Anti-tumour polycyclic carboxamides

A process for the preparation of a compound having the formula:

• in which positional numbering, where mentioned, refers to the system illustrated above, and one or more Z are attached to a ring carbon or carbons at any of positions 6 to 10, and in which:
• Q is O or S;
• Y is:
• i) hydrogen;
• ii) C1-C6 alkyl;
• or
• iii)-(CH2)nX(CH2)pU;
• the indices n and p are independently integers from 0 to 6;
• X is:
• a) CH2;
• b) C═O;
• c) CH═CH;
• d) O;
• e) S;
• f) NR;
• or
• g) an optionally substituted fully saturated, or partially unsaturated, or aromatic carbocycle or heterocycle;
• U is:
• a) hydrogen,
• b) CF3;
• c) halo;
• d) NR4R5;
• e) cyano;
• f) C(═O)NR4R5;
• g) OR4;
• h) CO2R5;
• i) G;
• j) NR4G;
• k) OG;
• G is an optionally substituted fully saturated, or partially unsaturated, or aromatic carbocycle or heterocycle;
• Z is:
• i) hydrogen;
• ii) halo;
• iii) OH;
• iv) CO2H;
• v) CO2R4;
• vi) SO2R4;
• vii) NR4R5;
• viii) nitro;
• ix) cyano;
• x) C1-C6 alkyl;
• xi) C1-C6 haloalkyl;
• xii) C1-C6 alkoxy;
• xiii) C1-C6 haloalkoxy;
• xiv) C1-C6 aminoalkyl;
• xv) C1-C6 aminoalkoxy;
• xvi) an aza functionality replacing a ring CH functionality;
• or
• xvii) a carbon or carbon/nitrogen framework bridging the 6-7, 7-8 or 8-9 positions so as to form an additional fused 5 to 6-membered carbocycle or heterocycle ring;
• R4 and R5 are each independently hydrogen, optionally substituted C1-C4 alkyl, or R4 and R5 can be taken together with a nitrogen atom to form an optionally substituted, saturated or unsaturated heterocyclic ring;
• or
• a pharmaceutically acceptable salt thereof, comprising:
• reacting a compound having the formula:
• with a compound having the formula YNH2, wherein Q, Z, and Y are the same as defined herein above.

A compound of the formula II or III

• in which one or more W and one or more Z in formula II, and one or more Z and C(═O) NR in formula III are attached to a ring carbon or carbons at any of positions 3, 4 and 6 to 10 and in which:
• Q is O or S;
• W is C(=Q)NR-M-(CH2)mR1, in which
• M is CHJ or G,
• R is H or a substituted or unsubstituted C1-C4 alkyl group,
• J is H or a substituted or unsubstituted C1-C6 alkyl group,
• G is a substituted or unsubstituted fully saturated, or partially unsaturated, or aromatic, carbocycle or heterocycle,
• R1 is C(NR2)NH2, NHC(═NR3)NH2 or NR4R5, in which
• each of R2 and R3 are independently H or a substituted or unsubstituted C1-C4 alkyl group,
• R4 and R5 are independently H or a substituted or unsubstituted C1-C4 alkyl group or R4 and R5 together with the nitrogen atom to which they are attached form a substituted or unsubstituted C1-C4 alkyl group, saturated or unsaturated heterocyclic group, and m is an integer from 0 to 6;
• Y is:
• i) hydrogen;
• ii) C1-C6 alkyl;
• or
• iii) —(CH2)nX(CH2)pU;
• the indices n and p are independently integers from 0 to 6;
• X is:
• a) CH2;
• b) C═O;
• c) CH═CH;
• d) O;
• e) S;
• f) NR;
• or
• g) an optionally substituted fully saturated, or partially unsaturated, or aromatic carbocycle or heterocycle;
• U is:
• a) hydrogen,
• b) CF3;
• c) halo;
• d) NR4R5;
• e) cyano;
• f) C(═O)NR4R5;
• g) OR4;
• h) CO2R5;
• i) G;
• j) NR4G;
• k) OG;
• Z is:
• i) hydrogen;
• ii) halo;
• iii) OH;
• iv) CO2H;
• v) CO2R4;
• vi) SO2R4;
• vii) NR4R5;
• viii) nitro;
• ix) cyano;
• x) C1-C6 alkyl;
• xi) C1-C6 haloalkyl;
• xii) C1-C6 alkoxy;
• xiii) C1-C6 haloalkoxy;
• xiv) C1-C6 aminoalkyl;
• xv) C1-C6 aminoalkoxy;
• xvi) an aza functionality replacing a ring CH functionality;
• or
• xvii) a carbon or carbon/nitrogen framework bridging the 6-7, 7-8 or 8-9 positions so as to form an additional fused 5 to 6-membered carbocycle or heterocycle ring;
• R4 and R5 are each independently hydrogen, substituted or unsubstituted C1-C4 alkyl, or R4 and R5 can be taken together with a nitrogen atom to form an optionally substituted, saturated or unsaturated heterocyclic ring;
• x is an integer from 2 to 4;
• and
• L is a linker group of valency x;
• or
• a pharmaceutically-acceptable salt thereof.

