NANOMATERIALS COMPRISING ESTER-LINKED ACETALS
The present disclosure describes compositions, preparations, nanoparticles (such as lipid nanoparticles), and/or nanomaterials and methods of their use.
1 . A compound of Formula A′:
or its N-oxide, or a pharmaceutically acceptable salt thereof, wherein
L 1 is absent, C 1-6 alkylenyl, or C 2-6 heteroalkylenyl;
each L 2 is independently optionally substituted C 2-15 alkylenyl or optionally substituted C 3-15 heteroalkylenyl;
L is C 1-10 alkylenyl or C 2-10 heteroalkylenyl;
X 2 is —OC(O)—, —C(O)O—, or —OC(O)O—;
X is absent, —OC(O)—, —C(O)O—, or —OC(O)O—;
R″ is hydrogen,
or an optionally substituted group selected from C 6-20 aliphatic, 3- to 12-membered cycloaliphatic, 7- to 12-membered bridged bicyclic comprising 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl;
each of R and R a is independently hydrogen, or an optionally substituted group selected from C 6-20 aliphatic, 3- to 12-membered cycloaliphatic, 7- to 12-membered bridged bicyclic comprising 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl
each of L 3 and L 3 , is independently absent, optionally substituted C 1-10 alkylenyl, or optionally substituted C 2-10 heteroalkylenyl;
R 1 is hydrogen, optionally substituted phenyl, optionally substituted 3- to 7-membered cycloaliphatic, optionally substituted 3- to 7-membered heterocyclyl comprising 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 5- to 6-membered monocyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 8- to 10-membered bicyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, —OR 2 , —C(O)OR 2 , —C(O)SR 2 , —OC(O)R 2 , —OC(O)OR 2 , —CN, —N(R 2 ) 2 , —C(O)N(R 2 ) 2 , —S(O) 2 N(R 2 ) 2 , —NR 2 C(O)R 2 , —OC(O)N(R 2 ) 2 , —N(R 2 )C(O)OR 2 , —NR 2 S(O) 2 R 2 , —NR 2 C(O)N(R 2 ) 2 , —NR 2 C(S)N(R 2 ) 2 , —NR 2 C(NR 2 )N(R 2 ) 2 , —NR 2 C(CHR 2 )N(R 2 ) 2 , —N(OR 2 )C(O)R 2 , —N(OR 2 )S(O) 2 R 2 , —N(OR 2 )C(O)OR 2 , —N(OR 2 )C(O)N(R 2 ) 2 , —N(OR 2 )C(S)N(R 2 ) 2 , —N(OR 2 )C(NR 2 )N(R 2 ) 2 , —N(OR 2 )C(CHR 2 )N(R 2 ) 2 , —C(NR 2 )N(R 2 ) 2 , —C(NR 2 )R 2 , —C(O)N(R 2 )OR 2 , —C(R 2 )N(R 2 ) 2 C(O)OR 2 , —CR 2 (R 3 ) 2 , —OP(O)(OR 2 ) 2 , or —P(O)(OR 2 ) 2 ; or
R 1 is
or a ring selected from 3- to 7-membered cycloaliphatic and 3- to 7-membered heterocyclyl comprising 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the cycloaliphatic or heterocyclyl ring is optionally substituted with 1-4 R 2 or R 3 groups;
each R 2 is independently hydrogen, oxo, —CN, —NO 2 , —OR 4 , —S(O) 2 R 4 , —S(O) 2 N(R 4 ) 2 , —(CH 2 ) n —R 4 , or an optionally substituted group selected from C 1-6 aliphatic, phenyl, 3- to 7-membered cycloaliphatic, 5- to 6-membered monocyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered heterocyclyl comprising 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or
two occurrences of R 2 , taken together with the atom(s) to which they are attached, form optionally substituted 4- to 7-membered heterocyclyl comprising 0-1 additional heteroatom selected from nitrogen, oxygen, and sulfur;
each R 3 is independently —(CH 2 ) n —R 4 ; or
two occurrences of R 3 , taken together with the atom(s) to which they are attached, form optionally substituted 5- to 6-membered heterocyclyl comprising 0-1 additional heteroatom selected from nitrogen, oxygen, and sulfur;
each R 4 is independently hydrogen, —OR 5 , —N(R 5 ) 2 , —OC(O)R 5 , —OC(O)OR 5 , —CN, —C(O)N(R 5 ) 2 , —NR 5 C(O)R 5 , —OC(O)N(R 5 ) 2 , —N(R 5 )C(O)OR 5 , —NR 5 S(O) 2 R 5 , —NR 5 C(O)N(R 5 ) 2 , —NR 5 C(S)N(R 5 ) 2 , —NR 5 C(NR 5 )N(R 5 ) 2 , or
each R 5 is independently hydrogen or optionally substituted C 1-6 aliphatic; or
two occurrences of R 5 , taken together with the atom(s) to which they are attached, form optionally substituted 4- to 7-membered heterocyclyl comprising 0-1 additional heteroatom selected from nitrogen, oxygen, and sulfur;
each R 6 is independently C 4-12 aliphatic; and
each n is independently 0 to 4.
