ASYMMETRIC CONJUGATE COMPOUNDS
The invention relates to compound of formula (I): A-X 1 -L-X 2 —B (I) and salts, solvates and tautomers thereof, which are useful as medicaments, in particular as anti-proliferative agents and for use as a drug in an antibody-drug conjugate; wherein A is a group selected from: X 1 and X 2 are independently selected from O, S, NR 28 , CR 28 R 29 , CR 28 R 29 O, C(═O), C(═O)NR 28 , NR 28 C(═O), C(O)—R A —C(O)—NH, C(O)—R A —NH—C(O), C(O)—NH—R A —C(O), NH—C(O)—R A —C(O), NH—C(O)—R A —C(O)—NH, NH—C(O)—R A —NH—C(O), C(O)—NH—R A —NH—C(O), C(O)—NH—R A —C(O)—NH, O—C(O) and C(O)—O or is absent; L is selected from an amino acid, a peptide chain having from 2 to 12 amino acids, a paraformaldehyde chain —(OCH 2 ) 1-24 —, a polyethylene glycol chain —(OCH 2 CH 2 ) 1-12 — and —(CH 2 ) m —Y 6 —(CH 2 ) n — wherein Y 6 is selected from —(CH 2 ) z — and a group (L1) a group (L1) that is selected from arylene, monocyclic heteroarylene, monocyclic cycloalkylene, monocyclic cycloalkenylene and monocyclic heterocyclylene groups optionally substituted with up to three optional substituent groups; and B is a polycyclic group selected from:
1 . A method of treatment of a patient suffering from a proliferative disease, comprising administering to said patient a therapeutically effective amount of an antibody-drug conjugate, wherein the drug is a compound of formula (I):
A-X 1 -L-X 2 —B (I)
and salts, solvates and tautomers thereof,
wherein;
A is a group selected from:
h is 0 or 1;
R 1 is selected from H and halogen;
either R 2 is selected from —CH 2 -halogen, C 1-6 alkyl and H, and R 3 is H;
or R 2 and R 3 together with the carbon atoms to which they are attached form a cyclopropyl ring;
p is 0 or 1; and when p is 1 then Y is C—R 7 , Y 2 is C—R 6 , Y 3 is C—R 5 and Y 4 is C—R 4 ;
and for (A1) and (A2) when p is 0 either (a) Y is selected from N—R 19 , O and S; Y 2 is selected from C—R 6 and N; and Y 3 is C—R 5 ; or (b) Y 3 is selected from N—R 19 , O and S; Y 2 is selected from C—R 6 and N; and Y is C—R 7 ;
and for (A3) when p is 0, Y is selected from N—R 9 , O and S; and Y 2 is selected from C—R 6 and N;
R 4 , R 5 , R 6 and R 7 are each independently selected from H and R 20 ,
or one of R 4 and R 5 , or R 5 and R 6 , or R 6 and R 7 together with the carbon atoms to which they are attached form a 6-membered aryl, or a 5- or 6-membered cyclic, heterocyclic, or heteroaryl ring optionally substituted with up to three independently selected optional R 20 groups;
R 8 is selected from selected from H, nitrogen protecting groups and R 20 ;
X 3 is selected from C═O, C—OH and C—R′″; or Y 5 is selected from C═O, C—OH, C—NH 2 and C—R′″; with the carbon forming part of the ring; and
when X 3 or Y 5 is C═O then represents an α,β-unsaturated double bond conjugated with the C═O; and when X 3 is C—OH or C—R′″ or Y 5 is C—OH, C—N H or C—R′″ then represents the double bonds of an aromatic 6-membered ring and R 3 is absent;
wherein R′″ is a prodrug moiety containing carbonyl, carbamoyl, glycosyl, O-amino, O-acylamino, para-aminobenzyl ether, peptidyl or phosphate groups;
