[1,2,4]Triazolo[1,5-a]Pyridine and [1,2,4]Triazolo[1,5-c]Pyrimidine Compounds and Their Use

摘要

The present invention pertains generally to the field of therapeutic compounds, and more specifically to certain triazolo compounds (referred to herein as TAZ compounds), and especially certain [1,2,4]triazolo[1,5-a]pyridine and [1,2,4]triazolo[1,5-c]pyrimidine compounds, which, inter alia, inhibit AXL receptor tyrosine kinase function. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit AXL receptor tyrosine kinase function, and in the treatment of diseases and conditions that are mediated by AXL receptor tyrosine kinase, that are ameliorated by the inhibition of AXL receptor tyrosine kinase function, etc., including proliferative conditions such as cancer, etc.

主权项

1. A compound selected from compounds of the following formula, and pharmaceutically acceptable salts thereof: wherein: —X═ is independently —CR6═ or —N═; and wherein: if —X═ is —CR6═, then:
—R5 is independently —R5A;—R6 is independently —R6A;—R7 is independently —R7A;—R8 is independently —R8A; and—W is independently —WA; wherein:
—R5A is independently -Q5A;—R6A is independently —H or -Q6A;—R7A is independently —H or -Q7A;—R8A is independently —H or -Q8A; and—WA is independently —RWA1; if —X═ is —N═, then:
—R5 is independently —R5B;—R7 is independently —R7B;—R8 is independently —R8B; and—W is independently —WB; wherein:
—R5B is independently -Q5B;—R7B is independently —H or -Q7B;—R8B is independently —H or -Q8B; and—WB is independently —RWB1; wherein: —RWA1 is independently:
—R1A1, —R1A2, —R1A3, —R1A4, —R1A5, —R1A6, —R1A7, —R1A8,-L1A-R1A4, -L1A-R1A5, -L1A-R1A6, -L1A-R1A7, or -L1A-R1A8; —RWB1 is independently:
—R1A2, —R1A3, —R1A4, —R1A5, —R1A6, —R1A7, —R1A8,-L1A-R1A4, -L1A-R1A5, -L1A-R1A7, or -L1A-R1A8; wherein:
each —R1A1 is independently saturated aliphatic C1-6alkyl;each —R1A2 is independently aliphatic C2-6alkenyl;each —R1A3 is independently aliphatic C2-6alkynyl;each —R1A4 is independently saturated C3-6cycloalkyl;each —R1A5 is independently C3-6cycloalkenyl;each —R1A6 is independently non-aromatic C3-8heterocyclyl;each —R1A7 is independently C6-10carboaryl;each —R1A8 is independently C5-10heteroaryl;each -L1A- is independently saturated aliphatic C1-3alkylene; wherein:
each —R1A4, —R1A5, —R1A6, —R1A7, and —R1A8 is optionally substituted, for example, with one or more substituents —R1B1 and/or one or more substituents —R1B2, andeach —R1A1, —R1A2, —R1A3, and -L1A- is optionally substituted, for example, with one or more substituents —R1B2, wherein:
each —R1B1 is independently:
—R1D1. —R1D2, —R1D3, —R1D4, —R1D5, —R1D6, —R1D7, —R1D8,-L1D-R1D4, -L1D-R1D5, -L1D-R1D6, -L1D-R1D7, or -L1D-R1D8;each —R1B2 is independently:—F, —Cl, —Br, —I,—CF3, —OCF3,—OH, -L1C-OH, —O-L1C-OH,—OR1C1, -L1C-OR1C1, —O-L1C-OR1C1,—SH, —SR1C1,—CN,—NO2,—NH2, —NHR1C1, —NR1C12, —NR1C2R1C3,-L1C-NH2, -L1C-NHR1C1, -L1C-NR1C12, -L1C-NR1C2R1C3,—O-L1C-NH2, —O-L1C-NHR1C1, —O-L1C-NR1C12, —O-L1C-NR1C2R1C3,—C(═O)OH, —C(═O)OR1C1,—C(═O)R1C1,—C(═O)NH2, —C(═O)NHR1C1, —C(═O)NR1C12, —C(═O)NR1C2R1C3,—NHC(═O)R1C1, —NR1C1C(═O)R1C1,—NHC(═O)OR1C1, —NR1C1C(═O)OR1C1,—OC(═O)NH2, —OC(═O)NHR1C1, —OC(═O)NR1C12, —OC(═O)NR1C2R1C3,—NHC(═O)NH2, —NHC(═O)NHR1C1,—NHC(═O)NR1C12, —NHC(═O)NR1C2R1C3,—NR1C1C(═O)NH2, —NR1C1C(═O)NHR1C1,—NR1C1C(═O)NR1C12, —NR1C1C(═O)NR1C2R1C3,—NHS(═O)2R1C1, —NR1C1S(═O)2R1C1,—S(═O)2NH2, —S(═O)2NHR1C1, —S(═O)2NR1C12, —S(═O)2NR1C2R1C3,—S(═O)R1C1, —S(═O)2R1C1, —OS(═O)2R1C1, or —S(═O)2OR1C1; wherein:
each -L1C- is independently saturated aliphatic C1-5alkylene;in each group —NR1C2R1C3, R1C2 and R1C3, taken together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly 2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N, and the other of said exactly 2 ring heteroatoms is independently N or O;each —R1C1 is independently:
—R1D1, —R1D2, —R1D3, —R1D4, —R1D5, —R1D6, —R1D7, —R1D8,-L1D-R1D4, -L1D-R1D5, -L1D-R1D6, -L1D-R1D7, or -L1D-R1D8,each —R1D1 is independently saturated aliphatic C1-6alkyl;each —R1D2 is independently aliphatic C2-6alkenyl;each —R1D3 is independently aliphatic C2-6alkynyl;each —R1D4 is independently saturated C3-6cycloalkyl;each —R1D5 is independently C3-6cycloalkenyl;each —R1D6 is independently non-aromatic C3-8heterocyclyl;each —R1D7 is independently C6-10carboaryl;each —R1D8 is independently C5-10heteroaryl;each -L1D- is independently saturated aliphatic C1-3alkylene; wherein:
