Tyrosine Kinase Inhibitors

Abstract

The present disclosure provides compounds and compositions thereof that are useful as, and exhibit desirable characteristics for, inhibitors of tyrosine kinases. Further disclosed herein are methods of treating cancer using these tyrosine kinase inhibitor compounds.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority under 35 U.S.C. §119(e) of U.S. Patent Application No. 62 / 876,520, filed July 19, 2019, the entire contents of which are incorporated by reference in their entirety.

[0002] Field The present disclosure relates generally to compounds, pharmaceutical compositions, and methods of using the compounds and compositions comprising them. The present disclosure specifically relates to tyrosine kinase inhibitor compounds and compositions comprising them, and the use of the compounds and compositions for the treatment of cancer. [Background technology]

[0003] background In recent years, inhibition of specific cancer-associated tyrosine kinases has emerged as an important approach for cancer therapy. Tyrosine kinases, as mediators of cell signaling, play a role in many diverse physiological pathways, including cell proliferation and differentiation. Deregulation of tyrosine kinase activity can lead to cellular transformation, which can lead to cancer development. Summary of the Invention

[0004] overview Disclosed herein are compounds used as tyrosine kinase inhibitors, pharmaceutical compositions containing the compounds, and methods of using the compounds and compositions for the treatment of cancer. Many of the disclosed compounds can cause covalent inhibition of specific tyrosine kinases, and therefore they exhibit high potency and excellent selectivity against these kinases. In some embodiments, the disclosure provides compounds of formula (I): TIFF0007628108000001.tif61128 or an optically pure stereoisomer, pharmaceutically acceptable salt, or solvate thereof. In some embodiments, n can be an integer selected from 0 to 2, and m can be an integer selected from 0 to 4.

[0005] In some embodiments, Ar1 is phenyl, naphthyl, anthracene, TIFF0007628108000002.tif191138.

[0006] Ar2 is phenyl, TIFF0007628108000003.tif55138.

[0007] B is -CO-, -COO-, -CONR4-, -NR4-, -(CH2) 1-5 It can be -, -O-, -OPO-, -OPO2-, -S-, -SO-, or -SO2-.

[0008] L is -O(CH2) 1-5 O-, -O(CH2) 1-5 NR4-, -NR4(CH2) 1-5 NR4-, -CONR4(CH2) 1-5 NR4-, -NR4CO(CH2) 1-5 NR4-, -(CH2) 1-5 NR4-, -(CH2) 1-5 O-, -(CH2) 1-5 OCO-, -(CH2) 1-5 CONR4-, TIFF0007628108000004.tif18128, each of which may be substituted by R6.

[0009] AA is, The amino acid may be a natural or unnatural amino acid selected from the group consisting of: TIFF0007628108000005.tif26128.

[0010] R1 can be selected from the group consisting of H, F, Br, Cl, CF3, CN, N3, NH2, NO2, OH, OCH3, methyl, ethyl, propyl, isopropyl, cyclopropyl, or -D-Ar3, where D is -CO-, -COO-, -CONR4-, -NR4-, -(CH2) 1-5Ar3 may be -, -O-, -OPO-, -OPO2-, -S-, -SO-, or -SO2-; TIFF0007628108000006.tif53138, each of which may be optionally substituted by F, Br, Cl, CF3, CN, N3, NH2, NO2, OH, OCH3, methyl, CH2CN, ethyl, propyl, isopropyl, or cyclopropyl.

[0011] In one aspect, R1 is It could be TIFF0007628108000007.tif11128.

[0012] R2 is H, F, Br, Cl, CF3, CN, N3, NH2, NO2, OH, OCH3, methyl, ethyl, propyl, isopropyl, TIFF0007628108000008.tif73138, each of which may be substituted by 1, 2, 3, or 4 R6.

[0013] In some embodiments, R3 is CO(CH2) 0-5 CH3, CONR4(CH2) 0-5 CH3, COO(CH2) 0-5 CH3, SO2(CH2) 0-5 CH3, CO(CH2) 0-5 CH=CH2, CONR4(CH2) 0-5 CH=CH2, COO(CH2) 0-5 CH=CH2, SO2(CH2) 0-5 CH=CH2, CO(CH2) 0-5 CH=CHCH3, COO(CH2) 0-5 CH=CHCH3, CONR4(CH2) 0-5 CH=CHCH3, SO2(CH2) 0-5 CH=CHCH3, CO(CH2) 0-5 C≡CH, COO(CH2) 0-5 C≡CH, CONR4(CH2) 0-5 C≡CH, SO2(CH2) 0-5 C≡CH, CO(CH2) 0-5C≡CCH3, COO(CH2) 0-5 C≡CCH3, CONR4(CH2) 0-5 C≡CCH3, and SO2(CH2) 0-5 C≡CCH3, each of which may be optionally substituted by 1, 2, 3, or 4 R6.

[0014] In some embodiments, R3 is TIFF0007628108000009.tif37138.

[0015] R4 can be H, methyl, ethyl, propyl, isopropyl, cyclopropyl, or cyclobutyl.

[0016] R5 is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, -CH2CH2SCH3, -CH2Ph, -CH2PhOH, -CH2OH, -CHOHCH3, -CH2CONH2, -CH2CH2CONH2, -CH2SH, -CH2SeH, -CH2COOH, -CH2CH2COOH, -CH2CH2CH2CH2NH2, It could be TIFF0007628108000010.tif29128.

[0017] Each R6 can independently be H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, F, Br, Cl, CF3, NO2, OH, OCH3, CN, or an amino group unsubstituted or substituted with methyl, ethyl, or propyl.

[0018] Compounds of formula (II): Also disclosed herein is TIFF0007628108000011.tif43128 or an optically pure stereoisomer, a pharmaceutically acceptable salt, or a solvate thereof.

[0019] In one embodiment, each D and E can independently be N or CH. m can be an integer selected from 0-4.

[0020] Ar is TIFF0007628108000012.tif65138.

[0021] L is -O(CH2) 1-5 O-, -O(CH2) 1-5 NR4-, -NR4(CH2) 1-5 NR4-, -CONR4(CH2) 1-5 NR4-, -NR4CO(CH2) 1-5 NR4-, -(CH2) 1-5 NR4-, -(CH2) 1-5 O-, -(CH2) 1-5 OCO-, -(CH2) 1-5 CONR4-, TIFF0007628108000013.tif18128, each of which may be substituted by R6.

[0022] In another embodiment, R1 can be selected from the group consisting of H, F, Br, Cl, CF3, CN, N3, NH2, NO2, OH, OCH3, methyl, ethyl, propyl, isopropyl, cyclopropyl, or -B-Ar1, where B is -CO-, -COO-, -CONR4-, -NR4-, -(CH2) 1-5 Ar1 may be -, -O-, -OPO-, -OPO2-, -S-, -SO-, or -SO2-; TIFF0007628108000014.tif55138, each of which may be optionally substituted by F, Br, Cl, CF3, CN, N3, NH2, NO2, OH, OCH3, methyl, CH2CN, ethyl, propyl, isopropyl, or cyclopropyl. It could be TIFF0007628108000015.tif11128.

[0023] R2 can be H, methyl, ethyl, propyl, isopropyl, cyclopropyl, or cyclobutyl, each of which can be substituted by 1, 2, 3, or 4 R6.

[0024] In some embodiments, R3 is CO(CH2) 0-5 CH3, CONR4(CH2) 0-5 CH3, COO(CH2) 0-5 CH3, SO2(CH2) 0-5 CH3, CO(CH2) 0-5 CH=CH2, CONR4(CH2) 0-5 CH=CH2, COO(CH2) 0-5 CH=CH2, SO2(CH2) 0-5 CH=CH2, CO(CH2) 0-5 CH=CHCH3, COO(CH2) 0-5 CH=CHCH3, CONR4(CH2) 0-5 CH=CHCH3, SO2(CH2) 0-5 CH=CHCH3, CO(CH2) 0-5 C≡CH, COO(CH2) 0-5 C≡CH, CONR4(CH2) 0-5 C≡CH, SO2(CH2) 0-5 C≡CH, CO(CH2) 0-5 C≡CCH3, COO(CH2) 0-5 C≡CCH3, CONR4(CH2) 0-5 C≡CCH3, and SO2(CH2) 0-5 C≡CCH3, each of which may be optionally substituted by 1, 2, 3, or 4 R6.

[0025] In some embodiments, R3 is TIFF0007628108000016.tif54138.

[0026] AA is, The amino acid may be a natural or unnatural amino acid selected from the group consisting of: TIFF0007628108000017.tif26128.

[0027] Each R4 can independently be H, methyl, ethyl, propyl, isopropyl, cyclopropyl, or cyclobutyl.

[0028] R5 is H, F, Br, Cl, CF3, CN, N3, NH2, NO2, OH, OCH3, methyl, ethyl, propyl, isopropyl, cyclopropyl, TIFF0007628108000018.tif73138, each of which may be optionally substituted by 1, 2, 3, or 4 R6.

[0029] R6 can independently be H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, F, Br, Cl, CF3, NO2, OH, OCH3, CN, or an amino group unsubstituted or substituted with methyl, ethyl, or propyl.

[0030] Compounds of formula (III): Further disclosed herein is TIFF0007628108000019.tif53128 or an optically pure stereoisomer, pharmaceutically acceptable salt, or solvate thereof. In one embodiment, n can be an integer selected from 0 to 5. Each B and D independently represents -CO-, -COO-, -CONR7-, -NR7-, -(CH2) 1-5 Each E and F can independently be N or CH.

[0031] L is -O(CH2) 1-5 O-, -O(CH2) 1-5 NR7-, -NR7(CH2) 1-5 NR7-, -CONR7(CH2) 1-5 NR7-, -NR7CO(CH2) 1-5 NR7-, -(CH2) 1-5 NR7-, -(CH2) 1-5 O-, -(CH2) 1-5 OCO-, -(CH2) 1-5 CONR7-, TIFF0007628108000020.tif18128, each of which may be substituted by R8.

[0032] In some embodiments, R1 may be selected from the group consisting of H, F, Br, Cl, CF3, CN, N3, NH2, NO2, OH, OCH3, methyl, CH2CN, ethyl, propyl, isopropyl, and cyclopropyl, each of which may be optionally substituted by 1, 2, 3, or 4 R8.

[0033] In another embodiment, R2 is H, F, Br, Cl, CF3, CN, N3, NH2, NO2, OH, OCH3, methyl, ethyl, propyl, isopropyl, cyclopropyl, TIFF0007628108000021.tif54138, each of which may be optionally substituted by 1, 2, 3, or 4 R8.

[0034] In yet another embodiment, R3 can be selected from the group consisting of H, CF3, methyl, ethyl, propyl, and isopropyl, each of which can be optionally substituted with 1, 2, 3, or 4 R8.

[0035] In certain embodiments, R4 can be H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl.

[0036] In some embodiments, R5 can be selected from the group consisting of H, methyl, ethyl, propyl, and isopropyl. Or R4 and R5 together are: TIFF0007628108000022.tif26128 can be formed.

[0037] In some embodiments, R6 is CO(CH2) 0-5 CH3, CONR7(CH2) 0-5 CH3, COO(CH2) 0-5 CH3, SO2(CH2) 0-5 CH3, CO(CH2) 0-5 CH=CH2, CONR7(CH2) 0-5 CH=CH2, COO(CH2) 0-5CH=CH2, SO2(CH2) 0-5 CH=CH2, CO(CH2) 0-5 CH=CHCH3, COO(CH2) 0-5 CH=CHCH3, CONR7(CH2) 0-5 CH=CHCH3, SO2(CH2) 0-5 CH=CHCH3, CO(CH2) 0-5 CCH, COO(CH2) 0-5 CCH, CONR7(CH2) 0-5 CCH, SO2(CH2) 0-5 CCH, CO(CH2) 0-5 CCCH3, COO(CH2) 0-5 CCCH3, CONR7(CH2) 0-5 CCCH3, and SO2(CH2) 0-5 CCCH3, each of which may be optionally substituted by 1, 2, 3, or 4 R8.

[0038] In some embodiments, R6 is TIFF0007628108000023.tif54138.

[0039] R7 can be H, methyl, ethyl, propyl, or isopropyl.

[0040] R8 can be H, F, Br, Cl, CF3, CN, N3, NH2, NO2, OH, OCH3, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl.

[0041] Compounds of formula (IV): Further disclosed herein is TIFF0007628108000024.tif44128 or an optically pure stereoisomer, a pharmaceutically acceptable salt, or a solvate thereof.

[0042] In one embodiment, each D and E can independently be N or CH. B can be -NR6-, -O-, -CONR6-, -COO-, -SO2-, or -SO2NR6-.

[0043] L is -O(CH2) 1-5 O-, -O(CH2) 1-5 NR6-, -NR6(CH2) 1-5 NR6-, -CONR6(CH2) 1-5 NR6-, -NR6CO(CH2) 1-5 NR6-, -(CH2) 1-5 NR6-, -(CH2) 1-5 O-, -(CH2) 1-5 OCO-, -(CH2) 1-5 CONR6-, TIFF0007628108000025.tif18128, each of which may be substituted by 1, 2, 3, or 4 R7.

[0044] Ar is phenyl, TIFF0007628108000026.tif55138.

[0045] In another embodiment, R1 can be selected from the group consisting of H, F, Cl, Br, OH, N3, NO2, CF3, CN, methyl, ethyl, propyl, and isopropyl. In some embodiments, R1 can be -G-Ar1, where G is -CO-, -COO-, -CONR6-, -NR6-, -(CH2) 1-5 Ar1 may be -, -O-, -OPO-, -OPO2-, -S-, -SO-, or -SO2-; TIFF0007628108000027.tif55138, each of which may be optionally substituted by F, Br, Cl, CF3, CN, N3, NH2, NO2, OH, OCH3, methyl, CH2CN, ethyl, propyl, isopropyl, or cyclopropyl. It could be TIFF0007628108000028.tif11128.

[0046] In yet another embodiment, R2 is H, F, Br, Cl, CF3, CN, N3, NH2, NO2, OH, OCH3, methyl, ethyl, propyl, isopropyl, TIFF0007628108000029.tif71138, each of which may be substituted by 1, 2, 3, or 4 R7.

[0047] In certain embodiments, R3 can be H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl, each of which can be substituted by 1, 2, 3, or 4 R7.

[0048] In some embodiments, R4 can be selected from the group consisting of H, methyl, ethyl, propyl, and isopropyl. Or R4 and R3 together are: TIFF0007628108000030.tif26128 can be formed.

[0049] In some embodiments, R5 is CO(CH2) 0-5 CH3, CONR6(CH2) 0-5 CH3, COO(CH2) 0-5 CH3, SO2(CH2) 0-5 CH3, CO(CH2) 0-5 CH=CH2, CONR6(CH2) 0-5 CH=CH2, COO(CH2) 0-5 CH=CH2, SO2(CH2) 0-5 CH=CH2, CO(CH2) 0-5 CH=CHCH3, COO(CH2) 0-5 CH=CHCH3, CONR6(CH2) 0-5 CH=CHCH3, SO2(CH2) 0-5 CH=CHCH3, CO(CH2) 0-5 C≡CH, COO(CH2) 0-5 C≡CH, CONR6(CH2) 0-5 C≡CH, SO2(CH2) 0-5 C≡CH, CO(CH2) 0-5 C≡CCH3, COO(CH2) 0-5C≡CCH3, CONR6(CH2) 0-5 C≡CCH3, and SO2(CH2) 0-5 C≡CCH3, each of which may be optionally substituted by 1, 2, 3, or 4 R7.

[0050] In some embodiments, R5 is TIFF0007628108000031.tif54138.

[0051] Each R6 can independently be H, methyl, ethyl, propyl, isopropyl, cyclopropyl, or cyclobutyl.

[0052] Each R7 can independently be H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, F, Br, Cl, CF3, NO2, OH, OCH3, CN, or an amino group unsubstituted or substituted with methyl, ethyl, or propyl.

[0053] Compounds of formula (V): Further disclosed herein is TIFF0007628108000032.tif62128 or an optically pure stereoisomer, pharmaceutically acceptable salt, or solvate thereof. In one embodiment, n can be an integer selected from 0 to 2. In another embodiment, m can be an integer selected from 0 to 3. In some embodiments, p can be an integer selected from 0 to 4. TIFF0007628108000033.tif2128 can be a single or double bond. B can be -CO-, -COO-, -CONR4-, -SO2-, -SO2NR4-, -SO-, -SONR4-, -OPO-, -OPONR4-, -OPO2-, or -OPO2NR4-.

[0054] In certain embodiments, Ar1 is TIFF0007628108000034.tif95138.

[0055] In another embodiment, Ar2 is TIFF0007628108000035.tif104144.

[0056] L is -O(CH2) 1-5 O-, -O(CH2) 1-5 NR4-, -NR4(CH2) 1-5 NR4-, -CONR4(CH2) 1-5 NR4-, -NR4CO(CH2) 1-5 NR4-, -(CH2) 1-5 NR4-, -(CH2) 1-5 O-, -(CH2) 1-5 OCO-, -(CH2) 1-5 CONR4-, TIFF0007628108000036.tif18128, each of which may be substituted by R6.

[0057] R1 may be selected from the group consisting of H, F, Br, Cl, CF3, CN, N3, NH2, NO2, OH, OCH3, methyl, ethyl, propyl, and isopropyl, each of which may be optionally substituted by 1, 2, 3, or 4 R6.

[0058] In some embodiments, R2 is CO(CH2) 0-5 CH3, CONR4(CH2) 0-5 CH3, COO(CH2) 0-5 CH3, SO2(CH2) 0-5 CH3, CO(CH2) 0-5 CH=CH2, CONR4(CH2) 0-5 CH=CH2, COO(CH2) 0-5 CH=CH2, SO2(CH2) 0-5 CH=CH2, CO(CH2) 0-5 CH=CHCH3, COO(CH2) 0-5 CH=CHCH3, CONR4(CH2) 0-5 CH=CHCH3, SO2(CH2) 0-5 CH=CHCH3, CO(CH2) 0-5C≡CH, COO(CH2) 0-5 C≡CH, CONR4(CH2) 0-5 C≡CH, SO2(CH2) 0-5 C≡CH, CO(CH2) 0-5 C≡CCH3, COO(CH2) 0-5 C≡CCH3, CONR4(CH2) 0-5 C≡CCH3, and SO2(CH2) 0-5 C≡CCH3, each of which may be optionally substituted by 1, 2, 3, or 4 R6.

[0059] In some embodiments, R2 is TIFF0007628108000037.tif38138.

[0060] R3 may be selected from the group consisting of H, F, Br, Cl, CF3, CN, N3, NH2, NO2, OH, OCH3, methyl, ethyl, propyl, and isopropyl, each of which may be optionally substituted by 1, 2, 3, or 4 R6.

[0061] R4 can be H, methyl, ethyl, propyl, or isopropyl.

[0062] AA is, The amino acid may be a natural or unnatural amino acid selected from the group consisting of: TIFF0007628108000038.tif26128.

[0063] R5 is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, -CH2CH2SCH3, -CH2Ph, -CH2PhOH, -CH2OH, -CHOHCH3, -CH2CONH2, -CH2CH2CONH2, -CH2SH, -CH2SeH, -CH2COOH, -CH2CH2COOH, -CH2CH2CH2CH2NH2, It could be TIFF0007628108000039.tif29128.

[0064] R6 can be H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, F, Br, Cl, CF3, NO2, OH, OCH3, CN, or an amino group that is unsubstituted or substituted with methyl, ethyl, or propyl.

[0065] Compounds of formula (VI): Further disclosed herein is TIFF0007628108000040.tif53128 or an optically pure stereoisomer, pharmaceutically acceptable salt, or solvate thereof. In some embodiments, n can be an integer selected from 0 to 4.

[0066] In one embodiment, A can be -CO-, -SO-, -SO2-, -OPO-, or -OPO2-. TIFF0007628108000041.tif2128 can be a single or double bond.

[0067] R1 may be selected from the group consisting of H, F, Br, Cl, CF3, CN, N3, NH2, NO2, OH, OCH3, methyl, ethyl, propyl, and isopropyl, each of which may be optionally substituted by 1, 2, 3, or 4 R8.

[0068] R2 may be selected from the group consisting of H, methyl, ethyl, propyl, and isopropyl, each of which may be optionally substituted with 1, 2, 3, or 4 R8.

[0069] In another embodiment, Ar is TIFF0007628108000042.tif104144.

[0070] L is -O(CH2) 1-5 O-, -O(CH2) 1-5 NR6-, -NR6(CH2) 1-5 NR6-, -CONR6(CH2) 1-5 NR6-, -NR6CO(CH2) 1-5 NR6-, -(CH2)1-5 NR6-, -(CH2) 1-5 O-, -(CH2) 1-5 OCO-, -(CH2) 1-5 CONR6-, TIFF0007628108000043.tif18128, each of which may be substituted by 1, 2, 3, or 4 R8.

[0071] In certain embodiments, R3 can be H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl, each of which can be optionally substituted with 1, 2, 3, or 4 R8.

[0072] In some embodiments, R4 can be selected from the group consisting of H, methyl, ethyl, propyl, and isopropyl. Or R4 and R3 together are: TIFF0007628108000044.tif26128 can be formed.

[0073] In some embodiments, R5 is CO(CH2) 0-5 CH3, CONR6(CH2) 0-5 CH3, COO(CH2) 0-5 CH3, SO2(CH2) 0-5 CH3, CO(CH2) 0-5 CH=CH2, CONR6(CH2) 0-5 CH=CH2, COO(CH2) 0-5 CH=CH2, SO2(CH2) 0-5 CH=CH2, CO(CH2) 0-5 CH=CHCH3, COO(CH2) 0-5 CH=CHCH3, CONR6(CH2) 0-5 CH=CHCH3, SO2(CH2) 0-5 CH=CHCH3, CO(CH2) 0-5 C≡CH, COO(CH2) 0-5 C≡CH, CONR6(CH2) 0-5 C≡CH, SO2(CH2) 0-5 C≡CH, CO(CH2) 0-5C≡CCH3, COO(CH2) 0-5 C≡CCH3, CONR6(CH2) 0-5 C≡CCH3, and SO2(CH2) 0-5 C≡CCH3, each of which may be optionally substituted by 1, 2, 3, or 4 R8.

[0074] In some embodiments, R5 is TIFF0007628108000045.tif37138.

[0075] Each R6 can independently be H, methyl, ethyl, propyl, or isopropyl.

[0076] R7 can be H, F, Br, Cl, CF3, CN, N3, NH2, NO2, OH, OCH3, methyl, ethyl, propyl, or isopropyl, each of which may be optionally substituted by 1, 2, 3, or 4 R8.

[0077] Each R8 can independently be H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, F, Br, Cl, CF3, NO2, OH, OCH3, CN, or an amino group unsubstituted or substituted with methyl, ethyl, or propyl.

[0078] The present disclosure also provides a compound of formula (VII): TIFF0007628108000046.tif62128 or an optically pure stereoisomer, pharmaceutically acceptable salt, or solvate thereof. In one embodiment, n can be an integer selected from 0 to 4.

[0079] In yet another embodiment, each R1 can be independently selected from the group consisting of H, F, Br, Cl, CF3, CN, N3, NH2, NO2, OH, OCH3, methyl, ethyl, propyl, and isopropyl, each of which can be optionally substituted by 1, 2, 3, or 4 R9.

[0080] In some embodiments, each R2 and R3 can be independently selected from the group consisting of H, methyl, ethyl, propyl, and isopropyl, each of which can be optionally substituted with 1, 2, 3, or 4 R9.

[0081] In certain embodiments, R4 can be selected from the group consisting of H, F, Br, Cl, CF3, CN, N3, NH2, NO2, OH, OCH3, methyl, ethyl, propyl, and isopropyl, each of which can be optionally substituted by 1, 2, 3, or 4 R9.

[0082] R5 may be selected from the group consisting of H, F, Br, Cl, CF3, CN, N3, NH2, NO2, OH, OCH3, methyl, ethyl, propyl, and isopropyl, each of which may be optionally substituted by 1, 2, 3, or 4 R9.

[0083] L is -O(CH2) 1-5 O-, -O(CH2) 1-5 NR 10 -, -NR6(CH2) 1-5 NR 10 -,-CONR 10 (CH2) 1-5 NR 10 -, -NR 10 CO(CH2) 1-5 NR 10 -, -(CH2) 1-5 NR 10 -, -(CH2) 1-5 O-, -(CH2) 1-5 OCO-, -(CH2) 1-5 CONR 10 -, TIFF0007628108000047.tif18128, each of which may be substituted by 1, 2, 3, or 4 R9.

[0084] or R5 and L together, TIFF0007628108000048.tif47128 may be formed. m may be an integer selected from 0 to 4.

[0085] R6 can be H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl, each of which can be optionally substituted by 1, 2, 3, or 4 R9.

[0086] In some embodiments, R7 can be selected from the group consisting of H, methyl, ethyl, propyl, and isopropyl. Or R6 and R7 together are: TIFF0007628108000049.tif26128 can be formed.

[0087] In some embodiments, R8 is CO(CH2) 0-5 CH3, CONR 10 (CH2) 0-5 CH3, COO(CH2) 0-5 CH3, SO2(CH2) 0-5 CH3, CO(CH2) 0-5 CH=CH2, CONR 10 (CH2) 0-5 CH=CH2, COO(CH2) 0-5 CH=CH2, SO2(CH2) 0-5 CH=CH2, CO(CH2) 0-5 CH=CHCH3, COO(CH2) 0-5 CH=CHCH3, CONR 10 (CH2) 0-5 CH=CHCH3, SO2(CH2) 0-5 CH=CHCH3, CO(CH2) 0-5 C≡CH, COO(CH2) 0-5 C≡CH, CONR 10 (CH2) 0-5 C≡CH, SO2(CH2) 0-5 C≡CH, CO(CH2) 0-5 C≡CCH3, COO(CH2) 0-5 C≡CCH3, CONR 10 (CH2) 0-5 C≡CCH3, and SO2(CH2)0-5 C≡CCH3, each of which may be optionally substituted by 1, 2, 3, or 4 R9.

[0088] In some embodiments, R8 is TIFF0007628108000050.tif54138.

[0089] Each R9 can independently be H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, F, Br, Cl, CF3, NO2, OH, OCH3, CN, or an amino group unsubstituted or substituted with methyl, ethyl, or propyl.

[0090] Each R 10 may independently be H, methyl, ethyl, propyl, or isopropyl.

[0091] Also disclosed herein are pharmaceutical compositions comprising compounds according to Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII).

[0092] Further disclosed herein are methods for treating cancer in a subject, comprising administering a compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII). In some embodiments, the cancer may be selected from the group consisting of breast cancer, lung cancer, bladder cancer, prostate cancer, ovarian cancer, endometrial cancer, rhabdomyosarcoma, liver cancer, and gastric cancer. In some embodiments, the method also comprises administering a chemotherapeutic agent, and the compound may be administered before, simultaneously with, or after administration of the chemotherapeutic agent.

[0093] Also disclosed herein are methods of inhibiting tyrosine kinase activity, comprising contacting a cell with a compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII). In some embodiments, the disclosed compounds exhibit covalent inhibition of FMS, KIT, FLT-3, FGR, or RON.