A pharmaceutical or veterinary composition comprising:

• a) a compound of the formula II or III
• in which one or more W and one or more Z in formula II, and one or more Z and C(=Q)NR in formula III are attached to a ring carbon or carbons at any of positions 3, 4 and 6 to 10 and in which:
• Q is O or S;
• W is C(=Q)NR-M-(CH2)mR1, in which
• M is CHJ or G,
• R is H or a substituted or unsubstituted C1-C4 alkyl group,
• J is H or a substituted or unsubstituted C1-C6 alkyl group,
• G is a substituted or unsubstituted fully saturated, or partially unsaturated, or aromatic, carbocycle or heterocycle,
• R1 is C(NR2)NH2, NHC(═NR3)NH2 or NR4R5, in which
• each of R2 and R3 are independently H or a substituted or unsubstituted C1-C4 alkyl group,
• R4 and R5 are independently H or a substituted or unsubstituted C1-C4 alkyl group or R4 and R5 together with the nitrogen atom to which they are attached form a substituted or unsubstituted C1-C4 alkyl group, saturated or unsaturated heterocyclic group, and
• m is an integer from 0 to 6;
• Y is:
• i) hydrogen;
• ii) C1-C6 alkyl;
• or
• iii) —(CH2)nX(CH2)pU;
• the indices n and p are independently integers from 0 to 6;
• X is:
• a) CH2;
• b) C═O;
• c) CH═CH;
• d) O;
• e) S;
• f) NR;
• or
• g) an optionally substituted fully saturated, or partially unsaturated, or aromatic carbocycle or heterocycle;
• U is:
• a) hydrogen,
• b) CF3;
• c) halo;
• d) NR4R5;
• e) cyano;
• f) C(═O)NR4R5;
• g) OR4;
• h) CO2R5;
• i) G;
• j) NR4G;
• k) OG;
• Z is:
• i) hydrogen;
• ii) halo;
• iii) OH;
• iv) CO2H;
• v) CO2R4;
• vi) SO2R4;
• vii) NR4R5;
• viii) nitro;
• ix) cyano;
• x) C1-C6 alkyl;
• xi) C1-C6 haloalkyl;
• xii) C1-C6 alkoxy;
• xiii) C1-C6 haloalkoxy;
• xiv) C1-C6 aminoalkyl;
• xv) C1-C6 aminoalkoxy;
• xvi) an aza functionality replacing a ring CH functionality;
• or
• xvii) a carbon or carbon/nitrogen framework bridging the 6-7, 7-8 or 8-9 positions so as to form an additional fused 5 to 6-membered carbocycle or heterocycle ring;
• R4 and R5 are each independently hydrogen, substituted or unsubstituted C1-C4 alkyl, or R4 and R5 can be taken together with a nitrogen atom to form an optionally substituted, saturated or unsaturated heterocyclic ring;
• x is an integer from 2 to 4;
• and
• L is a linker group of valency x;
• or
• a pharmaceutically-acceptable salt thereof, and
• b) a pharmaceutically or veterinarily acceptable carrier.

A method of treatment and/or prophylaxis of a cellular proliferative disorder, comprising administering a therapeutically effective amount of a compound of the formula II or III

• in which one or more W and one or more Z in formula II, and one or more Z and C(═O) NR in formula III are attached to a ring carbon or carbons at any of positions 3, 4 and 6 to 10 and in which:
• Q is O or S;
• W is C(=Q)NR-M-(CH2)mR1, in which
• M is CHJ or G,
• R is H or a substituted or unsubstituted C1-C4 alkyl group,
• J is H or a substituted or unsubstituted C1-C6 alkyl group,
• G is a substituted or unsubstituted fully saturated, or partially unsaturated, or aromatic, carbocycle or heterocycle,
• R1 is C(NR2)NH2, NHC(═NR3)NH2 or NR4R5, in which
• each of R2 and R3 are independently H or a substituted or unsubstituted C1-C4 alkyl group,
• R4 and R5 are independently H or a substituted or unsubstituted C1-C4 alkyl group or R4 and R5 together with the nitrogen atom to which they are attached form a substituted or unsubstituted C1-C4 alkyl group, saturated or unsaturated heterocyclic group, and
• m is an integer from 0 to 6;
• Y is:
• i) hydrogen;
• ii) C1-C6 alkyl;
• or
• iii)-(CH2)nX(CH2)pU;
• the indices n and p are independently integers from 0 to 6;
• X is:
• a) CH2;
• b) C═O;
• c) CH═CH;
• d) O
• e) S;
• f) NR;
• or
• g) an optionally substituted fully saturated, or partially unsaturated, or aromatic carbocycle or heterocycle;
• U is:
• a) hydrogen,
• b) CF3;
• c) halo;
• d) NR4R5;
• e) cyano;
• f) C(═O)NR4R5;
• g) OR4;
• h) CO2R5;
• i) G;
• j) NR4G;
• k) OG;
• Z is:
• i) hydrogen;
• ii) halo;
• iii) OH;
• iv) CO2H;
• v) CO2R4;
• vi) SO2R4;
• vii) NR4R5;
• viii) nitro;
• ix) cyano;
• x) C1-C6 alkyl;
• xi) C1-C6 haloalkyl;
• xii) C1-C6 alkoxy;
• xiii) C1-C6 haloalkoxy;
• xiv) C1-C6 aminoalkyl;
• xv) C1-C6 aminoalkoxy;
• xvi) an aza functionality replacing a ring CH functionality;
• or
• xvii) a carbon or carbon/nitrogen framework bridging the 6-7, 7-8 or 8-9 positions so as to form an additional fused 5 to 6-membered carbocycle or heterocycle ring;
• R4 and R5 are each independently hydrogen, substituted or unsubstituted C1-C4 alkyl, or
• R4 and R5 can be taken together with a nitrogen atom to form an optionally substituted, saturated or unsaturated heterocyclic ring;
• x is an integer from 2 to 4;
• and
• L is a linker group of valency x;
• or
• a pharmaceutically-acceptable salt thereof, to a subject in need thereof.