US2023242565A1PendingUtilityA1
Macrolides with Modified Desosamine Sugars and Uses Thereof
Est. expiryApr 28, 2037(~10.8 yrs left)· nominal 20-yr term from priority
Inventors:Andrew G. MyersZiyang ZhangTakehiro FukuzakiUdara Anulal Premachandra Ilandari DewageSenkara Rao AlluRoger B. ClarkJonathan F. LawrenceWesley Francis AustinXiben LiWenying WangSushmita D. LahiriYoshitaka Ichikawa
C07H 17/08C07H 15/18A61P 31/04
58
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Claims
Abstract
Provided are macrolide compounds for the treatment of infectious diseases. The macrolides disclosed herein include 14-membered ketolides and 14-15-membered azaketolides, and may comprise modified sugars which are desosamine analogues. The disclosed macrolides may have a bicyclic structure. Also provided are pharmaceutical compositions and methods of treating infectious diseases, and in particular, disease which results from Gram negative bacteria using the disclosed macrolides. This disclosure additionally provides methods of preparing the macrolides by a strategy that enables late-stage modification of the 6′-position of the sugar moiety, thereby allowing facile access to previously difficult-to-make macrolide compounds.
Claims
exact text as granted — not AI-modified1 . A compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
ring S is or
Z 1 is N(R S ) 2 or C(R S ) 3 and each R S is independently H, C 1 -C 6 alkyl, or C 2 -C 6 alkenyl;
Z is —C(═O)— or —NR Z2 —;
R Z2 is hydrogen, optionally substituted alkyl, acyl, or a nitrogen protecting group;
when Z is —NR Z2 —, one of b and c is CH 2 or —C(═O)—, and the other is a bond, or both b and c are a bond;
when Z is —C(═O)—, b and c are both a bond;
n is 0 or 1;
X is optionally substituted C 1-6 alkyl, —OR A or —NR B —(CR x R x ) t -A-(R y ) q ;
t is 0, 1, or 2;
q is 1, 2, or 3;
R A is hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, or —C(═O)—R S1 ;
R S1 is optionally substituted aryl or optionally substituted heteroaryl;
R B is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 cycloalkyl, or C(O)CH 2 NR x1 R y1 ;
each R x is independently hydrogen or C 1-3 alkyl;
A is arylene, heteroarylene, heterocyclylene, cycloalkylene, alkylene, alkenylene, or alkynylene, or a bond;
each R y is independently, hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, hydroxyl, cyano, dialkylamino, haloalkyl, C(O)OC 1-3 alkyl, C(O)OH, C(O)CH 2 NR x1 R y1 , C(O)NR x1 R y1 , C(O)C 1-6 alkyl, C 1-6 alkylsulfonyl, heteroaryl, or heteroaryloxy;
or when A is a bond, and t is 0, R B and R y together along with the nitrogen to which they are attached optionally form a 4, 5, 6, or 7-membered optionally substituted ring containing up to two additional heteroatoms;
R x1 and R y1 are each independently hydrogen, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 3 -C 6 cycloalkyl, or R x1 and R y1 together along with the nitrogen to which they are attached form a 4, 5, 6, or 7-membered optionally substituted ring containing up to two additional heteroatoms;
R 3′ is H, C 1-3 alkyl, OH, or oxo;
each of R S4a and R S4b is independently hydrogen, halogen, optionally substituted C 1-6 alkyl, or —OR SO ;
each R SN is independently hydrogen, optionally substituted C 1-6 alkyl, or a nitrogen protecting group, or two R SN groups attached to the same nitrogen atom are joined to form an optionally substituted heterocyclyl or heteroaryl ring;
each of R S4a and R S4b is independently hydrogen, halogen, optionally substituted C 1-6 alkyl, or —OR SO ;
each R SO is independently hydrogen, optionally substituted C 1-6 alkyl, a carbohydrate, or an oxygen protecting group;
each of R 1a and R 1b is independently hydrogen, halogen, or optionally substituted alkyl;
each of R 2a and R 2b is independently hydrogen, halogen, or optionally substituted alkyl;
R 3a is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or an oxygen protecting group;
or R 3a and R 6 are joined to form an optionally substituted heterocyclyl ring, or R 3a and R 10 are joined to form an optionally substituted heterocyclyl ring, or R 3a and R S are joined to form an optionally substituted heterocyclyl ring;
R 4 is hydrogen, halogen, or optionally substituted alkyl;
each of R 5a and R 5b is independently hydrogen, halogen, or optionally substituted alkyl;
R 6 is hydrogen, halogen, or optionally substituted alkyl;
R 10 is hydrogen, halogen, or optionally substituted alkyl;
R 7 is hydrogen, halogen, optionally substituted alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, or C 1 -C 6 -alkoxy; and
R 8 is hydrogen, halogen, or optionally substituted C 1-6 alkyl.
2 . The compound of claim 1 , wherein the compound is of Formula (I-a):
or a pharmaceutically acceptable salt thereof, wherein:
Z is —C(═O)— or —NR Z2 —;
R Z2 is hydrogen, optionally substituted alkyl, acyl, or a nitrogen protecting group;
p is 0 or 1, provided that p is 0 when Z is —C(═O)—;
X is optionally substituted C 1-6 alkyl, —OR A or —NR B —(CR x R x ) t -A-(R y ) q ;
R A is hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, or —C(═O)—R S1 ;
R S1 is optionally substituted aryl or optionally substituted heteroaryl;
R B is hydrogen or C 1-3 alkyl;
each R x is independently hydrogen or C 1-3 alkyl;
A is arylene, heteroarylene, heterocyclylene, alkylene, cycloalkylene, alkenylene, or alkynylene;
each R y is independently, hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, hydroxyl, cyano, dialkylamino, haloalkyl, C(O)OC 1-3 alkyl, C(O)OH, C(O)CH 2 NR x1 R y1 , C(O)NR x1 R y1 , C(O)C 1-6 alkyl, C 1-6 alkylsulfonyl, heteroaryl, or heteroaryloxy;
t is 0, 1, or 2;
q is 1, 2, or 3;
each of R S4a and R S4b is independently hydrogen, halogen, optionally substituted C 1-6 alkyl, or —OR SO ;
each R SN is independently hydrogen, optionally substituted C 1-6 alkyl, or a nitrogen protecting group, or two R SN groups attached to the same nitrogen atom are joined to form an optionally substituted heterocyclyl or heteroaryl ring;
each of R S4a and R S4b is independently hydrogen, halogen, optionally substituted C 1-6 alkyl, or —OR SO ;
each R SO is independently hydrogen, optionally substituted C 1-6 alkyl, a carbohydrate, or an oxygen protecting group;
each of R 1a and R 1b is independently hydrogen, halogen, or optionally substituted alkyl;
each of R 2a and R 2b is independently hydrogen, halogen, or optionally substituted alkyl;
R 3a is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or an oxygen protecting group;
R 4 is hydrogen, halogen, or optionally substituted alkyl;
each of R 5a and R 5b is independently hydrogen, halogen, or optionally substituted alkyl;
R 6 is hydrogen, halogen, or optionally substituted alkyl;
R 10 is hydrogen, halogen, or optionally substituted alkyl;
R 7 is hydrogen, halogen, or optionally substituted alkyl; and
R 8 is hydrogen, halogen, or optionally substituted C 1-6 alkyl.
