4-substituted aminoisoquinoline derivatives

Abstract

The present invention relates to 4-substituted isoquinoline compounds and derivatives thereof, and their use for treating cancer (e.g., acute myeloid leukemia).

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefit of U.S. Provisional Application Serial No. 62 / 461,295, filed February 21, 2017, and U.S. Provisional Application Serial No. 62 / 375,154, filed August 15, 2016, both of which are incorporated herein by reference in their entirety. Technical Field

[0003] This invention relates to 4-substituted aminoisoquinoline compounds and their derivatives, and their use in the treatment of cancer (e.g., acute myeloid leukemia). Background Technology

[0004] Human cells contain over 500 kinases that regulate important processes such as cell cycle regulation, proliferation, apoptosis, and migration. Inhibitors of protein kinases hold the potential to treat many diseases controlled by dysregulation of protein kinases. To date, more than 20 kinase inhibitors have been approved by the FDA for the treatment of various diseases.

[0005] Panatinib is an FDA-approved drug that is a 7-alkynylimidozono[1,5-b]pyridazine compound and is used for the treatment of CML. However, panatinib has toxic side effects, and some form of thrombosis occurs in approximately 40% of patients who use panatinib. Due to this adverse issue, the FDA temporarily suspended the sale of panatinib in 2014, and it is now given as a last resort for CML patients with ABL(T315I) mutations who have not responded to any other treatment (Geno, JF et al., Panatinib: Accelerated Non-Approval, Oncologist, 20(8), 847–848 (2015); Talbot, DR et al., Toxicological Sciences, 143(1), 147–155 (2015).

[0006] In efforts to develop kinase inhibitors targeting several disease-related kinases, 4-substituted isoquinolines have been found to be specific kinase inhibitors. Furthermore, the substitution patterns of these 4-substituted isoquinolines play a crucial role in kinase selectivity and, consequently, cancer selectivity. In particular, 4-alkynyl-substituted aminoisoquinolines exhibit excellent activity against a variety of kinases and effectively inhibit cancer proliferation. This important discovery facilitates the tailoring of 4-substituted aminoisoquinolines into compounds that inhibit various cancers. Additionally, the selectivity and toxicity of 4-alkynyl-substituted 1- or 3-aminoisoquinolines can be modulated, thus representing a new generation of alkyne-containing kinase inhibitors with desired drug-like properties. Summary of the Invention

[0007] On the one hand, the present invention is characterized by compounds represented by formula (IV):

[0008]

[0009] Or its pharmaceutically acceptable salts, N-oxides, hydrates, solvates, tautomers, or optical isomers.

[0010] in

[0011] W represents NR', alkenes, alkynes, and C. 1-8 Alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl containing 1-8 carbon atoms and heteroatoms, wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl optionally form a fused aryl or heteroaryl group with ring A;

[0012] U, Y, and Z are each either N or CR6, where R6 is either H or NR. a R b ;

[0013] R7 and R8 are independently H, alkyl, alkenyl, alkynyl, halogen, nitro, OR c SR c CN, haloalkyl, O-haloalkyl, (CO)R d NR a R b NH(CO)R d NH(CO)OR c NH(CO)NR a R b (CO)OR c (CO)NR a R b SO2NR a R b cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

[0014] Alternatively, R7 and R8, together with the carbon atoms attached to them, form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, each optionally independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, halogen, nitro, OR c SR c CN, haloalkyl, O-haloalkyl, NR a R b (CO)R d (CO)OR c (CO)NR a R b SO2NR a R b Substitution with -C(CH3)(=N-NHC(NH)NH2 substituents;

[0015] Ring A is a 5- or 6-membered aryl or heteroaryl group, wherein ring A is optionally selected from alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, halogen, nitro, OR c SR c CN, haloalkyl, O-haloalkyl, NR m R n (CO)R d (CO)OR c SO2NR m R n (CO)NR m R n C(NH)NR m R n NH(CO)R d NH(CO)OR c NH(CO)NR m R n Substitution of aryl and heteroaryl groups;

[0016] R m and R n Each independently is

[0017] H, OH,

[0018] Alkyl group, -(CH2) p -T、-aryl-(CH2) p -T、-(CH2) p -aryl-T, -heteroaryl-(CH2) p -T、-(CH2) p -heteroaryl-T, each optionally prefixed with alkyl, halogen, nitro, CN, haloalkyl, O-haloalkyl, OR c SR c NR a R b (CO)R d NH(CO)R d NH(CO)OR c NH(CO)NR a R b ,NHC(NH)NH2,(CO)OR c (CO)NR a R b SO2NR a R b , arylamino or heteroarylamino substitution,

[0019] Or R m and R nTogether with the nitrogen atom attached to them, they form a heterocyclic alkyl group, optionally prefixed with alkyl, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, halogen, nitro, CN, OR c SR c COR d NR a R b NH(CO)R d NH(CO)OR c NH(CO)NR a R b guanidine group, (CO)OR c Or (CO)NR a R b replace;

[0020] T is NR a R b OR c SR c O-(CH2) q -NR a R b Cycloalkyl, heterocycloalkyl, aryl, heteroaryl, guanidine group or isonicotinimidamide group;

[0021] R' is H, alkyl, or cycloalkyl;

[0022] R a R b R c and R d Each can be independently H, alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or -(CH2). q -cycloalkyl, -(CH) q -Heterocyclic alkyl, -(CH2) q -Aryl, -(CH) q -heteroaryl, -(CO)-alkyl, -(CO)-cycloalkyl, -(CO)-heterocyclic alkyl, -(SO2)-alkyl, -(SO2)-cycloalkyl or -(SO2)-heterocyclic alkyl, or R a and R b Together with the nitrogen atoms attached to them, they form heterocyclic alkyl groups, wherein the cycloalkyl, heterocyclic alkyl, aryl, and heteroaryl groups are each optionally substituted with groups consisting of alkyl, halogen, nitro, CN, haloalkyl, O-haloalkyl, OH, O-alkyl, SH, S-alkyl, NH2, NH(alkyl), and N(alkyl)2; and

[0023] p and q are each independently 0-8.

[0024] On the other hand, the present invention relates to pharmaceutical compositions comprising one or more compounds described herein or their pharmaceutically acceptable salts, N-oxides, hydrates, solvates, tautomers or optical isomers, and pharmaceutically acceptable carriers or diluents.

[0025] In another aspect, the present invention relates to a method for treating, preventing, inhibiting, or reducing the severity of cancer in a subject in which such treatment, prevention, inhibition, or reduction is desired, wherein the method comprises administering to the subject a therapeutically effective amount of a compound as described herein or a pharmaceutically acceptable salt, N-oxide, hydrate, solvate, tautomer, or optical isomer thereof, or a pharmaceutical composition comprising one or more compounds as described herein.

[0026] In another aspect, the present invention relates to a method for treating, preventing, inhibiting, or reducing the severity of a disease or disorder related to a protein kinase in a subject requiring such treatment, prevention, inhibition, or reduction, wherein the method comprises administering to the subject a therapeutically effective amount of a compound as described herein or a pharmaceutically acceptable salt, N-oxide, hydrate, solvate, tautomer, or optical isomer thereof, or a pharmaceutical composition comprising one or more compounds as described herein.

[0027] Details of one or more embodiments of the invention are set forth in the following description. Other features, objects, and advantages of the invention will become apparent from the specification, drawings, and claims. Attached Figure Description

[0028] Figure 1 illustrates how the length of the amide head group, the substitution mode, and the relative position to the alkyne moiety significantly affect the anticancer activity against the MV4-11 cell line (AML cell line).

[0029] Figure 2 illustrates that compound 1703 is effective for the MCF-7 cell line.

[0030] Figure 3 Compound 1703 was shown to be effective against the HeLa cell line.

[0031] Figure 4 4-substituted isoquinoline / quinoline / quinazoline / purine compounds were described.

[0032] Figure 5 The general structure of the compounds of the present invention is described.

[0033] Figure 6 The compounds of the present invention are described.

[0034] Figure 7 The method of replacing halogens on quinolones, isoquinolines, or quinazolines for the preparation of the compounds of the present invention is described.

[0035] Figure 8A , 8B The dose-response curve and protein blot analysis were depicted using 8C. Figure 8A Dose-response curves of HSW1651 for FLT3 and important FLT3 mutants. Figure 8B and 8C After treatment with HSM1651 and DMSO vector (V) as controls, the p-FLT3 / total FLT3 ratio in MV4-11 was [data missing]. Figure 8B ) and p-STAT5 / STAT5( Figure 8C Western blot analysis of protein expression. Scanned images were analyzed using ImageJ software.

[0036] Figure 9 Representative examples of the synthesized compounds are described.

[0037] Figure 10 The percentage inhibition of proliferation in the MV4-11 cell line with various analogues (100 nM) was depicted. Table 2 provides the IC50 values ​​for the selected compounds D7, D15, D6, A15, D28, D30, and midostaurin (compounds described in Table 2). Figure 9 middle).

[0038] Figure 11 D30 analogues were described, which were synthesized to investigate the effects of quinoline / quinazoline / isoquinoline core on anticancer activity and kinase inhibition.

[0039] Figure 12 The activity of HSN286(D30) against FLT3-driven MV4-11 and MOLM-14 was depicted, but the activity of other cancer cell lines and normal cell line MRC5 was not depicted.

[0040] Figure 13 Doped quizartinib (A) binding to the inactive form of wild-type FLT3 and docked HSN286 (B) binding to the inactive form of wild-type FLT3 are depicted. PDB#4xuf. Docking was performed using molecular docking software (Autodock Vina). The docked quizartinib matches the ligands in the FLT3 / quizartinib crystal structure. Key residues D835, Y842, and F691, which block the binding of the FLT3 inhibitor when mutated, are shown as bars.

[0041] Figure 14 The quzatinib in the docking structure (A) is depicted. FLT3 residues and HSN286 in docking structure (B) FLT3 residues within.

[0042] Figure 15 The superposition of FLT3 binding modes of quizartinib with the compounds of this invention is described.

[0043] Figure 16 Enzymatic inhibition of FLT3, FLT3ITD and Src kinases by the compounds of the present invention is described.

[0044] Figure 17A and 17B The protein blot analysis following treatment of MV4-11 with HSN286 is described. Figure 17A : Phosphate-FLT3 / FLT3, Phosphate SRC / SRC, and Phosphate-STAT3 / STAT3; and Figure 17B Phosphate-STAT5 / STAT5 and phosphate-p-38 / p-38. Cells were treated with DMSO vector (V) and HSN286 (9 nM and 45 nM) for 6 h, 24 h, and 48 h. Western blots containing anti-rabbit or anti-mouse antibodies were obtained. Scanned images were analyzed using ImageJ software.

[0045] Figure 18 The compounds of the present invention with different substitution methods are described.

[0046] Figure 19 The compounds of the present invention with different substitution methods are described.

[0047] Figure 20 The survival percentage of NSG mice injected with the AML cell line MV4-11 and treated with various compounds at 25 mg / kg, 3x / week was depicted on day 60. Detailed Implementation

[0048] On the one hand, the present invention is characterized by compounds represented by formula (IV):

[0049]

[0050] Or its pharmaceutically acceptable salts, N-oxides, hydrates, solvates, tautomers, or optical isomers.

[0051] in

[0052] W represents NR', alkenes, alkynes, and C. 1-8 Alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl containing 1-8 carbon atoms and heteroatoms, wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl optionally form a fused aryl or heteroaryl group with ring A;

[0053] U, Y, and Z are each either N or CR6, where R6 is either H or NR. a Rb ;

[0054] R7 and R8 are independently H, alkyl, alkenyl, alkynyl, halogen, nitro, OR c SR c CN, haloalkyl, O-haloalkyl, (CO)R d NR a R b NH(CO)R d NH(CO)OR c NH(CO)NR a R b (CO)OR c (CO)NR a R b SO2NR a R b cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

[0055] Alternatively, R7 and R8, together with the carbon atoms attached to them, form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, each optionally independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, halogen, nitro, OR c SR c CN, haloalkyl, O-haloalkyl, NR a R b (CO)R d (CO)OR c (CO)NR a R b SO2NR a R b Substitution with -C(CH3)(=N-NHC(NH)NH2 substituents;

[0056] Ring A is a 5- or 6-membered aryl or heteroaryl group, wherein ring A is optionally selected from alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, halogen, nitro, OR c SR c CN, haloalkyl, O-haloalkyl, NR m R n (CO)R d (CO)OR c SO2NR m R n (CO)NR m R n C(NH)NR m R n NH(CO)R d NH(CO)OR c NH(CO)NRm R n Substitution of aryl and heteroaryl groups;

[0057] R m and R n Each independently is

[0058] H, OH,

[0059] Alkyl group, -(CH2) p -T、-aryl-(CH2) p -T、-(CH2) p -aryl-T, -heteroaryl-(CH2) p -T、-(CH2) p -heteroaryl-T, each optionally prefixed with alkyl, halogen, nitro, CN, haloalkyl, O-haloalkyl, OR c SR c NR a R b (CO)R d NH(CO)R d NH(CO)OR c NH(CO)NR a R b ,NHC(NH)NH2,(CO)OR c (CO)NR a R b SO2NR a R b , arylamino or heteroarylamino substitution,

[0060] Or R m and R n Together with the nitrogen atom attached to them, they form a heterocyclic alkyl group, optionally prefixed with alkyl, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, halogen, nitro, CN, OR c SR c COR d NR a R b NH(CO)R d NH(CO)OR c NH(CO)NR a R b guanidine group, (CO)OR c Or (CO)NR a R b replace;

[0061] T is NR a R b OR c SRc O-(CH2) q -NR a R b , cycloalkyl, heterocycloalkyl, aryl, heteroaryl, guanidine group or isonicotinamide group;

[0062] R' is H, alkyl, or cycloalkyl;

[0063] R a R b R c and R d Each can be independently H, alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or -(CH2). q -cycloalkyl, -(CH) q -Heterocyclic alkyl, -(CH2) q -Aryl, -(CH) q -heteroaryl, -(CO)-alkyl, -(CO)-cycloalkyl, -(CO)-heterocyclic alkyl, -(SO2)-alkyl, -(SO2)-cycloalkyl or -(SO2)-heterocyclic alkyl, or R a and R b Together with the nitrogen atoms attached to them, they form heterocyclic alkyl groups, wherein the cycloalkyl, heterocyclic alkyl, aryl, and heteroaryl groups are each optionally substituted with groups consisting of alkyl, halogen, nitro, CN, haloalkyl, O-haloalkyl, OH, O-alkyl, SH, S-alkyl, NH2, NH(alkyl), and N(alkyl)2; and

[0064] p and q are each independently 0-8.

[0065] In some embodiments, the compounds of the present invention are represented by compounds of formula (V):

[0066]

[0067] Or its pharmaceutically acceptable salts, N-oxides, hydrates, solvates, tautomers, or optical isomers.

[0068] in

[0069] W is NR', -C≡C-, or a heterocyclic alkyl group containing a 5- or 6-membered ring, wherein R' is H or an alkyl group;

[0070] U, Y, and Z are each either N or CR6, where R6 is either H or NR. a R b ;

[0071] V, U1, Y1, and Z1 are each either N or CR6';

[0072] R1, R2, and R6' are each independently H, alkyl, cycloalkyl, halogen, nitro, or OR. c SR c CN, haloalkyl, O-haloalkyl or NR a R b ;

[0073] R3, R4, and R5 are each independently H, alkyl, cycloalkyl, heterocycloalkyl, halogen, nitro, or OR. c SR c CN, haloalkyl, O-haloalkyl, NR m R n (CO)R d (CO)OR c SO2NR m R n (CO)NR m R n C(NH)NR m R n NH(CO)R d NH(CO)OR c NH(CO)NR m R n aryl or heteroaryl;

[0074] R m and R n Each independently is

[0075] H, OH,

[0076] Alkyl group, -(CH2) p -T、-aryl-(CH2) p -T、-(CH2) p -aryl-T, -heteroaryl-(CH2) p -T、-(CH2) p -heteroaryl-T, each optionally prefixed with alkyl, cycloalkyl, halogen, nitro, CN, haloalkyl, O-haloalkyl, OR c SR c (CO)R d NR a R b NH(CO)R d NH(CO)OR c NH(CO)NR a R b ,NHC(NH)NH2,(CO)OR c (CO)NR a R b and SO2NR a Rb replace,

[0077] Or R m and R n Together with the nitrogen atom attached to them, they form a heterocyclic alkyl group, optionally prefixed with alkyl, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, halogen, nitro, CN, OR c SR c COR d NR a R b NH(CO)R d NH(CO)OR c NH(CO)NR a R b guanidine group, (CO)OR c and (CO)NR a R b replace;

[0078] T is NR a R b OR c SR c O-(CH2) q -NR a R b , cycloalkyl, heterocycloalkyl, aryl, heteroaryl, guanidine group or isonicotinamide group;

[0079] R a R b R c and R d Each can be independently H, alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or -(CH2). q -cycloalkyl, -(CH) q -Heterocyclic alkyl, -(CH2) q -Aryl, -(CH) q -heteroaryl, -(CO)-alkyl, -(CO)-cycloalkyl or -(CO)-heterocycloalkyl, or R a and R b Together with the nitrogen atoms attached to them, they form heterocyclic alkyl groups, wherein the cycloalkyl, heterocyclic alkyl, aryl, and heteroaryl groups are each optionally substituted with groups consisting of alkyl, halogen, nitro, CN, haloalkyl, O-haloalkyl, OH, O-alkyl, SH, S-alkyl, NH2, NH(alkyl), and N(alkyl)2; and

[0080] p and q are each independently 0-5.

[0081] In some implementations, R6 is NR a R b .

[0082] In some embodiments, one of R3, R4, and R5 is a heterocyclic alkyl group, CN, or NR. m R n (CO)R d (CO)OR c SO2NR m R n (CO)NR m R n C(NH)NR m R n Or NH(CO)R d .

[0083] In some implementations, one of R3, R4, and R5 is (CO)NR. m R n .

[0084] In some implementations, R m It is H, R n It is -(CH2) p -T、-aryl-(CH2) p -T、-(CH2) p -aryl-T or -heteroaryl-(CH2) p -T, each optionally prefixed with an alkyl group, halogen, or OR c replace.

[0085] In some implementations, T is NR a R b O-(CH2) q -NR a R b Heterocyclic alkyl, aryl, or heteroaryl.

[0086] In some implementations, R m and R n Together with the nitrogen atoms attached to them, they form a heterocyclic alkyl group, optionally replaced by alkyl, cycloalkyl, heterocyclic alkyl, or NR. a R b NH(CO)R d NH(CO)OR c and NH(CO)NR a R b replace.

[0087] In some embodiments, R1 and R2 are each independently H, alkyl, halogen, CN, OR c SR c Or NR a R b .

[0088] In some embodiments, the compounds of the present invention are compounds of the following formula:

[0089]

[0090]

[0091] Or its pharmaceutically acceptable salts, N-oxides, hydrates, solvates, tautomers, or optical isomers.

[0092] in

[0093] R1, R2, R 10 R 11 R 12 and R 13 Each can be independently H, alkyl, cycloalkyl, halogen, nitro, or OR. c SR c CN, haloalkyl, O-haloalkyl or NR a R b ;

[0094] R3, R4, and R5 are each independently H, alkyl, cycloalkyl, heterocycloalkyl, halogen, nitro, or OR. c SR c CN, haloalkyl, O-haloalkyl, NR m R n (CO)R d (CO)OR c SO2NR m R n (CO)NR m R n C(NH)NR m R n NH(CO)R d NH(CO)OR c NH(CO)NR m R n aryl or heteroaryl;

[0095] R6 is H or NR a R b ;

[0096] R m and R n Each independently is

[0097] H, OH,

[0098] Alkyl group, -(CH2) p -T、-aryl-(CH2) p -T、-(CH2)p -aryl-T, -heteroaryl-(CH2) p -T、-(CH2) p -heteroaryl-T, each optionally prefixed with alkyl, cycloalkyl, halogen, nitro, CN, haloalkyl, O-haloalkyl, OR c SR c (CO)R d NR a R b NH(CO)R d NH(CO)OR c NH(CO)NR a R b ,NHC(NH)NH2,(CO)OR c (CO)NR a R b and SO2NR a R b replace,

[0099] Or R m and R n Together with the nitrogen atom attached to them, they form a heterocyclic alkyl group, optionally prefixed with alkyl, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, halogen, nitro, CN, OR c SR c COR d NR a R b NH(CO)R d NH(CO)OR c NH(CO)NR a R b guanidine group, (CO)OR c and (CO)NR a R b replace;

[0100] T is NR a R b OR c SR c O-(CH2) q -NR a R b , cycloalkyl, heterocycloalkyl, aryl, heteroaryl, guanidine group or isonicotinamide group;

[0101] R a R b R c and R d Each can be independently H, alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or -(CH2). q-cycloalkyl, -(CH) q -Heterocyclic alkyl, -(CH2) q -Aryl, -(CH) q -heteroaryl, -(CO)-alkyl, -(CO)-cycloalkyl or -(CO)-heterocycloalkyl, or R a and R b Together with the nitrogen atoms attached to them, they form heterocyclic alkyl groups, wherein the cycloalkyl, heterocyclic alkyl, aryl, and heteroaryl groups are each optionally substituted with groups consisting of alkyl, halogen, nitro, CN, haloalkyl, O-haloalkyl, OH, O-alkyl, SH, S-alkyl, NH2, NH(alkyl), and N(alkyl)2; and

[0102] p and q are each independently 0-5.

[0103] In some implementations, R6 is NR a R b .

[0104] In some embodiments, one of R3, R4, and R5 is a heterocyclic alkyl group, CN, or NR. m R n (CO)R d (CO)OR c SO2NR m R n (CO)NR m R n C(NH)NR m R n Or NH(CO)R d .

[0105] In some implementations, one of R3, R4, and R5 is (CO)NR. m R n .

[0106] In some implementations, R m It is H, R n It is -(CH2) p -T、-aryl-(CH2) p -T、-(CH2) p -aryl-T or -heteroaryl-(CH2) p -T, each optionally prefixed with an alkyl group, halogen, or OR c replace.

[0107] In some implementations, T is NR a R b O-(CH2) q -NR a R bHeterocyclic alkyl, aryl, or heteroaryl.

[0108] In some implementations, R m and R n Together with the nitrogen atoms attached to them, they form a heterocyclic alkyl group, optionally replaced by alkyl, cycloalkyl, heterocyclic alkyl, or NR. a R b NH(CO)R d NH(CO)OR c and NH(CO)NR a R b replace.

[0109] In some embodiments, R1 and R2 are each independently H, alkyl, halogen, CN, OR c SR c Or NR a R b .

[0110] In some embodiments, the compounds of the present invention are compounds of the following formula:

[0111]

[0112]

[0113] Or its pharmaceutically acceptable salts, N-oxides, hydrates, solvates, tautomers, or optical isomers.

[0114] in

[0115] V, U1, Y1, and Z1 are each either N or CR6';

[0116] R1, R2, and R6' are each independently H, alkyl, cycloalkyl, halogen, nitro, or OR. c SR c CN, haloalkyl, O-haloalkyl or NR a R b ;

[0117] R3, R4, and R5 are each independently H, alkyl, cycloalkyl, heterocycloalkyl, halogen, nitro, or OR. c SR c CN, haloalkyl, O-haloalkyl, NR m R n (CO)R d (CO)OR c SO2NR m R n (CO)NR m R n C(NH)NRm R n NH(CO)R d NH(CO)OR c NH(CO)NR m R n aryl or heteroaryl;

[0118] R6 is H or NR a R b ;

[0119] R7 and R8 are independently H, alkyl, alkenyl, alkynyl, halogen, nitro, OR c SR c CN, haloalkyl, O-haloalkyl, (CO)R d NR a R b NH(CO)R d NH(CO)OR c NH(CO)NR a R b (CO)OR c (CO)NR a R b SO2NR a R b cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

[0120] R m and R n Each independently is

[0121] H, OH,

[0122] Alkyl group, -(CH2) p -T、-aryl-(CH2) p -T、-(CH2) p -aryl-T, -heteroaryl-(CH2) p -T、-(CH2) p -heteroaryl-T, each optionally prefixed with alkyl, cycloalkyl, halogen, nitro, CN, haloalkyl, O-haloalkyl, OR c SR c (CO)R d NR a R b NH(CO)R d NH(CO)OR c NH(CO)NR a R b ,NHC(NH)NH2,(CO)OR c (CO)NR a Rb and SO2NR a R b replace,

[0123] Or R m and R n Together with the nitrogen atom attached to them, they form a heterocyclic alkyl group, optionally prefixed with alkyl, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, halogen, nitro, CN, OR c SR c COR d NR a R b NH(CO)R d NH(CO)OR c NH(CO)NR a R b guanidine group, (CO)OR c and (CO)NR a R b replace;

[0124] T is NR a R b OR c SR c O-(CH2) q -NR a R b , cycloalkyl, heterocycloalkyl, aryl, heteroaryl, guanidine group or isonicotinamide group;

[0125] R a R b R c and R d Each can be independently H, alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or -(CH2). q -cycloalkyl, -(CH) q -Heterocyclic alkyl, -(CH2) q -Aryl, -(CH) q -heteroaryl, -(CO)-alkyl, -(CO)-cycloalkyl or -(CO)-heterocycloalkyl, or R a and R b Together with the nitrogen atoms attached to them, they form heterocyclic alkyl groups, wherein the cycloalkyl, heterocyclic alkyl, aryl, and heteroaryl groups are each optionally substituted with groups consisting of alkyl, halogen, nitro, CN, haloalkyl, O-haloalkyl, OH, O-alkyl, SH, S-alkyl, NH2, NH(alkyl), and N(alkyl)2; and

[0126] p and q are each independently 0-5.

[0127] In some implementations, R6 is NR a R b .

[0128] In some embodiments, one of R3, R4, and R5 is a heterocyclic alkyl group, CN, or NR. m R n (CO)R d (CO)OR c SO2NR m R n (CO)NR m R n C(NH)NR m R n Or NH(CO)R d .

[0129] In some implementations, one of R3, R4, and R5 is (CO)NR. m R n .

[0130] In some implementations, R m It is H, R n It is -(CH2) p -T、-aryl-(CH2) p -T、-(CH2) p -aryl-Tf or -heteroaryl-(CH2) p -T, each optionally prefixed with an alkyl group, halogen, or OR c replace.

[0131] In some implementations, T is NR a R b O-(CH2) q -NR a R b Heterocyclic alkyl, aryl, or heteroaryl.

[0132] In some implementations, R m and R n Together with the nitrogen atoms attached to them, they form a heterocyclic alkyl group, optionally replaced by alkyl, cycloalkyl, heterocyclic alkyl, or NR. a R b NH(CO)R d NH(CO)OR c and NH(CO)NR a R b replace.

[0133] In some embodiments, R1 and R2 are each independently H, alkyl, halogen, CN, OR c SR c Or NRa R b .

[0134] In some embodiments, the compound is a compound of the following formula:

[0135]

[0136]

[0137] Or its pharmaceutically acceptable salts, N-oxides, hydrates, solvates, tautomers, or optical isomers.

[0138] in

[0139] V, U1, Y1, and Z1 are each either N or CR6';

[0140] R1, R2, and R6' are each independently H, alkyl, cycloalkyl, halogen, nitro, or OR. c SR c CN, haloalkyl, O-haloalkyl or NR a R b ;

[0141] R3, R4, and R5 are each independently H, alkyl, cycloalkyl, heterocycloalkyl, halogen, nitro, or OR. c SR c CN, haloalkyl, O-haloalkyl, NR m R n (CO)R d (CO)OR c SO2NR m R n (CO)NR m R n C(NH)NR m R n NH(CO)R d NH(CO)OR c NH(CO)NR m R n aryl or heteroaryl;

[0142] R6 is H or NR a R b ;

[0143] R7 and R8 are independently H, alkyl, alkenyl, alkynyl, halogen, nitro, OR c SR c CN, haloalkyl, O-haloalkyl, (CO)R d NR a R bNH(CO)R d NH(CO)OR c NH(CO)NR a R b (CO)OR c (CO)NR a R b SO2NR a R b cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

[0144] R m and R n Each independently is

[0145] H, OH,

[0146] Alkyl group, -(CH2) p -T、-aryl-(CH2) p -T、-(CH2) p -aryl-T, -heteroaryl-(CH2) p -T、-(CH2) p -heteroaryl-T, each optionally prefixed with alkyl, cycloalkyl, halogen, nitro, CN, haloalkyl, O-haloalkyl, OR c SR c (CO)R d NR a R b NH(CO)R d NH(CO)OR c NH(CO)NR a R b ,NHC(NH)NH2,(CO)OR c (CO)NR a R b and SO2NR a R b replace,

[0147] Or R m and R n Together with the nitrogen atom attached to them, they form a heterocyclic alkyl group, optionally prefixed with alkyl, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, halogen, nitro, CN, OR c SR c COR d NR a R b NH(CO)R d NH(CO)OR c NH(CO)NR a R b guanidine group, (CO)ORc and (CO)NR a R b replace;

[0148] T is NR a R b OR c SR c O-(CH2) q -NR a R b , cycloalkyl, heterocycloalkyl, aryl, heteroaryl, guanidine group or isonicotinamide group;

[0149] R a R b R c and R d Each can be independently H, alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or -(CH2). q -cycloalkyl, -(CH) q -Heterocyclic alkyl, -(CH2) q -Aryl, -(CH) q -heteroaryl, -(CO)-alkyl, -(CO)-cycloalkyl or -(CO)-heterocycloalkyl, or R a and R b Together with the nitrogen atoms attached to them, they form heterocyclic alkyl groups, wherein the cycloalkyl, heterocyclic alkyl, aryl, and heteroaryl groups are each optionally substituted with groups consisting of alkyl, halogen, nitro, CN, haloalkyl, O-haloalkyl, OH, O-alkyl, SH, S-alkyl, NH2, NH(alkyl), and N(alkyl)2; and

[0150] p and q are each independently 0-5.

[0151] In some implementations, R6 is NR a R b .

[0152] In some embodiments, one of R3, R4, and R5 is a heterocyclic alkyl group, CN, or NR. m R n (CO)R d (CO)OR c SO2NR m R n (CO)NR m R n C(NH)NR m R n Or NH(CO)R d .

[0153] In some implementations, one of R3, R4, and R5 is (CO)NR. m R n .

[0154] In some implementations, R m It is H, R n It is -(CH2) p -T、-aryl-(CH2) p -T、-(CH2) p -aryl-T or -heteroaryl-(CH2) p -T, each optionally prefixed with an alkyl group, halogen, or OR c replace.

[0155] In some implementations, T is NR a R b O-(CH2) q -NR a R b Heterocyclic alkyl, aryl, or heteroaryl.

[0156] In some implementations, R m and R n Together with the nitrogen atoms attached to them, they form a heterocyclic alkyl group, optionally replaced by alkyl, cycloalkyl, heterocyclic alkyl, or NR. a R b NH(CO)R d NH(CO)OR c and NH(CO)NR a R b replace.

[0157] In some embodiments, R1 and R2 are each independently H, alkyl, halogen, CN, OR c SR c Or NR a R b .

[0158] In some embodiments, the compound is a compound of formula (XV):

[0159]

[0160] Or pharmaceutically acceptable salts, N-oxides, hydrates, solvates,

[0161] in

[0162] R' is H or an alkyl group;

[0163] R1, R2, R 10 R 11 R 12 and R13 Each can be independently H, alkyl, cycloalkyl, halogen, nitro, or OR. c SR c CN, haloalkyl, O-haloalkyl or NR a R b ;

[0164] R3, R4, and R5 are each independently H, alkyl, cycloalkyl, heterocycloalkyl, halogen, nitro, or OR. c SR c CN, haloalkyl, O-haloalkyl, NR m R n (CO)R d (CO)OR c SO2NR m R n (CO)NR m R n C(NH)NR m R n NH(CO)R d NH(CO)OR c NH(CO)NR m R n aryl or heteroaryl;

[0165] R m and R n Each independently is

[0166] H, OH,

[0167] Alkyl group, -(CH2) p -T、-aryl-(CH2) p -T、-(CH2) p -aryl-T, -heteroaryl-(CH2) p -T、-(CH2) p -heteroaryl-T, each optionally prefixed with alkyl, cycloalkyl, halogen, nitro, CN, haloalkyl, O-haloalkyl, OR c SR c (CO)R d NR a R b NH(CO)R d NH(CO)OR c NH(CO)NR a R b ,NHC(NH)NH2,(CO)OR c (CO)NR a R b and SO2NR a Rb replace,

[0168] Or R m and R n Together with the nitrogen atom attached to them, they form a heterocyclic alkyl group, optionally prefixed with alkyl, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, halogen, nitro, CN, OR c SR c COR d NR a R b NH(CO)R d NH(CO)OR c NH(CO)NR a R b guanidine group, (CO)OR c and (CO)NR a R b replace;

[0169] T is NR a R b OR c SR c O-(CH2) q -NR a R b , cycloalkyl, heterocycloalkyl, aryl, heteroaryl, guanidine group or isonicotinamide group;

[0170] R a R b R c and R d Each can be independently H, alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or -(CH2). q -cycloalkyl, -(CH) q -Heterocyclic alkyl, -(CH2) q -Aryl, -(CH) q -heteroaryl, -(CO)-alkyl, -(CO)-cycloalkyl or -(CO)-heterocycloalkyl, or R a and R b Together with the nitrogen atoms attached to them, they form heterocyclic alkyl groups, wherein the cycloalkyl, heterocyclic alkyl, aryl, and heteroaryl groups are each optionally substituted with groups consisting of alkyl, halogen, nitro, CN, haloalkyl, O-haloalkyl, OH, O-alkyl, SH, S-alkyl, NH2, NH(alkyl), and N(alkyl)2; and

[0171] p and q are each independently 0-5.

[0172] In some implementations, R' is H.

[0173] In some embodiments, one of R3, R4, and R5 is a heterocyclic alkyl group, CN, or NR. m R n (CO)R d (CO)OR c SO2NR m R n (CO)NR m R n C(NH)NR m R n Or NH(CO)R d .

[0174] In some implementations, one of R3, R4, and R5 is (CO)NR. m R n .

[0175] In some implementations, R m It is H, R n It is -(CH2) p -T、-aryl-(CH2) p -T、-(CH2) p -aryl-T or -heteroaryl-(CH2) p -T, each optionally prefixed with an alkyl group, halogen, or OR c replace.

[0176] In some implementations, T is NR a R b O-(CH2) q -NR a R b Heterocyclic alkyl, aryl, or heteroaryl.

[0177] In some implementations, R m and R n Together with the nitrogen atoms attached to them, they form a heterocyclic alkyl group, optionally replaced by alkyl, cycloalkyl, heterocyclic alkyl, or NR. a R b NH(CO)R d NH(CO)OR c and NH(CO)NR a R b replace.

[0178] In some embodiments, R1 and R2 are each independently H, alkyl, halogen, CN, OR c SR c Or NR a R b .

[0179] This invention provides compounds represented by formula (I):

[0180]

[0181] Or its pharmaceutically acceptable salts, N-oxides, hydrates, solvates, tautomers, or optical isomers.

[0182] in

[0183] Ring A is a 5- or 6-membered aryl or heteroaryl group, which may be optionally substituted;

[0184] Y and Z are each N or CR9, where R9 is H, alkyl, halogen, nitro, OH, SH, CN, O-alkyl, haloalkyl, O-haloalkyl, S-alkyl, (CO)-alkyl, (CO)-alkenyl, NR a R b (CO)OR c (CO)NR a R b Or SO2NR a R b , where R a R b and R c It is H or an alkyl group;

[0185] W represents azo compounds, alkenes, and alkynes, while C represents... 1-8 Alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl containing 1-8 carbon atoms and heteroatoms, wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl optionally form a fused aryl or heteroaryl group with ring A;

[0186] R6, R7, and R8 are each independently H, alkyl, alkenyl, alkynyl, halogen, nitro, OH, SH, CN, O-alkyl, haloalkyl, O-haloalkyl, S-alkyl, (CO)-alkyl, (CO)-alkene, NR a R b NH(CO)-alkyl, NH(CO)OR c NH(CO)NR a R b (CO)OR c (CO)NR a R b SO2NR a R b , cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

[0187] Alternatively, R7 and R8, together with the carbon atoms attached to them, form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, each optionally independently selected from alkyl, alkenyl, alkynyl, halogen, nitro, OH, SH, CN, O-alkyl, haloalkyl, O-haloalkyl, S-alkyl, (CO)-alkyl, (CO)-alkenyl, NR a R b (CO)OR c (CO)NR a R b SO2NR a R b The substituents of -C(CH3)(=N-NHC(NH)NH2, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are substituted, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally substituted by an amino, alkylamino, alkylamino, -NH(CO)-alkyl or -NH(CO)-alkenyl.

