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 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, or heteroaryl and R 10 is —O-alkylaryl, cycloalkyl, cycloalkylalkyl, cycloalkoxy, cycloalkylalkyloxy, heterocyclo, heterocycloalkyl, alkylheterocycloalkyl, heterocyclooxy, heterocyclolalkyloxy, aryl, arylalkyl, aryloxy, arylalkyloxy, heteroaryl, alkylheteroaryl, halo, cycloalkyl-S(O) m —, heterocyclo-S(O) m —, heterocycloalkyl-S(O) m —, cycloalkylamino, cycloalkylalkylamino, arylamino, heterocycloalkylamino, or sulfonamide, and wherein R 10 is optionally substituted one, two or three times;
m=2;
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 alkylene 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; and
R 15 is H, loweralkyl, halo, or loweralkoxy;
or a pharmaceutically acceptable salt thereof;
wherein the medical disorder is cancer and the drug is a chemotherapeutic.
2. The method of claim 1 , wherein the chemotherapeutic is selected from the group consisting of a tyrosine kinase inhibitor, an anti-programmed cell death-1 (PD-1) agent, a B-RAF inhibitor, a mTOR inhibitor, a PI3 kinase inhibitor, a dual mTOR-PI3K inhibitor, a MEK inhibitor, a RAS inhibitor, a ALK inhibitor, a HSP inhibitor, radioactive molecules, cytotoxins, and liposomes or other vesicles containing chemotherapeutic compounds.
3. The method of claim 2 , wherein the chemotherapeutic is selected from the group consisting of a tyrosine kinase inhibitor, an anti-programmed cell death-1 (PD-1) agent, and a B-RAF inhibitor.
4. The method of claim 2 , wherein the chemotherapeutic is selected from the group consisting of AZD-4547, gefitinib, crizotinib, vemurafenib, and methotrexate.
5. The method of claim 1 , wherein the cancer is a MERTK-negative (−/−) cancer.
6. The method of claim 5 , wherein the MERTK-negative (−/−) cancer is breast cancer.
7. The method of claim 1 , wherein the cancer is myeloid leukemia, lymphoblastic leukemia, melanoma, breast, lung, colon, liver, gastric, kidney, ovarian, uterine or brain cancer.
8. The method of claim 7 , wherein the cancer is acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL).
9. The method of claim 8 , wherein the AML or ALL is resistant to prior drug therapy.
10. The method of claim 8 , wherein the AML contains a mutation within the FLT3-TKD at amino acid F691 or D835.
11. The method of claim 1 , wherein the compound has the Formula (IIB):
12. The method of claim 11 , wherein said R 11 is —R 9 R 10 , where R 9 is aryl or heteroaryl and R 10 is optionally substituted heterocyclo, heterocycloalkyl, alkylheterocycloalkyl, heterocyclooxy, heterocycloalkyloxy, —O-alkylaryl, alkenyloxy, cycloalkoxy, cycloalkylalkyloxy, aryloxy, arylalkyloxy, cycloalkyl-S(O) m —, heterocyclo-S(O) m —, heterocycloalkyl-S(O) m —, cycloalkylamino, cycloalkylalkylamino, arylamino, or heterocycloalkylamino; and
wherein m=2.
13. The method of claim 12 , wherein said R 10 is optionally substituted alkylheterocycloalkyl, heterocycloalkyl-S(O) m —, cycloalkylamino, or heterocycloamino, wherein m=2.
14. The method of claim 13 , wherein said R 10 is selected from the group consisting of:
wherein the wavy line denotes the point of attachment of said R 10 to R 9 .
15. The method of claim 11 , wherein R 12 is —R 16 R 19 , where R 16 is a covalent bond or —CH 2 — and R 19 is cycloalkyl, cycloalkylalkyl, heterocyclo, or heterocycloalkyl, and wherein R 19 is optionally substituted one time.
16. The method of claim 15 , wherein R 12 is:
17. 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 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, or heteroaryl and R 10 is —O-alkylaryl, cycloalkyl, cycloalkylalkyl, cycloalkoxy, cycloalkylalkyloxy, heterocyclo, heterocycloalkyl, alkylheterocycloalkyl, heterocyclooxy, heterocyclolalkyloxy, aryl, arylalkyl, aryloxy, arylalkyloxy, heteroaryl, alkylheteroaryl, halo, cycloalkyl-S(O) m —, heterocyclo-S(O) m —, heterocycloalkyl-S(O) m —, cycloalkylamino, cycloalkylalkylamino, arylamino, heterocycloalkylamino, or sulfonamide, and wherein R 10 is optionally substituted one, two or three times;
m=2;
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 alkylene 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 s8 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; and
R 15 is H, loweralkyl, halo, or loweralkoxy;
or a pharmaceutically acceptable salt thereof;
wherein the medical disorder is a viral infection and the drug is an anti-viral.
18. The method of claim 17 , wherein the viral infection is caused by a virus selected from the group consisting of a Flavivirus, Hepacivirus, Pegivirus, Pestivirus, Filovirus, Togavirus, Coronavirus, Orthomyxovirus, Paramyxovirus, Calicivirus, and Lentivirus.
19. The method of claim 18 , wherein the virus is selected from the group consisting of Chikungunya, HCV, and HIV.
20. The method of claim 17 , wherein the anti-viral is selected from the group consisting of abacavir, acyclovir, adefovir, amantadine, amprenavir, ampligen, arbitol, atazanavir, balavir, boceprevir, boceprevirertet, brincidofovir, cidofovir, dolutegravir, darunavir, delavirdine, didanosine, docosanol, edoxudine, efavirenz, emtricitabine, epivir, enfuvirtide, entecavir, famciclovir, fomivirsen, fosamprenavir, foscarnet, fosfonet, ganciclovir, ibacitabine, imunovir, idoxuridine, imiquimod, indinavir, lamivudine, lopinavir, loviride, maraviroc, moroxydine, nelfinavir, nevirapine, nexavir, oseltamivir, penciclovir, peramivir, pleconaril, podophyllotoxin, raltegravir, ribavirin, rilpivirine, rimantadine, pyramidine, saquinavir, simeprevir, sofosbuvir, stavudine, telaprevir, tenofovir, tipranavir, trifluridine, trizivir, tromantadine, traporved, truvada, valaciclovir, valganciclovir, vicriviroc, vidarabine, viramidine, zalcitabine, zanamivir, and zidovudine.