Aminopyrimidine amide autophagy inhibitors and methods of use thereof
Described herein are compounds that are inhibitors of autophagy and their use in the treatment of disorders such as cancers.
1. A compound represented by:
or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein:
W is CH or N;
X is CH or N;
Y is C(R 33 ) or N;
provided that both X and Y are not N;
R 1 is selected from the group consisting of halogen, cyano, C 1 -C 5 alkyl, and C 3 -C 5 cycloalkyl, wherein C 1 -C 5 alkyl and C 3 -C 5 cycloalkyl may be optionally substituted by one, two or three independent occurrences of fluorine;
R 2 is selected from the group consisting of halogen, cyano, C 1 -C 5 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl, C 1 -C 5 alkoxy, and C 1 -C 5 alkoxy-C 2 -C 5 alkyl, wherein each C 1 -C 5 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl, and C 1 -C 5 alkoxy may be optionally substituted by one, two, or three independent occurrences of fluorine or cyano;
R 3 is selected from the group consisting of H, C 1 -C 3 alkyl, and C 3 -C 5 cycloalkyl, wherein C 1 -C 3 alkyl and C 3 -C 5 cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine;
R 33 is selected from the group consisting of H, halogen, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy, wherein C 1 -C 6 alkyl, and C 1 -C 6 alkoxy may be optionally substituted by one or more independent occurrences of fluorine;
R 4 is selected from the group consisting of B, D, NR 6 R 9 , NR 6 —(C(R 10 ) 2 ) p —NR 6 R 9 , and C(O)—D;
B is selected from an N-linked heterocyclyl having at least one nitrogen and optionally having an additional ring nitrogen or oxygen and heteroaryl, wherein B may be optionally substituted on one or more available carbons by R 7 and may be optionally substituted on an available nitrogen by R 9 ;
D is selected from a C-linked heterocyclyl having at least one nitrogen and optionally having an additional ring nitrogen or oxygen and heteroaryl, wherein D may be optionally substituted on one or more available carbons by R 7 and may be optionally substituted on an available nitrogen by R 9 ;
each occurrence of R 7 is independently selected from the group consisting of H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, cyano, and)(C(R 10 ) 2 ) h —NR 6 R 9 , wherein C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine, or two R 7 are joined together with the atom to which they are attached to form oxo;
R 6 is selected from the group consisting of H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 5 alkoxy-C 2 -C 5 alkyl, C(═O)R 5 , SO 2 R 5 , C-linked heterocyclyl having at least one nitrogen and optionally having an additional ring nitrogen or oxygen, and heteroaryl, wherein C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine;
R 9 is selected from the group consisting of H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 5 alkoxy-C 2 -C 5 alkyl, C(═O)R 5 , SO 2 R 5 , C-linked heterocyclyl having at least one nitrogen and optionally having an additional ring nitrogen or oxygen, and heteroaryl, wherein C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine;
R 5 is selected from the group consisting of H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and heterocyclyl, wherein C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine;
each occurrence of R 10 is independently selected from the group consisting of H, C 1 -C 3 alkyl, and C 3 -C 5 cycloalkyl, wherein C 1 -C 3 alkyl and C 3 -C 5 cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine, or two R 10 are joined together with the carbon to which they are attached to form a C 3 -C 5 cycloalkyl;
R L is selected from the group consisting of C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl, NR 11 R 12 , and
wherein each C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl may be optionally substituted by 1, 2, or 3 independent occurrences of fluorine;
U is N or CR 13 ;
V is selected from the group consisting of oxygen, C(R 34 ) 2 , and NR 6 ;
r is 0, 1, or 2;
q is 1, 2, or 3;
R 11 is selected from the group consisting of H, C 1 -C 3 alkyl, and C 3 -C 5 cycloalkyl, wherein C 1 -C 3 alkyl and C 3 -C 5 cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine;
R 12 is selected from the group consisting of H, C 1 -C 3 alkyl, and C 3 -C 5 cycloalkyl, wherein C 1 -C 3 alkyl and C 3 -C 5 cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine;
R 13 is selected from H and C 1 -C 3 alkyl;
each occurrence of R 34 is independently selected from H, C 1 -C 3 alkyl, and C 3 -C 5 cycloalkyl, wherein C 1 -C 3 alkyl and C 3 -C 5 cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine, or two R 34 are joined together with the carbon to which they are attached to form a C 3 -C 6 cycloalkyl;
L is —(C(R 10 ) 2 ) m —;
h is 1, 2, or 3;
m is 0, 1, 2, or 3;
n is 2, 3, or 4; and
p is 2 or 3;
provided that when r is 0 and q is 1, then U is not CR 13 and V is not O, and when r or q is 1, then U is not N and V is not O or NR 6 .