each —R1D4, —R1D5, —R1D6, —R1D7, and —R1D8 is optionally substituted, for example, with one or more substituents —R1E1 and/or one or more substituents —R1E2,each —R1D1, —R1D2, —R1D3, and -L1D- is optionally substituted, for example, with one or more substituents —R1E2, and wherein:
each —R1E1 is independently saturated aliphatic C1-4alkyl, phenyl, or benzyl;each —R1E2 is independently:—F, —Cl, —Br, —I,—CF3, —OCF3,—OH, -L1F-OH, —O-L1F-OH,—OR1F1, -L1F-OR1F1, —O-L1F-OR1F1,—SH, —SR1F1,—CN,—NO2,—NH2, —NHR1F1, —NR1F12, NR1F2R1F3,-L1F-NH2, -L1F-NHR1F1, -L1F-NR1F12, -L1F-NR1F2R1R3,—C(═O)OH, —C(═O)OR1F1,—C(═O)NH2, —C(═O)NHR1F1, C(═O)NR1F12, or —C(═O)NR1F2R1F3; wherein:
each —R1F1 is independently saturated aliphatic C1-4alkyl, phenyl, or benzyl;each -L1F- is independently saturated aliphatic C1-5alkylene; and in each group —NR1F2R1F3, R1F2 and R1F3, taken together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly 2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N, and the other of said exactly 2 ring heteroatoms is independently N or O; -Q5A is independently:
—R2A1, —R2A2, —R2A3, —R2A4, —R2A5, —R2A6, —R2A7, —R2A8,-L2A-R2A4, -L2A-R2A5, -L2A-R2A6, -L2A-R2A7, -L2A-R1A8,—F, —Cl, —Br, —I,—CF3, —OCF3,—OH, -L2C-OH, —O-L2C-OH,-L2C-OR2C1, —O-L2C-OR2C1,—O—R2D4, —O—R2D6, —O—R2D7, —O—R2D8,—O-L2D-R2D4, —O—R2D6, —O—R2D7, —O—R2D8,—SH, —SR2C1,—CN,—NO2,—NH2, —NHR2C1, —NR2C12, —NR2C2R2C3,-L2C-NH2, -L2C-NHR2C1, -L2C-NR2C12, -L2C-NR2C2R2C3,—O-L2C-NH2, —O-L2C-NHR2C1, —O-L-NR2C—NR2C12, —O-L2C-NR2C2R2C3,—C(═O)OH, —C(═O)OR2C1,—C(═O)R2C1,—C(═O)NH2, —C(═O)NHR2C1, —C(═O)NR2C12, —C(═O)NR2C2R2C3,—NHC(═O)R2C1, —NR2C1C(═O)R2C1,—NHC(═O)OR2C1, —NR2C1C(═O)OR2C1,—OC(═O)NH2, —OC(═O)NHR2C1, —OC(═O)NR2C12, —OC(═O)NR2C2R2C3,—NHC(═O)NH2, —NHC(═O)NHR2C1,—NHC(═O)NR2C12, —NHC(═O)NR2C2R2C3,—NR2C1C(═O)NH2, —NR2C1C(═O)NHR2C1,—NR2C1C(═O)NR1C12, —NR2C1C(═O)NR2C2R2C3,—NHS(═O)2R2C1, —NR1C1S(═O)2R2C1,—S(═O)2NH2, —S(═O)2NHR2C1, —S(═O)2NR2C12, —S(═O)2NR2C2R2C3,—S(═O)R2C1, —S(═O)2R2C1, —OS(═O)2R2C1, or —S(═O)2OR2C1; -Q8A is independently:
—R2A1, —R2A2, —R2A3, —R2A4, —R2A5, —R2A6, —R2A7, —R2A8,-L2A-R2A4, -L2A-R2A5, -L2A-R2A6, -L2A-R2A7, -L2A-R1A8,—F, —Cl, —Br, —I,—CF3, —OCF3,—OH, -L2C-OH, —O-L2C-OH,-L2C-OR2C1, —O-L2C-OR2C1,—SH, —SR2C1,—NO2,—NH2, —NHR2C1, —NR2C12, —NR2C2R2C3,-L2C-NH2, -L2C-NHR2C1, -L2C-NR2C12, -L2C-NR2C2R2C3,—O-L2C-NH2, —O-L2C-NHR2C1, —O-L2C-NR2C12, —O-L2C-NR2C2R2C3,—C