[0094] [The present invention 1001] Compounds according to formula (I): TIFF0007628108000051.tif56128 or an optically pure stereoisomer, pharmaceutically acceptable salt, or solvate thereof, During the ceremony, n is an integer selected from 0 to 2, m is an integer selected from 0 to 4, Ar 1 However, phenyl, naphthyl, anthracene, TIFF0007628108000052.tif193138 is selected from the group consisting of Ar 2 But phenyl, TIFF0007628108000053.tif60138 is selected from the group consisting of B is -CO-, -COO-, -CONR 4 -, -NR 4 -, -(CH 2 ) 1-5 -, -O-, -OPO-, -OPO 2 -, -S-, -SO-, or -SO 2 - and L is -O(CH 2 ) 1-5 O-, -O(CH 2 ) 1-5 NR 4 -, -NR 4 (CH 2 ) 1-5 NR 4 -,-CONR 4 (CH 2 ) 1-5 NR 4 -, -NR 4 CO(CH 2 ) 1-5 NR 4 -, -(CH 2) 1-5 NR 4 -, -(CH 2 ) 1-5 O-, -(CH 2 ) 1-5 OCO-, -(CH 2 ) 1-5 CONR 4 -、 TIFF0007628108000054.tif18128 and each of them is R 6 and optionally substituted by AA, TIFF0007628108000055.tif26128 a natural or unnatural amino acid selected from the group consisting of R 1 H, F, Br, Cl, CF 3 , C.N., N. 3 , N.H. 2 , NO 2 , OH, OCH 3 , methyl, ethyl, propyl, isopropyl, cyclopropyl, or -D-Ar 3 wherein D is selected from the group consisting of -CO-, -COO-, -CONR 4 -, -NR 4 -, -(CH 2 ) 1-5 -, -O-, -OPO-, -OPO 2 -, -S-, -SO-, or -SO 2 - and Ar 3 But phenyl, TIFF0007628108000056.tif35129 and each of them is F, Br, Cl, CF 3 , C.N., N. 3 , N.H. 2 , NO 2 , OH, OCH 3 , methyl, CH 2 optionally substituted by CN, ethyl, propyl, isopropyl, or cyclopropyl; R 2 H, F, Br, Cl, CF 3 , C.N., N. 3 , N.H. 2 , NO 2 , OH, OCH 3 , methyl, ethyl, propyl, isopropyl, TIFF0007628108000057.tif73138 each of which is selected from the group consisting of 1, 2, 3, or 4 R 6 and optionally substituted by R 3 CO(CH 2 ) 0-5 CH 3 ,CONR 4 (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 4 (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 4 (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 4 (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 C≡CCH 3 ,CONR 4 (CH 2 ) 0-5 C≡CCH 3 , and SO 2 (CH 2 ) 0-5 C≡CCH 3 each of which is selected from the group consisting of 1, 2, 3, or 4 R 6 and optionally substituted by R 4 is H, methyl, ethyl, propyl, isopropyl, cyclopropyl, or cyclobutyl; R 5 H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, -CH 2 CH 2 SCH 3 , -CH 2 Ph, -CH 2 PhOH, -CH 2 OH, -CHOHCH 3 , -CH 2 CONH 2 , -CH 2 CH 2 CONH 2 , -CH 2 SH, -CH 2 SeH, -CH 2 COOH, -CH 2 CH 2 COOH, -CH 2 CH 2 CH 2 CH 2 NH 2 、 TIFF0007628108000058.tif29128 and Each R 6 are independently H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, F, Br, Cl, CF 3 , NO 2 , OH, OCH 3 , CN, or an amino group that is unsubstituted or substituted with methyl, ethyl, or propyl; A compound according to formula (I), or an optically pure stereoisomer, pharmaceutically acceptable salt, or solvate thereof. [The present invention 1002] R 3 but, TIFF0007628108000059.tif37128 1001. A compound of the present invention selected from the group consisting of: [The present invention 1003] Compounds according to formula (II): TIFF0007628108000060.tif42128 or an optically pure stereoisomer, pharmaceutically acceptable salt, or solvate thereof, During the ceremony, each D and E is independently N or CH; m is an integer selected from 0 to 4, Ar, TIFF0007628108000061.tif65130 is selected from the group consisting of L is -O(CH 2 ) 1-5 O-, -O(CH 2 ) 1-5 NR 4 -, -NR 4 (CH 2 ) 1-5 NR 4 -,-CONR 4 (CH 2 ) 1-5 NR 4 -, -NR 4 CO(CH 2 ) 1-5 NR 4 -, -(CH 2 ) 1-5 NR 4 -, -(CH 2 ) 1-5 O-, -(CH 2 ) 1-5 OCO-, -(CH 2 ) 1-5 CONR 4 -、 TIFF0007628108000062.tif18128 and each of them is R 6 and optionally substituted by R 1 H, F, Br, Cl, CF 3 , C.N., N. 3 , N.H. 2 , NO 2 , OH, OCH 3 , methyl, ethyl, propyl, isopropyl, cyclopropyl, or -B-Ar 1 wherein B is -CO-, -COO-, -CONR 4 -, -NR 4 -, -(CH 2 ) 1-5 -, -O-, -OPO-, -OPO 2 -, -S-, -SO-, or -SO 2 - and Ar 1 But phenyl, TIFF0007628108000063.tif55133 and each of them is F, Br, Cl, CF 3 , C.N., N. 3 , N.H. 2 , NO 2 , OH, OCH 3 , methyl, CH 2 optionally substituted by CN, ethyl, propyl, isopropyl, or cyclopropyl; R 2 is H, methyl, ethyl, propyl, isopropyl, cyclopropyl, or cyclobutyl, each of which is selected from the group consisting of 1, 2, 3, or 4 R 6 is replaced by R 3 CO(CH 2 ) 0-5 CH 3 ,CONR 4 (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 4 (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 4 (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 4 (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 C≡CCH 3 ,CONR 4 (CH 2 ) 0-5 C≡CCH 3 , and SO 2 (CH 2 ) 0-5 C≡CCH 3 each of which is selected from the group consisting of 1, 2, 3, or 4 R 6 and optionally substituted by AA, TIFF0007628108000064.tif26128 a natural or unnatural amino acid selected from the group consisting of R 4 are independently H, methyl, ethyl, propyl, isopropyl, cyclopropyl, or cyclobutyl; R 5 H, F, Br, Cl, CF 3 , C.N., N. 3 , N.H. 2 , NO 2 , OH, OCH 3 , methyl, ethyl, propyl, isopropyl, cyclopropyl, TIFF0007628108000065.tif73138 each of which is selected from the group consisting of 1, 2, 3, or 4 R 6 and Each R 6 are independently H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, F, Br, Cl, CF 3 , NO 2 , OH, OCH 3 , CN, or an amino group that is unsubstituted or substituted with methyl, ethyl, or propyl; A compound according to formula (II), or an optically pure stereoisomer, pharmaceutically acceptable salt, or solvate thereof. [The present invention 1004] R 3 but, TIFF0007628108000066.tif37128 1003. A compound of the present invention selected from the group consisting of: [The present invention 1005] Compounds according to formula (III): TIFF0007628108000067.tif53128 or an optically pure stereoisomer, pharmaceutically acceptable salt, or solvate thereof, During the ceremony, n is an integer selected from 0 to 5, Each B and D independently represents -CO-, -COO-, or -CONR 7 -, -NR 7 -, -(CH 2 ) 1-5 -, -O-, -OPO-, -OPO 2 -, -S-, -SO-, or -SO 2 - and each E and F is independently N or CH; L is -O(CH 2 ) 1-5 O-, -O(CH 2 ) 1-5 NR 7 -, -NR 7 (CH 2 ) 1-5 NR 7 -,-CONR 7 (CH 2 ) 1-5 NR 7 -, -NR 7 CO(CH 2 ) 1-5 NR 7 -, -(CH 2 ) 1-5 NR 7 -, -(CH 2 ) 1-5 O-, -(CH 2 ) 1-5 OCO-, -(CH 2 ) 1-5 CONR 7 -、 TIFF0007628108000068.tif18128 and each of them has 1, 2, 3, or 4 R 8 and optionally substituted by R 1 H, F, Br, Cl, CF 3 , C.N., N. 3 , N.H. 2 , NO 2 , OH, OCH 3 , methyl, CH 2 CN, ethyl, propyl, isopropyl, and cyclopropyl, each of which is selected from the group consisting of 1, 2, 3, or 4 R 8 and optionally substituted by R 2 H, F, Br, Cl, CF 3 , C.N., N. 3 , N.H. 2 , NO 2 , OH, OCH 3 , methyl, ethyl, propyl, isopropyl, cyclopropyl, TIFF0007628108000069.tif74138 each of which is selected from the group consisting of 1, 2, 3, or 4 R 8 and optionally substituted by R 3 But H, CF 3 , methyl, ethyl, propyl, and isopropyl, each of which is selected from the group consisting of 1, 2, 3, or 4 R 8 may be replaced by R 4 is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl; R 5 is selected from the group consisting of H, methyl, ethyl, propyl, and isopropyl; or R 4 and R 5 together, TIFF0007628108000070.tif26128 Forming R 6 CO(CH 2 ) 0-5 CH 3 ,CONR 7 (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 7 (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 7 (CH 2 ) 0-5 CH=CHCH 3 , SO 2 (CH 2 ) 0-5 CH=CHCH 3 , CO(CH 2 ) 0-5 CCH, COO(CH 2 ) 0-5 CCH, CONR 7 (CH 2 ) 0-5 CCH, SO 2 (CH 2 ) 0-5 CCH, CO(CH 2 ) 0-5 CCCH 3 , COO(CH 2 ) 0-5 CCCH 3 ,CONR 7 (CH 2 ) 0-5 CCCH 3 , and SO 2 (CH 2 ) 0-5 CCCH 3 each of which may be selected from the group consisting of 1, 2, 3, or 4 R 8 may be replaced by R 7 is H, methyl, ethyl, propyl, or isopropyl, and R 8 H, F, Br, Cl, CF 3 , C.N., N. 3 , N.H. 2 , NO 2 , OH, OCH 3 , methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl; A compound according to formula (III), or an optically pure stereoisomer, pharmaceutically acceptable salt, or solvate thereof. [The present invention 1006] R 6 but, TIFF0007628108000071.tif37128 1005. A compound of the present invention selected from the group consisting of: Compounds according to formula (IV): TIFF0007628108000072.tif45128 or an optically pure stereoisomer, pharmaceutically acceptable salt, or solvate thereof, During the ceremony, B is -NR 6 -, -O-, -CONR 6 -, -COO-, -SO 2 -, or -SO 2 NR 6 - and each D and E is independently N or CH; 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 -、 TIFF0007628108000073.tif18128 and each of them has 1, 2, 3, or 4 R 7 and optionally substituted by Ar is phenyl, TIFF0007628108000074.tif55128 is selected from the group consisting of R 1 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 - and Ar 1 But phenyl, TIFF0007628108000075.tif55138 and each of them is F, Br, Cl, CF 3 , C.N., N. 3 , N.H. 2 , NO 2 , OH, OCH 3 , methyl, CH 2 optionally substituted by CN, ethyl, propyl, isopropyl, or cyclopropyl; R 2 H, F, Br, Cl, CF 3 , C.N., N. 3 , N.H. 2 , NO 2 , OH, OCH 3 , methyl, ethyl, propyl, isopropyl, TIFF0007628108000076.tif73138 each of which is selected from the group consisting of 1, 2, 3, or 4 R 7 and optionally substituted by R 3 is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl, each of which is selected from 1, 2, 3, or 4 R 7 may be replaced by R 4 is selected from the group consisting of H, methyl, ethyl, propyl, and isopropyl; or R 3 and R 4 together, TIFF0007628108000077.tif26128 Forming R 5 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 C≡CCH 3 ,CONR 6 (CH 2 ) 0-5 C≡CCH 3 , and SO 2 (CH 2 ) 0-5 C≡CCH 3 each of which is selected from the group consisting of 1, 2, 3, or 4 R 7 and optionally substituted by Each R 6 is independently H, methyl, ethyl, propyl, isopropyl, cyclopropyl, or cyclobutyl, and Each R 7 are independently H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, F, Br, Cl, CF 3 , NO 2 , OH, OCH 3 , CN, or an amino group that is unsubstituted or substituted with methyl, ethyl, or propyl; A compound according to formula (IV), or an optically pure stereoisomer, pharmaceutically acceptable salt, or solvate thereof. [The present invention 1007] R 5 but, TIFF0007628108000078.tif38128 1007. A compound of the present invention selected from the group consisting of: [The present invention 1008] A compound according to formula (V): TIFF0007628108000079.tif60128 or an optically pure stereoisomer, pharmaceutically acceptable salt, or solvate thereof, During the ceremony, n is an integer selected from 0 to 2, m is an integer selected from 0 to 3; p is an integer selected from 0 to 4, TIFF0007628108000080.tif2128 is a single bond or a double bond, B is -CO-, -COO-, -CONR 4 -, -SO 2 -, -SO 2 NR 4 -, -SO-, -SONR 4 -, -OPO-, -OPONR 4 -, -OPO 2 -, or -OPO 2 NR 4 - and Ar 1 but, TIFF0007628108000081.tif118138 is selected from the group consisting of Ar 2 but, TIFF0007628108000082.tif96138 is selected from the group consisting of L is -O(CH 2 ) 1-5 O-, -O(CH 2 ) 1-5 NR 4 -, -NR 4 (CH 2 ) 1-5 NR 4 -,-CONR 4 (CH 2 ) 1-5 NR 4 -, -NR 4 CO(CH 2 ) 1-5 NR 4 -, -(CH 2 ) 1-5 NR 4 -, -(CH 2 ) 1-5 O-, -(CH 2 ) 1-5 OCO-, -(CH 2 ) 1-5 CONR 4 -、 TIFF0007628108000083.tif18128 and each of them is R 6 and optionally substituted by R 1 H, F, Br, Cl, CF 3 , C.N., N. 3 , N.H. 2 , NO 2 , OH, OCH 3 , methyl, ethyl, propyl, and isopropyl, each of which is selected from the group consisting of 1, 2, 3, or 4 R 6 and optionally substituted by R 2 CO(CH 2 ) 0-5 CH 3 ,CONR 4 (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 4 (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 4 (CH 2 ) 0-5 CH=CHCH 3 , SO 2 (CH 2 ) 0-5 CH=CHCH 3 , CO(CH 2 ) 0-5 C≡CH, COO(CH2 ) 0-5 C≡CH, CONR 4 (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 C≡CCH 3 ,CONR 4 (CH 2 ) 0-5 C≡CCH 3 , and SO 2 (CH 2 ) 0-5 C≡CCH 3 each of which is selected from the group consisting of 1, 2, 3, or 4 R 6 and optionally substituted by R 3 H, F, Br, Cl, CF 3 , C.N., N. 3 , N.H. 2 , NO 2 , OH, OCH 3 , methyl, ethyl, propyl, and isopropyl, each of which is selected from the group consisting of 1, 2, 3, or 4 R 6 and optionally substituted by R 4 is H, methyl, ethyl, propyl, or isopropyl; AA, TIFF0007628108000084.tif26128 a natural or unnatural amino acid selected from the group consisting of R 5 H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, -CH 2 CH 2 SCH 3 , -CH 2 Ph, -CH 2 PhOH, -CH 2 OH, -CHOHCH 3 , -CH 2 CONH 2 , -CH 2 CH 2 CONH 2 , -CH 2 SH, -CH 2 SeH, -CH 2 COOH, -CH 2 CH 2 COOH, -CH 2 CH 2 CH 2 CH 2 NH 2 、 TIFF0007628108000085.tif29128 and R 6 H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, F, Br, Cl, CF 3 , NO 2 , OH, OCH 3 , CN, or an amino group that is unsubstituted or substituted with methyl, ethyl, or propyl; A compound according to formula (V), or an optically pure stereoisomer, pharmaceutically acceptable salt, or solvate thereof. [The present invention 1009] R 2 but, TIFF0007628108000086.tif38128 1009 compounds of the present invention selected from the group consisting of: [The present invention 1010] A compound according to formula (VI): TIFF0007628108000087.tif53128 or an optically pure stereoisomer, pharmaceutically acceptable salt, or solvate thereof, During the ceremony, n is an integer selected from 0 to 4, A is -CO-, -SO-, -SO 2 -, -OPO-, or -OPO 2 - and TIFF0007628108000088.tif2128 is a single bond or a double bond, R 1 H, F, Br, Cl, CF 3 , C.N., N. 3 , N.H. 2 , NO 2 , OH, OCH 3 , methyl, ethyl, propyl, and isopropyl, each of which is selected from the group consisting of 1, 2, 3, or 4 R 8 and optionally substituted by R 2 is selected from the group consisting of H, methyl, ethyl, propyl, and isopropyl, each of which is selected from the group consisting of 1, 2, 3, or 4 R 8 and optionally substituted by Ar, TIFF0007628108000089.tif95138 is selected from the group consisting of 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 -、 TIFF0007628108000090.tif18128 and each of them has 1, 2, 3, or 4 R 8 and optionally substituted by R 3 is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl, each of which is selected from 1, 2, 3, or 4 R 8 and optionally substituted by R 4 is selected from the group consisting of H, methyl, ethyl, propyl, and isopropyl; or R 4 and R 3 together, TIFF0007628108000091.tif26128 Forming R 5 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 C≡CCH 3 ,CONR 6 (CH 2 ) 0-5 C≡CCH 3 , and SO 2 (CH 2 ) 0-5 C≡CCH 3 each of which is selected from the group consisting of 1, 2, 3, or 4 R 8 and optionally substituted by Each R 6 are independently H, methyl, ethyl, propyl, or isopropyl; R 7 H, F, Br, Cl, CF 3 , C.N., N. 3 , N.H. 2 , NO 2 , OH, OCH 3 , methyl, ethyl, propyl, or isopropyl, each of which may have one, two, three, or four R 8 and Each R 8 are independently H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, F, Br, Cl, CF 3 , NO 2 , OH, OCH 3 , CN, or an amino group that is unsubstituted or substituted with methyl, ethyl, or propyl; A compound according to formula (VI), or an optically pure stereoisomer, pharmaceutically acceptable salt, or solvate thereof. [The present invention 1011] R 5 but, TIFF0007628108000092.tif38128 1011. A compound of the present invention selected from the group consisting of: [The present invention 1012] Compounds according to formula (VII): TIFF0007628108000093.tif63128 or an optically pure stereoisomer, pharmaceutically acceptable salt, or solvate thereof, During the ceremony, n is an integer selected from 0 to 4, Each R 1 are independently H, F, Br, Cl, CF 3 , C.N., N. 3 , N.H. 2 , NO 2 , OH, OCH 3 , methyl, ethyl, propyl, and isopropyl, each of which is selected from the group consisting of 1, 2, 3, or 4 R 9 and optionally substituted by Each R 2 and R 3 are independently selected from the group consisting of H, methyl, ethyl, propyl, and isopropyl, each of which is selected from 1, 2, 3, or 4 R 9 and optionally substituted by R 4 H, F, Br, Cl, CF 3 , C.N., N. 3 , N.H. 2 , NO 2 , OH, OCH 3 , methyl, ethyl, propyl, and isopropyl, each of which is selected from the group consisting of 1, 2, 3, or 4 R 9 and optionally substituted by R 5 H, F, Br, Cl, CF 3 , C.N., N. 3 , N.H. 2 , NO 2 , OH, OCH 3 , methyl, ethyl, propyl, and isopropyl, each of which is selected from the group consisting of 1, 2, 3, or 4 R 9 and optionally substituted by L is -O(CH 2 ) 1-5 O-, -O(CH 2 ) 1-5 NR 10 -, -NR 6 (CH 2 ) 1-5 NR 10 -,-CONR 10 (CH 2 ) 1-5 NR 10 -, -NR 10 CO(CH 2 ) 1-5 NR 10 -, -(CH 2 ) 1-5 NR 10 -, -(CH 2 ) 1-5 O-, -(CH 2 ) 1-5 OCO-, -(CH 2 ) 1-5 CONR 10 -、 TIFF0007628108000094.tif18128 and each of them has 1, 2, 3, or 4 R 9 and optionally substituted by or R 5 and L together, TIFF0007628108000095.tif47128 Forming m is an integer selected from 0 to 4, R 6 is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl, each of which is selected from 1, 2, 3, or 4 R 9 and optionally substituted by R 7 is selected from the group consisting of H, methyl, ethyl, propyl, and isopropyl; or R 6 and R 7 together, TIFF0007628108000096.tif26128 Forming R 8 CO(CH 2 ) 0-5 CH 3 ,CONR 10 (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 10 (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 10 (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 10 (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 C≡CCH 3 ,CONR 10 (CH 2 ) 0-5 C≡CCH 3 , and SO 2 (CH 2 ) 0-5 C≡CCH 3 each of which is selected from the group consisting of 1, 2, 3, or 4 R 9 and optionally substituted by Each R 9 are independently H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, F, Br, Cl, CF 3 , NO 2 , OH, OCH 3 , CN, or an amino group unsubstituted or substituted with methyl, ethyl, or propyl; and Each R 10 may independently be H, methyl, ethyl, propyl, or isopropyl; A compound according to formula (VII), or an optically pure stereoisomer, pharmaceutically acceptable salt, or solvate thereof. [The present invention 1013] R 8 but, TIFF0007628108000097.tif38138 1013. A compound of the present invention selected from the group consisting of: [The present invention 1014] A compound of the invention 1001, 1003, 1005, 1007, 1009, 1011, or 1013, which inhibits tyrosine kinases. [The present invention 1015] 1015 compounds of the present invention that exhibit covalent inhibition of FMS, KIT, FLT-3, FGR, or RON. [The present invention 1016] A pharmaceutical formulation comprising a compound of the invention 1001, 1003, 1005, 1007, 1009, 1011, or 1013 and a pharmaceutically acceptable carrier. [The present invention 1017] A method for treating cancer in a subject, comprising administering a compound of the present invention 1001, 1003, 1005, 1007, 1009, 1011, or 1013. [The present invention 1018] 1018. The method of claim 1018, wherein said cancer cells are breast cancer, myeloid cancer, lung cancer, bladder cancer, prostate cancer, ovarian cancer, endometrial cancer, rhabdomyosarcoma, liver cancer, gastric cancer, or intestinal cancer cells. [The present invention 1019] The method of claim 1018, further comprising administering a chemotherapeutic agent. [The present invention 1020] The method of claim 1020, wherein said compound is administered prior to, concurrently with, or after said administration of said chemotherapeutic agent. [The present invention 1021] A method of inhibiting tyrosine kinase activity, comprising contacting a cell with a compound of the invention 1001, 1003, 1005, 1007, 1009, 1011, or 1013. [The present invention 1022] The method of claim 1022, wherein the cells are cancer cells. [The present invention 1023] 1024. The method of claim 1023, wherein said cancer cells are breast cancer, myeloid cancer, lung cancer, bladder cancer, prostate cancer, ovarian cancer, endometrial cancer, rhabdomyosarcoma, liver cancer, gastric cancer, or intestinal cancer cells. Other features and advantages may become apparent from the following detailed description. DETAILED DESCRIPTION OF THE INVENTION

[0095] explanation The following are some acronyms used in this disclosure: n-BuOK refers to potassium tert-butoxide, DMF refers to dimethylformamide, Boc refers to tert-butyloxycarbonyl protecting group, DMSO refers to dimethyl sulfoxide, HATU refers to 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, DIEA refers to N,N-diisopropylethylamine, DIPEA refers to N,N-diisopropylethylamine, and TFA refers to trifluoroacetic acid.

[0096] The term "about" will be understood by those skilled in the art. Whether or not the term "about" is explicitly used, all quantities given herein refer to the actual given value, which is also meant to refer to an approximation to such a given value that would be reasonably estimated based on one skilled in the art.

[0097] An alkyl group refers to a monovalent group derived from an alkane by removing a hydrogen atom from any carbon atom, including straight-chain and branched-chain groups having 1 to 12 carbon atoms, typically 1 to about 10 carbon atoms, or in some embodiments, 1 to about 6 carbon atoms, or in other embodiments, 1, 2, 3, or 4 carbon atoms. Examples of straight-chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, and n-hexyl. Examples of branched-chain alkyl groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, and tert-butyl. Alkyl groups may be substituted or unsubstituted. Representative substituted alkyl groups may be mono-substituted or more than di-substituted, such as, but not limited to, mono-, di-, or tri-substituted. As used herein, the term alkyl refers to both cyclic and acyclic groups, unless otherwise specified.

[0098] The term "cyclic alkyl" or "cycloalkyl" refers to a monovalent group derived from a cycloalkane by removing a hydrogen atom from a ring carbon atom. Cycloalkyl groups are saturated or partially saturated non-aromatic structures having single or multiple rings, including isolated, fused, bridged, and spiro ring systems, having 3 to 14 carbon atoms, or in some embodiments, 3 to 12, or 3 to 10, or 3 to 8, or 3, 4, 5, 6, or 7 carbon atoms. Cycloalkyl groups can be substituted or unsubstituted. Representative substituted cycloalkyl groups can be mono-substituted or di- or more-substituted, such as mono-, di-, or tri-substituted, but are not limited thereto. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups. Examples of polycyclic ring systems include, but are not limited to, bis[4.4.0]decane, bis[2.2.1]heptane, spiro[2.2]pentane, and the like.

[0099] Alkenyl groups refer to straight-chain and branched-chain and cycloalkyl groups, as defined above, having one or more double bonds between two carbon atoms. Alkenyl groups can have from 2 to about 12 carbon atoms, or in some embodiments, from 1 to about 10 carbon atoms, or in other embodiments, from 1 to about 6 carbon atoms, or in other embodiments, from 1, 2, 3, or 4 carbon atoms. Alkenyl groups can be substituted or unsubstituted. Representative substituted alkenyl groups can be mono-substituted or di- or more-substituted, such as mono-, di-, or tri-substituted, but are not limited thereto. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, -CH=CH(CH), -CH=C(CH), -C(CH)=CH, cyclopentenyl, cyclohexenyl, butadienyl, pentadienyl, and hexadienyl, among others.

[0100] An alkynyl group refers to straight-chain, branched-chain, and cycloalkyl groups, as defined above, having one or more triple bonds between two carbon atoms. Alkynyl groups can have from 2 to about 12 carbon atoms, or in some embodiments, from 1 to about 10 carbon atoms, or in other embodiments, from 1 to about 6 carbon atoms, or in other embodiments, from 1, 2, 3, or 4 carbon atoms. Alkynyl groups can be substituted or unsubstituted. Representative substituted alkynyl groups can be mono-substituted or di- or more-substituted, such as mono-, di-, or tri-substituted, but are not limited thereto. Exemplary alkynyl groups include, but are not limited to, ethynyl, propargyl, and —C≡C(CH), among others.

[0101] Aryl groups are cyclic aromatic hydrocarbons, including single and multiple ring compounds, including multi-ring compounds containing other aryl groups and / or fused aryl groups. Aryl groups may contain 6 to about 18 ring carbons, or in some embodiments, 6 to 14 ring carbons, or even 6 to 10 ring carbons in other embodiments. Aryl groups also include heteroaryl groups, which are aromatic ring compounds containing five or more ring members, in which one or more ring carbon atoms are replaced with heteroatoms such as, but not limited to, N, O, and S. Aryl groups may be substituted or unsubstituted. Representative substituted aryl groups may be mono-substituted or more than di-substituted, such as, but not limited to, mono-, di-, or tri-substituted. Aryl groups include, but are not limited to, phenyl, biphenylenyl, triphenylenyl, naphthyl, anthryl, and pyrenyl groups.

[0102] Suitable heterocyclyl groups include cyclic groups having atoms of at least two different elements as ring members, one or more of which are heteroatoms, such as, but not limited to, N, O, or S. Heterocyclyl groups may contain 3 to about 20 ring members, or in some embodiments, 3 to 18 ring members, or about 3 to 15, 3 to 12, 3 to 10, or 3 to 6 ring members. The ring system in a heterocyclyl group may be unsaturated, partially saturated, and / or saturated. Heterocyclyl groups may be substituted or unsubstituted. Representative substituted heterocyclyl groups may be mono-substituted or di- or more substituted, such as, but not limited to, mono-, di-, or tri-substituted. Exemplary heterocyclyl groups include pyrrolidinyl, tetrahydrofuryl, dihydrofuryl, tetrahydrothienyl, tetrahydrothiopyranyl, piperidyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, azetidinyl, aziridinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, pyrazolinyl, triazolyl, and the like. Examples of thiazolyl radicals include, but are not limited to, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiazolinyl, oxetanyl, thietanyl, homopiperidyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxolanyl, dioxanyl, purinyl, quinolizinyl, cinnolinyl, phthalazinyl, pteridinyl, and benzothiazolyl radicals.

[0103] A polycyclic or polycyclyl group refers to two or more rings in which two or more carbons are common to two adjacent rings and the rings are "fused rings"; if the rings are connected by one common carbon atom, they are "spiro" ring systems. Rings that are connected through non-adjacent atoms are "bridged" rings. Polycyclic groups may be substituted or unsubstituted. Representative polycyclic groups may be substituted one or more times.

[0104] Halogen groups include F, Cl, Br, and I; nitro groups refer to -NO2; cyano groups refer to -CN; isocyano groups refer to -N≡C; and epoxy groups encompass essentially cyclic ether structures in which an oxygen atom is directly bonded to two adjacent or non-adjacent carbon atoms in a carbon chain or ring system. Epoxides are cyclic ethers with a three-atom ring.

[0105] An alkoxy group is a substituted or unsubstituted alkyl group as defined above, which is single-bonded to oxygen. The alkoxy group may be substituted or unsubstituted. Representative substituted alkoxy groups may be substituted by one or more substituents. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, isopropoxy, sec-butoxy, tert-butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy.

[0106] The terms "amine" and "amino" refer to derivatives of ammonia in which one or more hydrogen atoms have been replaced by substituents, including, but not limited to, alkyl, alkenyl, aryl, and heterocyclyl groups. A carbamate group refers to -O(C=O)NR1R2, where R1 and R2 are independently hydrogen, an aliphatic group, an aryl group, or a heterocyclyl group.

[0107] Pharmaceutically acceptable salts of the compounds described herein include conventional non-toxic salts or quaternary ammonium salts of the compounds, for example, derived from non-toxic organic or inorganic acids.For example, such conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc.; and salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isothiocyanic acid, etc. In other cases, the compounds described herein may contain one or more acidic functional groups, and therefore can form pharmaceutically acceptable salts with pharmaceutically acceptable bases. These salts can also be prepared in situ during the administration vehicle or dosage form manufacturing process, or by separately reacting the purified compound in its free acid form with a suitable base, such as a hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, ammonia, or a pharmaceutically acceptable organic primary, secondary, or tertiary amine. Representative alkali or alkaline earth salts include lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and the like. Representative organic amines useful for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like.

[0108] The present disclosure provides a compound of formula (I): TIFF0007628108000098.tif56128 or an optically pure stereoisomer, pharmaceutically acceptable salt, or solvate thereof is provided.

[0109] In some embodiments, n can be an integer selected from 0-2 and m can be an integer selected from 0-4.

[0110] In some embodiments, Ar1 is phenyl, naphthyl, anthracene, TIFF0007628108000099.tif191138.

[0111] Ar2 is phenyl, TIFF0007628108000100.tif55138.

[0112] B is -CO-, -COO-, -CONR4-, -NR4-, -(CH2) 1-5 It can be -, -O-, -OPO-, -OPO2-, -S-, -SO-, or -SO2-.

[0113] L is -O(CH2) 1-5 O-, -O(CH2) 1-5 NR4-, -NR4(CH2) 1-5 NR4-, -CONR4(CH2) 1-5 NR4-, -NR4CO(CH2) 1-5 NR4-, -(CH2) 1-5 NR4-, -(CH2) 1-5 O-, -(CH2) 1-5 OCO-, -(CH2) 1-5 CONR4-, TIFF0007628108000101.tif18128, each of which may be substituted by R6.

[0114] AA is, The amino acid may be a natural or unnatural amino acid selected from the group consisting of: TIFF0007628108000102.tif26128.

[0115] R1 can be selected from the group consisting of H, F, Br, Cl, CF3, CN, N3, NH2, NO2, OH, OCH3, methyl, ethyl, propyl, isopropyl, cyclopropyl, or -D-Ar3, where D is -CO-, -COO-, -CONR4-, -NR4-, -(CH2) 1-5Ar3 may be -, -O-, -OPO-, -OPO2-, -S-, -SO-, or -SO2-; TIFF0007628108000103.tif53138, each of which may be optionally substituted by F, Br, Cl, CF3, CN, N3, NH2, NO2, OH, OCH3, methyl, CH2CN, ethyl, propyl, isopropyl, or cyclopropyl.

[0116] In one aspect, R1 is It could be TIFF0007628108000104.tif11128.

[0117] R2 is H, F, Br, Cl, CF3, CN, N3, NH2, NO2, OH, OCH3, methyl, ethyl, propyl, isopropyl, TIFF0007628108000105.tif73138, each of which may be substituted by 1, 2, 3, or 4 R6.

[0118] In some embodiments, R3 is CO(CH2) 0-5 CH3, CONR4(CH2) 0-5 CH3, COO(CH2) 0-5 CH3, SO2(CH2) 0-5 CH3, CO(CH2) 0-5 CH=CH2, CONR4(CH2) 0-5 CH=CH2, COO(CH2) 0-5 CH=CH2, SO2(CH2) 0-5 CH=CH2, CO(CH2) 0-5 CH=CHCH3, COO(CH2) 0-5 CH=CHCH3, CONR4(CH2) 0-5 CH=CHCH3, SO2(CH2) 0-5 CH=CHCH3, CO(CH2) 0-5 C≡CH, COO(CH2) 0-5 C≡CH, CONR4(CH2) 0-5 C≡CH, SO2(CH2) 0-5 C≡CH, CO(CH2) 0-5C≡CCH3, COO(CH2) 0-5 C≡CCH3, CONR4(CH2) 0-5 C≡CCH3, and SO2(CH2) 0-5 C≡CCH3, each of which may be optionally substituted by 1, 2, 3, or 4 R6.

[0119] In some embodiments, R3 is TIFF0007628108000106.tif37138.

[0120] R4 can be H, methyl, ethyl, propyl, isopropyl, cyclopropyl, or cyclobutyl.

[0121] R5 is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, -CH2CH2SCH3, -CH2Ph, -CH2PhOH, -CH2OH, -CHOHCH3, -CH2CONH2, -CH2CH2CONH2, -CH2SH, -CH2SeH, -CH2COOH, -CH2CH2COOH, -CH2CH2CH2CH2NH2, It could be TIFF0007628108000107.tif29128.

[0122] Each R6 can independently be H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, F, Br, Cl, CF3, NO2, OH, OCH3, CN, or an amino group unsubstituted or substituted with methyl, ethyl, or propyl.

[0123] The present disclosure provides a compound of formula (II): TIFF0007628108000108.tif43128 or an optically pure stereoisomer, pharmaceutically acceptable salt, or solvate thereof is provided.

[0124] In one embodiment, each D and E can independently be N or CH. m can be an integer selected from 0-4.

[0125] Ar is TIFF0007628108000109.tif65138.

[0126] L is -O(CH2) 1-5 O-, -O(CH2) 1-5 NR4-, -NR4(CH2) 1-5 NR4-, -CONR4(CH2) 1-5 NR4-, -NR4CO(CH2) 1-5 NR4-, -(CH2) 1-5 NR4-, -(CH2) 1-5 O-, -(CH2) 1-5 OCO-, -(CH2) 1-5 CONR4-, TIFF0007628108000110.tif18128, each of which may be substituted by R6.

[0127] In another embodiment, R1 can be selected from the group consisting of H, F, Br, Cl, CF3, CN, N3, NH2, NO2, OH, OCH3, methyl, ethyl, propyl, isopropyl, cyclopropyl, or -B-Ar1, where B is -CO-, -COO-, -CONR4-, -NR4-, -(CH2) 1-5 Ar1 may be -, -O-, -OPO-, -OPO2-, -S-, -SO-, or -SO2-; TIFF0007628108000111.tif55138, each of which may be optionally substituted by F, Br, Cl, CF3, CN, N3, NH2, NO2, OH, OCH3, methyl, CH2CN, ethyl, propyl, isopropyl, or cyclopropyl. It could be TIFF0007628108000112.tif11128.

[0128] R2 can be H, methyl, ethyl, propyl, isopropyl, cyclopropyl, or cyclobutyl, each of which can be substituted by 1, 2, 3, or 4 R6.

[0129] In some embodiments, R3 is CO(CH2) 0-5 CH3, CONR4(CH2) 0-5 CH3, COO(CH2) 0-5 CH3, SO2(CH2) 0-5 CH3, CO(CH2) 0-5 CH=CH2, CONR4(CH2) 0-5 CH=CH2, COO(CH2) 0-5 CH=CH2, SO2(CH2) 0-5 CH=CH2, CO(CH2) 0-5 CH=CHCH3, COO(CH2) 0-5 CH=CHCH3, CONR4(CH2) 0-5 CH=CHCH3, SO2(CH2) 0-5 CH=CHCH3, CO(CH2) 0-5 C≡CH, COO(CH2) 0-5 C≡CH, CONR4(CH2) 0-5 C≡CH, SO2(CH2) 0-5 C≡CH, CO(CH2) 0-5 C≡CCH3, COO(CH2) 0-5 C≡CCH3, CONR4(CH2) 0-5 C≡CCH3, and SO2(CH2) 0-5 C≡CCH3, each of which may be optionally substituted by 1, 2, 3, or 4 R6.

[0130] In some embodiments, R3 is TIFF0007628108000113.tif37138.

[0131] AA is, The amino acid may be a natural or unnatural amino acid selected from the group consisting of: TIFF0007628108000114.tif26128.

[0132] Each R4 can independently be H, methyl, ethyl, propyl, isopropyl, cyclopropyl, or cyclobutyl.

[0133] R5 is H, F, Br, Cl, CF3, CN, N3, NH2, NO2, OH, OCH3, methyl, ethyl, propyl, isopropyl, cyclopropyl, TIFF0007628108000115.tif73136, each of which may be optionally substituted by 1, 2, 3, or 4 R6.

[0134] Each R6 can independently be H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, F, Br, Cl, CF3, NO2, OH, OCH3, CN, or an amino group unsubstituted or substituted with methyl, ethyl, or propyl.

[0135] The present disclosure also provides a compound of formula (III): TIFF0007628108000116.tif56128 or an optically pure stereoisomer, pharmaceutically acceptable salt, or solvate thereof. n can be an integer selected from 0 to 5. Each B and D independently represents -CO-, -COO-, -CONR7-, -NR7-, -(CH2) 1-5 Each E and F can independently be N or CH.

[0136] L is -O(CH2) 1-5 O-, -O(CH2) 1-5 NR7-, -NR7(CH2) 1-5 NR7-, -CONR7(CH2) 1-5 NR7-, -NR7CO(CH2) 1-5 NR7-, -(CH2) 1-5 NR7-, -(CH2) 1-5 O-, -(CH2) 1-5 OCO-, -(CH2) 1-5 CONR7-, TIFF0007628108000117.tif18128, each of which may be substituted by R8.

[0137] In some embodiments, R1 may be selected from the group consisting of H, F, Br, Cl, CF3, CN, N3, NH2, NO2, OH, OCH3, methyl, CH2CN, ethyl, propyl, isopropyl, and cyclopropyl, each of which may be optionally substituted by 1, 2, 3, or 4 R8.

[0138] In another embodiment, R2 is H, F, Br, Cl, CF3, CN, N3, NH2, NO2, OH, OCH3, methyl, ethyl, propyl, isopropyl, cyclopropyl, TIFF0007628108000118.tif53138, each of which may be optionally substituted by 1, 2, 3, or 4 R8.

[0139] In yet another embodiment, R3 can be selected from the group consisting of H, CF3, methyl, ethyl, propyl, and isopropyl, each of which can be optionally substituted with 1, 2, 3, or 4 R8.

[0140] In certain embodiments, R4 can be H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl. In some embodiments, R5 can be selected from the group consisting of H, methyl, ethyl, propyl, and isopropyl. Or R4 and R5 together are: TIFF0007628108000119.tif26128 can be formed.

[0141] In some embodiments, R6 is CO(CH2) 0-5 CH3, CONR7(CH2) 0-5 CH3, COO(CH2) 0-5 CH3, SO2(CH2) 0-5 CH3, CO(CH2) 0-5 CH=CH2, CONR7(CH2) 0-5 CH=CH2, COO(CH2) 0-5 CH=CH2, SO2(CH2) 0-5CH=CH2, CO(CH2) 0-5 CH=CHCH3, COO(CH2) 0-5 CH=CHCH3, CONR7(CH2) 0-5 CH=CHCH3, SO2(CH2) 0-5 CH=CHCH3, CO(CH2) 0-5 CCH, COO(CH2) 0-5 CCH, CONR7(CH2) 0-5 CCH, SO2(CH2) 0-5 CCH, CO(CH2) 0-5 CCCH3, COO(CH2) 0-5 CCCH3, CONR7(CH2) 0-5 CCCH3, and SO2(CH2) 0-5 CCCH3, each of which may be optionally substituted by 1, 2, 3, or 4 R8.

[0142] In some embodiments, R6 is TIFF0007628108000120.tif37135.

[0143] R7 can be H, methyl, ethyl, propyl, or isopropyl.

[0144] R8 can be H, F, Br, Cl, CF3, CN, N3, NH2, NO2, OH, OCH3, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl.

[0145] The present disclosure also provides a compound of formula (IV): TIFF0007628108000121.tif44128 or an optically pure stereoisomer, pharmaceutically acceptable salt, or solvate thereof is provided.

[0146] In one embodiment, each D and E can independently be N or CH. B can be -NR6-, -O-, -CONR6-, -COO-, -SO2-, or -SO2NR6-.

[0147] L is -O(CH2) 1-5 O-, -O(CH2) 1-5 NR6-, -NR6(CH2) 1-5 NR6-, -CONR6(CH2) 1-5 NR6-, -NR6CO(CH2) 1-5 NR6-, -(CH2) 1-5 NR6-, -(CH2) 1-5 O-, -(CH2) 1-5 OCO-, -(CH2) 1-5 CONR6-, TIFF0007628108000122.tif18128, each of which may be substituted by 1, 2, 3, or 4 R7.

[0148] Ar is phenyl, TIFF0007628108000123.tif55138.

[0149] In another embodiment, R1 can be selected from the group consisting of H, F, Cl, Br, OH, N3, NO2, CF3, CN, methyl, ethyl, propyl, and isopropyl. In some embodiments, R1 can be -G-Ar1, where G is -CO-, -COO-, -CONR6-, -NR6-, -(CH2) 1-5 Ar1 may be -, -O-, -OPO-, -OPO2-, -S-, -SO-, or -SO2-; TIFF0007628108000124.tif55138, each of which may be optionally substituted by F, Br, Cl, CF3, CN, N3, NH2, NO2, OH, OCH3, methyl, CH2CN, ethyl, propyl, isopropyl, or cyclopropyl. It could be TIFF0007628108000125.tif11128.

[0150] In yet another embodiment, R2 is H, F, Br, Cl, CF3, CN, N3, NH2, NO2, OH, OCH3, methyl, ethyl, propyl, isopropyl, TIFF0007628108000126.tif72138, each of which may be substituted by 1, 2, 3, or 4 R7.

[0151] In certain embodiments, R3 can be H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl, each of which can be substituted by 1, 2, 3, or 4 R7.

[0152] In some embodiments, R4 can be selected from the group consisting of H, methyl, ethyl, propyl, and isopropyl. Or R4 and R3 together are: TIFF0007628108000127.tif26128 can be formed.

[0153] In some embodiments, R5 is CO(CH2) 0-5 CH3, CONR6(CH2) 0-5 CH3, COO(CH2) 0-5 CH3, SO2(CH2) 0-5 CH3, CO(CH2) 0-5 CH=CH2, CONR6(CH2) 0-5 CH=CH2, COO(CH2) 0-5 CH=CH2, SO2(CH2) 0-5 CH=CH2, CO(CH2) 0-5 CH=CHCH3, COO(CH2) 0-5 CH=CHCH3, CONR6(CH2) 0-5 CH=CHCH3, SO2(CH2) 0-5 CH=CHCH3, CO(CH2) 0-5 C≡CH, COO(CH2) 0-5 C≡CH, CONR6(CH2) 0-5 C≡CH, SO2(CH2) 0-5 C≡CH, CO(CH2) 0-5 C≡CCH3, COO(CH2) 0-5 C≡CCH3, CONR6(CH2) 0-5 C≡CCH3, and SO2(CH2) 0-5C≡CCH3, each of which may be optionally substituted by 1, 2, 3, or 4 R7.

