IP Library › Granted Patent US 9,526,801

Granted Patent B2

US 9,526,801 · App. 14/994,378 · Granted Dec 27, 2016

Heteroarylene-bridged benzodiazepine dimers, conjugates thereof, and methods of making and using

Inventors: Ivar M. McDonald (East Haddam, CT); Naidu S. Chowdari (Sunnyvale, CA); Walter Lewis Johnson (San Francisco, CA); Yong Zhang (West Windsor, NJ); Robert M. Borzilleri (Carversville, PA); Sanjeev Gangwar (Foster City, CA)

Assignee: BRISTOL-MYERS SQUIBB COMPANY

A61K47/48715 A61K47/48384 A61K47/48569 C07D487/04 C07D519/00 C07K5/06052

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Quick Facts

Patent No.: US 9,526,801
App. No.: 14/994,378
Granted: Dec 27, 2016
Kind: B2

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Abstract

Benzodiazepine dimers having a structure represented by wherein X comprises a heteroaromatic moiety and is as further defined in the application; R 1 is and the other variables in formulae (I), (Ia), and (Ib) are as defined in the application. Such dimers are useful as anti-cancer agents, especially when used in an antibody-drug conjugate (ADC).

Claims (175)

1. A compound having a structure represented by formula (I)

wherein

X is selected from the group consisting of

R 1 is according to formula (Ia) or formula (Ib):

each G and G′ is C or N, with the proviso that no more than two Gs or two G's are N;

each R 2 is independently H or C 1 -C 5 alkyl;

each R 3 and R 4 is independently H, F, Cl, Br, OH, C 1 -C 3 alkyl, O(C 1 -C 3 alkyl), cyano, (CH 2 ) 0-5 NH 2 , or NO 2 ;

each double line in a diazepine ring system independently represents a single bond or a double bond;

each R 5 is H if the double line to the N to which it is attached is a single bond and is absent if the double line is a double bond;

each R 6 is H, OH, SO 3 Na, or SO 3 K if the double line to the C to which it is attached is a single bond and is absent if the double line is a double bond;

each R 7 , R 8 , R 9 , and R 10 is independently H, C 1 -C 5 alkyl, C≡C(CH 2 ) 1-5 X 2 , OH, O(C 1 -C 5 alkyl), cyano, NO 2 , F, Cl, Br, O(CH 2 CH 2 O) 1-8 (C 1-3 alkyl), (CH 2 ) 0-5 X 2 , O(CH 2 ) 2-5 X 2 , 3- to 7-membered cycloalkyl or heterocycloalkyl unsubstituted or substituted with (CH 2 ) 0-5 X 2 or O(CH 2 ) 2-5 X 2 , 5- to 6-membered aryl or heteroaryl unsubstituted or substituted with (CH 2 ) 0-5 X 2 or O(CH 2 ) 2-5 X 2 ,

or where a R 7 , R 8 , R 9 , or R 10 is attached to a G or G′ that is N, such R 7 , R 8 , R 9 , or R 10 is absent;

the dotted lines in ring C of formula (Ib) indicate the optional presence of a C1-C2, C2-C3, or C2-R 11 double bond;

R 11 is H, ═O, ═CH 2 , ═CH(C 1 -C 5 alkyl), CH═CH(CH 2 ) 1-5 X 2 , C≡C(CH 2 ) 1-5 X 2 , C 1 -C 5 alkyl, OH, O(C 1 -C 5 alkyl), cyano, NO 2 , F, Cl, Br, O(CH 2 CH 2 O) 1-8 (C 1-3 alkyl), (CH 2 ) 0-5 X 2 , 4- to 7-membered cycloalkyl, or heterocycloalkyl unsubstituted or substituted with (CH 2 ) 0-5 X 2 , O(CH 2 ) 2-5 X 2 , 3- to 7-membered cycloalkyl or heterocycloalkyl unsubstituted or substituted with (CH 2 ) 0-5 X 2 or O(CH 2 ) 2-5 X 2 , 5- to 6-membered aryl or heteroaryl unsubstituted or substituted with (CH 2 ) 0-5 X 2 or O(CH 2 ) 2-5 X 2 ;

