# US 10,308,631 B2 · Selective anti-cancer compounds

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- Number: US 10,308,631 B2
- Document ID: US10308631B2
- Status: Granted
- Kind: B2
- Application number: 15/580,978
- Filed: 2016-06-10
- Published: 2018-06-28
- Granted: 2019-06-04
- Earliest claimed: 2015-06-12
- Assignees: National University of Singapore
- Applicants: National University of Singapore
- Inventors: Sang Hyun Lee; Brian William Dymock; Mayumi Kitagawa; Cheng Shang See
- Web page: https://patentgrep.com/patent/US10308631B2

## CPC

- C07D 401/06: linked by a carbon chain containing only aliphatic carbon atoms
- A61K 31/4709: Non-condensed quinolines and containing further heterocyclic rings
- A61K 31/4725: containing further heterocyclic rings
- A61P 35/00: Antineoplastic agents
- A61P 39/00: General protective or antinoxious agents
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 401/14: containing three or more hetero rings
- C07D 405/14: containing three or more hetero rings
- C07D 471/04: Ortho-condensed systems
- C07D 495/14: Ortho-condensed systems
- C07D 519/00: Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

A compound of formula I, wherein the compound of formula I has the structure: wherein R1 to R5, Y, L, Z and X1 to X7 have meanings given in the description, said compounds having utility in the treatment of hyperproliferative disease.

## Claims

### Claim 1

A compound of formula I,
wherein,
Z represents N or CR4;
L represents C(R6a)═C(R6b);
X1 to X5 are independently N or CR8, provided that at least one of X1 and X2 is N;
X6 and X7 are independently N or CR9;
Y represents N or CR10;
R1 represents H, —C(O)R11a or —C(S)R11b;
R2 to R4, R8 and R10, at each occurrence, independently represents:
(a) H;
(b) halo;
(c) CN;
(d) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl (which latter three groups are unsubstituted or substituted by one or more substituents selected from halo, nitro, CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl (which latter three groups are unsubstituted or substituted by one or more substituents selected from OH, ═O, halo, C1-4 alkyl and C1-4 alkoxy), Cy1 (which Cy1 group is unsubstituted or is substituted by one or more substituents selected from halo, nitro, CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl (which latter three groups are optionally substituted by one or more substituents selected from OH, ═O, halo, C1-4 alkyl and C1-4 alkoxy), OR12a, S(O)qR12b, S(O)2NR12cR12d, NR12eS(O)2R12f, NR12gR12h, aryl and Het1);
(e) Cy2 (which Cy2 group is unsubstituted or is substituted by one or more substituents selected from halo, nitro, CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl (which latter three groups are optionally substituted by one or more substituents selected from OH, ═O, halo, C1-4 alkyl and C1-4 alkoxy), OR13a, S(O)qR13b, S(O)2NR13cR13d, NR13eS(O)2R13f, NR13gR13h, aryl and Het2),
(f) Heta (which Heta group is unsubstituted or substituted by one or more substituents selected from halo, nitro, CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl (which latter three groups are optionally substituted by one or more substituents selected from OH, ═O, halo, C1-4 alkyl and C1-4 alkoxy), OR14a, S(O)qR14b, S(O)2NR14cR14d, NR14eS(O)2R14f, NR14gR14h, aryl and Het3);
(g) OR15a;
(h) S(O)qR15b;
(i) S(O)2NR15cR15d;
(j) NR15eS(O)2R15f;
(k) NR15gR15h,
where R3, R4 and each R8, when present, may also, in addition, independently represent nitro;
R5 and R9, at each occurrence, independently represent H, halo, CN, nitro, C1-4 alkyl (which latter group is unsubstituted or substituted by one or more substituents selected from halo, nitro, CN, OR16a and NR16gR16h), OR17s, S(O)q(O)R17b, S(O)2NR17cR17d, NR17eS(O)2R17f or NR17gR17h;
R6a represents H, CN or —C(O)NR18aR18b;
R6b, independently at each occurrence, represents H, CN or C1-4 alkyl, which latter group is unsubstituted or substituted with halo or OR19;
R7a and R7b represent H or C1-4 alkyl, which latter group is unsubstituted or substituted with halo or OR20;
R11a and R11b, when present, represent,
(a) H;
