Quinoxaline Derivatives as Antitumor Agents

A method of killing a cell, promoting cell death or inhibiting cellular proliferation, comprising administering to the cell:

• (1) an effective amount of a compound having a structure of Formula I or a pharmaceutically acceptable salt thereof,
• wherein
• R1 is selected from H, Z-Q-Z, —C1-8alkyl-N(R2)(R4), —C1-8alkyl-OR3, 3- to 8-membered carbocyclic or heterocyclic, aryl, heteroaryl, and C1-4aralkyl;
• R2 and R4 are each independently for each occurrence selected from H, C1-4alkyl, C1-4aralkyl, aryl, heteroaryl, acyl, alkylsulfonyl, and arylsulfonyl, provided that when both R2 and R4 are on the same N atom and not both H they are different and that when both R2 and R4 are on the same N and either R2 or R4 is acyl, alkylsulfonyl, or arylsulfonyl, then the other is selected from H, C1-8alkyl, aryl, C1-4aralkyl, and heteroaryl;
• R3 is selected from H, C1-4alkyl, C1-4 aralkyl, aryl, and heteroaryl;
• W is selected from
• Q is selected from O and NR2;
• and
• Z is independently for each occurrence selected from C1-6alkyl, C2-6alkenyl, and C2-6alkynyl;
• and
• (2) an agent that increases the abundance of VDAC in the cell.

A method of killing a cell, promoting cell death or inhibiting cellular proliferation, comprising administering to the cell:

• (1) an effective amount of a compound having a structure of Formula I or a pharmaceutically acceptable salt thereof,
• wherein
• R1 is selected from H, Z-Q-Z, —C1-8alkyl-N(R2)(R4), —C1-8alkyl-OR3, 3- to 8-membered carbocyclic or heterocyclic, aryl, heteroaryl, and C1-4aralkyl;
• R2 and R4 are each independently for each occurrence selected from H, C1-4alkyl, C1-4aralkyl, aryl, heteroaryl, acyl, alkylsulfonyl, and arylsulfonyl, provided that when both R2 and R4 are on the same N atom and not both H they are different and that when both R2 and R4 are on the same N and either R2 or R4 is acyl, alkylsulfonyl, or arylsulfonyl, then the other is selected from H, C1-8alkyl, aryl, C1-4aralkyl, and heteroaryl;
• R3 is selected from H, C1-4alkyl, C1-4aralkyl, aryl, and heteroaryl;
• W is
• Q is selected from O and NR2;
• and
• Z is independently for each occurrence selected from C1-6alkyl, C2-6alkenyl, and C2-6alkynyl;
• and
• (2) an agent that increases the abundance of VDAC in the cell.

A method of killing a cell, promoting cell death or inhibiting cellular proliferation, comprising administering to the cell:

• (1) an effective amount of a compound having a structure of Formula I or a pharmaceutically acceptable salt thereof,
• wherein
• R1 is selected from H, Z-Q-Z, —C1-8alkyl-N(R2)(R4), —C1-4alkyl-OR3, 3- to 8-membered carbocyclic or heterocyclic, aryl, heteroaryl, and C1-4aralkyl;
• R2 and R4 are each independently for each occurrence selected from H, C1-4alkyl, C1-4aralkyl, aryl, heteroaryl, acyl, alkylsulfonyl, and arylsulfonyl, provided that when both R2 and R4 are on the same N atom and not both H they are different and that when both R2 and R4 are on the same N and either R2 or R4 is acyl, alkylsulfonyl, or arylsulfonyl, then the other is selected from H, C1-8alkyl, aryl, C1-4aralkyl, and heteroaryl;
• R3 is selected from H, C1-4alkyl, C1-4aralkyl, aryl, and heteroaryl;
• W is selected from
• Q is selected from O and NR2;
• and
• Z is independently for each occurrence selected from C1-6alkyl, C2-6alkenyl, and C2-6alkynyl;
• and
• (2) an agent that decreases the abundance of VDAC in the cell.