2. The compound of claim 1 , wherein R 4 is selected from the group consisting of:
wherein u is 1 or 2.
3. The compound of claim 1 , wherein R 4 is selected from the group consisting of:
4. The compound of claim 1 , wherein R 1 is selected from the group consisting of halogen, C 1 -C 5 alkyl, and C 3 -C 5 cycloalkyl, wherein C 1 -C 5 alkyl and C 3 -C 5 cycloalkyl may be optionally substituted with one, two, or three independent occurrences of fluorine.
5. The compound of claim 1 , wherein R 1 is selected from the group consisting of C 3 -C 5 cycloalkyl, C 1 -C 5 alkyl, halogen, CN, C 2 -C 5 alkenyl, and C 2 -C 5 alkynyl, wherein C 3 -C 5 cycloalkyl, C 1 -C 5 alkyl, C 2 -C 5 alkenyl, and C 2 -C 5 alkynyl may be optionally substituted with one, two, or three independent occurrences of fluorine.
6. The compound of claim 1 , wherein R 3 is selected from the group consisting of H and C 1 -C 3 alkyl, wherein C 1 -C 3 alkyl may be optionally substituted by one or more independent occurrences of fluorine.
7. The compound of claim 1 , wherein R L is selected from the group consisting of C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl, each of which may be optionally substituted by 1, 2, or 3 independent occurrences of fluorine.
8. The compound of claim 1 , wherein R L is NR 11 R 12 .
9. The compound of claim 1 , wherein R L is
wherein each C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl may be optionally substituted by 1, 2, or 3 independent occurrences of fluorine; U is N or CR 13 ; V is selected from the group consisting of oxygen, C(R 34 ) 2 , and NR 6 ; r is 0, 1, or 2; q is 1, 2, or 3; R 13 is selected from H and C 1 -C 3 alkyl; and each occurrence of R 34 is independently selected from H, C 1 -C 3 alkyl, and C 3 -C 5 cycloalkyl, wherein C 1 -C 3 alkyl and C 3 -C 5 cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine, or two R 34 are joined together with the carbon to which they are attached to form a C 3 -C 6 cycloalkyl; provided that when r is 0 and q is 1, then U is not CR 13 and V is not O, and when r or q is 1, then U is not N and V is not O or NR 6 .
10. The compound of claim 1 represented by:
or a pharmaceutically acceptable salt thereof, wherein:
n is 2, 3, or 4;
R 1 is selected from the group consisting of halogen, cyano, C 1 -C 5 alkyl, and C 3 -C 5 cycloalkyl, wherein C 1 -C 5 alkyl and C 3 -C 5 cycloalkyl may be optionally substituted by one, two or three independent occurrences of fluorine;
R 2 is selected from the group consisting of C 1 -C 2 alkyl and C 3 -C 4 cycloalkyl, and halogen, wherein C 1 -C 2 alkyl and C 3 -C 4 cycloalkyl may be optionally substituted by one, two or three independent occurrences of fluorine;
R 3 is selected from the group consisting of H, C 1 -C 3 alkyl, and C 3 -C 5 cycloalkyl, wherein C 1 -C 3 alkyl and C 3 -C 5 cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine;
R 4 is selected from the group consisting of:
R 9 is selected from the group consisting of H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C(═O)R 5 , SO 2 R 5 , C-linked heterocyclyl having at least one nitrogen and optionally having an additional ring nitrogen or oxygen and heteroaryl, wherein C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine;
R 5 is selected from the group consisting of H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and heterocyclyl, wherein C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine;
each occurrence of R 7 is independently selected from the group consisting of H, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl, wherein C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine, or two R 7 are joined together with the atom to which they are attached to form oxo;
R L is selected from the group consisting of C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl, NR 11 R 12 , and
wherein each C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl may be optionally substituted by 1, 2, or 3 independent occurrences of fluorine;
U is N or CR 13 ;
V is selected from the group consisting of oxygen, C(R 34 ) 2 , and NR 6 ;
r is 0, 1, or 2;
q is 1, 2, or 3;
R 6 is selected from the group consisting of H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C(═O)R 5 , SO 2 R 5 , C-linked heterocyclyl having at least one nitrogen and optionally having an additional ring nitrogen or oxygen and heteroaryl, wherein C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine;
R 11 is selected from the group consisting of H, C 1 -C 3 alkyl, and C 3 -C 5 cycloalkyl, wherein C 1 -C 3 alkyl and C 3 -C 5 cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine;
R 12 is selected from the group consisting of H, C 1 -C 3 alkyl, and C 3 -C 5 cycloalkyl, wherein C 1 -C 3 alkyl and C 3 -C 5 cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine;
R 13 is selected from H and C 1 -C 3 alkyl; and
each occurrence of R 34 is independently selected from H, C 1 -C 3 alkyl, and C 3 -C 5 cycloalkyl, wherein C 1 -C 3 alkyl and C 3 -C 5 cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine, or two R 34 are joined together with the carbon to which they are attached to form a C 3 -C 6 cycloalkyl;
provided when r is 0 and q is 1, then U is not CR 13 and V is not O, and when r or q is 1, then U is not N and V is not O or NR 6 .
