Substituted alkylamine derivatives and methods of use

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

• 762
• wherein each of A1 and A2 is independently C or N;
• wherein ring A is selected from
• a) 5- or 6-membered partially saturated heterocyclyl,
• b) 5- or 6-membered heteroaryl,
• c) 9- or 10-membered fused partially saturated heterocyclyl,
• d) 9-, 10- or 11-membered fused heteroaryl;
• e) naphthyl, and
• f) 4-, 5- or 6- membered cycloalkenyl;
• wherein X is selected from
• 763
• wherein Z is oxygen or sulfur;
• wherein Y is selected from
• 764
• wherein p is 0 to 2,
• wherein Ra and Rb are independently selected from H, halo, cyano, —NHR6 and C1-4-alkyl substituted with R2, or wherein Ra and Rb together form C3-C6 cycloalkyl;
• wherein Rz is selected from C1-C4 alkylenyl, where one of the CH2 groups may be substituted with an oxygen atom or an —NH—;
• wherein Rd is cycloalkyl;
• wherein R is selected from
• a) substituted or unsubstituted 5-6 membered heterocyclyl, and
• b) substituted or unsubstituted fused 9-, 10- or 11-membered heterocyclyl;
• wherein substituted R is substituted with one or more substituents independently selected from halo, —OR3, —SR3, —SO2R3, —CO2R3, —CONR3R3, —COR3, —NR3R3, —SO2NR3R3, —NR3C(O)OR3, —NR3C(O)R3, cycloalkyl, optionally substituted 5-6 membered heterocyclyl, optionally substituted phenyl, lower alkyl substituted with R2, cyano, nitro, lower alkenyl and lower alkynyl;
• wherein R1 is selected from
• a) substituted or unsubstituted 6-10 membered aryl,
• b) substituted or unsubstituted 5-6 membered heterocyclyl,
• c) substituted or unsubstituted 9-11 membered fused heterocyclyl,
• d) cycloalkyl, and
• e) cycloalkenyl,
• wherein substituted R1 is substituted with one or more substituents independently selected from halo, —OR3, —SR3, —CO2R3, —CONR3R3, —COR3, —NR3R3, —NH (C1-C4 alkylenylR14), —SO2R3, —SO2NR3R3, —NR3C(O)OR3, —NR3C(O)R3, optionally substituted cycloalkyl, optionally substituted 5-6 membered heterocyclyl, optionally substituted phenyl, lower alkyl substituted with R2, cyano, nitro, lower alkenyl and lower alkynyl;
• wherein R2 is one or more substituents independently selected from H, halo, —OR3, oxo, —SR3, —CO2R3, —COR3, —CONR3R3, —NR3R3, —SO2NR3R3, —NR3C(O)OR3, —NR3C(O)R3, cycloalkyl, optionally substituted phenylalkylenyl, optionally substituted 5-6 membered heterocyclyl, optionally substituted heteroarylalkylenyl, optionally substituted phenyl, lower alkyl, cyano, lower hydroxyalkyl, lower carboxyalkyl, nitro, lower alkenyl, lower alkynyl, lower aminoalkyl, lower alkylaminoalkyl and lower haloalkyl;
• wherein R3 is selected from H, lower alkyl, phenyl, 5-6 membered heterocyclyl, C3-C6 cycloalkyl, and lower haloalkyl;
• wherein R4 is independently selected from C2-C4 alkylenyl, C2-C4 alkenylenyl and C2-C4 alkynylenyl, where one of the CH2 groups may be substituted with an oxygen atom or an —NH—;
• wherein R5 is selected from H, lower alkyl, phenyl and lower aralkyl;
• and
• wherein R6 is selected from H or C1-6-alkyl;
• wherein R14 is selected from H, phenyl, 5-6 membered heterocyclyl and C3-C6 cycloalkyl;
• and pharmaceutically acceptable salts thereof;
• provided A is not naphthyl when X is —C(O)NH— and when R1 is phenyl when Y is —NCH2— and when R is 4-pyridyl;
• and further provided R is not unsubstituted 2-thienyl, 2-pyridyl or 3-pyridyl when Y is —NHCH2—.

