US2023286920A1PendingUtilityA1
Cyclooctynes for click chemistry
Assignee: MASSACHUSETTS INST TECHNOLOGYPriority: May 27, 2021Filed: May 1, 2023Published: Sep 14, 2023
Est. expiryMay 27, 2041(~14.8 yrs left)· nominal 20-yr term from priority
C07D 221/16C07D 231/54C07D 471/04C07D 249/16C07C 13/547C07C 2603/36
70
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Claims
Abstract
Provided herein are dibenzocyclooctyne compounds useful as reagents in 1,3-dipolar cycloaddition reactions, and methods for their preparation.
Claims
exact text as granted — not AI-modified1 . A compound of formula (I):
or a pharmaceutically acceptable salt thereof,
wherein:
R 1 and R 2 are, independently for each occurrence, F, Cl, Br, I, OTf, B(OH) 2 , CN, NHR 5 , NHS(O) 2 R 5 , OR 5 , OS(O) 2 R 5 , SR 5 , —CF 3 , —C(O)OC 1-6 alkyl, —C(O)N(C 1-6 alkyl) 2 , —C(O)R 5 , S(O) 2 R 5 , NO 2 , —C 1-6 alkyl, —C 1-6 alkenyl, or 5- to 10-membered heteroaryl substituted with 1, 2, 3, 4, or 5 R 6 groups, optionally wherein the alkyl and alkenyl are substituted with one or more R 5 groups;
R 3 and R 4 are, independently for each occurrence, H or —C 1-6 alkyl;
R 5 is selected from H, —C 1-6 -alkyl, —CF 3 , —C(O)OC 1-6 alkyl, or —C(O)N(C 1-6 alkyl) 2 ;
R 6 is selected from H, F, Cl, Br, I, OTf, CN, NH 2 , OR 5 , SR 5 , —CF 3 ; —C(O)R 5 , —C(O)OC 1-6 alkyl, NO 2 , or —C 1-6 alkyl;
n is 0, 1, or 2;
p is 0, 1, or 2;
X 1 is N or CH; and
X 2 is N + or C;
provided that when X 1 is N, X 2 is C; or when X 1 is CH, X 2 is N + .
2 . The compound of claim 1 , having a structure according to formula (Ia):
or a pharmaceutically acceptable salt thereof,
wherein:
R 1 and R 2 are, independently for each occurrence, F, Cl, Br, I, OTf, B(OH) 2 , CN, NHR 5 , NHS(O) 2 R 5 , OR 5 , OS(O) 2 R 5 , SR 5 , —CF 3 , —C(O)OC 1-6 alkyl, —C(O)N(C 1-6 alkyl) 2 , —C(O)R 5 , S(O) 2 R 5 , NO 2 , —C 1-6 alkyl, —C 1-6 alkenyl, or 5- to 10-membered heteroaryl substituted with 1, 2, 3, 4, or 5 R 6 groups, optionally wherein the alkyl and alkenyl are substituted with one or more R 5 group;
R 3 and R 4 are, independently for each occurrence, H or —C 1-6 alkyl;
R 5 is selected from H, —C 1-6 -alkyl, —CF 3 , —C(O)OC 1-6 alkyl, or —C(O)N(C 1-6 alkyl) 2 ;
R 6 is selected from H, F, Cl, Br, I, OTf, CN, NH 2 , OR 5 , SR 5 , —CF 3 , —C(O)R 5 , —C(O)OC 1-6 alkyl, NO 2 , —C 1-6 alkyl;
n is 0, 1, or 2; and
p is 0, 1, or 2.
3 . The compound of claim 2 , wherein R 3 and R 4 are H.
4 . The compound of claim 2 , wherein R 1 and R 2 are F, Cl, Br, I, OTf, or B(OH) 2 .
5 . The compound of claim 2 , wherein R 1 and R 2 are Cl.
6 . The compound of claim 2 , wherein n is 1 and p is 0.
7 . The compound of claim 1 , having a structure according to formula (Ib):
or a pharmaceutically acceptable salt thereof,
wherein R 1 is, independently for each occurrence, F, Cl, Br, I, OTf, B(OH) 2 or —C 1-6 -alkyl; and
n is 0, 1, or 2.
8 . The compound of claim 1 , wherein the compound of formula (I) is:
or a pharmaceutically acceptable salt thereof.
9 . A process of making a compound of formula (II):
or a pharmaceutically accepted salt thereof,
wherein:
R 1 and R 2 are, independently for each occurrence, F, Cl, Br, I, OTf, B(OH) 2 , CN, NHR 5 , NHS(O) 2 R 5 , OR 5 , OS(O) 2 R 5 , SR 5 , —CF 3 , —C(O)OC 1-6 alkyl, —C(O)N(C 1-6 alkyl) 2 , —C(O)R 5 , S(O) 2 R 5 , NO 2 , —C 1-6 alkyl, —C 1-6 alkenyl, or 5- to 10-membered heteroaryl substituted with 1, 2, 3, 4, or 5 R 6 groups, optionally wherein the alkyl and alkenyl are substituted with one or more R 5 group;
R 3 and R 4 are, independently for each occurrence, H or —C 1-6 alkyl;
R 5 is selected from H, —C 1-6 -alkyl, —CF 3 ; —C(O)OC 1-6 alkyl, or —C(O)N(C 1-6 alkyl) 2 ;
R 6 is selected from H, F, Cl, Br, I, OTf, CN, NH 2 , OR 5 , SR 5 , —CF 3 , —C(O)R 5 , —C(O)OC 1-6 alkyl, NO 2 , —C 1-6 alkyl;
n is 0, 1, or 2;
p is 0, 1, or 2; and
X is CH or N;
wherein the process comprises:
(A) combining a compound of formula (III):
with a compound of formula (IV):
and a non-nucleophilic base to provide the compound of formula (V):
and
(B) combining the compound of formula (V) with a carbodiimide to provide the compound of formula (II).
