US2016280732A1PendingUtilityA1
Moenomycin analogs, methods of synthesis, and uses thereof
Est. expiryApr 6, 2032(~5.7 yrs left)· nominal 20-yr term from priority
C07H 1/00C07F 9/65586C07H 5/06C07H 13/12
47
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Claims
Abstract
The present invention provides compounds of Formula (I): or a pharmaceutically acceptable form thereof; wherein R 1 , R 2 , R 3 , R 6 , R 7 , R 12 , R XX , R a , and R b are as defined herein, and G is a group of Formula (a), (b), or (c): wherein X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , Y, R c , R d , R z , a, d, e, x, n, and m are as defined herein. The present invention further provides pharmaceutical compositions comprising a compound of Formula (I), kits comprising such compositions, methods of use and treatment, and preparative methods.
Claims
exact text as granted — not AI-modified1 - 24 . (canceled)
25 . A method of synthesizing a compound of Formula (II):
or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isomer, enantiomer, diastereomer, or polymorph thereof;
the method comprising the steps of:
(i) providing moenomycin A:
(ii) removing the phosphoglycerate linker and moenocinol chain of moenomycin A, and optionally Rings A and/or D, to provide a saccharide group of Formula (II-S1):
wherein:
each of R 1 , R 2 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 is hydrogen;
each of R 3 and R 4 is C(═O)CH 3 ;
R 5 is hydrogen or Ring A:
R 12 K is hydrogen or Ring D:
wherein R 13 , R 14 , R 15 , and R 16 are each hydrogen;
(iii) reacting (II-S1) with a phosphitylation agent to provide a H-phosphonate diester of Formula (II-S2):
wherein R a is hydrogen or a hydroxyl protecting group; and
(iv) coupling (II-S2) with a compound of Formula (P1):
wherein:
R b is hydrogen or a hydroxyl protecting group; and
G is a group of Formula (a), (b), or (c):
wherein a is 3, 4, or 5;
wherein:
X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 are each independently hydrogen or halogen;
d is an integer between 1 and 25, inclusive; and
e is an integer of between 2 and 25, inclusive;
provided that at least one of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 is halogen; and
the sum of d and e is greater than 16;
or
wherein:
Y is —S—, —S—, —NR Y —, or an optionally substituted methylene group, wherein R Y is hydrogen, optionally substituted aliphatic, or an amino protecting group;
each instance of R c is independently —F, —Br, —I, —Cl, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, optionally substituted heteroaryl, —OR e , —SR e ,—NHR e , or —N(R e ) 2 , wherein each instance of R e is independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R e groups are joined to form a 5- to 6-membered optionally substituted heterocycyl or optionally substituted heteroaryl ring;
each instance of R d is independently —F, —Br, —I, —Cl, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, optionally substituted heteroaryl, —OR f , —SR f , —NHR f , or —N(R f ) 2 , wherein each instance of R f is independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R f groups are joined to form a 5- to 6-membered optionally substituted heterocycyl or optionally substituted heteroaryl ring;
R z is hydrogen, —F, —Br, —I, —Cl, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, optionally substituted heteroaryl, —OR g , —SR g , —NHR g , or —N(R g ) 2 , wherein each instance of R g is independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, or optionally substituted heteroaryl or two R g groups are joined to form a 5- to 6-membered optionally substituted heterocycyl or optionally substituted heteroaryl ring;
each instance of n is, independently, 0, 1, 2, 3, or 4;
each instance of m is, independently, 0, 1, 2, 3, or 4; and
x is 1, 2, 3, 4, 5, or 6;
to provide a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isomer, enantiomer, diastereomer, or polymorph thereof.