X 1 is selected from O, S, NR 21 , CR 21 R 22 , CR 21 R 22 O, C(═O), C(═O)NR 21 , NR 21 C(═O), C(O)—R A —C(O)—NH, C(O)—R A —NH—C(O), C(O)—NH—R A —C(O), NH—C(O)—R A —C(O), NH—C(O)—R A —C(O)—NH, NH—C(O)—R A —NH—C(O), C(O)—NH—R A —NH—C(O), C(O)—NH—R A —C(O)—NH, O—C(O) and C(O)—O or is absent;
L is selected from an amino acid, a peptide chain having from 2 to 12 amino acids, a paraformaldehyde chain —(OCH 2 ) 1-24 —, a polyethylene glycol chain —(OCH 2 CH 2 ) 1-12 — and —(CH 2 ) m —Y 6 —(CH 2 ) n — wherein
m is an integer selected from 0 to 12,
n is an integer selected from 0 to 12, and
Y 6 is selected from —(CH 2 ) z — and a group (L1) that is selected from arylene, monocyclic heteroarylene, monocyclic cycloalkylene, monocyclic cycloalkenylene and monocyclic heterocyclylene groups optionally substituted with up to three independently selected optional R 20 groups;
z is an integer selected from 1 to 5;
X 2 is selected from O, S, NR 23 , CR 23 R 24 , CR 23 R 24 O, C(═O), C(═O)NR 23 , NR 24 C(═O), C(O)—R A —C(O)—NH, C(O)—R A —NH—C(O), C(O)—NH—R A —C(O), NH—C(O)—R A —C(O), NH—C(O)—R A —C(O)—NH, NH—C(O)—R A —NH—C(O), C(O)—NH—R A —NH—C(O), C(O)—NH—R A —C(O)—NH, O—C(O) and C(O)—O or is absent;
B is a polycyclic group selected from:
the dotted lines indicate the optional presence of one or more double bonds;
q is 0 or 1;
and R 9 and R 10 are selected such that either:
(i) R 9 and R 10 together form a double bond;
(ii) R 9 is H and R 10 is OH;
(iii) R 9 is H and R 10 is OC 1-6 alkyl;
(iv) R 9 is selected from SO 3 H, nitrogen protecting groups and R 20 ; and
R 10 is H; or
(v) R 9 is H or C 1-6 alkyl, and R 10 is oxo or H;
R 11 , R 12 , R 13 and R 14 are independently selected from H, R 20 , R 25 , ═CH 2 , ═CH—(CH 2 ) s —CH 3 , ═CH—(CH 2 ) s —R 25 , ═O, (CH 2 )—OR 25 , (CH 2 ) s —CO 2 R 25 , (CH 2 ) s —NR 25 R 26 , O—(CH 2 ) t —NR 25 R 26 , NH—C(O)—R 25 , O—(CH 2 ) t —NH—C(O)—R 25 , O—(CH 2 ) t —C(O)—NH—R 25 , (CH 2 ) s —SO 2 R 25 , O—SO 2 R 25 , (CH 2 ) s —C(O)R 25 and (CH 2 ) s —C(O)NR 25 R 26 ;
or one of R 11 and R 12 , R 12 and R 13 , or R 13 and R 14 together with the carbon atoms to which they are attached form a 6-membered aryl, or a 5- or 6-membered cyclic, heterocyclic, or heteroaryl ring optionally substituted with up to three independently selected optional R 20 groups;
each s is an integer independently selected from 0 to 6;
each t is an integer independently selected from 1 to 6;
R 15 , R 16 , R 17 and R 18 are independently selected from H and R 20 ;
each R 20 is independently selected from (CH 2 ) j —OH, C 1-6 alkyl, OC 1-6 alkyl, OCH 2 Ph, (CH 2 ) j —CO 2 R 27 , O—(CH 2 ) k —NR 27 R 28 , (CH 2 ) j —NR 27 R 28 , C(═O)—NH—(CH 2 ) k —NR 27 R 28 , C(═O)—NH—C 6 H 4 —(CH 2 ) j —R 27 and C(═O)—NH—(CH 2 ) k —C(═NH)NR 27 R 28 ;
each j is an integer independently selected from 0 to 6;
each k is an integer independently selected from 1 to 6;
each R 19 , R 21 , R 22 , R 23 , R 24 , R 26 , R 27 and R 28 is independently selected from H and C 1-6 alkyl; and
each R 25 is independently selected from H, C 1-12 alkyl, C 5-9 heteroaryl, C 6-15 heteroarylalkyl, phenyl and C 7-12 aralkyl groups; wherein the heteroaryl, heteroarylalkyl, phenyl and aralkyl groups are optionally substituted with up to three independently selected optional R 20 groups;