2 . The compound of claim 1 , wherein the compound is a compound of Formula I″:
or its N-oxide, or a pharmaceutically acceptable salt thereof, wherein
R″ is hydrogen,
or an optionally substituted group selected from C 6-20 aliphatic, 3- to 12-membered cycloaliphatic, 7- to 12-membered bridged bicyclic comprising 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl.
3 . A compound of Formula II″:
or its N-oxide, or a pharmaceutically acceptable salt thereof, wherein
L 1 is absent, C 1-6 alkylenyl, or C 2-6 heteroalkylenyl;
each L 2 is independently optionally substituted C 2-15 alkylenyl or optionally substituted C 3-15 heteroalkylenyl;
L is C 1-10 alkylenyl or C 2-10 heteroalkylenyl;
X 2 is —OC(O)—, —C(O)O—, or —OC(O)O—;
each L 3 is independently absent, optionally substituted C 1-10 alkylenyl, or optionally substituted C 2-10 heteroalkylenyl;
each R is independently hydrogen, or an optionally substituted group selected from C 6-20 aliphatic, 3- to 12-membered cycloaliphatic, 7- to 12-membered bridged bicyclic comprising 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl;
R 1 is hydrogen, optionally substituted phenyl, optionally substituted 3- to 7-membered cycloaliphatic, optionally substituted 3- to 7-membered heterocyclyl comprising 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 5- to 6-membered monocyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 8- to 10-membered bicyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, —OR 2 , —C(O)OR 2 , —C(O)SR 2 , —OC(O)R 2 , —OC(O)OR 2 , —CN, —N(R 2 ) 2 , —C(O)N(R 2 ) 2 , —S(O) 2 N(R 2 ) 2 , —NR 2 C(O)R 2 , —OC(O)N(R 2 ) 2 , —N(R 2 )C(O)OR 2 , —NR 2 S(O) 2 R 2 , —NR 2 C(O)N(R 2 ) 2 , —NR 2 C(S)N(R 2 ) 2 , —NR 2 C(NR 2 )N(R 2 ) 2 , —NR 2 C(CHR 2 )N(R 2 ) 2 , —N(OR 2 )C(O)R 2 , —N(OR 2 )S(O) 2 R 2 , —N(OR 2 )C(O)OR 2 , —N(OR 2 )C(O)N(R 2 ) 2 , —N(OR 2 )C(S)N(R 2 ) 2 , —N(OR 2 )C(NR 2 )N(R 2 ) 2 , —N(OR 2 )C(CHR 2 )N(R 2 ) 2 , —C(NR 2 )N(R 2 ) 2 , —C(NR 2 )R 2 , —C(O)N(R 2 )OR 2 , —C(R 2 )N(R 2 ) 2 C(O)OR 2 , —CR 2 (R 3 ) 2 , —OP(O)(OR 2 ) 2 , or —P(O)(OR 2 ) 2 ;
R 1 is
or a ring selected from 3- to 7-membered cycloaliphatic and 3- to 7-membered heterocyclyl comprising 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the cycloaliphatic or heterocyclyl ring is optionally substituted with 1-4 R 2 or R 3 groups;
each R 2 is independently hydrogen, oxo, —CN, —NO 2 , —OR 4 , —S(O) 2 R 4 , —S(O) 2 N(R 4 ) 2 , —(CH 2 ) n —R 4 , or an optionally substituted group selected from C 1-6 aliphatic, phenyl, 3- to 7-membered cycloaliphatic, 5- to 6-membered monocyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered heterocyclyl comprising 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or
two occurrences of R 2 , taken together with the atom(s) to which they are attached, form optionally substituted 4- to 7-membered heterocyclyl comprising 0-1 additional heteroatom selected from nitrogen, oxygen, and sulfur;
each R 3 is independently —(CH 2 ) n —R 4 ; or
two occurrences of R 3 , taken together with the atom(s) to which they are attached, form optionally substituted 5- to 6-membered heterocyclyl comprising 0-1 additional heteroatom selected from nitrogen, oxygen, and sulfur;
each R 4 is independently hydrogen, —OR 5 , —N(R 5 ) 2 , —OC(O)R 5 , —OC(O)OR 5 , —CN, —C(O)N(R 5 ) 2 , —NR 5 C(O)R 5 , —OC(O)N(R 5 ) 2 , —N(R 5 )C(O)OR 5 , —NR 5 S(O) 2 R 5 , —NR 5 C(O)N(R 5 ) 2 , —NR 5 C(S)N(R 5 ) 2 , —NR 5 C(NR 5 )N(R 5 ) 2 , or
each R 5 is independently hydrogen or optionally substituted C 1-6 aliphatic; or
two occurrences of R 5 , taken together with the atom(s) to which they are attached, form optionally substituted 4- to 7-membered heterocyclyl comprising 0-1 additional heteroatom selected from nitrogen, oxygen, and sulfur;
each R 6 is independently C 4-12 aliphatic; and
each n is independently 0 to 4.