A method of treating angiogenesis in a subject, said method comprising administering an effective amount of a compound as in any of Formula I

• 765
• wherein each of A1 and A2 is independently C or N;
• wherein ring A is selected from
• a) 5- or 6-membered partially saturated heterocyclyl,
• b) 5- or 6-membered heteroaryl,
• c) 9- or 10-membered fused partially saturated heterocyclyl,
• d) 9-, 10- or 11-membered fused heteroaryl;
• e) naphthyl, and
• f) 4-, 5- or 6- membered cycloalkenyl;
• wherein X is selected from
• 766
• wherein Z is oxygen or sulfur;
• wherein Y is selected from
• 767
• wherein p is 0 to 2,
• wherein Ra and Rb are independently selected from H, halo, cyano, —NHR6 and C1-4-alkyl substituted with R2, or wherein Ra and Rb together form C3-C6 cycloalkyl;
• wherein Rz is selected from C1-C4 alkylenyl, where one of the CH2 groups may be substituted with an oxygen atom or an —NH—;
• wherein Rd is cycloalkyl;
• wherein R is selected from
• a) substituted or unsubstituted 5-6 membered heterocyclyl, and
• b) substituted or unsubstituted fused 9-, 10- or 11-membered heterocyclyl;
• wherein substituted R is substituted with one or more substituents independently selected from halo, —OR, —SR3, —SO2R3, —CO2R3, —CONR3R3, —COR3, —NR3R3, —SO2NR3R3, —NR3C(O)OR3, —NR3C(O)R3, cycloalkyl, optionally substituted 5-6 membered heterocyclyl, optionally substituted phenyl, lower alkyl substituted with R2, cyano, nitro, lower alkenyl and lower alkynyl;
• wherein R1 is selected from
• a) substituted or unsubstituted 6-10 membered aryl,
• b) substituted or unsubstituted 5-6 membered heterocyclyl,
• c) substituted or unsubstituted 9-11 membered fused heterocyclyl,
• d) cycloalkyl, and
• e) cycloalkenyl,
• wherein substituted R1 is substituted with one or more substituents independently selected from halo, —OR3, —SR3, —CO2R3, —CONR3R3, —COR3, —NR3R3, —NH(C1-C4 alkylenylR14), —SO2R3, —SO2NR3R3, —NR3C(O)OR3, —NR3C(O)R3, optionally substituted cycloalkyl, optionally substituted 5-6 membered heterocyclyl, optionally substituted phenyl, lower alkyl substituted with R2, cyano, nitro, lower alkenyl and lower alkynyl;
• wherein R2 is one or more substituents independently selected from H, halo, —OR3, oxo, —SR3, —CO2R3, —COR3, —CONR3R3, —NR3R3, —SO2NR3R3, —NR3C(O)OR3, —NR3C(O)R3, cycloalkyl, optionally substituted phenylalkylenyl, optionally substituted 5-6 membered heterocyclyl, optionally substituted heteroarylalkylenyl, optionally substituted phenyl, lower alkyl, cyano, lower hydroxyalkyl, lower carboxyalkyl, nitro, lower alkenyl, lower alkynyl, lower aminoalkyl, lower alkylaminoalkyl and lower haloalkyl;
• wherein R3 is selected from H, lower alkyl, phenyl, 5-6 membered heterocyclyl, C3-C6 cycloalkyl, and lower haloalkyl;
• wherein R4 is independently selected from C2-C4 alkylenyl, C2-C4 alkenylenyl and C2-C4 alkynylenyl, where one of the CH2 groups may be substituted with an oxygen atom or an —NH—;
• wherein R5 is selected from H, lower alkyl, phenyl and lower aralkyl;
• and
• wherein R6 is selected from H or C1-6-alkyl;
• wherein R14 is selected from H, phenyl, 5-6 membered heterocyclyl and C3-C6 cycloalkyl;
• and pharmaceutically acceptable salts thereof;
• provided A is not naphthyl when X is —C(O)NH— and when R1 is phenyl when Y is —NCH2— and when R is 4-pyridyl;
• and further provided R is not unsubstituted 2-thienyl, 2-pyridyl or 3-pyridyl when Y is —NHCH2—.