each R A is independently selected from:
NR B -T 1 -NR C — where R B and R c are each independently selected from H and C 1-8 alkyl, or together R B and R c join to form a ring and together are (CH 2 ) 2-3 , where T 1 is selected from —C(O), —C(O)(CH 2 ) 0-50 C(O) − , —C(O)PhC(O)— where Ph is 1,3- or 1,4-phenylene;
-het- wherein het is a mono-, bi-, or tricyclic heteroarylene of 5 to 12 members, containing one, two, or three heteroatoms independently selected from O, N, S, P and B, wherein het is optionally substituted up to three independently selected optional R 20 groups;
X A -T 2 -X A —, where T 2 is:
wherein each X A is independently selected from a bond, —NH—, —N(C 1-8 alkyl)-, —O— and —S—,
each R D , R E , R F , and R G are each independently H or R 20 , or R D and R E form a ring system, or R F and R G form a ring system, or both R D and R E , and R F and R G independently form ring systems, where said ring systems are independently selected from —C 1 -C 10 heterocyclyl or —C 3 -C 8 carbocyclycl, or R D , R E , R F , and R G are each bonds to different carbons on D, wherein f and g are each independently an integer from 0 to 50 and w is an integer from 1 to 50, and wherein D is a bond or is selected from the group consisting of —S—, —C 1 -C 8 alkylene-, —C 6 -C 14 arylene-, —C 6 -C 14 heteroarylene-, —C 1 -C 8 heteroalkylene-, —C 7 -C 22 aralkylene, —C 1 -C 10 heterocyclo and —C 3 -C 8 carbocyclo, where said —C 1 -C 8 alkylene-, —C 6 -C 14 arylene-, —C 6 -C 14 heteroarylene-, —C 1 -C 8 heteroalkylene-, —C 7 -C 22 aralkylene, —C 1 -C 10 heterocyclo and —C 3 -C 8 carbocyclo are optionally substituted up to three independently selected optional R 20 groups;
with the proviso that when the compound is:
that at least one of R 11 , R 12 and R 13 is independently selected from C 5-9 heteroaryl, C 6-15 heteroarylalkyl, phenyl and C 7-12 aralkyl groups and these groups are optionally substituted with up to three independently selected optional R 20 groups, or that one of R 11 and R 12 or R 12 and R 13 , or R 13 together with the carbon atoms to which they are attached form a 6-membered aryl, or a 5- or 6-membered cyclic, heterocyclic, or heteroaryl ring optionally substituted with up to three independently selected optional R 20 groups;
with the proviso that R 5 and R 6 are each independently selected from H and R 20 when B, q and A are selected as (B1), O and (A4) respectively;
with the proviso that when R 2 is C 1-6 alkyl or H, that R 9 and R 10 are selected from options (i), (ii), (iii) or (iv); and
with the proviso that when (v) R 9 is H or C 1-6 alkyl, and R 10 is oxo or H; then either R 2 is —CH 2 -halogen and R 3 is H;
or R 2 and R 3 together with the carbon atoms to which they are attached form a cyclopropyl ring.
2 . A method of treatment according to claim 1 , wherein one of R 11 and R 12 , R 12 and R 13 , or R 13 and R 14 together with the carbon atoms to which they are attached form a 6-membered aryl, or a 5- or 6-membered cyclic, heterocyclic, or heteroaryl ring optionally substituted with up to three independently selected optional R 20 groups.