26 . A method of synthesizing a compound of Formula (III):
or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isomer, enantiomer, diastereomer, or polymorph thereof;
the method comprising the steps of:
(i) providing moenomycin A:
(ii) removing the phosphoglycerate linker, moenocinol chain, and Rings A and B of moenomycin A, and optionally Ring D, to provide a saccharide group of Formula (III-S1):
wherein:
each of R 1 , R 2 , R 6 , R 7 , and R 8 is hydrogen;
each of R 3 and R 4 is —C(═O)CH 3;
R 12 is hydrogen or Ring D:
wherein R 13 , R 14 , R 15 , and R 16 are each hydrogen; and
R 17 is hydrogen or a hydroxyl protecting group;
(iii) reacting (III-S1) with a phosphitylation agent to provide a H-phosphonate diester of the formula (III-S2):
wherein R a is hydrogen or a hydroxyl protecting group; and
(iv) coupling (III-S2) with a compound of Formula (P1):
wherein:
R b is hydrogen or a hydroxyl protecting group; and
G is a group of Formula (a), (b), or (c):
wherein a is 3, 4, or 5;
wherein:
X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 are each independently hydrogen or halogen;
d is an integer between 1 and 25, inclusive; and
e is an integer of between 2 and 25, inclusive;
provided that at least one of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 is halogen; and
the sum of d and e is greater than 16;
or
wherein:
Y is —O, —S , —NR Y —, or an optionally substituted methylene group, wherein R Y is hydrogen, optionally substituted aliphatic, or an amino protecting group;
each instance of R c is independently —F, —Br, —I, —Cl, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, optionally substituted heteroaryl, —OR e , —SR e , —NHR e , or —N(R e ) 2 , wherein each instance of R e is independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R e groups are joined to form a 5- to 6-membered optionally substituted heterocycyl or optionally substituted heteroaryl ring;
each instance of R d is independently —F, —Br, —I, —Cl, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, optionally substituted heteroaryl, —OR f , —SR f , —NHR f , or —N(R f ) 2 , wherein each instance of R f is independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R f groups are joined to form a 5- to 6-membered optionally substituted heterocycyl or optionally substituted heteroaryl ring;
R z is hydrogen, —F, —Br, —I, —Cl, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, optionally substituted heteroaryl, —OR g , —SR g , —NHR g , or —N(R g ) 2 , wherein each instance of R g is independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, or optionally substituted heteroaryl or two R g groups are joined to form a 5- to 6-membered optionally substituted heterocycyl or optionally substituted heteroaryl ring;
each instance of n is, independently, 0, 1, 2, 3, or 4;
each instance of m is, independently, 0, 1, 2, 3, or 4; and
x is 1, 2, 3, 4, 5, or 6;
to provide a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isomer, enantiomer, diastereomer, or polymorph thereof.
27 . A method of synthesizing a compound of Formula (IV), comprising the steps of:
or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isomer, enantiomer, diastereomer,
or polymorph thereof;
the method comprising the steps of:
(i) providing moenomycin A:
(ii) removing the phosphoglycerate linker, moenocinol chain, and Rings A, B and C of moenomycin A, and optionally Ring D, to provide a saccharide group of Formula (IV-S1):
wherein:
each of R 1 , R 2 , R 6 , and R 7 is hydrogen;
R 3 is C(═O)CH 3;
R 12 is hydrogen or Ring D:
wherein R 13 , R 14 , R 15 , and R and R 16 are each hydrogen; and R 16 are each hydrogen; and
R 18 is hydrogen or a hydroxyl protecting group;
(iii) reacting (IV-S1) with a phosphitylation agent to provide an H-phosphonate diester of Formula (IV-S2):
wherein R a is hydrogen or a hydroxyl protecting group; and
(iv) coupling (IV-S2) with a compound of Formula (P1):
wherein:
R b is hydrogen or a hydroxyl protecting group; and
G is a group of Formula (a), (b), or (c):
wherein a is 3, 4, or 5;
wherein:
X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 are each independently hydrogen or halogen;
d is an integer between 1 and 25, inclusive; and
e is an integer of between 2 and 25, inclusive;
provided that at least one of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 is halogen; and
the sum of d and e is greater than 16;
or
wherein:
Y is —O—, —S—, —NR Y —, or an optionally substituted methylene group, wherein R Y is hydrogen, optionally substituted aliphatic, or an amino protecting group;
each instance of R c is independently —F, —Br, —I, —Cl, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, optionally substituted heteroaryl, —OR e , —SR e , —NHR e , or —N(R e ) 2 , wherein each instance of R e is independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R e groups are joined to form a 5- to 6-membered optionally substituted heterocycyl or optionally substituted heteroaryl ring;
each instance of R d is independently —F, —Br, —I, —Cl, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, optionally substituted heteroaryl, —OR f , —SR f , —NHR f , or —N(R f ) 2 , wherein each instance of R f is independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R f groups are joined to form a 5- to 6-membered optionally substituted heterocycyl or optionally substituted heteroaryl ring;
R z is hydrogen, —F, —Br, —I, —Cl, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, optionally substituted heteroaryl, —OR g , —SR g , —NHR g , or —N(R g ) 2 , wherein each instance of R g is independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, or optionally substituted heteroaryl or two R g groups are joined to form a 5- to 6-membered optionally substituted heterocycyl or optionally substituted heteroaryl ring;
each instance of n is, independently, 0, 1, 2, 3, or 4;
each instance of m is, independently, 0, 1, 2, 3, or 4; and
x is 1, 2, 3, 4, 5, or 6;
to provide a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isomer, enantiomer, diastereomer, or polymorph thereof.