(b) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl (which latter three groups are unsubstituted or substituted by one or more substituents selected from halo, nitro, ═O, CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl (which latter three groups are unsubstituted or substituted by one or more substituents selected from OH, ═O, halo, C1-4 alkyl and C1-4 alkoxy), OR21a, S(O)qR21b, S(O)2NR21cR21d, NR21eS(O)2R21f, NR21gR21h, aryl, Cy3 (which Cy3 group is unsubstituted or is substituted by one or more substituents selected from halo, nitro, CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl (which latter three groups are optionally substituted by one or more substituents selected from OH, ═O, halo, C1-4 alkyl and C1-4 alkoxy), OR22a, S(O)qR22b, S(O)2NR22cR22d, NR22eS(O)2R22f, NR22gR22h, aryl and Het4) and Het5);
(c) C3-10 cycloalkyl, C4-10 cycloalkenyl (which latter two groups are optionally substituted by one or more substituents selected from halo, OH, ═O, C1-6 alkyl and C1-6 alkoxy);
(d) Hetb (which Hetb group is unsubstituted or substituted by one or more substituents selected from halo, nitro, CN, C(O)OC1-4 alkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl (which latter three groups are optionally substituted by one or more substituents selected from Het8, OH, ═O, halo, C1-4 alkyl and C1-4 alkoxy), OR23a, S(O)qR23b, S(O)2NR23cR23d, NR23eS(O)2R23f, NR23gR23h, aryl and Het6),
(e) OR24a;
(f) NR24bS(O)2R24c;
(g) NR24dR24e;
R12a to R12h, R13a to R13h, R14a to R14h, R15a to R15h, R16a to R16h, R17a to R17h, R18a, R18b, R19, R20, R21a to R21h, R22a to R22h, R23a to R23h and R24a to R24e independently represent, at each occurrence, H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl (which latter three groups are optionally substituted by one or more substituents selected from halo, nitro, ═O, C(O)OC1-4 alkyl, CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl (which latter three groups are optionally substituted by one or more substituents selected from OH, ═O, halo, C1-4 alkyl and C1-4 alkoxy), OR25a, S(O)qR25b, S(O)2NR25cR25d, NR25eS(O)2R25f, NR25gR25h, aryl and Het7), C3-10 cycloalkyl, or C4-10 cycloalkenyl (which latter two groups are optionally substituted by one or more substituents selected from halo, OH, ═O, C1-6 alkyl and C1-6 alkoxy) or Hetc, or
R12-17c and R12-17d, R12-17g and R12-17h, R21-23c and R21-23d, R21-23g and R21-23h, R24b and R24c, and R24d and R24e may represent, together with the nitrogen atom to which they are attached, a 3- to 10-membered heterocyclic ring that may be aromatic, fully saturated or partially unsaturated and which may additionally contain one or more heteroatoms selected from O, S and N, which heterocyclic ring is optionally substituted by one or more substituents selected from halo, nitro, CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl (which latter three groups are optionally substituted by one or more substituents selected from OH, ═O, halo, C1-4 alkyl and C1-4 alkoxy);
Het1 to Het8 and Heta to Hetc independently represent a 4- to 14-membered heterocyclic groups containing one or more heteroatoms selected from O, S and N, which heterocyclic groups may comprise one, two or three rings and may be substituted by one or more substituents selected from ═O, halo, C1-6 alkyl, which latter group is optionally substituted by one or more substituents selected from halo, —OR26a, —NR26bR26c, —C(O)OR26d and —C(O)NR26eR26f;
Cy1 to Cy3, at each occurrence, independently represents a 3- to 10-membered aromatic, fully saturated or partially unsaturated carbocyclic ring;
R25a to R25h and R26a to R26f independently represent at each occurrence, H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl which latter three groups are optionally substituted by one or more substituents selected from halo, nitro, CN, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl (which latter three groups are optionally substituted by one or more substituents selected from OH, ═O, halo, C1-4 alkyl and C1-4 alkoxy), C3-6 cycloalkyl, or C4-6 cycloalkenyl (which latter two groups are optionally substituted by one or more substituents selected from halo, OH, ═O, C1-4 alkyl and C1-4 alkoxy),
q represents 0, 1 or 2, or
a pharmaceutically acceptable salt or solvate thereof.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein:
(a) X1 to X3 are independently N or CR8, X4 and X5 are independently CR8, and
X6 and X7 are independently CR9; and/or
(b) Y represents CR10 and/or Z represents CR4; and/or
(c) R1 represents H, or —C(O)R11a.

