Method of treating cancer with substituted amide derivatives

A method of reducing tumor size in a subject, said method comprising administering an effective amount of a compound of formula I

• R—X—W—Y—R1 I
• enantiomers, diastereomers, salts, solvates, and N-oxides thereof wherein
• R is
• T is selected from phenyl, 5-6-membered heteroaryl, or 5-6 membered heterocyclyl;
• Z is selected from N or CR7;
• Z1 is selected from N or CR7;
• W is an substituted or unsubstituted phenyl, a substituted or unsubstituted benzomorpholinyl, a substituted or unsubstituted 6-membered nitrogen containing heteroaryl;
• a substituted or unsubstituted c3-7cycloalkyl, c1-6alkyl and c1-6alkynyl;
• X is selected from O, S, S(═O), SO2, NR2 and CR3R4;
• Y is selected from —NRaC(═O)—(CR3R4)p—, —NRaC(═S)—(CR3R4)p—, —NRa—(CR3R4)p—, —NRa— (CR3R4)pC(═O)—, —NRa—(CR3R4)pC(═S)—, —NRaS(═O)t—, —NRaS(═O)t—(CR3R4)p—, —C(═O)NRa—(CR3R4)p—, and —NRa—(CR3R4)p—S(═O)t—, and where W is benzomorpholinyl Y may further include —C(═O);
• Ra is selected from H, alkyl, heterocyclyl, aryl, arylalkyl, heterocyclylalkyl, cycloalkyl, cycloalkylalkyl, alkenyl and alkynyl;
• wherein Ra is optionally substituted;
• R1 is a partially unsaturated or saturated ring selected from
• wherein J is N or CR4a;
• J2 is O or CR4aR4a;
• Q is a 1-5 membered saturated or partially unsaturated alkyl chain, or a 2-5 membered saturated or partially unsaturated heteroalkyl chain;
• R1 is optionally fused with an optionally substituted phenyl or an optionally substituted 5-6 membered heterocyclyl ring;
• wherein R1 is optionally substituted with one or more substituents independently selected from H, halo, hydroxyl, R5aRaN—, R5aRaN—C1-6 alkyl, R5(S═O)—C1-6 alkyl, NR5R5a—(C═O)—C1-6 alkyl, optionally substituted alkyl, alkenyl hydroxyalkyl, C1-6 alkoxy-C1-6 alkyl, alkenylalkyl, C1-6 alkylthio-C1-3 alkyl, —C1-6 alkyl-NRa—C(═O)—OR5, —C1-3 alkyl-NRa—(C═O)—R5, —C1-3 alkyl-C(═O)—C1-3 alkyl, aminoalkyl, hydroxy-substituted aminoalkyl, hydroxy-substituted haloalkyl, (heterocyclo)hydroxyalkyl, haloC1-6-alkyl, azidoalkyl, optionally substituted aryl-C1-6 alkyl, optionally substituted 5-6-membered heterocyclyl-C1-6 alkyl, optionally substituted C1-6-alkyl, optionally substituted C3-7 cycloalkyl, optionally substituted 5-6 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl, optionally, optionally substituted C3-6 cycloalkyl, substituted heteroarylalkyl, optionally substituted arylalkyl, and optionally substituted C6-10 aryl;
• R2 is selected from H, alkyl, haloalkyl, aryl, heterocyclyl, arylalkyl, heterocyclylalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl and R5-carbonyl;
• R3 and R4 are each independently selected from H, alkyl, aryl, heterocyclyl, arylalkyl, heterocyclylalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, R6 and alkyl substituted with R6;
• alternatively R3 and R4, together with the carbon atom they are attached to, form an optionally substituted 3-6 membered ring;
• R3a is absent or is selected from H, alkyl, aryl, heterocyclyl, arylalkyl, heterocyclylalkyl, cycloalkyl, cycloalkylalkyl, R6 and alkyl substituted with R6;
• R4a is absent or is selected from H, halo, —OR5—NRaR5, alkyl, aryl, heterocyclyl, arylalkyl, heterocyclylalkyl, cycloalkyl, cycloalkylalkyl, R6 and alkyl substituted with R6;
• R5 is independently selected at each occurrence from H, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylaminoalkyl, alkylthioalkyl, arylalkyl, heterocyclylalkyl, cycloalkylalkyl, aryl, heterocyclyl, alkenyl, alkynyl and cycloalkyl;
• R5a is independently selected at each occurrence from H, alkyl, haloalkyl, arylalkyl aminoalkyl, heterocyclylalkyl, cycloalkylalkyl, aryl, heterocyclyl, alkenyl, alkynyl and cycloalkyl;
• or when R5 and Ra, or R5a and Ra are bonded to the same nitrogen atom, Ra and R5, or Ra and R5a may independently optionally combine to form a heterocyclo ring.
