Therapeutic uses of selected pyrrolopyrimidine compounds with anti-mer tyrosine kinase activity
Uses of pyrrolopyrimidines with anti-Mer tyrosine kinase activity as anti-infective agents, immunostimulatory and immunomodulatory agents, anti-cancer agents (including against MerTK−/− tumors and ITD and TKD mutant forms of Acute Myeloid Leukemia (AML)), and as adjunctive agents in combination with chemotherapeutic, radiation or other standard of care for neoplasms.
1. A method for treating a host with a medical disorder in need of immunostimulatory adjunctive therapy in combination with a direct acting drug for the medical disorder, comprising administering an adjunctively immunostimulatory effective amount of a compound of Formula II, IIA, or IIB:
wherein:
one of X and X′ is N and the other of X and X′ is C;
one of the dashed lines is a single bond, between a ring carbon atom and a ring nitrogen atom, and the other of the dashed lines is a double bond, between two ring carbon atoms;
R 11 is —R 9 (R 10 ) n , where R 9 is alkyl, alkenyl, -alkylaryl, heterocyclo, aryl, heteroaryl and R 10 is —O-alkylaryl, cycloalkyl, cycloalkylalkyl, cycloalkoxy, cycloalkylalkyloxy, heterocyclo, heterocycloalkyl, alkylheterocycloalkyl, heterocyclooxy, heterocycloalkyloxy, aryl, arylalkyl, aryloxy, arylalkyloxy, heteroaryl, alkylheteroaryl, cycloalkylamino, cycloalkylalkylamino, and wherein R 10 is optionally substituted one, two or three times;
n=0, 1 or 2;
R 12 is —R 16 R 19 , where R 16 is a covalent bond or C 1 to C 3 alkyl and R 19 is cycloalkyl, cycloalkylalkyl, heterocyclo, heterocycloalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, and wherein R 19 is optionally substituted one, two or three times;
R 13 is NR 17 R 18 , where;
R 17 is selected from the group consisting of H, alkyl, hydroxyalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclo, heterocycloalkyl, alkylheterocycloalkyl, heteroaryl, heteroarylalkyl, and alkoxyalkyl, each of which is optionally substituted one, two or three times;
R 18 is selected from the group consisting of H, alkyl, hydroxyalkyl, aryl, arylalkyl; cycloalkyl, cycloalkylalkyl, heterocyclo, heterocycloalkyl, alkylheterocycloalkyl, heteroaryl, heteroarylalkyl, and alkoxyalkyl, each of which is optionally substituted one, two or three times; or
R 17 and R 18 together with the nitrogen to which they are bonded can form a heterocyclic group that can be optionally substituted;
R 14 is H, loweralkyl, halo, or loweralkoxy;
R 15 is H, loweralkyl, halo, or loweralkoxy;
or a pharmaceutically acceptable salt thereof.
2. The method of claim 1 , wherein the compound is:
wherein R 21 is heterocycle;
R 22 and R 23 are each independently hydrogen, alkyl, cycloalkyl, or cycloalkylalkyl.
3. The method of claim 1 , wherein the compound is:
4. The method of claim 1 , wherein the medical disorder is a viral infection.
5. The method of claim 1 , wherein the medical disorder is a bacterial infection.
6. The method of claim 4 , wherein the viral infection is caused by a virus selected from the group consisting of a Flavivirus, Hepacivirus, Pegivirus, Pestivirus, Filovirus, Togavaus, Coronavirus, Orthomyxovirus, Paramyxovirus, Calicivirus, and Lentivirus.
7. The method of claim 4 , wherein the virus is Chikungunya.
8. The method of claim 4 , wherein the virus is HCV.
9. The method of claim 4 , wherein the virus is HIV.
10. The method of claim 5 , wherein the bacterial infection is caused by a bacterium selected from the group consisting of Escherichia coli, Staphylococcus aureus, Enterococcus faecalis , and Streptococcus pneumoniae.
11. The method of claim 3 , wherein the medical disorder is a MERTK-negative (−/−) tumor or cancer.
12. The method of claim 11 , wherein the MERTK-negative (−/−) cancer is a MERTK-negative (−/−) breast cancer.