### Claim 3 (depends on 1)

The compound according to claim 1, wherein:
(a) R2 represents:
(i) H;
(ii) Br, Cl, F;
(iii) C1-4 alkyl which is unsubstituted or substituted by one or more substituents selected from halo, nitro, CN, C1-3 alkyl (which latter group is unsubstituted or substituted by one or more substituents selected from OH, ═O, halo, C1-4 alkyl and C1-4 alkoxy), Cy1 (which Cy1 group is unsubstituted or is substituted by one or more substituents selected from halo, CN, C1-3 alkyl (which latter group is unsubstituted or substituted by one or more substituents selected from OH, ═O, halo, C1-4 alkyl and C1-4 alkoxy), OR12a, NR12gR12h aryl and Het1);
(iv) Cy2 (which Cy2 group is unsubstituted or is substituted by one or more substituents selected from halo, CN, C1-3 alkyl (which latter group is optionally substituted by one or more substituents selected from OH, ═O, halo, C1-4 alkyl and C1-4 alkoxy), NR13gR13h aryl and Het2);
(v) Heta (which Heta group is unsubstituted or substituted by one or more substituents selected from halo, nitro, CN, C1-3 alkyl (which latter group is optionally substituted by one or more substituents selected from OH, ═O, halo, C1-4 alkyl and C1-4 alkoxy), OR14a, NR14gR14h, aryl and Het3);
(vi) OR15a; or
(vii) NR15gR15h; and/or
(b) R3, R4, R8 and R10, at each occurrence, independently represents:
(i) H;
(ii) Br, Cl, F;
(iii) CN;
(iv) C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl (which latter three groups are unsubstituted or substituted by one or more substituents selected from halo, nitro, CN, C1-3 alkyl (which latter group is unsubstituted or substituted by one or more substituents selected from OH, ═O, halo, C1-4 alkyl and C1-4 alkoxy), Cy1 (which Cy1 group is unsubstituted or is substituted by one or more substituents selected from halo, CN, C1-3 alkyl (which latter group is unsubstituted or substituted by one or more substituents selected from OH, ═O, halo, C1-4 alkyl and C1-4 alkoxy)), OR12a, NR12gR12h, aryl and Het1),
(v) Cy2 (which Cy2 group is unsubstituted or is substituted by one or more substituents selected from halo, CN, C1-3 alkyl (which latter group is unsubstituted or substituted by one or more substituents selected from OH, ═O, halo, C1-4 alkyl and C1-4 alkoxy), OR13a, NR13gR13h, aryl and Het2);
(vi) Heta (which Heta group is unsubstituted or substituted by one or more substituents selected from halo, nitro, CN, C1-3 alkyl (which latter group is optionally substituted by one or more substituents selected from OH, ═O, halo, C1-4 alkyl and C1-4 alkoxy), OR14a, NR14gR14h, aryl and Het3);
(vii) OR15a;
(viii) NR15gR15h; or
(ix) nitro; and/or
(c) R5 and R9, at each occurrence, independently represent H, Br, Cl, F, CN, nitro, C1-4 alkyl (which latter group is unsubstituted or substituted by one or more substituents selected from Br, Cl, F, OR16a and NR16gR16h), OR17a or NR17gR17h; and/or
(d) R6a represents H or CN; and
R6b, independently at each occurrence, represents H or C1-4 alkyl, which latter group is unsubstituted or substituted with F or OR19; and/or
(e) R11a represents,
(i) C1-5 alkyl which group is unsubstituted or substituted by one or more substituents selected from halo, ═O, CN, C1-3 alkyl (which latter group is unsubstituted or substituted by one or more substituents selected from OH, ═O, halo, C1-4 alkyl and C1-4 alkoxy), OR21a, NR21gR21h, aryl, Cy3 (which Cy3 group is unsubstituted or is substituted by one or more substituents selected from halo, nitro, CN, C1-3 alkyl (which latter group is unsubstituted or substituted by one or more substituents selected from OH, ═O, halo, C1-4 alkyl and C1-4 alkoxy), OR22a, NR22gR22h, aryl and Het4) and Het5;
(ii) C3-6 cycloalkyl which latter group is unsubstituted or substituted by one or more substituents selected from halo, OH, ═O, C1-4 alkyl and C1-4 alkoxy;
(iii) Hetb (which Hetb group is unsubstituted or substituted by one or more substituents selected from halo, nitro, CN, C(O)OC1-4 alkyl, C1-5 alkyl, (which latter group is unsubstituted or substituted by one or more substituents selected from Het8, OH, ═O, halo, C1-4 alkyl and C1-4 alkoxy), OR23a, NR23gR23h aryl and Het6);
(iv) OR24a; or
(v) NR24dR24e.

### Claim 4 (depends on 1)

The compound according to claim 1, wherein:
(a) R12a to R12h, R13a to R13h, R14a to R14h, R15a to R15h, R16a to R16h, R17a to R17h, R18a, R18b, R19, R20, R21a to R21h, R22a to R22h, R23a to R23h and R24a to R24e independently represent, at each occurrence, H, C1-4 alkyl, C2-4 alkenyl (which latter two groups are optionally substituted by one or more substituents selected from halo, nitro, ═O, C(O)OC1-4 alkyl, CN, C1-3 alkyl, C5-6 cycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from OH, ═O, halo, C1-4 alkyl and C1-4 alkoxy), OR25a, NR25gR25h, aryl and Het7), C4-6 cycloalkyl, or C5-6 cycloalkenyl (which latter two groups are optionally substituted by one or more substituents selected from halo, OH, ═O, C1-4 alkyl and C1-4 alkoxy) or Het1, or
R12-17c and R12-17d, R12-17g and R12-17h, R21-23c and R21-23d, R21-23g, and R21-23h, R24b and R24c, and R24d and R24e may represent, together with the nitrogen atom to which they are attached, a 3- to 6-membered heterocyclic ring that may be aromatic, fully saturated or partially unsaturated and which may additionally contain one or more heteroatoms selected from O, S and N, which heterocyclic ring is optionally substituted by one or more substituents selected from halo, nitro, CN, C1-3 alkyl (which latter group is unsubstituted or substituted by one or more substituents selected from OH, ═O, halo, C1-4 alkyl and C1-4 alkoxy); and/or
(b) Het1 to Het8 and Heta to Hetc independently represent a 4- to 10-membered heterocyclic group containing one or more heteroatoms selected from O, S and N, which heterocyclic groups may comprise one, two or three rings and may be substituted by one or more substituents selected from ═O, halo, C1-3 alkyl, which latter group is optionally substituted by one or more substituents selected from halo, —OR26a, —NR26bR26c,—C(O)OR26d and —C(O)NR26eR26f; and/or
(c) Cy1 to Cy3, at each occurrence, independently represent a 4- to 6-membered aromatic, fully saturated or partially unsaturated carbocyclic ring; and/or
(d) R25a to R25h and R26a to R26f independently represent at each occurrence, H, C1-4 alkyl, which latter group is optionally substituted by one or more substituents selected from halo, nitro, CN, C1-4 alkyl, (which latter group is unsubstituted or substituted by one or more substituents selected from OH, ═O, halo, C1-4 alkyl and C1-4 alkoxy), C3-6 cycloalkyl (which latter group is unsubstituted or substituted by one or more substituents selected from halo, OH, ═O, C1-4 alkyl and C1-4 alkoxy).