[0188] Ring A may optionally be substituted independently by substituents selected from the following:

[0189] Alkyl, alkenyl, alkynyl, halogen, nitro, OH, SH, CN, O-alkyl, haloalkyl, O-haloalkyl, S-alkyl, (CO)-alkyl, (CO)-alkenyl, NR a R b NH(CO)-alkyl, NH(CO)OR c NH(CO)NR a R b (CO)OR c SO2NR a R b ;

[0190] Cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each optionally substituted by a substituent independently selected from alkyl, aminoalkyl, heterocycloalkyl-alkyl, heterocycloalkyl, cycloalkyl-alkyl, and cycloalkyl; and

[0191] (CO)NR m R N or C NH)NR m R n , where R m and R n Each can be independently H, alkyl, or -(CH2). p -T, cycloalkyl, heterocyclic aryl, aryl, or heteroaryl, wherein -(CH2) p-T, cycloalkyl, heterocyclic aryl, aryl, and heteroaryl are each optionally prefixed with alkyl, halogen, nitro, CN, OH, SH, O-alkyl, S-alkyl, (CO)-alkyl, (CO)-alkenyl, NR a R b (CO)OR c (CO)NR a R b SO2NR a R b Substitution with cycloalkylamino, heterocycloalkylamino, arylamino, or heteroarylamino;

[0192] Or R m and R n Together with the nitrogen atoms attached to them, they form heterocyclic alkyl or heteroaryl groups, optionally surrounded by alkyl, halogen, nitro, CN, OH, SH, O-alkyl, S-alkyl, -CO-alkyl, -CO-olefin, NR a R b (CO)OR c Or (CO)NR a R b replace;

[0193] Where p is 0-8; and

[0194] Where T is NR a R b O-alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylamino, heterocycloalkylamino, arylamino, heteroarylamino, guanidine group or isonicotinamide group.

[0195] In some implementations, Y is N.

[0196] In some implementations, Z is CH.

[0197] In some embodiments, W is an azo group, -CH=CH-, -C≡C-, phenyl, or a 5- or 6-membered heteroaryl group. In other embodiments, W is an azo group. In some embodiments, W is -C≡C-.

[0198] In some implementations, R6 is (CO)NR m R n In other embodiments, R6 is C(NH)NR m R n .

[0199] In some implementations, R6 is NH2.

[0200] In some embodiments, the compound of formula (I) is represented by the following formula:

[0201]

[0202] in

[0203] R1 and R2 are each independently H, alkyl, alkenyl, alkynyl, halogen, nitro, OH, SH, CN, O-alkyl, haloalkyl, O-haloalkyl, S-alkyl, (CO)-alkyl, (CO)-alkene, NR a R b NH(CO)-alkyl, NH(CO)OR c NH(CO)NR a R b (CO)OR c (CO)NR a R b SO2NR a R b , cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

[0204] R3 is:

[0205] H or CN;

[0206] Cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each optionally substituted by a substituent independently selected from alkyl, aminoalkyl, heterocycloalkyl-alkyl, heterocycloalkyl, cycloalkyl-alkyl, and cycloalkyl; and

[0207] (CO)NR m R N or C (NH)NR m R n , where R m and R n Each can be independently H, alkyl, or -(CH2). p -T, cycloalkyl, heterocyclic aryl, aryl, or heteroaryl, wherein -(CH2) p -T, cycloalkyl, heterocyclic aryl, aryl, and heteroaryl are each optionally prefixed with alkyl, halogen, nitro, CN, OH, SH, O-alkyl, S-alkyl, (CO)-alkyl, (CO)-alkenyl, NR a R b (CO)OR c (CO)NR a R b SO2NR a R b Substitution with cycloalkylamino, heterocycloalkylamino, arylamino, or heteroarylamino;

[0208] Or R m and R nTogether with the nitrogen atoms attached to them, they form heterocyclic alkyl or heteroaryl groups, optionally surrounded by alkyl, halogen, nitro, CN, OH, SH, O-alkyl, S-alkyl, -CO-alkyl, -CO-olefin, NR a R b (CO)OR c Or (CO)NR a R b replace;

[0209] p is 0-8; and

[0210] T is NR a R b O-alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylamino, heterocycloalkylamino, arylamino, heteroarylamino, guanidine group or isonicotinamide group.

[0211] In some embodiments, the compound of formula (I) is represented by the following formula:

[0212]

[0213] in

[0214] E, Y2, Y3, Y4, and Y5 are respectively O, S, N, or NR. 14 , where R 14 It is H, alkyl, (CO)-alkyl, (CO)OR c (CO)NR a R b Or SO2NR a R b ;

[0215] R3 is:

[0216] H or CN;

[0217] Cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each optionally substituted by a substituent independently selected from alkyl, aminoalkyl, heterocycloalkyl-alkyl, heterocycloalkyl, cycloalkyl-alkyl, and cycloalkyl; and

[0218] (CO)NR m R N or C (NH)NR m R n , where R m and R n Each can be independently H, alkyl, or -(CH2). p -T, cycloalkyl, heterocyclic aryl, aryl, or heteroaryl, wherein -(CH2) p-T, cycloalkyl, heterocyclic aryl, aryl, and heteroaryl are each optionally prefixed with alkyl, halogen, nitro, CN, OH, SH, O-alkyl, S-alkyl, (CO)-alkyl, (CO)-alkenyl, NR a R b (CO)OR c (CO)NR a R b SO2NR a R b Substitution with cycloalkylamino, heterocycloalkylamino, arylamino, or heteroarylamino;

[0219] Or R m and R n Together with the nitrogen atoms attached to them, they form heterocyclic alkyl or heteroaryl groups, optionally surrounded by alkyl, halogen, nitro, CN, OH, SH, O-alkyl, S-alkyl, -CO-alkyl, -CO-olefin, NR a R b (CO)OR c Or (CO)NR a R b replace;

[0220] P is 0-8; and

[0221] T is NR a R b O-alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylamino, heterocycloalkylamino, arylamino, heteroarylamino, guanidine group or isonicotinamide group.

[0222] In some embodiments, the compound of formula (I) is represented by formula (Ia).

[0223]

[0224] in

[0225] R1, R2, R4, and R5 are each independently H, alkyl, alkenyl, alkynyl, halogen, nitro, OH, SH, CN, O-alkyl, haloalkyl, O-haloalkyl, S-alkyl, (CO)-alkyl, (CO)-alkene, NR a R b NH(CO)-alkyl, NH(CO)OR c NH(CO)NR a R b (CO)OR c (CO)NR a R b SO2NR a R b, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

[0226] R3 is:

[0227] H or CN;

[0228] Cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each optionally substituted by a substituent independently selected from alkyl, aminoalkyl, heterocycloalkyl-alkyl, heterocycloalkyl, cycloalkyl-alkyl, and cycloalkyl; and

[0229] (CO)NR m R N or C (NH)NR m R n , where R m and R n Each can be independently H, alkyl, or -(CH2). p -T, cycloalkyl, heterocyclic aryl, aryl, or heteroaryl, wherein -(CH2) p -T, cycloalkyl, heterocyclic aryl, aryl, and heteroaryl are each optionally prefixed with alkyl, halogen, nitro, CN, OH, SH, O-alkyl, S-alkyl, (CO)-alkyl, (CO)-alkenyl, NR a R b (CO)OR c (CO)NR a R b SO2NR a R b Substitution with cycloalkylamino, heterocycloalkylamino, arylamino, or heteroarylamino;

[0230] Or R m and R n Together with the nitrogen atoms attached to them, they form heterocyclic alkyl or heteroaryl groups, optionally surrounded by alkyl, halogen, nitro, CN, OH, SH, O-alkyl, S-alkyl, -CO-alkyl, -CO-olefin, NR a R b (CO)OR c Or (CO)NR a R b replace;

[0231] P is 0-8; and

[0232] T is NR a R b O-alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylamino, heterocycloalkylamino, arylamino, heteroarylamino, guanidine group or isonicotinamide group.

[0233] In some embodiments, the compound of formula (Ia) is represented by the compound of formula (II).

[0234]

[0235] in

[0236] R 10 R 11 R 12 and R 13 Each of the following can be independently H, alkyl, alkenyl, alkynyl, halogen, nitro, OH, SH, CN, O-alkyl, haloalkyl, O-haloalkyl, S-alkyl, (CO)-alkyl, (CO)-alkene, NR a R b (CO)OR c (CO)NR a R b SO2NR a R b -C(CH3)(=N-NHC(NH)NH2, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally substituted with an amino, alkylamino, dialkylamino, -NH(CO)-alkyl or -NH(CO)-alkenyl.

[0237] In some implementations, R6, R 10 R 11 R 12 and R 13 Each can be independently H, alkyl, alkynyl, halogen, OH, CN, amino, alkylamino, or dialkylamino.

[0238] In some implementations, R 11 It is an alkynyl group, optionally substituted with an amino, alkylamino, dialkylamino, or -NH(CO)-alkenyl group. In other embodiments, R 11 It is a halogen. In some embodiments, R 11 It is chlorine.

[0239] In some implementations, R6 is NH2.

[0240] In some implementations, R1, R2, R4, and R5 are each H.

[0241] In some embodiments, R3 is CN. In other embodiments, R3 is a heterocyclic alkyl or heteroaryl group, optionally substituted with alkyl, aminoalkyl, heterocyclic alkyl-alkyl, heterocyclic alkyl, cycloalkyl-alkyl, and cycloalkyl.

[0242] In some implementations, R3 is (CO)NR mR n In other embodiments, R3 is C(NH)NR m R n In some implementations, R m It is H, R n It is a heterocyclic alkyl group. In some embodiments, R m It is H, R n It is (CH2) p -T, optionally substituted with an alkyl group, a halogen, or OH. In some embodiments, p is 1-4.

[0243] In some implementations, T is NR a R b Or O-alkyl. In some embodiments, T is -N(alkyl)2. In some embodiments, T is N(CH3)2. In other embodiments, T is OCH3. In some embodiments, T is a heterocyclic alkylamino, guanidine, or isonicotinamide group. In some embodiments, T is a heterocyclic alkyl. In some embodiments, T is a 5- or 6-membered heterocyclic alkyl group. In some embodiments, T is piperidine or pyrrolidine.

[0244] In some implementations, R m It is H, R n It is aryl or heteroaryl. In other embodiments, R m and R n Together with the nitrogen atoms that connect them, they form heterocyclic alkyl groups. In some embodiments, R m and R n It is an alkyl group on its own.

[0245] In some embodiments, the compound of formula (II) is represented by the compound of formula (III):

[0246]

[0247] In some embodiments, the compound of formula (I) is derived from formula IV. a -IV f The compound is represented as:

[0248]

[0249] in

[0250] R1, R2, R4, R5, R 10 and R 13 Each of the following can be independently H, alkyl, alkenyl, alkynyl, halogen, nitro, OH, SH, CN, O-alkyl, haloalkyl, O-haloalkyl, S-alkyl, (CO)-alkyl, (CO)-alkene, NR a Rb NH(CO)-alkyl, NH(CO)OR c NH(CO)NR a R b (CO)OR c (CO)NR a R b SO2NR a R b , cycloalkyl, heterocycloalkyl, aryl or heteroaryl; and

[0251] R 11 and R 12 Each of the following can be independently H, alkyl, alkenyl, alkynyl, halogen, nitro, OH, SH, CN, O-alkyl, haloalkyl, O-haloalkyl, S-alkyl, (CO)-alkyl, (CO)-alkene, NR a R b (CO)OR c (CO)NR a R b SO2NR a R b -C(CH3)(=N-NHC(NH)NH2, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally substituted with an amino, alkylamino, dialkylamino, -NH(CO)-alkyl or -NH(CO)-alkenyl.

[0252] In some implementations, R m It is H, R n It is (CH2) p -T, optionally replaced by OH. In other embodiments, R m and R n Independently, it is an alkyl group. In some embodiments, p is 1-4. In some embodiments, T is NR. a R b Or O-alkyl. In some embodiments, T is N(CH3)2. In other embodiments, T is OCH3. In some embodiments, T is a heterocyclic alkyl group. In some embodiments, T is a 5- or 6-membered heterocyclic alkyl group. In some embodiments, T is piperidine or pyrrolidine.

[0253] In some implementations, R m and R n Together with the nitrogen atoms that connect them, they form 5- or 6-membered heterocyclic alkyl groups.

[0254] In some implementations, R6 is NH2.

[0255] In some implementations, R 11 It is a halogen. In some embodiments, R 11 It is chlorine.

[0256] In some embodiments, the compound of the present invention is

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263]

[0264] In some embodiments, the compound of the present invention is

[0265]

[0266]

[0267]

[0268] In some embodiments, the compound of the present invention is

[0269]

[0270]

[0271] In some embodiments, the compound of the present invention is

[0272]

[0273]

[0274] In some embodiments, the compound of the present invention is

[0275]

[0276]

[0277]

[0278]

[0279] In some embodiments, the compound of the present invention is

[0280]

[0281] In some embodiments, the compound of the present invention is

[0282]

[0283]

[0284] In some embodiments, the compound of the present invention is

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295]

[0296]

[0297] In some embodiments, the compound of the present invention is

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304]

[0305]

[0306] Or a pharmaceutically acceptable salt, N-oxide, hydrate, solvate, tautomer, or optical isomer thereof.

[0307] In some embodiments, the compound of formula (I) of the present invention is derived from formula V. a -V f The compound represents

[0308]

[0309] in

[0310] R1, R2, R4, and R5 are each independently H, alkyl, alkenyl, alkynyl, halogen, nitro, OH, SH, CN, O-alkyl, haloalkyl, O-haloalkyl, S-alkyl, (CO)-alkyl, (CO)-alkene, NR a R b NH(CO)-alkyl, NH(CO)OR c NH(CO)NR a R b (CO)OR c (CO)NR a R b SO2NR a R b , cycloalkyl, heterocycloalkyl, aryl or heteroaryl; and

[0311] R 11 and R 12 Each of the following can be independently H, alkyl, alkenyl, alkynyl, halogen, nitro, OH, SH, CN, O-alkyl, haloalkyl, O-haloalkyl, S-alkyl, (CO)-alkyl, (CO)-alkene, NR a R b (CO)OR c (CO)NR a R b SO2NR a R b -C(CH3)(=N-NHC(NH)NH2, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally substituted with an amino, alkylamino, dialkylamino, -NH(CO)-alkyl or -NH(CO)-alkenyl.

[0312] In some embodiments, the compound of formula (I) of the present invention is derived from formula VI. a -VIc The compound represents

[0313]

[0314] in

[0315] R', R1, R2, R4, and R5 are each independently H, alkyl, alkenyl, alkynyl, halogen, nitro, OH, SH, CN, O-alkyl, haloalkyl, O-haloalkyl, S-alkyl, (CO)-alkyl, (CO)-alkenyl, NR a R b NH(CO)-alkyl, NH(CO)OR c NH(CO)NR a R b (CO)OR c (CO)NR a R b SO2NR a R b , cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein each R' is the same or different;

[0316] R 11 and R 12 Each of the following can be independently H, alkyl, alkenyl, alkynyl, halogen, nitro, OH, SH, CN, O-alkyl, haloalkyl, O-haloalkyl, S-alkyl, (CO)-alkyl, (CO)-alkene, NR a R b (CO)OR c (CO)NR a R b SO2NR a R b -C(CH3) (=N-NHC(NH)NH2, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups is optionally substituted with an amino, alkylamino, dialkylamino, -NH(CO)-alkyl or -NH(CO)-alkenyl group; and

[0317] R 14 It is H, alkyl, (CO)-alkyl, (CO)OR c (CO)NR a R b Or SO2NR a R b .

[0318] In some embodiments, the compound of formula (I) of the present invention is derived from formula VII. a -VII c The compound represents

[0319]

[0320] in

[0321] R1, R2, R4, R5, R 16 R 17 R 18 and R 19 Each of the following can be independently H, alkyl, alkenyl, alkynyl, halogen, nitro, OH, SH, CN, O-alkyl, haloalkyl, O-haloalkyl, S-alkyl, (CO)-alkyl, (CO)-alkene, NR a R b NH(CO)-alkyl, NH(CO)OR c NH(CO)NR a R b (CO)OR c (CO)NR a R b SO2NR a R b , cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

[0322] R 11 and R 12 Each of the following can be independently H, alkyl, alkenyl, alkynyl, halogen, nitro, OH, SH, CN, O-alkyl, haloalkyl, O-haloalkyl, S-alkyl, (CO)-alkyl, (CO)-alkene, NR a R b (CO)OR c (CO)NR a R b SO2NR a R b -C(CH3) (=N-NHC(NH)NH2, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups is optionally substituted with an amino, alkylamino, dialkylamino, -NH(CO)-alkyl or -NH(CO)-alkenyl group; and

[0323] R 14 It is H, alkyl, (CO)-alkyl, (CO)OR c (CO)NR a R b Or SO2NR a R b .

[0324] In some embodiments, the compound of formula (I) of the present invention is derived from formula VIII. a -VIIIf The compound represents

[0325]

[0326] in

[0327] E is O, S, or NR 14 ;

[0328] R1, R2, R4, and R5 are each independently H, alkyl, alkenyl, alkynyl, halogen, nitro, OH, SH, CN, O-alkyl, haloalkyl, O-haloalkyl, S-alkyl, (CO)-alkyl, (CO)-alkene, NR a R b NH(CO)-alkyl, NH(CO)OR c NH(CO)NR a R b (CO)OR c (CO)NR a R b SO2NR a R b , cycloalkyl, heterocycloalkyl, aryl or heteroaryl; and

[0329] R 14 and R 15 Each can be independently H, alkyl, (CO)-alkyl, or (CO)OR. c (CO)NR a R b Or SO2NR a R b .

[0330] In some embodiments, the compound of formula (I) of the present invention is derived from formula IX. a -IX f The compound represents

[0331]

[0332] Where E is O, S, or NR 14 ;

[0333] R1, R2, R4, and R5 are each independently H, alkyl, alkenyl, alkynyl, halogen, nitro, OH, SH, CN, O-alkyl, haloalkyl, O-haloalkyl, S-alkyl, (CO)-alkyl, (CO)-alkene, NR a R b NH(CO)-alkyl, NH(CO)OR c NH(CO)NR a R b (CO)ORc (CO)NR a R b SO2NR a R b , cycloalkyl, heterocycloalkyl, aryl or heteroaryl; and

[0334] R 14 and R 15 Each can be independently H, alkyl, (CO)-alkyl, or (CO)OR. c (CO)NR a R b Or SO2NR a R b .

[0335] In some embodiments, the compounds of formula (I) of the present invention are represented by compounds of formulas Xa-Xf.

[0336]

[0337] in

[0338] E is O, S, or NR 14 ;

[0339] R1, R2, R4, R5, R 10 and R 13 Each of the following can be independently H, alkyl, alkenyl, alkynyl, halogen, nitro, OH, SH, CN, O-alkyl, haloalkyl, O-haloalkyl, S-alkyl, (CO)-alkyl, (CO)-alkene, NR a R b NH(CO)-alkyl, NH(CO)OR c NH(CO)NR a R b (CO)OR c (CO)NR a R b SO2NR a R b , cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

[0340] R1 and R 12 Each of the following can be independently H, alkyl, alkenyl, alkynyl, halogen, nitro, OH, SH, CN, O-alkyl, haloalkyl, O-haloalkyl, S-alkyl, (CO)-alkyl, (CO)-alkene, NR a R b (CO)OR c (CO)NR a R b SO2NR a Rb -C(CH3) (=N-NHC(NH)NH2, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein each of the alkyl, alkenyl, alkynyl ring, alkyl, heterocycloalkyl, aryl and heteroaryl is optionally substituted with an amino, alkylamino, dialkylamino, -NH(CO)-alkyl or -NH(CO)-alkenyl; and

[0341] R 14 and R 15 Each can be independently H, alkyl, (CO)-alkyl, or (CO)OR. c (CO)NR a R b Or SO2NR a R b .

[0342] In some embodiments, the compound of formula (I) of the present invention is derived from formula XI. a -XI f The compound represents

[0343]

[0344] in

[0345] E is O, S, or NR 14 ;

[0346] R1, R2, R4, and R5 are each independently H, alkyl, alkenyl, alkynyl, halogen, nitro, OH, SH, CN, O-alkyl, haloalkyl, O-haloalkyl, S-alkyl, (CO)-alkyl, (CO)-alkene, NR a R b NH(CO)-alkyl, NH(CO)OR c NH(CO)NR a R b (CO)OR c (CO)NR a R b SO2NR a R b , cycloalkyl, heterocycloalkyl, aryl or heteroaryl; and

[0347] R 14 and R 15 Each can be independently H, alkyl, (CO)-alkyl, or (CO)OR. c (CO)NR a R b Or SO2NR a R b .

[0348] The compounds of the present invention can be prepared by methods known in the art and by reaction schemes and experimental methods as described herein.

[0349] Scheme 1 provides a general reaction scheme for preparing the compounds of the present invention by halogenation followed by functionalization.

[0350] Option 1: Functionalization after halogenation

[0351]

[0352] For compounds containing alkynes, the compounds of the present invention can be prepared by the sedge coupling method as described in Scheme 2.

[0353] Option 2: Preparation of alkyne-containing compounds via sedge coupling method.

[0354]

[0355] Scheme 3 describes the preparation of the compound of the present invention via Suzuki coupling.

[0356] Option 3: Combine Suzuki puppets

[0357]

[0358] The compounds of the present invention can be prepared by functionalizing isoquinolinamine according to Scheme 4.

[0359] Option 4: Functionalization of isoquinolinamine

[0360]

[0361] Scheme 5 provides a general synthetic strategy for synthesizing functionalized 1-amino, 2-amino, or 3-aminoisoquinolines, quinolines / quinazolines, and isoquinolines using quinolines, isoquinolines, or quinazolineamines as nucleophiles.

[0362] Option 5: Synthesis of functionalized 1-amino, 2-amino, or 3-aminoisoquinolines, quinolines / quinazolines, and isoquinolines

[0363]

[0364] Scheme 6 provides a general synthetic strategy for synthesizing 4-substituted isoquinolines, quinolones, and quinazolines.

[0365] Scheme 6: Synthesis of 4-substituted isoquinolines, quinolones, and quinazolines

[0366]

[0367] Scheme 7 provides the synthesis of the target compound via coupling with Sophora flavescens.

[0368] Option 7: Synthesis of target compounds via coupling with Sophora flavescens

[0369]

[0370] Conditions: Pd(PPh3)2Cl2 (5 mol%), CuI (5 mol%), PPh3 (0.1 equivalent), triethylamine (22 equivalent), 50℃, 12h.

[0371] exist Figure 7 The general synthetic strategy for preparing the compounds of the present invention is described in the paper, which involves replacing the halogen on quinoline, isoquinoline, or quinazoline.

[0372] In some implementations, in Figure 4-6 The compounds of the present invention are described in [the document / document].

[0373] In some embodiments, as demonstrated in Scheme 8, the compounds of the present invention can be readily prepared by catalytic stigmatic or suzuki coupling of iodoaryl hydrocarbons with alkynes or olefin borates via Pd(PPh3)2Cl2 (stigma coupling) or Pd(PPh3)4 (suzuki coupling) (e.g., in Table 4).

[0374] Option 8: Synthesis of alkyne and olefin analogs of the compounds of the present invention

[0375]

[0376] NIS (N-iodosuccinimide); DIPEA (diisopropylethylamine); DMF (dimethylformamide)

[0377] In the compounds of this invention, the properties and substitution methods of the amide and amidine head groups significantly affect the anticancer properties of the compounds. By systematically altering the functionality of the amide and amidine, these compounds have been identified as being approximately two orders of magnitude more potent than the compound previously reported by Sintim et al. (PCT / US2015 / 041551).

[0378] As shown in Figure 1, in the compounds of the present invention, the length, substitution mode, and relative position of the amide head group significantly affect the anticancer activity against the MV4-11 cell line (AML cell line). For example, the nature of the amide group in the molecule shown in Figure 1 has a significant impact on the anticancer activity of the tested molecule.

[0379] For example, compounds HSM1669, M731, and HSM1684 differ from each other due to their simple methylene groups (CH2), but their anticancer activities against AML are 260 nM (HSM1669), 36 nM (HSM731), and 71 nM (HSM1684). It appears that the anticancer efficacy increases with the addition of another methylene group (HSM1669 to M731), but on the other hand, the anticancer efficacy decreases when another methylene group is added (M731 to HSM1684). Furthermore, depending on the nature of the amide linking group, the relative positions of the alkyne and amide moiety appear to affect the anticancer efficacy. For example, the relationship between M731 and HSM1688 (para vs. meta substitution) is similar to that between HSD79 and HSD82, but M731 exhibits higher anticancer activity than HSM1688 (36 nM vs. 250 nM; almost a fold difference), while HSD79 and HSD82 show similar anticancer activities (108 nM vs. 150 nM). This suggests that the effect of the substitution mode of the benzamide moiety on anticancer activity (para vs. meta vs. ortho) is context-dependent.

[0380] For the para-analytes M731, HSM1692, and HSD79 (analytes with different 4* positions), the anticancer activity (IC50) against MV4-11 was 36 nM, 450 nM, and 108 nM, respectively, indicating the necessity of the nitrogen group at the 4* position. However, for the meta-analytes HSM1688 and HSD82, the IC50 value was 250 nM for HSM1688 (nitrogen at the 4* position) and 150 nM for HSD82 (carbon at the 4* position). Therefore, placing the hydroxyl group at the 2-position of M731 (to generate HSM1702) significantly affected the anticancer properties (compare the IC50 of 36 nM for M731 versus 3 nM for HSM1702; a difference of an order of magnitude).

[0381] As used in this paper, all compounds starting with MXC are identical to HSM, N-1 = HSN and DGBI = HSD.

[0382] At various points in this specification, substituents of the compounds of the present invention are disclosed by group or range. Specifically, the present invention includes each and each individual subcombination of members of these groups and ranges. For example, the term "C" 1-5 The word "alkyl" is used specifically to disclose methyl, ethyl, C3 alkyl, C4 alkyl, and C5 alkyl.

[0383] Furthermore, this means that the compounds of the present invention are stable. As used herein, "stable" means a compound that is robust enough to withstand separation from the reaction mixture to a useful purity, and preferably capable of being formulated into an effective therapeutic agent. It should also be understood that certain features of the invention described in the context of individual embodiments for clarity may also be provided in combination in a single embodiment. Conversely, various features of the invention described in the context of individual embodiments for brevity may also be provided individually or in any suitable sub-combination.

[0384] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0385] In some implementations, the term "about" may allow for a degree of variability in the value or range, for example, within 10%, 5%, or 1% of the specified value or range limit.

[0386] In some embodiments, the term "alkyl" refers to a straight-chain or branched saturated hydrocarbon group. Examples of alkyl groups include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like. Alkyl groups may contain 1 to about 20, 2 to about 20, 1 to about 10, 1 to about 8, 1 to about 6, 1 to about 4, or 1 to about 3 carbon atoms.

[0387] As used herein, in some embodiments, the term "alkenyl" refers to an unsaturated monovalent chain containing at least one carbon atom with a double bond, which may optionally be branched. It should be understood that in embodiments including alkenyl groups, illustrative variations of these embodiments include lower alkenyl groups, such as C2-C6, C2-C4 alkenyl groups, etc.

[0388] As used herein, in some embodiments, the term "alkynyl" refers to an unsaturated monovalent chain containing at least one carbon atom with a triple bond, which may optionally be branched. It should be understood that in embodiments including an alkynyl group, illustrative variations of these embodiments include lower alkynyl groups, such as C2-C6, C2-C4 alkynyl groups, etc.

[0389] In some embodiments, "cycloalkyl" refers to a non-aromatic carbocyclic ring, including cyclic alkyl, alkenyl, and alkynyl groups. Cycloalkyl groups may include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) cyclic systems, including spirocyclic rings. In some embodiments, cycloalkyl groups may have 3 to about 20 carbon atoms, 3 to about 14 carbon atoms, 3 to about 10 carbon atoms, or 3 to 7 carbon atoms. Cycloalkyl groups may also have 0, 1, 2, or 3 double bonds and / or 0, 1, or 2 triple bonds. The definition of cycloalkyl also includes a portion having one or more aromatic rings fused to a cycloalkyl ring (i.e., having a common bond), such as benzo[a] derivatives of cyclopentane, cyclopentene, cyclohexane, etc. Cycloalkyl groups having one or more fused aromatic rings may be linked by aromatic or non-aromatic portions. One or more cyclic carbon atoms of the cycloalkyl group may be oxidized, for example, by having oxo or thio substituents. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptanetrienyl, norbornyl, norpinyl, norcarnyl, adamantyl, etc.

[0390] In some embodiments, "aryl" refers to a monocyclic or polycyclic aromatic hydrocarbon (e.g., having 2, 3, or 4 fused rings), such as phenyl, naphthyl, anthracene, phenanthrene, etc. In some embodiments, the aryl group has 6 to about 20 carbon atoms.

[0391] In some embodiments, "heteroaryl" refers to an aromatic heterocycle having at least one heteroatom ring member (e.g., sulfur, oxygen, or nitrogen). Heteroaryl groups include monocyclic and polycyclic (e.g., having 2, 3, or 4 fused rings) systems. Any cyclic N atom in a heteroaryl group may also be oxidized to form an N-oxo moiety. Examples of heteroaryl groups include, but are not limited to, pyridyl, N-oxopyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thiopheneyl, imidazolyl, thiazolyl, indoleyl, pyrroleyl, oxazolyl, benzofuranyl, benzothiopheneyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indoleyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothiopheneyl, purine, carbazoleyl, benzimidazolyl, dihydroindoleyl, etc. In some embodiments, the heteroaryl group has 1 to about 20 carbon atoms, and in another embodiment, the heteroaryl group has about 3 to about 20 carbon atoms. In some embodiments, the heteroaryl group contains 3 to about 14, 3 to about 7, or 5 to 6 cyclic atoms. In some embodiments, the heteroaryl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms. In some embodiments, the "heteroaryl" may optionally be substituted at any one or more positions capable of carrying hydrogen atoms.

[0392] In some embodiments, "heterocyclic alkyl" refers to a non-aromatic heterocycle in which one or more cyclic atoms are heteroatoms, such as O, N, or S atoms. Heterocyclic alkyl groups can include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) ring systems and spirocyclic rings. Example heterocyclic alkyl groups include morpholino, thiomorpholino, piperazine, tetrahydrofuran, tetrahydrothiophene, 2,3-dihydrobenzofuran, 1,3-benzo-m-dioxacyclopentene, benzo-1,4-dioxane, piperidinyl, pyrrolidinyl, isozolyl, isothiazolyl, pyrazolyl, oxazolyl, thiazolyl, imidazolyl, etc. The definition of heterocyclic alkyl also includes a portion having one or more aromatic rings fused with a non-aromatic heterocycle (i.e., having a common bond), such as phthalimide, naphthalimide, and benzo[a] derivatives of heterocycles. Heterocyclic alkyl groups having one or more fused aromatic rings can be linked by aromatic or non-aromatic portions. The definition of a heterocyclic alkyl group also includes a portion in which one or more cyclic atoms are replaced by one or two oxo or thio groups. In some embodiments, the heterocyclic alkyl group has 1 to about 20 carbon atoms, and in other embodiments, it has about 3 to about 20 carbon atoms. In some embodiments, the heterocyclic alkyl group contains 3 to about 20, 3 to about 14, 3 to about 7, or 5 to 6 cyclic atoms. In some embodiments, the heterocyclic alkyl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms. In some embodiments, the heterocyclic alkyl group contains 0 to 3 double bonds. In some embodiments, the heterocyclic alkyl group contains 0 to 2 triple bonds.

[0393] In some implementations, "halogenated" or "halogenated" includes fluorine, chlorine, bromine, and iodine. "Halogen substitution" or "halogenated" substitution refers to replacing one or more hydrogen atoms with F, Cl, Br, or I.

[0394] In some embodiments, "haloalkyl" refers to an alkyl group having one or more halogen substituents. Examples of haloalkyl groups include CF3, C2F5, CHF2, CCl3, CHCl2, C2Cl5, etc.

[0395] It should be understood that each of the alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkylene, and heterocyclic groups may optionally be substituted by independently selected groups (e.g., alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, carboxylic acids and their derivatives (including esters, amides and nitrites), hydroxyl, alkoxy, acyloxy, amino, alkyl and dialkylamino, amide, thio, etc., and combinations thereof).

[0396] In some embodiments, the term "substituted" means that a hydrogen moiety is replaced by a non-hydrogen moiety in a molecule or group. It can refer to "monosubstituted" or "polysubstituted." The terms "monosubstituted" or "polysubstituted" refer to substitution by one or more substituents up to the valence of the substituted group. For example, a monosubstituted group can be substituted by one substituent, and a polysubstituted group can be substituted by two, three, four, or five substituents. When a list of possible substituents is provided, the substituents can be selected independently from that group.

[0397] As used herein, the terms “optionally substituted” or “optionally substituent” mean that the group under discussion is either unsubstituted or substituted with one or more specified substituents. When the group under discussion is substituted with more than one substituent, the substituents may be the same or different. Such other functional groups are illustratively including, but are not limited to, amino, hydroxyl, CN, halogen, thiol, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, heteroarylheteroalkyl, nitro, sulfonic acid and its derivatives, carboxylic acid and its derivatives, etc. Illustratively, any amino, hydroxyl, CH, thiol, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, heteroarylheteroalkyl and / or sulfonic acid may be optionally substituted. In some embodiments, the functional group is a substituent of any of the variables described herein. Furthermore, when the terms “independently,” “independently is,” and “independently selected from” are used, it means that the group under discussion may be the same or different. Some terms defined in this paper may appear more than once in the structure, and in such cases, each term should be defined independently of the others.

[0398] In each of the foregoing embodiments and each of the following embodiments, it should be understood that the formula also includes any and all hydrates and / or solvates of the compound formula. It should be understood that certain functional groups, such as hydroxyl, amino, etc., form complexes and / or coordination compounds with water and / or various solvents in various physical forms of the compound. Therefore, the above formula should be understood to include and represent those various hydrates and / or solvates.

[0399] The compounds described herein may be asymmetric (e.g., having one or more stereocenters). Unless otherwise stated, all stereoisomers, such as enantiomers and diastereomers, are contemplated. Compounds of the present invention containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods for preparing the optically active forms from optically active starting materials are known in the art, such as by resolving racemic mixtures or by stereoselective synthesis. Many geometric isomers of alkenes, C=N double bonds, etc., may also be present in the compounds described herein, and all such stable isomers are contemplated in this invention. Cis and trans geometric isomers of the compounds of the present invention are described and can be isolated as mixtures of isomers or as individual isomers.

[0400] In cases where the compound contains asymmetric carbon atoms, the present invention relates to the D form, L form, and mixtures of D and L, and also to diastereomeric forms when more than one asymmetric carbon atom is present. Those compounds of the present invention containing asymmetric carbon atoms and typically produced as racemates can be isolated into optically active isomers in a known manner (e.g., using optically active acids). However, it is also possible to use an optically active starting material from the outset and then obtain the corresponding optically active or diastereomeric compound as the final product.

[0401] The compounds of this invention also include tautomer forms. Tautomer forms arise from the exchange of single bonds with adjacent double bonds and the accompanying proton migration. Tautomer forms include proton-tautomers, which are isomeric protonated states having the same empirical formula and total charge. Examples of proton-tautomers include keto-enol pairs, amide-imino pairs, lactam-lactamimide pairs, amide-imino pairs, enamine-imide pairs, and cyclic forms where the proton can occupy two or more positions in the heterocyclic system, such as 1H- and 3H-imidazolium, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomer forms can be brought into equilibrium by appropriate substitution or spatially locked into one form.

[0402] The compounds of the present invention may also include all isotopes of the atoms appearing in the intermediates or the final compound. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

[0403] In some embodiments, the term "compound" as used herein is intended to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structure shown.

[0404] In some embodiments, the compounds of the present invention are substantially isolated. "Substantially isolated" means that the compound is at least partially or substantially separated from the environment in which it is formed or detected. Partial isolation can include, for example, compositions rich in the compounds of the present invention. Substantially isolated can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compounds of the present invention or salts thereof. Methods for isolating compounds and their salts are conventional in the art.