(═O)R2C1,—C(═O)NH2, —C(═O)NHR2C1, —C(═O)NR2C12, —C(═O)NR2C2R2C3,—NHC(═O)R2C1, —NR2C1C(═O)R2C1,—NHC(═O)OR2C1, —NR2C1C(═O)OR2C1,—OC(═O)NH2, —OC(═O)NHR2C1, —OC(═O)NR2C12, —OC(═O)NR2C2R2C3,—NHC(═O)NH2, —NHC(═O)NHR2C1,—NHC(═O)NR2C12, —NHC(═O)NR2C2R2C3,—NR2C1C(═O)NH2, —NR2C1C(═O)NHR2C1,—NR2C1C(═O)NR1C12, —NR2C1C(═O)NR2C2R2C3,—NHS(═O)2R2C1, —NR1C1S(═O)2R2C1,—S(═O)2NH2, —S(═O)2NHR2C1, —S(═O)2NR2C12, —S(═O)2NR2C2R2C3,—S(═O)R2C1, —S(═O)2R2C1, —OS(═O)2R2C1, or —S(═O)2OR2C1; -Q5B is independently:
—R2A2, —R2A3, —R2A4, —R2A5, —R2A6, —R2A7, —R2A8,-L2A-R2A4, -L2A-R2A5, -L2A-R2A6, -L2A-R2A7, -L2A-R2A8,—F, —Cl, —Br, —I,—CF3, —OCF3,—OH, -L2C-OH, —O-L2C-OH,—OR2C1, -L2C-OR2C1, —O-L2C-OR2C1,—SH, —SR2C1,—CN,—NO2,—NH2, —NHR2C1, —NR2C12, —NR2C2R2C3,-L2C-NH2, -L2C-NHR2C1, -L2C-NR2C12, -L2C-NR2C2R2C3,—O-L2C-NH2, —O-L2C-NHR2C1, —O-L2C-NR2C12, —O-L2C-NR2C2R2C2,—C(═O)OH, —C(═O)OR2C1,—C(═O)R2C1,—C(═O)NH2, —C(═O)NHR2C1, —C(═O)NR2C12, —C(═O)NR2C2R2C3,—NHC(═O)R2C1, —NR2C1C(═O)R2C1,—NHC(═O)OR2C1, —NR2C1C(═O)OR2C1,—OC(═O)NH2, —OC(═O)NHR2C1, —OC(═O)NR2C12, —OC(═O)NR2C2R2C3,—NHC(═O)NH2, —NHC(═O)NHR2C1,—NHC(═O)NR2C12, —NHC(═O)NR2C2R2C3,—NR2C1C(═O)NH2, —NR2C1C(═O)NHR2C1,—NR2C1C(═O)NR1C12, —NR2C1C(═O)NR2C2R2C3,—NHS(═O)2R2C1, —NR1C1S(═O)2R2C1,—S(═O)2NH2, —S(═O)2NHR2C1, —S(═O)2NR2C12, —S(═O)2NR2C2R2C3,—S(═O)R2C1, —S(═O)2R2C1, —OS(═O)2R2C1, or —S(═O)2OR2C1; -Q8B is independently:
—R2A1, —R2A2, —R2A3, —R2A4, —R2A5, —R2A6, —R2A7, —R2A8,-L2A-R2A4, -L2A-R2A5, -L2A-R2A6, -L2A-R2A7, -L2A-R1A8,—F, —Cl, —Br, —I,—CF3, —OCF3,—OH, -L2C-OH, —O-L2C-OH,—OR2C1, -L2C-OR2C1, —O-L2C-OR2C1,—SH, —SR2C1,—CN,—NO2,—NH2, —NHR2C1, —NR2C12, —NR2C2R2C3,-L2C-NH2, -L2C-NHR2C1, -L2C-NR2C12, -L2C-NR2C2R2C3,—O-L2C-NH2, —O-L2C-NHR2C1, —O-L2C-NR2C12, —O-L2C-NR2C2R2C3,—C(═O)OH, —C(═O)OR2C1,—C(═O)R2C1,—C(═O)NH2, —C(═O)NHR2C1, —C(═O)NR2C12, —C(═O)NR2C2R2C3,—NHC(═O)R2C1, —NR2C1C(═O)R2C1,—NHC(═O)OR2C1, —NR2C1C(═O)OR2C1,—OC(═O)NH2, —OC(═O)NHR2C1, —OC(═O)NR2C12, —OC(═O)NR2C2R2C3,—NHC(═O)NH2, —NHC(═O)NHR2C1,—NHC(═O)NR2C12, —NHC(═O)NR2C2R2C3,—NR2C1C(═O)NH2, —NR2C1C(═O)NHR2C1,—NR2C1C(═O)NR1C12, —NR2C1C(═O)NR2C2R2C3,—NHS(═O)2R2C1, —NR1C1S(═O)2R2C1,—S(═O)2NH2, —S(═O)2NHR2C1, —S(═O)2NR2C12, —S(═O)2NR2C2R2C3,—S(═O)R2C1, —S(═O)2R2C1, —OS(═O)2R2C1, or —S(═O)2OR2C1; each of -Q6A, -Q7A, and -Q7B is independently:
