NOVEL ULK1 INHIBITORS AND METHODS USING SAME
In certain aspects, the invention provides a method for treating a disease or condition in a subject, the method comprising co-administering to a subject in need thereof a therapeutically effective amount of at least one ULK1-inhibiting pyrimidine, and a therapeutically effective amount of an mTOR inhibitor.
1 . A method for treating a disease or condition in a subject in need thereof, the method comprising administering to the subject in need thereof:
a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, having a structure of Formula A:
wherein in Formula A:
R 10 is selected from the group consisting of: halogen; —OR 11 , wherein R 11 is selected from the group consisting of H, optionally substituted aryl and optionally substituted heteroaryl; —NR 1 R 2 , wherein R 1 and R 2 are each individually selected from the group consisting of H, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted alkyl, or NR 1 R 2 together form a heterocycle;
or R 4 and R 10 together form a cyclic structure;
R 4 is selected from the group consisting of optionally substituted amino, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted alkoxy, N-heterocyclic, optionally substituted thiol, optionally substituted alkyl, hydroxyl and halogen;
R 5 is selected from the group consisting of H, hydroxyl, optionally substituted alkyl, halo, optionally substituted alkoxy, or optionally substituted aryl, optionally substituted carboxyl, cyano, and nitro,
or R 5 and R 6 together form a cyclic structure; and,
R 6 is H or haloalkyl.
2 . The method of claim 1 , wherein the method further comprises administering to the subject in need thereof a therapeutically effective amount of an mTOR inhibitor.
3 . The method of claim 1 , wherein the compound of Formula A is a compound selected from the group consisting of a 2-(substituted)amino-4-(substituted)amino-5-halo-pyrimidine, 2-(substituted)amino-4-(substituted)amino-5-(halo)alkyl-pyrimidine, 2-(substituted)amino-4-(substituted)oxo-5-halo-pyrimidine, 2-(substituted)amino-4-(substituted)oxo-5-(halo)alkyl-pyrimidine, 2-(substituted)amino-4-(substituted)thio-5-halo-pyrimidine, and 2-(substituted)amino-4-(substituted)thio-5-(halo)alkyl-pyrimidine.
4 . The method of claim 1 , wherein the disease or condition is at least one selected from the group consisting of pancreatic cancer and lung cancer.
5 . The method of claim 4 , wherein the disease or condition is non-small cell lung cancer.
6 . The method of claim 1 , wherein the disease or condition is mTOR-dependent.
7 . A method for treating an anticancer agent-resistant disease in a subject in need thereof, the method comprising administering to the subject having an anticancer agent-resistant disease a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, having a structure of Formula A:
wherein in Formula A:
R 10 is selected from the group consisting of: halogen; —OR 11 wherein R 11 is H, optionally substituted aryl, or optionally substituted heteroaryl; —NR 1 R 2 wherein R 1 and R 2 are each individually selected from the group consisting of H, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted alkyl, or NR 1 R 2 together form a heterocycle;
or R 4 and R 10 together form a cyclic structure;
R 4 is selected from the group consisting of optionally substituted amino, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted alkoxy, N-heterocyclic, optionally substituted thiol, optionally substituted alkyl, hydroxyl and halogen;
R 5 is selected from the group consisting of H, hydroxyl, optionally substituted alkyl, halo, optionally substituted alkoxy, or optionally substituted aryl, optionally substituted carboxyl, cyano, and nitro,
or R 5 and R 6 together form a cyclic structure; and
R 6 is H or haloalkyl.
8 . The method of claim 7 , wherein the anticancer agent-resistant disease comprises mTOR inhibitor-resistant cancer.
9 . The method of claim 8 , wherein the mTOR inhibitor-resistant cancer is at least one selected from the group consisting of non-small cell lung cancer and pancreatic cancer.
10 . The method of claim 1 , wherein the compound is selected from the group consisting of:
(i) a compound, or a pharmaceutically acceptable salt thereof, having a structure of:
wherein
R 1 is H;
R 2 is selected from the group consisting of
R 4 is selected from the group consisting of optionally substituted amino, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted alkoxy, N-heterocyclic, optionally substituted thiol, and optionally substituted alkyl;
R 5 is selected from the group consisting of H, hydroxy, optionally substituted alkyl, halo, optionally substituted alkoxy, and optionally substituted aryl; and
R 6 is H;
(ii) a compound, or a pharmaceutically acceptable salt thereof, having a structure of:
wherein
R 1 is H;
R 2 is selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted alkyl, or NR 1 R 2 together form a heterocycle;
R 4 is selected from the group consisting of optionally substituted aryloxy, optionally substituted heteroaryloxy, and optionally substituted alkoxy;
R 5 is selected from the group consisting of H, hydroxyl, optionally substituted alkyl, halo, optionally substituted alkoxy, and optionally substituted aryl; and
R 6 is H;
(iii) a compound, or a pharmaceutically acceptable salt thereof, having a structure of:
wherein:
R 1 is H;
R 2 is an optionally substituted heteroaryl fused ring;
R 4 is —NR 7 R 8 , wherein R 7 is H and R 8 is an optionally substituted heteroaryl fused ring;
R 5 is selected from the group consisting of H, hydroxyl, optionally substituted alkyl, halo, optionally substituted alkoxy, and optionally substituted aryl; and
R 6 is H.