[0405] In some implementations, the term "therapeuticly effective amount," as used herein, refers to the amount of an active compound or agent that elicits a biological or pharmaceutical response in an tissue system, animal, or human being sought by a researcher, veterinarian, physician, or other clinician, with the response including relief of symptoms of the disease or disorder to be treated. On the other hand, a therapeutically effective amount is an amount that can treat or alleviate a disease or its symptoms with a reasonable benefit / risk ratio suitable for any medical treatment.

[0406] Furthermore, it should be understood that, as described in Freirek, EJ, et al., Reports on Cancer Chemotherapy, 1966, 50(4), 219 (the disclosure of which is incorporated herein by reference), there exists an interrelationship between doses determined for humans and those determined for animals (including test animals, e.g., based on milligrams per square meter of body surface area). Body surface area can be approximately determined based on the patient's height and weight (see, e.g., Scientific Table, Guy Pharmaceuticals, Adley, New York, pp. 537-538 (1970)). Therapeutic effective amounts of the compounds described herein can be defined as any amount used to prevent the growth (or kill) of malignant cells or cancer cell populations, for example, that are found in patients requiring relief from such cancers or malignancies. Typically, such effective amounts range from about 5 mg / kg to about 500 mg / kg, about 5 mg / kg to about 250 mg / kg, and / or about 5 mg / kg to about 150 mg / kg, depending on the patient's weight. It should be understood that the effective dose can also vary depending on the route of administration, the use of optional excipients, and the possibility of co-administration of the compound with other conventional and unconventional therapeutic treatments (including other antitumor agents, radiotherapy, etc.).

[0407] In some embodiments, the phrase “pharmaceutically acceptable” is used herein to refer to those compounds, materials, compositions, and / or dosage forms that are suitable for contact with human and animal tissues within a reasonable medical judgment without excessive toxicity, irritation, allergic reactions, or other problems or complications, and in proportion to a reasonable benefit / risk ratio.

[0408] The compounds of the present invention also include “pharmaceutically acceptable salts” of the compounds described herein. As used herein, a “pharmaceutically acceptable salt” refers to a derivative of the disclosed compound wherein the parent compound is modified by converting an existing acid or base moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues (e.g., amines); basic or organic salts of acidic residues (e.g., carboxylic acids); and so on. Pharmaceutically acceptable salts of the compounds of the present invention include, for example, conventional non-toxic salts of parent compounds formed from non-toxic inorganic or organic acids. Pharmaceutically acceptable salts of the compounds of the present invention can be synthesized by conventional chemical methods from parent compounds containing a basic or acidic moiety. Generally, these salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of a suitable base or acid in water or in an organic solvent or a mixture of both; typically, non-aqueous media such as diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.

[0409] Pharmaceutically acceptable salts of the compounds of the present invention can be obtained by converting derivatives having tertiary amino groups into the corresponding quaternary ammonium salts in a manner known per se using a quaternizing agent. Examples of suitable quaternizing agents are alkyl halides, such as methyl iodide, ethyl bromide, and n-propyl chloride, as well as aryl alkyl halides, such as benzyl chloride or 2-phenylethyl bromide.

[0410] As used herein, “object” refers to an animal or a human. In some embodiments, the term “object” refers to a human. The pharmaceutical composition comprises the compound of claim 1 or a pharmaceutically acceptable salt, N-oxide, hydrate, solvate, tautomer, or optical isomer thereof, and a pharmaceutically acceptable carrier or diluent.

[0411] On the other hand, the present invention is characterized by a pharmaceutical composition comprising the compound of the present invention as described herein, or a pharmaceutically acceptable salt, N-oxide, hydrate, solvate, tautomer or optical isomer thereof, and a pharmaceutically acceptable carrier or diluent.

[0412] In some embodiments, the pharmaceutical composition includes a therapeutically effective amount of one or more compounds for treating cancer patients. It should be understood that the composition may contain other components and / or ingredients, including but not limited to other therapeutically active compounds, and / or one or more pharmaceutically acceptable carriers, diluents, excipients, etc.

[0413] The terms “pharmaceutically acceptable carrier” or “pharmaceutically acceptable diluent” are recognized in the art and refer to pharmaceutically acceptable materials, compositions, or carriers, such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials, which participate in carrying or transporting any test composition or its components. Each carrier must be “acceptable” in the sense of being compatible with the test composition and its components and harmless to the patient. Some examples of materials that can be used as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered astragalus gum; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and Soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer solution; and (21) other non-toxic compatible substances used in pharmaceutical preparations.

[0414] In addition to physiologically acceptable carriers, diluents, and / or adjuvants for the production of pharmaceutical compositions, a therapeutically effective dose of the compound according to the invention is used. The dose of the active compound may vary depending on the route of administration, the patient's age and weight, the nature and severity of the disease to be treated, and similar factors. The daily dose may be given as a single dose, which may be administered once or divided into two or more daily doses, and is typically 0.001-2000 mg. A daily dose of 0.1-500 mg (e.g., 0.1-100 mg) is particularly preferred.

[0415] Suitable forms of administration include oral, parenteral, intravenous, transdermal, topical, inhalation, intranasal, and sublingual formulations. Oral, parenteral, such as intravenous or intramuscular, and intranasal formulations, such as dry powder or sublingual formulations of the compounds according to the invention, are particularly preferred. Conventional galenic formulations are also used, such as tablets, sugar-coated tablets, capsules, dispersible powders, granules, aqueous solutions, alcoholic aqueous solutions, aqueous or oily suspensions, syrups, juices, or drops.

[0416] Solid drug forms may include inert components and carrier substances such as calcium carbonate, calcium phosphate, sodium phosphate, lactose, starch, mannitol, alginate, gelatin, guar gum, magnesium stearate, aluminum stearate, methylcellulose, talc, highly dispersed silica, silicone oil, higher molecular weight fatty acids (such as stearic acid), gelatin, agar, or vegetable or animal fats and oils, or solid high molecular weight polymers (such as polyethylene glycol); if desired, formulations suitable for oral administration may include additional flavoring agents and / or sweeteners.

[0417] Liquid drug forms may be sterile and / or contain excipients, where appropriate, such as preservatives, stabilizers, wetting agents, penetrants, emulsifiers, dispersants, solubilizers, salts, sugars or sugar alcohols for adjusting osmotic pressure or for buffering, and / or viscosity modifiers. Examples of these additives are tartrate and citrate buffers, ethanol, and chelating agents (e.g., ethylenediaminetetraacetic acid and its non-toxic salts). High molecular weight polymers (e.g., liquid polyethylene oxide, microcrystalline cellulose, carboxymethyl cellulose, polyvinylpyrrolidone, dextran, or gelatin) are suitable for adjusting viscosity. Examples of solid carrier substances are starch, lactose, mannitol, methyl cellulose, talc, highly dispersed silica, high molecular weight fatty acids (e.g., stearic acid), gelatin, agar, calcium phosphate, magnesium stearate, animal and vegetable fats, and solid high molecular weight polymers (e.g., polyethylene glycol).

[0418] Oily suspensions for parenteral or topical application may be synthetic or semi-synthetic vegetable oils, such as liquid fatty acid esters having 8-22 carbon atoms in each fatty acid chain, such as palmitic acid, lauric acid, tridecanoic acid, heptadecanoic acid, stearic acid, arachidic acid, myristic acid, benzyl acid, pentadecanoic acid, linoleic acid, transoleic acid, brasidic acid, erucic acid, or oleic acid, esterified with monohydric to trihydric alcohols (e.g., methanol, ethanol, propanol, butanol, pentanol, or their isomers, ethylene glycol, or glycerol) having 1 to 6 carbon atoms. Examples of such fatty acid esters include, in particular, commercially available caprylic / capric triglycerides, isopropyl myristate, isopropyl palmitate, isopropyl stearate, PEG 6-decanoic acid, caprylic / capric esters of saturated fatty alcohols, polyoxyethylene trioleate, ethyl oleate, waxy fatty acid esters (such as artificial duck tail fat), coconut fatty acid isopropyl ester, oleic acid ester, decyl oleate, ethyl lactate, dibutyl phthalate, diisopropyl adipate, and polyol fatty acid esters. Silicone oils of varying viscosities, or fatty alcohols (e.g., isotrexyl alcohol, 2-octyldodecyl alcohol, hexadecyl stearyl alcohol, or oleyl alcohol) or fatty acids (e.g., oleic acid) are also suitable. Additionally, vegetable oils such as castor oil, almond oil, olive oil, sesame oil, cottonseed oil, peanut oil, or soybean oil can be used.

[0419] Suitable solvents, gelling agents, and solubilizers are water or water-miscible solvents. Examples of suitable substances are alcohols, such as ethanol or isopropanol, benzyl alcohol, 2-octyldodecanool, polyethylene glycol, phthalates, adipates, propylene glycol, glycerol, di- or tripropylene glycol, waxes, methyl cellosolves, cellosolves, esters, morpholine, dioxane, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, cyclohexanone, etc.

[0420] Mixtures of gelling agents and film-forming agents are also entirely possible. In this case, ionic macromolecules are particularly used, such as sodium carboxymethyl cellulose, polyacrylic acid, polymethacrylic acid and its salts, sodium amylopectin semiglycolate, alginate or propylene glycol alginate as sodium salts, gum arabic, xanthan gum, guar gum or carrageenan. The following can be used as additional formulation aids: glycerin, paraffins of varying viscosities, triethanolamine, collagen, allantoin, and novantisolic acid. Surfactants, emulsifiers, or wetting agents, such as sodium dodecyl sulfate, fatty alcohol ether sulfates, disodium N-dodecyl-β-iminodipropionate, polyethoxylated castor oil or sorbitan monooleate, sorbitan monostearate, polysorbates (e.g., Tween), hexadecyl alcohol, lecithin, glyceryl monostearate, polyoxyethylene stearate, alkylphenol polyethylene glycol ethers, hexadecyltrimethylammonium chloride, or mono- / dialkyl polyethylene glycol ether monoethanolamine phosphate, may also be required in formulations. Stabilizers (e.g., montmorillonite or colloidal silica) used to stabilize emulsions or prevent the decomposition of active substances (e.g., antioxidants (e.g., tocopherol or butylated hydroxyanisole)) or preservatives (e.g., parabens) can also be used in the preparation of the desired formulations.

[0421] Parenteral formulations can be available in individual dosage units, such as ampoules or vials. Solutions of the active compound are preferred, particularly aqueous solutions, isotonic solutions, and suspensions. These injectable forms can be obtained as ready-to-use formulations or prepared directly just before use by mixing the active compound (e.g., a lyophilized form appropriately containing other solid carrier substances) with the desired solvent or suspension.

[0422] Intranasal preparations can exist as aqueous or oily solutions or as aqueous or oily suspensions. They can also exist as lyophilized products, prepared using a suitable solvent or suspending agent before use.

[0423] Inhalable formulations can exist in the form of powder, solution, or suspension. Preferably, inhalable formulations are in powder form, for example, as a mixture of the active ingredient and a suitable formulation adjuvant (such as lactose).

[0424] The formulation is produced, aliquoted, and sealed under conventional antimicrobial and aseptic conditions.

[0425] As described above, the compounds of the present invention can be administered as a combination therapy with other active agents, such as therapeutically active compounds useful in treating cancers (e.g., prostate cancer, ovarian cancer, lung cancer, or breast cancer). In some embodiments, the cancers are acute myeloid leukemia, chronic myeloid leukemia, ovarian cancer, cervical cancer, pancreatic cancer, breast cancer, brain cancer, skin cancer, lung cancer, prostate cancer, lymphoma, leukemia, colon cancer, head cancer, neck cancer, thyroid cancer, kidney cancer, liver cancer, and stomach cancer. For combination therapies, the active ingredients can be formulated as a composition containing several active ingredients in single-dose form and / or as a kit containing individual active ingredients in separate doses. The active ingredients used in combination therapies can be administered together or individually.

[0426] Another aspect of the invention is that the compounds of the invention as described herein are protein kinase inhibitors. Therefore, the invention is characterized by a method of inhibiting protein kinases, wherein the method comprises contacting the protein kinase with an effective amount of the compound of the invention. In some embodiments, such protein kinases include, but are not limited to, FLT3 and TrkC. In some embodiments, the protein kinases are Abl, Abl2, AFK, ALK, AMPK_group, ATM, ATR, Aurora kinase A, Aurora kinase B, Axl, BCKDK, BLK, BMPR1B, BMX, Brk, BRSK1, BTK, CaM-KIα, CaM-KIIα, CaMKK_group, CaM-KIV, CaM-KKα, CaM-KKβ, CCDPK, CCRK, CDK1, CDK11, CDK2, CDK4, CDK5, CDK6, CDK7, CDK9, CDK_group, CDPK, Chak1, CHK1, CHK 2. CK1α, CK1δ, CK1ε, CK1_group, CK2α, CK2_β, CK2_group, CLK1, CSF1R, Csk, DAPK1, DAPK2, DAPK3, DAPK_group, DCAMKL1, DMPK_group, DNA-PK, DYRK1A, DY RK1B, DYRK2, DYRK3, eEF2K, Eg3 kinase, EGFR, EIF2AK2, EphA2, EphA3, EphA4, EphA8, EphB1, EphB2, EphB3, EphB5, ErbB2, FAK, Fer, Fes, FGFR 1. FGFR3, FGFR4, FGFR_group, Fgr, FLT1, FLT3, FLT4, Fyn, GRK-1, GRK-2, GRK-3, GRK-4, GRK-5, GRK-6, GRK_group, GSK-3α, GSK-3β, GSK-3_group, HCK , HIPK2, HIPK3, HRI, ICK, IGF1R, IKK-α, IKK-β, IKK-εILK, InsR, IPL1, IRAK1, IRAK4, ITK, JAK1, JAK2, JAK3, JAK_group, JNK_group, KDR, KIS, Kit , KSR1, Lck, LIMK1, LIMK2, LKB1, LOK, Lyn, MAP2K1, MAP2K2, MAP2K3, MAP2K4, MAP2K6, MAP2K7, MAPK2_Group, MAP3K1, MAP3K11, MAP3K14, MAP 3K5,MAP3K7,MAP3K8,MAPK3_Group,MAP4K1,MAP4K2,MAP4K4,MAPK1,MAPK10,MAPK11,MAPK12,MAPK13,MAPK14,MAPK3,MAPK4,MAPK6,MAPK7,MAPK8, MAPK9, MAPK_group, MAPKAPK2, MARK_group, Mer, Met, MHCK, MLCK_group, Mnk1, Mnk2, MOS, MRCKa, MST1, MST3, mTOR, NDR1, NDR2, NEK1, NEK2, NEK6, NEK9, NEK_group, NLK, NuakK1, p37 kinase, p38_group, p70S6K, p70S6Kb, P70S6K_group, PA K1, PAK2, PAK3, PAK5, PAK6, PAK_ group, PASK, P-CIP2, PCTAIRE1, PDGFRα, PDGFRβ, PDGFR_ group, PDHK1, PDHK2, PDHK3, PDHK4, PDK-1, PDK-2, PDK_ group, PHK_ group, PIK3CA, PIK3CB, PIK3CD, PIK3CG, Pim-1, PKAα, Pka_ group, PKBβ, PKB_ group , PKCα, PKCβ, PKCδ, PKCε, PKCη, PKCγ, PKCι, PKCθ, PKCζ, PKC_group, PKD1, PKD2, PKD3, PKG1 / cGK-I, PKG2 / cGK- II, PKG2 / cGK_group, PKN1, PLK1, PLK2, PLK3, PRP4, PYK2, RAF1, Ret, ROCK1, ROCK2, Ron, RPL10, RSK-1, RSK-2, R SK-3, RSK-5, SDK1, SGK_group, SIK, Sky, Src, Src_group, STLK3, Syk, TBK1, Tec, TESK1, TESK2, TGFbR1, TGFbR2, Tie1, Tie2, titin kinase, TNK2, TRKA, TRKB, tropomyosin kinase, TSSK3, TXK, Tyk2, TYK2, VRK1, Wee1, Wnk1, WNK1, Yes, ZAP70. In some embodiments, each possibility represents a separate embodiment of the invention.

[0427] Another aspect of the invention is that the compounds of the invention described herein can be used to treat, prevent, inhibit, or alleviate the severity of diseases or disorders associated with protein kinases, wherein the method comprises administering a therapeutically effective amount of the compound of the invention or a pharmaceutically acceptable salt, N-oxide, hydrate, solvate, tautomer, or optical isomer thereof to a subject in need. In some embodiments, the protein kinase is one known in the art. In some embodiments, the protein kinase includes, but is not limited to, FLT3 and TrkC. In some embodiments, the protein kinases are Abl, Abl2, AFK, ALK, AMPK_group, ATM, ATR, Aurora kinase A, Aurora kinase B, Axl, BCKDK, BLK, BMPR1B, BMX, Brk, BRSK1, BTK, CaM-KIα, CaM-KIIα, CaMKK_group, CaM-KIV, CaM-KKα, CaM-KKβ, CCDPK, CCRK, CDK1, CDK11, CDK2, CDK4, CDK5, CDK6, CDK7, CDK9, CDK_group, C DPK, Chak1, CHK1, CHK2, CK1α, CK1δ, CK1ε, CK1 group, CK2α, CK2β, CK2 group, CLK1, CSF1R, Csk, DAPK1, DAPK2, DAPK3, DAPK group, DCAMKL1, DMPK group, DNA-PK, DYRK1A, DYRK1B, DYRK2, DYRK3, eEF2K, Eg3 kinase, EGFR, EIF2AK2, EphA2, EphA3, EphA4, EphA8, EphB1, EphB 2. EphB3, EphB5, ErbB2, FAK, Fer, Fes, FGFR1, FGFR3, FGFR4, FGFR_group, Fgr, FLT1, FLT3, FLT4, Fyn, GRK-1, GRK-2, GRK-3, GRK- 4. GRK-5, GRK-6, GRK_group, GSK-3α, GSK-3β, GSK-3_group, HCK, HIPK2, HIPK3, HRI, ICK, IGF1R, IKK-α, IKK-β, IKK-εILK, InsR, IPL1, IRAK1, IRAK4, ITK, JAK1, JAK2, JAK3, JAK_group, JNK_group, KDR, KIS, Kit, KSR1, Lck, LIMK1, LIMK2, LKB1, LOK, Lyn, MAP2K1, MAP2K2, MAP2K3, MAP2K4, MAP2K6, MAP2K7, MAPK2_group, MAP3K1, MAP3K11, MAP3K14, MAP3K5, MAP3K7, MAP3K8, MAPK3_group, MAP4K1, MAP4K2,MAP4K4, MAPK1, MAPK10, MAPK11, MAPK12, MAPK13, MAPK14, MAPK3, MAPK4, MAPK6, MAPK7, MAPK8, MAPK9, MAPK_Group, MAPKA PK2, MARK_Group, Mer, Met, MHCK, MLCK_Group, Mnk1, Mnk2, MOS, MRCKa, MST1, MST3, mTOR, NDR1, NDR2, NEK1, NEK2, NEK6, NEK9, NEK_ group, NLK, NuakK1, p37 kinase, p38_ group, p70S6K, p70S6Kb, P70S6K_ group, PAK1, PAK2, PAK3, PAK5, PAK6, PAK_ group, PASK, P-CIP2, PCTAIRE1, PDGFRα, PDGFRβ, PDGFR_ group, PDHK1, PDHK2, PDHK3, PDHK4, PDK-1, PDK-2, PDK_ group, PHK_ group, PIK3CA, PIK3CB, PIK3C D. PIK3CG, Pim-1, PKAα, Pka_group, PKBβ, PKB_group, PKCα, PKCβ, PKCδ, PKCε, PKCη, PKCγ, PKCι, PKCθ, PKCζ, PKC_group, PKD1, PKD 2. PKD3, PKG1 / cGK-I, PKG2 / cGK-II, PKG2 / cGK_group, PKN1, PLK1, PLK2, PLK3, PRP4, PYK2, RAF1, Ret, ROCK1, ROCK2, Ron, R PL10, RSK-1, RSK-2, RSK-3, RSK-5, SDK1, SGK_group, SIK, Sky, Src, Src_group, STLK3, Syk, TBK1, Tec, TESK1, TESK2, TGFbR1, TGFbR2, Tie1, Tie2, titin kinase, TNK2, TRKA, TRKB, tropomyosin kinase, TSSK3, TXK, Tyk2, TYK2, VRK1, Wee1, Wnk1, WNK1, Yes, ZAP70. In some embodiments, each possibility represents a separate embodiment of the invention.

[0428] In some embodiments, diseases or disorders related to protein kinases include, but are not limited to, cancer, diabetes, malaria, viral infections (e.g., HIV), cardiovascular disease and hypertension, CNS and neurodegeneration (e.g., Alzheimer's disease, Parkinson's disease, bipolar disorder, supranuclear palsy), osteoporosis, inflammatory and autoimmune diseases (e.g., rheumatoid arthritis, myelofibrosis, inflammatory bowel disease, Crohn's disease, colitis, psoriasis, systemic lupus erythematosus, keratoconjunctivitis sicca), and allergies (general allergic diseases, allergic asthma, allergic rhinitis). In some embodiments, diseases or disorders related to protein kinases include cancer, diabetes, malaria, viral infections, cardiovascular disease and hypertension, CNS and neurodegeneration, osteoporosis, pulmonary fibrosis, retinitis pigmentosa, wet macular degeneration, Duchenne muscular dystrophy, diabetic retinopathy, inflammatory and autoimmune diseases, or allergies. In some embodiments, diseases or disorders related to protein kinases include cancer.

[0429] On the other hand, the present invention relates to a method for treating, preventing, inhibiting or reducing the severity of cancer in a subject in which it is desired, wherein the method comprises administering to the subject a therapeutically effective amount of the compound described herein or a pharmaceutically acceptable salt, N-oxide, hydrate, solvate, tautomer or optical isomer thereof, or a pharmaceutical composition comprising one or more of the compounds described herein.

[0430] In some embodiments, the invention disclosed herein relates to a method of treating cancer patients, wherein aberrant kinase activity is influenced by administering a therapeutically effective amount of the disclosed compound to a patient requiring relief of said cancer. It should be understood herein that the compound described herein can be used alone or in combination with other compounds used to treat cancer, including those compounds that are therapeutically effective through the same or different modes of action. It should also be understood herein that the compound described herein can be used in combination with other compounds administered to treat other symptoms of cancer, such as nausea, vomiting, pain, etc.

[0431] In some embodiments, the cancer is selected from acute myeloid leukemia, chronic myeloid leukemia, ovarian cancer, cervical cancer, pancreatic cancer, breast cancer, brain cancer, skin cancer, lung cancer, prostate cancer, lymphoma, leukemia, colon cancer, head cancer, neck cancer, thyroid cancer, kidney cancer, liver cancer, and stomach cancer. In some embodiments, the cancer is acute myeloid leukemia.

[0432] Another aspect of the invention is that the compounds of the invention described herein can be used to treat, prevent, inhibit, or reduce the severity of cancer in a subject, wherein the method comprises administering to a subject in need a therapeutically effective amount of the compound of the invention or a pharmaceutically acceptable salt, N-oxide, hydrate, solvate, tautomer, or optical isomer thereof, or a pharmaceutical composition containing one or more of the compounds described herein. In some embodiments, cancers whose severity can be treated, prevented, inhibited, or reduced by the compounds of the invention described anywhere herein include, but are not limited to, ovarian cancer, pancreatic cancer, breast cancer, brain cancer, skin cancer, lung cancer, prostate cancer, lymphoma, leukemia, colon cancer, head cancer, cervical cancer, and stomach cancer. In some embodiments, cancers whose severity can be treated, prevented, inhibited, or reduced by the compounds of the invention described anywhere herein include, but are not limited to, acute myeloid leukemia, chronic myeloid leukemia, ovarian cancer, cervical cancer, pancreatic cancer, breast cancer, brain cancer, skin cancer, lung cancer, prostate cancer, lymphoma, leukemia, colon cancer, head cancer, cervical cancer, thyroid cancer, kidney cancer, liver cancer, and stomach cancer. In some embodiments, the cancer is breast cancer. In other embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is acute myeloid leukemia.

[0433] Another aspect of the invention is that the compounds described herein are protein kinase inhibitors. The compounds of the invention can be used to treat, prevent, inhibit, or reduce the severity of diseases or disorders associated with protein kinases, wherein the method comprises administering to a subject in need a therapeutically effective amount of the compound of the invention or a pharmaceutically acceptable salt, N-oxide, hydrate, solvate, tautomer, or optical isomer thereof. In some embodiments, the protein kinase is one known in the art. In some embodiments, the protein kinase includes, but is not limited to, FLT3 and TrkC.

[0434] In some embodiments, the protein kinases are Abl, Abl2, AFK, ALK, AMPK_group, ATM, ATR, Aurora kinase A, Aurora kinase B, Axl, BCKDK, BLK, BMPR1B, BMX, Brk, BRSK1, BTK, CaM-KIα, CaM-KIIα, CaMKK_group, CaM-KIV, CaM-KKα, CaM-KKβ, CCDPK, CCRK, CDK1, CDK11, CDK2, CDK4, CDK5, CDK6, CDK7, CDK9, CDK_group, CDPK, Chak1, CHK1, CHK2, CK1α, CK1δ, CK1ε, CK1_group, CK2 α, CK2_β, CK2_group, CLK1, CSF1R, Csk, DAPK1, DAPK2, DAPK3, DAPK_group, DCAMKL1, DMPK_group, DNA-PK, DYRK1A, DYRK1B, DYRK2, DYRK3, eEF2K, Eg3 kinase, EGFR, EIF2AK2, EphA2, EphA3, EphA4, EphA8, EphB1, EphB2, EphB3, EphB5, ErbB2, FAK, Fer, Fes, FGFR1, FGFR3, FGFR4, FGFR_group, Fgr, FLT1, FLT3, FLT4, Fyn, GRK-1, GR K-2, GRK-3, GRK-4, GRK-5, GRK-6, GRK_group, GSK-3α, GSK-3β, GSK-3_group, HCK, HIPK2, HIPK3, HRI, ICK, IGF1R, IKK-α, IKK-β, IKK-εILK, InsR, IPL1, IRAK1, I RAK4, ITK, JAK1, JAK2, JAK3, JAK_Group, JNK_Group, KDR, KIS, Kit, KSR1, Lck, LIMK1, LIMK2, LKB1, LOK, Lyn, MAP2K1, MAP2K2, MAP2K3, MAP2K4, MAP2K6, MAP2K7, M APK2_Group,MAP3K1,MAP3K11,MAP3K14,MAP3K5,MAP3K7,MAP3K8,MAPK3_Group,MAP4K1,MAP4K2,MAP4K4,MAPK1,MAPK10,MAPK11,MAPK12,MAPK13,MAPK14,MAPK 3. MAPK4, MAPK6, MAPK7, MAPK8, MAPK9, MAPK_group, MAPKAPK2, MARK_group, Mer, Met, MHCK, MLCK_group, Mnk1, Mnk2, MOS, MRCKa, MST1, MST3, mTOR, NDR1, NDR2, NEK1,NEK2, NEK6, NEK9, NEK_ group, NLK, NuakK1, p37 kinase, p38_ group, p70S6K, p70S6Kb, P70S6K_ group, PAK1, PAK2, PAK3, PAK5, PAK6, PAK_ group, PASK, P-CIP2, PCTAIRE1, PDGFRα, PDGFRβ, PDGFR_ group, PDHK1, PDHK2, PD HK3, PDHK4, PDK-1, PDK-2, PDK_group, PHK_group, PIK3CA, PIK3CB, PIK3CD, PIK3CG, Pim-1, PKAα, Pka_group , PKBβ, PKB_group, PKCα, PKCβ, PKCδ, PKCε, PKCη, PKCγ, PKCι, PKCθ, PKCζ, PKC_group, PKD1, PKD2, PKD3, PKG1 / cGK-I, PKG2 / cGK-II, PKG2 / cGK_group, PKN1, PLK1, PLK2, PLK3, PRP4, PYK2, RAF1, Ret, ROCK1, ROCK2, Ron, RPL10, RSK-1, RSK-2, RSK-3, RSK-5, SDK1, SGK_group, SIK, Sky, Src, Src_group, STLK3, Syk, TBK1, Tec, TESK1, TESK2, TGFbR1, TGFbR2, Tie1, Tie2, titin kinase, TNK2, TRKA, TRKB, tropomyosin kinase, TSSK3, TXK, Tyk2, TYK2, VRK1, Wee1, Wnk1, WNK1, Yes, ZAP70. In some embodiments, each possibility represents a separate embodiment of the invention.

[0435] In some embodiments, the diseases or disorders associated with protein kinases include those known in the art. In some embodiments, the diseases or disorders associated with protein kinases are cancer, diabetes, malaria, viral infections (such as HIV), cardiovascular disease and hypertension, CNS and neurodegeneration (such as Alzheimer's disease, Parkinson's disease, bipolar disorder, supranuclear palsy), osteoporosis, inflammatory and autoimmune diseases (such as rheumatoid arthritis, myelofibrosis, inflammatory bowel disease, Crohn's disease, colitis, psoriasis, systemic lupus erythematosus, keratoconjunctivitis sicca), and allergies (general allergic diseases, allergic asthma, allergic rhinitis). In some embodiments, each possibility represents a separate embodiment of the invention. In other embodiments, the compounds of the invention can be used to treat bacterial infections. Diseases or disorders associated with protein kinases include cancer, diabetes, malaria, viral infections, cardiovascular disease and hypertension, CNS and neurodegeneration, osteoporosis, pulmonary fibrosis, retinitis pigmentosa, wet macular degeneration, Duchenne muscular dystrophy, diabetic retinopathy, inflammatory and autoimmune diseases, or allergies. In some embodiments, the compounds of the present invention can be used to treat cancers such as acute myeloid leukemia, chronic myeloid leukemia, ovarian cancer, cervical cancer, pancreatic cancer, breast cancer, brain cancer, skin cancer, lung cancer, prostate cancer, lymphoma, leukemia, colon cancer, head cancer, neck cancer, thyroid cancer, kidney cancer, liver cancer, and stomach cancer. In some embodiments, the cancer is breast cancer. In other embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is acute myeloid leukemia.

[0436] Another aspect of the invention is that the compounds of the invention can be used to treat, prevent, inhibit, or reduce the severity of acute myeloid leukemia in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of the compound of the invention or a pharmaceutically acceptable salt, N-oxide, hydrate, solvate, tautomer, or optical isomer thereof.

[0437] Another aspect of the invention is that the compounds of the invention exhibit low nanomolar IC50 values ​​in their anticancer property tests, which is required for clinical application. The compounds of the invention are kinase inhibitors (especially FLT3, c-Kit, and TrK). For example, the compounds of the invention inhibit kinases such as FLT3, TrkC, and c-Kit at the protein level. In some embodiments, the compounds of the invention exhibit potent anticancer activity against acute myeloid leukemia (low nanomolar IC50 values). In some embodiments, the compounds of the invention also have activity against other cancer cell lines (such as pancreatic cancer, breast cancer, and ovarian cancer). In some embodiments, the cancers are acute myeloid leukemia, chronic myeloid leukemia, ovarian cancer, cervical cancer, pancreatic cancer, breast cancer, brain cancer, skin cancer, lung cancer, prostate cancer, lymphoma, leukemia, colon cancer, head cancer, neck cancer, thyroid cancer, kidney cancer, liver cancer, and stomach cancer. In some embodiments, the cancer is breast cancer. In other embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is acute myeloid leukemia.

[0438] In addition to targeting FLT-3, the compounds of the present invention also inhibit other protein kinases, such as TrkC, as well as c-MyC and Ras oncogenes. Due to the multi-targeting of oncogenic drivers, the compounds of the present invention exhibit superior anti-AML performance compared to mutant FLT-3 known in the art. Furthermore, due to their multi-targeting nature, the compounds of the present invention are also effective against other cancer cell lines, such as ovarian cancer, pancreatic cancer, breast cancer, brain cancer, skin cancer, lung cancer, prostate cancer, lymphoma, leukemia, colon cancer, head cancer, cervical cancer, and gastric cancer. In some embodiments, the cancer is breast cancer. In some embodiments, cancers that can be treated, prevented, inhibited, or have their severity reduced by the compounds of the present invention described anywhere herein include, but are not limited to, acute myeloid leukemia, chronic myeloid leukemia, ovarian cancer, cervical cancer, pancreatic cancer, breast cancer, brain cancer, skin cancer, lung cancer, prostate cancer, lymphoma, leukemia, colon cancer, head cancer, cervical cancer, thyroid cancer, kidney cancer, liver cancer, and gastric cancer. In other embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is prostate cancer. In some implementations, the cancer is acute myeloid leukemia.

[0439] The compounds of the present invention inhibit the proliferation of several cancer cell lines at nanomolar concentrations. Furthermore, the compounds of the present invention inhibit the phosphorylation of protein kinase FLT-3 and also inhibit the proliferation of FLT-3-driven cancers, such as MV4-11 (acute myeloid leukemia) with a low (e.g., single nanomolar) IC50 value. As potent kinase inhibitors, the compounds of the present invention can be used to treat cancer, malaria, arthritis, immune system-related diseases, and other disease states in which kinases play a key role in disease initiation or progression.

[0440] Those skilled in the art will understand that the present invention is not limited to what has been specifically shown and described above. Rather, the scope of the invention includes combinations and sub-combinations of the various features described above, as well as variations and modifications that would occur to those skilled in the art upon reading the specification and that are not found in the prior art.

[0441] Details of one or more embodiments of the invention are set forth in the following description. Other features, objects, and advantages of the invention will become apparent from the specification, drawings, and claims.

[0442] Example

[0443] Materials and methods

[0444] Solvents and reagents were purchased from commercial suppliers and were ready for use without further purification. Recordings were performed at 500 MHz using a Bruker Crown 500 spectrometer with a cryoprobe. 1 H NMR spectrum.

[0445] ESI-MS experiments were performed using an Agilent MSD / TOF mass spectrometer at the Bendley Center for Biosciences Metabolomics Facility (Purdue University). The instrument was calibrated to a resolution of 10,000 using appropriate polypropylene glycol standards, with 10% valleys between peaks.

[0446] Thin-layer chromatography was performed on TLC plates backed with silica gel 60F254 plastic. Unless otherwise specified, compounds were visualized using short- and long-wavelength UV light and iodine / silica gel staining. RediSep R24 micrometers were used. f Rapid column chromatography was performed using a Tridonic Isco Combi-Flash Rf+ silica disposable rapid column (catalog number 692203304). For purity estimated by HPLC, unless otherwise stated, the main peak represents ≥95% of the total combined peak area when monitored at 254 nm with a UV detector. All yields refer to isolated compounds.

[0447] Quezatinib (>99.5% purity) and crenolanib (>99.5% purity) were purchased from Chemietek.com. Unless otherwise specified, all materials were obtained from commercial suppliers for use as obtained. Solvents were purchased from Sigma and used directly without purification. NMR spectra were recorded at ambient temperature on a Bruker 400, 500, or 600 MHz spectrometer. Chemical shifts were reported in parts per million (δ) and calibrated using residual undeuterated solvent as an internal standard. ¹H NMR data were reported as follows: chemical shift (δppm) (multiplicity, coupling constant (Hz), integral). Multiplicity was reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad peak or a combination thereof.

[0448] In vitro kinase assay

[0449] The kinase / inhibitor interaction was measured using the Reaction Biology Corporation (www.reactionbiology.com, Malvern, PA) hotspot assay platform, as described above. The kinase and substrate were mixed in a buffer solution containing 20 mM HEPES, 10 mM MgCl2, 1 mM EGTA, 0.02% Brij35, 0.02 mg / mL BSA, 0.1 mM Na3VO4, 2 mM DTT, and 1% DMSO at pH 7.5. A single dose of the compound (500 nM) was then added to each reaction mixture. After incubation for 20 minutes, ATP (sigma) and [γ-] were added to a final total concentration of 100 μM. 33 P]ATP (PerkinElmer) was added at room temperature for 2 hours, then spotted onto P81 ion-exchange cellulose chromatography paper (Waltmann). The filter paper was washed with 0.75% phosphoric acid to remove unincorporated ATP. The percentage of residual kinase activity in the kinase-responsive carrier (DMSO) for each kinase / inhibitor pair was calculated using Prism 5 (GraphPad).

