Inhibitors of tyrosine kinase
The present disclosure provides compounds and compositions thereof which are useful as inhibitors of tyrosine kinase and which exhibit desirable characteristics for the same. Further disclosed herein are methods of treating cancer using these tyrosine kinase inhibitor compounds.
1 . A compound according to Formula (IV)
or an optically pure stereoisomer, pharmaceutically acceptable salt, or solvate thereof, wherein
B is —NR 6 —;
D is N;
E is N;
L is —O(CH 2 ) 1-5 O—, —O(CH 2 ) 1-5 NR 6 —, —NR 6 (CH 2 ) 1-5 NR 6 —, —CONR 6 (CH 2 ) 1-5 NR 6 —, —NR 6 CO(CH 2 ) 1-5 NR 6 —, (CH 2 ) 1-5 NR 6 —, —(CH 2 ) 1-5 O—, —(CH 2 ) 1-5 OCO—, —(CH 2 ) 1-5 CONR 6 —,
each of which is optionally substituted by one, two, three, or four R 7 ;
Ar is selected from the group consisting of
R 1 is H, F, Cl, Br, OH, N 3 , NO 2 , CF 3 , CN, methyl, ethyl, propyl, isopropyl, or -G-Ar 1 , wherein G is —CO—, —COO—, —CONR 6 —, —NR 6 —, —(CH 2 ) 1-5 —, —O—, —OPO—, —OPO 2 —, —S—, —SO—, or —SO 2 —, Ar 1 is phenyl,
each of which is optionally substituted by F, Br, Cl, CF 3 , CN, N 3 , NH 2 , NO 2 , OH, OCH 3 , methyl, CH 2 CN, ethyl, propyl, isopropyl, or cyclopropyl;
R 2 is selected from the group consisting of H, F, Br, Cl, CF 3 , CN, N 3 , NH 2 , NO 2 , OH, OCH 3 , methyl, ethyl, propyl, isopropyl,
each of which is optionally substituted by one, two, three, or four R 7 ;
R 3 is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl, each of which can be substituted by one, two, three, or four R 7 ;
R 4 is selected from the group consisting of H, methyl, ethyl, propyl, and isopropyl;
or R 3 and R 4 together form
R 5 is selected from the group consisting of CO(CH 2 ) 0-5 CH 3 , CONR 6 (CH 2 ) 0-5 CH 3 , COO (CH 2 ) 0-5 CH 3 , SO 2 (CH 2 ) 0-5 CH 3 , CO(CH 2 ) 0-5 CH═CH 2 , CONR 6 (CH 2 ) 0-5 CH═CH 2 , COO (CH 2 ) 0-5 CH═CH 2 , SO 2 (CH 2 ) 0-5 CH═CH 2 , CO(CH 2 ) 0-5 CH═CHCH 3 , COO (CH 2 ) 0-5 CH═CHCH 3 , CONR 6 (CH 2 ) 0-5 CH═CHCH 3 , SO 2 (CH 2 ) 0-5 CH═CHCH 3 , CO(CH 2 ) 0-5 C≡CH, COO (CH 2 ) 0-5 C≡CH, CONR 6 (CH 2 ) 0-5 C≡CH, SO 2 (CH 2 ) 0-5 C≡CH, CO(CH 2 ) 0-5 C≡CCH 3 , COO (CH 2 ) 0-5 CCCH 3 , CONR 6 (CH 2 ) 0-5 CCCH 3 , and SO 2 (CH 2 ) 0-5 C═CCH 3 , each of which is optionally substituted by one, two, three, or four R 7 ;
each R 6 is H; and
each R 7 is independently H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, F, Br, Cl, CF 3 , NO 2 , OH, OCH 3 , CN, or amino group unsubstituted or substituted with methyl, ethyl, or propyl.
2 . The compound of claim 1 , wherein R 5 is selected from the group consisting of
3 . The compound of claim 1 , wherein the compound exhibits covalent inhibition of macrophage colony-stimulating factor 1 receptor (FMS), mast/stem cell growth factor receptor Kit (KIT), FMS like tyrosine kinase 3 (FLT-3), feline Gardner-Rasheed sarcoma viral oncogene homolog (FGR), or macrophage-stimulating protein receptor (RON).
4 . A pharmaceutical formulation, comprising the compound according to claim 1 and a pharmaceutically acceptable carrier.
5 . A method for treating a myeloid cancer in a subject comprising administering the compound according to claim 1 .
6 . The method of claim 5 , wherein the myeloid cancer is selected from Acute Myeloid Leukemia (AML), Chronic Myelogenous Leukemia (CML), Myelodysplasia/Myelodysplastic Syndromes (MDS), Multiple Myeloma (MM), and Chronic Myeloproliferative Disorders.
7 . The method of claim 5 , further comprising administering a chemotherapeutic agent.
8 . The method of claim 7 , wherein the compound is administered prior to, simultaneously with or following the administration of the chemotherapeutic agent.
9 . A method of inhibiting FMS, KIT, FLT-3, FGR, or RON activity comprising contacting a cell with the compound according to claim 1 .
10 . The method of claim 9 , wherein the cell is a myeloid cancer cell.
11 . The method of claim 10 , wherein the myeloid cancer cell is selected from Acute Myeloid Leukemia (AML), Chronic Myelogenous Leukemia (CML), Myelodysplasia/Myelodysplastic Syndromes (MDS), Multiple Myeloma (MM), and Chronic Myeloproliferative Disorder cells.
12 . The compound of claim 1 , wherein the compound is selected from the group consisting of
or an optically pure stereoisomer, pharmaceutically acceptable salt, or solvate thereof.