• R6 is selected from cyano, —OR2, —SR2, halo, —SO2R2, —C(═O)R2, —SO2NR2R5, —NR5C(═O)OR2, —NR5C(═O)NR5R2, —NR5C(═O)R2, —CO2R2, —C(═O)NR2R5 and —NR2R5;
• R7 is selected from H, halo, cyano, —C(═O)NRaR5 and alkyl;
• R8 is one or more substituents independently selected at each occurrence from H, cyano, hydroxyl, halo, optionally substituted heterocyclyl, —C(═O)NRaR5, —OC(═O)NRaR5, —NRaC(═O)OR5, —NRaC(═O)—R5, R5RaN—O2S—, R5O2S—, R5O2SRaN—, R5RaN—, alkyl, aminoalkyl, alkylaminoalkyl, alkoxyalkyl, phenylalkyl, heterocyclylalkyl, alkoxy, haloalkoxy, alkylaminoalkoxy, arylalkoxy, heterocyclylalkoxy, cycloalkylalkoxy, heterocyclyl(hydroxyalkoxy), cycloalkyl(hydroxyalkoxy), aryl(hydroxyalkoxy), alkoxyalkoxy, aryloxyalkoxy, heterocyclyloxyalkoxy, cycloalkyloxyalkoxy, aryloxy, heterocyclyloxy, cycloalkyloxy;
• aryl and heteroaryl, alternatively where R8 comprises an NRaR5 moiety Ra and R5, together with the nitrogen atom they are attached to, may optionally form a substituted or unsubstituted 4-6 membered ring;
• R8* is one or more substituents independently selected at each occurrence from H, cyano, hydroxyl, halo, optionally substituted heterocyclyl, —NRaC(═O)NRaR5, NRaC(═NRb)—NR5, NRaC(═S)NRaR5, —OC(═O)NRaR5, —NRaC(═O)OR5, —NRaC(═O)—R5, R5RaN—O2S—, R5O2S—, R5O2SRaN—, R5RaN—, alkyl, aminoalkyl, alkylaminoalkyl, alkoxyalkyl, phenylalkyl, heterocyclylalkyl, alkoxy, haloalkoxy, alkylaminoalkoxy, arylalkoxy, heterocyclylalkoxy, cycloalkylalkoxy, heterocyclyl(hydroxyalkoxy), cycloalkyl(hydroxyalkoxy), aryl(hydroxyalkoxy), alkoxyalkoxy, aryloxyalkoxy, heterocyclyloxyalkoxy, cycloalkyloxyalkoxy, aryloxy, heterocyclyloxy, and cycloalkyloxy;
• alternatively where R8a comprises an NRaR5 moiety Ra and R5, together with the nitrogen atom they are attached to, may optionally form a substituted or unsubstituted 4-6 membered ring;
• p is 0, 1, 2, or 3;
• and
• t is 0, 1 or 2;
• wherein each alkyl, aryl, heteroaryl, cycloalkyl, alkenyl, alkynyl, heterocyclyl, and alkoxy moiety of any R, R1, R2, R3, R4, R5, R7, R8, R8*, and Ra is optionally independently substituted with one or more groups independently selected at each occurrence from halo, oxo, —NRaR5, —OR5a, —CO2R5, —C(═O)R5, (C1-C6)alkylamino, —NH—N═NH, (C1-C6)alkyl, (C1-C6)alkynyl, (C3-C6)cycloalkyl, (C1-C6)haloalkyl, di(C1-C6)alkylamino, (C1-C6)alkylamino-(C1-C6)alkyl, (C1-C6)hydroxyalkylamino, (C1-C6)alkylamino-(C1-C6)alkylamino, phenyl, heterocyclic, heteroaryl, —(CR3R4)palkyl-S(═O)-alkyl, and —(CR3R4)palkyl-S(O)2-alkyl.