[0154] In some embodiments, R5 is TIFF0007628108000128.tif37135.

[0155] Each R6 can independently be H, methyl, ethyl, propyl, isopropyl, cyclopropyl, or cyclobutyl.

[0156] Each R7 can independently be H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, F, Br, Cl, CF3, NO2, OH, OCH3, CN, or an amino group unsubstituted or substituted with methyl, ethyl, or propyl.

[0157] The present disclosure provides a compound of formula (V): TIFF0007628108000129.tif60128 or an optically pure stereoisomer, pharmaceutically acceptable salt, or solvate thereof. In one embodiment, n can be an integer selected from 0 to 2. In another embodiment, m can be an integer selected from 0 to 3. In some embodiments, p can be an integer selected from 0 to 4. TIFF0007628108000130.tif2128 can be a single or double bond. B can be -CO-, -COO-, -CONR4-, -SO2-, -SO2NR4-, -SO-, -SONR4-, -OPO-, -OPONR4-, -OPO2-, or -OPO2NR4-.

[0158] In certain embodiments, Ar1 is TIFF0007628108000131.tif96138.

[0159] In another embodiment, Ar2 is TIFF0007628108000132.tif95141.

[0160] L is -O(CH2) 1-5 O-, -O(CH2) 1-5 NR4-, -NR4(CH2) 1-5 NR4-, -CONR4(CH2) 1-5 NR4-, -NR4CO(CH2) 1-5 NR4-, -(CH2) 1-5 NR4-, -(CH2) 1-5 O-, -(CH2) 1-5 OCO-, -(CH2) 1-5 CONR4-, TIFF0007628108000133.tif18128, each of which may be substituted by R6.

[0161] R1 may be selected from the group consisting of H, F, Br, Cl, CF3, CN, N3, NH2, NO2, OH, OCH3, methyl, ethyl, propyl, and isopropyl, each of which may be optionally substituted by 1, 2, 3, or 4 R6.

[0162] In some embodiments, R2 is CO(CH2) 0-5 CH3, CONR4(CH2) 0-5 CH3, COO(CH2) 0-5 CH3, SO2(CH2) 0-5 CH3, CO(CH2) 0-5 CH=CH2, CONR4(CH2) 0-5 CH=CH2, COO(CH2) 0-5 CH=CH2, SO2(CH2) 0-5 CH=CH2, CO(CH2) 0-5 CH=CHCH3, COO(CH2) 0-5 CH=CHCH3, CONR4(CH2) 0-5 CH=CHCH3, SO2(CH2) 0-5 CH=CHCH3, CO(CH2) 0-5 C≡CH, COO(CH2) 0-5 C≡CH, CONR4(CH2)0-5 C≡CH, SO2(CH2) 0-5 C≡CH, CO(CH2) 0-5 C≡CCH3, COO(CH2) 0-5 C≡CCH3, CONR4(CH2) 0-5 C≡CCH3, and SO2(CH2) 0-5 C≡CCH3, each of which may be optionally substituted by 1, 2, 3, or 4 R6.

[0163] In some embodiments, R2 is TIFF0007628108000134.tif54138.

[0164] R3 may be selected from the group consisting of H, F, Br, Cl, CF3, CN, N3, NH2, NO2, OH, OCH3, methyl, ethyl, propyl, and isopropyl, each of which may be optionally substituted by 1, 2, 3, or 4 R6.

[0165] R4 can be H, methyl, ethyl, propyl, or isopropyl.

[0166] AA is, The amino acid may be a natural or unnatural amino acid selected from the group consisting of: TIFF0007628108000135.tif26128.

[0167] R5 is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, -CH2CH2SCH3, -CH2Ph, -CH2PhOH, -CH2OH, -CHOHCH3, -CH2CONH2, -CH2CH2CONH2, -CH2SH, -CH2SeH, -CH2COOH, -CH2CH2COOH, -CH2CH2CH2CH2NH2, It could be TIFF0007628108000136.tif29128.

[0168] R6 can be H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, F, Br, Cl, CF3, NO2, OH, OCH3, CN, or an amino group that is unsubstituted or substituted with methyl, ethyl, or propyl.

[0169] The present disclosure also provides a compound of formula (VI): TIFF0007628108000137.tif53128 or an optically pure stereoisomer, pharmaceutically acceptable salt, or solvate thereof, wherein n can be an integer selected from 0 to 4.

[0170] In one embodiment, A can be -CO-, -SO-, -SO2-, -OPO-, or -OPO2-. TIFF0007628108000138.tif2128 can be a single or double bond.

[0171] R1 may be selected from the group consisting of H, F, Br, Cl, CF3, CN, N3, NH2, NO2, OH, OCH3, methyl, ethyl, propyl, and isopropyl, each of which may be optionally substituted by 1, 2, 3, or 4 R8.

[0172] R2 may be selected from the group consisting of H, methyl, ethyl, propyl, and isopropyl, each of which may be optionally substituted with 1, 2, 3, or 4 R8.

[0173] In another embodiment, Ar is TIFF0007628108000139.tif104144.

[0174] L is -O(CH2) 1-5 O-, -O(CH2) 1-5 NR6-, -NR6(CH2) 1-5 NR6-, -CONR6(CH2) 1-5 NR6-, -NR6CO(CH2) 1-5 NR6-, -(CH2) 1-5NR6-, -(CH2) 1-5 O-, -(CH2) 1-5 OCO-, -(CH2) 1-5 CONR6-, TIFF0007628108000140.tif18128, each of which may be substituted by 1, 2, 3, or 4 R8.

[0175] In certain embodiments, R3 can be H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl, each of which can be optionally substituted with 1, 2, 3, or 4 R8.

[0176] In some embodiments, R4 can be selected from the group consisting of H, methyl, ethyl, propyl, and isopropyl. Or R4 and R3 together are: TIFF0007628108000141.tif24128 can be formed.

[0177] In some embodiments, R5 is CO(CH2) 0-5 CH3, CONR6(CH2) 0-5 CH3, COO(CH2) 0-5 CH3, SO2(CH2) 0-5 CH3, CO(CH2) 0-5 CH=CH2, CONR6(CH2) 0-5 CH=CH2, COO(CH2) 0-5 CH=CH2, SO2(CH2) 0-5 CH=CH2, CO(CH2) 0-5 CH=CHCH3, COO(CH2) 0-5 CH=CHCH3, CONR6(CH2) 0-5 CH=CHCH3, SO2(CH2) 0-5 CH=CHCH3, CO(CH2) 0-5 C≡CH, COO(CH2) 0-5 C≡CH, CONR6(CH2) 0-5 C≡CH, SO2(CH2) 0-5 C≡CH, CO(CH2) 0-5 C≡CCH3, COO(CH2)0-5 C≡CCH3, CONR6(CH2) 0-5 C≡CCH3, and SO2(CH2) 0-5 C≡CCH3, each of which may be optionally substituted by 1, 2, 3, or 4 R8.

[0178] In some embodiments, R5 is TIFF0007628108000142.tif38135.

[0179] Each R6 can independently be H, methyl, ethyl, propyl, or isopropyl.

[0180] R7 can be H, F, Br, Cl, CF3, CN, N3, NH2, NO2, OH, OCH3, methyl, ethyl, propyl, or isopropyl, each of which may be optionally substituted by 1, 2, 3, or 4 R8.

[0181] Each R8 can independently be H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, F, Br, Cl, CF3, NO2, OH, OCH3, CN, or an amino group unsubstituted or substituted with methyl, ethyl, or propyl.

[0182] The present disclosure also provides a compound of formula (VII): TIFF0007628108000143.tif62128 or an optically pure stereoisomer, pharmaceutically acceptable salt, or solvate thereof. In one embodiment, n can be an integer selected from 0 to 4.

[0183] In yet another embodiment, each R1 can be independently selected from the group consisting of H, F, Br, Cl, CF3, CN, N3, NH2, NO2, OH, OCH3, methyl, ethyl, propyl, and isopropyl, each of which can be optionally substituted by 1, 2, 3, or 4 R9.

[0184] In some embodiments, each R2 and R3 can be independently selected from the group consisting of H, methyl, ethyl, propyl, and isopropyl, each of which can be optionally substituted with 1, 2, 3, or 4 R9.

[0185] In certain embodiments, R4 can be selected from the group consisting of H, F, Br, Cl, CF3, CN, N3, NH2, NO2, OH, OCH3, methyl, ethyl, propyl, and isopropyl, each of which can be optionally substituted by 1, 2, 3, or 4 R9.

[0186] R5 may be selected from the group consisting of H, F, Br, Cl, CF3, CN, N3, NH2, NO2, OH, OCH3, methyl, ethyl, propyl, and isopropyl, each of which may be optionally substituted by 1, 2, 3, or 4 R9.

[0187] L is -O(CH2) 1-5 O-, -O(CH2) 1-5 NR 10 -, -NR6(CH2) 1-5 NR 10 -,-CONR 10 (CH2) 1-5 NR 10 -, -NR 10 CO(CH2) 1-5 NR 10 -, -(CH2) 1-5 NR 10 -, -(CH2) 1-5 O-, -(CH2) 1-5 OCO-, -(CH2) 1-5 CONR 10 -, TIFF0007628108000144.tif18128, each of which may be substituted by 1, 2, 3, or 4 R9.

[0188] or R5 and L together, TIFF0007628108000145.tif47128 may be formed. m may be an integer selected from 0 to 4.

[0189] R6 can be H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl, each of which can be optionally substituted by 1, 2, 3, or 4 R9.

[0190] In some embodiments, R7 can be selected from the group consisting of H, methyl, ethyl, propyl, and isopropyl. Or R6 and R7 together are: TIFF0007628108000146.tif26128 can be formed.

[0191] In some embodiments, R8 is CO(CH2) 0-5 CH3, CONR 10 (CH2) 0-5 CH3, COO(CH2) 0-5 CH3, SO2(CH2) 0-5 CH3, CO(CH2) 0-5 CH=CH2, CONR 10 (CH2) 0-5 CH=CH2, COO(CH2) 0-5 CH=CH2, SO2(CH2) 0-5 CH=CH2, CO(CH2) 0-5 CH=CHCH3, COO(CH2) 0-5 CH=CHCH3, CONR 10 (CH2) 0-5 CH=CHCH3, SO2(CH2) 0-5 CH=CHCH3, CO(CH2) 0-5 C≡CH, COO(CH2) 0-5 C≡CH, CONR 10 (CH2) 0-5 C≡CH, SO2(CH2) 0-5 C≡CH, CO(CH2) 0-5 C≡CCH3, COO(CH2) 0-5 C≡CCH3, CONR 10 (CH2) 0-5 C≡CCH3, and SO2(CH2)0-5 C≡CCH3, each of which may be optionally substituted by 1, 2, 3, or 4 R9.

[0192] In some embodiments, R8 is TIFF0007628108000147.tif38138.

[0193] Each R9 can independently be H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, F, Br, Cl, CF3, NO2, OH, OCH3, CN, or an amino group unsubstituted or substituted with methyl, ethyl, or propyl.

[0194] Each R 10 may independently be H, methyl, ethyl, propyl, or isopropyl.

[0195] The present disclosure also provides pharmaceutical formulations comprising a compound according to Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII), or an optically pure stereoisomer or pharmaceutically acceptable salt thereof. The present disclosure further provides methods for treating cancer in a subject, comprising administering to the subject a compound having the structure of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII), or an optically pure stereoisomer or pharmaceutically acceptable salt thereof. The present disclosure also provides methods for inhibiting kinase activity, comprising contacting a cell with a compound having the structure of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII), or an optically pure stereoisomer or pharmaceutically acceptable salt thereof. In some embodiments, the kinase can be feline Gardner-Rasheed sarcoma viral oncogene homolog (FGR), fms such as tyrosine kinase 3 (FLT3), macrophage colony-stimulating factor 1 receptor (FMS), mast cell / stem cell growth factor receptor Kit (KIT), macrophage-stimulating protein receptor (RON), cytoplasmic tyrosine-protein kinase BMX (BMX), or tyrosine-protein kinase Tec (TEC). The cell can be a cancer cell. The cancer cell can be a breast cancer, myeloid cancer, lung cancer, bladder cancer, prostate cancer, ovarian cancer, endometrial cancer, rhabdomyosarcoma, liver cancer, gastric cancer, or intestinal cancer cell.

[0196] The compounds of the present disclosure are generally synthesized by an appropriate combination of established synthetic methods.The techniques useful for synthesizing the compounds of the present disclosure are readily apparent to those skilled in the art and readily available.The following discussion is provided to illustrate certain methods among the various methods available for assembling the compounds of the present disclosure.However, this discussion is not intended to define the scope of reactions or reaction sequences useful for preparing the compounds of the present disclosure.

[0197] The synthesis of the compounds disclosed in this application is shown in Schemes 1-3 using Formula (III), Formula (IV), and Formula (VI) as examples. TIFF0007628108000148.tif126143 Scheme 1. Synthesis of tyrosine kinase inhibitor compounds in the present disclosure using formula (III) as an example. Note: Assumes B=D=-NH-, L=-NHCH2CH2NH-. TIFF0007628108000149.tif142142 Scheme 2. Synthesis of tyrosine kinase inhibitor compounds in the present disclosure using formula (IV) as an example. Note: -NH-, L = -NHCH2CH2NH-, Ar is Assume the file is TIFF0007628108000150.tif12128. TIFF0007628108000151.tif178143 Scheme 3. Synthesis of tyrosine kinase inhibitor compounds in the present disclosure using formula (VII) as an example. Note: TIFF0007628108000152.tif2128 is a double bond, and Ar is TIFF0007628108000153.tif19128L is assumed to be -CONHCH2CH2NH-.

[0198] Table 1 below lists all tyrosine kinase inhibitor compounds disclosed in the present application. Table 1. Tyrosine kinase inhibitor compounds of the present disclosure TIFF0007628108000154.tif200108TIFF0007628108000155.tif214108TIFF0007628108000156.tif225108TIFF00076281080 00157.tif214108TIFF0007628108000158.tif215108TIFF0007628108000159.tif219108TIFF0007628108000160.tif189128

[0199] The term "treatment" is used interchangeably herein with the term "therapeutic method" and refers to both (1) curing, delaying, alleviating symptoms, and / or halting progression of a diagnosed pathological condition, disease, or disorder, and (2) prevention / prophylactic measures. Those in need of treatment may include individuals already with a particular medical disease or disorder, as well as individuals who may eventually acquire the disorder (i.e., individuals in need of preventative measures).

[0200] The term "subject," as used herein, refers to any individual or patient on whom the subject method is performed. Generally, the subject is a human, although as will be understood by those skilled in the art, the subject may also be an animal.

[0201] The terms "therapeutically effective amount," "effective dose," "therapeutically effective dose," "effective amount," and the like refer to the amount of a compound of interest that elicits the biological or medical response in a tissue, system, animal, or human that is desired by administering the compound. Generally, the response is either alleviation of symptoms or a desired biological outcome in a patient. Such an amount should be sufficient to inhibit tyrosine kinase enzymatic activity.

[0202] Pharmaceutical compositions comprising a compound having the structure of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII) are also disclosed herein. A "pharmaceutically acceptable carrier" refers to a non-toxic carrier that may be administered to a patient together with a compound of the present disclosure and that does not destroy its pharmacological activity. Pharmaceutically acceptable carriers that may be used in these compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

[0203] Pharmaceutically acceptable carriers that may be used in the pharmaceutical compositions of the present disclosure include, but are not limited to, ion exchange agents, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, and self-emulsifying drug delivery systems (SEDDS), such as α-tocopherol, polyethylene glycol 1000 succinate, or other similar polymeric delivery matrices.

[0204] For pharmaceutical compositions containing only the compounds described herein as active ingredients, methods of administering these compositions may further include administering additional drugs or therapies to a subject. Such therapies include, but are not limited to, anemia therapy, diabetes therapy, hypertension therapy, cholesterol therapy, neuropharmacological drugs, drugs that regulate cardiovascular function, drugs that regulate inflammation, immune function, blood cell production, hormones and antagonists, drugs that affect gastrointestinal function, chemotherapy for microbial diseases, and / or chemotherapy for neoplastic diseases. Other pharmacological therapies may include any other drug or biological agent found in any drug class. For example, other drug classes may include allergy / cold / ENT therapy, painkillers, anesthetics, anti-inflammatory agents, antibacterial agents, antivirals, asthma / pulmonary therapy, cardiovascular therapy, dermatological therapy, endocrine / metabolic therapy, gastrointestinal therapy, cancer therapy, immunotherapy, neurotherapy, ophthalmology therapy, psychiatric therapy, or rheumatology therapy. Other examples of drugs or therapies that can be administered with the compounds described herein include matrix metalloproteinase inhibitors, lipoxygenase inhibitors, cytokine antagonists, immunosuppressants, cytokines, growth factors, immunomodulators, prostaglandins, or anti-vascular hyperproliferative compounds.

[0205] As used herein, the term "therapeutically effective amount" refers to an amount of an active compound or agent that elicits a biological or medical response in a tissue, system, animal, individual, or human that is desired by a researcher, veterinarian, physician, or other clinician, the response including one or more of the following: (1) preventing a disease, e.g., preventing a disease, condition, or disorder in an individual who may be predisposed to the disease, condition, or disorder but who has not yet experienced or exhibited the pathology or symptoms of the disease; (2) inhibiting a disease, e.g., inhibiting a disease, condition, or disorder (i.e., preventing further development of the pathology and / or symptoms) in an individual who is experiencing or exhibiting the pathology or symptoms of the disease, condition, or disorder; and (3) ameliorating a disease, e.g., ameliorating a disease, condition, or disorder (i.e., reversing the pathology and / or symptoms) in an individual who is experiencing or exhibiting the pathology or symptoms of the disease, condition, or disorder.

[0206] The compounds of the present disclosure can be used in conventional methods for controlling diseases described herein, including but not limited to cancer.Such treatment methods, their dosage levels and requirements can be selected by those skilled in the art from available methods and techniques.For example, the compounds of the present disclosure can be combined with pharmaceutically acceptable adjuvants for administration to patients suffering from cancer in a pharmaceutically acceptable manner and in an amount effective for treating cancer.

[0207] Alternatively, the compounds of the present disclosure may be used in compositions and methods for treating or protecting individuals from the diseases described herein, including but not limited to cancer, over a long period of time. The compounds may be used in such compositions alone or together with other compounds of the present disclosure in a manner consistent with the conventional use of such compounds in pharmaceutical compositions. For example, the compounds of the present disclosure may be combined with pharmaceutically acceptable adjuvants conventionally used in vaccines and administered in prophylactically effective amounts to protect individuals over a long period of time against the diseases described herein, including but not limited to cancer.

[0208] As used herein, "combination," "combined," and related terms refer to simultaneous or sequential administration of therapeutic agents according to the present disclosure. For example, the described compounds may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms, or together in a single unit dosage form. Thus, the present disclosure provides a single unit dosage form containing the described compounds, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. Two or more agents are typically considered to be administered "in combination" if a patient or individual is exposed to both agents simultaneously. In many embodiments, two or more agents are considered to be administered "in combination" if a patient or individual simultaneously exhibits therapeutically relevant drug levels in specific target tissues or samples (e.g., in the brain, serum, etc.).

[0209] When the compounds of the present disclosure are administered in combination therapy with other agents, they may be administered sequentially or simultaneously to a patient. Alternatively, a pharmaceutical or prophylactic composition according to the present disclosure includes a combination of ivermectin or any other compound described herein with another therapeutic or prophylactic agent. Additional therapeutic agents that are normally administered to treat a particular disease or condition may be referred to as "agents appropriate for the disease or condition being treated."

[0210] The compounds utilized in the compositions and methods of the present disclosure may be modified by appending appropriate functional groups to enhance selective biological properties. Such modifications are known in the art and include modifications that increase biological penetration into a given biological system (e.g., blood, lymphatic system, or central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism, and / or alter excretion rate.

[0211] According to a preferred embodiment, the compositions of the present disclosure are formulated for pharmaceutical administration to a subject or patient, e.g., a mammal, preferably a human. Such pharmaceutical compositions are used to ameliorate, treat, or prevent any of the diseases described herein, including, but not limited to, cancer, in a subject.

[0212] The agents of the present disclosure are often administered as pharmaceutical compositions containing an active therapeutic agent, i.e., and various other pharmaceutically acceptable ingredients. See Remington's Pharmaceutical Science (15th ed., Mack Publishing Company, Easton, Pa., 1980). The preferred form depends on the intended mode of administration and therapeutic application. The composition may also contain a pharmaceutically acceptable non-toxic carrier or diluent, defined as a vehicle commonly used to formulate pharmaceutical compositions for animal or human administration, depending on the desired formulation. The diluent is selected so as not to affect the biological activity of the combination. Examples of such diluents are distilled water, phosphate-buffered saline, Ringer's solution, dextrose solution, and Hank's solution. In addition, the pharmaceutical composition or formulation may also contain other carriers, adjuvants, or non-toxic, non-therapeutic, non-immunogenic stabilizers, etc.

[0213] In some embodiments, the present disclosure provides pharmaceutically acceptable compositions comprising a therapeutically effective amount of one or more of the described compounds, formulated with one or more pharmaceutically acceptable carriers (additives) and / or diluents, for use in the treatment of diseases described herein, including, but not limited to, cancer. While it is possible to administer the described compounds alone, it is preferable to administer the described compounds as pharmaceutical formulations (compositions) described herein. The described compounds, like other pharmaceuticals, may be formulated for administration in any convenient manner for use in human or veterinary medicine.

[0214] As described in detail, the pharmaceutical compositions of the present disclosure may be specifically formulated for administration in solid or liquid form, including, for example, those adapted for oral administration, e.g., drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., buccal, sublingual, and tablets targeted for systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, e.g., subcutaneous, intramuscular, intravenous, or epidural injection, e.g., sterile solutions or suspensions, or sustained release formulations; topical application, e.g., as a cream, ointment, or controlled release patch applied to the skin, lungs, or buccal cavity, or as a spray; vaginal, rectal, e.g., as a pessary, cream, or foam; sublingual; intraocular; transdermal; or nasal, pulmonary, and other mucosal surfaces.

[0215] Wetting agents, emulsifying agents, and lubricating agents, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring, and perfuming agents, preservatives, and antioxidants can also be present in the composition.

[0216] Examples of pharmaceutically acceptable antioxidants include water-soluble antioxidants such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, and the like; and metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0217] Formulations for use according to the present disclosure include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, and / or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which may be combined with a carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. The amount of active ingredient which may be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, this amount will range from about 1% to about 99% of the active ingredient. In some embodiments, this amount will range from about 5% to about 70%, about 10% to about 50%, or about 20% to about 40%.

[0218] In certain embodiments, the formulations described herein comprise an excipient selected from the group consisting of cyclodextrins, liposomes, micelle-forming agents such as bile acids, and polymeric carriers such as polyesters and polyanhydrides, and a compound of the present disclosure. In certain embodiments, the formulations make the compounds described herein orally bioavailable.

[0219] The method for preparing the formulation or composition comprising the described compound comprises combining the compound of the present disclosure with carrier and optionally one or more accessory ingredients.Generally, the formulation can be prepared by uniformly and intimately combining the compound of the present disclosure with liquid carrier or finely divided solid carrier or both, and then, if necessary, shaping the product.

[0220] The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (e.g., Tween 80, etc.) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are mannitol, water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any bland fixed oil may be used, including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives, are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated forms. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as those described in the Pharmacopeia Helvetica, or similar alcohols. Other commonly used surfactants, such as Tweens, Spans, and other emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms, may also be used for formulation purposes.

[0221] In some cases, in order to prolong the effect of drugs, it may be desirable to delay the absorption of drugs from subcutaneous or intramuscular injection.This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility.The absorption rate of drug then depends on its dissolution rate, which in turn depends on crystal size and crystalline form.Alternatively, the delayed absorption of parenterally administered drug forms can be achieved by dissolving or suspending the drug in oil vehicle.

[0222] Injectable depot forms can be prepared by forming microencapsulated matrices of the compound described in biodegradable polymers such as polylactide-polyglycolide.Depending on the ratio of drug to polymer and the properties of the specific polymer used, the drug release rate can be controlled.Other examples of biodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations can also be prepared by encapsulating the drug in liposomes or microemulsions that are compatible with body tissues.

[0223] The pharmaceutical compositions of the present disclosure can be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, and aqueous suspensions and solutions.For oral tablets, commonly used carriers include lactose and corn starch.Lubricants such as magnesium stearate are also typically added.For oral administration in capsule form, useful diluents include lactose and dried corn starch.For oral administration of aqueous suspensions, solutions, and propylene glycol, the active ingredient is combined with emulsifiers and suspending agents.If desired, certain sweeteners and / or flavorings and / or colorings can be added.

[0224] Formulations described herein suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored base, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base such as gelatin and glycerin, or sucrose and acacia), and / or as a mouthwash, each containing a predetermined amount of a compound of the present disclosure as an active ingredient. The compounds described herein may also be administered as a bolus, electuary, or paste.

[0225] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate, and / or any of the following: fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; binders, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; humectants, such as glycerol; disintegrants, such as cellulose acetate, cellulose acetate, cellulose stearate, and / or cellulose acetate. Disintegrants such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; solution retarders such as paraffin; absorption accelerators such as quaternary ammonium compounds; wetting agents such as cetyl alcohol, glycerol monostearate, and nonionic surfactants; absorbents such as kaolin and bentonite clay; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof, and coloring agents. In the case of capsules, tablets, and pills, the pharmaceutical compositions may also contain buffering agents. Solid compositions of a similar type may also be used as fillers in soft and hard-shell gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0226] Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surface active agents, or dispersing agents. Molded tablets may be made in a suitable machine in which a mixture of powdered compounds is moistened with an inert liquid diluent. When a solid carrier is used, the preparation may be in tablet form, placed in a hard gelatin capsule in powder or pellet form, or in the form of a troche or lozenge. The amount of solid carrier varies, for example, from about 25 to 800 mg, preferably from about 25 to 400 mg. When a liquid carrier is used, the preparation may be in the form of a sterile injectable liquid such as a syrup, emulsion, soft gelatin capsule, ampoule, or non-aqueous liquid suspension. Where the composition is in capsule form, any routine encapsulation method is suitable, for example using the above carriers in a hard gelatin capsule shell.

[0227] Tablets and other solid dosage forms, such as dragees, capsules, pills, and granules, can be optionally obtained or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. Alternatively or additionally, they can be formulated to provide delayed or controlled release of the active ingredient therein, for example, using various proportions of hydroxypropylmethylcellulose, other polymer matrices, liposomes, and / or microspheres to provide the desired release profile. They can also be formulated for rapid release, such as by lyophilization. They can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved in sterile water or some other sterile injectable medium immediately before use. These compositions can also optionally contain opacifying agents, and can be compositions that release the active ingredient only, or preferentially, in a certain part of the gastrointestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0228] The liquid dosage form for oral administration of the compound of the present disclosure includes pharmaceutically acceptable emulsion, microemulsion, solution, suspension, syrup and elixir.In addition to active ingredient, liquid dosage form can also contain the inert diluent commonly used in the art, such as water or other solvent, solubilizer and emulsifier, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oil (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and fatty acid ester of sorbitan, and their mixtures.

[0229] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming agents and preservatives.

[0230] Suspensions may contain, in addition to the active compound, suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0231] The pharmaceutical composition of the present disclosure can also be administered in the form of suppositories for rectal administration.These compositions can be prepared by mixing the compound of the present disclosure with suitable non-irritating excipients, which are solid at room temperature but liquid at rectal temperature, and therefore melt in rectum to release active ingredient.Such materials include but are not limited to cocoa butter, beeswax and polyethylene glycol.

[0232] Topical administration of the pharmaceutical compositions of the present disclosure is particularly useful when the desired treatment involves areas or organs easily accessible by topical application. For topical application to the skin, the pharmaceutical composition should be formulated in a suitable ointment containing the active ingredient suspended or dissolved in a carrier. Carriers for topical administration of the compounds of the present disclosure include, but are not limited to, mineral oil, liquid petroleum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the pharmaceutical composition can be formulated in a suitable lotion or cream containing the active compound suspended or dissolved in a carrier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water. The pharmaceutical compositions of the present disclosure may also be applied topically to the lower intestinal tract via a rectal suppository formulation or in a suitable enema formulation. Topically administered transdermal patches are also included in the present disclosure.

[0233] The pharmaceutical compositions of the present disclosure may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques known in the art of pharmaceutical formulation and may be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art.

[0234] For ophthalmic use, the pharmaceutical composition may be formulated as a micronized suspension in isotonic, pH-adjusted, sterile saline, or preferably as a solution in isotonic, pH-adjusted, sterile saline, with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutical composition may be formulated in an ointment such as petrolatum.

[0235] Transdermal patch has the additional advantage of providing controlled delivery of the compound of the present disclosure to the body.The compound can be dissolved or dispersed in a suitable medium to produce such a dosage form.Absorption enhancers can also be used to increase the flux of the compound through the skin.The rate of such flux can be controlled by providing a rate-controlling membrane or dispersing the compound in a polymer matrix or gel.

[0236] Examples of suitable aqueous and non-aqueous carriers that may be used in the pharmaceutical compositions of the present disclosure include water, ethanol, polyols (glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants.

[0237] Such compositions may also contain auxiliary agents such as preservatives, wetting agents, emulsifying agents, and dispersing agents. In certain embodiments, it may be desirable to include one or more antibacterial and / or antifungal agents, such as parabens, chlorobutanol, phenol sorbic acid, etc. Alternatively or additionally, it may be desirable to include isotonic agents such as sugars, sodium chloride, etc. in the composition. Furthermore, prolonged absorption of injectable pharmaceutical forms may be brought about by including agents that delay absorption, such as aluminum monostearate and gelatin.

[0238] In certain embodiments, the compounds or pharmaceutical preparations described are administered orally. In other embodiments, the compounds or pharmaceutical preparations described are administered intravenously. Alternative routes of administration include sublingual, intramuscular, and transdermal administration.

[0239] When the compounds described herein are administered to humans and animals as pharmaceuticals, they can be administered by themselves or in combination with a pharmaceutically acceptable carrier, for example, as a pharmaceutical composition containing 0.1% to 99.5% of the active ingredient. In some embodiments, 0.5% to 90% of the active ingredient can be used.

[0240] The preparations described herein may be administered orally, parenterally, topically, or rectally. They are, of course, administered in a form suitable for the relevant administration route. For example, they are administered in tablets or capsules by injection or infusion, in eye lotions, ointments, suppositories, etc. by injection, infusion, or inhalation, topically by lotions or ointments, and rectally by suppositories. Oral administration is preferred.

[0241] Such compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, e.g., by spray, rectally, vaginally, parenterally, intracisternally, and topically, e.g., by powders, ointments, drops, and the like, including buccal and sublingual.

[0242] Regardless of the route of administration selected, the compounds described herein, which may be used in a suitable hydrated form, and / or pharmaceutical compositions of the present disclosure are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art.

[0243] Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present disclosure may be varied to obtain an amount of the active ingredient effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration without toxicity to the patient.

[0244] The terms "administration of" and / or "administering" should be understood to mean providing a therapeutically effective amount of a pharmaceutical composition to a subject in need of treatment. The route of administration can be enteral, topical, or parenteral. Thus, routes of administration include, but are not limited to, intracutaneous, subcutaneous, intravenous, intraperitoneal, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, transdermal, transtracheal, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal, oral, sublingual, buccal, rectal, intravaginal, nasal, ocular administration, as well as injection, inhalation, and spray.

[0245] The term "cancer" refers to a group of diseases characterized by abnormal and uncontrolled cell growth that begins at one site (primary site) with the potential to invade and spread to other sites (secondary sites, metastases), differentiating cancer (malignant tumors) from benign tumors. Nearly every organ can be affected, resulting in over 100 types of cancer that can affect humans. Cancer can arise from many causes, including genetic predisposition, viral infection, exposure to ionizing radiation, exposure to environmental pollutants, tobacco and / or alcohol use, obesity, poor diet, lack of physical activity, or any combination thereof.