[0450] FLT3 docking method

[0451] CANDOCK docking package 1 Used to identify the docking posture of HSW630-1 at the binding site of the FLT3 kinase. The structure of FLT3 was obtained from the protein database (PDB#4XUF). The entire protein was considered flexible. No binding site was provided for CANDOCK; the location of the site was determined automatically by the program. CANDOCK used default parameters with interactive flexibility, a maximum number of iterations of 10, and only used the top 2% of the seed values ​​to generate complete ligands.

[0452] Cell lines and cultures

[0453] Molm-14 cells were a gift from Dr. Mark Reeves of Johns Hopkins University. THP-1, MV4-11, K-562, and MRC-5A cells were purchased from ATCC (ATCC, Manassas, Virginia). All cell lines were grown on RPMI 1640 (Life Technologies, Carlsbad, CA) supplemented with heat-inactivated 10% (v / v) fetal bovine serum at 37°C in a 5% CO2 atmosphere. Cell lines were grown and maintained according to ATCC recommendations.

[0454] IC 50 Proliferation assay

[0455] Cell lines were seeded into 96-well plates the afternoon before treatment. Approximately 18 hours later, the compound was semi-serially diluted in dimethyl sulfoxide (DMSO), then in growth medium, and added to the cells. The plates were incubated for 72 hours, followed by incorporation with Almar Blue (Life Technologies, Carlsbad, CA). Plates were read using a Berten-HT co-processor plate reader (Berten, Winnowski, Vermont) after an additional 4 hours of incubation at 37°C. Data were analyzed and plotted using GraphPad Prism software (Graphpad, La Jolla, CA).

[0456] Proliferation inhibition at 100 nM or 1 mM inhibitor concentration

[0457] To determine inhibition at 100 nM or 1 mM, 96-well plates were seeded in the afternoon prior to treatment. The plates were then treated the following day with the compound diluted in dimethyl sulfoxide (DMSO) and a DMSO control for 72 hours. Subsequently, the plates were treated for 4 hours with 10 μL of CellTiter-Blue cell viability assay (Promag, Madison, Wisconsin). The plates were then read on a plate reader (Berten, Winnowski, VT). Data were analyzed in Excel as the percentage of DMSO carriers.

[0458] IC 50 Measurement (proliferation assay)

[0459] Midottolin hydrate (control compound) was purchased from Sigma-Aldrich (St. Louis, Missouri) with >98% HPLC purity and was ready for use without further purification. Cell lines were seeded into 96-well plates the afternoon before treatment. Approximately 18 hours later, the compound was diluted in dimethyl sulfoxide (DMSO) and added to the cells. The plates were incubated for 72 hours, and cell viability was determined using the CellTiter-Blue cell viability assay (Promega, Madison, Wisconsin). Plates were read after an additional 4 hours of incubation at 37°C using a plate reader (Berten, Winnowski, Vermont). Data were analyzed and plotted using GraphPad Prism software (Graphpad, La Jolla, CA).

[0460] Protein blot

[0461] The effect of HSW630-1 on protein expression was tested in the MV4-11 leukemia cell line. Complete Mini supplement was used. TM Protease inhibitors and PHOStop TM Total protein extracts were prepared using RIPA buffer (Sigma) with a phosphatase inhibitor (Roche). Equal amounts of protein (up to 25 μg) were separated onto 4–12% NuPAGE gels in 1X MOPS or 1X MES buffer (Ingenieur) and transferred to PVDF membranes (Millipore). The membranes were blocked at room temperature with 5% milk powder in 1X TBS / 0.1% Tween 20 (TBST) for at least 1 hour and incubated overnight at 4°C with a human-specific primary antibody: FLT3, phosphate-FLT3, c-Myc (Cell Signaling Technology), KRAS (Santa Cruz), or mouse anti-β-actin (Sigma). The membranes were washed three times in TBST and incubated at room temperature for 1 hour with a horseradish peroxidase-conjugated secondary anti-rabbit or anti-mouse antibody (Cell Signaling Technology). The blots were washed again, and the signal was detected using the highest sensitivity chemiluminescent substrate (SuperSignalWest Femto Chemiluminescent Substrate) (Pierce) and exposed to [unclear - likely a specific environment or environment]. Autoradiographic film (Devril).

[0462] Example 1

[0463]

[0464] In a 50 ml round-bottom flask, add 50 mg of 6-bromo-isoquinoline-3-amine, 10 mol% bis(triphenylphosphine)palladium(II) dichloride, and 10 mol% triphenylphosphine. Purify three times with nitrogen before adding 5 ml of anhydrous DMF. Stir at 45 °C for 5 minutes, then add the corresponding alkyne to 1 ml of anhydrous DMF via syringe over 2 minutes. Add 2 ml of DIPEA and stir overnight. After the reaction is complete as indicated by TCL, add an equal volume of distilled water and extract three times (50 ml * 3) with DCM. Wash with brine and dry with anhydrous sodium sulfate to remove the solvent. Obtain the pure product by Combi-Flash extraction using 100% DCM to 35% MeOH.

[0465] Example 1A: 6-(3,3-dimethylbut-1-yn-1-yl)isoquinoline-3-amine

[0466]

[0467] 1 H NMR (500MHz, DMSO) δ8.78 (d, J=19.0Hz, 1H), 7.80–7.64 (m, 1H), 7.53 (s, 1H), 7.09 (ddd , J=97.0, 8.5, 1.5Hz, 1H), 6.55 (d, J=3.7Hz, 1H), 6.05 (d, J=62.4Hz, 2H), 1.28 (s, 9H). LR-MS(ESI)m / z,C 15 H 16 N2([M+H)) + The calculated value is 225.1, and the measured value is 225.3.

[0468] Example 1B: 6-(hexane-1,5-yn-1-yl)isoquinoline-3-amine

[0469]

[0470] LR-MS(ESI) m / z, C 15 H 12 N2([M+H)) + The calculated value is 221.1, and the measured value is 221.1.

[0471] Example 1C: 6-(cyclopropylethynyl)isoquinoline-3-amine

[0472]

[0473] LR-MS(ESI) m / z, C 14 H 12 N2([M+H)) +The calculated value is 209.1, and the measured value is 209.1.

[0474] Example 1D: 6-(3-(diethylamino)prop-1-yn-1-yl)isoquinoline-3-amine

[0475]

[0476] 1 H NMR (500MHz, CDCl3) δ7.72–7.63 (m, 2H), 7.54 (dd, J=7.6, 1.2Hz, 1H), 7.46 (td, J=7.6 , 2.8Hz, 1H), 7.26 (s, 1H), 3.50 (s, 2H), 2.56 (d, J=7.2Hz, 4H), 1.07 (t, J=7.2Hz, 6H). LR-MS(ESI)m / z,C 16 H 19 N3([M+H)) + The calculated value is 254.2, and the measured value is 254.2.

[0477] Example 1E: 6-(hex-1-yn-1-yl)isoquinoline-3-amine

[0478]

[0479] LR-MS(ESI) m / z, C 15 H 16 N2([M+H)) + The calculated value is 225.1, and the measured value is 225.6.

[0480] Example 1F: 6-ethynylisoquinoline-3-amine

[0481]

[0482] LR-MS(ESI) m / z, C 11 H8N2([M+H) + The calculated value is 169.1, and the measured value is 169.5.

[0483] Example 1G: tert-butyl (3-(3-aminoisoquinoline-6-yl)prop-2-yn-1-yl)carbamate

[0484]

[0485] 1H NMR (500MHz, MeOD) δ8.72 (s, 1H), 7.97 (s, 1H), 7.81–7.45 (m, 3H), 7.15 (dd, J=8.5, 1.1Hz, 1H), 6.71 (s, 1H), 4.08 (s, 2H), 1.47 (s, 9H); 13 C NMR (126MHz, DMSO) δ157.45, 155.76, 151.79, 138.47, 128.62, 127.88, 124.22, 124.08, 121.69, 97.05, 89.51, 82.19, 78.78, 30.65, 28.66. LR-MS(ESI)m / z,C 17 H 19 N3O2([M+H)) + The calculated value is 298.1, and the measured value is 298.4.

[0486] Example 1H: 6-(3-aminopropyl-1-yn-1-yl)isoquinoline-3-amine

[0487]

[0488] LR-MS(ESI) m / z, C 12 H 11 N3([M+H)) + The calculated value is 198.0, and the measured value is 198.6.

[0489] Example 1I: 6-(3-aminoisoquinoline-6-yl)hex-5-acetylenitizer

[0490]

[0491] LR-MS(ESI) m / z, C 15 H 13 N3([M+H)) + The calculated value is 236.1, and the measured value is 236.6.

[0492] Example 2

[0493]

[0494] In a 50 ml round-bottom flask, 1 equivalent of 6-chloro-isoquinoline-3-amine was dissolved in concentrated sulfuric acid at room temperature. After stirring the mixture for 5 minutes, sodium nitrate was immediately added, and the mixture was stirred overnight. After the reaction was complete as shown by TLC, 100 ml of cold water was added, and the mixture was extracted three times (50 ml x 3) with DCM, washed with brine, and dried over anhydrous sodium sulfate to remove the solvent. The crude product was then treated directly with 100 ml of aqueous sodium hydroxide solution, 5 equivalents of sodium dithionite were added, and the mixture was stirred overnight. After the reaction was complete as shown by TLC, an equal volume of distilled water was added, and the mixture was extracted three times (50 ml x 3) with DCM, washed with brine, and dried over anhydrous sodium sulfate to remove the solvent. The pure product was obtained by Combi-flash extraction using 100% DCM to 35% MeOH.

[0495] Example 2A: 6-Chloro-4-nitroisoquinoline-3-amine

[0496]

[0497] LR-MS(ESI)m / z, C9H6ClN3O2([M+H] + The calculated value is 224.1, and the measured value is 224.4.

[0498] Example 2B: 6-Chloroisoquinoline-3,4-diamine

[0499]

[0500] LR-MS(ESI)m / z, C9H8ClN3([M+H] + The calculated value is 194.0, and the measured value is 194.2.

[0501] Example 3: Pyrido[3,4-b]pyrazine-7-amine

[0502]

[0503] In a 50 mL round-bottom flask, 1 equivalent of pyridine-2,4,5-triamine was dissolved in anhydrous ethanol at room temperature. After stirring the mixture for 5 minutes, oxalaldehyde was immediately added, and the mixture was stirred overnight. After the reaction was complete as shown by TLC, 100 mL of cold water was added, and the mixture was extracted three times (50 mL x 3) with DCM, washed with brine, and dried over anhydrous sodium sulfate to remove the solvent. The pure product was obtained by Combi-flash extraction using 100% DCM to 35% MeOH.

[0504]

[0505] LR-MS(ESI) m / z, C7H6N4([M+H) +The calculated value is 147.0, and the measured value is 147.1.

[0506] Example 4: 3-Aminoisoquinoline-6-nitrile

[0507]

[0508] In a 50 ml round-bottom flask, add 50 mg of 6-bromo-isoquinoline-3-amine, 10 mol% tetra(triphenylphosphine)palladium(O), 1 mol% zinc, and 1.5 equivalents of zinc cyanide. Purify three times with nitrogen, then add 5 ml of anhydrous DMF. Stir overnight at 80 °C. After the reaction is complete as indicated by TCL, add an equal volume of distilled water, extract three times with DCM (50 ml * 3), wash with brine, and dry with anhydrous sodium sulfate to remove the solvent. Obtain the pure product by Combi-flash extraction with 100% DCM to 35% MeOH.

[0509]

[0510] 1 H NMR (500MHz, DMSO) δ8.95 (s, 1H), 8.18 (s, 1H), 7.67–7.50 (m, 2H), 7.35 (dd, J=8.4, 1.3Hz, 1H), 6.69 (s, 1H), 6.32 (s, 2H); LR-MS (ESI) m / z, C 10 H7N3([M+H) + The calculated value is 170.1, and the measured value is 170.6.

[0511] Example 5

[0512]

[0513] In a 250 mL round-bottom flask, 579 mg of 1 equivalent of 6-chloroisoquinoline-3-amine was dissolved in 150 mL of anhydrous MeOH at 0 °C and stirred for 5 min. Then, 675 mg of NIS was slowly added in portions over 10 min. The reaction was stopped by removing all solvent when TLC showed completion (usually within 15 min). 420 mg of 6-chloro-4-iodoisoquinoline-3-amine was obtained by rapid column chromatography or Combi-flash chromatography using 100% hexane-100% ethyl acetate.

[0514] In a 100 mL round-bottom flask, 290 mg of 1 equivalent of 4-ethynylbenzoic acid was dissolved in 50 mL of anhydrous DCM at 0 °C. 800 mg of HBTU was added and the mixture was stirred for another 10 minutes, followed by the addition of 1.1 equivalent of the corresponding amine. After 30 seconds, 1 equivalent of DIPEA was added, and the mixture was stirred overnight. The reaction was terminated by adding an equal volume of distilled water after TLC showed completion. The mixture was extracted three times (50 mL x 3) with DCM, washed with brine, and dried over anhydrous sodium sulfate to remove the solvent. Pure benzamide was obtained by Combi-flash extraction using 100% DCM to 20% MeOH.

[0515] In a 50 ml round-bottom flask, add 50 mg of 6-chloro-4-iodoisoquinoline-3-amine, 10 mol% bis(triphenylphosphine)palladium(II) dichloride, and 10 mol% triphenylphosphine. Purify three times with nitrogen, then add 5 ml of anhydrous DMF. Stir at 45 °C for another 5 minutes, then add the corresponding amount of benzamide to 1 ml of anhydrous DMF via syringe over 2 minutes. Add 2 ml of DIPEA and stir overnight. After the reaction is complete as indicated by TCL, add an equal volume of distilled water, extract three times with DCM (50 ml * 3), wash with brine, and dry with anhydrous sodium sulfate to remove the solvent. Obtain the pure product by Combi-flash extraction with 100% DCM to 35% MeOH.

[0516] Example 5A: 4-ethynyl-N-(3-morpholinylpropyl)benzamide

[0517]

[0518] LR-MS(ESI) m / z, C 16 H 20 N₂O₂([M+H)) + The calculated value is 273.2, and the measured value is 273.8.

[0519] Example 5B: N-(3-(dimethylamino)propyl)-3-ethynylbenzamide

[0520]

[0521] LR-MS(ESI) m / z, C 14 H 18 N₂O([M+H)) + The calculated value is 231.1, and the measured value is 231.6.

[0522] Example 5C: 4-ethynyl-N-(3-(4-methylpiperazin-1-yl)propyl)benzamide

[0523]

[0524] LR-MS(ESI) m / z, C 17 H 23 N3O([M+H)) + The calculated value is 286.1, and the measured value is 286.4.

[0525] Example 5D: 4-ethynyl-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)benzamide

[0526]

[0527] LR-MS(ESI) m / z, C 21 H 23 N3O([M+H)) + The calculated value is 334.2, and the measured value is 334.4.

[0528] Example 5E: N-(2-(dimethylamino)ethyl)-4-ethynylbenzamide

[0529]

[0530] LR-MS(ESI) m / z, C 13 H 16 N₂O([M+H)) + The calculated value is 217.1, and the measured value is 217.2.

[0531] Example 5F: 4-ethynyl-N-(3-(pyrrolidone-1-yl)propyl)benzamide

[0532]

[0533] LR-MS(ESI) m / z, C 16 H 20 N₂O([M+H)) + The calculated value is 257.1, and the measured value is 257.3.

[0534] Example 5G: 4-ethynyl-N-(3-(piperidin-1-yl)propyl)benzamide

[0535]

[0536] LR-MS(ESI) m / z, C 17 H 22 N₂O([M+H)) + The calculated value is 271.2, and the measured value is 271.6.

[0537] Example 5H: N-(5-(dimethylamino)pentyl)-4-ethynylbenzamide

[0538]

[0539] LR-MS(ESI) m / z, C 16 H 22 N₂O([M+H)) + The calculated value is 259.2, and the measured value is 259.6.

[0540] Example 5I: 4-ethynyl-N-(3-methoxypropyl)benzamide

[0541]

[0542] 1 H NMR (500MHz, CDCl3) δ7.73 (d, J=8.5Hz, 2H), 7.54 (d, J=8.5Hz, 2H), 3.62–3.51 (m, 4H), 3.39 (s, 3H), 1.90 (dd, J=6.5, 5.5Hz, 2H); 13 C NMR (126MHz, CDCl3) δ166.40, 134.78, 132.22, 126.82, 125.06, 82.61, 79.31, 72.19, 58.99, 39.01, 28.58. LR-MS(ESI)m / z,C 13 H 15 NO2([M+H] + The calculated value is 218.1, and the measured value is 218.3.

[0543] Example 5J: tert-butyl-4-(3-(4-ethynylbenzoylamino)propyl)piperazine-1-carboxylate

[0544]

[0545] LR-MS(ESI) m / z, C 21 H 29 N3O3([M+H)) + The calculated value is 217.1, and the measured value is 271.3.

[0546] Example 5K: N-(3-(dimethylamino)-2-hydroxypropyl)-4-ethynylbenzamide

[0547]

[0548] LR-MS(ESI) m / z, C 14 H 18N₂O₂([M+H)) + The calculated value is 217.1, and the measured value is 217.5.

[0549] Example 5L: 4-ethynyl-N-(2-hydroxy-3-(piperidin-1-yl)propyl)benzamide

[0550]

[0551] LR-MS(ESI) m / z, C 17 H 22 N₂O₂([M+H)) + The calculated value is 287.2, and the measured value is 287.4.

[0552] Example 5M: 2-ethynyl-N-(3-(piperidin-1-yl)propyl)benzamide

[0553]

[0554] LR-MS(ESI) m / z, C 17 H 22 N₂O([M+H)) + The calculated value is 271.1, and the measured value is 270.2.

[0555] Example 5N: 4-ethynyl-N-(4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)benzamide

[0556]

[0557] LR-MS(ESI) m / z, C 25 H 19 N5O([M+H)) + The calculated value is 406.2, and the measured value is 406.4.

[0558] Example 5O: 4-ethynyl-N-(2-(piperidin-1-yl)ethyl)benzamide

[0559]

[0560] 1 H NMR (500MHz, chloroform-d) δ7.74 (d, J=8.2Hz, 2H), 7.53 (d, J=8.2Hz, 2H), 7.13 (s, 1H), 3.52 (q, J=5.7Hz, 2 H), 3.18 (s, 1H), 2.56 (t, J=6.0Hz, 2H), 2.45 (s, 4H), 1.59 (p, J=5.6Hz, 4H), 1.46 (t, J=6.0Hz, 2H);13 C NMR (126MHz, CDCl3) δ166.53, 134.67, 132.24, 126.97, 125.14, 82.87, 79.34, 56.94, 54.24, 36.38, 25.89, 24.22.

[0561] Example 5P: N-(4-aminophenylethyl)-4-ethynylbenzamide

[0562]

[0563] 1 H NMR (500MHz, chloroform-d) δ7.64 (d, J=8.4Hz, 2H), 7.51 (d, J=8.5Hz, 2H), 7.01 (d, J=8.3Hz, 2H), 6. 66 (d, J=8.3Hz, 2H), 6.11 (s, 1H), 3.65 (q, J=6.6Hz, 2H), 3.18 (s, 1H), 2.81 (t, J=6.8Hz, 2H); 13 C NMR (126MHz, CDCl3) δ166.57, 145.01, 134.71, 132.29, 129.66, 128.54, 126.80, 125.22, 115.50, 82.78, 79.40, 41.37, 34.72.

[0564] Example 5Q: tert-butyl(1-(4-ethynylbenzoyl)piperidin-4-yl)carbamate

[0565]

[0566] 1 ¹H NMR (500 MHz, chloroform-d) δ 7.51 (d, J = 8.1 Hz, 2H), 7.33 (d, J = 8.3 Hz, 2H), 4.57–4.59 (2H), 3.69 (s, 2H), 3.14 (s, 1H), 3.08 (s, 1H), 2.95 (s, 1H), 1.99 (d, J = 47.4 Hz, 2H), 1.44–1.25 (¹¹H); 13 C NMR (126MHz, CDCl3) δ169.60, 155.05, 136.10, 132.26, 126.91, 123.63, 82.81, 79.67, 78.71, 47.88, 33.11, 32.15, 28.39.

[0567] Example 5R: tert-butyl (1-(3-ethynylbenzoyl)piperidin-4-yl)carbamate

[0568]

[0569] 1 ¹H NMR (500 MHz, chloroform-d) δ 7.52 (dd, J = 6.0, 2.3 Hz, 1H), 7.49 (s, 1H), 7.40–7.32 (m, 2H), 4.59–4.49 (NH & NH-CH, 2H), 3.69 (s, 2H), 3.11 (s, C≡CH & N-CH) a H b ,2H),2.96(s,N-CH a H b 1H), 2.05-1.94(2H), 1.45-1.28(-(CH3)3&CH2, 11H); 13 C NMR (126MHz, CDCl3) δ169.33, 155.04, 136.23, 133.24, 130.38, 128.67, 127.16, 122.62, 82.71, 79.67, 78.23, 47.89, 38.63, 32.15, 28.39.

[0570] Example 5S: [1,4'-dipiperidine]-1'-yl(4-ethynylphenyl)methyl ketone

[0571]

[0572] 1 ¹H NMR (500 MHz, chloroform-d) δ 7.50 (d, J = 7.8 Hz, 2H), 7.34 (d, J = 8.1 Hz, 2H), 4.72 (s, 1H), 3.73 (s, 1H), 3.13 (s, 1H), 2.98 (s, 1H), 2.74 (s, 1H), 2.53 (s, 5H), 1.93 (s, 1H), 1.77 (s, 1H), 1.63–1.40 (m, 7H); 13 C NMR (126MHz, CDCl3) δ169.41, 136.33, 132.23, 126.90, 123.49, 82.85, 78.62, 62.54, 50.29, 26.18, 24.55.

[0573] Example 5T: N-(4-(2-(dimethylamino)ethoxy)benzyl)-4-ethynylbenzamide

[0574]

[0575] 1H NMR (500MHz, chloroform-d) δ7.73 (d, J=8.4Hz, 2H), 7.51 (d, J=8.3Hz, 2H), 7.24 (d, J=8.5Hz, 2H), 6.87 (d, J=8.5Hz, 2H), 6. 53 (t, J=5.7Hz, 1H), 4.54 (d, J=5.5Hz, 2H), 4.06 (t, J=5.7Hz, 2H), 3.18 (s, 1H), 2.76 (t, J=5.6Hz, 2H), 2.36 (s, 6H); 13 C NMR (126MHz, CDCl3) δ166.46, 158.31, 134.42, 132.27, 130.28, 129.31, 126.98, 125.34, 114.85, 82.76, 79.52, 65.83, 58.17, 45.76, 43.69.

[0576] Example 5U: 3-ethynyl-N-(2-(piperidin-1-yl)ethyl)benzamide

[0577]

[0578] 1 H NMR (500MHz, chloroform-d) δ8.85 (s, 1H), 8.10 (s, 1H), 8.03 (dd, J=7.8, 1.5Hz, 1H), 7.55 (dd, J=7.5, 1.4Hz, 1H), 7 .36 (t, J=7.8Hz, 1H), 3.85 (q, J=5.5Hz, 2H), 3.19 (t, J=5Hz, 2H), 3.08 (bs, 5H), 1.97 (s, 4H), 1.61 (s, 2H); 13 C NMR (126MHz, CDCl3) δ166.99, 135.09, 133.60, 131.58, 128.62, 127.79, 122.51, 82.82, 78.10, 57.71, 54.32, 34.83, 22.86, 22.08.

[0579] Example 5V: N-(2-(1H-imidazol-4-yl)ethyl)-4-ethynylbenzamide

[0580]

[0581] 1H NMR (500MHz, DMSO-d6) δ8.66 (t, J=5.6Hz, 1H), 7.82 (d, J=8.3Hz, 2H), 7.60–7. 49(m, 3H), 6.82(s, 1H), 4.36(s, 1H), 3.50–3.43(m, 2H), 2.74(t, J=7.5Hz, 2H); 13 C NMR (126MHz, DMSO) δ165.73, 135.16, 135.12, 132.11, 127.89, 124.76, 117.11, 83.38, 83.27, 27.29.

[0582] Example 5W: tert-butyl-4-(4-ethynylbenzoylamino)cyclohexyl)carbamate

[0583]

[0584] 1 H NMR (500MHz, DMSO-d6) δ8.31 (d, J=7.9Hz, 1H), 7.82 (d, J=7.9Hz, 2H), 7.53 (d, J=7.9Hz, 2H), 6.75 (d, J=8.0 Hz, 1H), 4.36 (s, 1H), 3.74–3.61 (m, 1H), 3.18 (m, 1H), 1.81–1.73 (m, 4H), 1.36 (m, 11H), 1.26–1.14 (m, 2H); 13 C NMR (126MHz, DMSO) δ165.07, 155.33, 135.19, 132.00, 128.02, 124.69, 83.40, 83.23, 77.87, 49.04, 48.30, 31.91, 31.44, 28.74.

[0585] Example 5X: Bis-Boc-4-ethynyl-N-(4-guanidinocyclohexyl)benzamide

[0586]

[0587] 1H NMR (500MHz, chloroform-d) δ 11.53 (s, 1H), 8.27 (d, J = 8.3Hz, 1H), 7.71 (d, J = 8.0Hz, 2H), 7.54 (d, J = 8.3Hz, 2H), 5.90 (d, J = 7. 9Hz, 1H), 3.99 (d, J=45.1Hz, 1H), 3.19 (s, 1H), 2.15–2.10 (m, 4H), 1.50 (d, J=4.7Hz, 18H), 1.38 (q, J=5.2, 4.6Hz, 4H); 13 C NMR (126MHz, CDCl3) δ165.99, 163.78, 155.58, 153.30, 134.70, 132.29, 126.86, 125.29, 83.15, 82.77, 79.45, 79.25, 48.23, 48.14, 31.54, 31.50, 28.32, 28.12.

[0588] Example 6

[0589]

[0590] In a 50 ml round-bottom flask, 1 equivalent of 4-ethynylbenzaldehyde was dissolved in tBuOH, and immediately 1 equivalent of the corresponding diamine was added. The mixture was stirred at room temperature for 1 hour. 1.1 equivalents of iodine and 3 equivalents of potassium carbonate were added, and the mixture was refluxed overnight. After the reaction was complete as indicated by TCL, an equal volume of distilled water was added, and the mixture was extracted three times (50 ml * 3) with DCM, washed with brine, and dried over anhydrous sodium sulfate to remove the solvent. The pure product was obtained by Combi-flash extraction using 100% DCM to 35% MeOH.

[0591] Example 7: 4-Cyclopropyl-2-(4-ethynylphenyl)-4,5-dihydro-1H-imidazolium

[0592]

[0593] LR-MS(ESI) m / z, C 14 H 14 N2([M+H)) + The calculated value is 211.1, and the measured value is 211.3.

[0594] Example 8: 2-(4-ethynylphenyl)-4,5-dihydro-1H-imidazolium

[0595]

[0596] LR-MS(ESI) m / z, C 11 H 10 N2([M+H))+ The calculated value is 171.1, and the measured value is 171.3.

[0597] Example 9: 1-(2-(2-(4-ethynylphenyl)-4,5-dihydro-1H-imidazol-1-yl)ethyl)piperidine

[0598]

[0599] LR-MS(ESI) m / z, C 18 H 23 N3([M+H)) + The calculated value is 282.2, and the measured value is 282.4.

[0600] Example 10: 4-(2-(2-(4-ethynylphenyl)-4,5-dihydro-1H-imidazol-1-yl)ethyl)morpholine

[0601]

[0602] LR-MS(ESI) m / z, C 17 H 21 N3O([M+H)) + The calculated value is 211.1, and the measured value is 211.3.

[0603] Example 11: 2-(4-ethynylphenyl)-4,4-dimethyl-4,5-dihydro-1H-imidazolium

[0604]

[0605] LR-MS(ESI) m / z, C 13 H 14 N2([M+H)) + The calculated value is 199.1, and the measured value is 199.2.

[0606] Example 12: 4-((3-amino-6-chloroisoquinoline-4-yl)ethynyl)-N-(3-morpholinylpropyl)benzamide

[0607]

[0608] 1 H NMR (500MHz, MeOD) δ8.79 (s, 1H), 7.93-7.82 (m, 4H), 7.76 (d, J=8.4Hz, 2H), 7.25 (dd, J=8.6, 1 .9Hz, 1H), 3.72 (t, J=4.6Hz, 4H), 3.47 (t, J=6.9Hz, 2H), 2.58-2.49 (m, 6H), 1.93-1.81 (m, 2H);13 C NMR (125MHz, MeOD) δ167.91, 157.55, 151.88, 138.75, 138.03, 133.81, 131.01, 130.33, 127.09, 126.3 3. 123.67, 121.30, 120.77, 99.21, 90.21, 84.49, 66.25, 56.38, 53.35, 38.16, 25.52; LR-MS (ESI) m / z, C 25 H 26 ClN4O2([M+H) + The calculated value is 449.2, and the measured value is 449.3.

[0609] Example 13: 4-((3-amino-6-chloroisoquinoline-4-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)benzamide

[0610]

[0611] 1 H NMR (500MHz, DMSO) δ10.34 (s, 1H), 8.91 (s, 1H), 8.03 (d, J=8.3Hz, 2H), 7.96-7.85 (m, 3H), 7.74 (d, J=8.4Hz, 2H), 7.32-7.20(m, 3H), 6.88(s, 2H), 3.43(s, 2H), 2.63-2.31(m, 8H), 2.24(s, 3H); 13 C NMR (125MHz, DMSO) δ165.16, 158.79, 153.44, 138.78, 138.45, 137.47, 134.50, 131.64, 129.62, 128.32, 12 6.51, 123.54, 121.35, 120.76, 120.63, 99.58, 88.35, 86.33, 61.88, 54.71, 52.25, 45.47; LR-MS (ESI) m / z, C 30 H 29 ClN5O([M+H)) + The calculated value is 510.2, and the measured value is 510.5.

[0612] Example 14: 6-Chloro-4-((4-(4,5-dihydro-1H-imidazol-2-yl)phenyl)ethynyl)isoquinoline-3-amine

[0613]

[0614] 1H NMR (500MHz, DMSO) δ8.92 (s, 1H), 7.96 (d, J=8.6Hz, 1H), 7.93-7.81 (m, 5H), 7.28 (dd, J=8.6, 1.8Hz, 1H), 6.85 (s, 2H), 3.68 (s, 4H); 13 C NMR (125MHz, DMSO) δ163.73, 158.70, 153.30, 138.73, 137.42, 131.64, 131.56, 129.45, 127.78, 125.60, 123.52, 121.33, 120.61, 99.69, 88.45, 85.91, 49.51; LR-MS (ESI) m / z, C 20 H 15 ClN4([M+H)) + The calculated value is 347.1, and the measured value is 347.4.

[0615] Example 15: 3-((3-amino-6-chloroisoquinoline-4-yl)ethynyl)-N-(3-(dimethylamino)propyl)benzamide

[0616]

[0617] 1 H NMR (500MHz, DMSO) δ 8.90 (s, 1H), 8.64 (t, J = 5.4Hz, 1H), 8.16 (s, 1H), 7.92 (dd, J = 18.9, 8.2Hz, 2H), 7.86 (d, J = 1.3Hz, 1H), 7.82 (d, J = 7.9Hz, 1H), 7. 52 (t, J=7.7Hz, 1H), 7.26 (dd, J=8.6, 1.9Hz, 1H), 6.82 (s, 2H), 3.30 (dd, J =12.8, 6.7Hz, 2H), 2.35 (t, J = 7.1Hz, 2H), 2.19 (s, 6H), 1.73-1.60 (m, 2H); 13 C NMR (125MHz, DMSO) δ165.99, 158.69, 153.15, 138.77, 137.37, 135.51, 134.23, 131.58, 130.35, 129.09, 12 7.53, 123.49, 123.45, 121.30, 120.63, 99.47, 88.53, 84.37, 57.13, 45.32, 38.16, 27.21; LR-MS (ESI) m / z, C 23 H 24 ClN4O([M+H)) +The calculated value is 407.2, and the measured value is 407.2.

[0618] Example 16: 4-((3-amino-6-chloroisoquinoline-4-yl)ethynyl)-N-(3-(pyrrolidine-1-yl)propyl)benzamide

[0619]

[0620] 1 H NMR (500MHz, MeOD) δ8.80 (s, 1H), 7.97-7.84 (m, 4H), 7.77 (dd, J=5.8, 4.1Hz, 2H), 7.26 (dd, J=8.7, 2.0 Hz, 1H), 3.50 (t, J=6.8Hz, 2H), 3.33 (dt, J=3.3, 1.6Hz, 4H), 2.86-2.80 (m, 2H), 1.94 (d, J=3.6Hz, 6H); 13 C NMR (125MHz, MeOD) δ168.08, 157.58, 151.92, 138.76, 138.05, 133.59, 131.02, 130.36, 127.13, 126.4 3. 123.68, 121.30, 120.79, 99.19, 90.18, 84.55, 53.68, 53.37, 37.58, 27.33, 22.74; LR-MS (ESI) m / z, C 25 H 26 ClN4O([M+H)) + The calculated value is 433.2, and the measured value is 433.4.

[0621] Example 17: 4-((3-amino-6-chloroisoquinoline-4-yl)ethynyl)-N-(3-(4-methylpiperazin-1-yl)propyl)benzamide

[0622]

[0623] 1 H NMR (500MHz, MeOD) δ8.76 (s, 1H), 7.90-7.87 (m, 1H), 7.87-7.84 (m, 2H), 7.82 (d, J=8.6Hz, 1H), 7.75-7.71 (m, 2H), 7.22 (dd, J=8.6, 2.0Hz, 1H), 3.44 (t, J=6.9Hz, 2H), 2.77-2.37 (m, 10H), 2.28 (s, 3H), 1.83 (dd, J=14.5, 7.2Hz, 2H); 13C NMR (125MHz, MeOD) δ167.90, 157.57, 151.90, 138.77, 138.05, 133.85, 131.03, 130.36, 127.13, 126.34, 1 23.68, 121.32, 120.79, 99.23, 90.21, 84.51, 55.88, 54.24, 52.27, 44.56, 38.25, 25.80; LR-MS (ESI) m / z, C 26 H 29 ClN5O([M+H)) + The calculated value is 462.2, and the measured value is 462.2.

[0624] Example 18: 4-((3-amino-6-chloroisoquinoline-4-yl)ethynyl)-N-(3-(piperidin-1-yl)propyl)benzamide

[0625]

[0626] 1 H NMR (500MHz, MeOD) δ8.81 (s, 1H), 7.95 (s, 1H), 7.93 (d, J = 1.9Hz, 2H), 7.87 (d, J = 8.8Hz, 1H), 7.78 (d, J = 8.5Hz, 2H) , 7.27 (dd, J=8.6, 2.0Hz, 1H), 3.54 (t, J=6.6Hz, 2H), 3.33 (dt, J=3.3, 1.6Hz, 6H), 3.22-3.17 (m, 2H), 1.91 (s, 6H); 13 C NMR (125MHz, MeOD) δ168.53, 157.63, 152.01, 137.98, 133.10, 131.06, 130.41, 127.33, 125.30, 123.70, 121. 29, 117.28, 110.55, 99.15, 90.11, 86.23, 84.74, 54.45, 52.95, 36.48, 24.18, 22.99, 21.36; LR-MS (ESI) m / z, C 26 H 28 ClN4O([M+H)) + The calculated value is 447.2, and the measured value is 447.3.

[0627] Example 19: 4-((3-amino-6-chloroisoquinoline-4-yl)ethynyl)-N-(5-(dimethylamino)pentyl)benzamide

[0628]

[0629] 1 H NMR (500MHz, MeOD) δ7.92 (s, 1H), 7.90 (s, 1H), 7.86 (d, J = 8.7Hz, 1H), 7.76 (d, J = 8.3Hz, 1H), 7.43 (s, 2H), 7.26 (dd, J = 8.6, 1.9Hz, 1H), 3.45 (t, J=6.9Hz, 2H), 3.21-3.12 (m, 2H), 2.91 (s, 6H), 1.82 (dt, J=12.0, 8.0Hz, 2H), 1.77-1.68 (m, 2H), 1.49 (dt, J=15.0, 7.7Hz, 2H); 13 C NMR (125MHz, MeOD) δ167.99, 157.58, 151.86, 138.75, 138.05, 133.79, 131.02, 130.40, 127.16, 126.31, 125.9 3. 124.96, 123.70, 121.29, 99.25, 84.50, 57.52, 44.62, 42.04, 39.07, 28.53, 23.85, 23.35; LR-MS (ESI) m / z, C 25 H 28 ClN4O([M+H)) + The calculated value is 435.2, and the measured value is 435.3.