### Claim 5 (depends on 1)

The compound according to claim 1, wherein:
(a) L represents —C(CN)═C(H)—, Z represents CR4, and the compound of formula I is represented as a compound of formula Ia,
provided that no more than three of X1 to X7 represent N; and/or
(b) L represents —C(CN)═C(H)—, Z represents CR4, X1 represents N, and the compound of formula I may be represented as a compound of formula Ib,
provided that no more than three of X2 to X7 represent N; and/or
(c) L represents —C(CN)═C(H)—, X1 represents N, Z represents CR4, and X2 to X5 each represent CR8, and the compound of formula I may be represented as a compound of formula Ic,
and/or
(d) L represents —C(CN)═C(H)—, X1 represents N, X2 to X5 each represent CR8, Z represents CR4, and Y represents CR10, and the compound of formula I may be represented as a compound of formula Id,
and/or
(e) L represents —C(CN)═C(H)—, X1 represents N, X2 to X5 each represent CR8, Z represents CR4, Y represents CR10 and R5 represents H, and the compound of formula I may be represented as a compound of formula Ie,

### Claim 6 (depends on 1)

The compound according to claim 1, wherein when L represents —C(R6a)═C(R6b)—, the C═C double bond is in the E- or Z-configuration.

### Claim 7 (depends on 1)

The compound according to claim 1, wherein:
(a) R2 represents:
(i) H;
(ii) Br, Cl, F;
(iii) C1-4 alkyl which is unsubstituted or substituted by one or more substituents selected from F, C1-3 alkyl (which latter group is unsubstituted or substituted by one or more substituents selected from OH, ═O, F, C1-4 alkyl and C1-4 alkoxy), OR12a and NR12gR12h);
(iv) OR15a; or
(v) NR15gR15h); and/or
(b) R3, R4, R8 and R10, at each occurrence, independently represents H, Br, Cl, F, CN, C1-4 alkyl (which latter groups is unsubstituted or substituted by one or more substituents selected from F, C1-3 alkyl (which latter group is unsubstituted or substituted by one or more substituents selected from OH, ═O, halo, C1-4 alkyl and C1-4 alkoxy), OR12a and NR12gR12h), OR15a, NR15gR15h nitro); and/or
(c) R11a represents, C1-5 alkyl which group is unsubstituted or substituted by one or more substituents selected from F, ═O, C1-3 alkyl (which latter group is unsubstituted or substituted by one or more substituents selected from OH, ═O, F, C1-4 alkyl and C1-4 alkoxy), OR21a, NR21gR21h, Hetb (which Hetb group is unsubstituted or substituted by one or more substituents selected from Cl, Br, F, C(O)OC1-4 alkyl, C1-5 alkyl, (which latter group is unsubstituted or substituted by one or more substituents selected from Het8, OH, ═O, Cl, F, C1-4 alkyl and C1-4 alkoxy), OR23a, NR23gR23h), or OR24a; and/or
(d) R12a to R12h, R13a to R13h, R14a to R14h, R15a to R15h, R16a to R16h, R17a to R17h, R18a, R18b, R19, R20, R21a to R21h, R22a to R22h, R23a to R23h and R24a to R24e independently represent, at each occurrence, H, C1-4 alkyl (which latter group is unsubstituted or substituted by one or more substituents selected from Cl, F, ═O, C(O)OC1-4 alkyl, C1-3 alkyl, C5-6 cycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from OH, ═O, Cl, F, C1-4 alkyl and C1-4 alkoxy), OR25a, NR25gR25h aryl and Het7), C4-6 cycloalkyl (which latter group is unsubstituted or substituted by one or more substituents selected from Cl, F, OH, ═O, C1-4 alkyl and C1-4 alkoxy) or Hetc, or
R12-17c and R12-17d, R12-17g and R12-17h, R21-23c and R21-23d, R21-23g and R21-23h, R24b and R24c, and R24d and R24e may represent, together with the nitrogen atom to which they are attached, a 5- to 6-membered heterocyclic ring that may be aromatic, fully saturated or partially unsaturated and which may additionally contain one or more heteroatoms selected from O, S and N, which heterocyclic ring is unsubstituted or substituted by one or more substituents selected from halo, nitro, CN, C1-3 alkyl (which latter group is unsubstituted or substituted by one or more substituents selected from OH, ═O, Cl, F, C1-4 alkyl and C1-4 alkoxy); and/or
(e) Het1 to Het1 and Heta to Hetc independently represent a 5- to 8-membered heterocyclic group containing one or more heteroatoms selected from O, S and N, which heterocyclic groups may comprise one, two or three rings and may be substituted by one or more substituents selected from ═O, Cl, Br, F, C1-3 alkyl, which latter group is optionally substituted by one or more substituents selected from halo, —OR26a, —NR26bR26c, —C(O)OR26d and —C(O)NR26eR26f).

