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1. WO2020229982 - ANTIBODY DRUG CONJUGATES

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[ EN ]

WHAT IS CLAIMED IS:

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

a is an integer from 1 to 20;

b is an integer from 1 to 20;

m is 0, 1, 2, 3, or 4;

n is 0 or 1;

D-NH- is a portion of an amino-substituted compound, wherein the amino-substituted compound has the formula D-NH2;

each R1 is independently selected from C1-C4alkyl, O-C1-C4alkyl, and halogen;

R2 is selected from C1-C4alkyl and–(CH2CH2O)s-CH3; wherein s is an integer from 1 to

R3 and R3’ are each independently selected from hydrogen and C1-C3alkyl;

L is a cleavable linker; and

Ab is an antibody, antibody fragment or an antigen-binding fragment.

2. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:

a is an integer from 1 to 4;

b is an integer from 1 to 10; and

m is 0.

3. A compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: m is 0;

n is 0; and

R3 and R3’ are each hydrogen.

4. A compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein L is

wherein:

is the point of attachment to the nitrogen atom;

is the point of attachment to Ab;

t is an integer from 1 and 10;

W is absent or a self-immolative group;

Z is absent or a peptide of 2 to 5 amino acids;

U and U’ are independently absent or a spacer; and

Q is a heterobifunctional group;

provided that W and Z are not both absent.

5. A compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein W is a self-immolative group selected from

wherein:

is the point of attachment to the carbonyl group; and

the point of attachment to Z.

6. A compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein W is selected from


7. A compound of any one of claims 4 to 6, or a pharmaceutically acceptable salt thereof, wherein Z is a peptide capable of being enzymatically cleaved.

8. A compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein Z is cathepsin cleavable.

9. A compound of any one of claims 4 to 8, or a pharmaceutically acceptable salt thereof, wherein Z is a two-amino acid peptide selected from Val-Cit, Cit-Val, Val-Ala, Ala-Val, Phe-Lys, and Lys-Phe.

10. A compound of any one of claims 4 to 9, or a pharmaceutically acceptable salt thereof, wherein U and U’ are independently selected from

,


wherein:

the point of attachment to Z;

is the point of attachment to Q;


p is an integer from 1 to 6;

q is an integer from 1 to 20;

X is O or–CH2-; and

each r is independently 0 or 1.

11. A compound of any one of claims 4 to 10, or a pharmaceutically acceptable salt thereof, wherein Q is a heterobifunctional group which is attached to Ab through chemical or enzyme-mediated conjugation.

12. A compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein Q is selected from

;

wherein

is the point of attachment to U or, when U is absent, the point of attachment to Z; and

is the point of attachment to U’, or, when U’ is absent, the point of attachment to Ab.

13. A compound of claim 4, wherein

t is 1;

W is absent or a self-immolative group; and

Z is absent or a peptide of 2 amino acids.

14. A compound of any one of claims 1 to 13, wherein R2 is–CH3, or–(CH2CH2O)s-CH3 and s is an integer from 1 to 10.

15. A compound of any one of claims 1 to 14, wherein D-NH2 is an amino-substituted compound that modulates STING activity.

16. A compound of claim 15, wherein the amino-substituted compound that modulates STING activity comprises a guanine or an adenine derivative.

17. A compound of claim 15, wherein the amino-substituted compound that modulates STING activity is a compound of formula (II):

(II),

or a pharmaceutically acceptable salt thereof, wherein:

X10 is SH or OH;

X20 is SH or OH;

Ya is O, S, or CH2;

Yb is O, S, NH, or NRa, wherein Ra is C1-C4alkyl;

R10 is hydrogen, fluoro, OH, NH2, ORb, or NHRb;

R20 is hydrogen or fluoro;

R30 is hydrogen; R40 is hydrogen, fluoro, OH, NH2, ORb, or NHRb; or R30 and R40 are taken together to form CH2O;

R50 is hydrogen or fluoro;

Rb is C1-C6alkyl, halo(C1-C6)alkyl, or C3-C6cycloalkyl;

Ring A10 is an optionally substituted 5- or 6-membered monocyclic heteroaryl ring containing 1-4 heteroatoms selected from N, O, or S, or an optionally substituted 9 or 10 membered bicyclic heteroaryl ring containing 1-5 heteroatoms selected from N, O, or S; wherein ring A10 comprises at least one N atom in the ring, and wherein Yb is attached to a carbon atom of ring A10; and

Ring B10 is an optionally substituted 9 or 10-membered bicyclic heteroaryl ring containing from 2 to 5 heteroatoms selected from N, O, or S; wherein ring B10 comprises at least two N atoms in the ring;

provided that either ring A10 or ring B10 is attached to the carbonyl group of formula (I) through an -NH- group.