4 . A compound of Formula III′:
or its N-oxide, or a pharmaceutically acceptable salt thereof, wherein
L 1 is absent, C 1-6 alkylenyl, or C 2-6 heteroalkylenyl;
each L 2 is independently optionally substituted C 2-15 alkylenyl or optionally substituted C 3-15 heteroalkylenyl;
each L is independently C 1-10 alkylenyl or C 2-10 heteroalkylenyl;
each X 2 is independently —OC(O)—, —C(O)O—, or —OC(O)O—;
each L 3 is independently absent, optionally substituted C 1-10 alkylenyl, or optionally substituted C 2-10 heteroalkylenyl;
each R is independently hydrogen, or an optionally substituted group selected from C 6-20 aliphatic, 3- to 12-membered cycloaliphatic, 7- to 12-membered bridged bicyclic comprising 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl;
R 1 is hydrogen, optionally substituted phenyl, optionally substituted 3- to 7-membered cycloaliphatic, optionally substituted 3- to 7-membered heterocyclyl comprising 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 5- to 6-membered monocyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 8- to 10-membered bicyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, —OR 2 , —C(O)OR 2 , —C(O)SR 2 , —OC(O)R 2 , —OC(O)OR 2 , —CN, —N(R 2 ) 2 , —C(O)N(R 2 ) 2 , —S(O) 2 N(R 2 ) 2 , —NR 2 C(O)R 2 , —OC(O)N(R 2 ) 2 , —N(R 2 )C(O)OR 2 , —NR 2 S(O) 2 R 2 , —NR 2 C(O)N(R 2 ) 2 , —NR 2 C(S)N(R 2 ) 2 , —NR 2 C(NR 2 )N(R 2 ) 2 , —NR 2 C(CHR 2 )N(R 2 ) 2 , —N(OR 2 )C(O)R 2 , —N(OR 2 )S(O) 2 R 2 , —N(OR 2 )C(O)OR 2 , —N(OR 2 )C(O)N(R 2 ) 2 , —N(OR 2 )C(S)N(R 2 ) 2 , —N(OR 2 )C(NR 2 )N(R 2 ) 2 , —N(OR 2 )C(CHR 2 )N(R 2 ) 2 , —C(NR 2 )N(R 2 ) 2 , —C(NR 2 )R 2 , —C(O)N(R 2 )OR 2 , —C(R 2 )N(R 2 ) 2 C(O)OR 2 , —CR 2 (R 3 ) 2 , —OP(O)(OR 2 ) 2 , or —P(O)(OR 2 ) 2 ; or
R 1 is
or a ring selected from 3- to 7-membered cycloaliphatic and 3- to 7-membered heterocyclyl comprising 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the cycloaliphatic or heterocyclyl ring is optionally substituted with 1-4 R 2 or R 3 groups;
each R 2 is independently hydrogen, oxo, —CN, —NO 2 , —OR 4 , —S(O) 2 R 4 , —S(O) 2 N(R 4 ) 2 , —(CH 2 ) n —R 4 , or an optionally substituted group selected from C 1-6 aliphatic, phenyl, 3- to 7-membered cycloaliphatic, 5- to 6-membered monocyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered heterocyclyl comprising 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or
two occurrences of R 2 , taken together with the atom(s) to which they are attached, form optionally substituted 4- to 7-membered heterocyclyl comprising 0-1 additional heteroatom selected from nitrogen, oxygen, and sulfur;
each R 3 is independently —(CH 2 ) n —R 4 ; or
two occurrences of R 3 , taken together with the atom(s) to which they are attached, form optionally substituted 5- to 6-membered heterocyclyl comprising 0-1 additional heteroatom selected from nitrogen, oxygen, and sulfur;
each R 4 is independently hydrogen, —OR 5 , —N(R 5 ) 2 , —OC(O)R 5 , —OC(O)OR 5 , —CN, —C(O)N(R 5 ) 2 , —NR 5 C(O)R 5 , —OC(O)N(R 5 ) 2 , —N(R 5 )C(O)OR 5 , —NR 5 S(O) 2 R 5 , —NR 5 C(O)N(R 5 ) 2 , —NR 5 C(S)N(R 5 ) 2 , —NR 5 C(NR 5 )N(R 5 ) 2 , or
each R 5 is independently hydrogen or optionally substituted C 1-6 aliphatic; or
two occurrences of R 5 , taken together with the atom(s) to which they are attached, form optionally substituted 4- to 7-membered heterocyclyl comprising 0-1 additional heteroatom selected from nitrogen, oxygen, and sulfur;
each R 6 is independently C 4-12 aliphatic; and
each n is independently 0 to 4.