28 . The method of claim 25 , wherein G is a group of formula (a).
29 . The method of claim 28 , wherein the group of Formula (a) is:
30 . The method of claim 28 , wherein the group of Formula (a) is:
31 . The method of claim 28 , wherein the group of Formula (a) is:
32 . The method of claim 25 , wherein G is a group of formula (b).
33 . The method of claim 32 , wherein at least one of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 is halogen.
34 . The method of claim 33 , wherein X 1 and X 2 are each hydrogen, X 3 and X 4 are each fluoro, and X 5 , X 6 , and X 7 are each fluoro.
35 . The method of claim 33 , wherein the group of Formula (b) is selected from the group consisting of:
36 . The method of claim 33 , wherein the group of Formula (b) is:
37 . The method of claim 25 , wherein G is a group of Formula (c).
38 . The method of claim 37 , wherein the group of Formula (c) is:
wherein:
R c1 and R c2 are each independently —F, —Br, —I, —Cl, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, optionally substituted heteroaryl, —OR e , —SR e , —NHR e , or —N(R e ) 2 , wherein each instance of R e is independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R e groups are joined to form a 5- to 6-membered optionally substituted heterocycyl or optionally substituted heteroaryl ring;
R d1 and R d2 are each independently —F, —Br, —I, —Cl, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, optionally substituted heteroaryl, —OR f , —SR f , —NHR f , or —N(R f ) 2 , wherein each instance of R f is independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R f groups are joined to form a 5- to 6-membered optionally substituted heterocycyl or optionally substituted heteroaryl ring;
Y 1 and Y 2 are each independently corresponds to —O, —S—, —NR Y —, or an optionally substituted methylene group, wherein R Y is hydrogen, optionally substituted aliphatic, or an amino protecting group;
n1 and n2 are each independently 0, 1, 2, 3, or 4; and
m1 and m2 are each independently 0, 1, 2, 3, or 4.
39 . The method of claim 37 , wherein the group of Formula (c) is:
wherein:
R c1 , R c2 , R c3 , R c4 , R c5 , and R c6 are each independently —F, —Br, —I, —Cl, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, optionally substituted heteroaryl, —OR e , —SR e , —NHR e , or —N(R e ) 2 , wherein each instance of R e is independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R e groups are joined to form a 5- to 6-membered optionally substituted heterocycyl or optionally substituted heteroaryl ring;
R d1 , R d 2, R d3 , R d4 , R d5 , and R d6 are each independently —F, —Br, —I, —Cl, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, optionally substituted heteroaryl, —OR f , —SR f , —NHR f , or —N(R f ) 2 , wherein each instance of R f is independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R f groups are joined to form a 5- to 6-membered optionally substituted heterocycyl or optionally substituted heteroaryl ring;
Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , and Y 6 are each independently corresponds to —O—, —S—, —NR Y —, or an optionally substituted methylene group, wherein R Y is hydrogen, optionally substituted aliphatic, or an amino protecting group;
n1, n2, n3, n4, n5, and n6 are each independently 0, 1, 2, 3, or 4; and
m1, m2, m3, m4, m5, and m6 are each independently 0, 1, 2, 3, or 4.
40 . The method of claim 38 , wherein the group of Formula (c) is:
41 . The method of claim 25 , wherein step (ii) comprises removing the moenocinol chain, followed by removal of the phosphoglycerate linker.
42 . The method of claim 41 , wherein step (ii) comprises removing Ring A and Ring D of moenomycin A, followed by removing the moenocinol chain, followed by removal of the phosphoglycerate linker.
43 . The method of claim 25 , wherein step (ii) comprises removing the moenocinol chain using a Lewis acid.
44 . The method of claim 25 , wherein step (ii) comprises removing the phosphoglycerate linker using a base.Join the waitlist — get patent alerts
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