Methods of treatment associated with the granulocyte colony-stimulating factor receptor

1. A method for treating, preventing, reversing, halting, or slowing the progression of cancer selected from the group consisting of leukemia, non-small cell lung cancer, colon cancer, CNS cancer, skin cancer, ovarian cancer, renal cancer, prostate cancer, breast cancer, and myeloma, comprising administering to a subject in need thereof an effective amount of a compound of Formula (I) or (III):

a tautomer thereof, or a pharmaceutically acceptable salt thereof,

wherein:

R 1 is selected from hydrogen, OR 6 , NO 2 , CN, NR 6 R 7 , CO 2 R 6 , C(═O)NR 6 R 7 , SO 3 R 6 , SO 2 NR 6 R 8 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 2 -C 6 alkenyl, an optionally substituted C 2 -C 6 alkynyl, an optionally substituted C 1 -C 6 heteroalkyl, an optionally substituted C 3 -C 6 cycloalkyl, an optionally substituted C 3 -C 6 cycloalkenyl, an optionally substituted C 2 -C 6 heterocyclyl, an optionally substituted arylalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;

R 2 and R 3 are independently selected from hydrogen, an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 2 -C 6 alkenyl, an optionally substituted C 2 -C 6 alkynyl, an optionally substituted C 1 -C 6 heteroalkyl, an optionally substituted C 3 -C 8 cycloalkyl, an optionally substituted C 3 -C 8 cycloalkenyl, an optionally substituted C 1 -C 6 heterocycle, an optionally substituted aryl, and an optionally substituted heteroaryl;

R 4 is selected from hydrogen, an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 2 -C 6 alkenyl, an optionally substituted C 2 -C 6 alkynyl, an optionally substituted C 1 -C 6 heteroalkyl, an optionally substituted C 3 -C 8 cycloalkyl, an optionally substituted C 3 -C 8 cycloalkenyl, an optionally substituted C 1 -C 6 heterocycle, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted arylalkyl, an optionally substituted arylalkenyl, an optionally substituted arylalkynyl, and an optionally substituted heteroarylalkyl;

R 5 is selected from hydrogen, halogen, NO 2 , CN, CF 3 , OR 6 , CO 2 R 6 , C(═O)NR 6 R 7 , SO 3 R 6 , and SO 2 NR 6 R 8 , an optionally substituted aryl, an optionally substituted C 1 -C 6 alkyl, and an optionally substituted C 1 -C 6 heteroalkyl;

R 6 is selected from hydrogen, an optionally substituted C 1 -C 6 alkyl, a C 1 -C 6 heteroalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;

R 7 is selected from hydrogen, C(═O)R 8 , C(═O)NHR 8 , an optionally substituted C 1 -C 6 alkyl, and an optionally substituted C 1 -C 6 heteroalkyl; or —NR 6 R 7 is an optionally substituted non-aromatic heterocycle linked through a ring nitrogen;

R 8 is selected from hydrogen, an optionally substituted C 1 -C 6 alkyl, and an optionally substituted C 1 -C 6 heteroalkyl;

Q is selected from the group consisting of NR 6 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 8 cycloalkyl, an optionally substituted C 1 -C 6 heteroalkyl, and an optionally substituted non-aromatic heterocycle;

L 1 is selected from NH and CHR 2 ;

Z is O (oxygen) or S (sulfur); and

n is 1, 2 or 3.

2. The method of claim 1 , wherein the leukemia is selected from the group consisting of chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), T-cell prolymphocytic leukemia, large granular lymphocytic leukemia, adult T-cell leukemia, juvenile myelomonocytic leukemia, and hairy cell leukemia.

3. The method of claim 1 , with the proviso that if R 2 is methyl, R 4 is phenyl, L 1 is NH, and Q is N-Ph-R 1 in Formula I, R 1 of Formula I is not selected from the group of halogen, alkyl, substituted alkyl, carboxylic acid, and carboxylic esters.

4. The method of claim 1 , wherein the compound has the structure of Formula (Ia):

a tautomer thereof, or a pharmaceutically acceptable salt thereof,

wherein:

R 1 is selected from hydrogen, an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 6 cycloalkyl, an optionally substituted C 3 -C 6 cycloalkenyl, an optionally substituted C 2 -C 6 heterocyclyl, an optionally substituted aryl, and an optionally substituted heteroaryl;

R 2 and R 3 are independently selected from hydrogen, an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 8 cycloalkyl, an optionally substituted C 1 -C 6 heterocycle, an optionally substituted aryl, and an optionally substituted heteroaryl;

R 4 is selected from hydrogen, an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 8 cycloalkyl, an optionally substituted C 3 -C 8 cycloalkenyl, an optionally substituted C 1 -C 6 heterocycle, an optionally substituted aryl, and an optionally substituted heteroaryl;

Q is selected from an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 8 cycloalkyl, and an optionally substituted non-aromatic heterocycle; and

Z is O (oxygen) or S (sulfur).