11 . The method of claim 7 , wherein the compound is selected from the group consisting of:
(i) a compound, or a pharmaceutically acceptable salt thereof, having a structure of:
wherein
R 1 is H;
R 2 is selected from the group consisting
R 4 is selected from the group consisting of optionally substituted amino, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted alkoxy, N-heterocyclic, optionally substituted thiol, and optionally substituted alkyl;
R 5 is selected from the group consisting of H, hydroxy, optionally substituted alkyl, halo, optionally substituted alkoxy, and optionally substituted aryl; and
R 6 is H;
(ii) a compound, or a pharmaceutically acceptable salt thereof, having a structure of:
wherein
R 1 is H;
R 2 is selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted alkyl, or NR 1 R 2 together form a heterocycle;
R 4 is selected from the group consisting of optionally substituted aryloxy, optionally substituted heteroaryloxy, and optionally substituted alkoxy;
R 5 is selected from the group consisting of H, hydroxyl, optionally substituted alkyl, halo, optionally substituted alkoxy, and optionally substituted aryl; and
R 6 is H;
(iii) a compound, or a pharmaceutically acceptable salt thereof, having a structure of:
wherein:
R 1 is H;
R 2 is an optionally substituted heteroaryl fused ring;
R 4 is —NR 7 R 8 , wherein R 7 is H and R 8 is an optionally substituted heteroaryl fused ring;
R 5 is selected from the group consisting of H, hydroxyl, optionally substituted alkyl, halo, optionally substituted alkoxy, and optionally substituted aryl; and
R 6 is H.
12 . The method of claim 7 , wherein the compound of Formula A is a compound selected from the group consisting of a 2-(substituted)amino-4-(substituted)amino-5-halo-pyrimidine, 2-(substituted)amino-4-(substituted)amino-5-(halo)alkyl-pyrimidine, 2-(substituted)amino-4-(substituted)oxo-5-halo-pyrimidine, 2-(substituted)amino-4-(substituted)oxo-5-(halo)alkyl-pyrimidine, 2-(substituted)amino-4-(substituted)thio-5-halo-pyrimidine, and 2-(substituted)amino-4-(substituted)thio-5-(halo)alkyl-pyrimidine.
13 . A method for treating an autophagy-mediated condition in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of at least one ULK1 inhibitor.
14 . The method of claim 12 , wherein the compound has a structure of Formula I:
wherein in Formula I:
R 1 and R 2 are each individually selected from the group consisting of H, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted alkyl, or NR 1 R 2 together form a heterocycle;
R 4 is selected from the group consisting of optionally substituted amino, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted alkoxy, N-heterocyclic, optionally substituted thiol, and optionally substituted alkyl;
R 5 is selected from the group consisting of H, hydroxyl, optionally substituted alkyl, halo, optionally substituted alkoxy, and optionally substituted aryl; and
R 6 is H.
15 . The method of claim 13 , wherein the compound is selected from the group consisting of:
(i) a compound, or a pharmaceutically acceptable salt thereof, having a structure of:
wherein
R 1 is H;
R 2 is selected from the group consisting of
R 4 is selected from the group consisting of optionally substituted amino, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted alkoxy, N-heterocyclic, optionally substituted thiol, and optionally substituted alkyl;
R 5 is selected from the group consisting of H, hydroxy, optionally substituted alkyl, halo, optionally substituted alkoxy, and optionally substituted aryl; and
R 6 is H;
(ii) a compound, or a pharmaceutically acceptable salt thereof, having a structure of:
wherein
R 1 is H;
R 2 is selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted alkyl, or NR 1 R 2 together form a heterocycle;
R 4 is selected from the group consisting of optionally substituted aryloxy, optionally substituted heteroaryloxy, and optionally substituted alkoxy;
R 5 is selected from the group consisting of H, hydroxyl, optionally substituted alkyl, halo, optionally substituted alkoxy, and optionally substituted aryl; and
R 6 is H;
(iii) a compound, or a pharmaceutically acceptable salt thereof, having a structure of:
wherein:
R 1 is H;
R 2 is an optionally substituted heteroaryl fused ring;
R 4 is —NR 7 R 8 , wherein R 7 is H and R 8 is an optionally substituted heteroaryl fused ring;
R 5 is selected from the group consisting of H, hydroxyl, optionally substituted alkyl, halo, optionally substituted alkoxy, and optionally substituted aryl; and
R 6 is H.
16 . The method of claim 1 , wherein the compound of Formula A is a compound selected from the group consisting of a 2-(substituted)amino-4-(substituted)amino-5-halo-pyrimidine, 2-(substituted)amino-4-(substituted)amino-5-(halo)alkyl-pyrimidine, 2-(substituted)amino-4-(substituted)oxo-5-halo-pyrimidine, 2-(substituted)amino-4-(substituted)oxo-5-(halo)alkyl-pyrimidine, 2-(substituted)amino-4-(substituted)thio-5-halo-pyrimidine, and 2-(substituted)amino-4-(substituted)thio-5-(halo)alkyl-pyrimidine.