
155 . The compound of any one of claims 150 to 154 , wherein R 39 is H.
156 . The compound of any one of claims 150 to 154 , wherein R 39 is optionally substituted C 2 -C 20 alkyl.
157 . The compound of claim 156 , wherein R 39 is optionally substituted C 2 -C 12 alkyl.
158 . The compound of claim 157 , wherein R 39 is optionally substituted C 2 -C 10 alkyl.
159 . The compound of claim 158 , wherein R 39 is
160 . The compound of any one of claims 150 to 159 , wherein R 40a is optionally substituted C 3 -C 12 alkyl.
161 . The compound of claim 160 , wherein R 40a is optionally substituted C 3 -C 10 alkyl.
162 . The compound of claim 161 , wherein R 40a is
163 . The compound of claim 162 , wherein R 40a is
164 . The compound of any one of claims 150 to 159 , wherein R 40a is optionally substituted C 4 -C 20 alkyl.
165 . The compound of claim 164 , wherein R 40a is
166 . The compound of claim 165 , wherein R 40a is
167 . The compound of any one of claims 150 to 166 , wherein R 40a is
168 . The compound of any one of claims 150 to 167 , wherein R 40b is optionally substituted C 3 -C 12 alkyl.
169 . The compound of claim 168 , wherein R 40b is optionally substituted C 3 -C 10 alkyl.
170 . The compound of claim 169 , wherein R 40b is
171 . The compound of claim 170 , wherein R 40b is
172 . The compound of any one of claims 150 to 167 , wherein R 40b is optionally substituted C 4 -C 20 alkyl.
173 . The compound of claim 172 , wherein R 40b is
174 . The compound of claim 173 , wherein R 40b is
175 . The compound of any one of claims 150 to 174 , wherein R 40b is
176 . The compound of any one of claims 1 to 175 , wherein X is O.
177 . The compound of any one of claims 1 to 176 , wherein R 1a is H or optionally substituted C 1 -C 6 alkyl.
178 . The compound of any one of claims 1 to 177 , wherein R 1a is H.
179 . The compound of any one of claims 1 to 178 , wherein R 1b is H or optionally substituted C 1 -C 6 alkyl.
180 . The compound of any one of claims 1 to 179 , wherein R 1b is H.
181 . The compound of any one of claims 1 to 180 , wherein R 2 is H.
182 . The compound of any one of claims 1 to 181 , wherein R 4a is H.
183 . The compound of any one of claims 1 to 182 , wherein R 4b is H.
184 . The compound of any one of claims 1 to 183 , wherein represents a double bond.
185 . The compound of any one of claims 1 to 184 , wherein R 3 is H.
186 . The compound of any one of claims 1 to 185 , wherein R 3 is
187 . The compound of any one of claims 1 to 186 , wherein R 5a is H.
188 . The compound of any one of claims 1 to 187 , wherein R 5b is H.
189 . A compound having the structure of any one of compounds 1-42, 150, 154, 162-165, 169-172, and 184-209 in Table 1, or any pharmaceutically acceptable salt thereof.
190 . A compound having the structure of any one of compounds 43-50 and 175-178 in Table 2, or any pharmaceutically acceptable salt thereof.
191 . A compound having the structure of any one of compounds 51-67, 149, and 153 in Table 3, or any pharmaceutically acceptable salt thereof.
192 . A compound having the structure of any one of compounds 68-73, in Table 4, or any pharmaceutically acceptable salt thereof.
193 . A compound having the structure of any one of compounds 74-78 in Table 5, or any pharmaceutically acceptable salt thereof.
194 . A compound having the structure of any one of compounds 79 and 80 in Table 6, or any pharmaceutically acceptable salt thereof.
195 . A compound having the structure of any one of compounds 81-83, 85-87, 152, and 157 in Table 7, or any pharmaceutically acceptable salt thereof.
196 . A compound having the structure of any one of compounds 88-97 in Table 8, or any pharmaceutically acceptable salt thereof.
197 . A compound having the structure of any one of compounds 98-105, 180-182, and 210-213 in Table 9, or any pharmaceutically acceptable salt thereof.
198 . A compound having the structure of compound 106 in Table 10, or any pharmaceutically acceptable salt thereof.