5. The method of claim 4 , wherein:

R 1 is selected from hydrogen, and an optionally substituted C 1 -C 6 alkyl;

R 2 and R 3 are independently selected from hydrogen, and an optionally substituted C 1 -C 6 alkyl;

R 4 is selected from hydrogen, an optionally substituted C 1 -C 6 alkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;

Q is selected from an optionally substituted C 1 -C 6 alkyl, and an optionally substituted C 3 -C 8 cycloalkyl; and

Z is O (oxygen).

6. The method of claim 1 , wherein the compound is selected from:

a tautomer thereof, or pharmaceutically acceptable salt thereof.

7. The method of claim 1 , wherein the compound is selected from:

a tautomer thereof, or pharmaceutically acceptable salt thereof.

8. The method of claim 1 , wherein the compound is selected from:

a tautomer thereof, or pharmaceutically acceptable salt thereof.

9. The method of claim 4 , wherein the compound is:

10. The method of claim 1 , wherein the compound has the structure of Formula (IIIa):

a tautomer thereof, or a pharmaceutically acceptable salt thereof,

wherein:

R 1 is selected from hydrogen, OR 6 , NR 6 R 7 , CO 2 R 6 , C(═O)NR 6 R 7 , an optionally substituted C 2 -C 6 heterocyclyl, an optionally substituted arylalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;

R 2 is selected from hydrogen, an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 8 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;

R 4 is selected from hydrogen, an optionally substituted C 1 -C 6 alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted arylalkyl, and an optionally substituted heteroarylalkyl;

R 5 is selected from hydrogen, halogen, CN, CF 3 , OR 6 , an optionally substituted aryl, and an optionally substituted C 1 -C 6 alkyl;

R 6 is selected from hydrogen, an optionally substituted C 1 -C 6 alkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;

R 7 is selected from hydrogen, C(═O)R 8 , C(═O)NHR 8 , and an optionally substituted C 1 -C 6 alkyl; or —NR 6 R 7 is an optionally substituted non-aromatic heterocycle linked through a ring nitrogen;

R 8 is selected from hydrogen, and an optionally substituted C 1 -C 6 alkyl;

Q is selected from NR 6 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 8 cycloalkyl, and an optionally substituted non-aromatic heterocyclyl;

Z is O (oxygen) or S (sulfur); and

n is 1, or 2.

11. The method of claim 10 , wherein:

R 1 is selected from hydrogen, OR 6 , NR 6 R 7 , CO 2 R 6 , C(═O)NR 6 R 7 , an optionally substituted C 2 -C 6 heterocyclyl, an optionally substituted arylalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;

R 2 is selected from hydrogen, an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 8 cycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;

R 4 is selected from hydrogen, an optionally substituted C 1 -C 6 alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted arylalkyl, and an optionally substituted heteroarylalkyl;

R 5 is selected from hydrogen, halogen, CN, CF 3 , OR 6 , an optionally substituted aryl, and an optionally substituted C 1 -C 6 alkyl;

R 6 is selected from hydrogen, and an optionally substituted C 1 -C 6 alkyl;

R 7 is selected from hydrogen, C(═O)R 8 , C(═O)NHR 8 , and an optionally substituted C 1 -C 6 alkyl;

R 8 is selected from hydrogen, and an optionally substituted C 1 -C 6 alkyl;

Q is selected from NR 6 , an optionally substituted C 1 -C 4 alkyl, an optionally substituted C 3 -C 6 cycloalkyl, and an optionally substituted non-aromatic heterocyclyl;

Z is O (oxygen); and

n is 1.

12. The method of claim 11 , wherein:

R 1 is selected from hydrogen, OR 6 , NR 6 R 7 , C(═O)NR 6 R 7 , an optionally substituted arylalkyl, and an optionally substituted heteroaryl;

R 2 is selected from hydrogen, an optionally substituted C 1 -C 6 alkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;

R 4 is an optionally substituted aryl;

R 5 is selected from hydrogen, chloro, CN, CF 3 , OR 6 , an optionally substituted aryl, and an optionally substituted C 1 -C 6 alkyl;

R 6 is selected from hydrogen, and an optionally substituted C 1 -C 3 alkyl;

R 7 is selected from hydrogen, C(═O)R 8 , C(═O)NHR 8 , and an optionally substituted C 1 -C 3 alkyl;

R 8 is selected from hydrogen, and an optionally substituted C 1 -C 3 alkyl; and

Q is selected from optionally substituted C 1 -C 3 alkyl, an optionally substituted C 3 -C 6 cycloalkyl, and an optionally substituted non-aromatic heterocyclyl.