[0246] Exemplary cancers include acute lymphoblastic leukemia, adult; acute lymphoblastic leukemia, pediatric; acute myeloid leukemia, adult; adrenocortical carcinoma; adrenocortical carcinoma, pediatric; AIDS-related lymphoma; AIDS-related malignancies; anal cancer; astrocytoma, cerebellum, pediatric; astrocytoma, brain, pediatric; bile duct cancer, extrahepatic; bladder cancer; bladder cancer, pediatric; bone cancer, osteosarcoma / malignant fibrous histiocytoma; brain stem glioma, pediatric; brain tumor, adult; brain tumor, brain stem glioma, pediatric; brain tumor, cerebellar astrocytoma, pediatric; brain tumor, brain astrocytoma / malignant glioma, pediatric; brain tumor, ependymoma, pediatric; brain tumor, medulloblastoma, pediatric; brain Tumors, supratentorial primitive neuroectodermal tumor, pediatric;Brain tumors, visual pathway and hypothalamic glioma, pediatric;Brain tumors, pediatric (other);Breast cancer;Breast cancer and pregnancy;Breast cancer, pediatric;Breast cancer, male;Bronchial adenoma / carcinoid, pediatric;Carcinoid tumor, pediatric;Carcinoid tumor, gastrointestinal;Carcinoma, adrenal cortex;Carcinoma, pancreatic islet cell;Carcinoma of unknown primary;Central nervous system lymphoma, primary;Cerebellar astrocytoma, pediatric;Cerebral astrocytoma / malignant glioma, pediatric;Cervical cancer;Childhood cancer;Chronic lymphocytic leukemia;Chronic myeloid leukemia;Chronic myeloproliferative disorder;Clear cell sarcoma of the tendon sheath;Colon cancer;Colorectal cancer Intestinal cancer;Children's;Cutaneous T-cell lymphoma;Endometrial cancer;Ependymoma, children's;Epithelial carcinoma, ovarian;Esophageal cancer;Esophageal cancer, children's;Ewing's sarcoma family of tumors;Extracranial germ cell tumors, children's;Extragonadal germ cell tumors;Extrahepatic bile duct cancer;Eye cancer, intraocular melanoma;Eye cancer;Gallbladder cancer;Gastric (stomach) cancer;Gastric (stomach) cancer, children's;Gastrointestinal carcinoid tumors;Germ cell tumors, extracranial, children's;Germ cell tumors, extragonadal;Germ cell tumors, ovarian;Gestational trophoblastic tumor;Glioma, children's brainstem;Glioma, children's visual pathway and hypothalamic;Hairy cell leukemia;Head and neck cancer;Hepatocellular (liver) Pancreatic (hepatic) cancer, adult (primary); hepatocellular (liver) cancer, childhood (primary); Hodgkin's lymphoma, adult; Hodgkin's lymphoma, childhood; Hodgkin's lymphoma in pregnancy; Hypopharyngeal cancer; Hypothalamic and optic pathway glioma, childhood; Intraocular melanoma; Islet cell carcinoma (endocrine pancreas); Kaposi's sarcoma; Kidney cancer; Laryngeal cancer; Laryngeal cancer, childhood; Leukemia, acute lymphoblastic, adult; Leukemia, acute lymphoblastic, childhood; Leukemia, acute myeloid, adult; Leukemia, acute myeloid, childhood; Leukemia, chronic lymphocytic; Leukemia, chronic myeloid; Leukemia, hairy cell; Lip and oral cavity cancer; Liver cancer, adult (primary);Liver cancer, childhood (primary); Lung cancer, non-small cell; Lung cancer, small cell; Lymphoblastic leukemia, adult acute; Lymphoblastic leukemia, childhood acute; Lymphocytic leukemia, chronic; Lymphoma, AIDS-related; Lymphoma, central nervous system (primary); Lymphoma, cutaneous T-cell; Lymphoma, Hodgkin lymphoma, adult; Lymphoma, Hodgkin lymphoma, childhood; Lymphoma, Hodgkin in pregnancy; Lymphoma, non-Hodgkin, adult; Lymphoma, non-Hodgkin lymphoma, childhood; Lymphoma, non-Hodgkin in pregnancy; Lymphoma, primary central nervous system; Macroglobulinemia, Waldenstrom type; Male breast Cancer; Malignant mesothelioma, adult; Malignant mesothelioma, pediatric; Malignant thymoma; Medulloblastoma, pediatric; Melanoma; Melanoma, intraocular; Merkel cell carcinoma; Mesothelioma, malignant; Metastatic squamous cell carcinoma of unknown primary; Multiple endocrine neoplasia syndrome, pediatric; Multiple myeloma / plasma cell neoplasm; Mycosis fungoides; Myelodysplastic syndrome; Myeloid leukemia, chronic; Myeloid leukemia, acute, pediatric; Myeloma, multiple; Myeloproliferative disorders, chronic; Nasal cavity and paranasal sinus cancer; Nasopharyngeal carcinoma; Nasopharyngeal carcinoma, pediatric; Neuroblastoma; Non-Hodgkin's lymphoma, adult; Non-Hodgkin's lymphoma, pediatric; Non-Hodgkin's lymphoma in pregnancy; Non-small cell lung cancer; Oral Cavity cancer, pediatric;Oral cavity and lip cancer;Oropharyngeal cancer;Osteosarcoma / malignant fibrous histiocytoma of bone;Ovarian cancer, pediatric;Ovarian epithelial cancer;Ovarian germ cell tumor;Ovarian low malignant potential tumor;Pancreatic cancer;Pancreatic cancer, pediatric;Pancreatic islet cell cancer;Sinonasal and nasal cavity cancer;Parathyroid cancer;Penile cancer;Pheochromocytoma;Pineal and supratentorial primitive neuroectodermal tumor, pediatric;Pituitary tumor;Plasma cell neoplasm / multiple myeloma;Pleuropulmonary blastoma;Pregnancy and breast cancer;Pregnancy and Hodgkin's lymphoma;Pregnancy and non-Hodgkin's lymphoma;Primary central nervous system lymphoma;Primary liver cancer, adult;Primary liver cancer , children; prostate cancer; rectal cancer; renal cell (kidney) cancer; renal cell carcinoma, children; renal pelvis and ureter, transitional cell carcinoma; retinoblastoma; rhabdomyosarcoma, children; salivary gland cancer; salivary gland cancer, children; sarcoma, Ewing family tumor; sarcoma, Kaposi's sarcoma; sarcoma (osteosarcoma / malignant fibrous histiocytoma of bone); sarcoma, rhabdomyosarcoma, children; sarcoma, soft tissue, adults; sarcoma, soft tissue, children; Sézary syndrome; skin cancer; skin cancer, children; skin cancer (melanoma); skin cancer, Merkel cell; small cell lung cancer; small intestine cancer; soft tissue sarcoma, adults; soft tissue sarcoma, children; squamous cell carcinoma of the neck of unknown primary, metastatic;Stomach (Gastric) cancer; Gastric (Stomach) cancer, children; Supratentorial primary neuroectodermal tumor, children; T-cell lymphoma, skin; Testicular cancer; Thymoma, children; Thymoma, malignant; Thyroid cancer; Thyroid cancer, children; Transitional cell carcinoma of the renal pelvis and ureter; Cholioblastic tumor, during pregnancy; Cancer of unknown primary site, children; Unusual cancers of children; Ureter and renal pelvis, transitional cell carcinoma; Urethral cancer; Uterine sarcoma; Vaginal cancer; Optic pathway and hypothalamic glioma, children; Vulvar cancer; Waldenstrom's macroglobulinemia; and Wilms' tumor.

[0247] In certain aspects, cancers include lung cancer, breast cancer, colorectal cancer, prostate cancer, gastric cancer, liver cancer, cervical cancer, esophageal cancer, bladder cancer, non-Hodgkin's lymphoma, leukemia, pancreatic cancer, kidney cancer, endometrial cancer, head and neck cancer, lip cancer, oral cavity cancer, thyroid cancer, brain cancer, ovarian cancer, melanoma, gallbladder cancer, laryngeal cancer, multiple myeloma, nasopharyngeal cancer, Hodgkin's lymphoma, testicular cancer, and Kaposi's sarcoma.

[0248] In certain embodiments, the method further comprises administering a chemotherapeutic agent. The compounds of the present disclosure can be administered in combination with one or more additional therapeutic agents. Phrases such as "combination therapy," "combined with," and the like refer to the simultaneous use of two or more drugs or treatments to increase response. The tyrosine kinase inhibitors of the present disclosure can be used in combination with, for example, other drugs or treatments used to treat cancer. In various embodiments, the compounds are administered before, simultaneously with, or after the administration of a chemotherapeutic agent.

[0249] The term "anti-cancer therapy" refers to any therapy or treatment that can be used to treat cancer. Anti-cancer therapies include, but are not limited to, surgery, radiation therapy, chemotherapy, immunotherapy, and targeted therapy.

[0250] Examples of chemotherapeutic or anti-cancer agents include actinomycin, azacitidine, azathioprine, bleomycin, bortezomib, carboplatin, capecitabine, cisplatin, chlorambucil, cyclophosphamide, cytarabine, daunorubicin, docetaxel, doxifluridine, doxorubicin, epirubicin, epothilone, etoposide, fluorouracil, gemcitabine, hydroxyurea, Idarubicin, imatinib, irinotecan, mechlorethamine, mercaptopurine, methotrexate, mitoxantrone, oxaliplatin, paclitaxel, pemetrexed, teniposide, thioguanine, topotecan, barbican, vinblastine, vincristine, vindesine, vinorelbine, panitumamab, Erbitux (cetuximab), matuzumab, IMC-IIF8, TheraCIM hR3, denosumab, Avastin (bevacizumab), Humira (adalimumab), Herceptin (trastuzumab), Remicade (infiliximab), rituximab, Synagis (palivizumab), Milotarg (gemtuzumab)Ozogamicin), Raptiva (efalizumab), Tysabri (natalizumab), Zenapax (dacliximab), NeutroSpec (technetium (99mTc) fanolesomab), tocilizumab, ProstaScint (indium-Ill-labeled capromab pendetide), Bexar (tositumomab), Zevalin (ibritumomab tiuxetan (IDEC-Y2B8) conjugated to yttrium-90), Xolair (omalizumab), MabTher a (rituximab), ReoPro (abciximab), MabCampath (alemtuzumab), Simulect (basiliximab), LeukoScan (sulesomab), CEA-scan (arcitumomab), Veluma (nofetumomab), Panorex (edrecolomab), alemtuzumab, CDP870, natalizumab gilotrif (afatinib), Lynparza (olaparib), Perjeta (pertuzumab), Optivo (nivolumab), Bosulif (bosutinib), Cabometyx (cabozantinib), Ogibli (trastuzumab-dkst), Sutent (sunitinib malate), Adcetris (brentuximab vedotin), Alecensa (alectinib), Calquence (acalabrutinib), Yescarta (ciloleucel), Verzenio (abemaciclib), Keytruda (pembrolizumab), Alicopa (copanlisib), Nerlynx (neratinib), Imfinzi (Durval) Examples of immunotherapeutic agents include, but are not limited to, interleukins (Il-2, Il-7, Il-12), cytokines (interferon, G-CSF, imiquimod), chemokines (CCL3, CCl26, CXCL7), immunomodulatory imide drugs (thalidomide and its analogs).

[0251] In treatment, the dosage of the agent optionally ranges from about 0.0001 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 5 mg / kg, about 0.15 mg / kg to about 3 mg / kg, 0.5 mg / kg to about 2 mg / kg, and about 1 mg / kg to about 2 mg / kg of the subject's body weight. In other embodiments, the dosage ranges from about 100 mg / kg to about 5 g / kg, about 500 mg / kg to about 2 mg / kg, and about 750 mg / kg to about 1.5 g / kg of the subject's body weight. For example, depending on the type and severity of the disease, about 1 μg / kg to 15 mg / kg (e.g., 0.1 to 20 mg / kg) of the agent is a candidate dose for administration to a patient, e.g., by one or more separate administrations or by continuous infusion. Typical daily dosages range from about 1 μg / kg to 100 mg / kg or more, depending on the factors mentioned above. For repeated administration over several days or longer, depending on the condition, treatment is continued until the desired suppression of disease symptoms occurs. However, other administration regimens may be useful. The unit dose may be, for example, in the range of about 5 mg to 500 mg, for example, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, and 300 mg. The progress of therapy is monitored by conventional techniques and assays.

[0252] In some embodiments, the agent is administered to a human patient in an effective amount (or dose) of less than about 1 μg / kg, e.g., about 0.35 to about 0.75 μg / kg or about 0.40 to about 0.60 μg / kg. In some embodiments, the dose of the agent is about 0.35 μg / kg, or about 0.40 μg / kg, or about 0.45 μg / kg, or about 0.50 μg / kg, or about 0.55 μg / kg, or about 0.60 μg / kg, or about 0.65 μg / kg, or about 0.70 μg / kg, or about 0.75 μg / kg, or about 0.80 μg / kg, or about 0.85 μg / kg, or about 0.90 μg / kg, or about 0.95 μg / kg, or about 1 μg / kg. In various embodiments, the absolute dose of the agent is about 2 μg / subject to about 45 μg / subject, or about 5 to about 40 μg / subject, or about 10 to about 30 μg / subject, or about 15 to about 25 μg / subject, hi some embodiments, the absolute dose of the agent is about 20 μg, or about 30 μg, or about 40 μg.

[0253] In various embodiments, the dose of the agent may be determined by the weight of the human patient. For example, the absolute dose of the agent may be about 2 μg for a pediatric human patient weighing about 0 to about 5 kg (e.g., about 0, or about 1, or about 2, or about 3, or about 4, or about 5 kg), or about 3 μg for a pediatric human patient weighing about 6 to about 8 kg (e.g., about 6, or about 7, or about 8 kg), or about 5 μg for a pediatric human patient weighing about 9 to about 13 kg (e.g., 9, or about 10, or about 11, or about 12, or about 13 kg), or about 8 μg for a pediatric human patient weighing about 14 to about 20 kg (e.g., about 14, or about 16, or about 18, or about 20 kg), or about 8 μg for a pediatric human patient weighing about 21 to about 30 kg (e.g., about 21, or about 23, or about 25, or about 27, or about 30 kg). or about 12 μg for a pediatric human patient weighing about 31 to about 33 kg (e.g., about 31, or about 32, or about 33 kg), or about 13 μg for an adult human patient weighing about 34 to about 50 kg (e.g., about 34, or about 36, or about 38, or about 40, or about 42, or about 44, or about 46, or about 48, or about 50 kg), or about 20 μg for an adult human patient weighing about 51 to about 75 kg (e.g., about 51, or about 55, or about 60, or about 65, or about 70, or about 75 kg), or about 45 μg for an adult human patient weighing more than about 114 kg (e.g., about 114, or about 120, or about 130, or about 140, or about 150 kg).

[0254] In certain embodiments, the agents according to the methods provided herein are administered subcutaneously (sc), intravenously (iv), intramuscularly (im), intranasally, or topically. Administration of the agents described herein can independently be 1 to 4 times daily, 1 to 4 times monthly, 1 to 6 times per year, or once every 2, 3, 4, or 5 years. Administration can be daily or for a period of 1, 2, 3, 6 months, 1, 2, 3 years, or even for the lifetime of the human patient. Dosages can be administered as a single dose or divided into multiple doses. In some embodiments, the agent is administered about 1 to about 3 times (e.g., 1, or 2, or 3 times).

[0255] Below are presented examples that discuss the design and evaluation of the effectiveness of novel tyrosine kinase inhibitors contemplated for the uses discussed. The following examples are provided to further illustrate embodiments of the present disclosure, but are not intended to limit the scope of the disclosure. While they are typical of those that may be used, other procedures, methods, or techniques known to those skilled in the art may alternatively be used. [Example]

[0256] Example 1 (S,E)-N-(1-((2-((2-((4-(cyanomethyl)phenyl)amino)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)amino)ethyl)amino)-1-oxopropan-2-yl)-4-(dimethylamino)-N-methylbut-2-enamide (Compound 1) TIFF0007628108000161.tif146143 Scheme 4. Synthesis of compound 1.

[0257] TIFF0007628108000162.tif33128 To a solution of compound 1-1 (10 g, 55.0 mmol, 1.0 equiv.) and compound 1-2 (6.4 g, 66.0 mmol, 1.2 equiv.) in ethanol (100 mL) was added triethylamine (11.1 g, 110 mmol, 2.0 equiv.) at room temperature. The resulting suspension was then stirred at room temperature for 24 hours. The reaction was monitored by TLC. The ethanol was removed in vacuo. The residue was then diluted with ethyl acetate (200 mL) and water (100 mL). The organic and aqueous phases were separated. The aqueous phase was extracted with ethyl acetate (200 mL × 2). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (dichloromethane:methanol, 10:1) to give compound 1-3 (7.5 g, 56%) as a yellow solid. TLC: dichloromethane:methanol=10:1, UV 254 nm. f (Compound 3)=0.3

[0258] TIFF0007628108000163.tif35128To a solution of compound 1-3 (5 g, 20.5 mmol, 1.0 equiv.) and compound 1-4 (3.3 g, 24.6 mmol, 1.2 equiv.) in n-butanol (100 mL), p-toluenesulfonic acid (0.72 g, 4.1 mmol, 0.2 equiv.) was added at room temperature. The resulting suspension was then heated to 130 °C for 3 h. The reaction was monitored by TLC. n-butanol was removed in vacuo. The residue was then diluted with ethyl acetate (200 mL) and water (100 mL). The organic and aqueous phases were separated. The aqueous phase was extracted with ethyl acetate (200 mL × 2). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (dichloromethane:methanol, 10:1) to give compound 1-5 (6.2 g, 87%) as a yellow solid. TLC: dichloromethane:methanol = 10:1, UV 254 nm. f (Compound 5)=0.2

[0259] TIFF0007628108000164.tif38128 Compound 1-5 (1.3 g, 3.8 mmol, 1.0 equiv) and ethylenediamine (1.15 g, 19 mmol, 5.0 equiv) were dissolved in isopropanol (10 mL), 2 drops of concentrated HCl were added, and the mixture was then microwaved at 150° C. for 2 h. The solvent and excess ethylenediamine were removed in vacuo, and the residue was purified via reverse-phase column chromatography to give compound 1-7 (480 mg, 35%) as a white solid. 1 H NMR(400MHz,CD3OH):δ 8.55-8.45(br. s,1H),7.69-7.67(d,J=8.4Hz,2H),7.29-7.27(d,J=8.0Hz,2H),6.73-6.59(m,2H),5.81(s,1H),5.30-5.25 (m,1H),3.83(s,2H),3.68-3.41(m,7H),2.96(s,3H),2.80-2.65(m,6H),2.23(s,3H) and 1.31-1.29(m,3H). LCMS:[M+1]=560,[M-1]=558.

[0260] To a mixture of compound 1-7 (480 mg, 1.32 mmol, 1.0 equiv.), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (380 mg, 1.98 mmol, 1.5 equiv.), 1-hydroxybenzotriazole (357 mg, 2.64 mmol, 2.0 equiv.), and N,N-diisopropylethylamine (510 mg, 3.96 mmol, 3.0 equiv.) in dimethylformamide (10 mL) was added compound 1-8 (268 mg, 1.32 mmol, 1.0 equiv.). The mixture was stirred overnight at room temperature under a nitrogen atmosphere. TLC analysis of the reaction mixture indicated complete conversion to the desired product. Water was then added to the mixture, which was then extracted with ethyl acetate (3 × 10 mL). The organic layer was washed with brine. The residue was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane:methanol, 10:1) to give compound 1-9 (213 mg, 29%) as a white solid. TLC: dichloromethane:methanol = 10:1, UV 254 nm; R f (Compound 9)=0.1

[0261] A mixture of compound 1-9 (213 mg, 0.39 mmol, 1.0 equiv.) in trifluoroacetic acid / dichloromethane (2 mL / 2 mL) was stirred at room temperature for 2 hours under a nitrogen atmosphere. LCMS analysis of the reaction mixture showed complete conversion to the desired product. The residue was concentrated under reduced pressure to give compound 1-10 (310 mg, crude) as a yellow solid.

[0262] To a mixture of compound 1-10 (310 mg, 0.69 mmol, 1.0 equiv.), 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (393 mg, 1.04 mmol, 1.5 equiv.), and N,N-diisopropylethylamine (222 mg, 1.72 mmol, 2.5 equiv.) in dimethylformamide (10 mL) was added compound 1-11 (89 mg, 0.69 mmol, 1.0 equiv.). The mixture was stirred overnight at room temperature under a nitrogen atmosphere. TLC analysis of the reaction mixture indicated complete conversion to the desired product. Water was then added to the mixture, which was then extracted with ethyl acetate (3 × 10 mL). The organic layer was washed with brine. The residue was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified via reverse phase column chromatography to give compound 1 (8.0 mg, 21%) as a yellow solid. 1 H NMR(400MHz,CD3OH):δ 8.55-8.45(br. s,1H),7.69-7.67(d,J=8.4Hz,2H),7.29-7.27(d,J=8.0Hz,2H),6.73-6.59(m,2H),5.81(s,1H),5.30-5.25 (m,1H),3.83(s,2H),3.68-3.41(m,7H),2.96(s,3H),2.80-2.65(m,6H),2.23(s,3H) and 1.31-1.29(m,3H). LCMS:[M+1]=560,[M-1]=558.

[0263] Example 2 compound 2 TIFF0007628108000168.tif166129 Scheme 5. Synthesis of compound 2.

[0264] The synthesis of compound 1-7 is shown in Example 1. Compound 2-1 (127 mg, 0.55 mmol, 1.0 equiv.) was added to a mixture of compound 1-7 (200 mg, 0.55 mmol, 1.0 equiv.), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (159 mg, 0.83 mmol, 1.5 equiv.), 1-hydroxybenzotriazole (149 mg, 1.1 mmol, 2.0 equiv.), and N,N-diisopropylethylamine (213 mg, 1.65 mmol, 3.0 equiv.) in dimethylformamide (10 mL). The mixture was stirred overnight at room temperature under a nitrogen atmosphere. TLC analysis of the reaction mixture showed complete conversion to the desired product. Water was then added to the mixture, which was then extracted with ethyl acetate (3 × 10 mL). The organic layer was washed with brine. The residue was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane:methanol, 10:1) to give compound 2-2 (105 mg, 33%) as a white solid. TLC: dichloromethane:methanol = 10:1, UV 254 nm; R f (Compound 2-2)=0.1

[0265] To a solution of compound 2-2 (105 mg, 0.18 mmol, 1.0 equiv.) in methanol (10 mL), hydrochloric acid / methanol (4N, 5 mL) was added, and the mixture was stirred at 35° C. for 3 hours. LCMS analysis of the reaction mixture showed complete conversion to the desired product. The residue was concentrated under reduced pressure to give compound 2-3 (110 mg, crude) as a yellow solid.

[0266] To a mixture of compound 2-3 (110 mg, 0.23 mmol, 1.0 equiv.), propylphosphonic anhydride (110 mg, 0.35 mmol, 1.5 equiv.), and N,N-diisopropylethylamine (89 mg, 0.69 mmol, 3.0 equiv.) in dimethylformamide (10 mL) was added compound 2-4 (30 mg, 0.23 mmol, 1.0 equiv.). The mixture was stirred overnight at room temperature under a nitrogen atmosphere. TLC analysis of the reaction mixture showed complete conversion to the desired product. Water was then added to the mixture, which was then extracted with ethyl acetate (3 × 10 mL). The organic layer was washed with brine. The residue was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified via reverse-phase column chromatography to give compound 2 (39 mg, 29%) as a white solid. LCMS:[M+1]=588 HNMR(400MHz,DMSO):δ 10.47(m,1H),9.85(m,1H),8.20(m,2H),7.63(m,2H),7.35-7.33(m,2H),6.86(m,1H),6.60(m,1H),5.70(m,1H),4.7 5(s,1H),4.00(s,3H),3.88(s,2H),3.78(m,3H),3.75(m,3H),3.49(m,4H),3.13(m,4H),7.75(m,8H) and 2.22(s,3H).

[0267] Example 3 compound 3 TIFF0007628108000172.tif201152 Scheme 6. Synthesis of compound 3.

[0268] The synthesis of compound 1-7 is shown in Example 1. Compound 3-1 (77 mg, 0.36 mmol, 1.0 equiv.) was added to a mixture of compound 1-7 (130 mg, 0.36 mmol, 1.0 equiv.), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (103 mg, 0.54 mmol, 1.5 equiv.), 1-hydroxybenzotriazole (97 mg, 0.72 mmol, 2.0 equiv.), and N,N-diisopropylethylamine (139 mg, 1.08 mmol, 3.0 equiv.) in dimethylformamide (10 mL). The mixture was stirred overnight at room temperature under a nitrogen atmosphere. TLC analysis of the reaction mixture showed complete conversion to the desired product. Water was then added to the mixture, which was then extracted with ethyl acetate (3 × 10 mL). The organic layer was washed with brine. The residue was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane:methanol, 10:1) to give compound 3-2 (70 mg, 35%) as a white solid. TLC: dichloromethane:methanol = 10:1, UV 254 nm; R f (Compound 3-2)=0.3

[0269] To a solution of compound 3-2 (70 mg, 0.12 mmol, 1.0 equiv.) in methanol (10 mL), hydrochloric acid / methanol (4N, 5 mL) was added, and the mixture was stirred at 35° C. for 3 hours. LCMS analysis of the reaction mixture showed complete conversion to the desired product. The residue was concentrated under reduced pressure to give compound 3-3 (70 mg, crude) as a yellow solid.

[0270] To a mixture of compound 3-3 (70 mg, 0.15 mmol, 1.0 equiv.), 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (86 mg, 0.23 mmol, 1.5 equiv.), and N,N-diisopropylethylamine (48 mg, 0.37 mmol, 2.5 equiv.) in dimethylformamide (10 mL) was added compound 3-4 (89 mg, 20 mmol, 1.0 equiv.). The mixture was stirred overnight at room temperature under a nitrogen atmosphere. TLC analysis of the reaction mixture indicated complete conversion to the desired product. Water was then added to the mixture, which was then extracted with ethyl acetate (3 × 10 mL). The organic layer was washed with brine. The residue was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified via reverse phase column chromatography to give compound 3 (9.0 mg, 11%) as a yellow solid. LCMS: [M+1] = 572 H NMR (400 MHz, DMSO): δ 8.30 (m, 1H), 7.63-7.61 (m, 2H), 7.41-7.39 (m, 2H), 6.79-6.68 (m, 2H), 5.74 (m, 1H), 4.74-4.39 (m, 1H), 3.93-3.80 (m, 4H), 3.74-3.46 (m, 8H), 2.99-2.68 (m, 6H), 2.27 (s, 3H), and 2.22-1.94 (m, 6H).

[0271] Example 4 (2S)-N-[2-[[2-[4-(cyanomethyl)anilino]-6-[(5-cyclobutyl-1H-pyrazol-3-yl)amino]pyrimidin-4-yl]amino]ethyl]-2-[methyl(prop-2-enoyl-)amino]propanamide (Compound 4) TIFF0007628108000176.tif213143 Scheme 7. Synthesis of compound 4.

[0272] To a solution of MeCN (6.41 g, 156.04 mmol, 8.21 mL) in THF (200 mL), n-BuLi (2.5 M in hexanes, 62.4 mL) was added and stirred at −78° C. for 0.5 h. Then, a solution of ethyl cyclobutanecarboxylate (10 g, 78.02 mmol, 10.78 mL) in THF (200 mL) was added to the mixture and stirred at −78° C. for 0.5 h. The mixture was then warmed to −45° C. and stirred for 2 h. The mixture was quenched by the addition of HO (50 mL) at 25° C., then diluted with HO (100 mL), and extracted with EtOAc (80×3). The combined organic layers are washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 3-cyclobutyl-3-oxo-propanenitrile (10 g, crude) as a yellow oil, which is used directly in the next step. 1 H NMR (400MHz, DMSO-d6): δ = 3.6 (s, 2H), 2.98-2.96 (m, 1H), 2.90-2.89 (m, 1H), 2.8 (s, 2H), 2.72-2.70 (m, 2H), 2.55-2.52 (m, 2H).

[0273] To a solution of 3-cyclobutyl-3-oxo-propanenitrile (9.5 g, 77.14 mmol) in EtOH (10 mL) was added NHNH.H0 (4.25 g, 84.85 mmol, 4.12 mL). The mixture was stirred at 75 °C for 12 h. The mixture was quenched by adding H0 (50 mL) at 25 °C, then diluted with H0 (100 mL) and extracted with EtOAc (100 × 3). The combined organic layers were washed with brine (100 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® silica flash column, eluent of 0–10% DCM / MEOH (50 mL / min)) to give 5-cyclobutyl-1H-pyrazol-3-amine (4.7 g, 30.83 mmol, 40% yield, 90% purity) as a yellow oil. 1H NMR (400MHz, CDCl3): δ=5.94-5.48(m,2H),5.60(s,1H),3.43-3.32(m,1H),2.32-2.21(m,2H),2.14-2.03(m,2H),2.01-1.78(m,2H).

[0274] TIFF0007628108000179.tif38128 To a solution of 2,4,6-trichloropyrimidine (3 g, 16.36 mmol) in butan-1-ol (30 mL) was added DIPEA (6.34 g, 49.07 mmol) and 5-cyclobutyl-1H-pyrazol-3-amine (2.24 g, 16.36 mmol). The mixture was stirred at 80 °C for 1 h. The mixture was quenched by adding HO (50 mL) at 25 °C, then diluted with HO (100 mL) and extracted with EtOAc (100 × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, elution with a 0-100% ethyl acetate / petroleum ether gradient (50 mL / min)) to afford 2,6-dichloro-N-(5-cyclobutyl-1H-pyrazol-3-yl)pyrimidin-4-amine (3 g, 9.50 mmol, 58% yield, 90% purity) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6):δ=12.34(s,1H),10.80-10.62(m,1H),7.81(s,1H),5.86(s,1H),3.5 6-3.52(m,1H),2.33-2.30(m,2H),2.18-2.12(m,2H),2.02-1.97(m,1H),1.89-1.84(m,1H).

[0275] To a solution of 2,6-dichloro-N-(5-cyclobutyl-1H-pyrazol-3-yl)pyrimidin-4-amine (3 g, 10.56 mmol) in DMSO (20 mL) was added DIPEA (4.09 g, 31.67 mmol) and tert-butyl N-(2-aminoethyl)carbamate (2.03 g, 12.67 mmol). The mixture was stirred at 80 °C for 5 h. The mixture was quenched by adding HO (50 mL) at 25 °C, then diluted with HO (50 mL) and extracted with EtOAc (100 × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, elution with a 0–40% ethyl acetate / petroleum ether gradient (50 mL / min)) to afford tert-butyl N-[2-[[2-chloro-6-[(5-cyclobutyl-1H-pyrazol-3-yl)amino]pyrimidin-4-yl]amino]ethyl]carbamate (2.6 g, 5.74 mmol, 54% yield, 90% purity) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6):δ=12.01(s,1H),9.62(s,1H),7.25-7.01(m,1H),6.94-6.77(m,1H),6.40(s,2H),3.54-3.41(m,1H), 3.31(s,2H),3.11(d,J=5.2Hz,2H),2.32-2.22(m,2H),2.20-2.07(m,2H),1.98-1.91(m,1H),1.89-1.81(m,1H),1.38(s,9H).

[0276] A mixture of tert-butyl N-[2-[[2-chloro-6-[(5-cyclobutyl-1H-pyrazol-3-yl)amino]pyrimidin-4-yl]amino]ethyl]carbamate (2.6 g, 6.37 mmol), 2-(4-aminophenyl)acetonitrile (1.01 g, 7.65 mmol), Pd(OAc) (143 mg, 0.637 mmol), [2-(2-diphenylphosphanylphenoxy)phenyl]-diphenyl-phosphane (687 mg, 1.27 mmol), and CsCO (2.08 g, 6.37 mmol) in dioxane (20 mL) was degassed and purged with N three times, then the mixture was stirred at 100 °C under a N atmosphere for 12 h. The mixture was quenched by the addition of HO (50 mL) at 25 °C, then diluted with HO (50 mL) and extracted with EtOAc (50 × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, elution with 0–10% DCM / MeOH (50 mL / min)) to afford tert-butyl N-[2-[[2-[4-(cyanomethyl)anilino]-6-[(5-cyclobutyl-1H-pyrazol-3-yl)amino]pyrimidin-4-yl]amino]ethyl]carbamate (2 g, 2.78 mmol, 44% yield, 70% purity) as a brown solid. 1 H NMR(400MHz,DMSO-d6):δ=12.07-11.74(m,1H),9.15-8.74(m,2H),7.73(d,J=8.4Hz, 2H),7.24(d,J=8.4Hz,2H),6.91(s,1H),6.38-6.21(m,1H),6.04-5.84(m,1H),5.80( s,1H),3.96(s,2H),3.55-3.45(m,2H),3.38-3.35(m,1H),3.25-3.15(m,3H),2.31(d ,J=8.0Hz,2H),2.21-2.15(m,2H),2.01-1.95(m,1H),1.92-1.86(m,1H),1.43(s,9H).

[0277] A solution of tert-butyl N-[2-[[2-[4-(cyanomethyl)anilino]-6-[(5-cyclobutyl-1H-pyrazol-3-yl)amino]pyrimidin-4-yl]amino]ethyl]carbamate (2 g, 3.97 mmol) in HCl / dioxane (4 M, 30 mL) was stirred for 0.5 h at 25° C. The mixture was concentrated under reduced pressure to give 2-[4-[[4-(2-aminoethylamino)-6-[(5-cyclobutyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]amino]phenyl]acetonitrile (1.7 g, crude) as a pale yellow solid, which was used directly in the next step.

[0278] To a solution of 2-[4-[[4-(2-aminoethylamino)-6-[(5-cyanobutyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]amino]phenyl]acetonitrile (700 mg, 1.73 mmol) in DMF (5 mL) was added DIPEA (673 mg, 5.20 mmol), HATU (792 mg, 2.08 mmol), and (2S)-2-[tert-butoxycarbonyl(methyl)amino]propionic acid (211 mg, 1.04 mmol). The mixture was stirred at 0 °C for 0.5 h. The mixture was quenched by adding HO (50 mL) at 25 °C, then diluted with HO (50 mL), and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give tert-butyl N-[(1S)-2-[2-[[2-[4-(cyanomethyl)anilino]-6-[(5-cyclobutyl-1H-pyrazol-3-yl)amino]pyrimidin-4-yl]amino]ethylamino]-1-methyl-2-oxo-ethyl]-N-methyl-carbamate (1.2 g, crude) as a pale yellow solid.

[0279] TIFF0007628108000184.tif59128A solution of tert-butyl N-[(1S)-2-[2-[[2-[4-(cyanomethyl)anilino]-6-[(5-cyclobutyl-1H-pyrazol-3-yl)amino]pyrimidin-4-yl]amino]ethylamino]-1-methyl-2-oxo-ethyl]-N-methyl-carbamate (1.2 g, 2.04 mmol) in HCl / dioxane (4 M, 50 mL) was stirred at 25° C. for 0.5 h. The mixture was concentrated under reduced pressure to give (2S)—N-[2-[[2-[4-(cyanomethyl)anilino]-6-[(5-cyclobutyl-1H-pyrazol-3-yl)amino]pyrimidin-4-yl]amino]ethyl]-2-(methylamino)propanamide (1 g, crude) as a yellow solid, which was used directly in the next step.

[0280] The synthesis of (2S)-N-[2-[[2-[4-(cyanomethyl)anilino]-6-[(5-cyclobutyl-1H-pyrazol-3-yl)amino]pyrimidin-4-yl]amino]ethyl]-2-(methylamino)propanamide (4-11) is shown in Example 4. To a solution of 4-11 (100 mg, 0.205 mmol) in DCM (10 mL) and DIPEA (61 mg, 0.47 mmol) was added prop-2-enoyl chloride (22 mg, 0.245 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 h. The mixture was quenched by adding HO (50 mL) at 25 °C, then diluted with HO (50 mL) and extracted with DCM (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (water (0.04% NH 3. Purification by HCl (H2O + 10 mM NH4HCO3)-ACN) gave (2S)-N-[2-[[2-[4-(cyanomethyl)anilino]-6-[(5-cyclobutyl-1H-pyrazol-3-yl)amino]pyrimidin-4-yl]amino]ethyl]-2-[methyl(prop-2-enoyl)amino]propanamide (22 mg, 0.04 mmol, 20% yield, 98.9% purity) as a white solid. LCMS:R =10-80AB_4min_220&254_Shimadzu.lcm for 1.920 minutes, MS(ESI)m / z=543.5[M+H] + . 1 H NMR (400MHz, DMSO-d6): δ=11.80(s,1H),8.95-8.67(m,2H),8.12-7.87(m,1H),7.67(d,J=8.4Hz,2H),7. 19(d,J=8.4Hz,2H),6.76-6.68(m,1H),6.31(s,1H),6.20-6.04(m,2H),5.92(s,1H),5.71-5.61(m,1H), 5.03-4.59(m,1H),3.92(s,2H),3.51-3.42(m,2H),3.33-3.31(m,2H),3.29(s,1H),2.93-2.76(m,3H),2 .27(,J=8.4Hz,2H),2.12(m,J=2.4,9.2Hz,2H),1.99-1.93(m,1H),1.88-1.82(m,1H),1.27-1.21(m,3H). Chiral SFC:t R = 4.652 min (Instrument column: Chiralpak AS-3 100 x 4.6 mm, i.d., 3 um, Mobile phase: A:CO2 B:Ethanol (0.05% DEA), Gradient: 5% to 40% B for 4.5 min, hold at 40% for 2.5 min, then 5% B for 1 min; Flow rate: 2.8 mL / min, Column temperature: 40 °C, UV detection: 220 nm), ee% = 100%. [α] D 20 =-31.0 (c=0.10, MeOH).

[0281] Example 5 N-[(1S)-2-[2-[[2-[4-(cyanomethyl)anilino]-6-[(5-cyclobutyl-1H-pyrazol-3-yl)amino]pyrimidin-4-yl]amino]ethylamino]-1-methyl-2-oxo-ethyl]-N-methyl-but-2-ynamide (Compound 5) TIFF0007628108000186.tif129128 Scheme 8. Synthesis of compound 5.