199 . A compound having the structure of any one of compounds 107-108 in Table 11, or any pharmaceutically acceptable salt thereof.
200 . A compound having the structure of compound 109 in Table 12, or any pharmaceutically acceptable salt thereof.
201 . A compound having the structure of compounds 214-218 in Table 13, or any pharmaceutically acceptable salt thereof.
202 . A compound having the structure of any one of compounds 110-130, 155, 156, 160, 161, 166-168, 173, 174, 179, and 219-226 in Table 14, or any pharmaceutically acceptable salt thereof.
203 . A lipid nanoparticle comprising:
(i) an ionizable lipid; and
(ii) a structural component,
wherein the structural component comprises a compound of any one of claims 1 to 202 or any one of compounds 131-133 in Table 15.
204 . The lipid nanoparticle of claim 203 , wherein the lipid nanoparticle further comprises a nucleic acid molecule.
205 . A lipid nanoparticle comprising:
(i) an ionizable lipid;
(ii) a structural component;
(iii) optionally, a non-cationic helper lipid;
(iv) optionally, a PEG-lipid; and
(v) a nucleic acid molecule,
wherein the structural component comprises a compound of any one of claims 1 to 202 or any one of compounds 131-133 in Table 15 and optionally a structural lipid component.
206 . The lipid nanoparticle of any one of claims 203 to 205 , wherein the lipid nanoparticle comprises the compound of any one of claims 1 to 202 or any one of compounds 131-133 in Table 15 in an amount that enhances delivery of the nucleic acid molecule to a cell relative to a lipid nanoparticle lacking the compound.
207 . The lipid nanoparticle of any one of claims 203 to 206 , wherein the lipid nanoparticle further comprises one or more structural lipids or salts thereof.
208 . The lipid nanoparticle of claim 207 , wherein the one or more structural lipids is a sterol.
209 . The lipid nanoparticle of claim 208 , wherein the one or more structural lipids is a phytosterol.
210 . The lipid nanoparticle of claim 209 , wherein the phytosterol is β-sitosterol, campesterol, stigmasterol, or any combination thereof.
211 . The lipid nanoparticle of claim 209 or 210 , wherein the one or more structural lipids comprises a mixture of β-sitosterol, campesterol, and stigmasterol.
212 . The lipid nanoparticle of claim 211 , wherein the one or more structural lipids comprises about 40% of β-sitosterol, about 25% stigmasterol, and about 25% of campesterol.
213 . The lipid nanoparticle of claim 211 , wherein the one or more structural lipids comprises about 70% of β-sitosterol, about 10% stigmasterol, and about 10% of campesterol.
214 . The lipid nanoparticle of claim 208 , wherein the one or more structural lipids is a zoosterol.
215 . The lipid nanoparticle of claim 214 , wherein the zoosterol is cholesterol.
216 . The lipid nanoparticle of claim 207 , wherein the one or more structural lipids is any one of compounds 84, 134-148, 151, and 159 in Table 16.
217 . The lipid nanoparticle of claim 207 , wherein the one or more structural lipids is a composition of structural lipids.
218 . The lipid nanoparticle of claim 217 , wherein the composition of structural lipids is composition 183 in Table 17.
219 . The lipid nanoparticle of claim 208 , wherein composition 183 includes about 35% to about 45% of compound 141, about 20% to about 30% of compound 140, about 20% to about 30% compound 143, and about 5% to about 15% of compound 148.
220 . The lipid nanoparticle of any one of claims 207 to 219 , wherein the mol % of the one or more structural lipids is between about 1% and 50% of the mol % of the compound of any one of claims 1 to 202 or any one of compounds 131-133 in Table 15 present in the lipid nanoparticle.
221 . The lipid nanoparticle of any one of claims 207 to 219 , wherein the mol % of the one or more structural lipids is between about 10% and 40% of the mol % of the compound of any one of claims 1 to 202 or any one of compounds 131-133 in Table 15 present in the lipid nanoparticle.
222 . The lipid nanoparticle of any one of claims 207 to 221 , wherein the mol % of the one or more structural lipids is between about 20% and 30% of the mol % of the compound of any one of claims 1 to 202 present in the lipid nanoparticle.
