Modulators of RAS GTPase

1. A pharmaceutical composition comprising a therapeutically effective amount of a RAS modulating compound of the formula:

Cy 1 -Cy 2 —(CR 1 R 2 ) n —Y 1 —(CR 1 R 2 ) m -Cy 3

wherein:

Cy1 is a cyclic group selected from an oxadiazole and a thiadiazole;

Cy2 is a phenyl:

Cy3 is a pyrazole, wherein Cy1, Cy2 and Cy3 are optionally further substituted;

n and m are each independently 0, 1, 2, 3, 4, 5 or 6, wherein n+m is less than 7; each R1 and each R2 is independently H, an alkyl or a substituted alkyl; and

Y1 is selected from —CONR—, —NRCO—, —NRSO2- and —SO2NR— wherein R is H, an alkyl or a substituted alkyl;

or a salt thereof, and a pharmaceutically acceptable vehicle.

2. The pharmaceutical composition according to claim 1 , wherein the compound is of the formula:

wherein:

CL1 is Cy1;

CL6 and CL7 are each independently selected from hydrogen, halogen, —CN, —NO2, —OH, —ORa, —C(O)Ra, —CO2Ra, —O(CO)Ra, —C(O)NRaRb, —SRa, —SO2Ra, —SO2NRaRb, —NRaRb, —NRaC(O)Rb, —NRaC(O) 2 Rb, —NRaSO2Rb, —NRa(CO)NRbRc, unsubstituted or substituted C1-8 alkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted C3-8 cycloalkyl, unsubstituted or substituted C3-10 aryl, unsubstituted or substituted 5- to 10-membered heteroaryl, unsubstituted or substituted 3- to 10-membered heterocyclyl; wherein Ra, Rb and Rc are each independently selected from hydrogen, unsubstituted or substituted C1-6 haloalkyl, unsubstituted or substituted C1-6 alkyl, unsubstituted or substituted C3-6 cycloalkyl, unsubstituted or substituted C2-6 alkenyl, unsubstituted or substituted C2-6 alkynyl, unsubstituted or substituted C6-10 aryl, unsubstituted or substituted 5- to 10-membered heteroaryl, unsubstituted or substituted aryl-C1-4 alkyl, and unsubstituted or substituted aryloy-C1-4 alkyl; or two of Ra, Rb together or Ra and Rc together with the atom(s) to which they are attached, may form an unsubstituted or substituted 5-, 6- or 7-membered ring;

n is 1; and

CL2, CL3, CL4 and CL5 are each independently selected from hydrogen, alkyl and substituted alkyl.

3. The pharmaceutical composition according to claim 1 , wherein the compound is of the formula:

wherein:

CL1 is Cy1;

CL6 and CL7 are each independently selected from hydrogen, halogen, —CN, —NO2, —OH, —ORa, —C(O)Ra, —CO2Ra, —O(CO)Ra, —C(O)NRaRb, —SRa, —SO2Ra, —SO2NRaRb, —NRaRb, —NRaC(O)Rb, —NRaC(O) 2 Rb, —NRaSO2Rb, —NRa(CO)NRbRc, unsubstituted or substituted C1-8 alkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted C3-8 cycloalkyl, unsubstituted or substituted C3-10 aryl, unsubstituted or substituted 5- to 10-membered heteroaryl, unsubstituted or substituted 3- to 10-membered heterocyclyl; wherein Ra, Rb and Rc are each independently selected from hydrogen, unsubstituted or substituted C1-6 haloalkyl, unsubstituted or substituted C1-6 alkyl, unsubstituted or substituted C3-6 cycloalkyl, unsubstituted or substituted C2-6 alkenyl, unsubstituted or substituted C2-6 alkynyl, unsubstituted or substituted C6-10 aryl, unsubstituted or substituted 5- to 10-membered heteroaryl, unsubstituted or substituted aryl-C1-4 alkyl, and unsubstituted or substituted aryloy-C1-4 alkyl; or two of Ra, Rb together or Ra and Rc together with the atom(s) to which they are attached, may form an unsubstituted or substituted 5-, 6- or 7-membered ring;

n is 1; and

CL2, CL3, CL4 and CL5 are each independently selected from hydrogen, alkyl and substituted alkyl.

4. The pharmaceutical composition according to claim 2 , wherein the compound has a structure corresponding to the formula:

wherein:

CL11 is selected from hydrogen, halogen, —CN, —NO2, —OH, —ORa, —C(O)Ra, —CO2Ra, —O(CO)Ra, —C(O)NRaRb, —OC(O)NRaRb, —SRa, —SORa, —SO2Ra, —SO2NRaRb, —NRaRb, —NRaC(O)Rb, —NRaC(O) 2 Rb, —NRaSO2Rb, —NRa(CO)NRbRc, unsubstituted or substituted C1-8 alkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted C3-8 cycloalkyl, unsubstituted or substituted C3-10 aryl, unsubstituted or substituted 5- to 10-membered heteroaryl, unsubstituted or substituted 3- to 10-membered heterocyclyl; wherein Ra, Rb and Rc are each independently selected from hydrogen, unsubstituted or substituted C1-6 haloalkyl, unsubstituted or substituted C1-6 alkyl, unsubstituted or substituted C3-6 cycloalkyl, unsubstituted or substituted C2-6 alkenyl, unsubstituted or substituted C2-6 alkynyl, unsubstituted or substituted C6-10 aryl, unsubstituted or substituted 5- to 10-membered heteroaryl, unsubstituted or substituted aryl-C1-4 alkyl, and unsubstituted or substituted aryloy-C1-4 alkyl; or two of Ra, Rb together or Ra and Rc together with the atom(s) to which they are attached, may form an unsubstituted or substituted 5-, 6- or 7-membered ring.

5. The pharmaceutical composition according to claim 3 , wherein the compound is of the formula:

6. The pharmaceutical composition according to claim 4 , wherein the compound has the following structure:

7. The pharmaceutical composition according to claim 2 , wherein the compound has the following structure:

8. A method of modulating the activity of a target RAS in a sample, the method comprising:

contacting a sample comprising a target RAS with an effective amount of the pharmaceutical composition of claim 1 to modulate the activity of the target RAS.

9. A method of treating a subject for a RAS driven disease, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 1 .