### Claim 8 (depends on 1)

The compound according to claim 1, wherein:
(a) R2 represents Br, Cl or H;
(b) R3, R4, R8 and R10, at each occurrence, each represent H;
(c) R11a represents,
(i) C1-5 alkyl which group is unsubstituted or substituted by one or more substituents selected from Cl, F, ═O, CN, C1-3 alkyl (which latter group is unsubstituted or substituted by one or more substituents selected from OH, ═O, Cl, F, C1-4 alkyl and C1-4 alkoxy), OR21a, NR21gR21h;
(ii) C3-6 cycloalkyl which latter group is unsubstituted or substituted by one or more substituents selected from Cl, F, OH, ═O, C1-4 alkyl and C1-4 alkoxy;
(iii) Hetb (which Hetb group is unsubstituted or substituted by one or more substituents selected from Cl, Br, F, C(O)OC1-4 alkyl, C1-5 alkyl, (which latter group is unsubstituted or substituted by one or more substituents selected from Het1, OH, ═O, Cl, F, C1-4 alkyl and C1-4 alkoxy), OR23a, NR23gR23h);
(iv) OR24a; or
(v) NR24dR24e,
(d) R12a to R12h, R13a to R13h, R14a to R14h, R15a to R15h, R16a to R16h, R17a to R17h, R18a, R18b, R19, R20, R21a to R21h, R22a to R22h, R23a to R23h and R24a to R24e independently represent, at each occurrence, H, C1-3 alkyl (which latter group is unsubstituted or substituted by one or more substituents selected from F, ═O, C(O)OC1-4 alkyl, C1-3 alkyl (which latter group is unsubstituted or substituted by one or more substituents selected from OH, ═O, Cl, F, C1-4 alkyl and C1-4 alkoxy), OR25a, NR25gR25h).

### Claim 9 (depends on 1)

The compound according to claim 1, wherein:
(A) L represents —C(CN)═C(H)—, X1 represents N, X2 to X5 each represent CR8, X6 and X7 each represent CR9, Z represents CR4, Y represents CR10 and R5 represents H, and the compound of formula I may be represented as a compound of formula If,
provided that R4 is not Br or methylenepyrrolidine; and/or
provided that R2 is not Cl, F, or OR15a (where R15a comprises more than one carbon atom) or
NR15gR15h optionally wherein:
(i) R3 represents H; and/or R10 represents H or CH3; and/or R2 represents H, Br or OCH3; and/or R4 represents H or OCH3; and/or
(ii) R1 represents C(O)R11a and R11a represents:
(a) H;
(b) C1-6 alkyl (which group is unsubstituted or substituted by one or more substituents selected from ═O, C1-6 alkyl (which latter group is unsubstituted or substituted by one or more substituents selected from OH, ═O, C1-4 alkyl and C1-4 alkoxy), OR21a, NR21gR21h, aryl, Cy3, and Het5);
(c) C3-10 cycloalkyl (which group is optionally substituted by one or more substituents selected from halo, OH, ═O, C1-6 alkyl and C1-6 alkoxy);
(d) Hetb (which Hetb group is unsubstituted or substituted by one or more substituents selected from halo, nitro, CN, C(O)OC1-4 alkyl, C1-6 alkyl (which latter group is optionally substituted by one or more substituents selected from Het8, or more particularly, OH, ═O, halo, C1-4 alkyl and C1-4 alkoxy), OR23a, NR23gR23h aryl and Het6),
(e) OR24a;
NR24dR24e; and/or
(B) L represents —C(R6a)═C(H)—, X1 represents N, X2, X4 and X5 each represent CR8, X3 represents N or CR8, X6 and X7 each represent CR9, and R5 represents H, and the compound of formula I may be represented as a compound of formula Ig,
provided that when Rha represents CN:
R2 is not F, Br or OCH3; and/or
when Z is CR4, CR4 is not CCH3, optionally wherein:
R3 represents H or methylenepyrrolidinyl;
R2 and R3 independently represent H, OR15a, Cl or C1-6 alkyl (which latter group is unsubstituted or substituted by one or more substituents selected from OR12a, NR12gR12h, aryl and Het1); and/or
R4, when present, represents H or Br.