18. A compound of any one of claims 15 to 17, wherein the amino-substituted compound that modulates STING activity is

or a pharmaceutically acceptable salt thereof, wherein is the point of attachment to the carbonyl group of formula (I).

19. A compound of claim 15, wherein the amino-substituted compound that modulates STING activity is a compound of formula (III):

(III) ;

or a pharmaceutically acceptable salt thereof; wherein

X10 is SH or OH;

X20 is SH or OH;

Yc is O, S, or CH2;

Yd is O, S, or CH2;

B100 is a group represented by formula (B1-A) or formula (B1-B):

R13, R14, R15, R16 and R17 are each independently a hydrogen atom or a substituent;

R1000 is hydrogen or a bond to the carbonyl group of formula (I);

Y11, Y12, Y13, Y14, Y15 and Y16 are each independently N or CR1a, wherein R1a is hydrogen or a substituent;

Z11, Z12, Z13, Z14, Z15 and Z16 are each independently N or C;

R105 is a hydrogen atom or a substituent;

B200 is a group represented by formula (B2-A) or formula (B2-B):

R23, R24, R25, R26 and R27 are each independently a hydrogen atom or a substituent;

R100’ is hydrogen or a bond to the carbonyl group of formula (I);

Y21, Y22, Y23, Y24, Y25 and Y26 are each independently N or CR2a, wherein R2a is hydrogen or a substituent;

Z21, Z22, Z23, Z24, Z25 and Z26 are each independently N or C; and

R205 is a hydrogen atom or a substituent; wherein R105 and R205 are each independently attached to 2- or 3-position of the 5-membered ring they are attached to respectively;

provided that:

one of B100 or B200 is attached to the carbonyl group of formula (I) through an–NH- group.

20. A compound of claim 19, or a pharmaceutically acceptable salt thereof, of formula (IIIa):

(IIIa) ;

or a pharmaceutically acceptable salt thereof; wherein

B100 is a group represented by formula (B1-A) or formula (B1-B):

R13, R14, R15, R16 and R17 are each independently a hydrogen atom or a substituent;

R1000 is hydrogen or a bond to the carbonyl group of formula (I);

Y11, Y12, Y13, Y14, Y15 and Y16 are each independently N or CR1a, wherein R1a is hydrogen or a substituent;

Z11, Z12, Z13, Z14, Z15 and Z16 are each independently N or C;

R105 is a hydrogen atom or a substituent;

B200 is a group represented by formula (B2-A) or formula (B2-B):

R23, R24, R25, R26 and R27 are each independently a hydrogen atom or a substituent; R100’ is hydrogen or a bond to the carbonyl group of formula (I);

Y21, Y22, Y23, Y24, Y25 and Y26 are each independently N or CR2a, wherein R2a is hydrogen or a substituent;

Z21, Z22, Z23, Z24, Z25 and Z26 are each independently N or C; and

R205 is a hydrogen atom or a substituent; wherein R105 and R205 are each independently attached to 2- or 3-position of the 5-membered ring they are attached to respectively;

provided that:

one of B100 or B200 is:

wherein:

R18 is hydrogen or C1-6 alkyl; and

R19 is a halogen atom;

and the other is attached to the carbonyl group of formula (I) through an–NH- group.

21. A compound of claim 19 or 20 wherein the amino-substituted compound that modulates STING activity is:

or a pharmaceutically acceptable salt thereof, wherein is the point of attachment to the carbonyl group of formula (I).