[0630] Example 20: 4-((3-amino-6-chloroisoquinoline-4-yl)ethynyl)-N-(3-(dimethylamino)-2-hydroxypropyl)benzamide

[0631]

[0632] 1 H NMR (500MHz, MeOD) δ8.79 (s, 1H), 7.92 (s, 2H), 7.90 (s, 1H), 7.85 (d, J=8.7Hz, 1H), 7.76 (d, J=8.4Hz, 2H), 7.25 (dd, J= 8.6, 1.9Hz, 1H), 4.05-3.94 (m, 1H), 3.55 (dd, J=13.6, 4.8Hz, 1H), 3.42-3.35 (m, 1H), 2.47-2.43 (m, 2H), 2.33 (s, 6H); 13C NMR (125MHz, MeOD) δ168.24, 157.56, 151.88, 138.76, 138.05, 133.69, 131.00, 130.34, 127.18, 12 6.38, 123.67, 121.30, 120.78, 99.22, 90.21, 84.49, 67.43, 63.23, 44.75, 44.70; LR-MS (ESI) m / z, C 23 H 24 ClN4O2([M+H) + The calculated value is 423.2, and the measured value is 423.3.

[0633] Example 21: 4-((3-amino-6-chloroisoquinoline-4-yl)ethynyl)benzylnitrile

[0634]

[0635] 1 H NMR (500MHz, MeOD) δ8.84 (s, 1H), 7.94 (d, J = 1.6Hz, 1H), 7.89 (d, J = 8.7Hz, 1H), 7.85 ( d, J=8.4Hz, 2H), 7.80 (d, J=8.4Hz, 2H), 7.28 (dd, J=8.6, 1.9Hz, 1H); LR-MS (ESI) m / z, C 18 H 11 ClN3([M+H)) + The calculated value is 304.1, and the measured value is 304.1.

[0636] Example 22: 2-((3-amino-6-chloroisoquinoline-4-yl)ethynyl)-N-(3-(piperidin-1-yl)propyl)benzamide

[0637]

[0638] 1H NMR (500MHz, DMSO) δ8.90 (d, J=0.4Hz, 1H), 8.61 (s, 1H), 7.98 (d, J=2.0Hz, 1H), 7.93 ( d, J=8.6Hz, 1H), 7.88 (dd, J=7.7, 0.9Hz, 1H), 7.58–7.50 (m, 2H), 7.46 (td, J=7.5, 1.3H z, 1H), 7.26 (dd, J=8.6, 2.0Hz, 1H), 6.92 (s, 2H), 2.51 (dt, J=3.6, 1.8Hz, 3H), 2.30–2 .21(m, 2H), 2.16(s, 4H), 1.71–1.59(m, 2H), 1.42–1.30(m, 4H), 1.27(d, J=4.7Hz, 2H); 13 C NMR (126MHz, DMSO) δ168.30, 159.29, 153.12, 138.80, 138.68, 137.32, 132.81, 131.37, 130.23, 128.44, 127.80, 123.43, 121.69, 121.39, 120.54, 98.53, 88.83, 87.85, 56.93, 54.41, 39.65, 39.48, 38.55, 26.68, 26.00, 24.55.

[0639] Example 23: 4-((3-amino-6-chloroisoquinoline-4-yl)ethynyl)-N-(3-(1,3-dioxoisoindoline-2-yl)propyl)benzamide

[0640]

[0641] 1H NMR (500MHz, DMSO) δ8.92 (d, J=0.8Hz, 1H), 7.96 (d, J=8.6Hz, 1H), 7.92-7.77 (m, 8H), 7.71 (d, J=8.4Hz, 1H), 7.29 (dd, J=8.6, 2.0Hz, 1H), 6.85 (s, 2H), 3.65 (d, J=7.2Hz, 2H), 3.30 (s, 2H), 1.89 (q, J=7.1Hz, 2H); LR-MS (ESI) m / z, C 29 H 22 ClN4O3([M+H) + The calculated value is 509.1, and the measured value is 509.4.

[0642] Example 24: 4-((3-amino-6-chloroisoquinoline-4-yl)ethynyl)-N-(3-aminopropyl)benzamide

[0643]

[0644] 1 H NMR (500MHz, MeOD) δ8.71 (s, 1H), 7.93 (d, J=1.9Hz, 1H), 7.88-7.79 (m, 2H), 7.73 (d, J=8.6Hz, 1H), 7.69 -7.61 (m, 2H), 7.21 (dd, J=8.6, 2.0Hz, 1H), 3.45 (t, J=6.7Hz, 2H), 3.34-3.29 (m, 2H), 1.79-1.72 (m, 2H); 13 C NMR (125MHz, MeOD) δ168.26, 157.20, 151.91, 139.19, 138.80, 134.19, 131.71, 130.49, 127.61, 126 .43, 124.90, 122.52, 121.36, 100.08, 91.97, 85.03, 37.61, 33.97, 29.93, 25.19; LR-MS (ESI) m / z, C 21 H 19 The calculated value of ClN4ONa was 378.12, and the measured value was 401.30.

[0645] Example 25: tert-butyl((1r,4r)-4-(4-((3-amino-6-chloroisoquinoline-4-yl)ethynyl)benzoylamino)cyclohexyl)carbamate

[0646]

[0647] 1 H NMR (500MHz, methanol-d4) δ8.77 (s, 1H), 7.91–7.86 (m, 3H), 7.83 (d, J = 8.6Hz, 1H), 7.73 (d, J = 8.3Hz, 2H), 7.33 (d, J = 8.8Hz, 2H) , 7.23 (dd, J=8.6, 2.0Hz, 1H), 6.97 (d, J=8.7Hz, 1H), 4.53 (s, 2H), 4.29–4.16 (m, 2H), 3.23 (t, J=5.3Hz, 2H), 2.70 (s, 6H); 13C NMR (126MHz, MeOD) δ167.81, 157.59, 157.41, 151.93, 138.77, 138.06, 133.75, 131.87, 131.04, 130.38, 12 8.70, 127.21, 126.40, 123.69, 121.31, 120.80, 114.31, 99.24, 90.21, 84.52, 63.25, 56.96, 43.32, 42.63.

[0648] Example 26: tert-butyl(1-(4-((3-amino-6-chloroisoquinoline-4-yl)ethynyl)benzoyl)piperidin-4-yl)carbamate

[0649]

[0650] 1 H NMR (500MHz, DMSO-d6) δ8.90 (s, 1H), 7.94 (d, J = 8.6Hz, 1H), 7.85 (d, J = 2.0Hz, 1H), 7.81 (d, J = 8.3Hz, 2H), 7.40 (dd, J = 8.4, 3.0Hz, 2H), 7. 26 (dd, J=8.7, 1.9Hz, 1H), 6.88 (d, J=8.0Hz, 1H), 6.82 (s, 2H), 4.29 (s, 1H), 3.09 (s, 1H), 1.75 (d, J=41.7Hz, 3H), 1.37 (d, J=2.5Hz, 11H); 13 C NMR (126MHz, DMSO) δ168.85, 158.68, 155.29, 153.24, 138.78, 137.40, 136.17, 133.07, 131.82, 127.42, 124.44, 123.50, 1 21.32, 120.62, 99.47, 88.47, 85.12, 78.13, 55.38, 47.59, 40.50, 40.43, 40.33, 40.16, 40.00, 39.83, 39.66, 39.50, 28.72.

[0651] Example 27: 4-((3-amino-6-chloroisoquinoline-4-yl)ethynyl)-N-methyl-N-(3-(pyrrolidine-1-yl)propyl)benzamide

[0652]

[0653] 1H NMR (500MHz, methanol-d4) δ8.78 (s, 1H), 7.90 (s, 1H), 7.85 (d, J=8.6Hz, 1H), 7.78–7.74 (m, 2H), 7.50 (d, J=7.7Hz, 1H), 7.46 (d, J=7.8Hz, 1H), 7.24 (dd, J=8.6, 2.1Hz, 1H), 3.61 (t, J=7.1Hz , 1H), 3.31(t, J=1.9Hz, 3H), 3.10(s, 1H), 2.87–2.71(m, 3H), 2.42(s, 2H), 2.27(t, J=7.7H z, 1H), 2.06–1.96 (m, 1H), 1.85–1.67 (m, 3H), 1.65–1.50 (m, 3H), 1.45 (s, 1H), 1.27 (s, 1H); 13 C NMR (126MHz, MeOD) δ171.93, 157.57, 151.87, 138.80, 138.04, 135.93, 135.54 ,131.28,131.14,130.39,127.00,126.68,124.89,123.68,121.31,120.81,9 9.13, 90.22, 83.82, 55.35, 53.78, 53.65, 48.12, 47.94, 47.77, 47.60, 47.44, 47.27, 47.09, 45.25, 36.78, 31.99, 29.36, 24.83, 24.30, 23.39, 22.82, 22.67.

[0654] Example 28: tert-butyl((1r,4r)-4-(4-((3-amino-6-chloroisoquinoline-4-yl)ethynyl)benzoylamino)cyclohexyl)carbamate

[0655]

[0656] 1 H NMR (500MHz, DMSO-d6) δ8.90 (s, 1H), 8.29 (d, J = 7.9Hz, 1H), 7.94 (d, J = 8.6Hz, 1H), 7.91–7.85 (m, 3H), 7.83 (d, J = 8.1Hz, 2H), 7.26 (d, J = 8.6H) z, 1H), 6.84 (s, 2H), 6.74 (d, J=8.0Hz, 1H), 3.71 (dt, J=7.7, 3.8Hz, 1H), 1.83 (d, J=13.4Hz, 1H), 1.37 (s, 11H), 1.25 (dd, J=23.9, 12.4Hz, 2H). 13C NMR (126MHz, DMSO) δ165.22, 158.74, 155.35, 153.34, 138.76, 137.43, 134.36, 131.51, 127.88, 125.95, 123.53, 121.34, 1 20.63, 99.62, 88.41, 85.90, 77.87, 49.10, 48.33, 40.50, 40.33, 40.16, 40.00, 39.83, 39.66, 39.50, 31.96, 31.51, 28.75.

[0657] Example 29: 4-((3-amino-6-chloroisoquinoline-4-yl)ethynyl)-N-(4-aminophenylethyl)benzamide

[0658]

[0659] 1 H NMR (500MHz, DMSO-d6) δ8.90 (s, 1H), 8.59 (t, J = 5.6Hz, 1H), 7.94 (d, J = 8.6Hz, 1H), 7.90–7.80 (m, 5H), 7.26 (dd, J=8.7, 2.1Hz, 1H), 6.93–6.78 (m, 4H), 6.49 (d, J=8.2Hz, 2H), 4.84 (s, 2H), 3.43–3.36 (m, 2H), 2.69–2.63 (m, 2H); 13 C NMR (126MHz, DMSO) δ165.82, 158.74, 153.34, 147.29, 138.77, 137.44, 134.38, 132.91, 131.61, 129 .49, 127.75, 126.79, 125.97, 123.53, 121.35, 120.63, 114.48, 99.60, 88.43, 85.90, 41.99, 34.92.

[0660] Example 30: [1,4'-dipiperidine]-1'-yl(4-((3-amino-6-chloroisoquinoline-4-yl)ethynyl)phenyl)methyl ketone

[0661]

[0662] 1H NMR (500MHz, methanol-d4) δ8.79 (s, 1H), 7.91 (d, J = 12.6Hz, 1H), 7.88–7.81 (m, 1H), 7.78–7.72 (m, 2H), 7.48 (d, J = 8.3Hz, 2H), 7.25 ( d, J=8.3Hz, 1H), 4.74 (s, 1H), 3.85 (s, 1H), 3.17 (s, 1H), 2.82 (d, J=33.4Hz, 6H), 2.07 (s, 1H), 1.93 (s, 1H), 1.72–1.53 (m, 8H); 13 C NMR (126MHz, MeOD) δ170.27, 157.59, 151.86, 138.83, 138.07, 135.31, 131.20, 130.31, 126.91, 124.93, 123.74, 12 1.37, 120.93, 99.16, 90.41, 83.88, 62.58, 49.95, 48.11, 47.94, 47.77, 47.60, 47.43, 47.26, 47.09, 24.78, 23.31.

[0663] Example 31: (4-((3-amino-6-chloroisoquinoline-4-yl)ethynyl)phenyl)(4-aminopiperidin-1-yl)methyl ketone

[0664]

[0665] 1 H NMR (500MHz, DMSO-d6) δ8.90 (s, 1H), 8.53 (s, 1H), 8.15 (s, 3H), 7.94 (d, J = 8.6Hz, 1H), 7.83 (d, J = 8.5Hz, 2H), 7.42 (d, J = 8.3Hz, 2H), 7 .26 (m, 1H), 6.84 (s, 2H), 4.46 (s, 1H), 3.31 (s, 1H), 2.87 (s, 1H), 2.48 (d, J=2.7Hz, 2H), 1.99 (s, 1H), 1.91–1.87 (m, 1H), 1.47 (s, 2H); 13 C NMR (126MHz, DMSO) δ169.10, 158.67, 153.30, 138.78, 137.43, 135.77, 131.85, 131.62, 127.45, 124.63, 123 .52, 121.29, 120.60, 99.44, 88.41, 85.23, 47.82, 40.40, 40.33, 40.23, 40.07, 39.90, 39.73, 39.57, 39.40.

[0666] Example 32: 4-((3-amino-6-chloroisoquinoline-4-yl)ethynyl)-N-(2-(piperidin-1-yl)ethyl)benzamide

[0667]

[0668] 1 H NMR (500MHz, DMSO-d6) δ8.90 (s, 1H), 8.48 (s, 1H), 7.93 (d, J = 8.6Hz, 1H), 7.90 (d, J = 8.2Hz, 2H), 7.87 (d, J = 2.0Hz, 1H), 7.83 (d, J=8.1Hz, 2H), 7.26 (dd, J=8.6, 2.1Hz, 1H), 6.71 (s, 2H), 3.45 (s, 2H), 3.2 (s, 2H), 2.59 (s, 4H), 1.56 (s, 4H), 1.41 (s, 2H); 13 C NMR (126MHz, DMSO) δ166.08, 158.73, 153.28, 138.80, 137.45, 134.28, 131.59, 131.53, 12 7.82, 126.09, 123.57, 121.38, 120.73, 99.62, 88.62, 85.96, 57.62, 54.17, 25.44, 23.93.

[0669] Example 33: N-(2-(1H-imidazol-4-yl)ethyl)-4-((3-amino-6-chloroisoquinoline-4-yl)ethynyl)benzamide

[0670]

[0671] 1 H NMR (500MHz, DMSO-d6) δ8.90 (s, 1H), 8.69 (t, J = 5.6Hz, 1H), 7.94 (d, J = 8.6Hz, 1H), 7.91–7.82 (m, 5H), 7. 68 (s, 1H), 7.26 (dd, J=8.6, 2.1Hz, 1H), 6.88 (d, J=9.5Hz, 3H), 3.54–3.43 (m, 2H), 2.78 (t, J=7.5Hz, 2H); 13C NMR (126MHz, DMSO) δ165.89, 158.75, 153.37, 138.76, 137.44, 135.09, 134.77, 134.22, 131.62, 127.76, 126.05, 123.53, 121.34, 120.60, 117.03, 99.59, 88.35, 85.96, 27.18.

[0672] Example 34: 4-((3-amino-6-chloroisoquinoline-4-yl)ethynyl)-N-((1r,4r)-4-aminocyclohexyl)benzamide

[0673]

[0674] 1 H NMR (500MHz, DMSO-d6) δ8.90 (s, 1H), 8.38 (d, J = 7.7Hz, 1H), 8.02–7.92 (m, 4H), 7.91–7.81 (m, 5H), 7.27 (dd, J =8.7, 1.8Hz, 1H), 6.84 (s, 2H), 3.72 (s, 1H), 2.99 (s, 1H), 1.94 (d, J = 34.4Hz, 4H), 1.42 (q, J = 9.1, 8.4Hz, 4H); 13 C NMR (126MHz, DMSO) δ165.37, 153.37, 138.76, 137.43, 134.24, 131.52, 127.91, 126.03, 12 3.53, 121.32, 120.63, 118.96, 116.57, 99.60, 88.38, 85.96, 49.13, 47.87, 30.33, 29.72.

[0675] Example 35: 4-((3-amino-6-chloroisoquinoline-4-yl)ethynyl)-N-(4-(2-(dimethylamino)ethoxy)benzyl)benzamide

[0676]

[0677] 1H NMR (500MHz, methanol-d4) δ8.77 (s, 1H), 7.91–7.86 (m, 3H), 7.83 (d, J = 8.6Hz, 1H), 7.73 (d, J = 8.3Hz, 2H), 7.33 (d, J = 8.8Hz, 2H) , 7.23 (dd, J=8.6, 2.0Hz, 1H), 6.97 (d, J=8.7Hz, 1H), 4.53 (s, 2H), 4.29–4.16 (m, 2H), 3.23 (t, J=5.3Hz, 2H), 2.70 (s, 6H); 13 C NMR (126MHz, MeOD) δ167.81, 157.59, 157.41, 151.93, 138.77, 138.06, 133.75, 131.87, 131.04, 130.38, 12 8.70, 127.21, 126.40, 123.69, 121.31, 120.80, 114.31, 99.24, 90.21, 84.52, 63.25, 56.96, 43.32, 42.63.

[0678] Example 36: N-(2-(1H-imidazol-4-yl)ethyl)-3-((3-amino-6-chloroisoquinoline-4-yl)ethynyl)benzamide

[0679]

[0680] 1 H NMR (500MHz, DMSO-d6) δ8.90 (s, 1H), 8.69 (t, J=5.6Hz, 1H), 8.17 (d, J=1.8Hz, 1H), 7.95–7.81 (m, 4H), 7.53 (dd, J=16. 1, 8.2Hz, 2H), 7.26 (dd, J=8.6, 2.1Hz, 1H), 6.82 (d, J=12.8Hz, 3H), 3.50 (td, J=7.6, 5.6Hz, 2H), 2.78 (t, J=7.5Hz, 2H); 13 C NMR (126MHz, DMSO) δ166.01, 158.68, 153.15, 138.77, 137.40, 135.50, 135.15, 134.26, 131.58, 130.39, 129.10, 127.53 , 123.51, 123.45, 121.31, 120.63, 99.47, 88.54, 84.38, 40.47, 40.30, 40.14, 40.05, 39.97, 39.80, 39.64, 39.47, 27.35.

[0681] Example 37: 3-((3-amino-6-chloroisoquinoline-4-yl)ethynyl)-N-(3-(dimethylamino)-2-hydroxypropyl)benzamide

[0682]

[0683] 1 H NMR (500MHz, DMSO-d6) δ8.90 (s, 1H), 8.64 (t, J=5.7Hz, 1H), 8.22 (d, J=1.8Hz, 1H ), 7.98–7.81(m, 4H), 7.52(t, J=7.8Hz, 1H), 7.26(dd, J=8.6, 2.1Hz, 1H), 6.81(s , 2H), 5.09 (s, 1H), 3.89–3.83 (m, 1H), 3.42 (dt, J=13.4, 5.5Hz, 1H), 3.23–3.16 ( m, 1H), 2.54 (dd, J=12.4, 5.0Hz, 1H), 2.45 (dd, J=12.6, 7.6Hz, 1H), 2.34 (s, 6H); 13 C NMR (126MHz, DMSO) δ166.28, 158.70, 153.17, 138.76, 137.38, 135.32, 134.31, 131.60, 130.51, 12 9.08, 127.68, 123.51, 123.42, 121.30, 120.63, 99.47, 88.53, 84.38, 66.77, 63.21, 45.55, 45.00.

[0684] Example 38: BisBoc-1-(1-(4-((3-amino-6-chloroisoquinoline-4-yl)ethynyl)benzoyl)piperidin-4-yl)guanidine

[0685]

[0686] 1 H NMR (500MHz, methanol-d4) δ8.73 (s, 1H), 7.85 (d, J=2.0Hz, 1H), 7.78 (d, J=8.6Hz, 1H), 7.71 (d, J=8.3Hz, 2H), 7.45 (d, J=8.1Hz, 2H), 7.19 (dd, J=8. 6, 2.1Hz, 1H), 4.50 (s, 1H), 4.18 (q, J = 4.1Hz, 1H), 3.70 (s, 1H), 3.24 (s, 1H), 3.08 (s, 1H), 2.08 (s, 1H), 1.96 (s, 1H), 1.49 (d, J = 25.7Hz, 20H); 13C NMR (126MHz, MeOD) δ170.34, 163.15, 157.51, 155.43, 152.89, 151.81, 138.72, 137.98, 135.23, 131.22, 130.31, 126.90, 124.85, 123.66, 121.34, 120.74, 99.19, 90.27, 83.89, 83.30, 79.08, 48.13, 47.96, 47 .80, 47.63, 47.45, 47.37, 47.28, 47.11, 31.72, 30.94, 27.20, 26.86.

[0687] Example 39: General Synthesis of Isoquinoline

[0688] Most of the isoquinolines used are commercially available, but they can also be synthesized according to the following scheme.

[0689]

[0690] The general steps for synthesizing isoquinoline:

[0691] Diethoxyacetonitrile (15.5 mmol, 1 equivalent) was added to a 25% w / t sodium methoxide solution in methanol and stirred at room temperature for 24 hours. The corresponding amine (0.9 equivalent) was added and stirred again at room temperature for 24 hours. The reaction mixture was then concentrated under vacuum. The flask was then placed on ice, and concentrated sulfuric acid was added to achieve a final concentration of 1 M. The reaction was stirred for another 48 hours and then neutralized to pH ~7 with 4 M potassium hydroxide solution. The resulting precipitate was collected and extracted three times with CH₂Cl₂. The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography.

[0692] Example 39A: 6-(trifluoromethyl)isoquinoline-3-amine

[0693]

[0694] After the general steps described above, a brown solid was obtained. 1 H NMR (400MHz, MeOD) δ 8.84 (s, 1H), 7.92 (d, J = 8.8Hz, 1H), 7.83 (s, 1H), 7.31-7.29 (m, 1H), 6.84 (s, 1H). 13C NMR (100MHz, MeOD) δ158.36, 152.70, 139.69, 133.63, 133.32, 133.00, 132.6 8, 130.74, 126.98, 124.99, 124.28, 123.63, 123.58, 118.73, 118.70, 100.92. LRMS(ESI + ), C 10 The calculated value of H8F3N2[M+H] is 213.1, and the measured value is 213.4.

[0695] Example 39B: 6-(tert-butyl)isoquinoline-3-amine

[0696]

[0697] Following the general steps described above, a brown solid (370 mg, 13% yield) was obtained. 1 H NMR (500MHz, MeOD) δ 8.67 (s, 1H), 7.72 (d, J=8.8Hz, 1H), 7.46 (s, 1H), 7.36-7.34 (m, 1H), 6.80 (s, 1H), 1.37 (s, 9H). 13 C NMR (126MHz, MeOD) δ157.62, 155.86, 151.94, 141.81, 130.20, 129.78, 129.36, 124.15, 121.35, 102.05, 124.28, 36.86, 32.10. LRMS(ESI + ), C 13 H 17 The calculated value of N2[M+H] is 201.1, and the measured value is 201.2.

[0698] Example 39C: 6-Bromoisoquinoline-3-amine

[0699]

[0700] After the general steps described above, a brown solid was obtained. 1 H NMR (500MHz, D) 6 -DMSO) δ 8.79 (s, 1H), 7.78 (s, 1H), 7.71 (d, J=8.6Hz, 1H), 7.20 (d, J=8.4Hz, 1H), 6.54 (s, 1H), 6.10 (s, 2H). 13CNMR (126MHz, DMSO) δ157.62, 152.25, 140.12, 130.54, 126.41, 124.95, 124.69, 121.13, 96.35.

[0701] Example 39D: 6-Chloroisoquinoline-3-amine

[0702]

[0703] After the general steps described above, a brown solid was obtained. 1 H NMR (500MHz, D) 6 -DMSO) δ 8.80 (s, 1H), 7.79 (d, J=8.6Hz, 1H), 7.60 (s, 1H), 7.08 (d, J=8.4Hz, 1H), 6.55 (s, 1H), 6.10 (s, 2H). 13 CNMR (126MHz, DMSO) δ157.68, 152.13, 139.71, 135.50, 130.58, 123.11, 122.47, 121.02, 96.56.

[0704] Example 40: General steps of amide coupling

[0705]

[0706] HBTU (623 mg, 1.64 mmol, 1.2 equivalent), amine (1.64 mmol, 1.2 equivalent), and DIPEA (0.67 mL, 4.11 mmol, 3 equivalent) were added to a solution of ethynylbenzoic acid (200 mg, 1.37 mmol, 1 equivalent) in CH2Cl2 (10 mL) at 0 °C. The reaction mixture was brought to room temperature and stirred for 12 hours. Subsequently, the reaction mixture was diluted with CH2Cl2 (40 mL) and washed with water (2 × 40 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the crude compound. The compound was purified by rapid column chromatography.

[0707] Example 41: General steps of sow thistle coupling

[0708] A solution of iodinated, brominated, or chlorinated compounds (100 mg, 0.33 mmol, 1 equivalent) in triethylamine (1 mL, 7.2 mmol, 22 equivalents), Pd catalyst (5 mol%), CuI (5 mol%), and triphenylphosphine (10 mg, 0.04 mmol, 0.1 equivalents) was deoxygenated using argon vapor. A deoxygenated solution of alkynes (0.49 mmol, 1.5 equivalents) in DMF (3 mL) was slowly added to the solution over 15 minutes, and the reaction temperature was raised to 70 °C and stirred for 12 hours. The reaction was quenched at room temperature by adding NH4Cl (5 mL). The crude compound was extracted using EtOAc (3 × 40 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The purified product was obtained by rapid column chromatography.

[0709] Example 42: N 1 -(4-bromoquinoline-2-yl)-N 2 N 2 -Diethylethane-1,2-diamine

[0710]

[0711] 2,4-Dibromoquinoline (550 mg), N 2 N 2 Diethylethane-1,2-diamine (240 mg), Cs₂CO₃ (650 mg), and DMSO (4 mL) were placed in a round-bottom flask, and the mixture was heated to 150 °C for 12 h. The mixture was then cooled to room temperature and purified using rapid chromatography. 1 H NMR (500MHz, CDCl3) δ7.92 (d, J=8.3Hz, 1H), 7.79 (d, J=8.3Hz, 1H), 7.72–7.65 (m, 1H), 7.49 (td, J=7.8, 3.7 Hz, 1H), 6.55 (s, 1H), 6.46 (s, 1H), 3.29 (d, J=4.7Hz, 2H), 2.87 (t, J=6.0Hz, 2H), 2.67 (m, 6H), 1.14 (s, 6H). 13 C NMR (126MHz, CDCl3) δ151.10, 148.16, 143.39, 129.85, 128.80, 125.00, 119.99, 118.15, 101.86, 50.29, 46.41, 40.90, 11.96.

[0712] Example 43: Compound HSN225

[0713]

[0714] 1H NMR (500MHz, DMSO-d6) δ8.52 (t, J=5.7Hz, 1H), 8.27 (d, J=8.3Hz, 1H), 8.15 (s, 1H), 8.10 ( d, J=7.8Hz, 1H), 7.89 (d, J=8.4Hz, 2H), 7.78 (t, J=7.6Hz, 1H), 7.67 (d, J=8.4Hz, 2H), 7.5 7(t, J=7.0Hz, 1H), 7.38 (s, 2H), 4.73 (s, 1H), 3.76 (s, 1H), 3.42 (dt, J=13.2, 5.3Hz, 1H), 3.15(t, J=6.1Hz, 1H), 2.27(dd, J=12.4, 5.9Hz, 1H), 2.23–2.20(m, 1H), 2.17(s, 6H); 13C NMR (126MHz, DMSO) δ 166.08, 158.20, 147.78, 136.41, 134.02, 131.56, 131.16, 128.03, 126.78, 126.29, 124.93, 116.72, 102.89, 93.24, 89.28, 67.52, 64.33, 46.35, 45.28; HRMS (ESI+): C23H25N4O2(MH+) calculated value 389.1978, measured value 389.2018.

[0715] Example 44: 4-((4-(4,5-dihydro-1H-imidazol-2-yl)phenyl)ethynyl)isoquinoline-1-amine (HSM1795)

[0716]

[0717] 1 H NMR (500MHz, DMSO) δ8.27 (d, J=8.3Hz, 1H), 8.17–8.06 (m, 2H), 7.85 (d, J=7.9Hz, 2H), 7.77 (t, J= 7.5Hz, 1H), 7.63 (d, J=7.9Hz, 2H), 7.57 (d, J=7.5Hz, 1H), 7.37 (s, 2H), 6.97 (s, 1H), 3.34 (s, 4H); 13 C NMR (126MHz, DMSO) δ163.54, 158.16, 147.64, 136.44, 131.55, 131.16, 130.38, 127.82, 126.78, 125.34, 124.94, 116.75, 103.03, 93.42, 88.87, 55.48, 44.89; HR-MS (ESI) m / z, C 20 H17 N4([M+H)) + The calculated value is 313.1453, and the measured value is 313.1455.

[0718] Example 45: 4-((4-(4,5-dihydro-1H-imidazol-2-yl)phenyl)ethynyl)quinoline-2-amine (HSM1803)

[0719]

[0720] 1 H NMR (500MHz, DMSO) δ8.03 (dd, J=8.1, 0.8Hz, 1H), 7.91 (d, J=8.4Hz, 2H), 7.76 (d, J=8.4Hz, 2H) , 7.57–7.44 (m, 2H), 7.26 (ddd, J=8.1, 6.7, 1.4Hz, 1H), 7.00 (s, 1H), 6.59 (s, 2H), 3.62 (s, 4H); 13 C NMR (126MHz, DMSO) δ163.40, 158.16, 148.49, 132.19, 131.72, 130.37, 129.10, 127.9 5. 126.24, 125.64, 123.57, 122.52, 122.00, 115.50, 96.07, 86.97; HR-MS (ESI) m / z, C 20 H 17 N4([M+H)) + The calculated value is 313.1453, and the measured value is 313.1487.

[0721] Example 46: 4-((2-amino-6,7-dimethoxyquinazoline-4-yl)ethynyl)benzylnitrile (HSN364)

[0722]

[0723] 1 H NMR (500MHz, DMSO-d6) δ7.96 (q, J=8.5Hz, 4H), 7.28 (s, 1H), 6.87 (s, 1H), 6.61 (s, 2H), 3.90 (d, J=1.1Hz, 6H); 13 C NMR (126MHz, DMSO) δ160.53, 156.96, 150.97, 148.83, 147.55, 133.48, 133.27, 125.91, 118.74, 115.15, 112.82, 104.86, 103.86, 93.27, 89.06, 56.41, 56.07.

[0724] Example 47: 4-((4-(4,4-dimethyl-4,5-dihydro-1H-imidazol-2-yl)phenyl)ethynyl)-1-methylisoquinoline-3-amine (HSN370)

[0725]

[0726] 1 H NMR (500MHz, methanol-d4) δ8.01 (d, J=7.9Hz, 2H), 7.82 (d, J=8.0Hz, 2H), 7.71 (d, J=7.9Hz, 2H), 7.63(t, J=7.9Hz, 1H), 7.33–7.28(m, 1H), 3.58(s, 2H), 2.81(s, 3H), 1.38(s, 6H); 13 C NMR (126MHz, MeOD) δ159.31, 155.78, 138.09, 132.19, 131.08, 130.90, 127.89, 127.26, 12 6.88, 126.16, 123.20, 122.87, 121.33, 98.53, 89.81, 85.93, 62.63, 60.86, 27.24, 20.69.

[0727] Example 48: 4-((4-(4,4-dimethyl-4,5-dihydro-1H-imidazol-2-yl)phenyl)ethynyl)-6,7-dimethoxyquinazoline-2-amine (HSN335)

[0728]

[0729] 1 H NMR (500MHz, DMSO-d6) δ8.03 (d, J=9.9Hz, 3H), 7.97 (d, J=8.3Hz, 1H), 7.93 (s, 1H), 7.30 (s, 1 H), 6.88 (s, 1H), 6.61 (s, 2H), 3.91 (d, J=5.2Hz, 6H), 3.77 (s, 2H), 1.46 (s, 3H), 1.44 (s, 3H); 13 C NMR (126MHz, DMSO) δ162.00, 160.54, 156.99, 150.99, 148.86, 147.57, 133.71, 133.39, 12 9.33, 126.80, 126.12, 115.15, 104.90, 93.45, 89.08, 62.12, 57.30, 56.45, 56.15, 27.94.

[0730] Example 49: 3-((2-amino-6,7-dimethoxyquinazoline-4-yl)ethynyl)-4-methylbenzylnitrile (HSN368)

[0731]

[0732] 1 H NMR (500MHz, DMSO-d6) δ8.19 (d, J=1.6Hz, 1H), 7.87 (d, J=1.8Hz, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.30 (s, 1H), 6.88 (s, 1H), 6.62 (s, 2H), 3.89 (d, J=8.4Hz, 6H), 2.66 (s, 3H); 13 C NMR (126MHz, DMSO) δ160.55, 156.88, 150.90, 149.12, 147.52, 146.97, 136.34, 133.89, 131 .60, 122.56, 118.50, 115.11, 110.06, 104.88, 103.93, 91.52, 91.36, 56.05, 46.02, 21.44.

[0733] Example 50: Compound HSG33

[0734]

[0735] 1 H NMR (500MHz, methanol-d4) δ8.90 (d, J=4.5Hz, 1H), 8.43 (dd, J=8.5, 1.4Hz, 1H), 8.11 (dt, J=8.5, 0.9Hz, 1H) , 8.03–7.93 (m, 4H), 7.88 (ddd, J=8.4, 6.9, 1.4Hz, 1H), 7.80–7.76 (m, 2H), 3.90 (s, 2H), 1.58 (s, 6H); 13 C NMR (126MHz, methanol-d4) δ 164.44, 150.83, 148.75, 133.95, 131.87, 129.97, 129.69, 129.25, 128.76, 126.90, 125.44, 124.58, 97.95, 89.29, 63.32, 58.53, 27.92.

[0736] Example 51: Compound HSG39

[0737]

[0738] 1H NMR (500MHz, methanol-d4) δ9.02 (dd, J=4.4, 1.7Hz, 1H), 8.66 (dd, J=8.4, 1.7Hz, 1H), 8.32 (s, 1H) , 7.82 (q, J=8.2Hz, 4H), 7.61 (dd, J=8.4, 4.4Hz, 1H), 5.12 (s, 1H), 3.71 (s, 2H), 1.46 (s, 6H); 13 C NMR (126MHz, methanol-d4) δ 164.13, 161.49, 159.71, 155.45, 152.66, 151.48, 134.89, 132.41, 130.64, 128.36, 127.87, 122.96, 114.17, 107.49, 94.02, 88.07, 49.85, 28.75; HRMS (M+H): calculated value 342.1640, observed value 342.1715.

[0739] Example 52: Compound HSG42

[0740]

[0741] 1 H NMR (500MHz, methanol-d4) δ9.24–8.97 (m, 1H), 7.91 (dt, J=8.5, 0.9Hz, 1H), 7.86–7.76 (m, 2H), 7.77–7 .66 (m, 2H), 7.52 (dd, J=8.5, 7.4Hz, 1H), 7.29 (dd, J=7.4, 0.9Hz, 1H), 3.52 (s, 2H), 1.35 (s, 6H); 13 C NMR (126MHz, MeOD) δ163.98, 158.77, 149.57, 140.95, 134.17, 132.71, 132.40, 130.81 , 128.54, 127.13, 124.58, 123.58, 120.72, 100.91, 92.85, 85.89, 64.15, 62.96, 28.73.

[0742] Example 53: Compound HSG43

[0743]

[0744] 1H NMR (500MHz, methanol-d4) δ7.92 (d, J=8.9Hz, 1H), 7.85 (d, J=1.9Hz, 1H), 7.82–7.77 (m, 2H), 7.63 (dd, J=8.6, 1.9Hz, 1H), 7.61–7.56 (m, 2H), 7.51 (d, J=8.7Hz, 1H), 6.86 (d, J=8.9Hz, 1H), 3.51 (s, 2H), 1.34 (s, 6H); 13 C NMR (126MHz, MeOD) δ 164.02, 161.48, 160.37, 148.44, 139.04, 133.44, 132.41, 132.35, 131.00, 128.47, 127.32, 125.80, 124.28, 117.56, 114.36, 92.45, 89.03, 28.75; HRMS (M+H): calculated value 341.1688, observed value 341.1769.

