Granted Patent B2

US 12,194,023 · App. 17/297,848 · Granted Jan 14, 2025

Inventors: Scott Laughlin (Roslyn Heights, NY); Pratik Kumar (St. James, NY); Ting Jiang (Centereach, NY); Wei Huang (Stony Brook, NY)

Assignee: THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK

A61K31/403A61K31/4178A61K31/4188A61K47/543A61K47/545

Abstract

Claims (103)

1. A compound having the structure:

wherein

R 1 is H or a protecting group;

R 2 and R 3 are each independently H, halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl-C(O)NHR 6 , or C 1 -C 6 alkyl-C(O)OR 6 ,

wherein R 6 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkylaryl or L 1 -Y 1 ,

wherein R 6 is substituted or unsubstituted;

wherein L 1 is a chemical linker that is present or absent and Y 1 is biotin or a lipid,

or R 2 and R 3 combine to form a 3-7 membered cycloalkyl,

heterocycloalkyl, aryl or heteroaryl ring; and

R 4 and R 5 are each independently halo;

wherein when R 2 and R 3 are H, then the dashed line represents a bond that is present;

or a salt thereof.

2. The compound of claim 1 ,

wherein

R 1 is H, Boc, Nvoc or a light cleavable protecting group;

R 2 and R 3 are each independently H, halo, C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 1 -C 3 alkyl-C(O)NHR 6 , or C 1 -C 3 alkyl-C(O)OR 6 ,

wherein R 6 is H, C 1 -C 3 alkyl, C 2 -C 3 alkenyl or C 2 -C 3 alkynyl, or R 2 and R 3 combine to form a 3-7 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring; and

R 4 and R 5 are each independently F, Cl or Br.

3. The compound of claim 1 ,

wherein

R 1 is H, Boc or Nvoc;

R 2 and R 3 are each independently H or C 1 -C 3 alkyl; and

R 4 and R 5 are each F.

4. The compound of claim 1 having the structure:

5. A compound having the structure:

wherein

n is 0 or 1;

α is a bond which is absent or present,

wherein when α is present, then R 11 and R 12 are absent and when α is absent, R 11 and R 12 are present;

X 1 is H or L 3 -Y 3 ,

wherein L 3 is a chemical linker that is present or absent and Y 3 is a lipid, peptide, protein, sugar, nucleotide, antibody or imaging moiety;

R 1 is H or a protecting group;

R 2 and R 3 are each independently H, halo, alkyl, alkenyl, alkynyl, alkyl-C(O) NHR 13 , or alkyl-C(O)OR 13 ,

wherein R 13 is H or substituted or unsubstituted alkyl, alkenyl, alkynyl, heteroalkyl, amidoalkyl, amidoheteroalkyl, alkylaryl, alkylheteroaryl or L 4 -Y 4 ,

wherein L 4 is a chemical linker that is present or absent and Y 4 is a lipid, peptide, protein, sugar, nucleotide, antibody or imaging moiety;

R 4 and R 5 combine to form a carbonyl, or are each H, or one of R 4 and R 5 is H and the other is halo, —O(alkyl), substituted or unsubstituted —O(alkylaryl), CF 3 , OCF 3 , OCHF 2 or OSO 3 − , or R 4 and R 5 are each independently halo, alkyl, —O(alkyl), CF 3 , OCF 3 , OCHF 2 or OSO 3 − ;

R 9 and R 10 are each independently H, halo, alkyl, —O(alkyl), substituted or unsubstituted O (alkylaryl), CF 3 , OCF 3 , OCHF 2 or OSO 3 − ;

wherein one of R 4 and R 5 or one of R 9 and R 10 is other than H; and

R 11 and R 12 , when present, combine to form a 5-6 membered substituted or unsubstituted heterocycloalkyl, aryl or heteroaryl ring which is fused to the cyclopropanyl;

or a salt thereof.

6. The compound of claim 5 having the structure:

wherein

R 1 is H;

R 2 and R 3 are each independently H, halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl-C(O) NHR 6 , or C 1 -C 6 alkyl-C(O)OR 6 ,

wherein R 6 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkylaryl or L 1 -Y 1

wherein L 1 is a chemical linker that is present or absent and

Y 1 is biotin or a lipid;

R 7 and R 8 are each independently H, substituted or unsubstituted aryl or L 2 -Y 2 ,

wherein L 2 is a chemical linker that is present or absent and Y 2 is bovine serum albumin protein; and

R 4 and R 5 are each independently halo;

or a salt thereof.

7. The compound of claim 6 , wherein R 7 and R 8 are each independently H, phenyl, or substituted phenyl.

8. The compound of claim 6 having the structure:

9. A compound having the structure:

wherein

n is 0 or 1;

α is a bond which is absent or present,

wherein when α is present, then R 11 and R 12 are absent and when α is absent, R 11 and R 12 are present;

X 1 is H or L 3 -Y 3 ,

wherein L 3 is a chemical linker that is present or absent and Y 3 is a lipid, peptide, protein, sugar, nucleotide, antibody or imaging moiety;

R 1 is H or a protecting group;

R 2 and R 3 are each independently H, halo, alkyl, alkenyl, alkynyl, alkyl-C(O) NHR 13 , or alkyl-C(O)OR 13 ,

wherein R 13 is H or substituted or unsubstituted alkyl, alkenyl, alkynyl, heteroalkyl, amidoalkyl, amidoheteroalkyl, alklyaryl, alkylheteroaryl or L 4 -Y 4 ,

wherein L 4 is a chemical linker that is present or absent and Y 4 is a lipid, peptide, protein, sugar, nucleotide, antibody or imaging moiety;