22. A compound of formula (IV):

or a pharmaceutically acceptable salt thereof, wherein:

a is an integer from 1 to 20;

b is an integer from 1 to 20;

k is 0, 1, 2, or 3;

m is 0, 1, 2, 3, or 4;

D-NH– is a portion of an amino-substituted compound, where the amino-substituted compound has the formula D-NH2;

R2 is selected from H, C1-C4alkyl and–(CH2CH2O)s-CH3; wherein s is an integer from 1 to 10;

R4 is selected from hydrogen and any naturally occurring amino acid side chain;

R5 is selected from C1-C4alkyl, and O-C1-C4alkyl;

L is a cleavable linker; and

Ab is an antibody, antibody fragment or an antigen-binding fragment.

23. A compound of claim 22, or a pharmaceutically acceptable salt thereof, wherein L is

,

wherein:

is the point of attachment to the carbonyl group;

is the point of attachment to Ab;

W is a self-immolative group;

Z is absent or a peptide of 2 to 5 amino acids; and

U and U’ are independently absent or a spacer; and

Q is a heterobifunctional group.

24. A compound of formula (V):

(V);

or a pharmaceutically acceptable salt thereof, wherein:

X is O or CH2;

f is an integer from 1 to 10;

g is an integer from 1 to 20;

U and U’ are independently absent or a spacer;

Q is a heterobifunctional group; and

Ab is an antibody, antibody fragment or an antigen-binding fragment.

25. A compound of claim 24, wherein X is O.

26. A compound of formula (VI):


or a pharmaceutically acceptable salt thereof, wherein:

a is an integer from 1 to 20;

m is 0, 1, 2, 3, or 4;

n is 0 or 1;

D-NH- is a portion of an amino-substituted compound, wherein the amino-substituted compound has the formula D-NH2;

each R1 is independently selected from C1-C4alkyl, O-C1-C4alkyl, and halogen;

R2 is selected from C1-C4alkyl and–(CH2CH2O)s-CH3; wherein s is an integer from 1 to 10;

R3 and R3’ are each independently selected from hydrogen and C1-C3alkyl;

L is a cleavable linker; and

LP is a lipid.

27. The compound of claim 26, wherein the lipid is cholesterol or a phospholipid.

28. The compound of claim 27, wherein the lipid is a phospholipid.

29. The compound of claim 28, wherein the phospholipid is selected from a

phosphatidylcholine, a phosphatidylgycerol, a phosphatidic acid, a

phosphatidylethanolamine, a phosphatidylserine, a sphingomyelin, a soybean phospholipid, and an egg yolk phospholipid.

30. The compound of claim 28, wherein the phospholipid is a phosphatidylethanolamine, wherein the phosphadtidylethanolamine is 1,2-distearoyl-sn-glycero-3-phosphorylethanolamine.

31. A lipid complex comprising a compound of any one of claims 26 to 30.

32. The lipid complex of claim 31, wherein the lipid complex is in the form of a liposome.

33. The lipid complex of claim 31 or 32, further comprising one or more phospholipids.

34. The lipid complex of claim 33, wherein the one or more phospholipids are selected from a phosphatidylcholine, a phosphatidylgycerol, a phosphatidic acid, a

phosphatidylethanolamine, a phosphatidylserine, a sphingomyelin, a soybean phospholipid, and an egg yolk phospholipid.

35. The lipid complex of claim 34, wherein the phospholipid is a phosphatidylcholine, wherein the phosphatidylcholine is 1,2-distearoyl-sn-glycero-3-phosphocholine.

36. The lipid complex of any one of claims 31 to 35, which further comprises a fatty alcohol.

37. The lipid complex of any one of claims 31 to 36, which further comprises cholesterol.

38. The lipid complex of any one of claims 31 to 37, which further comprises at least one PEGylated lipid.

39. The lipid complex of claim 38, wherein the PEGylated lipid is selected from a PEGylated phospholipid and PEGylated diacylglycerol.

40. The liposome of claim 39, wherein the PEGylated lipid is N-(carbonyl-methoxypolyethyleneglycol 2000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine.

41. A pharmaceutical composition comprising a compound of any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

42. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a pharmaceutically acceptable amount of a compound of any of claims 1 to 40.

43. A method for stimulating an immune response in a subject in need thereof, the method comprising administering to the subject a pharmaceutically acceptable amount of a compound, lipid complex, or composition of any one of claims 1 to 41.