### Claim 10 (depends on 1)

The compound according to claim 1, wherein the compound of formula I is selected from the list:
(i) (Z)-2-(1H-indol-3-yl)-3-(5-isoquinolyl)prop-2-enenitrile;
(ii) (Z)-3-(5-isoquinolyl)-2-(5-methoxy-1H-indol-3-yl)prop-2-enenitrile;
(iii) 5-[(3aS,4S,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]-N-[3-[(Z)-1-cyano-2-(5-isoquinolyl)vinyl]-1H-indol-5-yl]pentanamide and/or 5-[(3aR,4R,6aS)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]-N-[3-[(Z)-1-cyano-2-(5-isoquinolyl)vinyl]-1H-indol-5-yl]pentanamide;
(iv) (Z)-2-(5-chloro-1H-indol-3-yl)-3-(5-isoquinolyl)prop-2-enenitrile;
(v) (Z)-2-(5-bromo-1H-indol-3-yl)-3-(5-isoquinolyl)prop-2-enenitrile;
(vi) (Z)-3-(5-isoquinolyl)-2-[1-[2-(4-methylpiperazin-1-yl)acetyl]indol-3-yl]prop-2-enenitrile;
(vii) N-[3-[3-[(Z)-1-cyano-2-(5-isoquinolyl)vinyl]indol-1-yl]-3-oxo-propyl]acetamide;
(viii) (Z)-2-[1-[5-[(3aS,4S,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoyl]indol-3-yl]-3-(5-isoquinolyl)prop-2-enenitrile and/or (Z)-2-[1-[5-[(3aR,4R,6aS)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoyl]indol-3-yl]-3-(5-isoquinolyl)prop-2-enenitrile;
(ix) tert-butyl 4-[3-[(Z)-1-cyano-2-(5-isoquinolyl)vinyl]indole-1-carbonyl]piperidine-1-carboxylate;
(x) (Z)-3-(5-isoquinolyl)-2-[1-(piperidine-4-carbonyl)indol-3-yl]prop-2-enenitrile;
(xi) (Z)-3-(5-isoquinolyl)-2-[1-(1-methylpiperidine-4-carbonyl)indol-3-yl]prop-2-enenitrile;
(xii) (Z)-3-(5-isoquinolyl)-2-[1-(1-(3-fluorophenyl)-piperidine-4-carbonyl)indol-3-yl]prop-2-enenitrile;
(xiii) (Z)-3-(5-isoquinolyl)-2-[1-(1-oxazol-4-yl-piperidine-4-carbonyl)indol-3-yl]prop-2-enenitrile;
(xiv) (Z)-3-(5-isoquinolyl)-2-[1-(1-(2-methoxyacetyl)-piperidine-4-carbonyl)indol-3-yl]prop-2-enenitrile;
(xv) (Z)-2-(6-bromo-1H-indol-3-yl)-3-(5-isoquinolyl)prop-2-enenitrile;
(xvi) (Z)-2-(6-chloro-1H-indol-3-yl)-3-(5-isoquinolyl)prop-2-enenitrile;
(xvii) (Z)-3-(5-isoquinolyl)-2-(6-methoxy-1H-indol-3-yl)prop-2-enenitrile;
(xviii) (Z)-2-(5,6-dimethoxy-1H-indol-3-yl)-3-(5-isoquinolyl)prop-2-enenitrile;
(xix) (Z)-3-(5-isoquinolyl)-2-(7-methyl-1H-indol-3-yl)prop-2-enenitrile;
(xx) 3-[(Z)-1-cyano-2-(5-isoquinolyl)vinyl]-N-methyl-1H-indole-7-carboxamide;
(xxi) 5-chloro-3-[(Z)-1-cyano-2-(5-isoquinolyl)vinyl]-N-methyl-1H-indole-7-carboxamide;
(xiii) (Z)-2-(5,7-dimethoxy-1H-indol-3-yl)-3-(5-isoquinolyl)prop-2-enenitrile;
(xxiii) (Z)-3-(5-isoquinolyl)-2-(7-methoxy-1H-indol-3-yl)prop-2-enenitrile;
(xxiv)N-[3-[(Z)-1-cyano-2-(5-isoquinolyl)vinyl]-1H-indol-7-yl]acetamide;
(xxv) (Z)-2-(7-chloro-1H-indol-3-yl)-3-(5-isoquinolyl)prop-2-enenitrile;
(xxvi) (Z)-2-(7-fluoro-1H-indol-3-yl)-3-(5-isoquinolyl)prop-2-enenitrile;
(xxvii) (Z)-2-[7-(2-fluorophenyl)-1H-indol-3-yl]-3-(5-isoquinolyl)prop-2-enenitrile;
(xxviii)(Z)-2-(1H-indol-3-yl)-3-(5-isoquinolyl)but-2-enenitrile;
(xxix) (Z)-3-(1H-indol-3-yl)-2-(5-isoquinolyl)prop-2-enenitrile;
(xxx) tert-butyl N-[3-[3-[(Z)-1-cyano-2-(5-isoquinolyl)vinyl]indol-1-yl]-3-oxopropyl-]carbamate;