A method of treating KDR-related disorders in a mammal, said method comprising administering an effective amount of a compound of Formula I

• 768
• wherein each of A1 and A2 is independently C or N;
• wherein ring A is selected from
• a) 5- or 6-membered partially saturated heterocyclyl,
• b) 5- or 6-membered heteroaryl,
• c) 9- or 10-membered fused partially saturated heterocyclyl,
• d) 9-, 10- or 11-membered fused heteroaryl;
• e) naphthyl, and
• f) 4-, 5- or 6- membered cycloalkenyl;
• wherein X is selected from
• 769
• wherein Z is oxygen or sulfur;
• wherein Y is selected from
• 770
• wherein p is 0 to 2,
• wherein Ra and Rb are independently selected from H, halo, cyano, —NHR6 and C1-4-alkyl substituted with R2, or wherein Ra and Rb together form C3-C6 cycloalkyl;
• wherein Rz is selected from C1-C4 alkylenyl, where one of the CH2 groups may be substituted with an oxygen atom or an —NH—;
• wherein Rd is cycloalkyl;
• wherein R is selected from
• a) substituted or unsubstituted 5-6 membered heterocyclyl, and
• b) substituted or unsubstituted fused 9-, 10- or 11-membered heterocyclyl;
• wherein substituted R is substituted with one or more substituents independently selected from halo, —OR3, —SR3, —SO2R3, —CO2R3, —CONR3R3, —COR3, —NR3R3, —SO2NR3R3, —NR3C(O)OR3, —NR3C(O)R3, cycloalkyl, optionally substituted 5-6 membered heterocyclyl, optionally substituted phenyl, lower alkyl substituted with R2, cyano, nitro, lower alkenyl and lower alkynyl;
• wherein R1 is selected from
• a) substituted or unsubstituted 6-10 membered aryl,
• b) substituted or unsubstituted 5-6 membered heterocyclyl,
• c) substituted or unsubstituted 9-11 membered fused heterocyclyl,
• d) cycloalkyl, and
• e) cycloalkenyl,
• wherein substituted R1 is substituted with one or more substituents independently selected from halo, —OR3, —SR3, —CO2R3, —CONR3R3, —COR3, —NR3R3, —NH(C1-4 alkylenylR14), —SO2R3, —SO2NR3R3, —NR3C(O)OR3, —NR3C(O)R3, optionally substituted cycloalkyl, optionally substituted 5-6 membered heterocyclyl, optionally substituted phenyl, lower alkyl substituted with R2, cyano, nitro, lower alkenyl and lower alkynyl;
• wherein R2 is one or more substituents independently selected from H, halo, —OR3, oxo, —SR3, —CO2R3, —COR3, —CONR3R3, —NR3R3, —SO2NR3R3, —NR3C(O)R3, —NR3C(O)R3, cycloalkyl, optionally substituted phenylalkylenyl, optionally substituted 5-6 membered heterocyclyl, optionally substituted heteroarylalkylenyl, optionally substituted phenyl, lower alkyl, cyano, lower hydroxyalkyl, lower carboxyalkyl, nitro, lower alkenyl, lower alkynyl, lower aminoalkyl, lower alkylaminoalkyl and lower haloalkyl;
• wherein R3 is selected from H, lower alkyl, phenyl, 5-6 membered heterocyclyl, C3-C6 cycloalkyl, and lower haloalkyl;
• wherein R4 is independently selected from C2-C4 alkylenyl, C2-C4 alkenylenyl and C2-C4 alkynylenyl, where one of the CH2 groups may be substituted with an oxygen atom or an —NH—;
• wherein R5 is selected from H, lower alkyl, phenyl and lower aralkyl;
• and
• wherein R6 is selected from H or C1-6-alkyl;
• wherein R14 is selected from H, phenyl, 5-6 membered heterocyclyl and C3-C6 cycloalkyl;
• and pharmaceutically acceptable salts thereof;
• provided A is not naphthyl when X is —C(O)NH— and when R1 is phenyl when Y is —NCH2— and when R is 4-pyridyl;
• and further provided R is not unsubstituted 2-thienyl, 2-pyridyl or 3-pyridyl when Y is —NHCH2—.