3 . The compound of claim 1 or 2 , wherein the compound is of Formula (I-b):
or a pharmaceutically acceptable salt thereof.
4 . The compound of claim 1 or 2 , wherein the compound is of Formula (I-c):
or a pharmaceutically acceptable salt thereof.
5 . The compound of claim 1 or 2 , wherein the compound is of Formula (I-d):
or a pharmaceutically acceptable salt thereof.
6 . The compound of claim 1 or 2 , wherein the compound is of Formula (I-f-i) or (I-f-ii):
or a pharmaceutically acceptable salt thereof.
7 . The compound of claim 1 or 2 , wherein the compound is of Formula (I-h-i) or (I-h-ii):
or a pharmaceutically acceptable salt thereof, wherein:
R B is hydrogen or C 1-3 alkyl;
each R x is independently hydrogen or C 1-3 alkyl;
X 1 is N or CRY;
X 2 is N or CRY;
provided no more than one of X 1 and X 2 is N;
each R y is independently, hydrogen, halogen, cyano, alkoxy, or haloalkyl;
t is 0, 1, or 2; and
q is 1 or 2.
8 . The compound of claim 1 or 2 , wherein the compound is of Formula (I-j-i) or (I-j-ii):
or a pharmaceutically acceptable salt thereof, wherein:
each R x is independently hydrogen or C 1-3 alkyl;
X 1 is N or CRY;
each R y is, independently, hydrogen, halogen, cyano, or haloalkyl; and
t is 0, 1, or 2.
9 . The compound of claim 1 or 2 , wherein the compound is of Formula (I-k) or (I-l):
or a pharmaceutically acceptable salt thereof,
wherein R Z4 is an optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, or optionally substituted alkynylene linker.
10 . The compound of claim 1 or 2 , wherein the compound is of Formula (I-m):
or a pharmaceutically acceptable salt thereof, wherein R Z5 is an optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, or optionally substituted alkynylene linker.
11 . The compound of claim 1 or 2 , or a pharmaceutically acceptable salt thereof, wherein X is —OR A .
12 . The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein R A is.
13 . The compound of any of claims 1 - 7 or 9 - 10 , or a pharmaceutically acceptable salt thereof, wherein R B is hydrogen or methyl.
14 . The compound of any of claims 1 - 7 or 9 - 10 , or a pharmaceutically acceptable salt thereof, wherein R B is hydrogen.
15 . The compound of any of claims 1 - 7 or 9 - 10 , or a pharmaceutically acceptable salt thereof, wherein A is arylene or heteroarylene.
16 . The compound of any of claims 1 - 6 or 9 - 10 , or a pharmaceutically acceptable salt thereof, wherein —NR B —(CR x R x ) t -A-(R y ) q is:
17 . The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein
is:
18 . The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein
is:
19 . The compound of any of claims 1 - 6 or 9 - 10 , or a pharmaceutically acceptable salt thereof, wherein —NR B —(CR x R x ) t -A-(R y ) q is:
20 . The compound of any of claims 1 - 6 or 9 - 10 , or a pharmaceutically acceptable salt thereof, wherein A is a 4-6 membered heterocyclylene comprising at least one oxygen atom and no nitrogen atoms.
21 . The compound of any of claims 1 - 6 or 9 - 10 , or a pharmaceutically acceptable salt thereof, wherein —R B —(CR x R x ) t -A-(R y ) q is:
22 . The compound of claim 1 or 2 , or a pharmaceutically acceptable salt thereof, wherein Z is —C(═O)—.
23 . The compound of claim 1 or 2 , or a pharmaceutically acceptable salt thereof, wherein Z is —NR Z2 —.
24 . The compound of any of claims 1 - 6 or 9 - 10 , or a pharmaceutically acceptable salt thereof, wherein the substituent N(R SN ) 2 is:
25 . The compound of any of claims 1 - 6 or 9 - 10 , or a pharmaceutically acceptable salt thereof, wherein the substituent N(R SN ) 2 is:
26 . The compound of claim 1 or 2 , or a pharmaceutically acceptable salt thereof, wherein R S4a and R S4b are both hydrogen.
27 . The compound of any of claims 1 - 10 , or a pharmaceutically acceptable salt thereof, wherein R SO is independently hydrogen, or an oxygen protecting group.
28 . The compound of any of claims 1 - 6 , or a pharmaceutically acceptable salt thereof, wherein R 3a is methyl.
29 . The compound of claim 1 or 2 , or a pharmaceutically acceptable salt thereof, wherein R 4 is optionally substituted methyl.
30 . The compound of any of claims 1 - 5 or 9 - 10 , or a pharmaceutically acceptable salt thereof, wherein R 6 is methyl.
31 . The compound of any of claims 1 - 5 or 9 - 10 , or a pharmaceutically acceptable salt thereof, wherein R 10 is hydrogen.
32 . The compound of any of claims 1 - 5 or 9 - 10 , or a pharmaceutically acceptable salt thereof, wherein R 10 is —F.
33 . The compound of claim 1 or 2 , or a pharmaceutically acceptable salt thereof, wherein R 1a is methyl; and R 1b is hydrogen.
34 . The compound of claim 1 or 2 , or a pharmaceutically acceptable salt thereof, wherein R 2a is hydrogen; and R 2b is methyl.
35 . The compound of claim 23 , or a pharmaceutically acceptable salt thereof, wherein R Z2 is hydrogen.
36 . The compound of claim 1 or 2 , or a pharmaceutically acceptable salt thereof, wherein R 5a is methyl; and R 5b is hydrogen.
37 . The compound of claim 1 or 2 , or a pharmaceutically acceptable salt thereof, wherein R 7 is ethyl.
38 . The compound of claim 1 or 2 , or a pharmaceutically acceptable salt thereof, wherein R 8 is methyl.