A compound having a structure of Formula I or a pharmaceutically acceptable salt thereof,

• wherein
• R1 is selected from H, Z-Q-Z, —C1-8alkyl-N(R2)(R4), —C1-8alkyl-OR3, 3- to 8-membered carbocyclic or heterocyclic, aryl, heteroaryl, and C1-4aralkyl;
• R2 and R4 are each independently for each occurrence selected from H, C1-4alkyl, C1-4aralkyl, aryl, heteroaryl, acyl, alkylsulfonyl, and arylsulfonyl, provided that when both R2 and R4 are on the same N atom and not both H they are different and that when both R2 and R4 are on the same N and either R2 or R4 is acyl, alkylsulfonyl, or arylsulfonyl, then the other is selected from H, C1-8alkyl, aryl, C1-4aralkyl, and heteroaryl;
• R3 is selected from H, C1-4alkyl, C1-4aralkyl, aryl, and heteroaryl;
• W is selected from
• Q is selected from O and NR2;
• and
• Z is independently for each occurrence selected from C1-6alkyl, C2-6alkenyl, and C2-6alkynyl.

A compound having a structure of Formula I or a pharmaceutically acceptable salt thereof,

• wherein
• R1 is selected from H, Z-Q-Z, —C1-8alkyl-N(R2)(R4), —C1-8alkyl-OR3, 3- to 8-membered carbocyclic or heterocyclic, aryl, heteroaryl, and C1-4aralkyl;
• R2 and R4 are each independently for each occurrence selected from H, C1-4alkyl, C1-4aralkyl, aryl, heteroaryl, acyl, alkylsulfonyl, and arylsulfonyl, provided that when both R2 and R4 are on the same N atom and not both H they are different and that when both R2 and R4 are on the same N and either R2 or R4 is acyl, alkylsulfonyl, or arylsulfonyl, then the other is selected from H, C1-8alkyl, aryl, C1-4aralkyl, and heteroaryl;
• R3 is selected from H, C1-4alkyl, C1-4aralkyl, aryl, and heteroaryl;
• W is
• Q is selected from O and NR2;
• and
• Z is independently for each occurrence selected from C1-6alkyl, C2-6alkenyl, and C2-6alkynyl.

A method of identifying a candidate therapeutic agent for inhibiting unwanted cell proliferation, comprising:

• (a) admixing a test agent and a VDAC protein or a protein complex comprising at least one VDAC protein and optionally one or more other proteins;
• (b) determining whether the test agent binds to the VDAC protein;
• and
• (c) if the test agent binds to the VDAC protein, contacting the test agent with a cell and determining if the test agent alters proliferation of the cell.

A method of reducing the growth rate of a tumor, comprising administering an amount of a therapeutic agent sufficient to reduce the growth rate of the tumor, wherein the therapeutic agent is:

• (a) an agent which enhances or inhibits the level of a VDAC protein;
• (b) an agent which enhances or inhibits activity of a VDAC protein;
• (c) an agent which binds to a VDAC protein;
• (d) an agent which binds, modulates, or binds and modulates a protein complex comprising at least one VDAC and optionally one or more other proteins;
• (e) an agent comprising a VDAC polypeptide or functional variants thereof;
• or
• (f) an agent comprising a nucleic acid encoding a VDAC polypeptide or functional variants thereof.

A method for treating a patient suffering from a cancer, comprising administering to the patient a therapeutic agent selected from:

• (a) an agent which enhances or inhibits the level of a VDAC protein;
• (b) an agent which enhances or inhibits activity of a VDAC protein;
• (c) an agent which binds to a VDAC protein;
• (d) an agent which binds, modulates, or binds and modulates a protein complex comprising at least one VDAC and optionally one or more other proteins;
• (e) an agent comprising a VDAC polypeptide or functional variants thereof;
• and
• (f) an agent comprising a nucleic acid encoding a VDAC polypeptide or functional variants thereof.

A compound having a structure of formula II or a pharmaceutically acceptable salt thereof,

• wherein
• Ar is a substituted phenyl;
• R1 is selected from H, C1-8alkyl, -Z-Q-Z, —C1-8alkyl-N(R2)(R4), —C1-8alkyl-OR3, 3- to 8-membered carbocyclic or heterocyclic, aryl, heteroaryl, and C1-4aralkyl;
• R2 and R4 are each independently for each occurrence selected from H, C1-4alkyl, C1-4aralkyl, aryl, heteroaryl, acyl, alkylsulfonyl, and arylsulfonyl, provided that when both R2 and R4 are on the same N and either R2 or R4 is acyl, alkylsulfonyl, or arylsulfonyl, then the other is selected from H, C1-8alkyl, aryl, C1-4aralkyl, aryl, and heteroaryl;
• R3 is selected from H, C1-4alkyl, C1-4aralkyl, aryl, and heteroaryl;
• R5 represents 0-4 substituents on the ring to which it is attached;
• W is
• Q is selected from O and NR2;
• and
• Z is independently for each occurrence selected from C1-6alkyl, C2-6alkenyl, and C2-6alkynyl.