A method of treating proliferative disorders in a mammal, said method comprising administering an effective amount of a compound of Formula I

• 771
• wherein each of A1 and A 2 is independently C or N;
• wherein ring A is selected from
• a) 5- or 6-membered partially saturated heterocyclyl,
• b) 5- or 6-membered heteroaryl,
• c) 9- or 10-membered fused partially saturated heterocyclyl,
• d) 9-, 10- or 11-membered fused heteroaryl;
• e) naphthyl, and
• f) 4-, 5- or 6-membered cycloalkenyl;
• wherein X is selected from
• 772
• wherein Z is oxygen or sulfur;
• wherein Y is selected from
• 773
• wherein p is 0 to 2,
• wherein Ra and Rb are independently selected from H, halo, cyano, —NHR6 and C1-4-alkyl substituted with R2, or wherein Ra and Rb together form C3-C6 cycloalkyl;
• wherein Rz is selected from C1-C4 alkylenyl, where one of the CH2 groups may be substituted with an oxygen atom or an —NH—;
• wherein Rd is cycloalkyl;
• wherein R is selected from
• a) substituted or unsubstituted 5-6 membered heterocyclyl, and
• b) substituted or unsubstituted fused 9-, 10- or 11-membered heterocyclyl;
• wherein substituted R is substituted with one or more substituents independently selected from halo, —OR3, —SR3, —SO2R3, —CO2R3, —CONR3R3, —COR3, —NR3R3, —SO2NR3R3, —NR3C(O)OR3, —NR3C(O)R3, cycloalkyl, optionally substituted 5-6 membered heterocyclyl, optionally substituted phenyl, lower alkyl substituted with R2, cyano, nitro, lower alkenyl and lower alkynyl;
• wherein R1 is selected from
• a) substituted or unsubstituted 6-10 membered aryl,
• b) substituted or unsubstituted 5-6 membered heterocyclyl,
• c) substituted or unsubstituted 9-11 membered fused heterocyclyl,
• d) cycloalkyl, and
• e) cycloalkenyl,
• wherein substituted R1 is substituted with one or more substituents independently selected from halo, —OR3, —SR3, —CO2R3, —CONR3R3, —COR3, —NR3R3, —NH(C1-C4 alkylenylR14), —SO2R3, —SO2NR3R3, —NR3C(O)OR3, —NR3C(O)R3, optionally substituted cycloalkyl, optionally substituted 5-6 membered heterocyclyl, optionally substituted phenyl, lower alkyl substituted with R2, cyano, nitro, lower alkenyl and lower alkynyl;
• wherein R2 is one or more substituents independently selected from H, halo, —OR3, oxo, —SR3, —CO2R3, —COR3, —CONR3R3, —NR3R3, —SO2NR3R3, —NR3C(O)OR3, —NR3C(O)R3, cycloalkyl, optionally substituted phenylalkylenyl, optionally substituted 5-6 membered heterocyclyl, optionally substituted heteroarylalkylenyl, optionally substituted phenyl, lower alkyl, cyano, lower hydroxyalkyl, lower carboxyalkyl, nitro, lower alkenyl, lower alkynyl, lower aminoalkyl, lower alkylaminoalkyl and lower haloalkyl;
• wherein R3 is selected from H, lower alkyl, phenyl, 5-6 membered heterocyclyl, C3-C6 cycloalkyl, and lower haloalkyl;
• wherein R4 is independently selected from C2-C4 alkylenyl, C2-C4 alkenylenyl and C2-C4 alkynylenyl, where one of the CH2 groups may be substituted with an oxygen atom or an —NH—;
• wherein R5 is selected from H, lower alkyl, phenyl and lower aralkyl;
• and
• wherein R6 is selected from H or C1-6-alkyl;
• wherein R14 is selected from H, phenyl, 5-6 membered heterocyclyl and C3-C6 cycloalkyl;
• and pharmaceutically acceptable salts thereof;
• provided A is not naphthyl when X is —C(O)NH— and when R1 is phenyl when Y is —NCH2— and when R is 4-pyridyl;
• and further provided R is not unsubstituted 2-thienyl, 2-pyridyl or 3-pyridyl when Y is —NHCH2—.