39 . The compound of claim 1 , wherein the compound is of Formula (II):
or a pharmaceutically acceptable salt thereof wherein:
ring S is
wherein Z 1 is N(R S ) 2 or C(R S ) 3 and each R S is independently H, C 1 -C 6 alkyl, or C 2 -C 6 alkenyl;
one of b or c is CH 2 and the other is a bond;
n is 0 or 1;
R 6 and R 10 are selected from H, CH 3 , and F, wherein when R 6 is H, R 10 is CH 3 , when R 10 is H, R 6 is CH 3 , and when R 10 is F, R 6 is CH 3 ;
R 1′ and R 2′ are each independently selected from H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, and C(O)CH 2 NR x1 R y1 , or R 1′ and R 2′ together along with the nitrogen to which they are attached form a 4, 5, 6, or 7-membered optionally substituted ring containing up to two additional heteroatoms;
R x1 and R y1 are each independently selected from H, optionally substituted C 1 -C 6 alkyl, and optionally substituted C 1 -C 6 cycloalkyl, or R x1 and R y1 together along with the nitrogen to which they are attached form a 4, 5, 6, or 7-membered optionally substituted ring containing up to two additional heteroatoms;
R 3′ is H, OH, or oxo;
R S4a and R S4b are each independently selected from H, CH 3 and OH, wherein both R S4a and R S4b cannot be OH;
R 3a is selected from H, C 1 -C 6 -alkyl, and C 2 -C 6 alkenyl;
R Z2 is selected from the group consisting of H and C 1 -C 6 -alkyl; and
R 13 is selected from H, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, and C 1 -C 6 -alkoxy.
40 . The compound of claim 1 or 39 , wherein the compound is of Formula (II-a):
or a pharmaceutically acceptable salt thereof, wherein:
n is 0 or 1;
R 6 and R 10 are selected from H, CH 3 , and F, wherein when R 6 is H, R 10 is CH 3 , when R 10 is H, R 6 is CH 3 , and when R 10 is F, R 6 is CH 3 ;
R 1′ and R 2′ are each independently selected from H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, and C(O)CH 2 NR x1 R y1 , or R 1′ and R 2′ together along with the nitrogen to which they are attached form a 4, 5, 6, or 7-membered optionally substituted ring containing up to two additional heteroatoms;
R x1 and R y1 are each independently selected from H, optionally substituted C 1 -C 6 alkyl, and optionally substituted C 1 -C 6 cycloalkyl, or R x1 and R y1 together along with the nitrogen to which they are attached form a 4, 5, 6, or 7-membered optionally substituted ring containing up to two additional heteroatoms;
R 3′ is H, OH, or oxo;
R S4a and R S4b are each independently selected from H, CH 3 and OH, wherein both R S4a and R S4b cannot be OH; and
R Z2 is selected from the group consisting of H and C 1 -C 6 alkyl.
41 . The compound of any of claims 1 , 39 , or 40 , or a pharmaceutically acceptable salt thereof, wherein n is 0 and R 3′ is H.
42 . The compound of any of claims 1 , 39 , or 40 , or a pharmaceutically acceptable salt thereof, wherein n is 1 and R 3′ is OH.
43 . The compound of any of claims 1 , 39 , or 40 , or a pharmaceutically acceptable salt thereof, wherein n is 0 and R 3′ is oxo.
44 . The compound of any of claims 1 , 39 , or 40 , or a pharmaceutically acceptable salt thereof, wherein n is 1 and R 3′ is oxo.
45 . The compound of any of claims 1 , 39 , or 40 , or a pharmaceutically acceptable salt thereof, wherein R 1′ and R 2′ are selected from H and optionally substituted C 1 -C 6 alkyl.
46 . The compound of any of claims 1 , 39 , or 40 , or a pharmaceutically acceptable salt thereof, wherein R 1′ and R 2′ are selected from H and C 1 -C 6 alkyl substituted with OR z , Halo, C(O)OR z , C(O)N(R z ) 2 , N(R z ) 2 , and optionally substituted cycloalkyl; and
each R z is independently H or optionally substituted C 1 -C 6 alkyl.
47 . The compound of any of claims 1 , 39 , or 40 , or a pharmaceutically acceptable salt thereof, wherein one of R 1′ and R 2′ , is H, and the other of R 1′ and R 2′ is C(O)CH 2 NR x1 R y1 .
48 . The compound of claim 47 , or a pharmaceutically acceptable salt thereof, wherein R x1 and R y1 are each independently selected from the group consisting of H, C 1 -C 6 alkyl, and C 1 -C 6 cycloalkyl, or R x1 and R y1 together along with the nitrogen to which they are attached form a 4, 5, 6, or 7-membered ring.
49 . The compound of any of claims 1 , 39 , or 40 , or a pharmaceutically acceptable salt thereof, wherein R 1′ and R 2′ are each independently selected from the group consisting of H, CH 3 , CH 2 CH 3 , isopropyl, tert-butyl,
wherein “ ” indicates the point of attachment.
50 . The compound of any of claims 1 , 39 , or 40 , or a pharmaceutically acceptable salt thereof, wherein R 1′ and R 2′ together along with the nitrogen to which they are attached form an optionally substituted ring containing up to two additional heteroatoms, and wherein NR 1′ R 2′ is selected from the group consisting of
wherein “ ” indicates the point of attachment.
51 . The compound of any of claims 1 , 39 , or 40 , wherein the compound is of Formula (II-b):
or a pharmaceutically acceptable salt thereof, wherein:
R 6 and R 10 are selected from H, CH 3 , and F, wherein when R 6 is H, R 10 is CH 3 , when R 10 is H, R 6 is CH 3 , and when R 10 is F, R 6 is CH 3 ;
R 1′ and R 2′ are each independently selected from H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, and C(O)CH 2 NR x1 R y1 , or R 1′ and R 2′ together along with the nitrogen to which they are attached form a 4, 5, 6, or 7-membered optionally substituted ring containing up to two additional heteroatoms;
R x1 and R y1 are each independently selected from H, optionally substituted C 1 -C 6 alkyl, and optionally substituted C 1 -C 6 cycloalkyl, or R x1 and R y1 together along with the nitrogen to which they are attached form a 4, 5, 6, or 7-membered optionally substituted ring containing up to two additional heteroatoms;
R S4a and R S4b are each independently selected from H, CH 3 and OH, wherein both R S4a and R S4b cannot be OH; and
R Z2 is selected from the group consisting of H and C 1 -C 6 alkyl.
52 . The compound of any of claims 1 , 39 , or 40 , wherein the compound is of Formula (I-c):
or a pharmaceutically acceptable salt thereof, wherein:
R 6 and R 10 are selected from H, CH 3 , and F, wherein when R 6 is H, R 10 is CH 3 , when R 10 is H, R 6 is CH 3 , and when R 10 is F, R 6 is CH 3 ;
R x1 and R y1 are each independently selected from H, optionally substituted C 1 -C 6 alkyl, and optionally substituted C 1 -C 6 cycloalkyl, or R x1 and R y1 together along with the nitrogen to which they are attached form a 4, 5, 6, or 7-membered optionally substituted ring containing up to two additional heteroatoms;
R S4a and R S4b are each independently selected from H, CH 3 and OH, wherein both R S4a and R S4b cannot be OH; and
R Z2 is selected from the group consisting of H and C 1 -C 6 alkyl.