[0745] Example 54: Compound HSG47

[0746]

[0747] 1 H NMR (500MHz, methanol-d4) δ8.77–8.53 (m, 1H), 7.86–7.78 (m, 2H), 7.74 (dt, J=1.7, 0.9Hz, 1H), 7.7 2–7.64 (m, 3H), 7.12 (dd, J=8.3, 1.6Hz, 1H), 3.52 (s, 2H), 2.51 (d, J=1.0Hz, 3H), 1.35 (s, 6H); 13 C NMR (126MHz, MeOD) δ 163.57, 157.57, 152.04, 143.52, 139.34, 132.07, 130.30, 129.16, 128.21, 126.93, 126.67, 122.82, 122.27, 100.25, 92.73, 86.20, 78.93, 78.86, 78.67, 78.41, 63.84, 62.72, 30.43, 28.72, 22.56; HRMS (M+H): calculated value 355.1844, observed value 355.1916.

[0748] Example 55: Compound HSG74

[0749]

[0750] 1¹H NMR (500 MHz, methanol-d⁴) δ 8.36–8.24 (m, 1H), 8.06–7.98 (m, 1H), 7.84 (s, 1H), 7.78–7.73 (m, 2H), 7.65–7.59 (m, 4H), 3.45 (s, 2H), 1.28 (s, 6H); 13 C NMR (126MHz, MeOD) δ163.89, 142.29, 132.54, 131.14, 131.06, 130.87, 130.11, 129 .52, 128.56, 127.66, 127.45, 126.74, 126.16, 122.66, 92.31, 90.05, 64.17, 63.00.

[0751] Example 56: Compound HSG001

[0752]

[0753] 1 ¹H NMR (500 MHz, methanol-d⁴) δ 8.23–8.14 (m, 2H), 8.08 (s, 1H), 7.87–7.78 (m, 3H), 7.70–7.64 (m, 2H), 7.60 (ddd, J = 8.3, 6.9, 1.2 Hz, 1H), 5.49 (s, 2H), 3.57 (s, 2H), 1.38 (s, 6H); 13 C NMR (126MHz, MeOD) δ164.54, 159.39, 147.42, 137.83, 134.32, 132.91, 132.66, 131.63, 129.47 , 128.04, 125.99, 125.24, 122.89, 118.25, 111.11, 105.33, 93.32, 91.86, 63.17, 58.59, 27.93.

[0754] Example 57: Compound HSG82

[0755]

[0756] 1H NMR (500MHz, DMSO-d6) δ9.79 (s, 1H), 8.05 (dd, J=8.1, 1.4Hz, 1H), 7.99 (d, J=1.8Hz, 1H), 7.81 (dt, J=7.9, 1.4Hz, 1H), 7. 72 (dt, J=7.7, 1.3Hz, 1H), 7.60–7.46 (m, 3H), 7.29 (ddd, J=8.1, 6.7, 1.4Hz, 1H), 7.01 (s, 1H), 6.60 (s, 2H), 5.97 (s, 2H); 13 C NMR (126MHz, DMSO) δ157.63, 149.91, 147.89, 133.96, 132.08, 129.91, 128.82, 128.77, 128.57, 126.52, 125.69, 125.12, 122.07, 121.55, 121.32, 114.96, 95.87, 85.10, 54.92.

[0757] Example 58: Compound HSG83

[0758]

[0759] 1 H NMR (500MHz, DMSO-d6) δ8.12 (s, 1H), 8.05 (dd, J=8.1, 1.4Hz, 1H), 8.03–7.92 (m, 2H), 7.87–7 .75(m, 2H), 7.56–7.50(m, 3H), 7.28(ddd, J=8.1, 6.7, 1.4Hz, 1H), 7.02(s, 1H), 6.60(s, 2H); 13 C NMR (126MHz, DMSO) δ166.98, 157.65, 147.98, 134.78, 131.73, 129.92, 128.52, 1 27.92, 125.75, 125.16, 124.13, 122.08, 121.49, 115.12, 109.23, 95.34, 86.75.

[0760] Example 59: 3-((2-aminoquinoline-4-yl)ethynyl)-N-(4-(2-(dimethylamino)ethoxy)benzyl)-4-methylbenzamide (HSN316)

[0761]

[0762] 1H NMR (500MHz, DMSO-d6) δ9.07 (t, J=6.0Hz, 1H), 8.17 (d, J=1.9Hz, 1H), 8.03 (dd, J =8.1, 1.4Hz, 1H), 7.88 (dd, J=8.0, 2.0Hz, 1H), 7.59–7.46 (m, 3H), 7.28 (ddd, J=8. 1, 6.6, 1.5Hz, 1H), 7.23 (d, J=8.6Hz, 2H), 7.02 (s, 1H), 6.88 (d, J=8.7Hz, 2H), 6.5 7 (s, 2H), 4.40 (d, J=5.9Hz, 2H), 3.99 (t, J=5.8Hz, 2H), 2.59 (s, 5H), 2.18 (s, 6H); 13 C NMR (126MHz, DMSO) δ165.40, 158.17, 157.90, 148.52, 143.70, 132.80, 131.97, 131.21, 130.43, 130.34, 129.23, 129.1 4. 128.96, 126.28, 125.47, 122.53, 121.92, 121.84, 115.57, 114.74, 94.59, 89.81, 66.22, 58.13, 45.98, 42.62, 20.93.

[0763] Example 60: Compound HSN303

[0764]

[0765] 1 H NMR (500MHz, DMSO-d6) δ9.25 (s, 1H), 9.16 (s, 1H), 8.11 (d, J = 2.4Hz, 1H), 8.02 (d, J = 8.1Hz, 1H), 7.69–7.56 (m, 6H), 7.54–7.50 (m, 2H), 7.25 (t, J=7.3Hz, 1H), 6.96 (s, 1H), 6.53 (s, 2H); 13 C NMR (126MHz, DMSO) δ158.16, 152.64, 148.49, 141.06, 139.56, 133.74, 133.20, 132.51, 130.23, 129.63, 127.3 1. 127.07, 126.22, 125.66, 123.74, 123.06, 122.38, 122.18, 118.90, 117.44, 115.11, 97.07, 84.72; HRMS (ESI + ):C 25 H 17ClF3N4O(MH + The calculated value is 481.1043, and the measured value is 481.1034.

[0766] Example 61: Compound HSN285

[0767]

[0768] 1 H NMR (500MHz, DMSO-d6) δ10.56 (s, 1H), 8.29 (d, J=1.9Hz, 1H), 8.21 (d, J=2.2H z, 1H), 8.06 (dd, J=8.0, 1.3Hz, 2H), 7.97 (dd, J=8.0, 2.0Hz, 1H), 7.70 (d, J=8. 5Hz, 1H), 7.61–7.48 (m, 3H), 7.29 (ddd, J=8.1, 6.6, 1.6Hz, 1H), 7.05 (s, 1H), 6 .59(s, 2H), 3.55(s, 2H), 3.15(s, 2H), 2.63(s, 3H), 2.37(s, 6H), 2.14(s, 3H); 13 C NMR (126MHz, DMSO) δ165.06, 158.17, 148.54, 144.50, 138.60, 132.83, 132.59, 131.69, 131.59, 130.59, 130.36, 129.40, 129.19, 127.7 4. 126.30, 125.50, 124.00, 122.55, 121.99, 121.92, 117.76, 115.63, 94.42, 90.11, 57.92, 55.19, 53.15, 49.06, 46.17, 21.04; HRMS (ESI + ):C 32 H 31 F3N5O(MH + The calculated value is 558.2481, and the measured value is 558.2479.

[0769] Example 62: 4-((4-(4,4-dimethyl-4,5-dihydro-1H-imidazol-2-yl)-3-fluorophenyl)ethynyl)quinoline-2-amine (HSM1856)

[0770]

[0771] 1H NMR (500MHz, DMSO) δ8.08 (d, J=8.0Hz, 1H), 7.89 (d, J=7.8Hz, 1H), 7.75 (s, 1H), 7.58–7.47 (m, 2H), 7.29 (dd, J=10.9, 4.0Hz, 1H), 7.05 (s, 1H), 6.66 (s, 2H), 3.61 (s, 2H), 1.38 (s, 6H); 13 C NMR (126MHz, DMSO) δ160.58, 157.18, 147.84, 140.91, 131.91, 131.34, 130.86, 128.05, 127.64, 125.57, 124.22, 122.68, 122.44, 105.95, 94.97, 87.12, 29.08.

[0772] Example 63: 4-(5-(2-aminoquinoline-4-yl)-1,3,4-diazol-2-yl)-N-hydroxybenzomidine (HSM1860)

[0773]

[0774] 1 H NMR (500MHz, DMSO) δ9.92 (d, J=9.2Hz, 1H), 8.80 (dd, J=17.4, 8.5Hz, 1H), 8.23–8.05 (m, 2H), 8 .00–7.92(m, 2H), 7.63–7.55(m, 2H), 7.39–7.26(m, 1H), 6.86–6.73(m, 2H), 6.10–5.90(m, 2H); 13 C NMR (126MHz, DMSO) δ164.26, 163.24, 158.07, 150.41, 149.43, 137.22, 130.3 1. 128.79, 127.17, 126.73, 126.57, 126.02, 123.66, 123.12, 118.17, 113.60.

[0775] Example 64: 3-((2-amino-6,7-dimethoxyquinazoline-4-yl)amino)benzyl nitrile (HSN295)

[0776]

[0777] 1H NMR (500MHz, DMSO-d6) δ10.79 (s, 1H), 8.36 (s, 1H), 8.14 (s, 2H), 7.90 (s, 2H), 7.75–7.53 (m, 2H), 7.00 (s, 1H), 3.92 (s, 6H); HRMS (ESI + ):C 17 H 16 N5O2(MH + The calculated value is 322.1304, and the measured value is 322.1314.

[0778] Example 65: 3-((2-amino-6,7-dimethoxyquinazoline-4-yl)amino)-N-hydroxybenzomidine (HSN301)

[0779]

[0780] 1 H NMR (500MHz, DMSO-d6) δ9.79 (s, 1H), 9.62 (s, 1H), 8.02–7.88 (m, 2H), 7.82 (s, 1H), 7.43 (d t, J=7.8, 1.5Hz, 1H), 7.40–7.35 (m, 1H), 6.81 (d, J=28.2Hz, 3H), 5.79 (s, 2H), 3.87 (s, 6H); 13 C NMR (126MHz, DMSO) δ158.43, 157.29, 155.27, 151.25, 146.28, 139.16, 134.27, 1 28.75, 124.18, 121.69, 120.61, 104.28, 103.53, 102.56, 56.70, 56.20; HRMS (ESI + ):C 17 H 19 N6O3(MH + The calculated value is 355.1519, and the measured value is 355.1515.

[0781] Example 66: N-(4-((2-amino-6,7-dimethoxyquinazoline-4-yl)amino)phenyl)-3-(piperidin-1-yl)propionamide (HSN304)

[0782]

[0783] 1H NMR (500MHz, DMSO-d6) δ10.57 (s, 1H), 10.53 (s, 1H), 8.09 (s, 1H), 7.69 (q, J=8.7Hz, 6H), 6.96 (s , 1H), 3.90 (s, 6H), 3.32 (t, J=5.1Hz, 6H), 3.22 (s, 2H), 2.94 (t, J=7.4Hz, 2H), 1.89–1.67 (m, 4H); 13 C NMR (126MHz, DMSO) δ168.38, 158.76, 155.79, 154.43, 147.14, 136.86, 133.30, 125.16, 119.70, 1 05.48, 103.00, 99.20, 74.35, 60.46, 58.49, 57.06, 56.53, 52.63, 31.05, 22.92, 21.87; HRMS (ESI + ):C 24 H 31 N6O3(MH + The calculated value is 451.2458, and the measured value is 451.2452.

[0784] Example 67: 4-((2-amino-6,7-dimethoxyquinazoline-4-yl)(methyl)amino)-N-hydroxybenzomididine (HSN318)

[0785]

[0786] 1 H NMR (500MHz, DMSO-d6) δ9.60 (s, 1H), 7.65 (d, J=8.6Hz, 2H), 7.13 (d, J=8.6Hz, 2H), 6.69 (s, 1H), 6.20 (s, 1H), 6.13 (s, 2H), 5.78 (s, 2H), 3.77 (s, 3H), 3.45 (s, 3H), 3.13 (s, 3H); 13 C NMR (126MHz, DMSO) δ162.04, 159.86, 154.14, 151.52, 150.71, 149.48, 144. 06, 130.25, 127.08, 124.86, 106.11, 105.37, 105.15, 55.84, 54.91, 41.42.

[0787] Example 68: 3-((2-amino-6,7-dimethoxyquinazoline-4-yl)ethynyl)-N-(4-(2-(dimethylamino)ethoxy)benzyl)-4-methylbenzamide (HSN317)

[0788]

[0789] 1 H NMR (500 MHz, DMSO-d6) δ 9.08 (t, J=5.9 Hz, 1H), 8.20 (d, J=1.9 Hz, 1H), 7.91 (dd, J=8.0, 1.9 Hz, 1H), 7.50 (d, J=8.1 Hz, 1H), 7.32 (s, 1H), 7.23 (d, J=8.6 Hz, 2H), 6.94–6.82 (m, 3H), 6.57 (s, 2H), 4.39 (d, J=5.8 Hz, 2H), 4.00 (t, J=5.8 Hz, 2H), 3.90 (s, 3H), 3.87 (s, 3H), 2.64 (s, 3H), 2.58 (t, J=5.8 Hz, 2H), 2.18 (s, 6H); 13 C NMR (126 MHz, DMSO) δ 165.27, 160.60, 157.92, 156.78, 150.80, 149.56, 147.42, 144.21, 132.93, 131.91, 131.79, 130.59, 129.58, 129.14, 121.11, 115.01, 114.74, 104.91, 103.96, 93.55, 90.21, 66.24, 58.14, 56.39, 55.91, 46.00, 42.63, 20.97.

[0790] Example 69: Compound HSN325

[0791]

[0792] 1 H NMR (500 MHz, DMSO-d6) δ 10.58 (s, 1H), 8.33 (d, J=1.9 Hz, 1H), 8.20 (d, J=2.2 Hz, 1H), 8.06 (d, J=8.6 Hz, 1H), 8.00 (dd, J=8.0, 2.0 Hz, 1H), 7.70 (d, J=8.5 Hz, 1H), 7.58 (d, J=8.1 Hz, 1H), 7.34 (s, 1H), 6.88 (s, 1H), 6.59 (s, 2H), 3.90 (d, J=7.0 Hz, 6H), 3.56 (s, 2H), 2.68 (s, 3H), 2.42 (s, 8H), 2.22 (s, 3H); 13C NMR (126MHz, DMSO) δ164.87, 160.60, 156.81, 150.83, 149.49, 147.45, 145.04, 138.64, 132.83, 132.46, 132.10, 131.75, 130. 75, 130.05, 123.94, 121.26, 117.71, 115.03, 104.91, 103.95, 93.31, 90.47, 57.80, 56.40, 55.94, 54.94, 52.74, 45.72, 21.08.

[0793] Example 70: 4-((6-chloro-3-(cyclopropaneformamido)isoquinoline-4-yl)ethynyl)-N-(2-(piperidin-1-yl)ethyl)benzamide (HSN329)

[0794]

[0795] 1 H NMR (500MHz, chloroform-d) δ8.80 (s, 1H), 7.99 (d, J=1.9Hz, 1H), 7.77 (m, 3H), 7.71 (d, J=8.4Hz, 1H), 7.66 (d, J=8.4Hz, 2H), 7.25 (d, J=2.0 Hz, 1H), 4.05 (t, J=6.2Hz, 2H), 2.60 (s, 2H), 2.46–2.33 (bs, 4H), 1.43–1.33 (m, 6H), 1.24–1.22 (m, 1H), 1.06 (m, 2H), 0.67 (m, 2H); 13 C NMR (126MHz, CDCl3) δ177.24, 173.16, 157.02, 152.12, 138.68, 138.29, 136.20, 131.63, 131.29, 130.06, 129 .42, 126.83, 124.68, 122.36, 121.32, 99.58, 85.80, 57.62, 54.47, 29.71, 25.70, 24.19, 18.50, 11.76, 9.43.

[0796] Example 71: 1-(3-((2-aminoquinoline-4-yl)ethynyl)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea (HSN333)

[0797]

[0798] 1H NMR (500MHz, DMSO-d6) δ9.25 (s, 1H), 9.03 (s, 1H), 8.11 (d, J = 2.6Hz, 1H), 8.01 (d, J = 8.1Hz, 1H), 7.87 (s, 1H), 7.65 (dd, J = 8.7, 2.5Hz, 1H), 7.61 (d, J = 8 .8Hz, 1H), 7.53 (d, J=5.5Hz, 2H), 7.49 (d, J=8.0Hz, 1H), 7.40 (t, J=7.8Hz, 1 H), 7.34 (d, J=7.5Hz, 1H), 7.27 (t, J=7.2Hz, 1H), 7.03 (s, 1H), 6.58 (s, 2H); 13 C NMR (126MHz, DMSO) δ158.13, 152.89, 148.48, 140.17, 139.66, 132.48, 130.31, 129.96, 129.21, 127.30, 127.06, 1 26.30, 126.18, 125.52, 124.36, 123.72, 122.98, 122.49, 122.26, 122.19, 121.82, 120.46, 117.40, 96.54, 85.25.

[0799] Example 72: 3-((8-amino-1,7-naphthid-5-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (HSN356)

[0800]

[0801] 1 ¹H NMR (500MHz, DMSO-d⁶) δ 10.57 (s, 1H), 8.88 (dd, J = 4.3, 1.6Hz, 1H), 8.46 (dd, J = 8.3, 1.6Hz, 1H), 8.28–8.19 (m, 3H), 8.08 (d, J = 8.5Hz, 1H), 7.89 (dd, J = 8.0, 2.0Hz, 1H), 7.85 (dd, J = 8.4, 4.2Hz, 1H), 7.69 (d, J = 8.5Hz, 1H), 7.53 (s, 2H), 7.50 (d, J = 8.1Hz, 1H), 3.57 (s, 2H), 2.60 (s, 3H), 2.48 (bs, combined with DMSO, 8H), 2.29 (s, 3H); 13C NMR (126MHz, DMSO) δ165.32, 158.56, 149.70, 148.18, 143.41, 138.78, 133.14, 132.64, 132.52, 132.21, 131.73, 131.36, 130.8 2. 130.33, 128.05, 127.99, 127.75, 127.06, 124.00, 123.42, 117.76, 102.11, 91.74, 90.52, 57.69, 54.64, 52.27, 45.89, 21.19.

[0802] Example 73: 3-((8-amino-1,7-naphthid-5-yl)ethynyl)-N-(4-(2-(dimethylamino)ethoxy)benzyl)-4-methylbenzamide (HSN357)

[0803]

[0804] 1 H NMR (500MHz, DMSO-d6) δ9.02 (t, J=6.0Hz, 1H), 8.87 (dd, J=4.2, 1.6Hz, 1H), 8.42 (dd, J=8.4, 1 .6Hz, 1H), 8.21 (s, 1H), 8.09 (d, J=1.8Hz, 1H), 7.84 (dd, J=8.4, 4.2Hz, 1H), 7.78 (dd, J=8.0, 1 .9Hz, 1H), 7.51 (s, 2H), 7.42 (d, J=8.0Hz, 1H), 7.23 (d, J=8.6Hz, 2H), 6.88 (d, J=8.7Hz, 2H), 4 .39 (d, J=5.9Hz, 2H), 4.00 (t, J=5.8Hz, 2H), 2.61 (t, J=5.8Hz, 2H), 2.56 (s, 3H), 2.20 (s, 6H); 13 C NMR (126MHz, DMSO) δ165.64, 158.51, 157.85, 149.68, 148.09, 142.60, 133.08, 132.67, 132.52, 132.08, 131.34, 13 0.43, 130.16, 129.13, 127.58, 127.04, 123.25, 114.73, 102.18, 91.86, 90.14, 66.09, 58.05, 45.89, 42.58, 21.08.

[0805] Example 74: 3-((1-aminoisoquinoline-4-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (HSN334)

[0806]

[0807] 1 H NMR (500MHz, DMSO-d6) δ10.52 (s, 1H), 8.29 (d, J = 8.3Hz, 1H), 8.21 (d, J = 2.2Hz, 1H), 8.1 9 (s, 2H), 8.11 (d, J = 8.7Hz, 1H), 8.06 (d, J = 8.5Hz, 1H), 7.86 (dd, J = 7.9, 1.9Hz, 1H), 7.8 0 (t, J=7.5Hz, 1H), 7.69 (d, J=8.5Hz, 1H), 7.57 (t, J=7.6Hz, 1H), 7.50 (d, J=8.0Hz, 1H), 7.38(s, 2H), 3.55(s, 2H), 3.15(d, J=3.7Hz, 1H), 2.61(s, 3H), 2.37(s, 7H), 2.14(s, 3H); 13 C NMR (126MHz, DMSO) δ165.34, 158.17, 147.70, 143.30, 138.67, 136.38, 132.66, 132.52, 131.68, 131.60, 130.62, 130.33, 12 7.87, 126.77, 125.00, 124.78, 123.99, 123.69, 117.74, 116.76, 103.16, 91.94, 91.71, 57.93, 55.20, 53.18, 46.20, 21.20.

[0808] Example 75: Compound HSN286

[0809]

[0810] 1H NMR (500MHz, DMSO-d6) δ10.54 (s, 1H), 8.92 (d, J = 0.8Hz, 1H), 8.38 (d, J = 2.0Hz, 1H), 8.2 1(d, J=2.2Hz, 1H), 8.05 (dd, J=8.5, 2.2Hz, 1H), 7.96 (d, J=8.6Hz, 1H), 7.88 (dd, J=8.0, 2.0Hz, 2H), 7.70 (d, J=8.6Hz, 1H), 7.51 (d, J=8.1Hz, 1H), 7.28 (dd, J=8.6, 2.0Hz, 1H), 6 .78(s, 2H), 3.55(s, 2H), 3.15(d, J=3.8Hz, 1H), 2.63(s, 3H), 2.37(s, 7H), 2.16(s, 3H); 13 C NMR (126MHz, DMSO) δ165.55, 158.55, 153.20, 143.27, 138.74, 138.69, 137.39, 132.82, 132.47, 131.70, 131.64, 131.49, 130.20, 12 8.05, 127.74, 125.90, 123.93, 123.48, 121.34, 120.68, 117.69, 98.17, 88.78, 88.59, 57.89, 55.14, 53.07, 46.08, 21.28; HRMS (ESI + ):C 32 H 30 F3N5O(MH + The calculated value is 592.2091, and the measured value is 592.2091.

[0811] Example 76: 3-((3-aminoisoquinoline-4-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (HSN352)

[0812]

[0813] 1H NMR (500MHz, DMSO-d6) δ10.54 (s, 1H), 8.90 (s, 1H), 8.36 (d, J=1.9Hz, 1H), 8.21 (s, 1H), 8.06 (d, J=8.5Hz, 1H), 7.95 (d, J=8.4Hz, 1H), 7.91 (d, J=8.1Hz, 1H), 7.87 (dd, J =7.9, 2.0Hz, 1H), 7.69 (t, J = 7.7Hz, 2H), 7.51 (d, J = 8.0Hz, 1H), 7.28 (d, J = 7.8Hz, 1 H), 6.55(s, 2H), 3.56(s, 2H), 3.37(s, 1H), 2.64(s, 3H), 2.38(bs, 7H), 2.17(s, 3H); 13 C NMR (126MHz, DMSO) δ165.57, 158.02, 153.10, 143.26, 138.70, 137.86, 132.79, 132.46, 132.20, 131.72, 131.37, 130.19, 1 29.16, 127.93, 127.75, 123.95, 123.66, 123.15, 122.71, 122.45, 97.88, 89.69, 89.38, 57.88, 55.11, 53.02, 46.02, 21.37.

[0814] Example 77: 3-((3-amino-8-chloroisoquinoline-4-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (HSN353)

[0815]

[0816] 1 H NMR (500MHz, DMSO-d6) δ10.53 (s, 1H), 9.10 (s, 1H), 8.37 (d, J=2.0Hz, 1H), 8.20 (d, J=2 .2Hz, 1H), 8.05 (dd, J=8.5, 2.2Hz, 1H), 7.94 (d, J=8.5Hz, 1H), 7.88 (dd, J=8.0, 2.0Hz, 1H), 7.70 (d, J=8.5Hz, 1H), 7.63 (dd, J=8.5, 7.4Hz, 1H), 7.51 (d, J=8.0Hz, 1H), 7.38 (d d, J=7.4, 0.9Hz, 1H), 6.82(s, 2H), 3.56(s, 2H), 2.63(s, 3H), 2.39(s, 8H), 2.18(s, 3H); 13C NMR (126MHz, DMSO) δ165.53, 158.44, 148.96, 143.46, 139.61, 138.69, 132.79, 132.62, 132.44, 132.38, 131.72, 131.57, 130.20, 1 28.14, 125.89, 123.94, 123.45, 123.38, 122.60, 118.91, 117.70, 117.65, 98.37, 90.06, 88.65, 57.86, 55.07, 52.96, 45.96, 21.37.

[0817] Example 78: Compound HSN247

[0818]

[0819] 1 H NMR (500MHz, methanol-d4) δ8.73 (s, 1H), 8.05 (d, J = 2.0Hz, 1H), 7.88 (d, J = 1.9Hz, 1H), 7.79 (d, J = 8.7Hz, 1H), 7.71 (dd, J = 7.9, 2.0Hz, 1H), 7.37 (d, J =8.0Hz, 1H), 7.20 (dd, J=8.7, 2.0Hz, 1H), 3.54 (t, J=7.0Hz, 2H), 2.86–2.78 (m, 2H), 2.74 (q, J=7.2Hz, 4H), 2.60 (s, 3H), 1.13 (t, J=7.2Hz, 6H); 13 C NMR (126MHz, MeOD) δ167.88, 157.31, 151.62, 142.91, 138.56, 137.95, 131.86, 130.31, 130.09, 129.53, 1 26.86, 123.66, 123.18, 121.37, 120.81, 98.11, 90.75, 87.08, 51.21, 46.89, 36.67, 19.97, 9.87; HRMS (ESI + ):C 25 H 28 ClN4O(MH + The calculated value is 435.1952, and the measured value is 435.1952.

[0820] Example 79: Compound HSN248

[0821]

[0822] 1H NMR (500MHz, methanol-d4) δ8.67 (s, 1H), 8.00 (d, J = 2.0Hz, 1H), 7.81 (d, J = 2.0Hz, 1H), 7.72 (d, J = 8.6Hz, 1H), 7.67 (dd, J = 7.9, 2.0Hz, 1H), 7.30 (d ; 13 C NMR (126MHz, MeOD) δ167.67, 157.22, 151.52, 142.74, 138.47, 137.87, 131.86, 130.23, 130.03, 129.45, 126.8 4. 123.62, 123.11, 121.39, 120.76, 98.20, 90.85, 87.12, 57.54, 54.11, 36.37, 25.05, 23.61, 20.02; HRMS (ESI + ):C 26 H 28 ClN4O(MH + The calculated value is 447.1952, and the measured value is 447.1946.

[0823] Example 80: 3-((3-amino-1-methylisoquinoline-4-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (HSN375)

[0824]

[0825] 1H NMR (500MHz, DMSO-d6) δ10.53 (s, 1H), 8.34 (d, J = 1.9Hz, 1H), 8.21 (d, J = 2.2Hz, 1H), 8.06 (d, J =7.9Hz, 1H), 8.02 (d, J = 8.3Hz, 1H), 7.97 (d, J = 8.4Hz, 1H), 7.85 (dd, J = 7.9, 2.0Hz, 1H), 7.70 (d , J = 8.5 Hz, 1H), 7.66 (t, J = 7.6 Hz, 1H), 7.50 (d, J = 8.1 Hz, 1H), 7.28 (ddd, J = 8.2, 6.8, 1.2 Hz, 1H), 6.44 (s, 2H), 3.58 (s, 2H), 2.77 (s, 3H), 2.63 (s, 3H), 2.57–2.37 (bs, 8H, combined with solvent), 2.29 (s, 3H); 13 C NMR (126MHz, DMSO) δ165.60, 159.76, 156.89, 143.08, 138.78, 138.07, 132.75, 132.23, 131.77, 131.73, 131.19, 130.17, 127. 73, 127.17, 123.95, 123.85, 123.29, 122.93, 121.10, 117.68, 97.47, 89.85, 88.16, 57.72, 54.77, 52.44, 49.07, 22.52, 21.39.

[0826] Example 81: 3-((3-amino-6-methylisoquinoline-4-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (HSN379)

[0827]

[0828] 1H NMR (500MHz, DMSO-d6) δ10.54 (s, 1H), 8.81 (d, J = 0.7Hz, 1H), 8.35 (d, J = 2.0Hz, 1H), 8.21 ( d, J=2.2Hz, 1H), 8.05 (dd, J=8.5, 2.2Hz, 1H), 7.87 (dd, J=8.0, 2.0Hz, 1H), 7.80 (d, J=8.3H z, 1H), 7.74–7.72 (m, 1H), 7.70 (d, J=8.6Hz, 1H), 7.51 (d, J=8.1Hz, 1H), 7.13 (dd, J=8.3, 1 .5Hz, 1H), 6.48(s, 2H), 3.56(s, 2H), 2.65(s, 3H), 2.47(s, 3H), 2.37(bs, 8H), 2.15(s, 3H); 13 C NMR (126MHz, DMSO) δ165.58, 158.09, 152.60, 143.24, 142.22, 138.70, 138.16, 132.79, 132.50, 131.72, 131.33, 130.21, 129.01, 1 27.88, 125.91, 125.34, 123.94, 123.74, 121.73, 120.96, 117.69, 97.80, 89.57, 89.32, 57.92, 55.20, 53.16, 46.19, 22.50, 21.33.

[0829] Example 82: 3-((3-amino-6-chloroisoquinoline-4-yl)ethynyl)-4-methyl-N-(4-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl)benzamide (HSN380)

[0830]

[0831] 1 H NMR (500MHz, DMSO-d6) δ10.73 (s, 1H), 8.93 (s, 1H), 8.40 (d, J = 2.0Hz, 1H), 8.30 (s, 1H), 8.15 (s, 1H), 7.96 (d, J = 8.6Hz, 1H), 7.89 (q, J = 1.3, 0.7Hz, 2H), 7.73 (s, 1H), 7.54 (d, J=8.1Hz, 1H), 7.49 (s, 1H), 7.28 (dd, J=8.6, 2. 0Hz, 1H), 6.93 (d, J=22.1Hz, 1H), 6.79 (s, 2H), 2.65 (s, 3H), 2.17 (s, 3H); 13C NMR (126MHz, DMSO) δ165.82, 162.76, 158.57, 153.26, 151.29, 143.66, 141.74, 138.75, 138.43, 137.41, 132.46, 131.66, 131.50, 131 .20, 130.34, 128.07, 125.19, 123.59, 123.51, 121.32, 120.68, 115.35, 114.71, 112.14, 108.27, 103.70, 98.06, 88.71, 21.31, 14.07.

[0832] Example 83: 5-((3-amino-6-chloroisoquinoline-4-yl)ethynyl)-6-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)nicotinamide (HSN387)

[0833]

[0834] 1 H NMR (500MHz, DMSO-d6) δ10.71 (s, 1H), 8.95 (d, J = 2.3Hz, 1H), 8.94 (s, 1H), 8.7 1 (d, J=2.3Hz, 1H), 8.19 (d, J=2.2Hz, 1H), 8.04 (dd, J=8.5, 2.2Hz, 1H), 7.96 (d , J=8.6Hz, 1H), 7.87 (d, J=2.0Hz, 1H), 7.72 (d, J=8.5Hz, 1H), 7.29 (dd, J=8.6, 2.0Hz, 1H), 6.92(s, 2H), 3.56(s, 2H), 2.84(s, 3H), 2.38(s, 8H), 2.17(s, 3H); 13 C NMR (126MHz, DMSO) δ164.32, 162.10, 158.88, 153.71, 147.25, 138.80, 138.65, 138.39, 137.55, 132.83, 131.81, 131.70, 128.1 7. 127.81, 125.85, 123.97, 123.55, 121.28, 120.62, 119.14, 117.69, 96.27, 90.91, 88.11, 57.88, 55.13, 53.06, 46.07, 24.37.

[0835] Example 84: 3-((3-amino-6-chloroisoquinoline-4-yl)ethynyl)-N-(3,5-dichloro-4-(2-(dimethylamino)ethoxy)phenyl)-4-methylbenzamide (HSN391)

[0836]

[0837] 1 H NMR (500MHz, DMSO-d6) δ10.47 (s, 1H), 8.92 (s, 1H), 8.34 (d, J = 1.9Hz, 1H), 7.96 (d, J = 8.7Hz, 1H), 7.94 (s, 2H), 7.88 (d, J = 1.9Hz, 1H), 7.84 (dd, J = 8.0 , 2.0Hz, 1H), 7.52 (d, J=8.1Hz, 1H), 7.28 (dd, J=8.6, 2.0Hz, 1H), 6.79 (s, 2 H), 4.02 (t, J=5.9Hz, 2H), 2.68 (t, J=5.9Hz, 2H), 2.63 (s, 3H), 2.23 (s, 6H); 13 C NMR (126MHz, DMSO) δ165.52, 158.57, 153.24, 147.01, 146.90, 143.45, 138.75, 137.40, 136.77, 132.60, 131.66, 13 1.46, 130.27, 128.63, 128.50, 128.02, 123.52, 121.33, 120.70, 113.72, 98.09, 88.73, 72.09, 58.71, 45.95, 21.29.

[0838] Example 85: 3-((3-amino-6-chloroisoquinoline-4-yl)ethynyl)-N-(6-(2-(dimethylamino)ethoxy)pyridin-3-yl)-4-methylbenzamide (HSN392)

[0839]

[0840] 1H NMR (500MHz, DMSO-d6) δ10.32 (s, 1H), 8.92 (s, 1H), 8.50 (d, J=2.7Hz, 1H), 8.36 (d, J= 1.8Hz, 1H), 8.03 (dd, J=8.9, 2.7Hz, 1H), 7.96 (d, J=8.6Hz, 1H), 7.89 (s, 1H), 7.86 (d, J =7.9Hz, 1H), 7.50 (d, J = 8.0Hz, 1H), 7.28 (dd, J = 8.6, 2.0Hz, 1H), 6.82 (d, J = 8.9Hz, 1H) , 6.79 (s, 2H), 4.30 (t, J=5.9Hz, 2H), 2.63 (s, 3H), 2.59 (t, J=5.9Hz, 2H), 2.19 (s, 6H); 13 C NMR (126MHz, DMSO) δ165.24, 159.98, 158.55, 153.20, 143.06, 139.32, 138.75, 137.39, 133.09, 132.85, 131.66, 13 1.42, 130.36, 130.18, 127.96, 123.50, 121.34, 120.68, 110.71, 98.21, 88.80, 88.55, 63.90, 58.13, 45.98, 21.27.

[0841] Example 86: 3-((3-amino-6,7-dichloroisoquinoline-4-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (HSN393)

[0842]

[0843] 1 H NMR (500MHz, DMSO-d6) δ10.53 (s, 1H), 8.91 (s, 1H), 8.38 (d, J = 1.9Hz, 1H), 8.27 (s, 1H), 8.20 (d, J = 2.2Hz, 1H), 8.05 (d, J = 7.1Hz, 2H), 7.8 8 (dd, J=7.9, 2.0Hz, 1H), 7.70 (d, J=8.5Hz, 1H), 7.51 (d, J=8.1Hz, 1H), 6.91 (s, 2H), 3.55 (s, 2H), 2.63 (s, 3H), 2.37 (s, 8H), 2.15 (s, 3H); 13C NMR (126MHz, DMSO) δ165.55, 158.60, 152.47, 143.36, 138.68, 137.06, 135.39, 132.84, 132.50, 131.72, 131.59, 130.67, 130.2 1, 128.14, 127.75, 124.96, 124.01, 123.94, 123.34, 121.29, 117.68, 98.38, 88.45, 88.16, 57.91, 55.17, 53.11, 46.13, 21.27.