[0282] To a solution of (2S)—N-[2-[[2-[4-(cyanomethyl)anilino]-6-[(5-cyclobutyl-1H-pyrazol-3-yl)amino]pyrimidin-4-yl]amino]ethyl]-2-(methylamino)propanamide (100 mg, 0.205 mmol) in DMF (10 mL) was added HATU (93 mg, 0.246 mmol), DIPEA (80 mg, 0.614 mmol), and but-2-ynoic acid (21 mg, 0.246 mmol). The mixture was stirred at 25° C. for 1 h. The mixture was quenched by adding HO (50 mL) at 25° C., then diluted with HO (50 mL), and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was then purified by preparative HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (0.04% NH3.H2O + 10mM NH4HCO3)-ACN]; B%: 25%-55%, 8 min) to give N-[(1S)-2-[2-[[2-[4-(cyanomethyl)anilino]-6-[(5-cyclobutyl-1H-pyrazol-3-yl)amino]pyrimidin-4-yl]amino]ethylamino]-1-methyl-2-oxo-ethyl]-N-methyl-but-2-ynamide (27.3 mg, 0.049 mmol, 24% yield, 98.62% purity) as a pale yellow solid. LCMS: t R =10-80AB_4min_220&254_Shimadzu.lcm for 1.971 minutes, MS(ESI)m / z=555.5[M+H] + . 1H NMR(400MHz,DMSO-d6):δ=11.80(s,1H),8.93-8.71(m,2H),8.08-7.95(m,1H),7.68(d,J=8.4Hz ,2H),7.19(d,J=8.0Hz,2H),6.40-6.06(m,2H),5.91(s,1H),4.93-4.86(m,1H),3.92(s,2H),3. 50-3.40(m,2H),3.31(s,2H),3.27(d,J=5.6Hz,1H),3.05(s,3H),2.27(d,J=8.4Hz,2H),2.16-2 .11(m,2H),2.01(d,J=14.4Hz,3H),1.96-1.91(m,1H),1.84(d,J=9.6Hz,1H),1.33-1.23(m,3H). Chiral SFC:t R = 5.335 min (instrument column: Chiralpak AD-3 100 x 4.6 mm, i.d., 3 um; mobile phase: 40% isopropanol (0.05% DEA) in CO2; flow rate: 2.8 mL / min, column temperature: 40 °C, UV detection: 220 nm), ee% = 98.86%. [α] D 20 =-17.0 (c=-108, MeOH).

[0283] Example 6 (2S)-N-[2-[[6-[(5-cyclobutylthiazol-2-yl)amino]-2-ethyl-pyrimidin-4-yl]amino]ethyl]-2-[methyl(prop-2-enoyl)amino]propanamide (Compound 6) TIFF0007628108000187.tif169143 Scheme 9. Synthesis of compound 6.

[0284] TIFF0007628108000188.tif37128To a solution of N-(6-chloro-2-ethyl-pyrimidin-4-yl)-5-cyclobutyl-thiazol-2-amine (1.3 g, 4.41 mmol) and tert-butyl N-(2-aminoethyl)carbamate (5 g, 31.21 mmol) in DMSO (30 mL), DIPEA (1.71 g, 13.23 mmol) was added. The mixture was stirred at 80 °C for 24 hours. The mixture was diluted with HO (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue is then purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, elution with a 0-50% ethyl acetate / petroleum ether gradient (60 mL / min)) to afford tert-butyl N-[2-[[6-[(5-cyclobutylthiazol-2-yl)amino]-2-ethyl-pyrimidin-4-yl]amino]ethyl]carbamate (1.5 g, 3.23 mmol, 73% yield, 90% purity) as a white solid, which is used directly in the next step.

[0285] A solution of tert-butyl N-[2-[[6-[(5-cyclobutylthiazol-2-yl)amino]-2-ethyl-pyrimidin-4-yl]amino]ethyl]carbamate (1.5 g, 3.58 mmol) in HCl / dioxane (4 M, 20 mL) was stirred for 1 h at 25° C. The mixture was concentrated under reduced pressure to give N-(2-aminoethyl)-N-(5-cyclobutylthiazol-2-yl)-2-ethyl-pyrimidine-4,6-diamine (2.8 g, crude) as a yellow solid, which was used directly in the next step.

[0286] To a solution of N6-(2-aminoethyl)-N4-(5-cyclobutylthiazol-2-yl)-2-ethyl-pyrimidine-4,6-diamine (1.2 g, 1.51 mmol) in DMF (10 mL) was added HATU (689 mg, 1.81 mmol), DIPEA (585 mg, 4.53 mmol), and (2S)-2-[tert-butoxycarbonyl(methyl)amino]propanoic acid (368 mg, 1.81 mmol). The mixture was stirred at 25 °C for 2 h. The mixture was diluted with HO (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was then purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, elution with a 0-10% ethyl acetate / petroleum ether gradient (60 mL / min)) to give tert-butyl N-[(1S)-2-[2-[[6-[(5-cyclobutylthiazol-2-yl)amino]-2-ethyl-pyrimidin-4-yl]amino]ethylamino]-1-methyl-2-oxo-ethyl]-N-methyl-carbamate (650 mg, 1.16 mmol, 77% yield) as a yellow solid.

[0287] A solution of tert-butyl N-[(1S)-2-[2-[[6-[(5-cyclobutylthiazol-2-yl)amino]-2-ethyl-pyrimidin-4-yl]amino]ethylamino]-1-methyl-2-oxo-ethyl]-N-methyl-carbamate (650 mg, 1.29 mmol) in HCl / dioxane (4 M, 0.32 mL) was stirred for 1 h at 25° C. The mixture was concentrated under reduced pressure to give (2S)-N-[2-[[6-[(5-cyclobutylthiazol-2-yl)amino]-2-ethyl-pyrimidin-4-yl]amino]ethyl]-2-(methylamino)propanamide (860 mg, crude) as a yellow oil, which was used directly in the next step.

[0288] To a solution of (2S)—N-[2-[[6-[(5-cyclobutylthiazol-2-yl)amino]-2-ethyl-pyrimidin-4-yl]amino]ethyl]-2-(methylamino)propanamide (350 mg, 0.52 mmol) in DCM (10 mL) was added DIPEA (135 mg, 1.04 mmol) and prop-2-enoyl chloride (47 mg, 0.52 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h. The mixture was diluted with HO (50 mL) and extracted with DCM (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was then purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent: 0-10% DCM / MeOH (40 mL / min)) to afford (2S)-N-[2-[[6-[(5-cyclobutylthiazol-2-yl)amino]-2-ethyl-pyrimidin-4-yl]amino]ethyl]-2-[methyl(prop-2-enoyl)amino]propanamide (18.8 mg, 0.04 mmol, 7% yield, 96.5% purity) as a white solid. LCMS: t R =10-80AB_4min_220&254_Shimadzu.lcm for 2.197 minutes, MS(ESI)m / z=458.2[M+H] + . 1 H NMR(400MHz,DMSO-d6):δ=10.88(s,1H),8.23-7.92(m,1H),7.17-6.96(m,2H),6.80-6.76( m,1H),6.24-6.11(m,1H),5.89(s,1H),5.80-5.67(m,1H),5.08-4.65(m,1H),3.73-3.64(m, 1H),3.36-3.26(m,4H),2.98-2.79(m,3H),2.68(q,J=7.6Hz,2H),2.42-2.36(m,2H),2.16-2 .08(m,2H),2.05-1.97(m,1H),1.94-1.85(m,1H),1.36-1.33(m,3H),1.29(t,J=7.2Hz,3H). Chiral SFC:t R= 2.953 min (instrument column: Chiralpak AS-3 100 x 4.6 mm, i.d., 3 um; mobile phase: A:CO2 B:ethanol (0.05% DEA) gradient: 5% to 40% B for 4.5 min, hold at 40% for 2.5 min, then 5% B for 1 min; flow rate: 2.8 mL / min; column temperature: 40 °C; UV detection: 220 nm), ee% = 96.90%. [α] D 20 =-123.0 (c=-108, MeOH).

[0289] Example 7 (2S)-N-[2-[6-[(5-cyclobutylthiazol-2-yl)amino]-2-ethyl-pyrimidin-4-yl]oxyethyl]-2-[methyl(prop-2-enoyl)amino]propanamide (Compound 7) TIFF0007628108000193.tif162144 Scheme 10. Synthesis of compound 7.

[0290] TIFF0007628108000194.tif28128To a solution of 4,6-dichloro-2-ethyl-pyrimidine (1 g, 5.65 mmol) in DMF (10 mL) was added CsCO (2.76 g, 8.47 mmol) and tert-butyl N-(2-hydroxyethyl)carbamate (911 mg, 5.65 mmol). The mixture was stirred at 80 °C for 2.5 h. The mixture was diluted with HO (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was then purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent: 0–20% ethyl acetate / petroleum ether gradient (40 mL / min)) to afford tert-butyl N-[2-(6-chloro-2-ethyl-pyrimidin-4-yl)oxyethyl]carbamate (600 mg, 1.99 mmol, 35% yield) as a colorless oil.

[0291] A mixture of tert-butyl N-[2-(6-chloro-2-ethyl-pyrimidin-4-yl)oxyethyl]carbamate (500 mg, 0.994 mmol), 5-cyclobutylthiazol-2-amine (230 mg, 1.49 mmol), [2-(2-aminophenyl)phenyl]methylsulfonyloxypalladium; dicyclohexyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane (180 mg, 0.20 mmol), and CsCO (645 mg, 1.99 mmol) in dioxane (2 mL) was degassed and purged with N three times, and then the mixture was stirred under N atmosphere at 80 °C for 1 h. The mixture was diluted with HO (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, elution with a 0–30% ethyl acetate / petroleum ether gradient (100 mL / min)) to afford tert-butyl N-[2-[6-[(5-cyclobutylthiazol-2-yl)amino]-2-ethyl-pyrimidin-4-yl]oxyethyl]carbamate (300 mg, 0.715 mmol, 72% yield) as a yellow oil.

[0292] A solution of tert-butyl N-[2-[6-[(5-cyclobutylthiazol-2-yl)amino]-2-ethyl-pyrimidin-4-yl]oxyethyl]carbamate (300 mg, 0.715 mmol) in HCl / dioxane (4 M, 10 mL) was stirred for 0.5 h at 25° C. The mixture was concentrated under reduced pressure to give N-[6-(2-aminoethoxy)-2-ethyl-pyrimidin-4-yl]-5-cyclobutyl-thiazol-2-amine (220 mg, crude) as a yellow oil, which was used directly in the next step.

[0293] To a solution of N-[6-(2-aminoethoxy)-2-ethyl-pyrimidin-4-yl]-5-cyclobutyl-thiazol-2-amine (220 mg, 0.689 mmol) in DMF (10 mL) was added HATU (314 mg, 0.826 mmol), DIEA (267 mg, 2.07 mmol), and (2S)-2-[tert-butoxycarbonyl(methyl)amino]propanoic acid (154 mg, 0.758 mmol). The mixture was stirred at 25 °C for 2 h. The mixture was diluted with HO (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was then purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent of 0–10% DCM / MeOH (40 mL / min)) to give tert-butyl N-[(1S)-2-[2-[6-[(5-cyclobutylthiazol-2-yl)amino]-2-ethyl-pyrimidin-4-yl]oxyethylamino]-1-methyl-2-oxo-ethyl]-N-methyl-carbamate (300 mg, 0.59 mmol, 86% yield) as a white solid.

[0294] A solution of tert-butyl N-[(1S)-2-[2-[6-[(5-cyclobutylthiazol-2-yl)amino]-2-ethyl-pyrimidin-4-yl]oxyethylamino]-1-methyl-2-oxo-ethyl]-N-methyl-carbamate (300 mg, 0.59 mmol) in HCl / dioxane (4 M, 3 mL) was stirred for 0.5 h at 25° C. The mixture was concentrated under reduced pressure to give (2S)-N-[2-[6-[(5-cyclobutylthiazol-2-yl)amino]-2-ethyl-pyrimidin-4-yl]oxyethyl]-2-(methylamino)propanamide (420 mg, crude) as a yellow oil, which was used directly in the next step.

[0295] TIFF0007628108000199.tif36143 To a solution of (2S)-N-[2-[6-[(5-cyclobutylthiazol-2-yl)amino]-2-ethyl-pyrimidin-4-yl]oxyethyl]-2-(methylamino)propanamide (420 mg, 0.59 mmol) in CHCl (10 mL) was added DIEA (153 mg, 1.18 mmol) and prop-2-enoyl chloride (54 mg, 0.59 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 h. The mixture was diluted with H0 (50 mL) and extracted with CHCl (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was then purified by preparative HPLC (water (0.04% NH 3. Purification by HCl (H2O + 10 mM NH4HCO3)-ACN) gave (2S)-N-[2-[6-[(5-cyclobutylthiazol-2-yl)amino]-2-ethyl-pyrimidin-4-yl]oxyethyl]-2-[methyl(prop-2-enoyl)amino]propanamide (29.2 mg, 0.06 mmol, 10% yield, 96% purity) as a white solid. LCMS: R =10-80AB_4min_220&254_Shimadzu.lcm for 2.214 minutes, MS(ESI)m / z=459.2[M+H] + . 1 H NMR(400MHz,MeOD):δ=7.04(d,J=1.2Hz,1H),6.79-6.61(m,1H),6.28-6.16(m ,1H),6.14(s,1H),5.79-5.67(m,1H),5.11(d,J=7.2Hz,1H),4.46-4.35(m,2H) ,3.75-3.50(m,3H),3.06-2.88(m,3H),2.83(q,J=7.6Hz,2H),2.48-2.38(m,2H ),2.25-2.14(m,2H),2.13-2.02(m,1H),2.01-1.89(m,1H),1.45-1.34(m,6H). Chiral SFC:t R= 2.711 min (instrument column: Chiralpak AS-3 100 × 4.6 mm, internal diameter: 3 μm, mobile phase: A: CO2, B: ethanol (0.05% DEA), gradient: 5% to 40% B for 4.5 min, hold at 40% for 2.5 min, then 5% B for 1 min, flow rate: 2.8 mL / min, column temperature: 40 °C, UV detection: 220 nm), ee% = 100%. [α] D 20 =-161(c=-108, MeOH).

[0296] Example 8 (E)-N-[(1S)-2-[2-[[6-[(5-cyclobutylthiazol-2-yl)amino]-2-ethyl-pyrimidin-4-yl]amino]ethylamino]-1-methyl-2-oxo-ethyl]-4-(dimethylamino)-N-methyl-but-2-enamide (Compound 8) TIFF0007628108000200.tif45128TIFF0007628108000201.tif78143Scheme 11. Synthesis of compound 8.

[0297] TIFF0007628108000202.tif50128 To a solution of N-(6-chloro-2-ethyl-pyrimidin-4-yl)-5-cyclobutyl-thiazol-2-amine (500 mg, 1.70 mmol) in DMSO (10 mL) was added DIEA (657 mg, 5.09 mmol) and tert-butyl N-(2-aminoethyl)carbamate (1.36 g, 8.48 mmol). The mixture was stirred at 80° C. for 12 hours. The mixture was poured into water (60 mL), filtered, and the filter cake was collected and dried to give tert-butyl N-[2-[[6-[(5-cyclobutylthiazol-2-yl)amino]-2-ethyl-pyrimidin-4-yl]amino]ethyl]carbamate (800 mg, 91% yield) as a brown solid. LCMS: t R =10-80AB_2min_220&254_Shimadzu.lcm for 1.070 minutes, MS(ESI)m / z=419.1[M+H] + .

[0298] A solution of tert-butyl N-[2-[[6-[(5-cyclobutylthiazol-2-yl)amino]-2-ethyl-pyrimidin-4-yl]amino]ethyl]carbamate (800 mg, 1.55 mmol) in HCl / dioxane (20 mL, 4 M) was stirred at 25° C. for 0.5 h. The mixture was concentrated under reduced pressure to give N-(2-aminoethyl)-N-(5-cyclobutylthiazol-2-yl)-2-ethyl-pyrimidine-4,6-diamine (800 mg, 97% yield) as a brown solid. LCMS: R =10-80 AB_2min_220&254_Shimadzu.lcm for 0.886 minutes, MS(ESI)m / z=318.9[M+H] + .

[0299] To a solution of N4-(2-aminoethyl)-N6-(5-cyclobutylthiazol-2-yl)-2-ethyl-pyrimidine-4,6-diamine (800 mg, 2.51 mmol) in DMF (10 mL) was added HATU (1.15 g, 3.01 mmol), (2S)-2-[tert-butoxycarbonyl(methyl)amino]propanoic acid (612 mg, 3.01 mmol), and DIEA (974 mg, 7.54 mmol). The mixture was stirred at 25 °C for 2 hours. The mixture was extracted with EtOAc (60 mL × 3). The combined organic layers were washed with HO (60 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent: 0-10% methanol / dichloromethane (40 mL / min)) to afford tert-butyl N-[(1S)-2-[2-[[6-[(5-cyclobutylthiazol-2-yl)amino]-2-ethyl-pyrimidin-4-yl]amino]ethylamino]-1-methyl-2-oxo-ethyl]-N-methyl-carbamate (600 mg, 47% yield) as a yellow solid. LCMS: t R=5-95 AB_1.5min_220&254_Shimadzu.lcm for 0.884 minutes, MS(ESI)m / z=504.2[M+H] + .

[0300] A solution of tert-butyl N-[(1S)-2-[2-[[6-[(5-cyclobutylthiazol-2-yl)amino]-2-ethyl-pyrimidin-4-yl]amino]ethylamino]-1-methyl-2-oxo-ethyl]-N-methyl-carbamate (600 mg, 1.19 mmol) in HCl / dioxane (20 mL, 4 M) was stirred at 25° C. for 0.5 h. The mixture was concentrated under reduced pressure to give (2S)-N-[2-[[6-[(5-cyclobutylthiazol-2-yl)amino]-2-ethyl-pyrimidin-4-yl]amino]ethyl]-2-(methylamino)propanamide (600 mg, 100% yield) as a yellow solid. LCMS: R =10-80 AB_2min_220&254_Shimadzu.lcm for 0.882 minutes, MS(ESI)m / z=404.0[M+H] + .

[0301] To a solution of (2S)-N-[2-[[6-[(5-cyclobutylthiazol-2-yl)amino]-2-ethyl-pyrimidin-4-yl]amino]ethyl]-2-(methylamino)propanamide (150 mg, 0.371 mmol) in DMF (10 mL) was added DIEA (144 mg, 1.12 mmol), HATU (169 mg, 0.446 mmol), and (E)-4-(dimethylamino)but-2-enoic acid (52 mg, 0.408 mmol). The mixture was stirred at 25 °C for 2 hours. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30mm*3um; water (0.04% HCl)-ACN; 30-60% B; gradient time: 8 min; flow rate: 25 mL / min) to give (E)-N-[(1S)-2-[2-[[6-[(5-cyclobutylthiazol-2-yl)amino]-2-ethyl-pyrimidin-4-yl]amino]ethylamino]-1-methyl-2-oxo-ethyl]-4-(dimethylamino)-N-methyl-but-2-enamide (14 mg, 7% yield, 96.56% purity) as a white solid. LCMS: t R =10-80 AB_4min_E_Shimadzu.lcm for 1.180 minutes, MS(ESI)m / z=515.3[M+H] + . 1 H NMR(400MHz,MeOD-d4):δ=6.99(s,1H),6.83-6.69(m,1H),6.56-6.45(m,1H),5.86 (s,1H),5.06-5.01(m,1H),3.71-3.63(m,1H),3.50-3.44(m,3H),3.40-3.33(m,1H) ,3.15-3.07(m,2H),3.02-2.87(m,2H),2.74-2.68(m,3H),2.46-2.38(m,2H),2.26( s,4H),2.23-2.14(m,4H),2.09-2.02(m,1H),2.00-1.90(m,1H),1.44-1.36(m,6H).

[0302] Example 9 (2S)-N-[2-[[2-methyl-6-[(5-phenylthiazol-2-yl)amino]pyrimidin-4-yl]amino]ethyl]-2-[methyl(prop-2-enoyl)amino]propanamide (Compound 9) TIFF0007628108000207.tif190136 Scheme 12. Synthesis of compound 9.

[0303] To a solution of 4,6-dichloro-2-methyl-pyrimidine (930 mg, 5.71 mmol) and 5-phenylthiazol-2-amine (914 mg, 5.19 mmol) in THF (50 mL) was added t-BuOK (1.16 g, 10.37 mmol) at 0° C. The mixture was stirred at 25° C. for 12 hours. The mixture was quenched by adding HO (20 mL) at 0° C. and then extracted with EtOAc (30 mL×2). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Biotage 4 g silica flash column, eluent: 0-50% ethyl acetate in petroleum ether gradient (20 mL / min)) to give N-(6-chloro-2-methyl-pyrimidin-4-yl)-5-phenyl-thiazol-2-amine (1.5 g, 62% yield, 97% purity) as a pale yellow solid. LCMS: R =0-60AB_4min_220&254_Shimadzu.lcm for 3.158 minutes, MS(ESI)m / z=303.1[M+H] + . 1 H NMR (400MHz, DMSO-d6): δ=7.80(s,1H),7.58(d,J=7.6Hz,2H),7.38(t,J=8.0Hz,1H),7.24(t,J=7.6Hz,2H),6.74(s,1H),1.79(s,3H).

[0304] A mixture of N-(6-chloro-2-methyl-pyrimidin-4-yl)-5-phenyl-thiazol-2-amine (1.5 g, 4.95 mmol), tert-butyl N-(2-aminoethyl)carbamate (2.38 g, 14.86 mmol), DIPEA (1.28 g, 9.91 mmol) in DMSO (30 mL) was stirred at 100° C. for 12 h. The mixture was quenched by adding HO (50 mL) and then diluted with HO (50 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Biotage 12 g silica flash column, elution with a 0-50% ethyl acetate gradient in petroleum ether (60 mL / min)) to afford tert-butyl N-[2-[[2-methyl-6-[(5-phenylthiazol-2-yl)amino]pyrimidin-4-yl]amino]ethyl]carbamate (1.5 g, 71% yield) as a yellow solid. LCMS: R =10-80AB_4min_220&254_Shimadzu.lcm for 2.129 minutes, MS(ESI)m / z=427.3[M+H] + .

[0305] A solution of tert-butyl N-[2-[[2-methyl-6-[(5-phenylthiazol-2-yl)amino]pyrimidin-4-yl]amino]ethyl]carbamate (500 mg, 1.17 mmol) in HCl / dioxane (30 mL, 4 M) was stirred at 25° C. for 0.5 h. The mixture was concentrated under reduced pressure to give N-(2-aminoethyl)-2-methyl-N-(5-phenylthiazol-2-yl)pyrimidine-4,6-diamine (425 mg, 99% yield, HCl salt) as a pale yellow solid. LCMS: R =10-80AB_2min_220&254_Shimadzu.lcm for 0.892 minutes, MS(ESI)m / z=327.2[M+H] + .

[0306] To a solution of N4-(2-aminoethyl)-2-methyl-N6-(5-phenylthiazol-2-yl)pyrimidine-4,6-diamine (380 mg, 1.05 mmol, HCl salt) in DMF (20 mL) was added HATU (477 mg, 1.26 mmol), DIPEA (406 mg, 3.14 mmol), and (2S)-2-[tert-butoxycarbonyl(methyl)amino]propanoic acid (234 mg, 1.15 mmol). The mixture was stirred at 25 °C for 1 h. The mixture was partitioned between HO (10 mL) and EtOAc (20 mL). The combined organic layer was separated, washed with HO (20 mL × 5), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Biotage 12 g silica flash column, elution with a 0-50% ethyl acetate gradient in petroleum ether (40 mL / min)) to afford tert-butyl N-methyl-N-[(1S)-1-methyl-2-[2-[[2-methyl-6-[(5-phenylthiazol-2-yl)amino]pyrimidin-4-yl]amino]ethylamino]-2-oxo-ethyl]carbamate (392 mg, 73% yield) as a pale yellow solid. LCMS: t R =10-80AB_2min_220&254_Shimadzu.lcm for 1.108 minutes, MS(ESI)m / z=512.4[M+H] + .

[0307] To a solution of tert-butyl N-methyl-N-[(1S)-1-methyl-2-[2-[[2-methyl-6-[(5-phenylthiazol-2-yl)amino]pyrimidin-4-yl]amino]ethylamino]-2-oxo-ethyl]carbamate (392 mg, 0.77 mmol) in dioxane (20 mL), HCl / dioxane (20 mL, 4 M) was added. The mixture was stirred at 25° C. for 2 hours. The mixture was concentrated under reduced pressure to give (2S)-2-(methylamino)-N-[2-[[2-methyl-6-[(5-phenylthiazol-2-yl)amino]pyrimidin-4-yl]amino]ethyl]propanamide (460 mg, crude) as a yellow solid. LCMS: t R =10-80AB_2min_220&254_Shimadzu.lcm for 0.913 minutes, MS(ESI)m / z=412.3[M+H] + .

[0308] To a solution of (2S)-2-(methylamino)-N-[2-[[2-methyl-6-[(5-phenylthiazol-2-yl)amino]pyrimidin-4-yl]amino]ethyl]propanamide (200 mg, 0.49 mmol) in DCM (10 mL) and DIPEA (188 mg, 1.46 mmol) was added prop-2-enoyl chloride (39 mg, 0.44 mmol). The mixture was stirred at 0 °C for 1 h. The mixture was quenched by adding HO (15 mL) at 25 °C and then extracted with DCM (50 mL × 3). The combined organic layers were washed with saturated aqueous NaCl (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Agela DuraShell C18 150 x 25 mm x 5 μm, water (0.04% NH 3.Purification by HCl (H2O + 10 mM NH4HCO3)-ACN; 25-55% B; gradient time: 8 min; flow rate: 25 mL / min) afforded (2S)-N-[2-[[2-methyl-6-[(5-phenylthiazol-2-yl)amino]pyrimidin-4-yl]amino]ethyl]-2-[methyl(prop-2-enoyl)amino]propanamide (60 mg, 27% yield) as a white solid. LCMS: t R =10-80AB_4min_220&254_Shimadzu.lcm for 1.959 minutes, MS(ESI)m / z=466.3[M+H] + . 1 H NMR(400MHz,DMSO-d6):δ=8.08-7.89(m,1H),7.74(s,1H),7.57(d,J=7.2H z,2H),7.39(t,J=8.0Hz,2H),7.25(t,J=7.6Hz,1H),7.07(s,1H),6.77-6.7 0(m,1H),6.16-6.04(m,2H),5.86(s,1H),5.71-5.61(m,1H),5.02-4.97(m, 1H),3.25-3.21(m,4H),2.91&2.74(s,3H),2.38(s,3H),1.29-1.22(m,3H). Chiral SFC:t R = 4.349 min (instrument column: Chiralcel OD-3 100 x 4.6 mm, i.d., 3 um, mobile phase: A: CO2, B: ethanol (0.05% DEA), gradient: 5% to 40% B for 4.5 min, hold at 40% for 2.5 min, then 5% B for 1 min, flow rate: 2.8 mL / min, column temperature: 40 °C; UV detection: 220 nm), ee% = 98.126%. [α] D 20 =-15.0 (c=0.10, MeOH).

[0309] Example 10 (2S)-N-[2-[[2-methyl-6-[(5-phenylthiazol-2-yl)amino]pyrimidin-4-yl]amino]ethyl]-2-[methyl(propanoyl)amino]propanamide (Compound 10) TIFF0007628108000214.tif107138 Scheme 13. Synthesis of compound 10.

[0310] The synthesis of (2S)-2-(methylamino)-N-[2-[[2-methyl-6-[(5-phenylthiazol-2-yl)amino]pyrimidin-4-yl]amino]ethyl]propanamide (11-7) is shown in Example 11. To a solution of 11-7 (300 mg, 0.67 mmol, HCl salt) in DMF (5 mL) was added propanoyl chloride (61 mg, 0.67 mmol) and DIPEA (173 mg, 1.34 mmol). The mixture was stirred at 25 °C for 2 h. The mixture was quenched by adding HO (5 mL) at 25 °C, then diluted with HO (10 mL) and extracted with EtOAc (50 mL × 3). The combined organic layer was washed with saturated aqueous NaCl (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Agela DuraShell C18 150 x 25 mm x 5 μm, water (0.04% NH 3. Purification by HCl (HO + 10 mM NH4HCO3)-ACN; 35-65% B; gradient time: 8 min; flow rate: 25 mL / min) afforded (2S)-N-[2-[[2-methyl-6-[(5-phenylthiazol-2-yl)amino]pyrimidin-4-yl]amino]ethyl]-2-[methyl(propanoyl)amino]propanamide (46 mg, 14% yield, 96% purity) as a white solid. LCMS: t R =10-80AB_4min_220&254_Shimadzu.lcm for 1.946 minutes, MS(ESI)m / z=468.4[M+H] + . 1 HNMR(400MHz,DMSO-d6):δ=11.08(s,1H),8.01&7.77(s,1H),7.73(s,1H),7.57(d,J=7.6Hz,2H),7.39(t,J=8.0Hz,2H),7.25(t,J=7.6Hz,1H),7.05( s,1H),5.85(s,1H),5.00-4.92(m,1H),3.27-3.22(m,4H),2.78&2.65(s,3 H),2.34(s,3H),2.32-2.28(m,2H),1.27-1.17(m,3H),1.00-0.95(m,3H). Chiral SFC:t R= 4.373 min (Instrument column: Chiralcel OD-3 100 x 4.6 mm, i.d., 3 um, Mobile phase: A: CO2, B: Ethanol (0.05% DEA) Gradient: 5% to 40% B for 4.5 min, hold at 40% for 2.5 min, then 5% B for 1 min, Flow rate: 2.8 mL / min, Column temperature: 40 °C; UV detection: 220 nm), ee% = 96.476%. [α] D 20 = -7.0 (c = 0.10, MeOH).

[0311] Example 11 (E)-4-(Dimethylamino)-N-methyl-N-[(1S)-1-methyl-2-[2-[[2-methyl-6-[(5-phenylthiazol-2-yl)amino]pyrimidin-4-yl]amino]ethylamino]-2-oxo-ethyl]but-2-enamide (Compound 11) TIFF0007628108000215.tif135146 Scheme 14. Synthesis of compound 11.

[0312] To a solution of N-(6-chloro-2-methyl-pyrimidin-4-yl)-5-phenyl-thiazol-2-amine (500 mg, 1.65 mmol) in DMSO (10 mL) was added DIEA (640 mg, 4.95 mmol) and tert-butyl N-(2-aminoethyl)carbamate (2.65 g, 16.51 mmol). The mixture was stirred at 90° C. for 12 hours. The mixture was poured into water (60 mL), filtered, and the filter cake was collected and dried to give tert-butyl N-[2-[[2-methyl-6-[(5-phenylthiazol-2-yl)amino]pyrimidin-4-yl]amino]ethyl]carbamate (2.5 g, 99% yield) as a brown solid. LCMS: t R =10-80AB_2min_220&254_Shimadzu.lcm for 1.050 minutes, MS(ESI)m / z=427.0[M+H] + .

[0313] A solution of tert-butyl N-[2-[[2-methyl-6-[(5-phenylthiazol-2-yl)amino]pyrimidin-4-yl]amino]ethyl]carbamate (1 g, 0.914 mmol) in HCl / dioxane (30 mL, 4 M) was stirred at 25° C. for 0.5 h. The mixture was concentrated under reduced pressure to give N-(2-aminoethyl)-2-methyl-N-(5-phenylthiazol-2-yl)pyrimidine-4,6-diamine (480 mg, 97% yield) as a brown solid. LCMS: R =10-80 AB_2min_220&254_Shimadzu.lcm for 0.875 minutes, MS(ESI)m / z=326.9[M+H] + .

[0314] To a solution of N4-(2-aminoethyl)-2-methyl-N6-(5-phenylthiazol-2-yl)pyrimidine-4,6-diamine (480 mg, 1.47 mmol) in DMF (10 mL) was added HATU (670 mg, 1.76 mmol), (2S)-2-[tert-butoxycarbonyl(methyl)amino]propanoic acid (358 mg, 1.76 mmol), and DIEA (570 mg, 4.41 mmol). The mixture was stirred at 25 °C for 2 h. The mixture was extracted with EtOAc (60 mL × 3). The combined organic layers were washed with HO (60 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent: 0-10% methanol / dichloromethane (40 mL / min)) to afford tert-butyl N-methyl-N-[(1S)-1-methyl-2-[2-[[2-methyl-6-[(5-phenylthiazol-2-yl)amino]pyrimidin-4-yl]amino]ethylamino]-2-oxo-ethyl]carbamate (360 mg, 48% yield) as a yellow solid. LCMS: t R=5-95 AB_1.5min_220&254_Shimadzu.lcm for 0.871 min, MS(ESI)m / z=512.2[M+H] + .

[0315] A solution of tert-butyl N-methyl-N-[(1S)-1-methyl-2-[2-[[2-methyl-6-[(5-phenylthiazol-2-yl)amino]pyrimidin-4-yl]amino]ethylamino]-2-oxo-ethyl]carbamate (360 mg, 0.703 mmol) in HCl / dioxane (20 mL, 4 M) was stirred at 25° C. for 0.5 h. The mixture was concentrated under reduced pressure to give (2S)-2-(methylamino)-N-[2-[[2-methyl-6-[(5-phenylthiazol-2-yl)amino]pyrimidin-4-yl]amino]ethyl]propanamide (363 mg, 99% yield) as a yellow solid. LCMS: R =0-60 AB_2min_220&254_Shimadzu.lcm for 0.867 minutes, MS(ESI)m / z=412.0[M+H] + .

[0316] To a solution of (2S)-2-(methylamino)-N-[2-[[2-methyl-6-[(5-phenylthiazol-2-yl)amino]pyrimidin-4-yl]amino]ethyl]propanamide (150 mg, 0.364 mmol) in DMF (10 mL) was added HATU (166 mg, 0.437 mmol), (E)-4-(dimethylamino)but-2-enoic acid (52 mg, 0.401 mmol), and DIEA (141 mg, 1.09 mmol). The mixture was stirred at 25° C. for 2 hours. The mixture was stirred at 25° C. for 0.5 hours. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Xtimate C18 75*30mm*3um; water (0.04% HCl)-ACN; 30-60% B; gradient time: 8 min; flow rate: 25 mL / min) to give (E)-4-(dimethylamino)-N-methyl-N-[(1S)-1-methyl-2-[2-[[2-methyl-6-[(5-phenylthiazol-2-yl)amino]pyrimidin-4-yl]amino]ethylamino]-2-oxo-ethyl]but-2-enamide (17.9 mg, 9% yield, 98.49% purity) as a white solid. LCMS: t R =0-60 AB_4min_E_Shimadzu.lcm for 1.121 minutes, MS(ESI)m / z=523.2[M+H] + . 1 H NMR(400MHz,MeOD-d4):δ=7.59-7.57(m,3H),7.39(t,J=36Hz,2H),7.28(t,J=36Hz,1H),6.83-6.79(m,1H),6.57-6.53(m,1H),5.91(s,1H),5.0 5-5.03(m,1H),3.48-3.45(m,3H),3.40-3.36(m,1H),3.15-3.08(m,2H) ,3.02-2.88(m,3H),2.47(s,3H),2.26-2.24(m,6H),1.45-1.36(m,3H).

[0317] Example 12 (2S)-N-[2-[[2-methyl-6-[(5-phenylthiazol-2-yl)amino]-4-pyridyl]oxy]ethyl]-2-[methyl(prop-2-enoyl)amino]propanamide (Compound 12) TIFF0007628108000221.tif156140 Scheme 15. Synthesis of compound 12.

[0318] To a solution of tert-butyl N-(2-hydroxyethyl)carbamate (2.29 g, 14.20 mmol) in DMF (30 mL) was added NaH (681 mg, 17.04 mmol, 60% purity) and stirred at 0 °C for 0.5 h. Then, 2,4-dichloro-6-methyl-pyridine (2.3 g, 14.20 mmol) was added to the reaction mixture and stirred at 25 °C for 5 h. The mixture was quenched by adding HO (50 mL) at 25 °C, then diluted with HO (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was then purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, elution with a 0–30% ethyl acetate / petroleum ether gradient (40 mL / min)) to afford tert-butyl N-[2-[(2-chloro-6-methyl-4-pyridyl)oxy]ethyl]carbamate (700 mg, 2.44 mmol, 17% yield) as a yellow oil.