53 . The compound of any of claims 1 , 39 , or 40 , wherein the compound is of Formula (II-d):
or a pharmaceutically acceptable salt thereof, wherein:
R 6 and R 10 are selected from H, CH 3 , and F, wherein when R 6 is H, R 10 is CH 3 , when R 10 is H, R 6 is CH 3 , and when R 10 is F, R 6 is CH 3 ;
R 1′ and R 2′ are each independently selected from H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, and C(O)CH 2 NR x1 R y1 , or R 1′ and R 2′ together along with the nitrogen to which they are attached form a 4, 5, 6, or 7-membered optionally substituted ring containing up to two additional heteroatoms;
R x1 and R y1 are each independently selected from H, optionally substituted C 1 -C 6 alkyl, and optionally substituted C 1 -C 6 cycloalkyl, or R x1 and R y1 together along with the nitrogen to which they are attached form a 4, 5, 6, or 7-membered optionally substituted ring containing up to two additional heteroatoms;
R S4a and R S4b are each independently selected from H, CH 3 and OH, wherein both R S4a and R S4b cannot be OH; and R Z2 is selected from the group consisting of H and C 1 -C 6 alkyl.
54 . A compound of Formula (III):
or a pharmaceutically acceptable salt thereof, wherein:
Z is —C(═O)— or —NR Z2 —;
when Z is —NR Z2 —, one of b and c is CH 2 or —C(═O)—, and the other is a bond, or both b and c are a bond;
when Z is —C(═O)—, b and c are both a bond;
each instance of R 1a , R 1b , R 2a , and R 2b is independently hydrogen, halogen, carbonyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocylyl, optionally substituted aryl, optionally substituted heteroaryl, or wherein R 1a and R 1b or R 2a and R 2b can be taken together to form a carbonyl or
R Z2 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, guanidino, a nitrogen protecting group, —C(═O)R Z8 , —C(═O)N(R Z8 ) 2 , or —C(═O)OR Z8 , or a group of formula:
R Z9 is optionally substituted heteroalkylene, optionally substituted heteroalkenylene, optionally substituted heteroalkynylene, optionally substituted alkylene, optionally substituted alkenylene, or optionally substituted alkynylene;
R 4 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl;
R 5a and R 5b are each independently hydrogen, halogen, silyl, optionally substituted alkyl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl;
R 7 and R 8 are each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
R 9 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —C(═O)R Z8 , —C(═O)OR Z8 , —C(═O)N(R Z8 ) 2 , an oxygen protecting group, or a carbohydrate;
R 10 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, —OR Z8 , —SR Z8 , —N(R Z8 ) 2 , or acyl;
G 3 is —O—, —S—, or —N(R G1 )—, wherein R G1 is hydrogen, optionally substituted alkyl, or a nitrogen protecting group;
G 1 is —OR 12 or —NR 13 R 14 ;
provided when G 1 is —OR 12 , then R 11 and R 12 are joined as a group of formula —C(═O)— to provide a cyclic carbonate, or R 11 and R 12 are not joined, and R 11 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group, and R 12 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group, or a group of formula:
or provided when G 1 is —NR 13 R 14 , then R 11 and R 13 are joined as a group of formula —C(═O)— to provide a cyclic carbamate, or R 11 and R 13 are not joined, R 11 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group, R 13 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group;
R 14 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group, —C(═O)R Z8 , or —C(═O)OR Z8 , or a group of formula:
or R 13 and R 14 are joined to form an optionally substituted heterocyclyl or optionally substituted heteroaryl;
each instance of L C1 and L C2 is independently a bond, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, optionally substituted heteroalkynylene, or combinations thereof;
each instance of A 1 is independently a leaving group (LG), —SH, —OH, —NH 2 , —NH—, NH 2 , —N 3 , —O—NH 2 , —C(═O)R X1 ,
A is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —NH—, —NH—NH—, —NH—O—, —O—NH—, —S—,—O—,
Q is —NH—, —NH—NH—, —O—NH—, —NH—O—, —S—, or —O—;
W is O, S, or NR W1 ;
R W1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a nitrogen protecting group;
R W2 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or two R W2 groups are joined to form an optionally substituted cyclic moiety;
R X1 is hydrogen, halogen, or —OR X2 , wherein R X2 is hydrogen, optionally substituted alkyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group;
R 23 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and
each instance of R Z8 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocylyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R Z8 groups are joined to form an optionally substituted heterocylyl or optionally substituted heteroaryl ring.
55 . The compound of claim 54 , which is a compound of Formula (III-a):
or a pharmaceutically acceptable salt thereof, wherein:
R Z4 is optionally substituted heteroalkylene, optionally substituted alkylene, optionally substituted alkenylene, or optionally substituted alkynylene.
56 . The compound of claim 54 , which is a compound of Formula (III-b-i) or Formula (III-b-ii):
or a pharmaceutically acceptable salt thereof, wherein:
R Z4 is optionally substituted heteroalkylene, optionally substituted alkylene, optionally substituted alkenylene, or optionally substituted alkynylene.
57 . The compound of claim 54 , which is a compound of Formula (III-c-i) or Formula (III-c-ii):
or a pharmaceutically acceptable salt thereof, wherein:
R Z4 is optionally substituted heteroalkylene, optionally substituted alkylene, optionally substituted alkenylene, or optionally substituted alkynylene.
58 . The compound of claim 54 , which is a compound of Formula (III-d-i) or Formula (III-d-i):
or a pharmaceutically acceptable salt thereof, wherein:
R Z4 is optionally substituted heteroalkylene, optionally substituted alkylene, optionally substituted alkenylene, or optionally substituted alkynylene.
59 . The compound of claim 54 , which is a compound of Formula (III-e-i) or Formula (III-e-ii):
or a pharmaceutically acceptable salt thereof, wherein:
R Z4 is optionally substituted heteroalkylene, optionally substituted alkylene, optionally substituted alkenylene, or optionally substituted alkynylene.
60 . The compound of claim 54 , which is a compound of Formula (III-f-i) or Formula (III-f-ii):
or a pharmaceutically acceptable salt thereof, wherein:
R Z4 is optionally substituted heteroalkylene, optionally substituted alkylene, optionally substituted alkenylene, or optionally substituted alkynylene.
61 . The compound of claim 54 , which is a compound of Formula (III-g-i) or Formula (III-g-ii):
or a pharmaceutically acceptable salt thereof, wherein:
R Z4 is optionally substituted heteroalkylene, optionally substituted alkylene, optionally substituted alkenylene, or optionally substituted alkynylene;
each of R S4a , R S4b , R S5a , and R S5b is independently hydrogen, optionally substituted alkyl, or —OR SO ;
each instance of R SO is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted heterocyclyl, or an oxygen protecting group; and
R SN is independently hydrogen, optionally substituted alkyl, or a nitrogen protecting group; or optionally two R SN are taken with the intervening atoms to form a heterocyclic ring.