223 . The lipid nanoparticle of any one of claims 207 to 222 , wherein the mol % of the one or more structural lipids is about 30% of the mol % of the compound of any one of claims 1 to 202 present in the lipid nanoparticle.
224 . The lipid nanoparticle of any one of claims 203 to 223 , wherein the lipid nanoparticle comprises one or more non-cationic helper lipids.
225 . The lipid nanoparticle of claim 224 , wherein the one or more non-cationic helper lipids is a phospholipid, fatty acid, or any combination thereof.
226 . The lipid nanoparticle of claim 225 , wherein the phospholipid is a phospholipid that comprises a phosphocholine moiety, a phosphoethanolamine moiety, or a phosphor-1-glycerol moiety.
227 . The lipid nanoparticle of claim 225 or 226 , wherein the phospholipid is 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), 1,2-dimyristoyl-sn-glycero-phosphocholine (DMPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-diundecanoyl-sn-glycero-phosphocholine (DUPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1,2-di-O-octadecenyl-sn-glycero-3-phosphocholine (18:0 Diether PC), 1-oleoyl-2-cholesterylhemisuccinoyl-sn-glycero-3-phosphocholine (OChemsPC), 1-hexadecyl-sn-glycero-3-phosphocholine (C16 Lyso PC), 1,2-dilinolenoyl-sn-glycero-3-phosphocholine, 1,2-diarachidonoyl-sn-glycero-3-phosphocholine, or 1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine.
228 . The lipid nanoparticle of claim 227 , wherein the phospholipid is DSPC.
229 . The lipid nanoparticle of claim 225 or 226 , wherein the phospholipid is 1,2-dioleoyl-sn-glycero-3-phosphoethanola mine (DOPE), 1,2-diphytanoyl-sn-glycero-3-phosphoethanolamine (ME 16.0 PE), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, 1,2-dilinoleoyl-sn-glycero-3-phosphoethanolamine, 1,2-dilinolenoyl-sn-glycero-3-phosphoethanolamine, 1,2-diarachidonoyl-sn-glycero-3-phosphoethanolamine, 1,2-didocosahexaenoyl-sn-glycero-3-phosphoethanolamine, or 1,2-dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol) sodium salt (DOPG).
230 . The lipid nanoparticle of claim 225 or 226 , wherein the phospholipid is sphingomyelin.
231 . The lipid nanoparticle of claim 225 , wherein the fatty acid is a long-chain fatty acid.
232 . The lipid nanoparticle of claim 231 , wherein the fatty acid is palmitic acid, stearic acid, palmitoleic acid, oleic acid, or any combination thereof.
233 . The lipid nanoparticle of claim 232 , wherein the fatty acid is oleic acid.
234 . The lipid nanoparticle of claim 232 , wherein the fatty acid is stearic acid.
235 . The lipid nanoparticle of any one of claims 203 to 234 , wherein the lipid nanoparticle comprises one or more PEG-lipids.
236 . The lipid nanoparticle of claim 235 , wherein the one or more PEG-lipids is a PEG-modified phosphatidylethanolamine, a PEG-modified phosphatidic acid, a PEG-modified ceramide, a PEG-modified dialkylamine, a PEG-modified diacylglycerol, a PEG-modified dialkylglycerol, or mixtures thereof.
237 . The lipid nanoparticle of claim 235 or 236 , wherein the one or more PEG-lipids is PEG-c-DOMG, PEG-DMG, PEG-DLPE, PEG-DMPE, PEG-DPPC, or PEG-DSPE lipid.
238 . The lipid nanoparticle of claim 237 , wherein the one or more PEG-lipids is PEG-DMG.
239 . The lipid nanoparticle of any one of claims 203 to 238 , wherein the lipid nanoparticle comprises about 30 mol % to about 60 mol % one or more ionizable lipids, about 0 mol % to about 30 mol % one or more non-cationic helper lipids, about 18.5 mol % to about 48.5 mol % structural component, and about 0 mol % to about 10 mol % one or more PEG-lipids.
240 . The lipid nanoparticle of any one of claims 203 to 239 , wherein the lipid nanoparticle comprises about 35 mol % to about 55 mol % one or more ionizable lipids, about 5 mol % to about 25 mol % one or more non-cationic helper lipids, about 30 mol % to about 40 mol % structural component, and about 0 mol % to about 10 mol % one or more PEG-lipids.