[0319] A mixture of tert-butyl N-[2-[(2-chloro-6-methyl-4-pyridyl)oxy]ethyl]carbamate (700 mg, 2.44 mmol), 5-phenylthiazol-2-amine (473 mg, 2.69 mmol), [2-(2-aminophenyl)phenyl]methylsulfonyloxy-palladium; dicyclohexyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane (443 mg, 0.488 mmol), CsCO (1.59 g, 4.88 mmol) in dioxane (20 mL) was degassed and purged with N three times, then the mixture was stirred at 80 °C under N atmosphere for 12 h. The mixture was quenched by the addition of HO (50 mL) at 25 °C, then diluted with HO (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was then purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, elution with a 0–50% ethyl acetate / petroleum ether gradient (60 mL / min)) to give tert-butyl N-[2-[[2-methyl-6-[(5-phenylthiazol-2-yl)amino]-4-pyridyl]oxy]ethyl]carbamate (587 mg, 1.38 mmol, 56% yield) as a brown solid.

[0320] A solution of tert-butyl N-[2-[[2-methyl-6-[(5-phenylthiazol-2-yl)amino]-4-pyridyl]oxy]ethyl]carbamate (587 mg, 1.38 mmol) in HCl / dioxane (4 M, 0.34 mL) was stirred for 0.5 h at 25° C. The mixture was concentrated under reduced pressure to give N-[4-(2-aminoethoxy)-6-methyl-2-pyridyl]-5-phenyl-thiazol-2-amine (700 mg, crude, HCl salt) as a yellow solid, which was used directly in the next step.

[0321] To a solution of N-[4-(2-aminoethoxy)-6-methyl-2-pyridyl]-5-phenyl-thiazol-2-amine (0.7 g, 1.35 mmol) in DMF (20 mL) was added HATU (616 mg, 1.62 mmol), DIPEA (524 mg, 4.05 mmol), and (2R)-2-[tert-butoxycarbonyl(methyl)amino]propanoic acid (274 mg, 1.35 mmol). The mixture was stirred at 25 °C for 2 h. The mixture was quenched by adding HO (50 mL) at 25 °C, then diluted with HO (50 mL), and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue that was then purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, elution with a 0–70% ethyl acetate / petroleum ether gradient (40 mL / min)) to give tert-butyl N-methyl-N-[(1S)-1-methyl-2-[2-[[2-methyl-6-[(5-phenylthiazol-2-yl)amino]-4-pyridyl]oxy]ethylamino]-2-oxo-ethyl]carbamate (550 mg, 1.07 mmol, 80% yield) as a yellow solid.

[0322] A solution of tert-butyl N-methyl-N-[(1S)-1-methyl-2-[2-[[2-methyl-6-[(5-phenylthiazol-2-yl)amino]-4-pyridyl]oxy]ethylamino]-2-oxo-ethyl]carbamate (550 mg, 1.07 mmol) in HCl / dioxane (4 M, 10 mL) was stirred for 0.5 h at 25° C. The mixture was concentrated under reduced pressure to give (2S)-2-(methylamino)-N-[2-[[2-methyl-6-[(5-phenylthiazol-2-yl)amino]-4-pyridyl]oxy]ethyl]propanamide (690 mg, crude, HCl salt) as a yellow solid, which was used directly in the next step.

[0323] To a solution of (2S)-2-(methylamino)-N-[2-[[2-methyl-6-[(5-phenylthiazol-2-yl)amino]-4-pyridyl]oxy]ethyl]propanamide (390 mg, 0.654 mmol) in CHCl (10 mL) was added DIPEA (254 mg, 1.96 mmol) and prop-2-enoyl chloride (59 mg, 0.654 mmol). The mixture was stirred at 0 °C for 0.5 h. The mixture was quenched by adding HO (50 mL) at 25 °C, then diluted with HO (50 mL) and extracted with DCM (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was then purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent: 0-10% DCM / MeOH (40 mL / min)) to afford (2S)-N-[2-[[2-methyl-6-[(5-phenylthiazol-2-yl)amino]-4-pyridyl]oxy]ethyl]-2-[methyl(prop-2-enoyl)amino]propanamide (75.6 mg, 0.159 mmol, 24% yield, 98% purity) as a white solid. LCMS: t R =10-80AB_4min_220&254_Shimadzu.lcm for 1.562 minutes, MS(ESI)m / z=466.2[M+H] + . 1 H NMR(400MHz,DMSO-d6):δ=11.13(s,1H),8.32-8.01(m,1H),7.78-7.73(m,1H),7.58(d ,J=7.2Hz,2H),7.40(t,J=7.6Hz,2H),7.28-7.22(m,1H),6.79-6.68(m,1H),6.46(s,1 H),6.40(d,J=1.6Hz,1H),6.18-6.04(m,1H),5.74-5.59(m,1H),5.06-4.61(m,1H),4. 10-4.01(m,2H),3.53-3.41(m,2H),2.94-2.75(m,3H),2.44(s,3H),1.30-1.23(m,3H). Chiral SFC:t R= 4.609 min (instrument column: Chiralcel OD-3 100 x 4.6 mm, i.d., 3 um, mobile phase: A: CO2, B: ethanol (0.05% DEA), gradient: 5% to 40% B for 4.5 min, hold 40% for 2.5 min, then 5% B for 1 min, flow rate: 2.8 mL / min, column temperature: 40 °C, detection: 220 nm), ee% = 100%. [α] D 20 =-76.0 (c=0.10, MeOH).

[0324] Example 13 (2S)-N-[2-[2-methyl-6-[(5-phenylthiazol-2-yl)amino]pyrimidin-4-yl]oxyethyl]-2-[methyl(prop-2-enoyl)amino]propanamide (Compound 13) TIFF0007628108000228.tif120143 Scheme 16. Synthesis of compound 13.

[0325] To a solution of 4,6-dichloro-2-methyl-pyrimidine (5 g, 30.67 mmol) in DMF (80 mL) was added CsCO (14.99 g, 46.01 mmol) and tert-butyl N-(2-hydroxyethyl)carbamate (4.94 g, 30.67 mmol). The mixture was stirred at 80 °C for 2 h. The mixture was quenched by adding HO (50 mL) at 25 °C, then diluted with HO (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was then purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, elution with a 0-40% ethyl acetate / petroleum ether gradient (40 mL / min)) to afford tert-butyl N-[2-(6-chloro-2-methyl-pyrimidin-4-yl)oxyethyl]carbamate (4 g, 13.90 mmol, 45% yield) as a yellow oil. 1H NMR (400MHz, DMSO-d6): δ=6.99(m,J=5.2Hz,1H),6.89(s,1H),4.33(m,J=5.6Hz,2H),3.29(m,J=5.6Hz,2H),2.50(s,3H),1.36(s,9H).

[0326] A mixture of tert-butyl N-[2-(6-chloro-2-methyl-pyrimidin-4-yl)oxyethyl]carbamate (1.2 g, 4.17 mmol), 5-phenylthiazol-2-amine (808 mg, 4.59 mmol), Xantphos (483 mg, 0.834 mmol), Pd(OAc) (94 mg, 0.417 mmol), and KCO (865 mg, 6.26 mmol) in dioxane (30 mL) was degassed and purged with N three times, and then the mixture was stirred under a N atmosphere at 80 °C for 2 h. The mixture was quenched by adding HO (50 mL) at 25 °C, then diluted with HO (50 mL), and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue that was then purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, elution with a 0–40% ethyl acetate / petroleum ether gradient (60 mL / min)) to give tert-butyl N-[2-[2-methyl-6-[(5-phenylthiazol-2-yl)amino]pyrimidin-4-yl]oxyethyl]carbamate (0.8 g, 1.87 mmol, 45% yield) as a yellow solid.

[0327] A solution of tert-butyl N-[2-[2-methyl-6-[(5-phenylthiazol-2-yl)amino]pyrimidin-4-yl]oxyethyl]carbamate (0.8 g, 1.87 mmol) in HCl / dioxane (4 M, 20 mL) was stirred at 25 °C for 0.5 h. The mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with HO (50 mL), the pH was adjusted to 8-9 by adding aqueous NaHCO, and then extracted with DCM (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was then purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent of 0–10% DCM / MeOH (40 mL / min)) to afford N-[6-(2-aminoethoxy)-2-methyl-pyrimidin-4-yl]-5-phenyl-thiazol-2-amine (580 mg, 1.77 mmol, 95% yield) as a yellow solid.

[0328] To a solution of N-[6-(2-aminoethoxy)-2-methyl-pyrimidin-4-yl]-5-phenyl-thiazol-2-amine (580 mg, 1.77 mmol) in DMF (10 mL) was added HATU (808 mg, 2.13 mmol), DIEA (687 mg, 5.31 mmol), and (2S)-2-[tert-butoxycarbonyl(methyl)amino]propanoic acid (396 mg, 1.95 mmol). The mixture was stirred at 25 °C for 2 h. The mixture was quenched by adding HO (50 mL) at 25 °C, then diluted with HO (50 mL), and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue that was then purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, elution with 0–10% DCM / MEOH (40 mL / min)) to give tert-butyl N-methyl-N-[(1S)-1-methyl-2-[2-[2-methyl-6-[(5-phenylthiazol-2-yl)amino]pyrimidin-4-yl]oxyethylamino]-2-oxo-ethyl]carbamate (350 mg, 0.683 mmol, 38% yield) as a yellow solid.

[0329] A solution of tert-butyl N-methyl-N-[(1S)-1-methyl-2-[2-[2-methyl-6-[(5-phenylthiazol-2-yl)amino]pyrimidin-4-yl]oxyethylamino]-2-oxo-ethyl]carbamate (350 mg, 0.683 mmol) in HCl / dioxane (4 M, 20 mL) was stirred for 0.5 h at 25° C. The mixture was concentrated under reduced pressure to give (2S)-2-(methylamino)-N-[2-[2-methyl-6-[(5-phenylthiazol-2-yl)amino]pyrimidin-4-yl]oxyethyl]propanamide (367 mg, 0.676 mmol, 99% yield, 76% purity) as a yellow solid, which was used directly in the next step.

[0330] To a solution of (2S)-2-(methylamino)-N-[2-[2-methyl-6-[(5-phenylthiazol-2-yl)amino]pyrimidin-4-yl]oxyethyl]propanamide (367 mg, 0.676 mmol) in CHCl (20 mL) was added DIEA (262 mg, 2.03 mmol) and prop-2-enoyl chloride (61 mg, 0.676 mmol) at 0° C. The mixture was stirred at 0° C. for 0.5 h. The mixture was quenched by adding HO (50 mL) at 25° C., then diluted with HO (50 mL) and extracted with DCM (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was then purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent: 0-10% methanol in dichloromethane (40 mL / min)) to afford (2S)-N-[2-[2-methyl-6-[(5-phenylthiazol-2-yl)amino]pyrimidin-4-yl]oxyethyl]-2-[methyl(prop-2-enoyl)amino]propanamide (53.3 mg, 113.10 μmol, 17% yield, 99% purity) as a white solid. LCMS: t R =10-80AB_4min_220&254_Shimadzu.lcm for 1.980 minutes, MS(ESI)m / z=467.2[M+H] + . 1 H NMR(400MHz,DMSO)δ=11.53(s,1H),8.29-8.01(m,1H),7.87-7.78(m,1H),7.61 (d,J=7.2Hz,2H),7.41(d,J=7.6Hz,2H),7.33-7.24(m,1H),6.79-6.66(m,1H),6 .22(s,1H),6.16-6.03(m,1H),5.74-5.57(m,1H),5.06-4.59(m,1H),4.36-4.2 6(m,2H),3.53-3.38(m,2H),2.93-2.74(m,3H),2.53(s,3H),1.29-1.21(m,3H). Chiral SFC:t R= 4.609 min (instrument column: Chiralcel OD-3 100 x 4.6 mm, i.d., 3 um, mobile phase: A: CO2, B: ethanol (0.05% DEA), gradient: 5% to 40% B for 4.5 min, hold at 40% for 2.5 min, then 5% B for 1 min, flow rate: 2.8 mL / min, column temperature: 40 °C, detection: 220 nm), ee% = 98.63%. [α] D 20 =-239.0 (c=0.10, MeOH).

[0331] Example 14 (3S)-N-[2-[2-methyl-6-[(5-phenylthiazol-2-yl)amino]pyrimidin-4-yl]oxyethyl]-4-prop-2-enoyl-morpholine-3-carboxamide (Compound 14) TIFF0007628108000235.tif121146 Scheme 17. Synthesis of compound 14.

[0332] A mixture of tert-butyl N-[2-(6-chloro-2-methyl-pyrimidin-4-yl)oxyethyl]carbamate (3 g, 10.43 mmol), 5-phenylthiazol-2-amine (2.02 g, 11.47 mmol), Xantphos (1.21 g, 2.09 mmol), Pd(OAc) (234 mg, 1.04 mmol), and KCO (2.16 g, 15.64 mmol) in dioxane (50 mL) was degassed and purged with N three times, and then the mixture was stirred under N at 80 °C for 2 h. The mixture was cooled to ambient temperature, then water (20 mL) was added, and extracted with ethyl acetate (50 mL × 3). The organic layer was concentrated, and the residue was purified by flash column chromatography on silica gel (0% to 40% ethyl acetate in petroleum ether) to give tert-butyl N-[2-[2-methyl-6-[(5-phenylthiazol-2-yl)amino]pyrimidin-4-yl]oxyethyl]carbamate (2.33 g, 48% yield) as a yellow solid.

[0333] A solution of tert-butyl N-[2-[2-methyl-6-[(5-phenylthiazol-2-yl)amino]pyrimidin-4-yl]oxyethyl]carbamate (2.33 g, 5.45 mmol) in HCl / dioxane (4 M, 30 mL) was stirred at 20 °C for 0.5 h. The mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with HO (20 mL), the pH was adjusted to 8-9 by adding aqueous NaHCO 3 , and then filtered. The filter cake was dried to give N-[6-(2-aminoethoxy)-2-methyl-pyrimidin-4-yl]-5-phenyl-thiazol-2-amine (1.5 g, 84% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6):δ=7.80(s,1H),7.62-7.59(m,2H),7.40(t,J=7.6Hz,3H), 6.24(s,1H),4.26-4.20(m,2H),3.30(s,2H),2.88(t,J=5.6Hz,2H),2.52(s,3H).

[0334] A solution of (3S)-4-tert-butoxycarbonylmorpholine-3-carboxylic acid (311 mg, 1.34 mmol), HATU (557 mg, 1.47 mmol), and DIEA (474 ​​mg, 3.67 mmol) in DMF (6 mL) was stirred for 0.5 hours, and then N-[6-(2-aminoethoxy)-2-methyl-pyrimidin-4-yl]-5-phenyl-thiazol-2-amine (400 mg, 1.22 mmol) was added. The mixture was stirred at 25° C. for 2 hours. The mixture was quenched by adding water (10 mL) at 25° C. and then extracted with ethyl acetate (15 mL×3). The organic layer was concentrated and purified by flash column chromatography on silica gel (0% to 3% methanol in dichloromethane) to give tert-butyl (3S)-3-[2-[2-methyl-6-[(5-phenylthiazol-2-yl)amino]pyrimidin-4-yl]oxyethylcarbamoyl]morpholine-4-carboxylate (827 mg, 87% purity) as a yellow solid.

[0335] A solution of tert-butyl (3S)-3-[2-[2-methyl-6-[(5-phenylthiazol-2-yl)amino]pyrimidin-4-yl]oxyethylcarbamoyl]morpholine-4-carboxylate (827 mg, 1.33 mmol) in HCl / dioxane (4 M, 20 mL) was stirred at 25 °C for 1 h. The mixture was concentrated in vacuo. The residue was dissolved in methanol (10 mL) and adjusted to pH = 8 by adding saturated aqueous NaHCO3. The precipitate was filtered and dried to give (3S)-N-[2-[2-methyl-6-[(5-phenylthiazol-2-yl)amino]pyrimidin-4-yl]oxyethyl]morpholine-3-carboxamide (400 mg, 65% yield) as a yellow solid.

[0336] To a solution of (3S)—N-[2-[2-methyl-6-[(5-phenylthiazol-2-yl)amino]pyrimidin-4-yl]oxyethyl]morpholine-3-carboxamide (100 mg, 0.23 mmol) in DCM (2 mL) was added TEA (46 mg, 0.45 mmol) and prop-2-enoyl chloride (21 mg, 0.23 mmol) at 0° C. The mixture was stirred at 25° C. for 0.5 h. The mixture was concentrated under vacuum and purified by preparative HPLC (1_Welch Xtimate 75*40mm*3um; mobile phase: [water (0.225% FA)-ACN]; B%: 35% to 65%, 10 min) to give (3S)-N-[2-[2-methyl-6-[(5-phenylthiazol-2-yl)amino]pyrimidin-4-yl]oxyethyl]-4-prop-2-enoyl-morpholine-3-carboxamide (11.1 mg, 10% yield) as a yellow solid. LCMS: t R =10-80 AB_4 min_220&254_Shimadzu.lcm for 1.674 minutes, MS(ESI)m / z=495.3[M+H] + . 1H NMR (400MHz, DMSO-d6): δ=11.52(s,1H),8.25-8.13(m,1H),7.81(s,1H),7. 60(d,J=7.2Hz,2H),7.41(t,J=7.6Hz,2H),7.31-7.25(m,1H),6.91-6.44(m, 1H),6.61-6.43(m,1H),6.30-6.01(m,2H),5.79-5.58(m,1H),4.84-4.48(m ,1H),4.38-4.10(m,4H),3.85-3.76(m,1H),3.63-3.39(m,5H),2.53(s,3H). Chiral SFC:t R = 5.225 min, Column: (S,S)-Whelk-0-3 50um*4.6mm, ID, 1.8um, Mobile phase: A:CO2, B:Ethanol (0.05% DEA), Gradient: 5% to 40% B for 4 min, hold 40% for 2.5 min, then 5% B for 1 min, Flow rate: 2.5mL / min, Column temperature: 35°C, ABPR: 1500psi. Acq Method: Whelk0_3_EtOH_DEA_5_40_25ML.ee% = 96.46%.

[0337] Example 15 (2S)-4-Methyl-N-[2-[2-methyl-6-[(5-phenylthiazol-2-yl)amino]pyrimidin-4-yl]oxyethyl]-1-prop-2-enoyl-piperazine-2-carboxamide (Compound 15) TIFF0007628108000241.tif140149 Scheme 18. Synthesis of compound 15.

[0338] TIFF0007628108000242.tif56142To a solution of (2S)-1-tert-butoxycarbonyl-4-(9H-fluoren-9-yl)methoxycarbonyl)piperazine-2-carboxylic acid (580 mg, 1.28 mmol) in DMF (6 mL), HATU (557 mg, 1.47 mmol) and DIEA (316 mg, 2.44 mmol) were added. After 0.5 h, N-[6-(2-aminoethoxy)-2-methyl-pyrimidin-4-yl]-5-phenyl-thiazol-2-amine (400 mg, 1.22 mmol) was added. The mixture was stirred at 25 °C for 2 h. The mixture was concentrated in vacuo to give a residue that was purified by flash column chromatography on silica gel (0% to 63% ethyl acetate in petroleum ether) to give O1-tert-butyl O4-(9H-fluoren-9-yl)methyl)(2S)-2-[2-[2-methyl-6-[(5-phenylthiazol-2-yl)amino]pyrimidin-4-yl]oxyethylcarbamoyl]piperazine-1,4-dicarboxylate (740 mg, 76% yield) as a yellow solid.

[0339] To a solution of O1-tert-butyl O4-(9H-fluoren-9-yl)methyl)(2S)-2-[2-[2-methyl-6-[(5-phenylthiazol-2-yl)amino]pyrimidin-4-yl]oxyethylcarbamoyl]piperazine-1,4-dicarboxylate (740 mg, 0.97 mmol) in MeCN (10 mL) was added piperazine (2.18 g, 25.25 mmol). The mixture was stirred at 25° C. for 0.5 h. The mixture was concentrated in vacuo to give a residue that was purified by flash column chromatography on silica gel (0% to 3% methanol in dichloromethane with the addition of 0.1% ammonia (v / v)) to give tert-butyl (2S)-2-[2-[2-methyl-6-[(5-phenylthiazol-2-yl)amino]pyrimidin-4-yl]oxyethylcarbamoyl]piperazine-1-carboxylate (440 mg, 82% yield) as a yellow solid.

[0340] To a solution of tert-butyl (2S)-2-[2-[2-methyl-6-[(5-phenylthiazol-2-yl)amino]pyrimidin-4-yl]oxyethylcarbamoyl]piperazine-1-carboxylate (420 mg, 0.78 mmol) in MeOH (10 mL) was added HCHO (35 mg, 1.17 mmol), NaBHCN (73 mg, 1.17 mmol), and AcOH (117 mg, 1.95 mmol). The mixture was stirred at 25 °C for 2 h. The mixture was filtered, and the filtrate was concentrated in vacuo to give tert-butyl (2S)-4-methyl-2-[2-[2-methyl-6-[(5-phenylthiazol-2-yl)amino]pyrimidin-4-yl]oxyethylcarbamoyl]piperazine-1-carboxylate (640 mg, crude) as a brown gum.

[0341] A solution of tert-butyl (2S)-4-methyl-2-[2-[2-methyl-6-[(5-phenylthiazol-2-yl)amino]pyrimidin-4-yl]oxyethylcarbamoyl]piperazine-1-carboxylate (640 mg, 1.16 mmol) in HCl / dioxane (4 M, 20 mL) was stirred for 1 h at 25° C. Water (20 mL) was added to the mixture, and the pH was adjusted to 8 with NaHCO3, followed by extraction with ethyl acetate (30 mL × 3). The organic layer was concentrated to give (2S)-4-methyl-N-[2-[2-methyl-6-[(5-phenylthiazol-2-yl)amino]pyrimidin-4-yl]oxyethyl]piperazine-2-carboxamide (305 mg, 58% yield) as a yellow solid.

[0342] TIFF0007628108000246.tif55137To a solution of (2S)-4-methyl-N-[2-[2-methyl-6-[(5-phenylthiazol-2-yl)amino]pyrimidin-4-yl]oxyethyl]piperazine-2-carboxamide (100 mg, 0.22 mmol) in DCM (2 mL) was added DIEA (57 mg, 0.44 mmol) and prop-2-enoyl chloride (20 mg, 0.22 mmol) at 0°C. The mixture was stirred at 0°C for 0.2 hours. The mixture was filtered, and then the filtrate was concentrated in vacuo to give a residue. It was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30 mm*3 um; mobile phase: [water (0.04% NH 3. Purification by HPLC with HCl (H2O + 10 mM NH4HCO3)-ACN; B%: 27% to 53%, 9 min) gave (2S)-4-methyl-N-[2-[2-methyl-6-[(5-phenylthiazol-2-yl)amino]pyrimidin-4-yl]oxyethyl]-1-prop-2-enoyl-piperazine-2-carboxamide (14.1 mg, 12% yield) as a white solid. LCMS: t R =10-80CD_4min_Pos_220&254_Shimadzu.1cm 1.991 min, MS(ESI) m / z=508.3[MH] + . 1 H NMR (400MHz, CDCl3): δ=11.02(s,1H),7.75-7.50(m,3H),7.41(t,J=7.2Hz,2H),7.35-7. 32(m,1H),6.78-6.45(m,1H),6.31(d,J=3.6Hz,1H),6.05(s,1H),5.71(d,J=10.8Hz,1H), 5.23(s,1H),4.63-4.32(m,3H),3.81-3.61(m,2H),3.53-3.38(m,1H),3.35-2.92(m,1H), 2.75(d,J=10.8Hz,1H),2.59(d,J=3.6Hz,3H),2.25(d,J=14.4Hz,3H),2.12-2.01(m,3H). Chiral SFC:t R= 4.859 min, Column: (S,S)-Whelk-0-3 50um*4.6mm, ID, 1.8um, Mobile Phase: A:CO2, B:Ethanol (0.05% DEA), Gradient: 5% to 40% B for 4 min, hold at 40% for 2.5 min, then 5% B for 1 min, Flow Rate: 2.8 mL / min, Column Temperature: 35°C, ABPR: 1500 psi. Acq Method: Whelk0_3_EtOH_DEA_5_40_28ML. ee% = 98.86%. [α] D 20 =-44.0 (c=0.05, MeOH).

[0343] Example 16 N-Methyl-N-[(1S)-1-methyl-2-[2-[2-methyl-6-[(5-phenylthiazol-2-yl)amino]pyrimidin-4-yl]oxyethylamino]-2-oxoethyl]but-2-enamide (Compound 16) TIFF0007628108000247.tif110143 Scheme 19. Synthesis of compound 16.

[0344] A solution of (2S)-2-[tert-butoxycarbonyl(methyl)amino]propanoic acid (273 mg, 1.34 mmol), HATU (557 mg, 1.47 mmol), and DIEA (474 ​​mg, 3.67 mmol) in DMF (6 mL) was stirred for 0.5 hours, and then N-[6-(2-aminoethoxy)-2-methyl-pyrimidin-4-yl]-5-phenyl-thiazol-2-amine (400 mg, 1.22 mmol) was added. The mixture was stirred at 25° C. for 2 hours. The mixture was quenched by adding water (10 mL) at 25° C. and then extracted with ethyl acetate (15 mL×3). The organic layer was concentrated and purified by flash column chromatography on silica gel (0% to 3% methanol in dichloromethane) to give tert-butyl N-methyl-N-[(1S)-1-methyl-2-[2-[2-methyl-6-[(5-phenylthiazol-2-yl)amino]pyrimidin-4-yl]oxyethylamino]-2-oxoethyl]carbamate (920 mg, 79% purity) as a yellow solid.

[0345] A solution of tert-butyl N-methyl-N-[(1S)-1-methyl-2-[2-[2-methyl-6-[(5-phenylthiazol-2-yl)amino]pyrimidin-4-yl]oxyethylamino]-2-oxo-ethyl]carbamate (920 mg, 1.42 mmol) in TIFF0007628108000249.tif42128HCl / dioxane (4 M, 20 mL) was stirred for 1 hour at 25° C. The mixture was concentrated in vacuo to give a residue, which was then dissolved in methanol (10 mL) and adjusted to pH=8 by adding saturated aqueous NaHCO3. The precipitate was filtered and dried to give (2S)-2-(methylamino)-N-[2-[2-methyl-6-[(5-phenylthiazol-2-yl)amino]pyrimidin-4-yl]oxyethyl]propanamide (425 mg, 57% yield) as a yellow solid.

[0346] To a solution of (2S)-2-(methylamino)-N-[2-[2-methyl-6-[(5-phenylthiazol-2-yl)amino]pyrimidin-4-yl]oxyethyl]propanamide (100 mg, 0.24 mmol) in DCM (2 mL) was added TEA (49 mg, 0.48 mmol) and but-2-enoyl chloride (29 mg, 0.27 mmol) at 0° C. The mixture was stirred at 25° C. for 0.5 h. The mixture was concentrated in vacuo to give a residue, which was purified by preparative HPLC (Welch Ximate 75*40mm*3um; mobile phase: [water (0.225% FA)-ACN]; B%: 40%-70%, 10 min) to give N-methyl-N-[(1S)-1-methyl-2-[2-[2-methyl-6-[(5-phenylthiazol-2-yl)amino]pyrimidin-4-yl]oxyethylamino]-2-oxoethyl]but-2-enamide (16.6 mg, 13% yield) as a yellow solid. LCMS: t R =10-80 AB_4 min_220&254_Shimadzu.lcm for 1.1.832 minutes, MS(ESI)m / z=481.3[M+H] + .1 H NMR(400MHz,DMSO-d6):δ=11.51(s,1H),8.24-7.92(m,1H),7.81(s,1H),7.61(d,J=7.6Hz,2H) ,7.41(t,J=8.0Hz,2H),7.28(t,J=7.2Hz,1H),6.76-6.56(m,1H),6.46-6.34(m,1H),6.20(s,1 H),5.97-5.80(m,1H),5.11-4.95(m,1H),4.39-4.21(m,2H),3.52-3.36(m,2H),3.32-3.29(m, 1H), 3.22-3.08 (m, 1H), 2.90-2.65 (m, 3H), 2.53 (s, 3H), 2.15-1.75 (s, 2H), 1.29-1.14 (m, 3H).

[0347] Example 17 (2S)-2-[methyl(prop-2-enoyl)amino]-N-[2-[[2-methyl-6-[[5-(4-pyridyl)thiazol-2-yl]amino]pyrimidin-4-yl]amino]ethyl]propanamide (Compound 17) TIFF0007628108000251.tif136141 Scheme 20. Synthesis of compound 17.

[0348] To a solution of N-(6-chloro-2-methyl-pyrimidin-4-yl)-5-(4-pyridyl)thiazol-2-amine (4.5 g, 14.81 mmol) in DMSO (5 mL) was added DIPEA (1.91 g, 14.81 mmol) and tert-butyl N-(2-aminoethyl)carbamate (4.75 g, 29.63 mmol). The mixture was stirred at 80 °C for 12 h. The mixture was quenched by adding HO (50 mL) at 25 °C, then diluted with HO (50 mL) and extracted with EtOAc (50 × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, elution with a 0-70% ethyl acetate / petroleum ether gradient (60 mL / min)) to afford tert-butyl N-[2-[[2-methyl-6-[[5-(4-pyridyl)thiazol-2-yl]amino]pyrimidin-4-yl]amino]ethyl]carbamate (4 g, 9.36 mmol, 63% yield) as a yellow solid.

[0349] A solution of tert-butyl N-[2-[[2-methyl-6-[[5-(4-pyridyl)thiazol-2-yl]amino]pyrimidin-4-yl]amino]ethyl]carbamate (4 g, 9.36 mmol) in HCl / dioxane (4 M, 20 mL) was stirred for 0.5 h at 25° C. The mixture was concentrated under reduced pressure to give N-(2-aminoethyl)-2-methyl-N-[5-(4-pyridyl)thiazol-2-yl]pyrimidine-4,6-diamine (3 g, 9.16 mmol, 98% yield) as a brown solid, which was used directly in the next step.

[0350] To a solution of N6-(2-aminoethyl)-2-methyl-N4-[5-(4-pyridyl)thiazol-2-yl]pyrimidine-4,6-diamine (2 g, 6.11 mmol) in DMF (50 mL) was added DIPEA (2.37 g, 18.33 mmol), HATU (2.79 g, 7.33 mmol), and (2S)-2-[tert-butoxycarbonyl(methyl)amino]propanoic acid (1.37 g, 6.72 mmol). The mixture was stirred at 25 °C for 2 h. The mixture was quenched by the addition of HO (50 mL) at 25 °C, then diluted with HO (50 mL), and extracted with EtOAc (50 × 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, elution with a 0–70% ethyl acetate / petroleum ether gradient (80 mL / min)) to afford tert-butyl N-methyl-N-[(1S)-1-methyl-2-[2-[[2-methyl-6-[[5-(4-pyridyl)thiazol-2-yl]amino]pyrimidin-4-yl]amino]ethylamino]-2-oxo-ethyl]carbamate (3 g, 5.85 mmol, 95% yield) as a brown solid.

[0351] A solution of tert-butyl N-methyl-N-[(1S)-1-methyl-2-[2-[[2-methyl-6-[[5-(4-pyridyl)thiazol-2-yl]amino]pyrimidin-4-yl]amino]ethylamino]-2-oxo-ethyl]carbamate (4 g, 7.80 mmol) in HCl / dioxane (4 M, 50 mL) was stirred for 0.5 h at 25° C. The mixture was concentrated under reduced pressure to give (2S)-2-(methylamino)-N-[2-[[2-methyl-6-[[5-(4-pyridyl)thiazol-2-yl]amino]pyrimidin-4-yl]amino]ethyl]propanamide (2.4 g, 5.82 mmol, 74% yield) as a pale yellow solid, which was used directly in the next step.

[0352] To a solution of (2S)-2-(methylamino)-N-[2-[[2-methyl-6-[[5-(4-pyridyl)thiazol-2-yl]amino]pyrimidin-4-yl]amino]ethyl]propanamide (200 mg, 0.48 mmol) in DCM (10 mL) was added DIPEA (188 mg, 1.45 mmol) and prop-2-enoyl chloride (44 mg, 0.48 mmol). The mixture was stirred at 0 °C for 0.5 h. The mixture was quenched by adding HO (50 mL) at 25 °C, then diluted with HO (50 mL) and extracted with EtOAc (50 × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated. The residue was purified by preparative HPLC (water (0.04% NH3.H2O + 10 mM NH4HCO3)-ACN) to give (2S)-2-[methyl(prop-2-enoyl)amino]-N-[2-[[2-methyl-6-[[5-(4-pyridyl)thiazol-2-yl]amino]pyrimidin-4-yl]amino]ethyl]propanamide (1.8 mg, 0.0037 mmol, 0.8% yield, 96.0% purity) as a pale yellow solid. LCMS: t R =10-80AB_4min_220&254_Shimadzu.lcm for 1.806 minutes, MS(ESI)m / z=467.2[M+H] + . 1 H NMR(400MHz,MeOD)δ=8.50-8.43(m,2H),7.93(s,1H),7.64-7.54(m,2H),6.77-6.59(m,1H),6.30-6.13(m,1H),5.89 (s,1H),5.80-5.66(m,1H),5.00-4.98(m,1H),3.45-3.36(m,4H),3.05-2.86(m,3H),2.47(s,3H),1.43-1.35(m,3H). Chiral SFC:t R= 3.727 min (instrument column: Chiralpak AS-3 100 x 4.6 mm, i.d., 3 um; mobile phase: A: CO2, B: ethanol (0.05% DEA) gradient: 5% to 40% B for 4.5 min, hold at 40% for 2.5 min, then 5% B for 1 min; flow rate: 2.8 mL / min; column temperature: 40 °C; detection: 220 nm), ee% = 98.14%. [α] D 20 = -25.0 (c = 0.1, MeOH).

[0353] Example 18 N-Methyl-N-[(1S)-1-methyl-2-[2-[[2-methyl-6-[[5-(4-pyridyl)thiazol-2-yl]amino]pyrimidin-4-yl]amino]ethylamino]-2-oxo-ethyl]but-2-ynamide (Compound 18) TIFF0007628108000257.tif87144 Scheme 21. Synthesis of compound 18.

[0354] The synthesis of (2S)-2-(methylamino)-N-[2-[[2-methyl-6-[[5-(4-pyridyl)thiazol-2-yl]amino]pyrimidin-4-yl]amino]ethyl]propanamide (17-6) is shown in Example 17. To a solution of (2S)-2-(methylamino)-N-[2-[[2-methyl-6-[[5-(4-pyridyl)thiazol-2-yl]amino]pyrimidin-4-yl]amino]ethyl]propanamide (17-6, 300 mg, 0.73 mmol) in DMF (15 mL) was added HATU (332 mg, 0.87 mmol), DIPEA (282 mg, 2.18 mmol), and but-2-ynoic acid (73 mg, 0.87 mmol). The mixture was stirred at 25 °C for 2 h. The mixture was quenched by the addition of HO (50 mL) at 25 °C, then diluted with HO (50 mL) and extracted with EtOAc (50 × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated. The residue was purified by preparative HPLC (water (0.04% NH.HO + 10 mM NHHCO)-ACN) to give N-methyl-N-[(1S)-1-methyl-2-[2-[[2-methyl-6-[[5-(4-pyridyl)thiazol-2-yl]amino]pyrimidin-4-yl]amino]ethylamino]-2-oxo-ethyl]but-2-ynamide (42.1 mg, 0.088 mmol, 12% yield, 99.5% purity) as a pale yellow solid. LCMS: t R =10-80AB_4min_220&254_Shimadzu.lcm for 1.468 minutes, MS(ESI)m / z=479.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ=11.32(s,1H),8.55-8.47(m,2H),8.10-7.92(m,2H),7.59-7.52(m,2H),7.13(s,1H),5.87(s,1H),4.94-4 .80(m,1H),3.29-3.23(m,4H),2.75-2.74(m,1H),3.04-2.71(m,2H),2.44-2.31(m,3H),2.01(d,J=14.8Hz,3H),1.36-1.21(m,3H). Chiral SFC:t R= 4.717 min (Instrument column: Chiralcel OD-3 100 4.6 mm, i.d., 3 μm, Mobile phase: A: CO2, B: Ethanol (0.05% DEA) Gradient: 5% to 40% B for 4 min, hold at 40% for 2.5 min, then 5% B for 1.5 min, Flow rate: 2.8 mL / min, Column temperature: 40 °C, Detection: 220 nm), ee% = 99.74%.