[0844] Example 87: 3-((3-amino-6-fluoroisoquinoline-4-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (HSN394)

[0845]

[0846] 1 H NMR (500MHz, methanol-d4) δ8.93 (s, 1H), 8.37 (d, J = 1.9Hz, 1H), 8.25 (d, J = 2.2Hz, 1H), 8.10–8.02 (m, 2H), 7.95 (dd, J = 8.0, 2.0Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.66 (dd, J=10.6, 2.4Hz, 1H), 7.57 (d, J=8.0Hz, 1H), 7.19 (td, J=8.8, 2.5Hz, 1H), 3.69 (s, 2H), 2.74 (s, 3H), 2.56 (s, 8H), 2.35 (s, 3H); 13 C NMR (126MHz, MeOD) δ165.94, 163.90, 157.90, 152.39, 143.40, 139.79, 138.30, 132.68, 132.55, 132.45, 132.37, 131.40, 130.88, 12 9.95, 127.77, 123.71, 123.45, 117.68, 113.24, 113.04, 109.71, 106.14, 105.96, 98.05, 88.03, 57.65, 54.78, 52.42, 44.91, 20.48.

[0847] Example 87: 3-((2-amino-6,7-dimethoxyquinazoline-4-yl)ethynyl)-N-(3,5-dichloro-4-(2-(dimethylamino)ethoxy)phenyl)-4-methylbenzamide (HSN400)

[0848]

[0849] 1 H NMR (500MHz, DMSO-d6) δ10.49 (s, 1H), 8.29 (s, 1H), 7.97 (dd, J=8.1, 1.9Hz, 1H), 7.94 (s, 2H), 7.58 (d, J=8.1Hz, 1H), 7.33 (s, 1H), 6.88 (s, 1H), 6.58 (s, 2H), 4.03 (t, J=5.9Hz, 2H), 3.90 (d, J=7.5Hz, 6H), 2.70 (t, J=5.9Hz, 2H), 2.67 (s, 3H), 2.24 (s, 6H); 13 CNMR (126MHz, DMSO) δ164.81, 160.60, 156.82, 150.85, 149.47, 147.46, 147.06, 145.21, 136.68, 132.59, 132.09, 130. 80, 130.00, 128.50, 121.33, 120.74, 115.04, 104.91, 103.95, 93.22, 90.54, 71.98, 58.65, 56.41, 55.95, 45.88, 21.10.

[0850] Example 88: 3-((2-amino-6,7-dimethoxyquinazoline-4-yl)ethynyl)-N-(6-(2-(dimethylamino)ethoxy)pyridin-3-yl)-4-methylbenzamide (HSN401)

[0851]

[0852] 1 H NMR (500MHz, DMSO-d6) δ10.37 (s, 1H), 8.50 (d, J = 2.7Hz, 1H), 8.31 (d, J = 2.0Hz , 1H), 8.04 (dd, J=8.9, 2.7Hz, 1H), 7.99 (dd, J=8.0, 2.0Hz, 1H), 7.57 (d, J=8.1H z, 1H), 7.34 (s, 1H), 6.88 (s, 1H), 6.83 (d, J=8.9Hz, 1H), 6.59 (s, 2H), 4.31 (t, J =5.9Hz, 2H), 3.90(s, 3H), 3.89(s, 3H), 2.68(s, 3H), 2.60(s, 2H), 2.20(s, 6H); 13C NMR (126MHz, DMSO) δ164.54, 160.61, 160.02, 156.82, 150.84, 149.52, 147.46, 144.83, 139.33, 133.08, 132.86, 132.03, 1 30.73, 130.29, 129.97, 121.24, 115.04, 110.71, 104.92, 103.96, 93.38, 90.46, 63.86, 58.09, 56.41, 55.96, 45.94, 21.08.

[0853] Example 89: 3-((2-amino-9-methyl-9H-purin-6-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (HSN403)

[0854]

[0855] 1 ¹H NMR (500 MHz, methanol-d⁴) δ 8.20 (s, 1H), 8.12 (s, 2H), 7.94 (d, J = 7.6 Hz, 1H), 7.88 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.41 (d, J = 8.1 Hz, 1H), 3.71 (s, 3H), 3.64 (s, 2H), 2.73–2.43 (11H), 2.34 (s, 3H); 13 C NMR (126MHz, MeOD) δ165.96, 160.53, 145.12, 140.63, 137.87, 132.48, 132.25, 131.53, 131.14, 129.77, 128.84, 1 28.53, 127.15, 125.42, 123.53, 121.30, 117.67, 117.62, 94.14, 87.90, 57.44, 54.52, 52.07, 44.38, 28.40, 19.54.

[0856] Example 90: 4-((3-amino-6-chloroisoquinoline-4-yl)ethynyl)-5-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)pyridineamide (HSN404)

[0857]

[0858] 1H NMR (500MHz, DMSO-d6) δ10.94 (s, 1H), 8.96 (s, 1H), 8.69 (s, 1H), 8.57 (s, 1H), 8.38 (d, J = 2.2Hz, 1H), 8.16 (d, J = 7.9Hz, 1H), 7.97 (d, J = 8.6 Hz, 1H), 7.87 (s, 1H), 7.69 (d, J=8.5Hz, 1H), 7.29 (dd, J=8.6, 2.0Hz, 1H), 7.11 (s, 2H), 3.55 (s, 2H), 2.65 (s, 3H), 2.38 (s, 8H), 2.16 (s, 3H); 13 C NMR (126MHz, DMSO) δ163.27, 159.25, 154.54, 149.38, 148.11, 139.01, 138.02, 137.74, 137.12, 132.94, 132.73, 131.7 8. 131.60, 124.35, 124.17, 123.57, 121.26, 120.59, 117.99, 96.18, 94.13, 87.32, 57.90, 55.17, 53.11, 46.12, 18.19.

[0859] Example 91: 3-((6,7-dimethoxyquinazoline-4-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (HSN405)

[0860]

[0861] 1 H NMR (500MHz, DMSO-d6) δ10.56 (s, 1H), 9.09 (s, 1H), 8.38 (s, 1H), 8.20 (s, 1H), 8.03 (dd, J=16.2, 8.2Hz, 2H), 7.70 (d, J=8.5Hz, 1H) , 7.59 (d, J=8.0Hz, 1H), 7.56 (s, 1H), 7.40 (s, 1H), 4.02 (s, 3H), 4.00 (s, 3H), 3.55 (s, 2H), 2.71 (s, 3H), 2.39 (bs, 8H), 2.15 (s, 3H); 13C NMR (126MHz, DMSO) δ164.82, 156.92, 153.87, 151.69, 148.28, 147.81, 145.23, 138.58, 132.86, 132.61, 132.23, 131.73, 1 30.80, 130.29, 123.96, 121.18, 121.07, 117.70, 107.19, 103.15, 95.41, 90.31, 57.90, 56.40, 55.16, 53.10, 46.12, 21.12.

[0862] Example 92: 3-((2-amino-9H-purin-6-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (HSN408)

[0863]

[0864] 1 H NMR (500MHz, DMSO-d6) δ10.58 (s, 1H), 8.25 (s, 1H), 8.21 (d, J=2.2Hz, 1H), 8.11 (s, 1H), 8.06 (d, J=8.5Hz, 1H), 7.98 (dd, J=8. 0, 1.9Hz, 1H), 7.70 (d, J=8.5Hz, 1H), 7.55 (d, J=8.1Hz, 1H), 6.52 (s, 2H), 3.56 (s, 2H), 2.60 (s, 3H), 2.38 (s, 8H), 2.17 (s, 3H). 13 C NMR (126MHz, DMSO) δ164.93, 160.92, 155.15, 145.09, 142.20, 140.44, 138.62, 132.73, 132.55, 131.71, 131.57, 13 0.64, 129.74, 128.07, 127.74, 125.89, 124.01, 121.53, 117.74, 92.44, 90.21, 57.88, 55.12, 53.03, 46.04, 20.84.

[0865] Example 93: 3-((2-amino-6,7-dimethoxyquinazoline-4-yl)ethynyl)-N-(3-chloro-4-(2-(dimethylamino)ethoxy)phenyl)-4-methylbenzamide (HSN409)

[0866]

[0867] 1H NMR (500MHz, DMSO-d6) δ10.32 (s, 1H), 8.29 (d, J=2.0Hz, 1H), 7.98 (dd, J=8.0, 1.9Hz, 1H), 7.94 (d, J=2.5Hz, 1H), 7.66 (dd, J=9.0, 2.6Hz, 1H), 7.56 (d, J =8.1Hz, 1H), 7.34 (s, 1H), 7.17 (d, J = 9.0Hz, 1H), 6.88 (s, 1H), 6.59 (s, 2H), 4.12(t, J=5.7Hz, 2H), 3.90(s, 3H), 3.89(s, 3H), 2.67(s, 5H), 2.25(s, 6H); 13 C NMR (126MHz, DMSO) δ164.36, 160.60, 156.81, 150.83, 150.60, 149.52, 147.45, 144.77, 133.25, 133.06, 132.02, 130.69, 129.9 4. 122.36, 121.30, 121.22, 120.59, 115.04, 114.40, 104.91, 103.96, 93.40, 90.44, 67.84, 57.93, 56.40, 55.95, 46.10, 21.07.

[0868] Example 93: 3-((3-amino-6-chloroisoquinoline-4-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)benzamide (HSN415)

[0869]

[0870] 1 H NMR (500MHz, DMSO-d6) δ10.26 (s, 1H), 8.92 (s, 1H), 8.35 (s, 1H), 7.96 (d, J= 8.6Hz, 1H), 7.89 (d, J=2.0Hz, 1H), 7.85 (dd, J=8.0, 2.0Hz, 1H), 7.72 (d, J=8 .4Hz, 2H), 7.49 (d, J=8.0Hz, 1H), 7.28 (dd, J=8.6, 2.0Hz, 1H), 7.26 (d, J=8. 2Hz, 2H), 6.78 (s, 2H), 3.43 (s, 2H), 2.63 (s, 3H), 2.42 (bs, 8H), 2.23 (s, 3H). 13C NMR (126MHz, DMSO) δ165.21, 158.53, 153.18, 142.89, 138.75, 138.46, 137.38, 133.34, 131.66, 131.44, 130.12, 1 29.62, 128.01, 123.50, 123.37, 121.34, 120.68, 120.63, 98.27, 88.83, 88.49, 61.93, 54.85, 52.42, 45.44, 21.25.

[0871] Example 94: 6-((3-amino-6-chloroisoquinoline-4-yl)ethynyl)-5-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)pyridineamide (HSN416)

[0872]

[0873] 1 H NMR (500MHz, DMSO-d6) δ10.85 (s, 1H), 8.98 (s, 1H), 8.35 (d, J = 2.2Hz, 1H), 8.17 (d, J = 8.5Hz, 1H), 8.06–8.00 (m, 2H), 7.99 (d, J = 8.6Hz, 1H), 7.94 (s, 1H), 7.72 (d, J=8.6Hz, 1H), 7.31 (dd, J=8.6, 2.0Hz, 1H), 6.88 (s, 2H), 3.57 (s, 2H), 2.66 (s, 3H), 2.38 (s, 8H), 2.16 (s, 3H); 13 C NMR (126MHz, DMSO) δ163.02, 159.17, 154.17, 148.08, 141.92, 139.53, 139.39, 138.90, 137.89, 137.71, 132.82, 131.7 5. 131.67, 124.16, 123.76, 121.94, 121.42, 120.71, 117.96, 97.81, 88.52, 87.59, 57.90, 55.13, 53.07, 46.07, 19.94.

[0874] Example 95: 3-((6-amino-1H-pyrazolo[3,4-d]pyrimidin-4-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (HSN422)

[0875]

[0876] 1 H NMR (500MHz, DMSO-d6) δ10.55 (s, 1H), 8.31 (d, J = 2.0Hz, 1H), 8.20 (d, J = 2.2Hz, 1H), 8.07 (d, J = 1.2Hz, 1H), 8.05 (dd, J = 8.5, 2.3Hz, 1H), 7. 99 (dd, J=8.0, 2.0Hz, 1H), 7.70 (d, J=8.6Hz, 1H), 7.57 (d, J=8.1Hz, 1H), 6.91 (s, 2H), 3.55 (s, 2H), 2.61 (s, 3H), 2.38 (s, 8H), 2.15 (s, 3H); 13 C NMR (126MHz, DMSO) δ164.93, 162.69, 157.33, 145.26, 138.57, 133.48, 132.88, 132.64, 132.14, 131.73, 13 0.69, 130.15, 125.89, 124.00, 120.96, 109.69, 108.67, 92.11, 90.25, 57.92, 55.19, 53.15, 46.17, 20.90.

[0877] Example 96: 3-((6-amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (HSN423)

[0878]

[0879] 1 H NMR (500MHz, DMSO-d6) δ10.57 (s, 1H), 8.32 (d, J=2.0Hz, 1H), 8.21 (d, J=2.2Hz, 1H), 8.09 (s, 1H), 8.05 (dd, J=8.5, 2.2Hz, 1H), 8.00 (dd, J=8 ... 13C NMR (126MHz, DMSO) δ164.92, 162.68, 155.49, 145.39, 145.30, 138.61, 132.87, 132.58, 132.23, 131.74, 130.69, 1 30.21, 127.76, 125.88, 124.00, 120.86, 117.74, 109.03, 92.39, 90.05, 57.83, 55.00, 52.83, 45.83, 33.58, 20.90.

[0880]

[0881] Example 97: 3-((2-amino-6,7-dimethoxyquinazoline-4-yl)ethynyl)-4-methyl-N-(2-(piperidin-1-yl)ethyl)benzamide (HSN432)

[0882] 1 H NMR (500MHz, chloroform-d) δ8.79 (s, 1H), 7.98 (d, J=1.9Hz, 1H), 7.82 (dd, J=8.9, 5.6Hz, 1H), 7.65 (dd, J=7.9, 2.0Hz, 1H), 7.61 (dd, J=10.4, 2.5Hz, 1H), 7.37 ( d, J=8.0Hz, 1H), 7.07 (td, J=8.6, 2.4Hz, 1H), 6.52 (s, 1H), 5.25 (bs, 2H), 3. 61 (q, J=5.9Hz, 2H), 3.18-3.03 (m, 8H), 2.81 (t, J=6.1Hz, 2H), 2.64 (s, 3H); 13 C NMR (126MHz, CDCl3) δ166.75, 156.68, 151.74, 143.25, 132.13, 131.61, 131.53, 130.30, 130.06, 126.7 1. 123.56, 120.38, 114.22, 114.01, 107.15, 106.96, 98.35, 87.81, 55.53, 50.81, 37.01, 29.71, 21.30.

[0883] Example 98: 3-((2-amino-6,7-dimethoxyquinazoline-4-yl)ethynyl)-4-methyl-N-(2-(piperidin-1-yl)ethyl)benzamide (HSN433)

[0884] 1H NMR (500MHz, DMSO-d6) δ8.50 (t, J=5.6Hz, 1H), 8.15 (d, J=1.9Hz, 1H), 7.86 (dd, J=8.0, 1.9Hz, 1H), 7.49 (d, J=8.1Hz, 1H), 7.32 (s, 1H), 6.87 (s, 1H), 6 .58(s, 2H), 3.90(s, 3H), 3.88(s, 3H), 3.36(q, J=6.6Hz, 2H), 2.63(s, 3H), 2.42 (t, J=7.1Hz, 2H), 2.36 (bs, 4H), 1.47 (p, J=5.6Hz, 4H), 1.36 (bs, 2H); 13 C NMR (126MHz, DMSO) δ165.27, 160.60, 156.79, 150.80, 149.57, 147.43, 144.10, 133.07, 131.65, 130.54, 129. 48, 121.07, 115.01, 104.91, 103.96, 93.56, 90.21, 58.14, 56.40, 55.93, 54.57, 37.52, 26.07, 24.52, 20.97.

[0885] Example 99: 3-((6,7-dimethoxyquinazoline-4-yl)ethynyl)-4-methyl-N-(2-(piperidin-1-yl)ethyl)benzamide (HSN434)

[0886]

[0887] 1 H NMR (500MHz, chloroform-d) δ9.14 (s, 1H), 8.16 (d, J=1.9Hz, 1H), 7.81 (dd, J=8.0, 1.9Hz, 1H), 7.57 (s, 1H), 7.38 (d, J=8.0Hz, 1H), 7.33 (s, 1H), 7.25 (s, 1H), 4.08 (s, 3H), 4.08 (s, 3H), 3.59 (q, J=5.4Hz, 2H), 2.70 (s, 3H), 2.65 (t, J=5.9Hz, 2H), 2.54 (s, 4H), 1.67–1.63 (m, 4H), 1.48 (bs, 2H); 13C NMR (126MHz, CDCl3) δ166.27, 156.49, 153.78, 151.27, 148.58, 148.39, 144.26, 132.64, 131.68, 130.08, 128 .56, 121.63, 121.53, 106.82, 103.20, 95.62, 89.89, 57.22, 56.58, 56.37, 54.35, 36.31, 25.54, 24.04, 21.09.

[0888] Example 100: 3-((8-amino-1,7-naphthid-5-yl)ethynyl)-N-(3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)-4-methylbenzamide (HSN445)

[0889]

[0890] 1 ¹H NMR (500MHz, DMSO-d⁶) δ 10.29 (s, 1H), 8.88 (dd, J = 4.2, 1.6Hz, 1H), 8.46 (dd, J = 8.4, 1.6Hz, 1H), 8.24 (s, 1H), 8.16 (d, J = 2.0Hz, 1H), 7.88–7.82 (m, 2H), 7.69 (dd, J = 15.1, 2.4Hz, 1H), 7.52 (s, 2H), 7.50–7.45 (m, 2H), 7.06–6.99 (m, 1H), 2.98 (s, 4H), 2.59 (s, 3H), 2.48 (s, 4H, merged with DMSO peak), 2.23 (s, 3H); 13 C NMR (126MHz, DMSO) δ164.82, 158.56, 153.76, 149.71, 148.18, 143.13, 136.19, 134.41, 133.14, 132.97, 132.53, 131.37 , 130.69, 130.28, 127.94, 127.07, 123.37, 119.55, 116.79, 109.07, 102.13, 91.80, 90.46, 55.12, 50.58, 46.15, 21.17.

[0891] Example 101: 3-((2-amino-6,7-dimethoxyquinazoline-4-yl)ethynyl)-N-(3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)-4-methylbenzamide (HSN446)

[0892]

[0893] 1 H NMR (500MHz, DMSO-d6) δ10.34 (s, 1H), 8.29 (d, J=2.0Hz, 1H), 7.98 (dd, J=8.0 , 2.0Hz, 1H), 7.70 (dd, J=15.1, 2.4Hz, 1H), 7.57 (d, J=8.1Hz, 1H), 7.46 (dd, J= 8.7, 1.5Hz, 1H), 7.34 (s, 1H), 7.07–6.98 (m, 1H), 6.88 (s, 1H), 6.59 (s, 2H), 3 .91(s, 3H), 3.89(s, 3H), 2.97(s, 4H), 2.67(s, 3H), 2.46(s, 4H), 2.21(s, 3H); 13 C NMR (126MHz, DMSO) δ164.36, 160.61, 156.81, 153.74, 150.83, 149.52, 147.46, 144.75, 136.25, 133.13, 132.01, 130.70, 129.9 7. 121.20, 119.57, 116.74, 115.04, 109.03, 108.82, 104.92, 103.97, 93.41, 90.43, 56.41, 55.96, 55.18, 50.66, 46.26, 21.07.

[0894] Example 102: 3-((2-amino-6,7-dimethoxyquinazoline-4-yl)ethynyl)-N-(4-(2-(dimethylamino)ethoxy)phenyl)-4-methylbenzamide (HSN447)

[0895]

[0896] 1 H NMR (500MHz, DMSO-d6) δ10.21 (s, 1H), 8.29 (d, J=1.9Hz, 1H), 7.98 (dd, J=8.0, 2.0Hz, 1H), 7.67 (d, J=9.1Hz, 2H), 7.56 (d, J=8.1Hz, 1H), 7.35 (s, 1H) , 6.93 (d, J=9.1Hz, 2H), 6.88 (s, 1H), 6.59 (s, 2H), 4.02 (t, J=5.9Hz, 2H), 3 .91(s, 3H), 3.89(s, 3H), 2.67(s, 3H), 2.60(t, J=5.8Hz, 2H), 2.20(s, 6H); 13C NMR (126MHz, DMSO) δ164.16, 160.61, 156.81, 155.32, 150.83, 149.56, 147.45, 144.50, 133.44, 132.55, 132.00, 130.6 4. 129.92, 122.38, 121.15, 115.04, 114.84, 104.92, 103.98, 93.52, 90.37, 66.42, 58.22, 56.41, 55.96, 46.06, 21.04.

[0897] Example 103: 5-((8-amino-1,7-naphthid-5-yl)ethynyl)-6-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)nicotinamide (HSN459)

[0898]

[0899] 1 H NMR (500MHz, DMSO-d6) δ10.68 (s, 1H), 8.94 (d, J=2.3Hz, 1H), 8.88 (dd, J=4.2, 1.6Hz, 1H), 8.51 (d, J=2.2Hz, 1H), 8.47 (dd, J=8.3, 1.6Hz, 1H), 8.27 ( s, 1H), 8.20 (d, J=2.2Hz, 1H), 8.04 (dd, J=8.5, 2.2Hz, 1H), 7.72 (d, J=8.5 Hz, 1H), 7.60 (s, 2H), 3.56 (s, 2H), 2.81 (s, 3H), 2.39 (s, 8H), 2.19 (s, 3H); 13 C NMR (126MHz, DMSO) δ164.07, 162.31, 158.81, 149.79, 148.63, 147.41, 138.39, 137.88, 133.13, 132.79, 132.48, 13 1.80, 131.35, 127.97, 127.14, 124.00, 118.93, 117.74, 101.58, 92.83, 90.00, 57.84, 55.05, 52.93, 45.94, 24.30.

[0900] Example 104: 5-((1-aminoisoquinoline-4-yl)ethynyl)-6-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)nicotinamide (HSN461)

[0901]

[0902] 1 H NMR (500MHz, DMSO-d6) δ10.66 (s, 1H), 8.93 (d, J = 2.3Hz, 1H), 8.48 (d, J = 2.3Hz, 1H), 8.2 9 (d, J=8.1Hz, 1H), 8.22 (s, 1H), 8.20 (d, J=2.2Hz, 1H), 8.11 (d, J=8.1Hz, 1H), 8.04 (dd, J =8.4, 2.2Hz, 1H), 7.81 (ddd, J = 8.1, 6.9, 1.2Hz, 1H), 7.72 (d, J = 8.5Hz, 1H), 7.58 (ddd, J =8.3, 6.9, 1.3Hz, 1H), 7.45(s, 2H), 3.56(s, 2H), 2.81(s, 3H), 2.37(s, 8H), 2.14(s, 3H); 13 C NMR (126MHz, DMSO) δ164.08, 162.21, 158.42, 148.15, 147.27, 138.36, 137.64, 136.33, 132.87, 131.78, 131.71, 127.9 5. 126.86, 125.03, 124.74, 124.00, 119.15, 117.74, 116.71, 102.62, 94.26, 89.98, 57.91, 55.20, 53.18, 46.21, 24.30.

[0903] Example 105: 2-((8-amino-1,7-naphthidin-5-yl)ethynyl)-5-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)thiazole-4-carboxamide (HSN482)

[0904]

[0905] 1 H NMR (500MHz, methanol-d4) δ8.85 (dd, J=4.3, 1.6Hz, 1H), 8.41 (dd, J=8.3, 1.6Hz, 1H), 8.19 (d, J=2.2Hz, 1H), 8.16 (s, 1H), 7.89 (dd , J=8.5, 2.2Hz, 1H), 7.77 (dd, J=8.4, 4.2Hz, 1H), 7.72 (d, J=8.5Hz, 1H), 3.64 (s, 2H), 2.85 (s, 3H), 2.54 (s, 8H), 2.32 (s, 3H); 13CNMR (126MHz, MeOD) δ160.63, 158.73, 149.46, 147.71, 143.98, 143.00, 137.35, 132.56, 132.43, 1 31.13, 128.57, 126.49, 123.10, 117.26, 101.20, 90.03, 85.49, 57.45, 54.54, 52.12, 44.43, 11.54.

[0906] Example 106: 4-((1-aminoisoquinoline-4-yl)ethynyl)-3-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (HSN485)

[0907]

[0908] 1 H NMR (500MHz, methanol-d4) δ8.18 (t, J=8.7Hz, 2H), 8.11 (d, J=21.9Hz, 2H), 7.93 (d, J=8.5Hz, 1H), 7.88 (s, 1H), 7.80 (t, J=8.4Hz, 2 H), 7.75 (d, J=8.5Hz, 1H), 7.65 (d, J=8.0Hz, 1H), 7.59 (t, J=7.8Hz, 1H), 3.64 (s, 2H), 2.66 (s, 3H), 2.51 (s, 8H), 2.29 (s, 3H); 13 CNMR (126MHz, MeOD) δ166.84, 157.63, 145.29, 139.48, 137.88, 136.44, 133.42, 132.59, 131.24, 131.15, 131.10, 128.31, 1 27.22, 126.52, 124.78, 124.69, 123.78, 123.57, 117.71, 116.91, 104.82, 92.18, 91.36, 57.51, 54.59, 52.29, 44.58, 19.87.

[0909] Example 107: 4-((3-amino-6-chloroisoquinoline-4-yl)ethynyl)-3-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (HSN486)

[0910]

[0911] 1H NMR (500MHz, methanol-d4) δ8.79 (s, 1H), 8.14 (s, 1H), 7.95 (m, 2H), 7.90 (s, 1H), 7.85 (d, J=8.7Hz, 1H), 7.81 (dd, J=8 .0, 1.8Hz, 1H), 7.76 (m, 2H), 7.25 (dd, J=8.7, 2.0Hz, 1H), 3.67 (s, 2H), 2.69 (s, 3H), 2.61 (bs, 8H), 2.40 (s, 3H); 13 C NMR (126MHz, MeOD) δ166.72, 157.47, 151.95, 139.46, 138.68, 138.09, 137.94, 133.86, 132.42, 131.49, 131.19, 130.41, 1 28.39, 126.61, 124.88, 123.71, 123.59, 121.38, 120.85, 117.78, 98.24, 90.49, 88.94, 57.39, 54.44, 51.86, 44.17, 20.04.

[0912] Example 108: 4-((1-aminoisoquinoline-4-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (HSN489)

[0913]

[0914] 1 H NMR (500MHz, methanol-d4) δ8.18 (t, J=9.3Hz, 2H), 8.13 (d, J=2.3Hz, 1H), 8.08 (s, 1H), 7.98 (d, J=8.6Hz, 2H), 7.94 (dd, J=8.4, 2.3Hz, 1H), 7.81 (ddd, J=8.2, 6.9, 1.2Hz, 1H), 7.76 (d, J=8.5Hz, 1H), 7.71 (d, J=8.6Hz, 2H), 7.60 (ddd, J=8.3, 7.0, 1.3Hz, 1H), 3.65 (s, 2H), 2.52 (s, 8H), 2.30 (s, 3H); 13C NMR (126MHz, MeOD) δ166.67, 157.66, 145.36, 137.86, 136.51, 133.47, 132.65, 131.18, 131.12, 130.88, 128.83 , 127.54, 126.53, 124.72, 123.75, 123.61, 117.76, 116.90, 104.56, 92.42, 88.07, 57.50, 54.58, 52.27, 44.56.

[0915] Example 109: 4-((3-amino-6-chloroisoquinoline-4-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (HSN490)

[0916]

[0917] 1 H NMR (500MHz, DMSO-d6) δ10.56 (s, 1H), 8.92 (s, 1H), 8.21 (s, 1H), 8.06 (s, 1H), 8.04 (d, J = 8.3Hz, 2H), 7.99–7.91 (m, 3H) , 7.89 (s, 1H), 7.70 (d, J=8.5Hz, 1H), 7.28 (dd, J=8.6, 2.0Hz, 1H), 6.89 (s, 2H), 3.56 (s, 2H), 2.38 (s, 8H), 2.17 (s, 3H); 13 C NMR (126MHz, DMSO) δ165.49, 158.82, 153.50, 138.78, 138.64, 137.48, 133.93, 132.55, 131.71, 131.61, 12 8.35, 126.85, 124.05, 123.56, 121.34, 120.62, 117.77, 99.50, 88.25, 86.55, 57.88, 55.11, 53.02, 46.03.

[0918] Example 110: 3-((8-amino-1,7-naphthid-5-yl)ethynyl)-4-methyl-N-(4-(morpholinomethyl)-3-(trifluoromethyl)phenyl)benzamide (HSN514)

[0919]

[0920] 1H NMR (500MHz, DMSO-d6) δ10.53 (s, 1H), 8.88 (d, J = 4.3Hz, 1H), 8.45 (d, J = 8.4Hz, 1H), 8.24 (s, 1H), 8.21 (d, J = 8.8Hz, 2H), 8.09–8.04 (m, 1H), 7.8 7(d, J=9.2Hz, 1H), 7.86–7.82(m, 1H), 7.72(d, J=8.5Hz, 1H), 7.53(s, 2 H), 7.51 (d, J=8.0Hz, 1H), 3.62–3.52 (m, 6H), 2.60 (s, 3H), 2.37 (s, 4H); 13 C NMR (126MHz, DMSO) δ165.33, 158.56, 149.71, 148.19, 143.43, 138.75, 133.12, 132.67, 132.52, 132.00, 131.83, 131.35, 13 0.78, 130.34, 128.04, 127.84, 127.06, 125.88, 123.94, 123.42, 117.74, 102.10, 91.74, 90.53, 66.69, 58.33, 53.76, 21.19.

[0921] Example 111: 3-((8-amino-1,7-naphthid-5-yl)ethynyl)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methylbenzamide (HSN515)

[0922]

[0923] 1 H NMR (500MHz, DMSO-d6) δ10.52 (s, 1H), 8.88 (dd, J=4.2, 1.6Hz, 1H), 8.46 (dd, J=8.3 , 1.6Hz, 1H), 8.24 (s, 1H), 8.20 (dd, J=4.0, 2.1Hz, 2H), 8.06 (dd, J=8.5, 2.2Hz, 1H) , 7.86 (ddd, J=12.6, 8.1, 3.1Hz, 2H), 7.70 (d, J=8.5Hz, 1H), 7.53 (s, 2H), 7.51 (d, J =8.1Hz, 1H), 3.55 (s, 2H), 2.60 (s, 3H), 2.47-2.23 (bs, 10H), 0.97 (t, J = 7.1Hz, 3H); 13C NMR (126MHz, DMSO) δ165.32, 158.57, 149.71, 148.19, 143.42, 138.65, 133.12, 132.69, 132.52, 131.67, 131.36, 130.79, 130.3 4. 128.03, 127.71, 127.07, 123.98, 123.72, 123.42, 117.73, 102.10, 91.74, 90.53, 57.93, 53.27, 52.82, 52.03, 21.19, 12.45.

[0924] Example 112: 5-((1-aminoisoquinoline-4-yl)ethynyl)-1-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide (HSN516)

[0925]

[0926] 1 H NMR (500MHz, DMSO-d6) δ10.50 (s, 1H), 8.31–8.27 (m, 2H), 8.23 ​​(s, 1H), 8.06 (dd, J=8.5, 2.2Hz, 1H), 8.03 (d, J=8.3Hz, 1H), 7.79 (ddd, J=8.2, 6.9, 1. 2Hz, 1H), 7.66 (d, J=8.5Hz, 1H), 7.58 (ddd, J=8.3, 6.9, 1.2Hz, 1H), 7.50 ( s, 2H), 7.13 (s, 1H), 4.10 (s, 3H), 3.55 (s, 2H), 2.39 (bs, 8H), 2.19 (s, 3H); 13 C NMR (126MHz, DMSO) δ160.11, 158.62, 148.44, 145.71, 138.34, 136.18, 132.29, 131.82, 131.59, 128.01, 126.9 3. 125.04, 124.68, 123.96, 117.70, 116.61, 110.76, 101.63, 95.36, 80.85, 57.85, 55.06, 52.93, 45.94, 38.36.

[0927] Example 113: 3-((6-amino-4-cyanopyridin-3-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (HSN517)

[0928]

[0929] 1 H NMR (500MHz, DMSO-d6) δ10.53 (s, 1H), 8.38 (d, J = 0.7Hz, 1H), 8.19 (d, J = 2.3Hz, 1H), 8.09 (d, J = 2.0Hz, 1H), 8.04 (dd, J = 8.5, 2.2Hz, 1H), 7.89 (dd, J = 8 .0, 2.0Hz, 1H), 7.69 (d, J=8.5Hz, 1H), 7.49 (d, J=8.1Hz, 1H), 7.07 (s, 2H), 6.84(d, J=0.8Hz, 1H), 3.55(s, 2H), 2.54(s, 3H), 2.38(s, 8H), 2.18(s, 3H); 13 C NMR (126MHz, DMSO) δ165.18, 159.51, 153.13, 143.94, 138.63, 132.70, 132.49, 131.71, 130.83, 130.43, 128.54, 12 7.74, 123.98, 122.52, 122.29, 117.69, 116.64, 111.01, 106.74, 92.10, 89.37, 57.86, 55.09, 52.99, 46.00, 20.93.

[0930] Example 114: General steps for preparing the compounds in Table 4

[0931] 6-Chloroisoquinoline-3-amine (3.2 mmol) was iodinated with N-iodosuccinimide (675 mg) and purified by rapid column chromatography (part 1). 4-ethynylbenzaldehyde (1 equivalent) was dissolved in tert-butanol, and the corresponding diamine (1 equivalent) was added and stirred at room temperature for 1 hour. 1.1 equivalents of iodine and 3 equivalents of potassium carbonate were added, and the mixture was refluxed overnight. The crude product was purified by column chromatography (part 2). Pure part 1 (50 mg), 10 mol% palladium(II) dichloride, and 10 mol% triphenylphosphine were added, purified three times with nitrogen, and then anhydrous DMF (5 mL) was added. The reaction mixture was stirred at 45 °C for another 5 minutes, and then 1 mL of the corresponding pure part 2 (1.1 equivalent) in anhydrous DMF was added via syringe over 2 minutes. DIPEA (2 mL) was then added and stirred overnight. The crude product was purified by column chromatography.

[0932] Example 115: Synthesis steps of HSM1859

[0933] Following the same procedure described above, 6-chloroisoquinoline-3-amine (3.2 mmol) was iodinated with N-iodosuccinimide (675 mg) and purified by rapid column chromatography. A solution of the iodinated compound (1 equivalent), Pd(PPh3)4 (20 mol%), and cesium carbonate (1 equivalent) in 1,4-dioxane / water (1 mL) was deoxygenated using argon vapor. The deoxygenated solution of 4-vinylbenzyl nitrile (0.49 mmol, 1.5 equivalent) in DMF (3 mL) was slowly added to the solution over 15 minutes, the reaction temperature was raised to 70 °C, and the mixture was stirred for 12 hours. The reaction was quenched by adding water (5 mL) at room temperature, followed by rapid column chromatography. After purification, the product was dissolved in 2 mL of absolute ethanol, 1 mL of hydroxylamine solution was added, and the mixture was refluxed for 6 hours. After TLC showed complete consumption of the starting material, the ethanol was removed under vacuum, and the pure product was obtained by rapid column chromatography.

[0934] Example 116: 6-Chloro-4-((4-(4,5-dihydro-1H-imidazol-2-yl)phenyl)ethynyl)isoquinoline-3-amine (HSM1651)

[0935]

[0936] Following the general procedure IV described above, a yellow solid was obtained. 1 H NMR (500MHz, DMSO-d6) δ8.92 (s, 1H), 7.96 (d, J=8.6Hz, 1H), 7.93-7.81 (m, 5H), 7.28 (dd, J=8.6, 1.8Hz, 1H), 6.85 (s, 2H), 3.68 (s, 4H); 13 C NMR (125MHz, DMSO-d6) δ163.73, 158.70, 153.30, 138.73, 137.42, 131.64, 131.56, 12 9.45, 127.78, 125.60, 123.52, 121.33, 120.61, 99.69, 88.45, 85.91, 49.51; HRMS (ESI + ):C 20 H 16 The calculated value of ClN4[M+H] is 347.1063, and the measured value is 347.1057.