62 . The compound of claim 54 , which is a compound of Formula (III-h-i) or Formula (III-h-ii):
or a pharmaceutically acceptable salt thereof, wherein:
R Z4 is optionally substituted heteroalkylene, optionally substituted alkylene, optionally substituted alkenylene, or optionally substituted alkynylene;
each of R S5a and R S5b is independently hydrogen, optionally substituted alkyl, or —OR SO ;
each instance of R SO is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted heterocyclyl, or an oxygen protecting group; and
R SN is independently hydrogen, optionally substituted alkyl, or a nitrogen protecting group; or optionally two R SN are taken with the intervening atoms to form a heterocyclic ring.
63 . The compound of claim 54 , which is a compound of Formula (III-i-i) or Formula (III-i-ii):
or a pharmaceutically acceptable salt thereof, wherein:
R Z4 is optionally substituted heteroalkylene, optionally substituted alkylene, optionally substituted alkenylene, or optionally substituted alkynylene;
X is hydrogen, optionally substituted C 1-6 alkyl, —OR A , or —NR B —(CR x R x ) t -A-(R y ) q ;
t is 0, 1, or 2;
q is 1, 2, or 3;
R A is hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, or —C(═O)—R S1 ;
R S1 is optionally substituted aryl or optionally substituted heteroaryl;
R B is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 cycloalkyl, or C(O)CH 2 NR x1 R y1 ;
each R x is independently hydrogen or C 1-3 alkyl;
A is arylene, heteroarylene, heterocyclylene, cycloalkylene, alkylene, alkenylene, alkynylene, or a bond;
each R y is independently, hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, hydroxyl, cyano, dialkylamino, haloalkyl, C(O)OC 1-3 alkyl, C(O)OH, C(O)CH 2 NR x1 R y1 , C(O)NR x1 R y1 , C(O)C 1-6 alkyl, C 1-6 alkylsulfonyl, heteroaryl, or heteroaryloxy;
or when A is a bond and t is 0, R B and R y together along with the nitrogen to which they are attached optionally form a 4, 5, 6, or 7-membered optionally substituted ring containing up to two additional heteroatoms;
R x1 and R y1 are each independently hydrogen, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 3 -C 6 cycloalkyl, or R x1 and R y1 together along with the nitrogen to which they are attached form a 4, 5, 6, or 7-membered optionally substituted ring containing up to two additional heteroatoms; and
R SO is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted heterocyclyl, or an oxygen protecting group.
64 . The compound of claim 54 , which is a compound of Formula (III-j-i) or Formula (III-j-ii):
or a pharmaceutically acceptable salt thereof, wherein:
X is hydrogen, optionally substituted C 1-6 alkyl, —OR A , or —NR B —(CR x R x ) t -A-(R y ) q ;
t is 0, 1, or 2;
q is 1, 2, or 3;
R A is hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, or —C(═O)—R S1 ;
R S1 is optionally substituted aryl or optionally substituted heteroaryl;
R B is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 cycloalkyl, or C(O)CH 2 NR x1 R y1 ;
each R x is independently hydrogen or C 1-3 alkyl;
A is arylene, heteroarylene, heterocyclylene, cycloalkylene, alkylene, alkenylene, alkynylene, or a bond;
each R y is independently, hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, hydroxyl, cyano, dialkylamino, haloalkyl, C(O)OC 1-3 alkyl, C(O)OH, C(O)CH 2 NR x1 R y1 , C(O)NR x1 R y1 , C(O)C 1-6 alkyl, C 1-6 alkylsulfonyl, heteroaryl, or heteroaryloxy;
or when A is a bond and t is 0, R B and R y together along with the nitrogen to which they are attached optionally form a 4, 5, 6, or 7-membered optionally substituted ring containing up to two additional heteroatoms;
R x1 and R y1 are each independently hydrogen, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 3 -C 6 cycloalkyl, or R x1 and R y1 together along with the nitrogen to which they are attached form a 4, 5, 6, or 7-membered optionally substituted ring containing up to two additional heteroatoms; and
R SO is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted heterocyclyl, or an oxygen protecting group.
65 . The compound of claim 54 , which is a compound of Formula (III-k-i) or Formula (III-k-ii):
or a pharmaceutically acceptable salt thereof, wherein:
X is hydrogen, optionally substituted C 1-6 alkyl, —OR A , or —NR B —(CR x R x ) t -A-(R y ) q ;
t is 0, 1, or 2;
q is 1, 2, or 3;
R A is hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, or —C(═O)—R S1 ;
R S1 is optionally substituted aryl or optionally substituted heteroaryl;
R B is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 cycloalkyl, or C(O)CH 2 NR x1 R y1 ;
each R x is independently hydrogen or C 1-3 alkyl;
A is arylene, heteroarylene, heterocyclylene, cycloalkylene, alkylene, alkenylene, alkynylene, or a bond;
each R y is independently, hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, hydroxyl, cyano, dialkylamino, haloalkyl, C(O)OC 1-3 alkyl, C(O)OH, C(O)CH 2 NR x1 R y1 , C(O)NR x1 R y1 , C(O)C 1-6 alkyl, C 1-6 alkylsulfonyl, heteroaryl, or heteroaryloxy;
or when A is a bond and t is 0, R B and R y together along with the nitrogen to which they are attached optionally form a 4, 5, 6, or 7-membered optionally substituted ring containing up to two additional heteroatoms;
R x1 and R y1 are each independently hydrogen, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 3 -C 6 cycloalkyl, or R x1 and R y1 together along with the nitrogen to which they are attached form a 4, 5, 6, or 7-membered optionally substituted ring containing up to two additional heteroatoms; and
R SO is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted heterocyclyl, or an oxygen protecting group.