[0355] Example 19 (2S)-N-[2-[methyl-[2-methyl-6-[[5-(4-pyridyl)thiazol-2-yl]amino]pyrimidin-4-yl]amino]ethyl]-2-[methyl(prop-2-enoyl)amino]propanamide (Compound 19) TIFF0007628108000258.tif138140 Scheme 22. Synthesis of compound 19.

[0356] TIFF0007628108000259.tif39139To a solution of N-(6-chloro-2-methyl-pyrimidin-4-yl)-5-(4-pyridyl)thiazol-2-amine (300 mg, 0.99 mmol) in DMSO (10 mL), DIEA (766 mg, 5.93 mmol) and tert-butyl N-[2-(methylamino)ethyl]carbamate (860 mg, 4.94 mmol) were added. The mixture was stirred at 80° C. for 2 hours. Water (20 mL) was added to the mixture, which was then extracted with ethyl acetate (20 mL×3). The organic phase was separated, concentrated, and purified by flash column chromatography on silica gel (0% to 5% methanol in dichloromethane) to give tert-butyl N-[2-[methyl-[2-methyl-6-[[5-(4-pyridyl)thiazol-2-yl]amino]pyrimidin-4-yl]amino]ethyl]carbamate (420 mg, 68% yield) as a yellow solid.

[0357] To a solution of tert-butyl N-[2-[methyl-[2-methyl-6-[[5-(4-pyridyl)thiazol-2-yl]amino]pyrimidin-4-yl]amino]ethyl]carbamate (420 mg, 0.95 mmol) in DCM (2 mL) was added HCl / dioxane (10 mL, 4 M). The mixture was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure to give N-(2-aminoethyl)-N,2-dimethyl-N-[5-(4-pyridyl)thiazol-2-yl]pyrimidine-4,6-diamine (498 mg, crude) as a yellow solid, which was used directly in the next step without further purification.

[0358] TIFF0007628108000261.tif33138To a solution of (2S)-2-[tert-butoxycarbonyl(methyl)amino]propanoic acid (249 mg, 1.22 mmol) in DMF (7 mL), HATU (532 mg, 1.40 mmol), DIEA (301 mg, 2.33 mmol), and N4-(2-aminoethyl)-N4,2-dimethyl-N6-[5-(4-pyridyl)thiazol-2-yl]pyrimidine-4,6-diamine (398 mg, 1.17 mmol) were added. The mixture was stirred at 50°C for 1 hour. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0% to 7% methanol in dichloromethane) to give the product tert-butyl N-methyl-N-[(1S)-1-methyl-2-[2-[methyl-[2-methyl-6-[[5-(4-pyridyl)thiazol-2-yl]amino]pyrimidin-4-yl]amino]ethylamino]-2-oxo-ethyl]carbamate (175 mg, 24% yield) as a yellow oil.

[0359] To a solution of tert-butyl N-methyl-N-[(1S)-1-methyl-2-[2-[methyl-[2-methyl-6-[[5-(4-pyridyl)thiazol-2-yl]amino]pyrimidin-4-yl]amino]ethylamino]-2-oxo-ethyl]carbamate (175 mg, 0.33 mmol) in DCM (2 mL) was added 4 M HCl / dioxane (10 mL). The mixture was stirred at 25° C. for 1 h. The mixture was concentrated to give (2S)-2-(methylamino)-N-[2-[methyl-[2-methyl-6-[[5-(4-pyridyl)thiazol-2-yl]amino]pyrimidin-4-yl]amino]ethyl]propanamide (211 mg, crude) as a yellow solid, which was used directly in the next step without further purification.

[0360] To a solution of (2S)-2-(methylamino)-N-[2-[methyl-[2-methyl-6-[[5-(4-pyridyl)thiazol-2-yl]amino]pyrimidin-4-yl]amino]ethyl]propanamide (171 mg, 0.40 mmol) in 3H2O (5 mL) and THF (5 mL) was added Na2CO3 (127 mg, 1.20 mmol), followed by prop-2-enoyl chloride (36 mg, 0.40 mmol) at 0 °C. The mixture was stirred at 25 °C for 0.5 h. The mixture was extracted with ethyl acetate (30 mL × 3). The organic layer was concentrated, and the residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30mm*3um; mobile phase: water (0.04% NH3.H2O + 10mM NH4HCO3)-ACN; B%: 15-55%, 14 min; flow rate: 25mL / min) to give (2S)-N-[2-[methyl-[2-methyl-6-[[5-(4-pyridyl)thiazol-2-yl]amino]pyrimidin-4-yl]amino]ethyl]-2-[methyl(prop-2-enoyl)amino]propanamide (3.3mg, 2% yield) as a yellow solid. LCMS: t R=10-80 AB_4 min_220&254_Shimadzu.lcm for 0.718 minutes, MS(ESI)m / z=481.3[M+H] + . 1 H NMR (400MHz, CDCl3): δ=8.58(d,J=4.0Hz,2H),7.78(s,1H),7.42(d,J=4.0Hz,2H),7.01(s,1H),6.54-6.30(m,2H),5.82-5.72( m,2H),5.14-5.09(m,1H),3.87-3.70(m,2H),3.56-3.42(m,2H),3.02(s,3H),2.95(s,3H),2.52(s,3H),1.33(d,J=8.0Hz,3H). Chiral SFC:t R = 4.239 min, Column: Chiralpak ND-3 100um*4.6mm, I.D., 3um, Mobile phase: 40% isopropanol (0.05% DEA) in CO2, Flow rate: 2.8mL / min, Column temperature: 35°C, ABPR: 1500psi. Acq Method: ND_3_IPA_DEA_40_28ML. ee% = 96.54%. [α] D 20 =-13.3 (c=0.03, MeOH).

[0361] Example 20 (2S)-2-[methyl(prop-2-enoyl)amino]-N-[(3S)-1-[2-methyl-6-[[5-(4-pyridyl)thiazol-2-yl]amino]pyrimidin-4-yl]pyrrolidin-3-yl]propanamide (Compound 20) TIFF0007628108000264.tif123143 Scheme 23. Synthesis of compound 20.

[0362] TIFF0007628108000265.tif36136 A mixture of N-(6-chloro-2-methyl-pyrimidin-4-yl)-5-(4-pyridyl)thiazol-2-amine (1.26 g, 4.15 mmol), tert-butyl N-[(3S)-pyrrolidin-3-yl]carbamate (927 mg, 4.98 mmol), DIEA (643 mg, 4.98 mmol) in DMSO (50 mL) was stirred at 80 °C for 2 hours. Water (30 mL) was added to the mixture, which was then extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium nitrate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (0% to 100% ethyl acetate in petroleum ether) to give tert-butyl N-[(3S)-1-[2-methyl-6-[[5-(4-pyridyl)thiazol-2-yl]amino]pyrimidin-4-yl]pyrrolidin-3-yl]carbamate (1.61 g, 68% yield) as a yellow solid.

[0363] To a solution of tert-butyl N-[(3S)-1-[2-methyl-6-[[5-(4-pyridyl)thiazol-2-yl]amino]pyrimidin-4-yl]pyrrolidin-3-yl]carbamate (1.51 g, 3.33 mmol) in DCM (15 mL) was added 4 M HCl / dioxane (50 mL). The mixture was stirred at 25 °C for 1 hour. The mixture was concentrated under reduced pressure to give N-[6-[(3S)-3-aminopyrrolidin-1-yl]-2-methyl-pyrimidin-4-yl]-5-(4-pyridyl)thiazol-2-amine (1.91 g, crude) as a yellow solid.

[0364] To a solution of (2S)-2-[tert-butoxycarbonyl(methyl)amino]propanoic acid (604 mg, 2.97 mmol) in DMF (20 mL) was added HATU (1.29 g, 3.40 mmol), DIEA (731 mg, 5.66 mmol), and N-[6-[(3S)-3-aminopyrrolidin-1-yl]-2-methyl-pyrimidin-4-yl]-5-(4-pyridyl)thiazol-2-amine (1 g, 2.83 mmol). The mixture was stirred at 25° C. for 1 h. The mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (0% to 10% methanol in dichloromethane) to give tert-butyl N-methyl-N-[(1S)-1-methyl-2-[[(3S)-1-[2-methyl-6-[[5-(4-pyridyl)thiazol-2-yl]amino]pyrimidin-4-yl]pyrrolidin-3-yl]amino]-2-oxo-ethyl]carbamate (1.14 g, 60% yield) as a yellow solid.

[0365] To a solution of tert-butyl N-methyl-N-[(1S)-1-methyl-2-[[(3S)-1-[2-methyl-6-[[5-(4-pyridyl)thiazol-2-yl]amino]pyrimidin-4-yl]pyrrolidin-3-yl]amino]-2-oxo-ethyl]carbamate (1.14 g, 2.11 mmol) in DCM (3 mL) was added HCl / dioxane (4 M, 30 mL). The mixture was stirred at 25° C. for 1 h. The mixture was concentrated under reduced pressure to give (2S)-2-(methylamino)-N-[(3S)-1-[2-methyl-6-[[5-(4-pyridyl)thiazol-2-yl]amino]pyrimidin-4-yl]pyrrolidin-3-yl]propanamide (1.51 g, crude) as a yellow solid.

[0366] To a solution of (2S)-2-(methylamino)-N-[(3S)-1-[2-methyl-6-[[5-(4-pyridyl)thiazol-2-yl]amino]pyrimidin-4-yl]pyrrolidin-3-yl]propanamide (150 mg, 0.34 mmol) in THF (2 mL) and HO (2 mL) was added NaCO (109 mg, 1.03 mmol). Then, prop-2-enoyl chloride (31 mg, 0.34 mmol) was added at 0 °C. The mixture was stirred at 25 °C for 0.5 h. The mixture was extracted with ethyl acetate (30 mL × 3). The organic layer was concentrated, and the residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30mm*3um; mobile phase: water (0.05% NH3.H2O + 10mM NH4HCO3)-ACN; B%: 35-55%, 10 min; flow rate: 25 mL / min) to give (2S)-2-[methyl(prop-2-enoyl)amino]-N-[(3S)-1-[2-methyl-6-[[5-(4-pyridyl)thiazol-2-yl]amino]pyrimidin-4-yl]pyrrolidin-3-yl]propanamide (5.3 mg, 3% yield) as a yellow solid. LCMS: t R =10-80 AB_4min_220&254_Shimadzu.lcm for 0.701 min, MS(ESI)m / z=493.3[M+H] + . 1 H NMR (400MHz, CDCl3): δ=8.57(d,J=4.0Hz,2H),7.76(s,1H),7.43(d,J=8.0Hz,2H),6.65-6.58(m,1H),6.40-6.36(m,1H),5.78-5.76(m,1) H),5.59(s,1H),5.19-5.13(m,1H),4.45(s,1H),3.64-3.48(m,4H),3.09(s,3H),2.46(s,3H),2.25-2.04(m,2H),1.41(d,J=4.0Hz,3H). Chiral SFC:t R= 5.238 min, Column: Chiral MD-3 100um*4.6mm, I.D., 3um, Mobile Phase: A:CO2, B:Ethanol (0.05% DEA), Gradient: 5% to 40% B for 4 min, hold at 40% for 2.5 min, then 5% B for 1.5 min, Flow Rate: 2.8 mL / min, Column Temperature: 35°C, ABPR: 1500 psi. Acq Method: MD_3_EtOH_DEA_5_40_28ML_8min. ee% = 98.32%. [α] D 20 =-13.3 (c=0.03, MeOH).

[0367] Example 21 (2S)-N-[(3S)-1-[2-methyl-6-[[5-(4-pyridyl)thiazol-2-yl]amino]pyrimidin-4-yl]pyrrolidin-3-yl]-1-prop-2-enoyl-pyrrolidine-2-carboxamide (Compound 21) TIFF0007628108000270.tif159143 Scheme 24. Synthesis of compound 21.

[0368] The synthesis of N-[6-[(3S)-3-aminopyrrolidin-1-yl]-2-methyl-pyrimidin-4-yl]-5-(4-pyridyl)thiazol-2-amine (25-4) is shown in Example 16. To a solution of (2S)-1-tert-butoxycarbonylpyrrolidine-2-carboxylic acid (958 mg, 4.45 mmol) in DMF (20 mL) was added HATU (1.94 g, 5.09 mmol), DIEA (1.10 g, 8.48 mmol), and N-[6-[(3S)-3-aminopyrrolidin-1-yl]-2-methyl-pyrimidin-4-yl]-5-(4-pyridyl)thiazol-2-amine (1.5 g, 4.24 mmol). The mixture was stirred for 1 hour at 25° C. The mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (0% to 10% methanol in dichloromethane) to give the product, tert-butyl (2S)-2-[[(3S)-1-[2-methyl-6-[[5-(4-pyridyl)thiazol-2-yl]amino]pyrimidin-4-yl]pyrrolidin-3-yl]carbamoyl]pyrrolidine-1-carboxylate (754 mg, 27% yield) as a yellow solid.

[0369] To a solution of tert-butyl (2S)-2-[[(3S)-1-[2-methyl-6-[[5-(4-pyridyl)thiazol-2-yl]amino]pyrimidin-4-yl]pyrrolidin-3-yl]carbamoyl]pyrrolidine-1-carboxylate (754 mg, 1.37 mmol) in DCM (2 mL) was added 4 M HCl / dioxane (15 mL). The mixture was stirred at 25° C. for 1 h. The mixture was concentrated under reduced pressure to give (2S)—N-[(3S)-1-[2-methyl-6-[[5-(4-pyridyl)thiazol-2-yl]amino]pyrimidin-4-yl]pyrrolidin-3-yl]pyrrolidine-2-carboxamide (939 mg, crude) as a yellow solid, which was used directly in the next step without further purification.

[0370] To a solution of (2S)-N-[(3S)-1-[2-methyl-6-[[5-(4-pyridyl)thiazol-2-yl]amino]pyrimidin-4-yl]pyrrolidin-3-yl]pyrrolidine-2-carboxamide (150 mg, 0.33 mmol) in THF (2 mL) and HO (2 mL) was added NaCO (106 mg, 1.00 mmol). Then, prop-2-enoyl chloride (30 mg, 0.33 mmol) was added at 0 °C. The mixture was stirred at 25 °C for 0.5 h. The mixture was extracted with ethyl acetate (30 mL × 3). The organic layer was concentrated, and the residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30mm*3um; mobile phase: water (0.04% NH3.H2O + 10mM NH4HCO3)-ACN; B%: 14-44%, 12 min; flow rate: 25 mL / min) to give (2S)-N-[(3S)-1-[2-methyl-6-[[5-(4-pyridyl)thiazol-2-yl]amino]pyrimidin-4-yl]pyrrolidin-3-yl]-1-prop-2-enoyl-pyrrolidine-2-carboxamide (10.2 mg, 6% yield) as a red solid. LCMS: t R =10-80CD_7min_Pos_220&254_Shimadzu.lcm for 2.319 minutes, MS(ESI)m / z=505.2[M+H] + . 1 H NMR (400MHz, CDCl3): δ=9.99(s,1H),9.26(s,1H),8.59(d,J=4.0Hz,2H),7.56(s,1H),7.45(d,J=4.0Hz,2H) ,6.57-6.42(m,2H),5.74(d,J=12.0Hz,2H),4.79(s,1H),4.37(s,1H),3.95-3.31(m,6H),2.51-1.99(m,9H). Chiral SFC:t R= 5.238 min, Column: Chiralpak OJ-3 100um*4.6mm, I.D., 3um, Mobile Phase: A:CO2, B:Ethanol (0.05% DEA), Gradient: 5% to 40% B for 4 min, hold at 40% for 2.5 min, then 5% B for 1.5 min, Flow Rate: 2.8 mL / min, Column Temperature: 35°C, ABPR: 1500 psi. Acq Method: OJ_3_EtOH_DEA_5_40_28ML_8min. ee% = 100%. [α] D 20 =-36.7 (c=0.03, MeOH).

[0371] Example 22 (2S)-N-[2-[[2-methyl-6-[[5-(4-pyridyl)thiazol-2-yl]amino]pyrimidin-4-yl]amino]ethyl]-1-prop-2-enoyl-pyrrolidine-2-carboxamide (Compound 22) TIFF0007628108000274.tif178154 Scheme 25. Synthesis of compound 22.

[0372] TIFF0007628108000275.tif39141 To a solution of N-(6-chloro-2-methyl-pyrimidin-4-yl)-5-(4-pyridyl)thiazol-2-amine (300 mg, 0.99 mmol) in DMSO (10 mL) was added DIEA (766 mg, 5.93 mmol) and tert-butyl N-(2-aminoethyl)carbamate (791 mg, 4.94 mmol). The mixture was stirred at 80° C. for 4 hours. Water (20 mL) was added to the mixture, which was then extracted with ethyl acetate (20 mL×3). The organic phase was separated, concentrated, and purified by flash column chromatography on silica gel (0% to 5% methanol in dichloromethane) to give the product, tert-butyl N-[2-[[2-methyl-6-[[5-(4-pyridyl)thiazol-2-yl]amino]pyrimidin-4-yl]amino]ethyl]carbamate (485 mg, 85% yield) as a yellow solid.

[0373] To a solution of tert-butyl N-[2-[[2-methyl-6-[[5-(4-pyridyl)thiazol-2-yl]amino]pyrimidin-4-yl]amino]ethyl]carbamate (485 mg, 1.13 mmol) in DCM (2 mL) was added HCl / dioxane (10 mL, 4 M). The mixture was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure to give N-(2-aminoethyl)-2-methyl-N-[5-(4-pyridyl)thiazol-2-yl]pyrimidine-4,6-diamine (471 mg, crude) as a yellow solid, which was used directly in the next step without further purification.

[0374] To a solution of (2S)-1-tert-butoxycarbonylpyrrolidine-2-carboxylic acid (188 mg, 0.87 mmol) in DMF (6 mL) was added HATU (379 mg, 1.00 mmol) and DIEA (215 mg, 1.66 mmol). Then, N4-(2-aminoethyl)-2-methyl-N6-[5-(4-pyridyl)thiazol-2-yl]pyrimidine-4,6-diamine (272 mg, 0.83 mmol) was added. The mixture was stirred at 50 °C for 1 hour. The mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (0% to 8% methanol in dichloromethane with the addition of 0.1% ammonia (v / v)) to give the product tert-butyl (2S)-2-[2-[[2-methyl-6-[[5-(4-pyridyl)thiazol-2-yl]amino]pyrimidin-4-yl]amino]ethylcarbamoyl]pyrrolidine-1-carboxylate (206 mg, 47% yield) as a yellow oil.

[0375] To a solution of tert-butyl (2S)-2-[2-[[2-methyl-6-[[5-(4-pyridyl)thiazol-2-yl]amino]pyrimidin-4-yl]amino]ethylcarbamoyl]pyrrolidine-1-carboxylate (206 mg, 0.39 mmol) in DCM (2 mL) was added 4 M HCl / dioxane (5 mL). The mixture was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure to give (2S)-N-[2-[[2-methyl-6-[[5-(4-pyridyl)thiazol-2-yl]amino]pyrimidin-4-yl]amino]ethyl]pyrrolidine-2-carboxamide (189 mg, crude) as a yellow solid, which was used directly in the next step without further purification.

[0376] To a solution of (2S)-N-[2-[[2-methyl-6-[[5-(4-pyridyl)thiazol-2-yl]amino]pyrimidin-4-yl]amino]ethyl]pyrrolidine-2-carboxamide (189 mg, 0.45 mmol) in THF (5 mL) and HO (5 mL) was added NaCO (142 mg, 1.34 mmol). Then, prop-2-enoyl chloride (40 mg, 0.45 mmol) was added at 0 °C. The mixture was stirred at 25 °C for 0.5 h. The mixture was extracted with ethyl acetate (30 mL × 3). The organic layer was concentrated, and the residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30mm*3um, mobile phase: water (0.04% NH3.H2O + 10mM NH4HCO3)-ACN; B%: 10-50%, 14 min; flow rate: 25mL / min) to give (2S)-N-[2-[[2-methyl-6-[[5-(4-pyridyl)thiazol-2-yl]amino]pyrimidin-4-yl]amino]ethyl]-1-prop-2-enoyl-pyrrolidine-2-carboxamide (16.9mg, 8% yield) as a yellow solid. LCMS: t R =10-80 AB_4 min_220&254_Shimadzu.lcm for 0.636 minutes, MS(ESI)m / z=479.3[M+H] + . 1H NMR(400MHz, CDCl3): δ=10.05(s,1H),8.56-8.54(d,J=8.0Hz,2H),7.78(s,1H ),7.57(s,1H),7.42-7.41(d,J=4.0Hz,2H),6.56-6.42(m,2H),5.99(s,1H),5. 80-5.67(m,1H),5.46(s,1H),4.56-4.54(m,1H),3.77-3.56(m,3H),3.47-3.26 (m,2H),3.27-3.26(m,1H),2.49(s,3H),2.27-2.14(m,2H),2.07-1.97(m,2H). Chiral SFC:t R = 3.100 min, Column: Chiral MJ-3 100um*4.6mm, I.D., 3um, Mobile Phase: A:CO2, B:Ethanol (0.05% DEA), Gradient: 5% to 40% B for 4 min, hold at 40% for 2.5 min, then 5% B for 1.5 min, Flow Rate: 2.8 mL / min, Column Temperature: 35°C, ABPR: 1500 psi. Acq Method: MJ_3_EtOH_DEA_5_40_28ML_8min. ee% = 100%. [α] D 20 =-10.0 (c=0.06, MeOH).

[0377] Example 23 5-[(5-Fluoro-2-oxo-indolin-3-ylidene)methyl]-4-methyl-N-[2-[[(2S)-2-[methyl(prop-2-enoyl)amino]propanoyl]amino]ethyl]-1H-pyrrole-3-carboxamide (Compound 23) TIFF0007628108000280.tif136140 Scheme 26. Synthesis of compound 23.

[0378] TIFF0007628108000281.tif24128POCl3 (16.82 g, 109.68 mmol) was added dropwise to DMF (8.02 g, 109.68 mmol) at 0 °C. The mixture was stirred at 25 °C for 1 hour. A solution of ethyl 4-methyl-1H-pyrrole-3-carboxylate (4 g, 26.11 mmol) in DMF (50 mL) was added thereto at 0 °C. The mixture was then warmed to 25 °C and stirred for 1 hour. The mixture was poured onto ice (20 g). The pH of the mixture was adjusted to 7-8 by adding 2 M NaOH, and a white solid was formed. The mixture is filtered, and the filter cake is washed with water (2 mL × 2) and concentrated under reduced pressure to give ethyl 5-formyl-4-methyl-1H-pyrrole-3-carboxylate (4.2 g, 23.18 mmol, 89% yield) as a white solid, which is used directly in the next step. 1 H NMR (400MHz, DMSO-d6): δ=12.42(s,1H),9.76(s,1H),7.67(d,J=3.6Hz,1H),4.25(q,J=7.2Hz,2H),2.56(s,3H),1.32(t,J=7.2Hz,3H).

[0379] To a solution of ethyl 5-formyl-4-methyl-1H-pyrrole-3-carboxylate (4.2 g, 23.18 mmol) in EtOH (40 mL) and HO (20 mL), NaOH (13.91 g, 347.7 mmol) was added. The mixture was stirred at 100 °C for 12 h. The pH of the mixture was adjusted to 5-6 with 2 M HCl. The resulting mixture was filtered, and the filter cake was washed with water (2 mL × 2) and concentrated under reduced pressure to give 5-formyl-4-methyl-1H-pyrrole-3-carboxylic acid (3.2 g, 20.90 mmol, 90% yield) as a brown solid, which was used directly in the next step. 1 H NMR (400MHz, DMSO-d6): δ = 12.40 (s, 1H), 12.15 (brs, 1H), 9.70 (s, 1H), 7.58 (d, J = 3.6Hz, 1H), 2.50 (s, 3H).

[0380] To a solution of 5-formyl-4-methyl-1H-pyrrole-3-carboxylic acid (0.5 g, 3.27 mmol) in EtOH (10 mL) was added tetrahydropyrrole (23 mg, 0.326 mmol) and 5-fluoroindolin-2-one (493 mg, 3.27 mmol). The mixture was stirred at 80 °C for 3 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give 5-[(5-fluoro-2-oxo-indolin-3-ylidene)methyl]-4-methyl-1H-pyrrole-3-carboxylic acid (800 mg, 2.79 mmol, 85% yield) as a yellow solid, which was used directly in the next step. 1 H NMR (400 MHz, DMSO-d): δ = 13.78 (s, 1H), 11.01 (s, 1H), 7.87-7.77 (m, 3H), 7.02-6.92 (m, 1H), 6.86 (dd, J = 8.4 and 4.4 Hz, 1H), 2.56-2.53 (m, 3H).

[0381] To a solution of 5-[(5-fluoro-2-oxo-indolin-3-ylidene)methyl]-4-methyl-1H-pyrrole-3-carboxylic acid (800 mg, 2.79 mmol) in DMF (20 mL) was added HATU (1.28 g, 3.35 mmol), TEA (848 mg, 8.38 mmol), and tert-butyl N-(2-aminoethyl)carbamate (493 mg, 3.07 mmol). The mixture was stirred at 25 °C for 2 h. The mixture is quenched by adding HO (20 mL) at 25 °C, and the mixture is extracted with EtOAc (30 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure to give tert-butyl N-[2-[[5-[(5-fluoro-2-oxo-indolin-3-ylidene)methyl]-4-methyl-1H-pyrrole-3-carbonyl]amino]ethyl]carbamate (1 g, 2.33 mmol, 83% yield) as a yellow solid, which is used directly in the next step.

[0382] To a solution of tert-butyl N-[2-[[5-[(5-fluoro-2-oxo-indolin-3-ylidene)methyl]-4-methyl-1H-pyrrole-3-carbonyl]amino]ethyl]carbamate (1 g, 2.33 mmol) in HCl / dioxane (4 M, 20 mL). The mixture was stirred at 25 °C for 0.5 h. The mixture was concentrated under reduced pressure to give N-(2-aminoethyl)-5-[(5-fluoro-2-oxo-indolin-3-ylidene)methyl]-4-methyl-1H-pyrrole-3-carboxamide (700 mg, 2.13 mmol, 91% yield) as a yellow solid, which was used directly in the next step.

[0383] To a solution of N-(2-aminoethyl)-5-[(5-fluoro-2-oxo-indolin-3-ylidene)methyl]-4-methyl-1H-pyrrole-3-carboxamide (700 mg, 2.13 mmol) in DMF (10 mL) was added HATU (973 mg, 2.56 mmol), TEA (827 mg, 8.17 mmol), and (2S)-2-[tert-butoxycarbonyl(methyl)amino]propanoic acid (520 mg, 2.56 mmol). The mixture was stirred at 25° C. for 2 h. The mixture is concentrated under reduced pressure, and the residue is purified by flash column (PE: EtOAc = 1:0 to 1:1) to give tert-butyl N-[(1S)-2-[2-[[5-[(5-fluoro-2-oxo-indolin-3-ylidene)methyl]-4-methyl-1H-pyrrole-3-carbonyl]amino]ethylamino]-1-methyl-2-oxo-ethyl]-N-methyl-carbamate (0.8 g, 1.56 mmol, 73% yield) as a yellow solid, which is used directly in the next step. 1H NMR(400MHz,DMSO-d6):δ=13.69(s,1H),10.96(s,1H),8.03-7.85(m,2H),7.84-7.73(m,3H),7.04-6.91(m,1H),6.86(dd, J = 8.0 and 4.4Hz, 1H), 4.65-4.16 (m, 1H), 3.29-3.21 (m, 4H), 2.74 (s, 3H), 2.54 (s, 3H), 1.38 (s, 9H), 1.24 (d, J = 5.6Hz, 3H).

[0384] To a solution of tert-butyl N-[(1S)-2-[2-[[5-[(5-fluoro-2-oxo-indolin-3-ylidene)methyl]-4-methyl-1H-pyrrole-3-carbonyl]amino]ethylamino]-1-methyl-2-oxo-ethyl]-N-methyl-carbamate (0.8 g, 1.56 mmol) in HCl / dioxane (4 M, 20 mL). The mixture was stirred at 25 °C for 0.5 h. The mixture is concentrated under reduced pressure to give 5-[5-fluoro-2-oxo-indolin-3-ylidene)methyl]-4-methyl-N-[2-[[(2S)-2-(methylamino)propanoyl]amino]ethyl]-1H-pyrrole-3-carboxamide (0.6 g, 1.45 mmol, 93% yield) as a yellow solid, which is used directly in the next step.

[0385] To a solution of 5-[(5-fluoro-2-oxo-indolin-3-ylidene)methyl]-4-methyl-N-[2-[[(2S)-2-(methylamino)propanoyl]amino]ethyl]-1H-pyrrole-3-carboxamide (300 mg, 0.726 mmol) in DCM (10 mL) was added DIEA (188 mg, 1.45 mmol) and prop-2-enoyl chloride (66 mg, 0.726 mmol). The mixture was stirred at 0 °C for 1 h. The mixture was quenched by the addition of HO (50 mL) at 25 °C, then diluted with HO (50 mL) and extracted with DCM (50 × 3). The combined organic layers were washed with brine (50 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give a residue. The residue was then purified by preparative HPLC (water (0.04% NH3.H2O + 10 mM NH4HCO3)-ACN) to give the product (130 mg, 85% purity) as a white solid, which was further separated by SFC (column: DAICEL CHIRALPAK AD (250 mm * 50 mm, 10 um); mobile phase: [0.1% NH3.H2O ETOH]; B%: 35% - 35%, min) to give 5-[(5-fluoro-2-oxo-indolin-3-ylidene)methyl]-4-methyl-N-[2-[[(2S)-2-[methyl(prop-2-enoyl)amino]propanoyl]amino]ethyl]-1H-pyrrole-3-carboxamide (11.8 mg, 0.025 mmol, 3% yield, 97.5% purity) as a yellow solid. LCMS: t R =10-80AB_4min_220&254_Shimadzu.lcm for 2.515 minutes, MS(ESI)m / z=468.5[M+H] + . 1H NMR (400 MHz, DMSO-d6): δ = 13.68 (s, 1H), 10.96 (s, 1H), 8.14-7.86 (m, 2H), 7.82-7.76 (m, 2H), 7.01-6.93 (m, 1H), 6.86 (dd, J = 8.4 and 4.4 Hz, 1H), 6.79-6.68 (m, 1H), 6.18-6.02 (m, 1H), 5.74-5.59 (m, 1H), 5.04-4.56 (m, 1H), 3.25-3.20 (m, 4H), 2.94-2.75 (m, 3H), 2.53 (s, 3H), 1.33-1.22 (m, 3H). Chiral SFC: t R = 3.198 min (instrument column: Chiralcel OJ-3 100 x 4.6 mm, i.d., 3 μm, mobile phase: A: CO2, B: ethanol (0.05% DEA), gradient: 5% to 40% B for 4.5 min, hold at 40% for 2.5 min, then 5% B for 1 min, flow rate: 2.8 mL / min, column temperature: 40 °C, detection: 220 nm), ee% = 97.22%. [α] D 20 =-10.0 (c=0.1, MeOH).

[0386] Example 24 5-[(5-Fluoro-2-oxo-indolin-3-ylidene)methyl]-4-methyl-N-[2-[[(2S)-2-[methyl(propanoyl)amino]propanoyl]amino]ethyl]-1H-pyrrole-3-carboxamide (Compound 24) TIFF0007628108000289.tif105132 Scheme 27. Synthesis of compound 24.

[0387] The synthesis of 5-[(5-fluoro-2-oxo-indolin-3-ylidene)methyl]-4-methyl-N-[2-[[(2S)-2-(methylamino)propanoyl]amino]ethyl]-1H-pyrrole-3-carboxamide (23-11) is shown in Example 23. To a solution of 5-[(5-fluoro-2-oxo-indolin-3-ylidene)methyl]-4-methyl-N-[2-[[(2S)-2-(methylamino)propanoyl]amino]ethyl]-1H-pyrrole-3-carboxamide (23-11, 160 mg, 0.387 mmol) and EtN (39 mg, 0.387 mmol) in DCM (20 mL) was added propanoyl chloride (71 mg, 0.774 mmol). The mixture was stirred at 25 °C for 1 hour. The mixture was quenched with water (5 mL) and extracted with DCM (50 mL × 3). The combined organic layers were then dried over Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (Biotage 12 g silica flash column; elution with a gradient of 0-10% methanol in dichloromethane (30 mL / min)) to afford 5-[(5-fluoro-2-oxo-indolin-3-ylidene)methyl]-4-methyl-N-[2-[[(2S)-2-[methyl(propanoyl)amino]propanoyl]amino]ethyl]-1H-pyrrole-3-carboxamide (25.2 mg, 13% yield) as a yellow solid. LCMS: t R =0-60 AB_4 min_220&254_Shimadzu.lcm for 2.418 minutes, MS(ESI)m / z=470.3[M+H] + . 1 H NMR(400MHz,DMSO-d6):δ=13.68(s,1H),10.98(s,1H),8.07-7.94(m,1H),7.82-7.77(m,4H),6.97-6.84(m,2H),5.01-4.46 (m,1H),3.28-3.23(m,4H),2.82,2.67(s,3H),2.67-2.54(m,3H),2.36-2.32(m,2H),1.29-1.19(m,3H),1.00-0.96(m,3H). Chiral SFC:t R= 5.366 min (instrument column: Chiralpak AD-3 100 × 4.6 mm, internal diameter, 3 μm, mobile phase: A: CO2, B: ethanol (0.05% DEA), gradient: 5% to 40% B for 4.5 min, hold at 40% for 2.5 min, then 5% B for 1 min, flow rate: 2.8 mL / min, column temperature: 40 °C, detection: 220 nm), ee% = 100%. [α] D 20 =-36.0 (c=0.1, MeOH).

[0388] Example 25 5-[(5-Fluoro-2-oxo-indolin-3-ylidene)methyl]-4-methyl-N-[2-[[(2S)-2-[methyl(propanoyl)amino]propanoyl]amino]ethyl]-1H-pyrrole-3-carboxamide (Compound 25) TIFF0007628108000290.tif102142 Scheme 28. Synthesis of compound 25.