3 . A compound of formula (I):
A-X 1 -L-X 2 —B (I)
and salts, solvates and tautomers thereof,
wherein;
A is a group selected from:
h is 0 or 1;
R 1 is selected from H and halogen;
either R 2 is selected from —CH 2 -halogen, C 1-6 alkyl and H, and R 3 is H;
or R 2 and R 3 together with the carbon atoms to which they are attached form a cyclopropyl ring;
p is 0 or 1; and when p is 1 then Y is C—R 7 , Y 2 is C—R 6 , Y 3 is C—R 5 and Y 4 is C—R 4 ;
and for (A1) and (A2) when p is 0 either (a) Y is selected from N—R 19 , O and S; Y 2 is selected from C—R 6 and N; and Y 3 is C—R 5 ; or (b) Y 3 is selected from N—R 19 , O and S; Y 2 is selected from C—R 6 and N; and Y is C—R 7 ;
and for (A3) when p is 0, Y is selected from N—R 19 , O and S; and Y 2 is selected from C—R 6 and N;
R 4 , R 5 , R 6 and R 7 are each independently selected from H and R 20 ,
or one of R 4 and R 5 , or R 5 and R 6 , or R 6 and R 7 together with the carbon atoms to which they are attached form a 6-membered aryl, or a 5- or 6-membered cyclic, heterocyclic, or heteroaryl ring optionally substituted with up to three independently selected optional R 20 groups;
R 8 is selected from selected from H, nitrogen protecting groups and R 20 ;
X 3 is selected from C═O, C—OH and C—R′″; or Y 5 is selected from C═O, C—OH, C—NH 2 and C—R′″; with the carbon forming part of the ring; and
when X 3 or Y 5 is C═O then represents an α,β-unsaturated double bond conjugated with the C═O; and when X 3 is C—OH or C—R′″; or Y 5 is C—OH, C—NH 2 or C—R′″ then represents the double bonds of an aromatic 6-membered ring and R 3 is absent;
wherein R′″ is a prodrug moiety containing carbonyl, carbamoyl, glycosyl, O-amino, O-acylamino, para-aminobenzyl ether, peptidyl or phosphate groups
X 1 is selected from O, S, NR 21 , CR 21 R 22 , CR 21 R 22 O, C(═O), C(═O)NR 21 , NR 21 C(═O), C(O)—R A —C(O)—NH, C(O)—R A —NH—C(O), C(O)—NH—R A —C(O), NH—C(O)—R A —C(O), NH—C(O)—R A —C(O)—NH, NH—C(O)—R A —NH—C(O), C(O)—NH—R A —NH—C(O), C(O)—NH—R A —C(O)—NH, O—C(O) and C(O)—O or is absent;
L is selected from an amino acid, a peptide chain having from 2 to 12 amino acids, a paraformaldehyde chain —(OCH 2 ) 1-24 —, a polyethylene glycol chain —(OCH 2 CH 2 ) 1-12 — and —(CH 2 ) m —Y 6 —(CH 2 ) n — wherein
m is an integer selected from 0 to 12,
n is an integer selected from 0 to 12, and
Y 6 is selected from —(CH 2 ) z — and a group (L1) that is selected from arylene, monocyclic heteroarylene, monocyclic cycloalkylene, monocyclic cycloalkenylene and monocyclic heterocyclylene groups optionally substituted with up to three independently selected optional R 20 groups;
z is an integer selected from 1 to 5;
X 2 is selected from O, S, NR 23 , CR 23 R 24 , CR 23 R 24 O, C(═O), C(═O)NR 23 , NR 24 C(═O), C(O)—R A —C(O)—NH, C(O)—R A —NH—C(O), C(O)—NH—R A —C(O), NH—C(O)—R A —C(O), NH—C(O)—R A —C(O)—NH, NH—C(O)—R A —NH—C(O), C(O)—NH—R A —NH—C(O), C(O)—NH—R A —C(O)—NH, O—C(O) and C(O)—O or is absent;
B is a polycyclic group selected from:
the dotted lines indicate the optional presence of one or more double bonds;
q is 0 or 1;
and R 9 and R 10 are selected such that either:
(i) R 9 and R 10 together form a double bond;
(ii) R 9 is H and R 10 is OH;
(iii) R 9 is H and R 10 is OC 1-6 alkyl;