66 . A compound of Formula (IV):
or a pharmaceutically acceptable salt thereof, wherein:
Z is —C(═O)— or —NR Z2 —;
when Z is —NR Z2 —, one of b and c is CH 2 or —C(═O)—, and the other is a bond, or both b and c are a bond;
when Z is —C(═O)—, b and c are both a bond;
each instance of R 1a , R 1b , R 2a , and R 2b is independently hydrogen, halogen, carbonyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocylyl, optionally substituted aryl, optionally substituted heteroaryl, or wherein R 1a and R 1b or R 2a and R 2b can be taken together to form a carbonyl or
R Z2 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, guanidino, a nitrogen protecting group, —C(═O)R Z8 , —C(═O)N(R Z8 ) 2 , or —C(═O)OR Z8 , or a group of formula:
R Z7 is optionally substituted heteroalkylene, optionally substituted heteroalkenylene, optionally substituted heteroalkynylene, optionally substituted alkylene, optionally substituted alkenylene, or optionally substituted alkynylene;
R 4 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl;
R 5a and R 5b are each independently hydrogen, halogen, silyl, optionally substituted alkyl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl;
R 6 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, —OR Z8 , —SR Z8 , —N(R Z8 ) 2 , or acyl;
R 7 and R 8 are each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
R 9 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —C(═O)R Z8 , —C(═O)OR Z8 , —C(═O)N(R Z8 ) 2 , an oxygen protecting group, or a carbohydrate;
R 10 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, —OR Z8 , —SR Z8 , —N(R Z8 ) 2 , or acyl;
G 3 is —O—, —S—, or —N(R G1 )—, wherein R G1 is hydrogen, optionally substituted alkyl, or a nitrogen protecting group;
G 1 is —O— or —NR 13 —;
R 11 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group;
R 13 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group, —C(═O)R Z8 , or —C(═O)OR Z8 , or a group of formula:
or R 11 and R 13 are joined as a group of formula —C(═O)— to provide a cyclic carbamate;
each instance of L C1 and L C2 is independently a bond, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, optionally substituted heteroalkynylene, or combinations thereof;
each instance of A 1 is independently a leaving group (LG), —SH, —OH, —NH 2 , —NH—, NH 2 , —N 3 , —O—NH 2 , —C(═O)R X1 ,
A is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —NH—, —NH—NH—, —NH—O—, —O—NH—, —S—,—O—,
Q is —NH—, —NH—NH—, —O—NH—, —NH—O—, —S—, or —O—;
W is O, S, or NR W1 ;
R W1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a nitrogen protecting group;
R W2 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or two R W2 groups are joined to form an optionally substituted cyclic moiety;
R X1 is hydrogen, halogen, or —OR X2 ; wherein R X2 is hydrogen, optionally substituted alkyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group;
R 23 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and
each instance of R Z8 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocylyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R Z8 groups are joined to form an optionally substituted heterocylyl or optionally substituted heteroaryl ring.
67 . The compound of claim 66 , which is a compound of Formula (IV-a):
or a pharmaceutically acceptable salt thereof, wherein:
R Z6 is optionally substituted heteroalkylene, optionally substituted alkylene, optionally substituted alkenylene, or optionally substituted alkynylene.
68 . The compound of claim 66 , which is a compound of Formula (IV-b):
or a pharmaceutically acceptable salt thereof, wherein:
R Z6 is optionally substituted heteroalkylene, optionally substituted alkylene, optionally substituted alkenylene, or optionally substituted alkynylene.
69 . The compound of claim 66 , which is a compound of Formula (IV-c):
or a pharmaceutically acceptable salt thereof, wherein:
R Z6 is optionally substituted heteroalkylene, optionally substituted alkylene, optionally substituted alkenylene, or optionally substituted alkynylene.
70 . The compound of claim 66 , which is a compound of Formula (IV-d):
or a pharmaceutically acceptable salt thereof, wherein:
R Z6 is optionally substituted heteroalkylene, optionally substituted alkylene, optionally substituted alkenylene, or optionally substituted alkynylene.
71 . The compound of claim 66 , which is a compound of Formula (IV-e):
or a pharmaceutically acceptable salt thereof, wherein:
R Z6 is optionally substituted heteroalkylene, optionally substituted alkylene, optionally substituted alkenylene, or optionally substituted alkynylene.
72 . The compound of claim 66 , which is a compound of Formula (IV-f):
or a pharmaceutically acceptable salt thereof, wherein:
R Z6 is optionally substituted heteroalkylene, optionally substituted alkylene, optionally substituted alkenylene, or optionally substituted alkynylene.
73 . The compound of claim 66 , which is a compound of Formula (IV-g):
or a pharmaceutically acceptable salt thereof, wherein:
R Z6 is optionally substituted heteroalkylene, optionally substituted alkylene, optionally substituted alkenylene, or optionally substituted alkynylene;
each of R S4a , R S4b , R S5a , and R S5b is independently hydrogen, optionally substituted alkyl, or —OR SO ;
each instance of R SO is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted heterocyclyl, or an oxygen protecting group; and
R SN is independently hydrogen, optionally substituted alkyl, or a nitrogen protecting group; or optionally two R SN are taken with the intervening atoms to form a heterocyclic ring.
74 . The compound of claim 66 , which is a compound of Formula (IV-h):
or a pharmaceutically acceptable salt thereof, wherein:
R Z6 is optionally substituted heteroalkylene, optionally substituted alkylene, optionally substituted alkenylene, or optionally substituted alkynylene;
each of R S5a and R S5b is independently hydrogen, optionally substituted alkyl, or —OR SO ;
each instance of R SO is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted heterocyclyl, or an oxygen protecting group; and
R SN is independently hydrogen, optionally substituted alkyl, or a nitrogen protecting group; or optionally two R SN are taken with the intervening atoms to form a heterocyclic ring.
75 . The compound of claim 66 , which is a compound of Formula (IV-i):
or a pharmaceutically acceptable salt thereof, wherein:
R Z6 is optionally substituted heteroalkylene, optionally substituted alkylene, optionally substituted alkenylene, or optionally substituted alkynylene;
X is hydrogen, optionally substituted C 1-6 alkyl, —OR A , or —NR B —(CR x R x ) t -A-(R y ) q ;
t is 0, 1, or 2;
q is 1, 2, or 3;
R A is hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, or —C(═O)—R S1 ;
R S1 is optionally substituted aryl or optionally substituted heteroaryl;
R B is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 cycloalkyl, or C(O)CH 2 NR x1 R y1 ;
each R x is independently hydrogen or C 1-3 alkyl;
A is arylene, heteroarylene, heterocyclylene, cycloalkylene, alkylene, alkenylene, alkynylene, or a bond;
each R y is independently, hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, hydroxyl, cyano, dialkylamino, haloalkyl, C(O)OC 1-3 alkyl, C(O)OH, C(O)CH 2 NR x1 R y1 , C(O)NR x1 R y1 , C(O)C 1-6 alkyl, C 1-6 alkylsulfonyl, heteroaryl, or heteroaryloxy;
or when A is a bond and t is 0, R B and R y together along with the nitrogen to which they are attached optionally form a 4, 5, 6, or 7-membered optionally substituted ring containing up to two additional heteroatoms;
R x1 and R y1 are each independently hydrogen, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 3 -C 6 cycloalkyl, or R x1 and R y1 together along with the nitrogen to which they are attached form a 4, 5, 6, or 7-membered optionally substituted ring containing up to two additional heteroatoms; and
R SO is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted heterocyclyl, or an oxygen protecting group.