5 . The compound according to claim 1 , wherein the compound is of Formula I″-a:
or its N-oxide, or a pharmaceutically acceptable salt thereof.
6 . The compound according to claim 1 , wherein the compound is of Formula I″-b:
or its N-oxide, or a pharmaceutically acceptable salt thereof.
7 . The compound according to claim 1 , wherein the compound is of Formula I″-c:
or its N-oxide, or a pharmaceutically acceptable salt thereof.
8 . The compound according to claim 4 , wherein the compound is of Formula III-a:
or its N-oxide, or a pharmaceutically acceptable salt thereof.
9 - 10 . (canceled)
11 . The compound according to claim 1 , wherein L 1 is C 1-5 alkylenyl.
12 . (canceled)
13 . The compound according to claim 1 , wherein each L 2 is independently optionally substituted C 2-9 alkylenyl.
14 . (canceled)
15 . The compound according to claim 1 , wherein each L is independently C 1-5 alkylenyl.
16 . The compound according to claim 1 , wherein each of L 3 and L 3a is absent.
17 . (canceled)
18 . The compound according to claim 1 , wherein each of L 3 and L 3a is independently C 1-5 alkylenyl.
19 . The compound according to claim 1 , wherein R″ is hydrogen,
or an optionally substituted group selected from C 6-20 aliphatic, 3- to 12-membered cycloaliphatic, 1-adamantyl, and phenyl.
20 - 21 . (canceled)
22 . The compound according to claim 19 , wherein R″ is optionally substituted C 6-20 aliphatic.
23 - 26 . (canceled)
27 . The compound according to claim 1 , wherein each of R and R a is independently hydrogen or an optionally substituted group selected from C 6-20 aliphatic, 3- to 12-membered cycloaliphatic, 1-adamantyl, and phenyl.
28 - 33 . (canceled)
34 . The compound according to claim 1 , wherein each of -L 3 -R″, -L 3 -R and -L 3a -R a is independently selected from the group consisting of
35 . The compound according to claim 1 , wherein each of
is independently selected from the group consisting of
36 . The compound according to claim 1 , wherein R 1 is hydrogen, optionally substituted phenyl, optionally substituted 3- to 7-membered cycloaliphatic, optionally substituted 3- to 7-membered heterocyclyl comprising 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 5- to 6-membered monocyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 8- to 10-membered bicyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, —OR 2 , —C(O)OR 2 , —C(O)SR 2 , —N(R 2 ) 2 , —C(O)N(R 2 ) 2 , —S(O) 2 N(R 2 ) 2 , —NR 2 C(O)R 2 , —NR 2 S(O) 2 R 2 , —NR 2 C(O)N(R 2 ) 2 , —CR 2 (R 3 ) 2 , —OP(O)(OR 2 ) 2 , or —P(O)(OR 2 ) 2 .
37 . (canceled)
38 . The compound according to claim 1 , wherein each R 2 is independently hydrogen, —(CH 2 ) n —R 4 , or an optionally substituted group selected from phenyl, and 5- to 6-membered monocyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two occurrences of R 2 , taken together with the atom(s) to which they are attached, form optionally substituted 4- to 7-membered heterocyclyl comprising 0-1 additional heteroatom selected from nitrogen, oxygen, and sulfur.
39 - 42 . (canceled)
43 . The compound according to claim 1 , wherein R 1 is selected from the group consisting of
44 . A compound selected from:
or a pharmaceutically acceptable salt thereof.
45 . A lipid nanoparticle (LNP) preparation comprising an ionizable lipid, wherein the ionizable lipid is a compound according to claim 1 .
46 . A lipid nanoparticle (LNP) preparation comprising
an ionizable lipid, wherein the ionizable lipid is a compound according to claim 44 .
47 - 53 . (canceled)
54 . A pharmaceutical composition comprising a LNP preparation of claim 45 and a pharmaceutically acceptable excipient.
55 . A method for administering a therapeutic and/or prophylactic agent to a subject in need thereof, the method comprising administering the LNP preparation of claim 45 to the subject.
56 . A method for treating a disease or a disorder in a subject in need thereof, the method comprising administering the LNP preparation of claim 45 wherein the therapeutic and/or prophylactic agent is effective to treat the disease.
57 . (canceled)
58 . A method of delivering a therapeutic and/or prophylactic agent to a mammalian cell derived from a subject, the method comprising contacting the cell of the subject having been administered the LNP preparation of claim 45 .
59 - 64 . (canceled)