(iv) R 9 is selected from SO 3 H, nitrogen protecting groups and R 20 ; and
R 10 is H; or
(v) R 9 is H or C 1-6 alkyl, and R 10 is oxo or H
R 11 , R 12 , R 13 and R 14 are independently selected from H, R 20 , R 25 , ═CH 2 , ═CH—(CH 2 ) s —CH 3 , ═CH—(CH 2 ) s —R 25 , ═O, (CH 2 ) s —OR 25 , (CH 2 ) s —CO 2 R 25 , (CH 2 ) s —NR 25 R 26 , O—(CH 2 ) t —NR 25 R 26 , NH—C(O)—R 25 , O—(CH 2 ) t —NH—C(O)—R 25 , O—(CH 2 ) t —C(O)—NH—R 25 , (CH 2 ) s —SO 2 R 25 , O—SO 2 R 25 , (CH 2 )S—C(O)R 25 and (CH 2 ) 1 —C(O)NR 25 R 26 ;
or one of R 11 and R 12 , R 12 and R 13 , or R 13 and R 14 together with the carbon atoms to which they are attached form a 6-membered aryl, or a 5- or 6-membered cyclic, heterocyclic, or heteroaryl ring optionally substituted with up to three independently selected optional R 20 groups;
each s is an integer independently selected from 0 to 6;
each t is an integer independently selected from 1 to 6;
R 15 , R 16 , R 17 and R 18 are independently selected from H and R 20 ;
each R 20 is independently selected from (CH 2 ) j —OH, C 1-6 alkyl, OC 1-6 alkyl, OCH 2 Ph, (CH 2 ) j —CO 2 R 27 , O—(CH 2 ) k —NR 27 R 28 , (CH 2 ) j —NR 27 R 28 , C(═O)—NH—(CH 2 ) k —NR 27 R 28 ; C(═O)—NH—C 6 H 4 —(CH 2 ) j —R 27 and C(═O)—NH—(CH 2 ) k —C(═NH)NR 27 R 28 ;
each j is an integer independently selected from 0 to 6;
each k is an integer independently selected from 1 to 6;
each R 19 , R 21 , R 22 , R 23 , R 24 , R 26 , R 27 and R 28 is independently selected from H and C 1-6 alkyl; and
each R 25 is independently selected from H, C 1-12 alkyl, C 5-9 heteroaryl, C 6-15 heteroarylalkyl, phenyl and C 7-12 aralkyl groups; wherein the heteroaryl, heteroarylalkyl, phenyl and aralkyl groups are optionally substituted with up to three independently selected optional R 20 groups;
each R A is independently selected from:
NR B -T 1 -NR C — where R B and R c are each independently selected from H or C 1-8 alkyl, or together R B and R c join to form a ring and together are (CH 2 ) 2-3 , where T 1 is selected from —C(O), —C(O)(CH 2 ) 0-50 C(O) − , —C(O)PhC(O)— where Ph is 1,3- or 1,4-phenylene;
-het- wherein het is a mono-, bi-, or tricyclic heteroarylene of 5 to 12 members, containing one, two, or three heteroatoms independently selected from O, N, S, P and B, wherein het is optionally substituted up to three independently selected optional R 20 groups;
X A -T 2 -X A —, where T 2 is:
wherein each X A is independently selected from a bond, —NH—, —N(C 1-8 alkyl)-, —O— and —S—,
each R D , R E , R F , and R G are each independently H or R 20 , or R D and R E form a ring system, or R F and R G form a ring system, or both R D and R E , and R F and R G independently form ring systems, where said ring systems are independently selected from —C 1 -C 10 heterocyclyl or —C 3 -C 8 carbocyclycl, or R D , R E , R E , and R G are each bonds to different carbons on D, wherein f and g are each independently an integer from 0 to 50 and w is an integer from 1 to 50, and wherein D is a bond or is selected from the group consisting of —S—, —C 1 -C 8 alkylene-, —C 6 -C 14 arylene-, —C 6 -C 14 heteroarylene-, —C 1 -C 8 heteroalkylene-, —C 7 -C 22 aralkylene, —C 1 -C 10 heterocyclo and —C 3 -C 8 carbocyclo, where said —C 1 -C 8 alkylene-, —C 6 -C 14 arylene-, —C 6 -C 14 heteroarylene-, —C 1 -C 8 heteroalkylene-, —C 7 -C 22 aralkylene, —C 1 -C 10 heterocyclo and —C 3 -C 8 carbocyclo are optionally substituted up to three independently selected optional R 20 groups;