76 . The compound of claim 66 , which is a compound of Formula (IV-j):
or a pharmaceutically acceptable salt thereof, wherein:
X is hydrogen, optionally substituted C 1-6 alkyl, —OR A , or —NR B —(CR x R x ) t -A-(R y ) q ;
t is 0, 1, or 2;
q is 1, 2, or 3;
R A is hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, or —C(═O)—R S1 ;
R S1 is optionally substituted aryl or optionally substituted heteroaryl;
R B is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 cycloalkyl, or C(O)CH 2 NR x1 R y1 ;
each R x is independently hydrogen or C 1-3 alkyl;
A is arylene, heteroarylene, heterocyclylene, cycloalkylene, alkylene, alkenylene, alkynylene, or a bond;
each R y is independently, hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, hydroxyl, cyano, dialkylamino, haloalkyl, C(O)OC 1-3 alkyl, C(O)OH, C(O)CH 2 NR x1 R y1 , C(O)NR x1 R y1 , C(O)C 1-6 alkyl, C 1-6 alkylsulfonyl, heteroaryl, or heteroaryloxy;
or when A is a bond and t is 0, R B and R y together along with the nitrogen to which they are attached optionally form a 4, 5, 6, or 7-membered optionally substituted ring containing up to two additional heteroatoms;
R x1 and R y1 are each independently hydrogen, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 3 -C 6 cycloalkyl, or R x1 and R y1 together along with the nitrogen to which they are attached form a 4, 5, 6, or 7-membered optionally substituted ring containing up to two additional heteroatoms; and
R SO is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted heterocyclyl, or an oxygen protecting group.
77 . The compound of claim 66 , which is a compound of Formula (IV-k):
or a pharmaceutically acceptable salt thereof, wherein:
X is hydrogen, optionally substituted C 1-6 alkyl, —OR A , or —NR B —(CR x R x ) t -A-(R y ) q ;
t is 0, 1, or 2;
q is 1, 2, or 3;
R A is hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, or —C(═O)—R S1 ;
R S1 is optionally substituted aryl or optionally substituted heteroaryl;
R B is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 cycloalkyl, or C(O)CH 2 NR x1 R y1 ;
each R x is independently hydrogen or C 1-3 alkyl;
A is arylene, heteroarylene, heterocyclylene, cycloalkylene, alkylene, alkenylene, alkynylene, or a bond;
each R y is independently, hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, hydroxyl, cyano, dialkylamino, haloalkyl, C(O)OC 1-3 alkyl, C(O)OH, C(O)CH 2 NR x1 R y1 , C(O)NR x1 R y1 , C(O)C 1-6 alkyl, C 1-6 alkylsulfonyl, heteroaryl, or heteroaryloxy;
or when A is a bond and t is 0, R B and R y together along with the nitrogen to which they are attached optionally form a 4, 5, 6, or 7-membered optionally substituted ring containing up to two additional heteroatoms;
R x1 and R y1 are each independently hydrogen, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 3 -C 6 cycloalkyl, or R x1 and R y1 together along with the nitrogen to which they are attached form a 4, 5, 6, or 7-membered optionally substituted ring containing up to two additional heteroatoms; and
R SO is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted heterocyclyl, or an oxygen protecting group.
78 . The compound of claim 66 , which is a compound of Formula (IV-1):
or a pharmaceutically acceptable salt thereof, wherein:
X is hydrogen, optionally substituted C 1-6 alkyl, —OR A , or —NR B —(CR x R x ) t -A-(R y ) q ;
t is 0, 1, or 2;
q is 1, 2, or 3;
R A is hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, or —C(═O)—R S1 ;
R S1 is optionally substituted aryl or optionally substituted heteroaryl;
R B is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 cycloalkyl, or C(O)CH 2 NR x1 R y1 ;
each R x is independently hydrogen or C 1-3 alkyl;
A is arylene, heteroarylene, heterocyclylene, cycloalkylene, alkylene, alkenylene, alkynylene, or a bond;
each R y is independently, hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, hydroxyl, cyano, dialkylamino, haloalkyl, C(O)OC 1-3 alkyl, C(O)OH, C(O)CH 2 NR x1 R y1 , C(O)NR x1 R y1 , C(O)C 1-6 alkyl, C 1-6 alkylsulfonyl, heteroaryl, or heteroaryloxy;
or when A is a bond and t is 0, R B and R y together along with the nitrogen to which they are attached optionally form a 4, 5, 6, or 7-membered optionally substituted ring containing up to two additional heteroatoms;
R x1 and R y1 are each independently hydrogen, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 3 -C 6 cycloalkyl, or R x1 and R y1 together along with the nitrogen to which they are attached form a 4, 5, 6, or 7-membered optionally substituted ring containing up to two additional heteroatoms; and
R SO is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted heterocyclyl, or an oxygen protecting group.
79 . A compound selected from the group consisting of:
Compound
No.
Structure
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
59
60
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
127
128
129
130
131
132
133
134
135
136
137
138
139
140
141
142
143
144
145
146
147
148
149
150
151
152
153
154
155
156
157
158
159
160
161
162
163
164
165
166
167
168
169
170
171
172
173
174
175
176
177
178
179
180
181
182
183
184
185
186
187
188
189
190
191
192
193
194
195
196
197
198
199
200
201
202
203
204
205
206
207
208
209
210
211
212
213
214
215
216
217
218
219
220
221
222
223
224
225
226
227
228
229
230
and pharmaceutically acceptable salts thereof.
80 . A composition comprising:
(a) compound of Formula (II)
or a pharmaceutically acceptable salt thereof, and
(b) a compound of Formula (I-a)
wherein:
ring S is
wherein Z 1 is N(R S ) 2 or C(R S ) 3 and each R S is independently H, C 1 -C 6 alkyl, or C 2 -C 6 alkenyl;
one of b or c is CH 2 and the other is a bond;
n is 0 or 1;
R 6 and R 10 are selected from H, CH 3 , and F, wherein when R 6 is H, R 10 is CH 3 , when R 10 is H, R 6 is CH 3 , and when R 10 is F, R 6 is CH 3 ;
R 1′ and R 2′ are each independently selected from H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, and C(O)CH 2 NR x1 R y1 , or R 1′ and R 2′ together along with the nitrogen to which they are attached form a 4, 5, 6, or 7-membered optionally substituted ring containing up to two additional heteroatoms;
R x1 and R y1 are each independently selected from H, optionally substituted C 1 -C 6 alkyl, and optionally substituted C 1 -C 6 cycloalkyl, or R x1 and R y1 together along with the nitrogen to which they are attached form a 4, 5, 6, or 7-membered optionally substituted ring containing up to two additional heteroatoms;
R 3′ is H, OH, or oxo;
R Sa and R S4b are each independently selected from H, CH 3 and OH, wherein both R Sa and R S4b cannot be OH;
R 3a is selected from H, C 1 -C 6 -alkyl, and C 2 -C 6 alkenyl;
R Z2 is selected from the group consisting of H and C 1 -C 6 -alkyl; and
R 13 is selected from H, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, and C 1 -C 6 -alkoxy;
and wherein each R group in the compound of Formula (II) and the compound of Formula (II-a) are the same.