241 . The lipid nanoparticle of any one of claims 203 to 240 , wherein the lipid nanoparticle comprises about 50 mol % one or more ionizable lipids, about 10 mol % one or more non-cationic helper lipids, about 38.5 mol % structural component, and about 1.5 mol % one or more PEG-lipids.
242 . The lipid nanoparticle of any one of claims 203 to 241 , wherein the nucleic acid molecule is RNA or DNA.
243 . The lipid nanoparticle of any one of claims 203 to 242 , wherein the nucleic acid is DNA.
244 . The lipid nanoparticle of claim 243 , wherein the nucleic acid molecule is ssDNA.
245 . The lipid nanoparticle of claim 243 , wherein the nucleic acid is DNA comprising CRISPR.
246 . The lipid nanoparticle of any one of claims 203 to 242 , wherein the nucleic acid is RNA.
247 . The lipid nanoparticle of claim 246 , wherein the nucleic acid molecule is a shortmer, an antagomir, an antisense, a ribozyme, a small interfering RNA (siRNA), an asymmetrical interfering RNA (aiRNA), a microRNA (miRNA), a Dicer-substrate RNA (dsRNA), a small hairpin RNA (shRNA), or a messenger RNA (mRNA).
248 . The lipid nanoparticle of claim 242 or 247 , wherein the nucleic acid molecule is an mRNA.
249 . The lipid nanoparticle of claim 248 , wherein the mRNA is a modified mRNA comprising one or more modified nucleobases.
250 . The lipid nanoparticle of claim 248 or 249 , wherein the mRNA comprises one or more of a stem loop, a chain terminating nucleoside, a polyA sequence, a polyadenylation signal, and a 5′ cap structure.
251 . The lipid nanoparticle of any one of claims 203 to 250 , wherein the structural component comprises a compound of any one of claims 1 to 82 or 176 to 188 .
252 . The lipid nanoparticle of any one of claims 203 to 250 , wherein the structural component comprises a compound of any one of claims 83 to 86 or 176 to 188 .
253 . The lipid nanoparticle of any one of claims 203 to 250 , wherein the structural component comprises a compound of any one of claims 87 to 104 or 176 to 188 .
254 . The lipid nanoparticle of any one of claims 203 to 250 , wherein the structural component comprises a compound of any one of claims 105 to 108 or 176 to 188 .
255 . The lipid nanoparticle of any one of claims 203 to 250 , wherein the structural component comprises a compound of any one of claims 109 to 112 or 176 to 188 .
256 . The lipid nanoparticle of any one of claims 203 to 250 , wherein the structural component comprises a compound of any one of claims 113 to 116 or 176 to 188 .
257 . The lipid nanoparticle of any one of claims 203 to 250 , wherein the structural component comprises a compound of any one of claims 117 to 120 or 176 to 188 .
258 . The lipid nanoparticle of any one of claims 203 to 250 , wherein the structural component comprises a compound of any one of claims 121 to 125 or 176 to 188 .
259 . The lipid nanoparticle of any one of claims 203 to 250 , wherein the structural component comprises a compound of any one of claims 126 to 129 or 176 to 188 .
260 . The lipid nanoparticle of any one of claims 203 to 250 , wherein the structural component comprises a compound of any one of claims 130 to 137 or 176 to 188 .
261 . The lipid nanoparticle of any one of claims 203 to 250 , wherein the structural component comprises a compound of any one of claims 138 to 142 or 176 to 188 .
262 . The lipid nanoparticle of any one of claims 203 to 250 , wherein the structural component comprises a compound of any one of claims 143 to 149 or 176 to 188 .
263 . The lipid nanoparticle of any one of claims 203 to 250 , wherein the structural component comprises a compound of any one of claims 150 to 188 .
264 . The lipid nanoparticle of any one of claims 203 to 250 , wherein the structural component comprises a compound of any one of claims 189 - 202 .
265 . The lipid nanoparticle of any one of claims 203 to 250 , wherein the lipid nanoparticle further comprises an additional compound of any one of claims 1 to 202