R 4 and R 5 combine to form a carbonyl, or are each H, or one of R 4 and R 5 is H and the other is halo, —O(alkyl), —O(alkylaryl), CF 3 , OCF 3 , OCHF 2 or OSO 3 − , or R 4 and R 5 are each independently halo, alkyl, —O(alkyl), CF 3 , OCF 3 , OCHF 2 or OSO 3 − ;

R 9 and R 10 are each independently H, halo, alkyl, —O(alkyl), O(alkylaryl), CF 3 , OCF 3 , OCHF 2 or OSO 3 − ; wherein two of R 4 and R 5 are other than H and R 9 and R 10 are each H; or wherein two of R 9 and R 10 are other than H and R 4 and R 5 are each H; or wherein one of R 4 and R 5 is other than H and one of R 9 and R 10 is other than H, and

R 11 and R 12 , when present, combine to form a 5-6 membered substituted or unsubstituted heterocycloalkyl, aryl or heteroaryl ring which is fused to the cyclopropanyl.

10. The compound of claim 5 having the structure:

wherein

n is 0 or 1;

R 1 is H or a protecting group;

R 2 and R 3 are each independently H, halo, alkyl, alkenyl, alkynyl, alkyl-C(O) NHR 13 , or alkyl-C(O)OR 13 ,

wherein R 13 is H or substituted or unsubstituted alkyl, alkenyl, alkynyl, heteroalkyl, amidoalkyl, amidoheteroalkyl, alklyaryl, alkylheteroaryl or L 4 -Y 4 ,

wherein L 4 is a chemical linker that is present or absent and Y 4 is a lipid, peptide, protein, sugar, nucleotide, antibody or imaging moiety;

R 4 and R 5 combine to form a carbonyl, or are each H, or one of R 4 and R 5 is H and the other is halo, —O(alkyl), —O(alkylaryl), CF 3 , OCF 3 , OCHF 2 or OSO 3 − , or R 4 and R 5 are each independently halo, alkyl, —O(alkyl), CF 3 , OCF 3 , OCHF 2 or OSO 3 − ;

R 9 and R 10 are each independently H, halo, alkyl, —O(alkyl), —O (alkylaryl), CF 3 , OCF 3 , OCHF 2 or OSO 3 − ; wherein one of R 4 and R 5 or one of R 9 and R 10 is other than H;

or a salt thereof.

11. The compound of claim 10 , wherein

(a) R 1 is H, a light cleavable amine protecting group, an enzyme cleavable protecting group, or a carbamate protecting group having the structure

wherein Z 1 is substituted or unsubstituted alkylaryl, substituted or unsubstituted alkylheteroaryl or a pyranoside; and/or

(b) one of R 9 and R 10 is H and the other is —O(alkylaryl).

12. The compound of claim 11 , wherein Z 1 is

13. The compound of claim 5 , having the structure:

wherein

n is 0 or 1;

R 1 is H;

R 2 and R 3 are each independently H, halo, alkyl, alkenyl, alkynyl, alkyl-C(O)NHR 13 , or alkyl-C(O)OR 13 ,

wherein R 13 is H or a substituted or unsubstituted alkyl, alkenyl, alkynyl, heteroalkyl, amidoalkyl, amidoheteroalkyl, alklyaryl, alkylheteroaryl or L 4 -Y 4 ,

wherein L 4 is a chemical linker that is present or absent and Y 4 is a lipid, peptide, protein, sugar, nucleotide, antibody or imaging moiety,

R 4 and R 5 combine to form a carbonyl, or are each H, or one of R 4 and R 5 is H and the other is halo, —O(alkyl), —O(alkylaryl), CF 3 , OCF 3 , OCHF 2 or OSO 3 − , or R 4 and R 5 are each independently halo, alkyl, —O(alkyl), CF 3 , OCF 3 , OCHF 2 or OSO 3 − ;

R 9 and R 10 are each independently H, halo, alkyl, —O(alkyl), —O(alkylaryl), CF 3 , OCF 3 , OCHF 2 or OSO 3 − , wherein one of R 4 and R 5 or one of R 9 and R 10 is other than H;

R 11 and R 12 combine to form a 5-6 membered substituted or

unsubstituted heterocycloalkyl, aryl or heteroaryl ring which is fused to the cyclopropanyl; or R 11 and R 12 combine to form a dihydropyridazine, which is fused to the cyclopropanyl;

or a salt thereof.

14. The compound of claim 13 having the structure:

wherein

R 14 and R 15 are each independently H, halo, alkyl, alkenyl, alkynyl, alkyl-C(O) NHR 16 , or alkyl-C(O)OR 16 ,

wherein R 16 is H, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, heteroalkyl, amidoalkyl, amidoheteroalkyl, alkylaryl, alkylheteroaryl or L 5 -Y 5 ,

wherein L 5 is a chemical linker that is present or absent and Y 5 is a lipid, peptide, protein, sugar, nucleotide, antibody or imaging moiety; or a salt thereof.

15. The compound of claim 10 , wherein the —O(alkylaryl) is

wherein R 14 , R 15 , R 16 , R 17 and R 18 are each independently H, halo, alkyl, —O(alkyl), CF 3 , OCF 3 , OCHF 2 , OSO 3 − , SO 3 H, NO 2 or CN.

16. The compound of claim 5 having the structure:

17. The compound of claim 5 having the structure:

Assignments (1)

Continuity (2)

References Cited (57)