[0937] Example 117: 6-Chloro-4-((4-(1-(2-(piperidin-1-yl)ethyl)-4,5-dihydro-1H-imidazol-2-yl)phenyl)ethynyl)isoquinoline-3-amine

[0938]

[0939] Following the general procedure IV described above, a yellow solid was obtained. 1 H NMR (500MHz, DMSO-d6) δ8.93 (s, 1H), 7.99-7.78 (m, 6H), 7.29 (dd, J=8.6, 2.0Hz, 1H), 6.86 (s, 2H), 3.53-3.46 (m, 2 H), 3.42 (dd, J=7.9, 3.1Hz, 2H), 3.25-3.16 (m, 2H), 2.38 (dd, J=24.1, 22.3Hz, 6H), 1.55-1.47 (m, 4H), 1.39 (s, 2H); 13 C NMR (126MHz, DMSO-d6) δ206.36, 166.05, 158.59, 157.55, 153.58, 138.92, 137.12, 133.90, 131.37, 128.40, 126.15 , 123.15, 121.23, 120.71, 99.32, 88.09, 86.12, 72.35, 67.21, 60.93, 54.76, 45.46, 32.08, 26.11, 23.84; HRMS (ESI + ):C 27 H 29 The calculated value of ClN5[M+H] is 458.2111, and the measured value is 458.2110.

[0940] Example 118: 6-Chloro-4-((4-(4-cyclopropyl-4,5-dihydro-1H-imidazol-2-yl)phenyl)ethynyl)isoquinoline-3-amine

[0941]

[0942]

[0943] Following the general procedure IV described above, a yellow solid was obtained. 1 H NMR (500MHz, MeOD) δ8.83 (s, 1H), 7.88 (ddd, J=62.4, 45.2, 5.0Hz, 6H), 7.29 (dd, J=8.7, 1.9Hz, 1H), 4.05-3. 90 (m, 1H), 3.67 (dd, J=11.9, 8.0Hz, 1H), 3.53 (dd, J=18.2, 7.9Hz, 1H), 1.10-0.98 (m, 1H), 0.66-0.29 (m, 4H). HRMS(ESI + ):C 23 H 20 The calculated value of ClN4[M+H] is 387.1376, and the measured value is 387.1.

[0944] Example 119: 6-Chloro-4-((4-(4,4-dimethyl-4,5-dihydro-1H-imidazol-2-yl)phenyl)ethynyl)isoquinoline-3-amine

[0945]

[0946] Following the general procedure IV described above, a yellow solid was obtained. 1 H NMR (500MHz, MeOD) δ8.75 (s, 1H), 7.88 (d, J = 1.2Hz, 1H), 7.81 (d, J = 7.4Hz, 3H) , 7.70 (d, J=8.2Hz, 2H), 7.22 (dd, J=8.7, 1.9Hz, 1H), 3.53 (s, 2H), 1.35 (s, 6H); 13 C NMR (126MHz, MeOD) δ162.62, 157.51, 151.80, 138.75, 138.02, 131.01, 130.32, 129.49, 127 .18, 125.73, 123.67, 121.34, 120.78, 99.38, 90.34, 84.27, 62.77, 61.61, 27.34; HRMS (ESI + ):C 22 H 20 The calculated value of ClN4[M+H] is 350.1376, and the measured value is 375.1368.

[0947] Example 120: 4-((4-(4,5-dihydro-1H-imidazol-2-yl)phenyl)ethynyl)-1H-pyrrolo[2,3-c]pyridine-5-amine

[0948]

[0949] Following the general procedure IV described above, a yellow solid was obtained. 1 H NMR (500MHz, MeOD) δ8.27 (s, 1H), 7.90 (d, J = 8.5Hz, 2H), 7.79 (d, J = 8.5Hz, 2H), 7.53 (d, J = 2.9Hz, 1H), 6.50 (dd, J = 2.8, 0.7Hz, 1H), 3.96 (s, 4H); 13C NMR (126MHz, MeOD) δ165.52, 153.08, 143.40, 136.88, 133.96, 132.14, 131.63, 131.27, 128.33, 128.20, 127.85, 99.54, 96.35, 87.85, 41.16; HRMS (ESI + ):C 18 H 16 The calculated value of N5[M+H] is 302.1406, and the measured value is 302.1399.

[0950] Example 121: 4-((4-(4,5-dihydro-1H-imidazol-2-yl)phenyl)ethynyl)zolin-3-amine

[0951]

[0952] Following the general procedure IV described above, a yellow solid was obtained. 1 H NMR (500MHz, DMSO-d6) δ8.19 (d, J=8.5Hz, 1H), 8.03 (d, J=2.1Hz, 1H), 7.91 (d, J=11. 9Hz, 3H), 7.75–7.68 (m, 1H), 7.56–7.48 (m, 1H), 7.11 (d, J=17.1Hz, 3H), 3.62 (s, 4H); 13 C NMR (126MHz, DMSO-d6) δ163.46, 157.83, 145.17, 132.88, 132.59, 132.25, 131.49, 130.35 , 127.69, 127.32, 126.36, 125.17, 124.06, 123.77, 103.13, 94.50, 83.62, 41.23; HRMS (ESI + ):C 19 H 16 The calculated value of N5[M+H] is 314.1406, and the measured value is 314.1396.

[0953] Example 122: 4-((3-amino-6-chloroisoquinoline-4-yl)ethynyl)benzylnitrile

[0954]

[0955] Following the general procedure IV described above, a yellow solid was obtained. 1H NMR (500MHz, DMSO-d6) δ8.91 (s, 1H), 7.91 (ddd, J=12.4, 9.9, 5.0Hz, 6H), 7.26 (d, J=8.6Hz, 1H), 6.95 (s, 2H); 13 C NMR (126MHz, DMSO-d6) δ159.04, 153.96, 138.83, 137.63, 132.78, 132.41, 131.61 , 128.36, 123.61, 121.33, 120.58, 119.18, 110.60, 98.86, 88.51, 87.73; HRMS (ESI + ):C 18 H 11 The calculated value of ClN3[M+H] is 304.0642, and the measured value is 304.1411.

[0956] Example 123: 4-((4-(4,5-dihydro-1H-imidazol-2-yl)phenyl)ethynyl)isoquinoline

[0957]

[0958] Following the general procedure IV described above, a yellow solid was obtained. 1 H NMR (500MHz, DMSO-d6) δ9.37 (s, 1H), 8.79 (s, 1H), 8.35 (d, J = 8.2Hz, 1H), 8.24 (d, J = 8.0Hz, 1H), 7.96 (dd, J=19.4, 7.8Hz, 3H), 7.81 (dd, J=13.7, 7.7Hz, 3H), 3.65 (s, 4H); 13 C NMR (126MHz, DMSO-d6) δ163.43, 153.15, 146.66, 134.95, 132.48, 131.96, 131.31 , 128.96, 128.85, 127.93, 127.85, 124.84, 124.02, 115.01, 96.65, 86.36, 50.06. HRMS(ESI + ):C 20 H 16 The calculated value of N3[M+H] is 298.1344, and the measured value is 298.1341.

[0959] Example 124: 3-((3-amino-6-chloroisoquinoline-4-yl)ethynyl)-N-hydroxybenzomidine

[0960]

[0961] Following the general procedure IV described above, a yellow solid was obtained. 1 H NMR (500MHz, DMSO-d6) δ9.75 (s, 1H), 8.92 (s, 1H), 8.04 (s, 1H), 7.96 (d, J=8.6Hz, 1H), 7.88 (s, 1H), 7.78 (d, J=7.5Hz, 1H), 7.72 (d, J=7.8Hz, 1H), 7.46 (t, J=7.7Hz, 1H), 7.28 (d, J=8.5Hz, 1H), 6.80 (s, 2H), 5.93 (s, 2H); 13 C NMR (126MHz, DMSO-d6) δ158.57, 153.00, 150.66, 138.73, 137.33, 134.15, 132.13, 13 1.55, 128.89, 128.65, 125.84, 123.48, 123.22, 121.31, 120.63, 99.88, 88.73, 83.91. HRMS(ESI + ):C 18 H 14 The calculated value of ClN4O[M+H] is 337.0856, and the measured value is 337.0873.

[0962] Example 125: 4-((3-amino-6-chloroisoquinoline-4-yl)ethynyl)-N-hydroxybenzomidine

[0963]

[0964] Following the general procedure IV described above, a yellow solid was obtained. 1 H NMR (500MHz, DMSO-d6) δ9.79 (s, 1H), 8.91 (s, 1H), 7.95 (d, J=8.6Hz, 1H), 7.88 (d, J=1 .4Hz, 1H), 7.80–7.72(m, 4H), 7.27(dd, J=8.6, 1.9Hz, 1H), 6.80(s, 2H), 5.90(s, 2H); 13 C NMR (126MHz, DMSO-d6) δ158.53, 153.00, 150.71, 138.69, 137.32, 133.41, 131.53, 125.81, 123.66, 123.47, 121.35, 120.62, 99.94, 88.76, 84.85. HRMS(ESI + C 18 H 14 The calculated value of ClN4O[M+H] is 337.0856, and the measured value is 337.0865.

[0965] Example 126: (E)-4-(2-(3-amino-6-chloroisoquinoline-4-yl)vinyl)-N-hydroxybenzomidine

[0966]

[0967] Following the synthesis step V, a yellow solid was obtained. 1 H NMR 500MHz, DMSO-d6) δ9.66 (d, J=6.2Hz, 1H), 8.88–8.75 (m, 1H), 7.89 (dt, J=17.8, 5.5Hz, 2H), 7.77–7. 63(m, 4H), 7.33(t, J=17.4Hz, 1H), 7.28–7.09(m, 1H), 7.06–6.94(m, 1H), 6.24(s, 2H), 5.83(s, 2H), 13 C NMR (126MHz, DMSO-d6) δ154.75, 151.48, 151.00, 138.28, 136.75, 136.24, 134.02, 1 32.80, 131.32, 126.82, 125.88, 122.80, 122.59, 121.50, 121.20, 104.46; HRMS(ESI + ):C 18 H 16 The calculated value of ClN4O[M+H] is 339.1013, and the measured value is 339.1010.

[0968] Example 127: Activity study on AML cell line MV4-11

[0969] Cells were added to 96-well plates at 2000 cells per well for adherent cell lines and 4000 cells per well for suspension cell lines, and incubated overnight. The next day, the plates were treated with compounds to achieve final concentrations of 100 μM, 10 μM, 5 μM, 1 μM, 500 nM, 100 nM, 10 nM, and 10 pM. The plates were then stored in an incubator for 72 hours. On the third day, cell viability was measured in each well with 20 μL of CellTiter-Blue cell viability assay and incubated for 4 hours. After 4 hours, the fluorescence intensity was selected on a plate reader: excitation: 560 / 10, emission: 590 / 10. IC50 was performed on a GraphPad Prism 7. 50 analyze.

[0970] Table 1: IC50 values ​​selected for AML cell lines and MV4-11

[0971]

[0972]

[0973] Table 2: IC50 against MV4-11 (AML cell line)

[0974] HSM1683 42.1±1.3 HSM1693 14.8±1.4 HSM1702 5.5±1.3 HSM1662 6.2±1.3 HSM1673 25.0±1.4

[0975] Example 128: In vitro kinase assay

[0976] The kinase / inhibitor interaction was measured using the Reaction Biology Corporation (www.reactionbiology.com, Malvern, PA) hotspot assay platform, as described above. The kinase and substrate were mixed in a buffer solution containing 20 mM HEPES, 10 mM MgCl2, 1 mM EGTA, 0.02% Brij35, 0.02 mg / mL BSA, 0.1 mM Na3VO4, 2 mM DTT, and 1% DMSO at pH 7.5. A single dose of the compound (500 nM) was then added to each reaction mixture. After incubation for 20 minutes, ATP (sigma) and [γ-] were added. 33 P]ATP (PerkinElmer) was added at room temperature for 2 hours to a final total concentration of 100 μM, and then spotted onto P81 ion-exchange cellulose chromatography paper (Watman). The filter paper was washed with 0.75% phosphoric acid to remove unincorporated ATP. The percentage of residual kinase activity in the kinase-containing carrier (DMSO) for each kinase / inhibitor pair was calculated using Prism5 (GraphPad). At a concentration of 500 nM, HSM1856 inhibited 70% of BTK (Bruton's tyrosine kinase) activity, and HSN325 blocked 96% of RET activity.

[0977] IC50 proliferation assay – Cell lines and primary cells were seeded into 96-well plates the afternoon before treatment. Approximately 18 hours later, the compound was semi-serially diluted in dimethyl sulfoxide (DMSO) and then in growth medium, and added to the cells. The plates were incubated for 72 hours, then Almar Blue (Life Technologies, Carlsbad, CA) was added. After a further 4 hours of incubation at 37°C, the plates were read using a Berten-HT co-processor plate reader (Berten, Winnowski, Vermont). Data were analyzed and plotted using GraphPadPrism software (Graphpad, La Jolla, CA). The results are summarized in Table 3.

[0978] Table 3: Antitumor activity of selected compounds

[0979]

[0980]

[0981] *n / a: Not determined.

[0982] HSM1856 showed IC50 (inhibition of proliferation) against leukemia cell lines MV4-11 and K562. It also inhibited MiaPaca-2 and HLY-1, with IC50 values ​​of 0.4 and 0.08 μM, respectively. It was also effective against pancreatic cancer cell lines-2 (pancreatic cell line), HLY-1 (lymphoma cell line), MV4-11 (AML cell line), and K562 (CML cell line).

[0983] Example 129: Inhibition of FLT3, FLT3ITD and FLT3D835Y

[0984] The compounds of this invention are μFLT3 inhibitors (Table 4 shows the percentage of enzyme inhibition at 0.5 μM). Detailed characterization of one of HSM1651 compounds showed that it inhibits FLT3, FLT3ITD, and FLT3D835Y, with IC50 values ​​of 40 nM, 100 nM, and 56 nM, respectively. Figure 8A ).

[0985] Table 4: FLT3 inhibition curves and antiproliferative activity of the compounds of the present invention against different leukemia cancer cell lines.

[0986]

[0987]

[0988]

[0989] ae: These will be tested cell lines with their respective ICs 50 Related.

[0990] *In these cell assays, hydroxyamidine can be used as a prodrug of amidine.

[0991] Example 130: Inhibition of c-Kit and TrkC enzymes

[0992] The compounds of this invention inhibit both c-Kit and TrkC enzymes. Table 5 provides the percentage inhibition of TrkC / c-Kit activity by compounds with stable linker groups at a concentration of 500 nM in the presence of 100 μM radiolabeled ATP.

[0993] Table 5: Inhibition % of Trkc / C-Kit activity

[0994]

[0995] The compounds of this invention can also effectively inhibit AML cell lines (Table 5). Blot analysis of MV4-11 cells treated with HSM1651 showed that FLT3 phosphorylation and downstream STAT5 phosphorylation were reduced in the presence of HSM1651. Figure 8B and 8C Some alkyne analogues exhibit considerable anti-proliferation properties (HSM1819 has an IC50 of 20 nM). 50 Its potency is only 4 times lower than that of claranil, which underwent clinical trials (IC50). 50 =5nM). Regarding the structure-activity relationship of alkyne / olefin analogs, it appears that modification of the isoquinoline ring significantly affects kinase inhibition and antiproliferative activity. For the alkyne series, HSM1813 (H at position 3 and no Cl at position 6) is not a potent inhibitor of MV4-11 proliferation (Table 5, entry 10). HSM1651 (amino at position 3 and Cl at position 6) is a good inhibitor of MV4-11 and MOLM-14 proliferation, while compounds HSM1781, 1798, and 1796 (which differ from HSM1651 in their isoquinoline moiety) are ineffective antiproliferative agents in AML cell lines. The amidine group also appears to be important for antiproliferative activity. The cyano analog HSM1611 is ineffective against MV4-11 and MOLM-14, while the hydroxymidine analog derived from HSM1611 (HSM1819) is a very effective antiproliferative agent in AML cell lines. Hydroxymididine HSM1819 inhibits FLT3 and FLT3ITD in vitro, with IC50 values ​​of 217 and 240 nM, respectively. HSM1820, another hydroxymididine analog, inhibits FLT3 and FLT3ITD in vitro, with IC50 values ​​of 359 and 350 nM, respectively.

[0996] Example 131: Study on antiproliferative activity

[0997] The antiproliferative activity against AML cell lines, MV4-11 (FLT3-driven cell line), and three other solid tumors (MCF7, breast; HCT116, colon, and HeLa cells) was investigated (Tables 6A and 6B). Figure 10 ).

[0998] Table 6A: Percentage of inhibition of cancer cell line proliferation in the presence of compound (1 μM)

[0999]

[1000] Table 6B: Percentage inhibition of cancer cell proliferation in the presence of the compound (1 μM)

[1001]

[1002] These cell proliferation studies indicate that MV4-11 appears to be more sensitive to compounds than other cell lines (Table 6A). At 1 μM, most compounds significantly inhibited MV4-11. To identify the functional groups of compounds that effectively inhibit cancer cell proliferation, lower concentrations of compounds (100 nM) were used to screen for compounds targeting MV4-11. Figure 10 These experiments show that selecting effective amide compounds A7, A10, A15, A16, A18, A20, B15, and D30 (such as...) Figure 10 (As shown in the image). At 100 nM, these selected compounds inhibited MV4-11 at levels similar to midotulin, a pantothenic acid kinase inhibitor that recently completed a full Phase III clinical trial. Figure 10 Typically, amides containing basic amines are included in the compound library to improve water solubility, but it appears that the presence of a basic amine in the side chain of the compound also promotes actual inhibition of MV4-11 proliferation. For example, compounds A1, A2, A21, and A25, which do not have a basic amine side chain, are inactive against MV4-11, while many other compounds containing a basic amine chain are active against MV4-11. In the presence of mouse liver microsomes, the stability of the active compounds showed that compounds with D-substitution (e.g., D30) performed significantly better in liver microsome stability assays compared to other analogs.

[1003] Example 132: Inhibition of proliferation of MV4-11 and MOLM-14 (IC50) 50 )

[1004] Compound D30 contains a 1-methyl-4-(2-(trifluoromethyl)benzyl)piperazine group, which is present in many kinase inhibitors, including panatinib. Panatinib, used to treat imatinib-resistant CML, has been shown to inhibit FLT3-driven AML. Unfortunately, panatinib has caused adverse cardiovascular effects (Geno, JF et al., Oncologist, 20(8), 847–848 (2015)), and is now given a black box warning and is considered a last resort drug for CML (Talbot, DR et al., Toxicology, 143(1), 147–155 (2015). It was withdrawn from the US market in 2014 due to blood clotting and cardiovascular adverse reactions, so it may not be an ideal treatment for AML, especially for older patients. Therefore, if the kinase selectivity of compounds containing a 1-methyl-4-(2-(trifluoromethyl)benzyl)piperazine group can be modulated by intelligent substitution on the isoquinoline core or by using isoquinoline isomers, analogs of D30 were further investigated. Compounds HSN352, HSN353, HSN334, HSN356, HSN285 and HSN325 (containing 3-aminoisoquinoline, 1-aminoisoquinoline, 2-aminoquinoline and 2-aminoquinazoline) were prepared by coupling with sage. Figure 11 These compounds were identified as having inhibitory (IC50) proliferation effects against MV4-11 and MOLM-14 (FLT3-driven AML cell lines). 50 (Table 6B).

[1005] HSN286 is an IC for MV-4-11 and MOLM-14. 50 The concentrations were 0.5 nM and 0.7 nM, respectively (Table 7). 1-Aminoisoquinoline analogs, HSN334 and HSN356, were also potent inhibitors of proliferation in MV4-11 and MOLM-14. The inhibitory effects of isoquinoline compounds on AML proliferation were similar to (or even slightly better than) midostaurin (Table 7). Generally, the percentage inhibition of the FLT3 enzymatic reaction (the percentage inhibition obtained at 500 nM of the compound, reaction biology) correlated well with the inhibition of proliferation in the AML cell lines MV4-11 and MOLM-14. Not all aminoquinoline compounds are potent inhibitors of AML cell line proliferation. For example, HSN248, HSN178, HSN247, MXC1702, and HSN315, which also contain a 2-aminoquinoline core, are only mild inhibitors of AML proliferation or FLT3 enzyme activity. However, the 1-methyl-4-(2-(trifluoromethyl)benzyl)piperazine moiety (… Figure 11The moiety of 1-methyl-4-(2-(trifluoromethyl)benzyl)piperazine (found in panatinib) is not the sole determinant of FLT3 inhibition. 2-Aminoquinoline and quinazoline analogs—HSN285 and HSN325—both contain this moiety, but they are neither potent inhibitors of FLT3 nor active against MV4-11 or MOLM-14 cell lines. Therefore, the potency of these compounds appears to be attributed to the combination or synergistic effect of the 1-methyl-4-(2-(trifluoromethyl)benzyl)piperazine moiety (found in panatinib) with the aminoisoquinoline moiety.

[1006] Table 7: Active IC 50 (Proliferation) and FMS-like tyrosine kinase 3 inhibition

[1007]

[1008] a- FLT3 inhibition at 412 nM.

[1009] Example 133: Selectivity

[1010] To test selectivity, HSN286 was tested against various other cancer cell lines and normal cell lines (MRC5, lung fibrosis cell line). Figure 12 When tested against the non-FLT3AML cell line human erythroleukemia cell-1 (Kasumi-1), the IC50 of HSN286 was determined. 50 The concentration of HSN286 exceeds 10,000 nM. The compound HSN286 showed an IC50 concentration against HL60, acute promyelocytic leukemia cell lines, and THP1 (another non-FLT3-driven AML cell line). 50 The values ​​were 2156 nM and 2315 nM, respectively (i.e., the activity against the aforementioned cell lines was more than 2000-fold lower compared to the FLT3-driven cell lines MV4-11 or MOLM-14). Furthermore, the IC50 of compound HSN286 against MRC5 was... 50 1266nM (with MV4-11 or MOLM-14 IC) 50 (Compared to more than 1000 times lower). Therefore, it appears that HSN286 is selective for FLT3-driven leukemia (at least in the cell lines tested).

[1011] Example 134: Docking with inactive conformational isomers

[1012]

[25] HSN286, 334, 356 and 248 were conjugated to inactive conformational isomers of FLT3 (the crystal structure of quezatinib, an effective FLT3 inhibitor, was resolved in a complex with FLT3 and PDB#4xuf) to reveal that the compounds bind to ATP-binding sites and adjacent sites. Figure 13The binding sites of the compound partially overlap with those of quizartinib, but the binding modes differ somewhat. Figure 14 and 15 ).

[1013] Example 135: Binding with FLT3 secondary mutation

[1014] Although drugs currently on the market or in clinical trials are relatively successful in killing AML leukemia cells, they currently cannot address secondary mutations that occur after TKI treatment, such as FLT3 (D385V). The binding of HSN286, HSN336, HSN334, HSN248, and HSN247 to several FLT3 secondary mutations was investigated (Table 8). Interestingly, HSN356 can bind to K... d It binds to 19 nM FLT3 (D835V), while a similar compound, HSN334, is K. d Poor conjugates of 120 nM FLT3 (D835V) (Table 8).

[1015] Table 8: Discovery of XK d The Elect service identified Kd of isoquinoline analogs that bind to FLT3, FLT3-ITD, and FLT3(D835V).

[1016] FLT3 6.5nM 1.3nM 5.1 nM 53nM 47nM FLT 3(IDT) 27.6 nM 6.7nM 19nM 450nM 330nM FLT3(D835V) 120nM 19nM 120nM ND ND

[1017] Example 136: Inhibition of Src family kinases

[1018] Most clinically successful kinase inhibitors are multi-kinase inhibitors. For example, sorafenib, used to treat renal cell carcinoma, hepatocellular carcinoma, and radioactive iodine-resistant thyroid cancer, also inhibits several kinases, such as RAF, MEK, ERK, VEGFR, PDGFR, FLT3, c-KIT, FGFR-1, and DDR2. Another multi-kinase inhibitor, dasatinib, is a first-line treatment for CML, and Ph + ALL inhibits multiple kinases. These include BCR-ABL, YES, EPHA8, c-KIT, SRC, LCK, DDR2, FRK, FYN, ARG, BTK, and HCK. Despite the diversity of these multi-kinase inhibitors, safe and tolerable doses have been found for cancer treatment. The success of these multi-kinase inhibitors can be partly attributed to the simultaneous inhibition of different kinase axes.

[1019] In addition, the study investigated whether HSN286 and its analogues also inhibit other cancer-related kinases. Besides FLT3, Src family kinases (such as BLK, FGR, FYN, HCK, LYN, SRC, and YES) have been shown to play a decisive role in leukemia. Lopez et al. recently demonstrated that CDK6 overexpression in FTL3-ITD-positive AML was achieved via Src family kinases, specifically HCK (Lopez, S. et al., Tumor Targeting, 7(23), 51163-51173(2016)). HCK is expressed in greater quantities in human primary leukemia stem cells than in normal human hematopoietic stem cells. One study showed that drug resistance was reduced when HCK was targeted with small molecules (Ishikawa, F. et al., Scientific Translation of Medicine, 5(181), 181(2013)). Other protein kinases (such as SYK, BRAF, p38 (p38MAPK), PDGFRα / β, FGFR1, RET, FLT4, Tie2) are also associated with leukemia. All of this data further reinforces the consensus in the field that leukemia is a heterogeneous disease, and therefore targeting the aforementioned multiple kinase pathways could yield better results. Therefore, HSN286 and its analogues were tested to determine whether they also target kinases that play a decisive role in AML. Kinase screening services Reaction Biology and Discovery X were used to characterize the inhibition of kinase activity (enzyme activity in the presence of a 500 nM compound). HSN286 and its analogues effectively inhibited FLT3 and Src family kinases, but not other kinases such as Aurora kinase A, CDK6, or PIK3Ca (Table 9). Inhibition of the Src-kinase family may be clinically important because these kinases are downstream of FLT3. In the presence of FLT3 mutations, inhibition of Src family kinases can still lead to proliferation inhibition.

[1020] Table 9: Discovery of XK d K determined by Elect service d (nM)

[1021]

[1022]

[1023] Example 137: Inhibition of FLT3 kinase activity by midostaurin

[1024] In addition to the binding assay (Table 9), the IC50 values ​​of midostaurin, HSN286, 334, and 356 on the inhibitory activity of FLT3 kinase were also determined. 50 Value. Although midostaurin and HSN356 are superior to HSN286 and HSN334, all four compounds inhibit FLT3 (value) at low nanomolar values. Figure 16 Midotolin and HSN356 are single-digit ICs. 50It inhibits FLT3 and FLT3ITD. However, in the case of Src kinase, HSN286 is the most effective (IC50). 50 (4.5 nM). HSN356 is also an effective inhibitor of Src kinase, IC50... 50 It is 14.9 nM.

[1025] Example 138: Phosphorylation of FLT3 and SRC kinases

[1026] To determine whether compounds could affect the phosphorylation of FLT3, SRC kinase, and downstream effectors or kinases (e.g., STAT3

[44] , STAT5

[45] , and p-38

[46] ), Western blot analysis was performed on all proteins to determine whether they could indeed target FLT3 and related signaling axes in the cell (target binding or confirmation, Fig. 17). All proteins were obtained from MV4-11 treated with HSN286 for FLT3 / phosphorylated FLT3, STAT5 / phosphorylated STAT5, STAT3 / phosphorylated STAT3, and SRC kinase / phosphorylated SRC and p-38 / phosphorylated p-38. Consistent with in vitro kinase inhibition data, HSN286 inhibited the phosphorylation of FLT3, STAT5, STAT3, and p-38 (Fig. 17). The level of SRC kinase increased over time (the amount at the 48-hour time point was greater than that at the 6-hour and 24-hour time points). Unfortunately, despite repeated attempts to obtain clearer bands, the band for phosphorylated SRC kinase remained blurred. Despite the technical challenges of phosphorus-SRC blotting, it was determined that at the 48-hour time point, the level of unphosphorylated SRC kinase increased with the addition of compound HSN286 (in Figure 17, the bands corresponding to the vector are compared with those of HSN286 at 9 and 45 nM). The blot analysis confirmed that the inhibition of MV4-11 proliferation was due to inhibition of the FLT3 signaling axis.

[1027] The compounds of this invention are novel FLT3 inhibitors that inhibit the problematic D835 secondary mutant. 4-Alkyne-substituted aminoisoquinolines (easily obtained via conjugation with sage) but not the related quinolines are potent FLT3 and SRC-kinase inhibitors. In-depth structure-activity relationship (SAR) studies revealed that the FLT3 inhibitory properties and antiproliferative activity against FLT3-driven cancer cell lines MV4-11 and MOLM-14 are determined by the substitution mode and nature of the benzamide. SAR studies have identified 3-amino and 1-aminoisoquinoline benzamides, compounds D30 (HSN286), HSN334, and HSN356 as potent FLT3 kinase inhibitors. Some of these novel kinase inhibitors also inhibit the proliferation of FLT3-driven AML cell lines at concentrations as low as 500 pM. In addition to FLT3, compounds that also inhibit Src-family kinases and FGFR kinases have been identified. It was also shown that different isoquinolines can be combined with a 1-methyl-4-(2-(trifluoromethyl)benzyl)piperazine group (the dominant moiety in kinase inhibitors) to develop analogs with different kinase selectivities (a “plug-and-play” strategy). This discloses a novel class of aminoisoquinoline benzamide kinase inhibitors with high potential for clinical translation.

[1028] Example 139: Binding constant of the compound of the present invention

[1029] The substitution mechanism of aminoisoquinoline plays an important role in the kinase binding, in vitro and in vivo efficacy of the compound. Figure 18 Table 10 provides the binding constants Kd (found X KdElect) for compounds targeting FLT3, ABL1, and clinically relevant mutants that lead to drug resistance.

[1030] Table 10: Binding constants (K) of the compounds of the present invention d Unit = nM)

[1031]

[1032] From K d The data in Table 10 clearly demonstrate that the activity of the claimed compounds can be modulated to target specific kinases or drug-resistant mutants. Therefore, these compounds can be developed for drug-resistant AML (e.g., AML carrying the FLT3 (ITD, F691L) mutation) or CML (carrying the T315I mutation).

[1033] Example 140: Percentage of kinase inhibition data

[1034] To further illustrate the maintainability of the claimed compound, the inhibitory activity of several kinases was evaluated using compounds with different substitution mechanisms. Figure 19(and Tables 11-16) (using compounds at 500 nM), (Reaction Biology, Malvern, Pennsylvania).

[1035] Table 11: Percentage of kinase inhibition data: HSN286, HSN325 and HSM1702

[1036]

[1037]

[1038] Other percentages of kinase inhibition data: HSN286, HSN325, and HSM1702

[1039] HSN286c-kit(61), DAPK1(9), FGFR2(96), FGFR3(88), FGFR4(82), MEKK2(52), PDGFRb(96), RIPK2(25), RIPK3(96), RIPK4(32); HSM1702c-kit(83).

[1040] Table 12: Percentage of kinase inhibition data for HSN334, HSN356, and HSN285

[1041] AKT1 0 0 0 ALK 0 0 1 AXL 5 4 0 BRAF 96 100 64 BTK 46 65 0 c-kit 73 87 31 c-MER 0 0 3 c-Met 14 15 23 EGFR 61 59 0 EPHA5 97 96 0 EPHB2 98 100 3 ERBB2 / HER2 31 64 0 FGFR1 96 96 0 FGR 100 99 0 FLT1 / VEGFR1 79 94 3 FLT3 100 99 28 FLT4 / VEGFR3 79 94 6 KDR / VEGFR2 94 97 15 PDGFRa 86 92 30 PKCa 0 0 6 RAF1 96 100 90 ROS / ROS1 0 0 0 TIE2 / TEK 99 100 0 TRKB 41 75 0 TRKC ND 59 0 YES / YES1 100 100 0

[1042] Other percentages of kinase inhibition data: HSN334, HSN356, and HSN285

[1043] HSN334RET(100);

[1044] HSN356RET(100);

[1045] HSN285c-Src(0), DAPK(14), FGFR2(0), FGFR3(0), FGFR4(0), MEKK2(0), PDGFRb(46), RIPK2(0), RIPK3(0), RIPK4(25).

[1046] Table 13: Percentage of kinase inhibition data: HSN248

[1047] c-kit 93 c-Src 23 FGFR1 9 FLT3 73 RET 52 TRKC 83

[1048] Table 14: Percentage of kinase inhibition data: HSN178

[1049] c-Src 1 FGFR1 3 FLT3 67 RET 0

[1050] Table 15: Percentage of kinase inhibition data: HSN247

[1051] c-kit 86 c-Src 3 FGFR1 6 FLT3 75 RET 3 TRKC 77

[1052] Table 16: Percentage of kinase inhibition data: HSN353 and HSN352

[1053] c-kit 82 78 c-Src 98 100 FGFR1 93 100 FLT3 94 93

[1054] Example 141: In vivo efficacy study

[1055] HSN356, HSN334, HSN286, HSN461, and HSN431 exhibit similar in vitro efficacy against the AML cell line MV4-11 (all possessing IC50 <1 nM against MV4-11), but these compounds exhibit different efficacies in vivo. For example, while both HSN286 and HSN431 are 3-aminoisoquinolines, HSN286 is ineffective in vivo, while HSN431 is effective. Figure 20 Similarly, HSN334 differs from HSN356 and HSN461 only in that carbon is converted to nitrogen, but the survival percentage of mice injected with the MV4-11 cell line of HSN334 is different from that of both HSN356 and HSN461.

[1056] Methods: Six-week-old female NSG mice were intravenously injected with 1x10⁻⁶ luciferase-expressing enzyme (MV4-11). 6 Log-growing MV4-11 cells. Leukemia cells expressing luciferase were imaged using the IVIS Precision System (PerkinElmer, Waltham, MA). On the day of imaging, mice were anesthetized by intraperitoneal injection of 150 mg / kg luciferin (PerkinElmer, Waltham, MA) and then placed in the imaging chamber. Maximum luminescence was recorded, and the average was taken across each treatment group. Ten days after cell injection, mice were imaged, then grouped to ensure similar leukemia burden and drug administration was initiated. During the experiment, mice were administered the drug carrier (10% DMSO / 10% Tween 20 / 80% saline) or 25 mg / kg of the compound three times weekly. Mice were weighed and observed five days a week, with imaging performed weekly.

[1057] Example 142: Activity against lung cancer

[1058] In addition to AML, the compounds of this invention are also active against several other cancers. For example, the claimed compounds are active against lung cancer (Table 17). This is to be expected because the compounds can be modulated to inhibit different kinases that drive specific tumors (Tables 11-16).

[1059] Table 17: IC50 for NCI H1703(NSCLC) / nM

[1060] HSN356 88 HSN379 13 HSN334 98 HSN286 50 HSN459 38 HSN461 157 HSN431 247

[1061] Example 143: Inhibition of proliferation of K562 cell line (CML)

[1062] The compounds of this invention strongly inhibit the proliferation of the K562 cell line (CML) (Table 18).

[1063] Table 18: Inhibition of proliferation in K562 cell line (CML)

[1064] HSL45 25.3±0.1nM HSL58 94.5±0.1nM HSN178 1443±0.21nM HSN285 1102±0.08nM HSN316 913±0.1nM HSN334 6.1±0.1nM HSN356 1.8±0.03nM HSL43 10.1±0.1nM HSL47 161.1±0.11nM HSL64 1932±0.41nM HSN247 25.7±0.31nM HSN286 3.5±0.02nM HSN317 1483±0.1nM HSN352 2.4±0.06nM HSN375 8.8±0.4nM HSL44 43.5±0.14nM HSL56 95.4±0.23nM HSM1702 5057±0.45nM HSN248 7.0±0.1nM HSN315 203±0.1nM HSN325 44±0.1nM HSN353 5.2±0.02nM HSN393 7.3±0.04nM

[1065] Although the invention has been set forth and described in detail in the accompanying drawings and the foregoing description, such description is to be regarded as illustrative rather than restrictive in nature, and it should be understood that only certain embodiments have been shown and described, and all variations and modifications within the spirit of the invention are also expected.

Claims

1. A compound selected from the following: and .

2. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

3. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 2, in the preparation of a product for treating, inhibiting, alleviating, or reducing the severity of cancer in a subject in need.

4. The use according to claim 3, wherein the cancer is leukemia.

5. The use according to claim 3, wherein the cancer is selected from acute myeloid leukemia and chronic myeloid leukemia.

6. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 2, in the preparation of a product for treating, inhibiting, alleviating, or reducing the severity of a protein kinase-related disease or condition in a subject in need, wherein said disease or condition is cancer.

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