—R2A1, —R2A2, —R2A3, —R2A4, —R2A5, —R2A6, —R2A7, —R2A8,-L2A-R2A4, -L2A-R2A5, -L2A-R2A6, -L2A-R2A7, -L2A-R1A8,—F, —Cl, —Br, —I,—CF3, —OCF3,—OH, -L2C-OH, —O-L2C-OH,—OR2C1, L2C-OR2C1, —O-L2C-OR2C1,—SH, —SR2C1,—CN,—NO2,—NH2, —NHR2C1, —NR2C12, —NR2C2R2C3,-L2C-NH2, -L2C-NHR2C1, -L2C-NR2C12, -L2C-NR2C2R2C3,—O-L2C-NH2, —O-L2C-NHR2C1, —O-L2C-NR2C12, —O-L2C-NR2C2R2C3,—C(═O)OH, —C(═O)OR2C1,—C(═O)R2C1,—C(═O)NH2, —C(═O)NHR2C1, —C(═O)NR2C12, —C(═O)NR2C2R2C3,—NHC(═O)R2C1, —NR2C1C(═O)R2C1,—NHC(═O)OR2C1, —NR2C1C(═O)OR2C1,—OC(═O)NH2, —OC(═O)NHR2C1, —OC(═O)NR2C12, —OC(═O)NR2C2R2C3,—NHC(═O)NH2, —NHC(═O)NHR2C1,—NHC(═O)NR2C12, —NHC(═O)NR2C2R2C3,—NR2C1C(═O)NH2, —NR2C1C(═O)NHR2C1,—NR2C1C(═O)NR1C12, —NR2C1C(═O)NR2C2R2C3,—NHS(═O)2R2C1, —NR1C1S(═O)2R2C1,—S(═O)2NH2, —S(═O)2NHR2C1, —S(═O)2NR2C12, —S(═O)2NR2C2R2C3,—S(═O)R2C1, —S(═O)2R2C1, —OS(═O)2R2C1, or —S(═O)2OR2C1; wherein:
each —R2A1 is independently saturated aliphatic C1-6alkyl;each —R2A2 is independently aliphatic C2-6alkenyl;each —R2A3 is independently aliphatic C2-6alkynyl;each —R2A4 is independently saturated C3-6cycloalkyl;each —R2A5 is independently C3-6cycloalkenyl;each —R2A6 is independently non-aromatic C3-8heterocyclyl;each —R2A7 is independently C6-10carboaryl;each —R2A8 is independently C5-10heteroaryl;each -L2A- is independently saturated aliphatic C1-3alkylene; wherein:
each —R2A4, —R2A5, —R2A6, —R2A7, and —R2A8 is optionally substituted, for example, with one or more substituents —R2B1 and/or one or more substituents —R2B2, and each —R2A1, —R2A2, —R2A3, and -L2A- is optionally substituted, for example, with one or more substituents —R2B2, wherein:
each —R2B1 is independently:
—R2D1, —R2D2, —R2D3, —R2D4, —R2D5, —R2D6, —R2D7, —R2D8,-L2D-R2D4, -L2D-R2D5, -L2D-R2D6, -L2D-R2D7, or -L2D-R2D8;each —R2B2 is independently:—F, —Cl, —Br, —I,—CF3, —OCF3,—OH, -L2C-OH, —O-L2C-OH,—OR2C1, -L2C-OR2C1, —O-L2C-OR2C1,—SH, —SR2C1,—CN,—NO2,—NH2, —NHR2C1, —NR2C12, —NR2C2R2C3,-L2C-NH2, -L2C-NHR2C1, -L2C-NR2C12, -L2C-NR2C2R2C3,—O-L2C-NH2, —O-L2C-NHR2C1, —O-L2C-NR2C12, —O-L2C-NR2C2R2C3,—C(═O)OH, —C(═O)OR2C1,—C(═O)R2C1,—C(═O)NH2, —C(═O)NHR2C1, —C(═O)NR2C12, —C(═O)NR2C2R2C3,—NHC(═O)R2C1, —NR2C1C(═O)R2C1,—NHC(═O)OR2C1, —NR2C1C(═O)OR2C1,—OC(═O)NH2, —OC(═O)NHR2C1, —OC(═O)NR2C12, —OC(═O)NR2C2R2C3,—NHC(═O)NH2, —NHC(═O)NHR2C1,—NHC(═O)NR2C12, —NHC(═O)NR2C2R2C3,—NR2C1C(═O)NH2, —NR2C1C(═O)NHR2C1,—NR2C1C(═O)NR2C12, —NR2C1C(═O)NR2C2R2C3,—NHS(═O)2R2C1, —NR2C1S(═O)2R2C1,—S(═O)2NH2, —S(═O)2NHR2C1, —S(═O)2NR2C12, —S(═O)2NR2C2R2C3,—S(═O)R2C1, —S(═O)2R2C1, —OS(═O)2R2C1, or —S(═O)2OR2C1; wherein:
each -L2C- is independently saturated aliphatic C1-5alkylene;in each group —NR2C2R2C3, R2C2 and R2C3, taken together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly 2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N, and the other of said exactly 2 ring heteroatoms is independently N or O;each —R2C1 is independently:
—R2D1, —R2D2, —R2D3, —R2D4, —R2D5, —R2D6, —R2D7, —R2D8,-L2D-R2D4, -L2D-R2D5, -L2D-R2D6, -L2D-R2D7, or -L2D-R2D8;each —R2D1 is independently saturated aliphatic C1-6alkyl;each —R2D2 is independently aliphatic C2-6alkenyl;each —R2D3 is independently aliphatic C2-6alkynyl;each —R2D4 is independently saturated C3-6cycloalkyl;each —R2D5 is independently C3-6cycloalkenyl;each —R2D6 is independently non-aromatic C3-8heterocyclyl;each —R2D7 is independently C6-10carboaryl;each —R2D8 is independently C5-10heteroaryl;each -L2D- is independently saturated aliphatic C1-3alkylene; wherein:
each —R2D4, —R2D5, —R2D6, —R2D7, and —R2D8 is optionally substituted, for example, with one or more substituents —R2E1 and/or one or more substituents —R2E2,each —R2D1, —R2D2, —R2D3, and -L2D- is optionally substituted, for example, with one or more substituents —R2E2, and wherein:
each —R2E1 is independently saturated aliphatic C1-4alkyl, phenyl, or benzyl;each —R2E2 is independently:—F, —Cl, —Br, —I,—CF3, —OCF3,—OH, -L2F-OH, —O-L2F-OH,—OR2F1, -L2F-OR2F1, —O-L2F-OR2F1,—SH, —SR2F1,—CN,—NO2,—NH2, —NHR2F1, —NR2F12, —NR2F2R2F3,-L2F-NH2, -L2F-NHR2F1, -L2F-NR2F12, -L2F-NR2F2R2F3,—C(═O)OH, —C(═O)OR2F1,—C(═O)NH2, —C(═O)NHR2F1, —C(═O)NR2F12, or —C(═O)NR2F2R2F3; wherein:
each —R2F1 is independently saturated aliphatic C1-4alkyl, phenyl, or benzyl;each -L2F- is independently saturated aliphatic C1-5alkylene; and in each group —NR2F2R2F3, R2F2 and R2F3, taken together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly 2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N, and the other of said exactly 2 ring heteroatoms is independently N or O.