A compound having a structure of formula III or a pharmaceutically acceptable salt thereof,

• wherein
• Ar is a substituted phenyl;
• R1 is selected from H, C1-8alkyl, -Z-Q-Z, —C1-8alkyl-N(R2)(R4), —C1-8alkyl-OR3, 3- to 8-membered carbocyclic or heterocyclic, aryl, heteroaryl, and C1-4aralkyl;
• R2 and R4 are each independently for each occurrence selected from H, C1-4alkyl, C1-4aralkyl, aryl, heteroaryl, acyl, alkylsulfonyl, and arylsulfonyl, provided that when both R2 and R4 are on the same N atom and either R2 or R4 is acyl, alkylsulfonyl, or arylsulfonyl, then the other is selected from H, C1-8alkyl, aryl, C1-4aralkyl, and heteroaryl;
• R3 is selected from H, C1-4alkyl, C1-4aralkyl, aryl, and heteroaryl;
• R5 represents 0-4 substituents on the ring to which it is attached;
• W is selected from
• Q is selected from O and NR2;
• and
• Z is independently for each occurrence selected from C1-6alkyl, C2-6alkenyl, and C2-6alkynyl.

A compound having a structure of formula IV or a pharmaceutically acceptable salt thereof,

• wherein
• Ar is substituted phenyl;
• R1 is C1-8alkyl;
• R2 and R4 are each independently for each occurrence selected from H and C1-8alkyl;
• R5 represents 0-4 substituents on the ring to which it is attached;
• W is selected from
• and
• Q is selected from O and NR2.

A compound having a structure of formula V or a pharmaceutically acceptable salt thereof,

• wherein
• R1 is selected from H and C1-8alkyl;
• R2 is selected from H and C1-8alkyl;
• R3 is selected from halogen, alkoxy and C1-8alkyl;
• R4 is selected from H, halogen, alkoxy and C1-8alkyl;
• R5 is selected from H, halogen and nitro;
• and
• n is 1 or 2.

A method of killing a cell, promoting cell death or inhibiting cellular proliferation, comprising administering to the cell an effective amount of a compound having a structure of Formula I or a pharmaceutically acceptable salt thereof,

• wherein
• R1 is selected from H, Z-Q-Z, —C1-8alkyl-N(R2)(R4), —C1-8alkyl-OR3, 3- to 8-membered carbocyclic or heterocyclic, aryl, heteroaryl, and C1-4aralkyl;
• R2 and R4 are each independently for each occurrence selected from H, C1-4alkyl, C1-4aralkyl, aryl, heteroaryl, acyl, alkylsulfonyl, and arylsulfonyl, provided that when both R2 and R4 are on the same N atom and not both H they are different and that when both R2 and R4 are on the same N and either R2 or R4 is acyl, alkylsulfonyl, or arylsulfonyl, then the other is selected from H, C1-8alkyl, aryl, C1-4aralkyl, and heteroaryl;
• R3 is selected from H, C1-4alkyl, C1-4aralkyl, aryl, and heteroaryl;
• W is selected from
• Q is selected from O and NR2;
• and
• Z is independently for each occurrence selected from C1-6alkyl, C2-6alkenyl, and C2-6alkynyl.

A method of killing a cell, promoting cell death or inhibiting cellular proliferation, comprising administering to the cell an effective amount of a compound having a structure of Formula II or a pharmaceutically acceptable salt thereof,

• wherein
• Ar is a substituted phenyl;
• R1 is selected from H, C1-8alkyl, -Z-Q-Z, —C1-8alkyl-N(R2)(R4), —C1-8alkyl-OR3, 3- to 8-membered carbocyclic or heterocyclic, aryl, heteroaryl, and C1-4aralkyl;
• R2 and R4 are each independently for each occurrence selected from H, C1-4alkyl, C1-4aralkyl, aryl, heteroaryl, acyl, alkylsulfonyl, and arylsulfonyl, provided that when both R2 and R4 are on the same N and either R2 or R4 is acyl, alkylsulfonyl, or arylsulfonyl, then the other is selected from H, C1-8alkyl, aryl, C1-4aralkyl, aryl, and heteroaryl;
• R3 is selected from H, C1-4alkyl, C1-4aralkyl, aryl, and heteroaryl;
• R5 represents 0-4 substituents on the ring to which it is attached;
• W is
• Q is selected from O and NR2;
• and
• Z is independently for each occurrence selected from C1-6alkyl, C2-6alkenyl, and C2-6alkynyl.