[0389] The synthesis of 5-[(5-fluoro-2-oxo-indolin-3-ylidene)methyl]-4-methyl-N-[2-[[(2S)-2-(methylamino)propanoyl]amino]ethyl]-1H-pyrrole-3-carboxamide (23-11) is shown in Example 23. To a solution of 5-[(5-fluoro-2-oxo-indolin-3-ylidene)methyl]-4-methyl-N-[2-[[(2S)-2-(methylamino)propanoyl]amino]ethyl]-1H-pyrrole-3-carboxamide (23-11, 150 mg, 0.363 mmol), HATU (166 mg, 0.435 mmol), and DIEA (141 mg, 1.09 mmol) in DMF (10 mL) was added but-2-ynoic acid (34 mg, 0.40 mmol). The mixture was stirred at 25 °C for 2 hours. The mixture was diluted with water (20 mL) and extracted with EtOAc (50 mL × 3). The combined organic layer was then washed with saturated aqueous NaCl (20 mL × 7), dried over Na SO , filtered, and concentrated. The residue was purified by preparative HPLC (basic conditions) to give N-[2-[[(2S)-2-[but-2-ynoyl(methyl)amino]propanoyl]amino]ethyl]-5-[(5-fluoro-2-oxo-indolin-3-ylidene)methyl]-4-methyl-1H-pyrrole-3-carboxamide (67 mg, 38% yield) as a yellow solid. LCMS: R =10-80 AB_4 min_220&254_Shimadzu.lcm for 2.167 minutes, MS(ESI)m / z=480.2[M+H] + . 1 H NMR(400MHz,DMSO-d6):δ=13.68(s,1H),10.97(s,1H),7.99-7.81(m,2H),7.81-7.75(m,3H),6.96-6.86(m ,2H),4.92-4.80(m,1H),3.35-3.20(m,4H),3.04-2.72(m,3H),2.01(d,J=15.6Hz,3H),1.34-1.23(m,3H). Chiral SFC:t R= 5.366 min (instrument column: Chiralpak AD-3 100 x 4.6 mm, i.d., 3 μm, mobile phase: A: CO2, B: ethanol (0.05% DEA), gradient: 5% to 40% B for 4.5 min, hold at 40% for 2.5 min, then 5% B for 1 min, flow rate: 2.8 mL / min, column temperature: 40 °C, detection: 220 nm), ee% = 99.28%. [α] D 20 =-56.0 (c=0.1, MeOH).

[0390] Example 26 N-(2-((S)-2-((E)-4-(dimethylamino)-N-methylbut-2-enamido)propanamido)ethyl)-5-((Z)-(5-fluoro-2-oxoindolin-3-ylidene)methyl)-4-methyl-1H-pyrrole-3-carboxamide (Compound 26) TIFF0007628108000291.tif139140 Scheme 29. Synthesis of compound 26.

[0391] TIFF0007628108000292.tif23128POCl3 (2.12 g, 13.83 mmol) was added dropwise to DMF (1.01 g, 13.84 mmol) at 0 °C. The mixture was stirred at 15 °C for 1 hour. A solution of ethyl 4-methyl-1H-pyrrole-3-carboxylate (0.5 g, 3.26 mmol) in DMF (8 mL) was added thereto at 0 °C. The mixture was then warmed to 15 °C and stirred for 1 hour. The mixture was poured onto ice (20 g). The pH of the mixture was adjusted to 7-8 by adding 2 M NaOH, and a white solid was formed. The mixture was filtered, and the filter cake was washed with water (2 mL × 2). The filter cake was dried to give ethyl 5-formyl-4-methyl-1H-pyrrole-3-carboxylate (523 mg, 94% purity, 83% yield) as a white solid. LCMS: R =5-95 AB_1.5min_220&254_ 0.687 min at Agil.lcm, MS(ESI)m / z=182.1[M+H] + . HPLC:t R=10-80 AB_8min 2.08min. met(Ultimate C18 3um, 3.0*50mm). 1 H NMR (400MHz, CDCl3): δ=9.78(brs,1H),9.71(s,1H),7.64(s,1H),4.31(q,J=7.2Hz,2H),2.61(s,2H),1.36(t,J=7.2Hz,3H).

[0392] To a solution of ethyl 5-formyl-4-methyl-1H-pyrrole-3-carboxylate (400 mg, 2.21 mmol) in EtOH (5 mL) and HO (3 mL) was added NaOH (106 mg, 2.65 mmol). The mixture was then heated to 100 °C and stirred for 2 h. Another batch of NaOH (530 mg, 13.25 mmol) was added. The mixture was stirred at 100 °C for 2 h. The pH of the mixture was adjusted to 5-6 with 2 N HCl, and the resulting mixture was filtered. The filter cake was washed with water (2 mL × 2). The filter cake was dried to give 5-formyl-4-methyl-1H-pyrrole-3-carboxylic acid (284 mg, 84% yield) as a white solid. LCMS: t R =5-95 AB_1.5 min_220&254_0.342 min at Agilent.lcm, MS(ESI)m / z=154.1[M+H] + . 1 H NMR (400MHz, DMSO-d6): δ = 12.26 (br s, 1H), 9.70 (s, 1H), 7.56 (s, 1H), 2.50 (s, 3H).

[0393] TIFF0007628108000294.tif26128 To a solution of 5-formyl-4-methyl-1H-pyrrole-3-carboxylic acid (280 mg, 1.83 mmol) in EtOH (5 mL) was added tetrahydropyrrole (13 mg, 0.183 mmol) and 5-fluoroindolin-2-one (276 mg, 1.83 mmol). The mixture was then heated to 80° C. and stirred for 3 hours. The mixture was filtered, and the filter cake was washed with EtOAc (2 mL×2). The filter cake was dried to give 5-[(Z)-(5-fluoro-2-oxo-indolin-3-ylidene)methyl]-4-methyl-1H-pyrrole-3-carboxylic acid (432 mg, 100% pure, 83% yield) as a yellow solid. LCMS: t R =5-95 AB_1.5 min_220&254_0.823 min at Agilent.lcm, MS(ESI)m / z=287.1[M+H] + . 1 H NMR (400 MHz, DMSO-d): δ = 13.78 (s, 1H), 12.13 (brs, 1H), 11.01 (s, 1H), 7.86-7.78 (m, 3H), 7.00-6.92 (m, 1H), 6.85 (dd, J = 8.4 and 4.4 Hz, 1H), 2.54 (s, 3H).

[0394] TIFF0007628108000295.tif25128To a solution of 5-[(Z)-(5-fluoro-2-oxo-indolin-3-ylidene)methyl]-4-methyl-1H-pyrrole-3-carboxylic acid (390 mg, 1.36 mmol) in DMF (10 mL), HATU (622 mg, 1.63 mmol) and TEA (414 mg, 4.09 mmol) were added. The mixture was stirred at 15 °C for 0.5 h. tert-Butyl N-(2-aminoethyl)carbamate (218 mg, 1.36 mmol) was added. The mixture was stirred at 15 °C for 2 h. Water (20 mL) was added. The mixture was stirred at 20 °C for 10 min. The mixture was filtered, and the filter cake was washed with EtOAc (3 mL × 3). The filter cake was dried to give tert-butyl N-[2-[[4-methyl-5-[(Z)-(2-oxoindolin-3-ylidene)methyl]-1H-pyrrole-3-carbonyl]amino]ethyl]carbamate (502 mg, crude) as a yellow solid. 1 H NMR(400MHz,DMSO-d6):δ=13.67(brs,1H),10.96(s,1H),7.95(s,1H),7.90-7.84(m,1H),7.83-7.75(m,3 H),6.99-6.92(m,1H),6.91-6.82(m,2H),3.23-3.20(m,2H),3.08-3.04(m,2H),2.53(s,3H),1.38(s,9H).

[0395] To a solution of tert-butyl N-[2-[[5-[(Z)-(5-fluoro-2-oxo-indolin-3-ylidene)methyl]-4-methyl-1H-pyrrole-3-carbonyl]amino]ethyl]carbamate (500 mg, 1.17 mmol) in DCM (6 mL) was added TFA (15.40 g, 135.06 mmol). The mixture was stirred at 20° C. for 1 hour. The solvent was removed under reduced pressure. The residue was triturated with EtOAc (20 mL) at 15° C. for 20 minutes. The mixture was filtered, and the filter cake was washed with EtOAc (2 mL × 2). The filter cake was dried to give N-(2-aminoethyl)-5-[(Z)-(5-fluoro-2-oxo-indolin-3-ylidene)methyl]-4-methyl-1H-pyrrole-3-carboxamide (510 mg, crude, TFA salt) as a yellow solid.

[0396] TIFF0007628108000297.tif49139To a solution of (2S)-2-[tert-butoxycarbonyl(methyl)amino]propanoic acid (190 mg, 0.932 mmol) in DMF (9 mL), HATU (387 mg, 1.02 mmol), N-(2-aminoethyl)-5-[(Z)-(5-fluoro-2-oxo-indolin-3-ylidene)methyl]-4-methyl-1H-pyrrole-3-carboxamide (375 mg, 0.848 mmol), and TEA (343 mg, 3.39 mmol) were added. The mixture was stirred at 20 °C for 2 hours. Water (20 mL) was added. The mixture was filtered, and the filter cake was washed with EtOAc (5 mL × 3). The filter cake was dried to give tert-butyl N-[(1S)-2-[2-[[5-[(Z)-(5-fluoro-2-oxo-indolin-3-ylidene)methyl]-4-methyl-1H-pyrrole-3-carbonyl]amino]ethylamino]-1-methyl-2-oxo-ethyl]-N-methyl-carbamate (406 mg, crude) as a yellow solid.

[0397] To a solution of tert-butyl N-[(1S)-2-[2-[[5-[(Z)-(5-fluoro-2-oxo-indolin-3-ylidene)methyl]-4-methyl-1H-pyrrole-3-carbonyl]amino]ethylamino]-1-methyl-2-oxo-ethyl]-N-methyl-carbamate (490 mg, 0.954 mmol) in DCM (4 mL) was added TFA (9.24 g, 81.04 mmol). The mixture was stirred at 20° C. for 2 hours. The solvent was removed under reduced pressure. The residue was diluted with EA (10 mL) and stirred at 15° C. for 0.5 hours. The mixture was filtered, and the filter cake was washed with EtOAc (5 mL×3). The filter cake was dried to give 5-[(Z)-(5-fluoro-2-oxo-indolin-3-ylidene)methyl]-4-methyl-N-[2-[[(2S)-2-(methylamino)propanoyl]amino]ethyl]-1H-pyrrole-3-carboxamide (453 mg, crude, TFA salt) as a yellow solid. LCMS: R =10-80 AB_2.0 min_220&254_Shimadzu.lcm for 1.255 minutes, MS(ESI)m / z=414.3[M+H] + .

[0398] To a solution of 4-(dimethylamino)but-2-enoic acid (54 mg, 0.417 mmol), 5-[(Z)-(5-fluoro-2-oxo-indolin-3-ylidene)methyl]-4-methyl-N-[2-[[(2S)-2-(methylamino)propanoyl]amino]ethyl]-1H-pyrrole-3-carboxamide (200 mg, 0.379 mmol, TFA salt), and TEA (153 mg, 1.52 mmol) in DMF (3 mL) was added HATU (159 mg, 0.417 mmol). The mixture was stirred at 20 °C for 1 h. The mixture was filtered and the residue was purified by preparative HPLC (column: Agela DuraShell C18 250*25mm*10um, water (0.04% NH 3.Purification by HCl (H2O + 10 mM NH4HCO3)-ACN; 25-55% B; gradient time: 8 min; flow rate: 25 mL / min) afforded N-(2-((S)-2-((E)-4-(dimethylamino)-N-methylbut-2-enamido)propanamido)ethyl)-5-((Z)-(5-fluoro-2-oxoindolin-3-ylidene)methyl)-4-methyl-1H-pyrrole-3-carboxamide (19 mg, 92% purity, 9% yield) as a yellow solid. LCMS: t R =10-80 AB_2 min_220&254_Shimadzu.lcm for 1.205 minutes, MS(ESI)m / z=525.4[M+H] + . 1 H NMR(400MHz,CD3OD-d4):δ=7.66-7.63(m,2H),7.48(d,J=8.4Hz,1H),6.95-6.84(m,2H),6.82-6.70(m,1H),6.62-6.51(m,1H),5.05- 4.94(m,1H),3.55-3.38(m,4H),3.15(d,J=6.0Hz,1H),3.07(s,3H),3.01-2.88(m,1H),2.57(s,3H),2.26(s,6H),1.46-1.39(m,3H). Chiral SFC:t R = 3.370 min (Instrument column: Chiralpak AS-3 100 x 4.6 mm, i.d., 3 um; Mobile phase: A:CO2 B:Ethanol (0.05% DEA), Gradient: 5% to 40% B for 4.5 min, hold at 40% for 2.5 min, then 5% B for 1 min; Flow rate: 2.8 mL / min, Column temperature: 40 °C, UV detection: 220 nm), ee% = 100%. [α] D 20 =-42.0 (c=0.10, MeOH).

[0399] Example 27 (2S)-N-[[(6S)-2-[(5-fluoro-2-oxo-indolin-3-ylidene)methyl]-3-methyl-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl]-2-[methyl(prop-2-enoyl)amino]propanamide (compound 27), and (2S)-N-[[(6R)-2-[(5-fluoro-2-oxo-indolin-3-ylidene)methyl]-3-methyl-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl]-2-[methyl(prop-2-enoyl)amino]propanamide (Compound 28) TIFF0007628108000300.tif62128TIFF0007628108000301.tif169142Scheme 30. Synthesis of compounds 27 and 28.

[0400] To a solution of 3,4,5-trimethoxybenzoic acid (25 g, 117.81 mmol) in MeOH (80 mL) and NH (400 mL), Na (13.54 g, 0.589 mmol) was added. The mixture was stirred at −78 °C for 3 h. The mixture was quenched by adding NH Cl (10 g) at −60 °C and concentrated under reduced pressure to give a residue. The residue was dissolved in ice water, and the solution was acidified with 2 M HCl to pH 4–5. The mixture was extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na SO , filtered, and concentrated under reduced pressure to give 3,5-dimethoxycyclohexa-2,5-diene-1-carboxylic acid (22 g, crude) as a white solid, which was used directly in the next step. 1 H NMR (400MHz, DMSO-d6): δ = 4.77 (d, J = 3.6 Hz, 2H), 3.83-3.78 (m, 1H), 3.54-3.48 (m, 6H), 2.68 (d, J = 7.2Hz, 2H).

[0401] To a solution of 3,5-dimethoxycyclohexa-2,5-diene-1-carboxylic acid (22 g, 0.119 mmol) in THF (200 mL) was added LiAlH (18.13 g, 0.478 mmol). The mixture was stirred at 0 °C for 2 h. The mixture was quenched by adding HO (15 mL) at 25 °C, followed by 2 M NaOH (15 mL) and HO (60 mL). The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to give (3,5-dimethoxycyclohexa-2,5-dien-1-yl)methanol (20 g, 118 mmol, 98% yield) as a colorless oil, which was used directly in the next step. 1 H NMR (400MHz, DMSO-d6): δ=4.73-4.68(m,3H),3.49(s,6H),3.26(t,J=6.0Hz,2H),2.95(m,J=3.2,6.6Hz,1H),2.69-2.63(m,2H).

[0402] A solution of (3,5-dimethoxycyclohexa-2,5-dien-1-yl)methanol (8 g, 47.0 mmol) in AcOH (100 mL) and HO (25 mL) was stirred at 100 °C for 15 min. The mixture was then removed from the heating bath, and 2-oxopropanal oxime (4.91 g, 56.40 mmol) was added portionwise over 15 min with stirring. The mixture was heated to 50 °C, and Zn (9.22 g, 141.01 mmol) was added portionwise. The resulting mixture was at 100 °C for 4 h and then cooled to room temperature. The mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with HO (20 mL) and extracted with DCM (20 mL × 3). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give a residue. The residue was then purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, elution with a 0-100% ethyl acetate / petroleum ether gradient (80 mL / min)) to afford (3-methyl-4-oxo-1,5,6,7-tetrahydroindol-6-yl)methyl acetate (800 mg, 3.62 mmol, 8% yield) and 6-(hydroxymethyl)-3-methyl-1,5,6,7-tetrahydroindol-4-one (2.5 g, 13.95 mmol, 30% yield) as yellow solids. 1 H NMR(400MHz,DMSO-d6):δ=11.00(s,1H),6.47(d,J=0.8Hz,1H),4.07-3.98(m,2H),2.83(dd,J=4.0,15. 2Hz, 1H), 2.59-2.53 (m, 1H), 2.49-2.42 (m, 1H), 2.35-2.21 (m, 2H), 2.13 (d, J=1.2Hz, 3H), 2.04 (s, 3H). 1 H NMR(400MHz,DMSO-d6):δ=10.95(s,1H),6.44(d,J=0.8Hz,1H),4.70-4.62(m,1H),3.18(d,J=5.2H z,2H),2.80(dd,J=4.4,15.8Hz,1H),2.48-2.37(m,1H),2.30-2.14(m,4H),2.13(d,J=1.2Hz,3H).

[0403] To a solution of 6-(hydroxymethyl)-3-methyl-1,5,6,7-tetrahydroindol-4-one (2.5 g, 13.95 mmol) in TIFF0007628108000305.tif26128i-PrOH (50 mL) was added NaBH (1.06 g, 27.90 mmol). The mixture was stirred at 80 °C for 12 hours. The mixture was quenched by adding saturated NH Cl (30 mL) at 20 °C and then extracted with EtOAc (30 mL × 2). The combined organic layers were dried over Na SO , filtered, and concentrated under reduced pressure to give a residue. The residue was then purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, elution with a 0–70% ethyl acetate / petroleum ether gradient (60 mL / min)) to afford (3-methyl-4,5,6,7-tetrahydro-1H-indol-6-yl)methanol (1.3 g, 6.29 mmol, 35% yield, 80% purity) as a brown oil.

[0404] TIFF0007628108000306.tif23128POCl3 (557 mg, 3.63 mmol) was added dropwise to DMF (664 mg, 9.08 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 hour. Then, a solution of (3-methyl-4,5,6,7-tetrahydro-1H-indol-6-yl)methanol (600 mg, 3.63 mmol) in DCE (10 mL) was added dropwise thereto at 0 °C. The mixture was then stirred at 85 °C for another 4 hours. The mixture was cooled to 25 °C, quenched with saturated aqueous NaOAc (20 mL), and stirred at 90 °C for 4 hours. The mixture was concentrated under reduced pressure, quenched with ice water, and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue that was then purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® silica flash column, elution with a 0–50% ethyl acetate / petroleum ether gradient (40 mL / min)) to give 6-(chloromethyl)-3-methyl-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde (300 mg, 1.42 mmol, 39% yield) as a brown solid.

[0405] To a solution of 6-(chloromethyl)-3-methyl-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde (300 mg, 1.42 mmol) in DMF (5 mL) was added (1,3-dioxoisoindolin-2-yl)potassium (315 mg, 1.70 mmol) and NaI (425 mg, 2.83 mmol). The mixture was stirred at 90 °C for 12 h. The mixture was quenched by adding HO (50 mL) at 25 °C, then diluted with HO (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was then purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, elution with a 0–30% ethyl acetate / petroleum ether gradient (40 mL / min)) to afford 6-[(1,3-dioxoisoindolin-2-yl)methyl]-3-methyl-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde (185 mg, 0.574 mmol, 40% yield) as a yellow solid.

[0406] To a solution of 6-[(1,3-dioxoisoindolin-2-yl)methyl]-3-methyl-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde (185 mg, 0.574 mmol) in EtOH (5 mL) was added piperidine (5 mg, 0.057 mmol) and 5-fluoroindolin-2-one (104 mg, 0.689 mmol). The mixture was stirred at 80° C. for 12 h. The mixture was stirred at 0° C. for 0.5 h, and the mixture was filtered and dried to give 2-[[2-[(5-fluoro-2-oxo-indolin-3-ylidene)methyl]-3-methyl-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl]isoindolin-1,3-one (230 mg, 0.454 mmol, 79% yield, 90% purity) as a yellow solid, which was used directly in the next step.

[0407] To a solution of 2-[[2-[(5-fluoro-2-oxo-indolin-3-ylidene)methyl]-3-methyl-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl]isoindoline-1,3-dione (230 mg, 0.505 mmol) in EtOH (5 mL) was added NH2NH2 (34 mg, 1.01 mmol). The mixture was stirred at 25 °C for 12 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give 3-[[6-(aminomethyl)-3-methyl-4,5,6,7-tetrahydro-1H-indol-2-yl]methylene]-5-fluoro-indolin-2-one (150 mg, 0.461 mmol, 91% yield) as a yellow solid, which was used directly in the next step.

[0408] To a solution of 3-[[6-(aminomethyl)-3-methyl-4,5,6,7-tetrahydro-1H-indol-2-yl]methylene]-5-fluoro-indolin-2-one (120 mg, 0.369 mmol) in DMF (5 mL) was added HATU (168 mg, 0.443 mmol), DIEA (48 mg, 0.369 mmol), and (2S)-2-[tert-butoxycarbonyl(methyl)amino]propanoic acid (83 mg, 0.406 mmol). The mixture was stirred at 25 °C for 1 h. The mixture was quenched by adding HO (50 mL) at 25 °C, then diluted with HO (50 mL), and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue that was then purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, elution with a 0–50% ethyl acetate / petroleum ether gradient (40 mL / min)) to give tert-butyl N-[(1S)-2-[[2-[(5-fluoro-2-oxo-indolin-3-ylidene)methyl]-3-methyl-4,5,6,7-tetrahydro-1H-indol-6-yl]methylamino]-1-methyl-2-oxo-ethyl]-N-methyl-carbamate (150 mg, 0.294 mmol, 80% yield) as a yellow solid.

[0409] TIFF0007628108000311.tif26142A solution of tert-butyl N-[(1S)-2-[[2-[(5-fluoro-2-oxo-indolin-3-ylidene)methyl]-3-methyl-4,5,6,7-tetrahydro-1H-indol-6-yl]methylamino]-1-methyl-2-oxo-ethyl]-N-methyl-carbamate (150 mg, 0.294 mmol) in HCl / dioxane (4 M, 10 mL) was stirred at 25° C. for 0.5 h. The mixture was concentrated under reduced pressure to give (2S)—N-[[2-[(5-fluoro-2-oxo-indolin-3-ylidene)methyl]-3-methyl-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl]-2-(methylamino)propanamide (220 mg, 0.29 mmol, 99% yield, 59% purity, HCl salt) as a yellow solid, which was used directly in the next step.

[0410] To a solution of (2S)-N-[[2-[(5-fluoro-2-oxo-indolin-3-ylidene)methyl]-3-methyl-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl]-2-(methylamino)propanamide (220 mg, 0.290 mmol, HCl salt) in DCM (5 mL) was added DIEA (114 mg, 0.87 mmol) and prop-2-enoyl chloride (26 mg, 0.29 mmol). The mixture was stirred at 0 °C for 0.5 h. The mixture was quenched by adding HO (50 mL) at 25 °C, then diluted with HO (50 mL) and extracted with DCM (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue that was then purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, elution with 0–10% dichloromethane:methanol (40 mL / min)) to give (2S)—N-[[2-[(5-fluoro-2-oxo-indolin-3-ylidene)methyl]-3-methyl-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl]-2-[methyl(prop-2-enoyl)amino]propanamide (100 mg, 0.215 mmol, 74% yield) as a red solid.

[0411] The racemic product (100 mg) was purified by chiral SFC (column: DAICEL CHIRALCEL OD (250 mm * 30 mm, 10 μm); condition: 0.1% NH3.H2O ETOH) to give the desired product as a yellow solid, which was then purified by preparative HPLC (column: Phenomenex luna C18 Further separation was carried out using a 100*40mm*3um (conditions: water (0.225% FA)-ACN) to obtain (2S)-N-[[(6R)-2-[(5-fluoro-2-oxo-indolin-3-ylidene)methyl]-3-methyl-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl]-2-[methyl(prop-2-enoyl)amino]propanamide (15.2 mg, 0.033 mmol) , 16% yield, 100% purity) and (2S)-N-[[(6S)-2-[(5-fluoro-2-oxo-indolin-3-ylidene)methyl]-3-methyl-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl]-2-[methyl(prop-2-enoyl)amino]propanamide (15.7 mg, 0.034 mmol, 17% yield, 100% purity) were obtained as yellow solids. LCMS: t R =10-80AB_4min_220&254_Shimadzu.lcm for 2.319 minutes, MS(ESI)m / z=465.3[M+H] + . 1 H NMR(400MHz,DMSO-d6):δ=13.35(s,1H),10.77(s,1H),8.35-7.81(m,1H),7. 72-7.65(m,2H),6.90-6.74(m,3H),6.19-6.07(m,1H),5.75-5.65(m,1H),5.0 6-4.59(m,1H),3.16-3.07(m,2H),3.00-2.80(m,3H),2.75(dd,J=4.8,17.2H z,1H),2.40-2.32(m,2H),2.23(s,3H),1.99-1.81(m,2H),1.47-1.15(m,5H). Chiral SFC:t R= 4.678 min (Column: Chiral MD-3 100 × 4.6 mm, internal diameter, 3 μm, Mobile phase: A: CO2, B: Ethanol (0.05% DEA) Gradient: 5% to 40% B for 4.5 min, hold at 40% for 2.5 min, then 5% B for 1 min, Flow rate: 2.8 mL / min, Column temperature: 40 °C), ee% = 98.78%. LCMS: t R =10-80AB_4min_220&254_Shimadzu.lcm for 2.322 minutes, MS(ESI)m / z=465.3[M+H] + . 1 H NMR(400MHz,DMSO-d6):δ=13.35(s,1H),10.76(s,1H),8.18-7.90(m,1H), 7.72-7.63(m,2H),6.89-6.68(m,3H),6.22-6.06(m,1H),5.80-5.62(m,1H ),5.07-4.62(m,1H),3.24-3.05(m,2H),2.98-2.79(m,3H),2.78-2.69(m, 1H), 2.40-2.32(m, 2H), 2.23(s, 3H), 2.01-1.82(m, 2H), 1.51-1.11(m, 5H). Chiral SFC:t R = 5.030 min (Column: Chiral MD-3 100 × 4.6 mm, inner diameter, 3 μm, Mobile phase: A: CO2, B: Ethanol (0.05% DEA) Gradient: 5% to 40% B for 4.5 min, hold at 40% for 2.5 min, then 5% B for 1 min, Flow rate: 2.8 mL / min, Column temperature: 40 °C), ee% = 100%.

[0412] Example 28 (E)-4-(dimethylamino)-N-[(1S)-2-[[(6S)-2-[(Z)-(5-fluoro-2-oxo-indolin-3-ylidene)methyl]-3-methyl-4,5,6,7-tetrahydro-1H-indol-6-yl]methylamino]-1-methyl-2-oxo-ethyl]-N-methyl-but-2-enamide (compound 29), and (E)-4-(Dimethylamino)-N-[(1S)-2-[[(6R)-2-[(Z)-(5-fluoro-2-oxo-indolin-3-ylidene)methyl]-3-methyl-4,5,6,7-tetrahydro-1H-indol-6-yl]methylamino]-1-methyl-2-oxo-ethyl]-N-methyl-but-2-enamide (Compound 30) TIFF0007628108000314.tif147149 Scheme 31. Synthesis of compounds 29 and 30.

[0413] The synthesis of (2S)-N-[[(6S)-2-[(5-fluoro-2-oxo-indolin-3-ylidene)methyl]-3-methyl-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl]-2-(methylamino)propanamide (27-15) is shown in Example 20. To a solution of (2S)-N-[[(6S)-2-[(5-fluoro-2-oxo-indolin-3-ylidene)methyl]-3-methyl-4,5,6,7-tetrahydro-1H-indol-6-yl]methyl]-2-(methylamino)propanamide (27-15, 280 mg, 0.501 mmol, HCl salt) and (E)-4-(dimethylamino)but-2-enoic acid (71 mg, 0.551 mmol) in DMF (5 mL) was added HATU (229 mg, 0.601 mmol) and DIEA (194 mg, 1.50 mmol). The mixture was stirred at 25 °C for 2 h. The mixture was quenched by adding HO (50 mL) at 25 °C, then diluted with HO (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue that was then purified by preparative HPLC (water (0.05% NH.HO+10 mM NHHCO)—ACN) to give (E)-4-(dimethylamino)-N-((2S)-1-(((2-((Z)-(5-fluoro-2-oxoindolin-3-ylidene)methyl)-3-methyl-4,5,6,7-tetrahydro-1H-indol-6-yl)methyl)amino)-1-oxopropan-2-yl)-N-methylbut-2-enamide (40 mg, 0.073 mmol, 15% yield, 95% purity) as a yellow solid.

[0414] The racemic product (40 mg) was separated by chiral SFC (column: Chiralcel OD-3 100 × 4.6 mm, i.d., 3 μm, mobile phase: A: CO2, B: ethanol (0.05% DEA), gradient: 5% to 40% B for 4.5 min, hold at 40% for 2.5 min, then 5% B for 1 min, flow rate: 2.8 mL / min) and purified with (E)-4-(dimethylamino)-N-[(1S)-2-[[(6S)-2-[(Z)-(5-fluoro-2-oxo-indolin-3-ylidene)methyl]-3-methyl-4,5,6,7-tetrahydro-1H-indol-6-yl]methylamino]-1-methyl-2-oxo-ethyl]-N-methyl-butadiene. 1-methyl-2-oxo-ethyl]-N-methyl-but-2-enamide (9.6 mg, 0.018 mmol, 23% yield, 97.5% purity) as a yellow solid, and (E)-4-(dimethylamino)-N-[(1S)-2-[[(6R)-2-[(Z)-(5-fluoro-2-oxo-indolin-3-ylidene)methyl]-3-methyl-4,5,6,7-tetrahydro-1H-indol-6-yl]methylamino]-1-methyl-2-oxo-ethyl]-N-methyl-but-2-enamide (12.6 mg, 0.023 mmol, 31% yield, 96.9% purity) as a yellow solid. LCMS: t R =10-80AB_4min_220&254_Shimadzu.lcm for 1.818 minutes, MS(ESI)m / z=522.3[M+H] + . 1 H NMR (400 MHz, methanol-d4): δ = 7.50 (s, 1H), 7.33 (dd, J = 2.0, 9.2 Hz, 1H), 6.89-6.77 (m, 3H), 6.69-6.59 (m, 1H), 5.12-4.90 (m, 1H), 3.27-3.19 (m, 2H), 3.12-2.95 (m, 3H), 2.79 (dd, J = 4.8, 17.2 Hz, 1H), 2.59 (d, J = 15.6 Hz, 1H), 2.42-2.27 (m, 8H), 2.23 (s, 3H), 2.15-1.95 (m, 3H), 1.46-1.39 (m, 3H), 1.30 (s, 2H). Chiral SFC: t R= 4.355 min (column: Chiralpak OD-3 100 × 4.6 mm, i.d., 3 μm, mobile phase: A: CO2, B: methanol (0.05% DEA), gradient: 5% to 40% B for 4.5 min, hold 40% for 2.5 min, then 5% B for 1 min, flow rate: 2.8 mL / min, column temperature: 40 °C), ee% = 100%, [α] D 20 = -138 (c = 1.0, MeOH). LCMS: t R =10-80AB_4min_220&254_Shimadzu.lcm for 1.827 minutes, MS(ESI)m / z=522.3[M+H] + . 1 H NMR (400 MHz, methanol-d4): δ = 7.50 (s, 1H), 7.33 (dd, J = 2.0, 9.2 Hz, 1H), 6.89-6.77 (m, 3H), 6.69-6.59 (m, 1H), 5.12-4.90 (m, 1H), 3.27-3.19 (m, 2H), 3.12-2.95 (m, 3H), 2.79 (dd, J = 4.8, 17.2 Hz, 1H), 2.59 (d, J = 15.6 Hz, 1H), 2.42-2.27 (m, 8H), 2.23 (s, 3H), 2.15-1.95 (m, 3H), 1.46-1.39 (m, 3H), 1.30 (s, 2H). Chiral SFC: t R = 4.570 min (Column: Chiralpak OD-3 100 × 4.6 mm, inner diameter, 3 μm, Mobile phase: A: CO2, B: Methanol (0.05% DEA), Gradient: 5% to 40% B for 4.5 min, hold at 40% for 2.5 min, then 5% B for 1 min, Flow rate: 2.8 mL / min, Column temperature: 40 °C), ee% = 95.16%. [α] D 20 = 37 (c = 1.0, MeOH).

[0415] Example 29 Characterization of the Kinase Inhibitory Properties of the Disclosed Compounds Compound inhibition of recombinant kinases (FGR, FLT3, FMS, KIT, or RON) was measured using a caliper mobility shift assay, which is based on the difference in capillary electrophoretic mobility of fluorescently tagged peptides as a result of phosphorylation by the kinase under study. The reaction was initiated by adding various concentrations of compound (initially in DMSO) to a solution of the kinase in assay buffer, followed by a mixture of ATP and fluorescently tagged peptide substrate in assay buffer. The concentrations of enzyme, ATP, and peptide were pre-optimized to achieve 15% substrate conversion and ensure initial rate measurements. After a 3-hour incubation at room temperature, the kinase reaction was quenched by adding concentrated EDTA solution before analysis on a LabChip EZ Reader II. Percent inhibition was obtained by comparison with a DMSO control.

[0416] Table 2 below summarizes the assay conditions for characterizing the kinase inhibitory properties of the disclosed compounds.

[0417] Table 2: Assay conditions for characteristic differential kinase inhibitory properties. TIFF0007628108000317.tif51139

[0418] (Table 3) Table 3 below summarizes the kinase inhibitory properties of the disclosed compounds. TIFF0007628108000318.tif159129+++: Less than 10 nmol / L ++: ≥ 10 nmol / L and < 100 nmol / L +: ≥ 100nmol / L and < 1000nmol / L -:1000nmol / L or more N / A: Not available

[0419] The cell viability assay was performed based on the following simple procedure: Cells were seeded at a density of 5K / well with a volume of 180 μL in 96-well white plates and clear-bottom plates. 20 μL of vehicle or compound was added to the wells at the appropriate concentration. The final volume was 200 μL, with a final concentration of DMSO = 0.1%, 11 points, triplicate. The cells were then treated in a TC incubator for 72 hours at 37°C. An equal volume (200 μL) of CellTiter-Glo reagent (Promega) was added to the wells and protected from light for 15 minutes at room temperature. Chemiluminescence was measured with EnSight (Perkin Elmer). GI was calculated using GraphPad Prism nonlinear regression, a four-parameter Log[inhibitor] response. 50 was calculated. Table 4 below shows the results of the FLT3 cell-based assay.

[0420] Table 4: Tyrosine kinase inhibitor compounds in the cell viability assay of the present disclosure. TIFF0007628108000319.tif120138+++: Less than 10 nmol / L ++: ≥ 10 nmol / L and < 100 nmol / L +: ≥ 100nmol / L and < 1000nmol / L -:1000nmol / L or more N / A: Not available

[0421] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific compositions and procedures described herein which equivalents are considered to be within the scope of this disclosure and are covered by the following claims.

Claims

1. A compound selected from the group consisting of: or an optically pure stereoisomer, a pharma- ceutically acceptable salt, or solvate thereof.

2. 13. A pharmaceutical formulation comprising a compound of claim 1, or an optically pure stereoisomer, a pharma- ceutically acceptable salt, or solvate thereof, and a pharma- ceutically acceptable carrier.

3. A pharmaceutical composition for treating cancer in a subject, comprising the compound of claim 1, or an optically pure stereoisomer, pharma- ceutically acceptable salt, or solvate thereof.

4. 4. The pharmaceutical composition of claim 3, wherein the cancer is breast cancer, myeloid cancer, lung cancer, bladder cancer, prostate cancer, ovarian cancer, endometrial cancer, rhabdomyosarcoma, liver cancer, gastric cancer, or intestinal cancer.

5. The pharmaceutical composition of claim 3 , which is administered in combination with a chemotherapeutic agent.

6. The pharmaceutical composition of claim 5 , which is administered prior to, simultaneously with, or following administration of the chemotherapeutic agent.

7. A pharmaceutical composition for use in a method for inhibiting tyrosine kinase activity comprising the compound of claim 1, or an optically pure stereoisomer, pharma- ceutically acceptable salt, or solvate thereof, comprising: The method comprises contacting a cell with a compound of claim 1, or an optically pure stereoisomer, a pharma- ceutically acceptable salt, or a solvate thereof.

8. The pharmaceutical composition of claim 7 , wherein the cell is a cancer cell.

9. 9. The pharmaceutical composition of claim 8, wherein the cancer cells are breast cancer, myeloid cancer, lung cancer, bladder cancer, prostate cancer, ovarian cancer, endometrial cancer, rhabdomyosarcoma, liver cancer, gastric cancer, or intestinal cancer cells.

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