11. The compound of claim 1 represented by:
or a pharmaceutically acceptable salt thereof, wherein:
n is 2, 3, or 4;
R 1 is selected from the group consisting of halogen, cyano, C 1 -C 5 alkyl, and C 3 -C 5 cycloalkyl, wherein C 1 -C 5 alkyl and C 3 -C 5 cycloalkyl may be optionally substituted by one, two or three independent occurrences of fluorine;
R 2 is selected from the group consisting of C 1 -C 2 alkyl and C 3 -C 4 cycloalkyl, and halogen, wherein C 1 -C 2 alkyl and C 3 -C 4 cycloalkyl may be optionally substituted by one, two or three independent occurrences of fluorine;
R 3 is selected from the group consisting of H, C 1 -C 3 alkyl, and C 3 -C 5 cycloalkyl, wherein C 1 -C 3 alkyl and C 3 -C 5 cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine;
R 4 is selected from the group consisting of:
R 9 is independently selected from the group consisting of H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C(═O)R 5 , SO 2 R 5 , C-linked heterocyclyl having at least one nitrogen and optionally having an additional ring nitrogen or oxygen and heteroaryl, wherein C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine;
R 5 is selected from the group consisting of H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and heterocyclyl, wherein C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine;
each occurrence of R 7 is independently selected from the group consisting of H, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl, wherein C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine, or two R 7 are joined together with the atom to which they are attached to form oxo;
R L is selected from the group consisting of C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl, NR 11 R 12 , and
wherein each C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl may be optionally substituted by 1, 2, or 3 independent occurrences of fluorine;
U is N or CR 13 ;
V is selected from the group consisting of oxygen, C(R 34 ) 2 , and NR 6 ;
r is 0, 1, or 2;
q is 1, 2, or 3;
R 6 is selected from the group consisting of H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C(═O)R 5 , SO 2 R 5 , C-linked heterocyclyl having at least one nitrogen and optionally having an additional ring nitrogen or oxygen and heteroaryl, wherein C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine;
R 11 is selected from the group consisting of H, C 1 -C 3 alkyl, and C 3 -C 5 cycloalkyl, wherein C 1 -C 3 alkyl and C 3 -C 5 cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine;
R 12 is selected from the group consisting of H, C 1 -C 3 alkyl, and C 3 -C 5 cycloalkyl, wherein C 1 -C 3 alkyl and C 3 -C 5 cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine;
R 13 is selected from H and C 1 -C 3 alkyl; and
each occurrence of R 34 is independently selected from H, C 1 -C 3 alkyl, and C 3 -C 5 cycloalkyl, wherein C 1 -C 3 alkyl and C 3 -C 5 cycloalkyl may be optionally substituted by one or more independent occurrences of fluorine, or two R 34 are joined together with the carbon to which they are attached to form a C 3 -C 6 cycloalkyl;
provided when r is 0 and q is 1, then U is not CR 13 and V is not O, and when r or q is 1, then U is not N and V is not O or NR 6 .