R 11′ is absent if a C1-C2, C2-C3, or C2-R 11 double bond is present and otherwise is H;

each X 2 is independently H, F, Cl, Br, OH, O(C 1 -C 3 alkyl), O(C 1 -C 3 alkylene), CO 2 H, N 3 , CN, NO 2 , CO 2 (C 1 -C 3 alkyl), NH 2 , NH(C 1 -C 5 alkyl), N(C 1 -C 5 alkyl) 2 , SH, CHO, N(CH 2 CH 2 ) 2 N(C 1 -C 3 alkyl), NHNH 2 , or C(═O)NHNH 2 ;

each Y is independently CH 2 , C═O, or CHR 12 ; wherein each R 12 is independently F, Cl, Br, or C 1 -C 3 alkyl; and

Y′ and Y″ are independently CH 2 , C═O, or CHR 12 ; wherein each R 12 is independently F, Cl, Br, or C 1 -C 3 alkyl, with the proviso that at least one of Y′ and Y″ is present;

wherein a heterocycloalkyl group has 1 to 2 carbons replaced with a heteroatom independently selected from N, O, or S, where the N and S optionally may be oxidized and the N optionally may be quaternized; and

wherein a heteroaryl group has 1 to 4 heteroatoms independently selected from N, O, or S, where the N and S optionally may be oxidized and the N optionally may be quaternized;

or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 , wherein X is

3. A compound according to claim 1 , having a structure represented by formula (IIa):

4. A compound according to claim 3 , wherein X is

5. A compound according to claim 3 , having a structure represented by formula (IIa″)

wherein

R 5 is H if the double line to the N to which it is bonded is a single bond and absent if the double line is a double bond;

R 6 is H if the double line to the C to which it is bonded is a single bond and absent if the double line is a double bond;

each R 9 is independently H, OH, OMe, NH 2 , NMe 2 , O(CH 2 CH 2 O) 1-8 Me, OCH 2 CH 2 OH, or

and

X 3 is H, OH, OMe, Me, CH 2 OH, O(allyl), Cl, or CO 2 Me.

6. A compound according to claim 5 , selected from the group consisting of

7. A compound according to claim 1 , having a structure represented by formula (IIb)

8. A compound according to claim 7 , wherein X is

9. A compound according to claim 7 , having a structure represented by formula (IIb″)

wherein

R 9 is H, OH, OMe, NH 2 , NMe 2 , O(CH 2 CH 2 O) 1-8 Me, OCH 2 CH 2 OH, or

R 11 is H, ═CH 2 , CH═CHMe, ═CHMe, C≡CCH 2 NH 2 ,

R 11′ is absent if a C1-C2, C2-C3, or C2-R 11 double bond is present and otherwise is H;

X 3 is H, OH, OMe, Me, CH 2 OH, O(allyl), Cl, or CO 2 Me;

at least one of the double lines in a diazepine ring system is a double bond;

R 5 is H if the double line to the N to which it is attached is a single bond and absent if the double line is a double bond; and

R 6 is H if the double line to the C to which it is attached is a single bond and absent if the double line is a double bond.

10. A compound according to claim 1 ,

wherein

one G′ is N and the others are C;

at least one of the double lines in a diazepine ring system is a double bond;

R 5 is H if the double line to the N to which it is attached is a single bond and absent if the double line is a double bond; and

R 6 is H if the double line to the C to which it is attached is a single bond and absent if the double line is a double bond.

11. A compound according to claim 10 , wherein X is

12. A compound having a structure represented by formula (IIIa), (IIIb), (IIIc) or (IIIc′″):

wherein

T is a self-immolating group;

t is 0 or 1;

AA a and each AA b are independently selected from the group consisting of alanine, β-alanine, γ-aminobutyric acid, arginine, asparagine, aspartic acid, γ-carboxyglutamic acid, citrulline, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, norleucine, norvaline, ornithine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine;

u is 0 or 1;

p is 1, 2, 3, or 4;

q is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 (preferably 2, 3, 4, or 8);

r is 1, 2, 3, 4, or 5;

s is 0 or 1;

R 31 is

X 4 is S—S, O or NH;

R 1 is according to formula (Ia) or formula (Ib):