13. The method of claim 10 , wherein R 1 is C(═O)NR 6 R 7 .

14. A method of inhibiting proliferation of a neoplastic cell selected from the group consisting of a leukemia cell, a lung cancer cell, a kidney cancer cell, and a liver cancer cell, comprising: contacting the cell with an effective amount of a compound of Formula (I) or (III):

a tautomer thereof, or a pharmaceutically acceptable salt thereof,

wherein:

R 1 is selected from hydrogen, OR 6 , NO 2 , CN, NR 6 R 7 , CO 2 R 6 , C(═O)NR 6 R 7 , SO 3 R 6 , SO 2 NR 6 R 8 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 2 -C 6 alkenyl, an optionally substituted C 2 -C 6 alkynyl, an optionally substituted C 1 -C 6 heteroalkyl, an optionally substituted C 3 -C 6 cycloalkyl, an optionally substituted C 3 -C 6 cycloalkenyl, an optionally substituted C 2 -C 6 heterocyclyl, an optionally substituted arylalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;

R 2 and R 3 are independently selected from hydrogen, an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 2 -C 6 alkenyl, an optionally substituted C 2 -C 6 alkynyl, an optionally substituted C 1 -C 6 heteroalkyl, an optionally substituted C 3 -C 8 cycloalkyl, an optionally substituted C 3 -C 8 cycloalkenyl, an optionally substituted C 1 -C 6 heterocycle, an optionally substituted aryl, and an optionally substituted heteroaryl;

R 4 is selected from hydrogen, an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 2 -C 6 alkenyl, an optionally substituted C 2 -C 6 alkynyl, an optionally substituted C 1 -C 6 heteroalkyl, an optionally substituted C 3 -C 8 cycloalkyl, an optionally substituted C 3 -C 8 cycloalkenyl, an optionally substituted C 1 -C 6 heterocycle, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted arylalkyl, an optionally substituted arylalkenyl, an optionally substituted arylalkynyl, and an optionally substituted heteroarylalkyl;

R 5 is selected from hydrogen, halogen, NO 2 , CN, CF 3 , OR 6 , CO 2 R 6 , C(═O)NR 6 R 7 , SO 3 R 6 , and SO 2 NR 6 R 8 , an optionally substituted aryl, an optionally substituted C 1 -C 6 alkyl, and an optionally substituted C 1 -C 6 heteroalkyl;

R 6 is selected from hydrogen, an optionally substituted C 1 -C 6 alkyl, a C 1 -C 6 heteroalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;

R 7 is selected from hydrogen, C(═O)R 8 , C(═O)NHR 8 , an optionally substituted C 1 -C 6 alkyl, and an optionally substituted C 1 -C 6 heteroalkyl; or —NR 6 R 7 is an optionally substituted non-aromatic heterocycle linked through a ring nitrogen;

R 8 is selected from hydrogen, an optionally substituted C 1 -C 6 alkyl, and an optionally substituted C 1 -C 6 heteroalkyl;

Q is selected from the group consisting of NR 6 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 8 cycloalkyl, an optionally substituted C 1 -C 6 heteroalkyl, and an optionally substituted non-aromatic heterocycle;

L 1 is selected from NH and CHR 2 ;

Z is O (oxygen) or S (sulfur); and

n is 1, 2 or 3.

15. The method of claim 14 , wherein the neoplastic cell comprises a leukemia cell.

16. The method of claim 10 , wherein R 4 is an optionally substituted aryl.

17. The method of claim 16 , wherein R 4 is an aryl optionally substituted with C 1 -C 3 alkyl, or C 1 -C 3 alkoxy.

18. The method of claim 10 , wherein R 5 is CF 3 .

19. The method of claim 10 , wherein Q is optionally substituted C 1 -C 3 alkyl.

20. The method of claim 10 , wherein Z is oxygen.

21. A method for treating, preventing, reversing, halting, or slowing the progression of cancer selected from the group consisting of leukemia, non-small cell lung cancer, colon cancer, CNS cancer, skin cancer, ovarian cancer, renal cancer, prostate cancer, breast cancer, and myeloma, comprising administering to a subject in need thereof an effective amount of a compound is selected from Formula (II), or (IV):

a tautomer thereof, or a pharmaceutically acceptable salt thereof,

wherein:

R 3 is selected from hydrogen, an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 2 -C 6 alkenyl, an optionally substituted C 2 -C 6 alkynyl, an optionally substituted C 1 -C 6 heteroalkyl, an optionally substituted C 3 -C 8 cycloalkyl, an optionally substituted C 3 -C 8 cycloalkenyl, an optionally substituted C 1 -C 6 heterocycle, an optionally substituted aryl, and an optionally substituted heteroaryl;