12. The compound of claim 1 selected from the group consisting of: N-(3-((5-cyclopropyl-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pivalamide, N-(3-((5-bromo-2-((2-isopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((5-cyclopropyl-2-((2-isopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((4-methyl-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((5-chloro-2-((2-isopropoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((5-chloro-2-((2-methyl-4-(piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-N-methylcyclobutanecarboxamide, N-methyl-N-(3-((2-((2-methyl-4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((5-chloro-2-((2-methyl-4-(1-methylpiperidin-4-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-N-methylcyclobutanecarboxamide, N-methyl-N-(3-((2-((2-methyl-4-(1-methylpiperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((4-methyl-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((4-methyl-6-morpholinopyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-isopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((5-cyclopropyl-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((5-bromo-2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-ethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octan-4-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-3,3-difluorocyclobutane-1-carboxamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)isobutyramide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pivalamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclopropanecarboxamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)oxetane-3-carboxamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)tetrahydrofuran-3-carboxamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)tetrahydro-2H-pyran-4-carboxamide, N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)oxetane-3-carboxamide, N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)tetrahydrofuran-3-carboxamide, N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)tetrahydro-2H-pyran-4-carboxamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N-methylcyclobutanecarboxamide, N-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N-methylcyclobutanecarboxamide, N-(3-((2-((2-ethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N-methylcyclobutanecarboxamide, N-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octan-4-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N-methylcyclobutanecarboxamide, N-(3-((2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N-methylcyclobutanecarboxamide, N-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-N-methylcyclobutanecarboxamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-3,3-difluoro-N-methylcyclobutane-1-carboxamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N-methylisobutyramide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N-methylpivalamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N-methyloxetane-3-carboxamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N-methyltetrahydrofuran-3-carboxamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N-methyltetrahydro-2H-pyran-4-carboxamide, N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-N-methylcyclobutanecarboxamide, N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-N-methyloxetane-3-carboxamide, N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-N-methyltetrahydrofuran-3-carboxamide, N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-N-methyltetrahydro-2H-pyran-4-carboxamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1-methylazetidine-3-carboxamide, N-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1-methylazetidine-3-carboxamide, N-(3-((2-((2-ethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1-methylazetidine-3-carboxamide, N-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octan-4-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1-methylazetidine-3-carboxamide, N-(3-((2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1-methylazetidine-3-carboxamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N,1-dimethylazetidine-3-carboxamide, N-(3-((5-chloro-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1-methylazetidine-3-carboxamide, N-(3-((5-chloro-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-N,1-dimethylazetidine-3-carboxamide, N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1-methylazetidine-3-carboxamide, N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-N,1-dimethylazetidine-3-carboxamide, N-(3-((2-((2-bromo-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-bromo-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-bromo-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octan-4-yl)-2-bromophenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-bromo-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-bromo-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-chloro-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-chloro-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octan-4-yl)-2-chlorophenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-chloro-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-cyano-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-cyano-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((4-(4-methylpiperazin-1-yl)-2-(trifluoromethyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-(difluoromethyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-N-methylcyclobutanecarboxamide, N-(3-((5-chloro-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyridin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyridin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyridin-4-yl)amino)propyl)cyclobutanecarboxamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azetidine-1-carboxamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-N-methylazetidine-1-carboxamide, 3-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,1-dimethylurea, 1-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3,3-trimethylurea, N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)azetidine-1-carboxamide, N-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidine-1-carboxamide, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-3,3-dimethylazetidine-1-carboxamide, 3-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,1-dimethylurea, N-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-2,2-dimethylazetidine-1-carboxamide, 3-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,1-dimethylurea, 1-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,3,3-trimethylurea, and pharmaceutically acceptable salts, enantiomers, stereoisomers, and tautomers thereof.
13. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.
14. A pharmaceutical composition comprising a compound of claim 1 , one or more additional therapeutic agents, and a pharmaceutically acceptable excipient.
15. The pharmaceutical composition of claim 14 , wherein the composition comprises one additional therapeutic agent.
16. The pharmaceutical composition of claim 14 , wherein the additional therapeutic agent is a MAPKAP pathway inhibitor.
17. The pharmaceutical composition of claim 16 , wherein the MAPKAP pathway inhibitor is selected from the group consisting of a MEK inhibitor, an ERK inhibitor, a RAF inhibitor, and a Ras inhibitor.
18. The pharmaceutical composition of claim 17 , wherein the MEK inhibitor is selected from the group consisting of trametinib, selumetinib, cobimetinib, binimetinib, and pharmaceutically acceptable salts thereof; the ERK inhibitor is selected from the group consisting of ulixertinib, SCH772984, LY3214996, ravoxertinib, VX-11e, and pharmaceutically acceptable salts thereof; the RAF inhibitor is selected from the group consisting of LY3009120, LXH254, RAF709, dabrafenib, vemurafenib, and pharmaceutically acceptable salts thereof; or the Ras inhibitor is selected from the group consisting of AMG-510, MRTX849, and pharmaceutically acceptable salts thereof.
19. The pharmaceutical composition of claim 14 , wherein the additional therapeutic agent is a chemotherapeutic agent.
20. The pharmaceutical composition of claim 19 , wherein the chemotherapeutic agent is a selected from the group consisting of anti-tubulin agents, vinorelbine, DNA-alkylating agents, DNA intercalating agents, 5-fluorouracil, capecitabine, cytarabine, decitabine, 5-aza cytadine, gemcitabine, and methotrexate.