(xxxi) (Z)-2-[1-(3-amino-1-oxo-propyl)indol-3-yl]-3-(5-isoquinolyl)prop-2-enenitrile;
(xxxii) tert-butyl N-[5-[3-[(Z)-1-cyano-2-(5-isoquinolyl)vinyl]indol-1-yl]-5-oxo-pentyl]carbamate;
(xxxiii) (Z)-2-[1-(5-amino-1-oxo-pentyl)indol-3-yl]-3-(5-isoquinolyl)prop-2-enenitrile;
(xxxiv) tert-butyl N-[6-[3-[(Z)-1-cyano-2-(5-isoquinolyl)vinyl]indol-1-yl]-6-oxo-hexyl]carbamate;
(xxxv) (Z)-2-(1-(6-aminohexanoyl)-1H-indol-3-yl)-3-(isoquinolin-5-yl)acrylonitrile;
(xxxvi) (Z)-2-(1H-indazol-3-yl)-3-(5-isoquinolyl)prop-2-enenitrile;
(xxxvii) (Z)-3-(5-isoquinolyl)-2-(4-methyl-1H-indol-3-yl)prop-2-enenitrile;
(xxxviii) (Z)-3-(5-isoquinolyl)-2-(4-methoxy-1H-indol-3-yl)prop-2-enenitrile;
(xxxlx) (Z)-2-(4,5-dimethoxy-1H-indol-3-yl)-3-(5-isoquinolyl)prop-2-enenitrile;
(xl) (Z)-2-(4-chloro-1H-indol-3-yl)-3-(5-isoquinolyl)prop-2-enenitrile;
(xli) 4-chloro-3-[(Z)-1-cyano-2-(5-isoquinolyl)vinyl]-1H-indole-5-carboxamide;
(xlii) (Z)-2-(1H-indol-3-yl)-3-(5-quinolyl)prop-2-enenitrile;
(xliii) 5-((E)-2-(1H-indol-3-yl)vinyl)isoquinoline;
(xliv) 4-((E)-2-(1H-indol-3-yl)vinyl)-2,7-naphthyridine;
(xlv) 5-((E)-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)vinyl)isoquinoline;
(xlvi) 4-((E)-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)vinyl)-2,7-naphthyridine;
(xlvii) [3-[(E)-2-(5-isoquinolyl)vinyl]-1H-indol-5-yl]azinic acid;
(xlviii) (Z)-2-(1H-indol-3-yl)-3-(2,7-naphthyridin-4-yl)prop-2-enenitrile;
(xlix) (Z)-3-(5-isoquinolyl)-2-[5-(3-pyrrolidin-1-ylpropoxy)-1H-indol-3-yl]prop-2-enenitrile;
(l) (Z)-3-(5-isoquinolyl)-2-[5-(2-methoxyethoxy)-1H-indol-3-yl]prop-2-enenitrile;
(li) (Z)-2-(6-chloro-1H-indol-3-yl)-3-(5-isoquinolyl)prop-2-enenitrile;
(lii) (Z)-2-(7-bromo-1H-indol-3-yl)-3-(5-isoquinolyl)prop-2-enenitrile;
(liii) tert-butyl N-[3-[3-[(Z)-1-cyano-2-(5-isoquinolyl)vinyl]indol-1-yl]-3-oxo-propyl]carbamate;
(liv) (Z)-2-[1-(3-aminopropanoyl)indol-3-yl]-3-(5-isoquinolyl)prop-2-enenitrile;
(lv) 5-[(3aS,4S,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]-N-[3-[3-[(Z)-1-cyano-2-(5-isoquinolyl)vinyl]indol-1-yl]-3-oxo-propyl]pentanamide and/or 5-[(3aR,4R,6aS)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]-N-[3-[3-[(Z)-1-cyano-2-(5-isoquinolyl)vinyl]indol-1-yl]-3-oxo-propyl]pentanamide;
(lvi) (Z)-2-(5-(2-(1,3-dioxolan-2-yl)ethoxy)-1H-indol-3-yl)-3-(isoquinolin-5-yl)acrylonitrile;
(lvii) (Z)-3-(isoquinolin-5-yl)-2-(1-(1-(5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanoyl)piperidine-4-carbonyl)-1H-indol-3-yl)acrylonitrile;
(lviii) (Z)-2-(1-(2-(2-methoxyethoxy)acetyl)-1H-indol-3-yl)-3-(isoquinolin-5-yl)acrylonitrile;
(lix) (Z)-3-(isoquinolin-5-yl)-2-(6-((pyrrolidin-1-yl)methyl)-1H-indol-3-yl)acrylonitrile;
(lx) (Z)-3-(isoquinolin-5-yl)-2-(5-((pyrrolidin-1-yl)methyl)-1H-indol-3-yl)acrylonitrile;
(lxi) (Z)-3-(isoquinolin-5-yl)-2-(7-((pyrrolidin-1-yl)methyl)-1H-indol-3-yl)acrylonitrile; and
(lxii) (Z)-2-(1H-indazol-3-yl)-3-(isoquinolin-5-yl)acrylonitrile.