81 . A pharmaceutical composition comprising a compound of any of claims 1 - 79 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
82 . A pharmaceutical composition comprising the composition of claim 80 .
83 . A kit for treating an infectious disease comprising a container, a compound of any of claims 1 - 79 , or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 81 or 82 , and instructions for administering to a subject in need thereof.
84 . A method of treating an infectious disease comprising administering an effective amount of a compound of any of claims 1 - 79 , or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 81 or 82 , to a subject in need thereof.
85 . The method of claim 84 , wherein the infectious disease is a bacterial infection.
86 . The method of claim 85 , wherein the bacterial infection is an infection with a Gram positive bacteria.
87 . The method of claim 85 , wherein the bacterial infection is an infection with a Gram negative bacteria.
88 . The method of claim 85 , wherein the bacterial infection is a Staphylococcus infection, an Acinetobacter infection, a Klebsiella infection, an Escherichia infection, or a Pseudomonas infection.
89 . The method of claim 84 , wherein the infectious disease is a parasitic infection.
90 . A method of preparing a compound of Formula (I-a):
or a salt thereof, the method comprising reductively aminating a compound of Formula (D):
or salt thereof, with NR B —(CR x R x ) t -A-(R y ) q , to yield a compound of Formula (I-a), wherein:
X is —NR B —(CR x R x ) t -A-(R y ) q ; and
Z, R B , R x , t, A, R y , q, R 1a , R 1b , R 2a , R 2b , R 3a , R 4 , R 5a , R 5b , R 6 , R 7 , R 8 , R SO , and R SN are as defined in claim 2 .
91 . The method of claim 90 further comprising deprotecting and oxidizing a compound of Formula (C):
or salt thereof, to yield a compound of Formula (D), wherein:
Z, R 1a , R 1b , R 2a , R 2b , R 3a , R 4 , R 5a , R 5b , R 6 , R 7 , R 8 , R SO , and R SN are as defined in claim 1 ; and
R C is —(C═O)Ph or —O-allyl.
92 . The method of claim 91 further comprising cyclizing a compound of Formula (B):
or salt thereof, to yield a compound of Formula (C), wherein:
Z, R 1a , R 1b , R 2a , R 2b , R 3a , R 4 , R 5a , R 5b , R 6 , R 7 , R 8 , R SO , and R SN are as defined in claim 2 ;
R C is —(C═O)Ph or —O-allyl;
P 1 is hydrogen, silyl, optionally substituted alkyl, or optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen, nitrogen, or thiol protecting group;
G 3 is —O—, —S—, or —N(R G1 )—, wherein R G1 is hydrogen, optionally substituted alkyl, or a nitrogen protecting group;
G 4 is of formula:
each instance of X G2 is —OR 15 , —SR 15 , or —N(R 5 ) 2 ;
each instance of R 15 is independently silyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R 15 groups are joined to form an optionally substituted heterocyclyl or heteroaryl ring; and
each instance of R 16a is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
93 . The method of any of claims 90 - 92 , wherein R SO is —(C═O)Ph.
94 . The method of claim 92 further comprising one or more deprotecting steps to yield the compound of Formula (I-a), wherein:
X is —NR B —(CR x R x ) t -A-(R y ) q ; and
Z, R B , R x , t, A, R y , q, R 1a , R 1b , R 2a , R 2b , R 3a , R 4 , R 5a , R 5b , R 6 , R 7 , R 8 , and R SN are as defined in claim 2 ; and
R SO is hydrogen.
95 . A method of preparing a compound of Formula (V):
or a salt thereof, the method comprising contacting a compound of formula (V-a):
or a salt thereof, with a thiol to form a compound of Formula (V), wherein:
P 4 is hydrogen, optionally substituted alkyl, or an oxygen protecting group;
R C is hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —C(═O)-L S2 -R S1 , or an oxygen protecting group;
L S2 is a bond, —NR S1 —, —O—, or —S—, or a linking group selected from the group consisting of optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, and optionally substituted heteroalkynylene, and combinations thereof;
R S1 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom, or two R S1 groups attached to the same nitrogen atom are joined to form an optionally substituted heterocyclyl or heteroaryl ring;
each of R S4a and R S4b is independently hydrogen, halogen, optionally substituted C 1 -C 6 alkyl, or —OR SO ;
each of R S6a and R S6b is independently hydrogen, halogen, or optionally substituted C 1 -C 6 alkyl;
each R SN is independently hydrogen, optionally substituted C 1 -C 6 alkyl, or a nitrogen protecting group, or two R SN groups attached to the same nitrogen atom are joined to form an optionally substituted heterocyclyl or heteroaryl ring;
each R SO is independently hydrogen, optionally substituted C 1 -C 6 alkyl, a carbohydrate, or an oxygen protecting group; and
R TG is methyl, ethyl, phenyl, pyrimidinyl, pyridinyl, benzothiazolyl, benzooxazolyl, or tetrazolyl.
96 . The method of claim 95 further comprising protecting or alkylating a compound of Formula (V-b):
or a salt thereof, with an alkylating or protecting agent to form a compound of Formula (V-a).
97 . The method of claim 96 further comprising reducing and alkylating a compound of Formula (V-c):
or a salt thereof, with a reducing agent and alkylating agent to form a compound of Formula (V-b).
98 . The method of any of claims 90 - 97 further comprising the steps of:
deprotecting a compound of Formula (V), or a salt thereof, to yield a compound of Formula (V′-a):
or a salt thereof; and
alkylating a compound of Formula (V′-a), or a salt thereof, to yield a compound of Formula (V′-b):
or a salt thereof.
99 . The method of claim 95 , wherein R C is —(C═O)Ph.
100 . The method of any of claims 95 , 96 , or 98 , wherein each R SN is, independently, C 1-6 alkyl.
101 . The method of claim 100 , wherein each R SN is methyl.
102 . The method of claim 95 or 96 , wherein R SO is —(C═O)Ph.
103 . The method of any of claims 95 - 98 , wherein both R S4a and R S4b are hydrogen.
104 . The method of any of claims 95 - 98 , wherein both R S6a and R S6b are hydrogen.
105 . The method of claim 95 or 98 , wherein —SR TG is:
106 . The method of claim 95 , wherein the compound of Formula (V) is of the formula:
107 . The method of claim 98 , wherein the compound of Formula (V′-b) is of the formula:
108 . A compound selected from the group consisting of
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