X is selected from the group consisting of

each G and G′ is C or N, with the proviso that no more than two Gs or two G's are N;

each R 2 is independently H or C 1 -C 5 alkyl;

each R 3 and R 4 is independently H, F, Cl, Br, OH, C 1 -C 3 alkyl, O(C 1 -C 3 alkyl), cyano, (CH 2 ) 0-5 NH 2 , or NO 2 ;

each double line in a diazepine ring system independently represents a single bond or a double bond;

each R 5 is H if the double line to the N to which it is attached is a single bond and is absent if the double line is a double bond;

each R 6 is H, OH, SO 3 Na, or SO 3 K if the double line to the C to which it is attached is a single bond and is absent if the double line is a double bond;

or where a R 7 , R 8 , R 9 , or R 10 is attached to a G or G′ that is N, such R 7 , R 8 , R 9 , or R 10 is absent;

the dotted lines in ring C of formula (Ib) indicate the optional presence of a C1-C2, C2-C3, or C2-R 11 double bond;

R 11 is absent if a C1-C2, C2-C3, or C2-R 11 double bond is present and otherwise is H;

X 3 is H, OH, OMe, Me, or CH 2 OH;

each R 50 is independently H, O(C 1 -C 3 alkyl), O(C 2 -C 3 alkylene), O(C 2 -C 3 alkynyl), F, Cl, Br, or CN;

each Y is independently CH 2 , C═O, or CHR 12 ; wherein each R 12 is independently F, Cl, Br, or C 1 -C 3 alkyl; and

Y′ and Y″ are independently CH 2 , C═O, or CHR 12 ; wherein each R 12 is independently F, Cl, Br, or C 1 -C 3 alkyl, with the proviso that at least one of Y′ and Y″ is present;

wherein a heteroaryl group has 1 to 4 heteroatoms independently selected from N, O, or S, where the N and S optionally may be oxidized and the N optionally may be quaternized.

13. A compound according to claim 12 , having a structure represented by formula (IIIa′)

wherein

each R 9 is independently H, C 1 -C 3 alkyl, O(CH 2 CH 2 O) 1-4 H, (CH 2 CH 2 O) 1-4 (C1-C 3 alkyl), OH, Cl, F, or Br;

R 5 is H if the double line to the N to which it is bonded is a single bond and absent if the double line is a double bond; and

R 6 is H if the double line to the C to which it is bonded is a single bond and absent if the double line is a double bond.

14. A compound according to claim 12 , having a structure represented by formula (IIIb) wherein u is 1 and X is

15. A compound according to claim 12 , having a structure represented by formula (IIIb″)

wherein

each R 9 is independently H, C 1 -C 3 alkyl, O(CH 2 CH 2 O) 1-4 H, (CH 2 CH 2 O) 1-4 (C1-C 3 alkyl), OH, Cl, F, or Br;

X 3 is H, OH, OMe, Me, CH 2 OH, O(allyl), Cl, or CO 2 Me;

R 5 is H if the double line to the N to which it is bonded is a single bond and absent if the double line is a double bond; and

R 6 is H if the double line to the C to which it is bonded is a single bond and absent if the double line is a double bond.

16. A compound selected from the group consisting of

17. A compound according to claim 12 , having a structure represented by formula (IIIc) wherein u is 1 and X is

18. A compound according to claim 17 , having a structure represented by formula (IIIc″)

wherein

X 3 is H, OH, OMe, Me, CH 2 OH, O(allyl), Cl, or CO 2 Me;

at least one of the double lines in a diazepine ring system is a double bond;

R 5 is H if the double line to the N to which it is attached is a single bond and absent if the double line is a double bond;

R 6 is H if the double line to the C to which it is attached is a single bond and absent if the double line is a double bond; and

R 9 is H, O(CH 2 CH 2 O) 1-4 H, (CH 2 CH 2 O) 1-4 (C1-C 3 alkyl), OH, Cl, F, or Br.

19. A compound selected from the group consisting of

20. A conjugate having a structure represented by formula (IVa), (IVb), (IVc) or (IVc′″):

wherein

Ab is an antibody;

R 40 is

where the open valence of R 40 that is bonded to Ab is denoted by an asterisk (*) and the open valence of R 40 that is bonded to (CH 2 ) r is denoted by a wavy line ( )

m is 1, 2, 3, or 4;