A method of treating HGF mediated disorders in a subject, said method comprising administering an effective amount of a compound of formula I

• R—X—W—Y—R1 I
• enantiomers, diastereomers, salts, solvates, and N-oxides thereof wherein
• R is
• T is selected from phenyl, 5-6-membered heteroaryl, or 5-6 membered heterocyclyl;
• Z is selected from N or CR7;
• Z1 is selected from N or CR7;
• W is an substituted or unsubstituted phenyl, a substituted or unsubstituted benzomorpholinyl, a substituted or unsubstituted 6-membered nitrogen containing heteroaryl;
• a substituted or unsubstituted c3-7cycloalkyl, c1-6alkyl and c1-6alkynyl;
• X is selected from O, S, S(═O), SO2, NR2 and CR3R4;
• Y is selected from —NRaC(═O)—(CR3R4)p—, —NRaC(═S)—(CR3R4)p—, —NRa—(CR3R4)p—, —NRa— (CR3R4)pC(═O)—, —NRa—(CR3R4)pC(═S)—, —NRaS(═O)t, —NRaS(═O)t(CR3R4)p—, —C(═O)NRa—(CR3R4)p—, and —NRa—(CR3R4)p—S(═O)t—, and where W is benzomorpholinyl Y may further include —C(═O);
• Ra is selected from H, alkyl, heterocyclyl, aryl, arylalkyl, heterocyclylalkyl, cycloalkyl, cycloalkylalkyl, alkenyl and alkynyl;
• wherein Ra is optionally substituted;
• R1 is a partially unsaturated or saturated ring selected from
• wherein J is N or CR4a;
• J2 is O or CR4aR4a;
• Q is a 1-5 membered saturated or partially unsaturated alkly chain, or a 2-5 membered saturated or partially unsaturated heteroalkyl chain;
• R1 is optionally fused with an optionally substituted phenyl or an optionally substituted 5-6 membered heterocyclyl ring;
• wherein R1 is optionally substituted with one or more substituents independently selected from H, halo, hydroxyl, R5aRaN—, R5aRaN—C1-6 alkyl, R5(S═O)—C1-6 alkyl, NR5R5a—(C═O)—C1-6 alkyl, optionally substituted alkyl, alkenyl hydroxyalkyl, C1-6 alkoxy-C1-6 alkyl, alkenylalkyl, C1-6 alkylthio-C1-3 alkyl, —C1-6 alkyl-NRa—C(═O)—OR5, —C1-3 alkyl-NRa—(C═O)—R5, —C1-3 alkyl-C(═O)—C1-3 alkyl, aminoalkyl, hydroxy-substituted aminoalkyl, hydroxy-substituted haloalkyl, (heterocyclo)hydroxyalkyl, haloC1-6-alkyl, azidoalkyl, optionally substituted aryl-C1-6 alkyl, optionally substituted 5-6-membered heterocyclyl-C1-6 alkyl, optionally substituted C1-6-alkyl, optionally substituted C3-7 cycloalkyl, optionally substituted 5-6 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl, optionally, optionally substituted C3-6 cycloalkyl, substituted heteroarylalkyl, optionally substituted arylalkyl, and optionally substituted C6-10 aryl;
• R2 is selected from H, alkyl, haloalkyl, aryl, heterocyclyl, arylalkyl, heterocyclylalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl and R5-carbonyl;
• R3 and R4 are each independently selected from H, alkyl, aryl, heterocyclyl, arylalkyl, heterocyclylalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, R6 and alkyl substituted with R6;
• alternatively R3 and R4, together with the carbon atom they are attached to, form an optionally substituted 3-6 membered ring;
• R3a is absent or is selected from H, alkyl, aryl, heterocyclyl, arylalkyl, heterocyclylalkyl, cycloalkyl, cycloalkylalkyl, R6 and alkyl substituted with R6;
• R4a is absent or is selected from H, halo, —OR5—NRaR5, alkyl, aryl, heterocyclyl, arylalkyl, heterocyclylalkyl, cycloalkyl, cycloalkylalkyl, R6 and alkyl substituted with R6;
• R5 is independently selected at each occurrence from H, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylaminoalkyl, alkylthioalkyl, arylalkyl, heterocyclylalkyl, cycloalkylalkyl, aryl, heterocyclyl, alkenyl, alkynyl and cycloalkyl;
• R5a is independently selected at each occurrence from H, alkyl, haloalkyl, arylalkyl aminoalkyl, heterocyclylalkyl, cycloalkylalkyl, aryl, heterocyclyl, alkenyl, alkynyl and cycloalkyl;
• or when R5 and Ra, or R5a and Ra are bonded to the same nitrogen atom, Ra and R5, or Ra and R5a may independently optionally combine to form a heterocyclo ring.