A method of killing a cell, promoting cell death or inhibiting cellular proliferation, comprising administering to the cell an effective amount of a compound having a structure of Formula III or a pharmaceutically acceptable salt thereof,

• wherein
• Ar is a substituted phenyl;
• R1 is selected from H, C1-8alkyl, -Z-Q-Z, —C1-8alkyl-N(R2)(R4), —C1-8alkyl-OR3, 3- to 8-membered carbocyclic or heterocyclic, aryl, heteroaryl, and C1-4aralkyl;
• R2 and R4 are each independently for each occurrence selected from H, C1-4alkyl, C1-4aralkyl, aryl, heteroaryl, acyl, alkylsulfonyl, and arylsulfonyl, provided that when both R2 and R4 are on the same N atom and either R2 or R4 is acyl, alkylsulfonyl, or arylsulfonyl, then the other is selected from H, C1-8alkyl, aryl, C1-4aralkyl, and heteroaryl;
• R3 is selected from H, C1-4alkyl, C1-4aralkyl, aryl, and heteroaryl;
• R5 represents 0-4 substituents on the ring to which it is attached;
• W is selected from
• Q is selected from O and NR2;
• Z is independently for each occurrence selected from C1-6alkyl, C2-6alkenyl, and C2-6alkynyl;
• and
• wherein Ar does not have an ethoxy substituent at a position ortho to the bond to the nitrogen of the quinazolinone ring.

A method of killing a cell, promoting cell death or inhibiting cellular proliferation, comprising administering to the cell an effective amount of a compound having a structure of Formula IV or a pharmaceutically acceptable salt thereof,

• wherein
• Ar is substituted phenyl;
• R1 is C1-8alkyl;
• R2 and R4 are each independently for each occurrence selected from H and C1-8alkyl;
• R5 represents 0-4 substituents on the ring to which it is attached;
• W is selected from
• and
• Q is selected from O and NR2.

A method of killing a cell, promoting cell death or inhibiting cellular proliferation, comprising administering to the cell an effective amount of a compound having a structure of Formula V or a pharmaceutically acceptable salt thereof,

• wherein
• R1 is selected from H and C1-8alkyl;
• R2 is selected from H and C1-8alkyl;
• R3 is selected from halogen, alkoxy and C1-8alkyl;
• R4 is selected from H, halogen, alkoxy and C1-8alkyl;
• R5 is selected from H, halogen and nitro;
• and
• n is 1 or 2.

A method of preparing a compound represented by formula F,

• comprising reacting a compound D,
• with an amine HNR2 wherein,
• HNR2 is equivalent to HW;
• Ar is a substituted phenyl;
• R1 is selected from H, C1-8alkyl, -Z-Q-Z, —C1-8alkyl-N(R2)(R4), —C1-8alkyl-OR3, 3- to 8-membered carbocyclic or heterocyclic, aryl, heteroaryl, and C1-4aralkyl;
• R2 and R4 are each independently for each occurrence selected from H, C1-4alkyl, C1-4aralkyl, aryl, heteroaryl, acyl, alkylsulfonyl, and arylsulfonyl, provided that when both R2 and R4 are on the same N atom they are either both H or are different and that when both R2 and R4 are on the same N and either R2 or R4 is acyl, alkylsulfonyl, or arylsulfonyl, then the other is selected from H, C1-8alkyl, aryl, C1-4aralkyl, and heteroaryl;
• R3 is selected from H, C1-4alkyl, C1-4aralkyl, aryl, and heteroaryl;
• R5 represents 0-4 substituents on the ring to which it is attached;
• W is selected from
• Q is selected from O and NR2;
• Z is independently for each occurrence selected from C1-6alkyl, C2-6alkenyl, and C2-6alkynyl.