with the proviso that when R 2 is C 1-6 alkyl or H, that R 9 and R 10 are selected from options (i), (ii), (iii) or (iv); and
with the proviso that when (v) R 9 is H or C 1-6 alkyl, and R 10 is oxo or H; then either R 2 is —CH 2 -halogen and R 3 is H;
or R 2 and R 3 together with the carbon atoms to which they are attached form a cyclopropyl ring.
4 . A compound of formula (I) and salts, solvates and tautomers thereof according to claim 3 , wherein A is (A1).
5 . A compound of formula (I) according to claim 3 , wherein the compound has the formula (III):
and salts, solvates and tautomers thereof.
6 . A compound of formula (I) according to claim 3 , wherein the compound has the formula (VI):
and salts, solvates and tautomers thereof.
7 . A compound of formula (I) according to claim 3 , wherein the compound has the formula (IX):
and salts, solvates and tautomers thereof.
8 . A compound of formula (I) according to claim 3 , wherein the compound has the formula (XII):
and salts, solvates and tautomers thereof.
9 . A compound of formula (I) according to claim 3 , wherein the compound has the formula (XIV):
and salts, solvates and tautomers thereof.
10 . A compound of formula (I) and salts, solvates and tautomers thereof according to claim 3 , wherein one of R 11 and R 12 , R 12 and R 13 , or R 13 and R 14 together with the carbon atoms to which they are attached form a 6-membered aryl, or a 5- or 6-membered cyclic, heterocyclic, or heteroaryl ring optionally substituted with up to three independently selected optional R 20 groups.
11 . A compound of formula (I) and salts, solvates and tautomers thereof according to claim 3 , wherein X 1 is selected from C(═O) and NHC(═O).
12 . A compound of formula (I) and salts, solvates and tautomers thereof according to claim 3 , wherein X 2 is selected from O and CH 2 , or is absent.
13 . A compound of formula (I) and salts, solvates and tautomers thereof according to claim 3 , wherein L is selected from —(CH 2 ) m —(CH 2 ) z —(CH 2 ) n —,
and
R 29 , R 30 and R 31 are each independently selected from H and R 20 .
14 . A compound of formula (I) and salts, solvates and tautomers thereof according to claim 3 , wherein L is —(CH 2 ) 3 —.
15 . A pharmaceutical composition comprising a compound of formula (I) and salts, solvates and tautomers thereof of claim 3 and a pharmaceutically acceptable carrier or diluent.
16 . A method of treatment of a patient suffering from a proliferative disease, comprising administering to said patient a therapeutically effective amount of a compound of formula (I) and salts, solvates and tautomers thereof of claim 3 .
17 . A method of treatment according to claim 16 , wherein the proliferative disease is selected from bladder cancer, bone cancer, bowel cancer, brain cancer, breast cancer, cervical cancer, colon cancer, head and neck cancer, leukemia, liver cancer, lung cancer, lymphoma, melanoma, oesophageal cancer, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, renal cancer, retinoblastoma, sarcoma, skin cancer, stomach cancer, testicular cancer, thyroid cancer and uterine cancer.