R 4 is selected from hydrogen, an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 2 -C 6 alkenyl, an optionally substituted C 2 -C 6 alkynyl, an optionally substituted C 1 -C 6 heteroalkyl, an optionally substituted C 3 -C 8 cycloalkyl, an optionally substituted C 3 -C 8 cycloalkenyl, an optionally substituted C 1 -C 6 heterocycle, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted arylalkyl, an optionally substituted arylalkenyl, an optionally substituted arylalkynyl, and an optionally substituted heteroarylalkyl;

R 5 is selected from hydrogen, halogen, NO 2 , CN, CF 3 , OR 6 , CO 2 R 6 , C(═O)NR 6 R 7 , SO 3 R 6 , and SO 2 NR 6 R 8 , an optionally substituted aryl, an optionally substituted C 1 -C 6 alkyl, and an optionally substituted C 1 -C 6 heteroalkyl;

R 6 is selected from hydrogen, an optionally substituted C 1 -C 6 alkyl, a C 1 -C 6 heteroalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;

R 7 is selected from hydrogen, C(═O)R 8 , C(═O)NHR 8 , an optionally substituted C 1 -C 6 alkyl, and an optionally substituted C 1 -C 6 heteroalkyl; or —NR 6 R 7 is an optionally substituted non-aromatic heterocycle linked through a ring nitrogen;

R 8 is selected from hydrogen, an optionally substituted C 1 -C 6 alkyl, and an optionally substituted C 1 -C 6 heteroalkyl;

R 9 is selected from hydrogen, an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 2 -C 6 alkenyl, an optionally substituted C 2 -C 6 alkynyl, an optionally substituted C 1 -C 6 heteroalkyl, an optionally substituted C 3 -C 8 cycloalkyl, an optionally substituted C 3 -C 8 cycloalkenyl, an optionally substituted C 1 -C 6 heterocycle, an optionally substituted heteroaryl, an optionally substituted arylalkyl, an optionally substituted arylalkenyl, an optionally substituted arylalkynyl, an optionally substituted heteroarylalkyl, an optionally substituted heteroarylalkenyl, and an optionally substituted heteroarylalkynyl;

W is selected from O (oxygen) and NH;

X is N (nitrogen) or CR 2 ;

Y is selected from an optionally substituted C 1 -C 6 alkyl, C 2 -C 6 alkenyl, an optionally substituted C 1 -C 6 heteroalkyl, an optionally substituted C 1 -C 6 heteroalkenyl, an optionally substituted phenylalkenyl, and an optionally substituted heterocyclealkenyl; and

n is 1, 2 or 3.

22. The method of claim 21 , wherein the compound has the structure of Formula (IIa) or (IIb):

a tautomer thereof, or a pharmaceutically acceptable salt thereof,

wherein:

R 3 is selected from hydrogen, an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 8 cycloalkyl, an optionally substituted C 1 -C 6 heterocycle, an optionally substituted aryl, and an optionally substituted heteroaryl;

R 4 is selected from an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 8 cycloalkyl, an optionally substituted C 1 -C 6 heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted arylalkyl, and an optionally substituted heteroarylalkyl; and

R 9 is selected from hydrogen, an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 8 cycloalkyl, an optionally substituted C 1 -C 6 heterocyclyl, an optionally substituted heteroaryl, an optionally substituted arylalkyl, and an optionally substituted heteroarylalkyl.

23. The method of claim 22 , wherein:

R 3 is selected from hydrogen, and an optionally substituted C 1 -C 3 alkyl;

R 4 is selected from an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 8 cycloalkyl, and an optionally substituted aryl; and

R 9 is selected from an optionally substituted C 1 -C 6 alkyl, an optionally substituted arylalkyl, an optionally substituted arylalkenyl, an optionally substituted arylalkynyl, and an optionally substituted heteroarylalkyl.

24. The method of claim 21 , wherein the compound has the structure of Formula (IVa) or (IVb):

a tautomer thereof, or a pharmaceutically acceptable salt thereof,

wherein:

R 4 is selected from an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 8 cycloalkyl, an optionally substituted C 1 -C 6 heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted arylalkyl, and an optionally substituted heteroarylalkyl;

R 5 is selected from halogen, CN, CF 3 , OR 6 , an optionally substituted aryl, and an optionally substituted C 1 -C 6 alkyl;

R 6 is selected from hydrogen, an optionally substituted C 1 -C 6 alkyl, an optionally substituted aryl, and an optionally substituted heteroaryl; and

R 9 is selected from hydrogen, an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 8 cycloalkyl, an optionally substituted C 1 -C 6 heterocyclyl, an optionally substituted heteroaryl, an optionally substituted arylalkyl, and an optionally substituted heteroarylalkyl.

25. The method of claim 21 , wherein the compound is selected from:

a tautomer thereof, or pharmaceutically acceptable salt thereof.