10 . The process of claim 9 , wherein the compound of formula (II), has a structure according to formula (IIa):
wherein R 1 is, independently for each occurrence, F, Cl, Br, I, OTf, B(OH) 2 or —C 1-6 -alkyl;
n is 0, 1, or 2; and
X is CH or N.
11 . The process of claim 9 , wherein the compound of formula (II), has a structure selected from the group consisting of:
wherein R 1 is Cl; and
n is 0 or 1.
12 . The process of claim 9 , wherein the compound of formula (II), has a structure selected from the group consisting of:
13 . The process of claim 9 , wherein the non-nucleophilic base is an alkyl lithium.
14 . The process of claim 9 , wherein the non-nucleophilic base is lithium bis(trimethylsilyl)amide.
15 . The process of claim 9 , wherein the carbodiimide is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC).
16 . The process of claim 9 , wherein step (B) comprises an alkylidene carbene rearrangement.
17 . A process of making a compound of formula (VIa):
or regioisomer thereof,
wherein:
R 1 and R 2 are, independently for each occurrence, F, Cl, Br, I, OTf, B(OH) 2 , CN, NHR 5 , NHS(O) 2 R 5 , OR 5 , OS(O) 2 R 5 , SR 5 , —CF 3 , —C(O)OC 1-6 alkyl, —C(O)N(C 1-6 alkyl) 2 , —C(O)R 5 , S(O) 2 R 5 , NO 2 , —C 1-6 alkyl, —C 1-6 alkenyl, or 5- to 10-membered heteroaryl substituted with 1, 2, 3, 4, or 5 R 6 groups, optionally wherein the alkyl and alkenyl are substituted with one or more R 5 groups;
R 3 and R 4 are, independently for each occurrence, H or —C 1-6 alkyl;
R 5 is selected from H, —C 1-6 -alkyl, —CF 3 ; —C(O)OC 1-6 alkyl, or —C(O)N(C 1-6 alkyl) 2 ;
R 6 is selected from H, F, Cl, Br, I, OTf, CN, NH 2 , OR 5 , SR 5 , —CF 3 , —C(O)R 5 , —C(O)OC 1-6 alkyl, NO 2 , —C 1-6 alkyl;
R 7 is C 1-6 alkyl optionally substituted with one or more C 6-10 aryl or 5- to 10-membered heteroaryl;
n is 0, 1, or 2;
p is 0, 1, or 2;
X is CH or N; and
Y is O or NH;
wherein the process comprises combining a compound of formula (II):
with a compound of formula (VIIa):
to provide the compound of formula (VIa).
18 . The process of claim 17 , wherein the compound of formula (VIIa) is selected from the group consisting of:
19 . The process of claim 17 , wherein the compound of formula (II) has a structure according to formula (IIa):
wherein:
R 1 is, independently for each occurrence, F, Cl, Br, I, OTf, B(OH) 2 or —C 1-6 -alkyl;
n is 0, 1, or 2; and
X is CH or N.
20 . The process of claim 17 , wherein the compound of formula (II), has a structure selected from the group consisting of:
wherein R 1 is Cl; and
wherein n is 0 or 1.
21 . The process of claim 17 , wherein the compound of formula (II), has a structure selected from the group consisting of:
22 . A process of making a compound of formula (VIb):
or a regioisomer thereof,
wherein:
R 1 and R 2 are, independently for each occurrence, F, Cl, Br, I, OTf, B(OH) 2 , CN, NHR 5 , NHS(O) 2 R 5 , OR 5 , OS(O) 2 R 5 , SR 5 , —CF 3 , —C(O)OC 1-6 alkyl, —C(O)N(C 1-6 alkyl) 2 , —C(O)R 5 , S(O) 2 R 5 , NO 2 , —C 1-6 alkyl, —C 1-6 alkenyl, or 5- to 10-membered heteroaryl substituted with 1, 2, 3, 4, or 5 R 6 groups, wherein the alkyl and alkenyl are optionally substituted with one or more R 5 groups;
R 3 and R 4 are, independently for each occurrence, H or —C 1-6 alkyl;
R 5 is selected from H, —C 1-6 -alkyl, —CF 3 ; —C(O)OC 1-6 alkyl, or —C(O)N(C 1-6 alkyl) 2 ;
R 6 is selected from H, F, Cl, Br, I, OTf, CN, NH 2 , OR 5 , SR 5 , —CF 3 , —C(O)R 5 , —C(O)OC 1-6 alkyl, NO 2 , —C 1-6 alkyl;
R 7 is C 1-6 alkyl optionally substituted with one or more C 6-10 aryl or 5- to 10-membered heteroaryl;
n is 0, 1, or 2;
p is 0, 1, or 2;
X is CH or N; and
Y is O or NH;
wherein the process comprises combining a compound of formula (II):
with a compound of formula (VIIb):
to provide the compound of formula (VIb).
23 . The process of claim 22 , wherein the compound of formula (VIIb) is:
24 . The process of claim 22 , wherein the compound of formula (II) has a structure according to formula (IIa):
wherein:
R 1 is, independently for each occurrence, F, Cl, Br, I, OTf, B(OH) 2 or —C 1-6 -alkyl;
n is 0, 1, or 2; and
X is CH or N.
25 . The process of claim 22 , wherein the compound of formula (II), has a structure selected from the group consisting of:
wherein R 1 is Cl; and
wherein n is 0 or 1.
26 . The process of claim 22 , wherein the compound of formula (II), has a structure selected from the group consisting of:Join the waitlist — get patent alerts
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