• R6 is selected from cyano, —OR2, —SR2, halo, —SO2R2, —C(═O)R2, —SO2NR2R5, —NR5C(═O)OR2, —NR5C(═O)NR5R2, —NR5C(═O)R2, —CO2R2, —C(═O)NR2R5 and —NR2R5;
• R7 is selected from H, halo, cyano, —C(═O)NRaR5 and alkyl;
• R8 is one or more substituents independently selected at each occurrence from H, cyano, hydroxyl, halo, optionally substituted heterocyclyl, —C(═O)NRaR5, —OC(═O)NRaR5, —NRaC(═O)OR5, —NRaC(═O)—R5, R5RaN—O2S—, R5O2S—, R5O2SRaN—, R5RaN—, alkyl, aminoalkyl, alkylaminoalkyl, alkoxyalkyl, phenylalkyl, heterocyclylalkyl, alkoxy, haloalkoxy, alkylaminoalkoxy, arylalkoxy, heterocyclylalkoxy, cycloalkylalkoxy, heterocyclyl(hydroxyalkoxy), cycloalkyl(hydroxyalkoxy), aryl(hydroxyalkoxy), alkoxyalkoxy, aryloxyalkoxy, heterocyclyloxyalkoxy, cycloalkyloxyalkoxy, aryloxy, heterocyclyloxy, cycloalkyloxy;
• aryl and heteroaryl, alternatively where R8 comprises an NRaR5 moiety Ra and R5, together with the nitrogen atom they are attached to, may optionally form a substituted or unsubstituted 4-6 membered ring;
• R8* is one or more substituents independently selected at each occurrence from H, cyano, hydroxyl, halo, optionally substituted heterocyclyl, —NRaC(═O)NRaR5, NRaC(═NRb)—NR5, NRaC(═S)NRaR5, —OC(═O)NRaR5, —NRaC(═O)OR5, —NRaC(═O)—R5, R5RaN—O2S—, R5O2S—, R5O2SRaN—, R5RaN—, alkyl, aminoalkyl, alkylaminoalkyl, alkoxyalkyl, phenylalkyl, heterocyclylalkyl, alkoxy, haloalkoxy, alkylaminoalkoxy, arylalkoxy, heterocyclylalkoxy, cycloalkylalkoxy, heterocyclyl(hydroxyalkoxy), cycloalkyl(hydroxyalkoxy), aryl(hydroxyalkoxy), alkoxyalkoxy, aryloxyalkoxy, heterocyclyloxyalkoxy, cycloalkyloxyalkoxy, aryloxy, heterocyclyloxy, and cycloalkyloxy;
• alternatively where R8a comprises an NRaR5 moiety Ra and R5, together with the nitrogen atom they are attached to, may optionally form a substituted or unsubstituted 4-6 membered ring;
• p is 0, 1, 2, or 3;
• and
• t is 0, 1 or 2;
• wherein each alkyl, aryl, heteroaryl, cycloalkyl, alkenyl, alkynyl, heterocyclyl, and alkoxy moiety of any R, R1, R2, R3, R4, R5, R7, R8, R8*, and Ra is optionally independently substituted with one or more groups independently selected at each occurrence from halo, oxo, —NRaR5, —OR5a, —CO2R5, —C(═O)R5, (C1-C6)alkylamino, —NH—N═NH, (C1-C6)alkyl, (C1-C6)alkynyl, (C3-C6)cycloalkyl, (C1-C6)haloalkyl, di(C1-C6)alkylamino, (C1-C6)alkylamino-(C1-C6)alkyl, (C1-C6)hydroxyalkylamino, (C1-C6)alkylamino-(C1-C6)alkylamino, phenyl, heterocyclic, heteroaryl, —(CR3R4)palkyl-S(═O)-alkyl, and —(CR3R4)palkyl-S(O)2-alkyl.