### Claim 11 (depends on 10)

The compound according to claim 10, wherein the compound of formula I is selected from the list:
(i) (Z)-2-(1H-indol-3-yl)-3-(5-isoquinolyl)prop-2-enenitrile;
(ii) (Z)-3-(5-isoquinolyl)-2-(5-methoxy-1H-indol-3-yl)prop-2-enenitrile;
(iii) 5-[(3aS,4S,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]-N-[3-[(Z)-1-cyano-2-(5-isoquinolyl)vinyl]-1H-indol-5-yl]pentanamide and/or 5-[(3aR,4R,6aS)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]-N-[3-[(Z)-1-cyano-2-(5-isoquinolyl)vinyl]-1H-indol-5-yl]pentanamide;
(iv) (Z)-2-(5-chloro-1H-indol-3-yl)-3-(5-isoquinolyl)prop-2-enenitrile;
(v) (Z)-2-(5-bromo-1H-indol-3-yl)-3-(5-isoquinolyl)prop-2-enenitrile;
(vi) (Z)-3-(5-isoquinolyl)-2-[1-[2-(4-methylpiperazin-1-yl)acetyl]indol-3-yl]prop-2-enenitrile;
(vii) N-[3-[3-[(Z)-1-cyano-2-(5-isoquinolyl)vinyl]indol-1-yl]-3-oxo-propyl]acetamide;
(viii) tert-butyl 4-[3-[(Z)-1-cyano-2-(5-isoquinolyl)vinyl]indole-1-carbonyl]piperidine-1-carboxylate;
(ix) (Z)-3-(5-isoquinolyl)-2-[1-(piperidine-4-carbonyl)indol-3-yl]prop-2-enenitrile;
(x) (Z)-3-(isoquinolin-5-yl)-2-(7-methoxy-1H-indol-3-yl)acrylonitrile;
(xi) (Z)-3-(isoquinolin-5-yl)-2-(6-methoxy-1H-indol-3-yl)acrylonitrile;
(xii) (Z)-tert-butyl (3-(3-(1-cyano-2-(isoquinolin-5-yl)vinyl)-1H-indol-1-yl)-3-oxopropyl)carbamate;
(xiii) N-(3-(3-((Z)-1-cyano-2-(isoquinolin-5-yl)vinyl)-1H-indol-1-yl)-3-oxopropyl)-5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamide;
(xiv) N-(3-((Z)-1-cyano-2-(isoquinolin-5-yl)vinyl)-1H-indol-5-yl)acetamide
(xv) (Z)-2-(6-bromo-1H-indol-3-yl)-3-(5-isoquinolyl)prop-2-enenitrile;
(xvi) (Z)-2-(7-bromo-1H-indol-3-yl)-3-(5-isoquinolyl)prop-2-enenitrile;
(xvii) (Z)-2-[1-(3-aminopropanoyl)indol-3-yl]-3-(5-isoquinolyl)prop-2-enenitrile;
(xviii) (Z)-3-(isoquinolin-5-yl)-2-(1-(1-(5-((3 aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanoyl)piperidine-4-carbonyl)-1H-indol-3-yl)acrylonitrile; and
(xix) (Z)-2-(1-(2-(2-methoxyethoxy)acetyl)-1H-indol-3-yl)-3-(isoquinolin-5-yl)acrylonitrile.

### Claim 12 (depends on 10)

The compound according to claim 10, wherein the compound of formula I is (Z)-2-(1H-indol-3-yl)-3-(5-quinolyl)prop-2-enenitrile, (Z)-tert-butyl 4-(3-(1-cyano-2-(isoquinolin-5-yl)vinyl)-1H-indole-1-carbonyl)piperidine-1-carboxylate and (Z)-2-[1-[5-[(3 aR,4R,6aS)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoyl]indol-3-yl]-3-(5-isoquinolyl)prop-2-enenitrile.

### Claim 13 (depends on 10)

The compound according to claim 10, wherein the compound of formula I is selected from the list:
(a) 5-((E)-2-(1H-indol-3-yl)vinyl)isoquinoline;
(b) 4-((E)-2-(1H-indol-3-yl)vinyl)-2,7-naphthyridine;
(c) 5-((E)-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)vinyl)isoquinoline;
(d) 4-((E)-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)vinyl)-2,7-naphthyridine;
(e) (Z)-2-(1H-indol-3-yl)-3-(2,7-naphthyridin-4-yl)prop-2-enenitrile;
(f) (Z)-3-(5-isoquinolyl)-2-[5-(3-pyrrolidin-1-ylpropoxy)-1H-indol-3-yl]prop-2-enenitrile;
(g) (Z)-3-(5-isoquinolyl)-2-[5-(2-methoxyethoxy)-1H-indol-3-yl]prop-2-enenitrile;
(h) (Z)-2-(5-(2-(1,3-dioxolan-2-yl)ethoxy)-1H-indol-3-yl)-3-(isoquinolin-5-yl)acrylonitrile;
(i) (Z)-3-(isoquinolin-5-yl)-2-(6-((pyrrolidin-1-yl)methyl)-1H-indol-3-yl)acrylonitrile;
(j) (Z)-3-(isoquinolin-5-yl)-2-(5-((pyrrolidin-1-yl)methyl)-1H-indol-3-yl)acrylonitrile;
(k) (Z)-3-(isoquinolin-5-yl)-2-(7-((pyrrolidin-1-yl)methyl)-1H-indol-3-yl)acrylonitrile; and
(l) (Z)-2-(1H-indazol-3-yl)-3-(isoquinolin-5-yl)acrylonitrile.

### Claim 14 (depends on 1)

A pharmaceutical formulation including a compound of formula I, as defined in claim 1, in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier.

### Claim 15 (depends on 1)

A compound of formula I, as defined in claim 1, for use in medicine.

### Claim 16 (depends on 1)

A combination product comprising:
(a)
(A) a compound of formula I, as defined in claim 1, and
(B) an anti-autophagy and/or chemoprotective agent,
wherein each of components (A) and (B) is formulated in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier; or
(b)
(I) a compound of formula I, as defined in claim 1, and
(II) an antimitotic agent,
wherein each of components (I) and (II) is formulated in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier.

### Claim 17 (depends on 1)

A method of treatment of a cancer, which method comprises the administration of an effective amount of a compound of formula I, as defined in claim 1 to a patient having said cancer.

### Claim 18 (depends on 1)

A method of treatment of a cancer, which method comprises the administration of an effective amount of a compound of formula I, as defined in claim 1, and an anti-autophagy and/or chemoprotective agent to a patient having said cancer.

### Claim 19 (depends on 16)

A method of treatment of a cancer, which method comprises the administration of an effective amount of a combination product as defined in claim 16 (a) to a patient having said cancer.

### Claim 20 (depends on 16)

A method of treatment of a cancer, which method comprises the administration of an effective amount of a combination product as defined in claim 16 (b) to a patient having said cancer.