Compounds for treating spinal muscular atrophy

Abstract

Provided herein are compounds, compositions thereof and uses therewith for treating spinal muscular atrophy. In a specific embodiment, provided herein are compounds of a form that may be used to modulate the inclusion of exon 7 of SMN2 into mRNA that is transcribed from the SMN2 gene. In another specific embodiment, provided herein are compounds of a form that may be used to modulate the inclusion of exon 7 of SMN1 into mRNA that is transcribed from the SMN1 gene. In yet another embodiment, provided herein are compounds of a form that may be used to modulate the inclusion of exon 7 of SMN1 and SMN2 into mRNA that is transcribed from the SMN1 and SMN2 genes, respectively.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

This application
5′-CGCGGATCCATAATTCCCCCACCACCTC-3′  (SEQ ID NO. 16)
Reverse primer:
5′-CGCGGATCCGTGCTGCTCTATGCCAGCA-3′  (SEQ ID NO. 17)

The 5′ end of each primer was designed to add a BamHI restriction endonuclease recognition site at both the 5′ end of exon 6 (GGATCC) (SEQ ID NO. 18) and the 3′ end after the 23^th nucleotide of exon 8. Using the BamHI restriction endonuclease recognition sites, the PCR fragment was cloned into a derivative of the original pcDNA 3.1/Hygro vector which was modified as disclosed in United States Patent Publication US2005/0048549.

New UTRs were added to the modified vector using the HindIII site and the BamHI restriction sites comprising a 5′DEG UTR: 5′-TAGCTTCTTACCCGTACTCCACCGTTGGCAGCACGATCGCACGTCCCACGT GAACCATTGGTAAACCCTG-3′ (SEQ ID NO. 19) was cloned into the modified pcDNA3.1/Hygro vector together with a start codon upstream of the BamHI restriction site; and

a 3′DEG UTR: 5′-ATCGAAAGTACAGGACTAGCCTTCCTAGCAACCGCGGGCTGGGAGTCTGA GACATCACTCAAGATATATGCTCGGTAACGTATGCTCTAGCCATCTAACTATTCCCT ATGTCTTATAGGG-3′ (SEQ ID NO. 20) was cloned into the modified pcDNA3.1/Hygro vector using the NotI restriction endonuclease recognition site and the XhoI restriction endonuclease recognition site with a stop codon immediately downstream of the NotI restriction site. In addition, a firefly luciferase gene lacking its start codon was cloned into the vector using the BamHI and NotI restriction sites.

The resulting minigene comprises, in 5′ to 3′ order: the 5′-DEG UTR, the start codon, six additional nucleotides forming a BamHI restriction site, the nucleic acid residues of exon 6, the nucleic acid residues of intron 6 of SMN2, the nucleic acid residues of exon 7 of SMN2, the nucleic acid residues of intron 7 of SMN2, and the first 23 nucleic acid residues of exon 8 of SMN2, an additional six nucleotides forming a BamHI restriction site and the firefly luciferase gene lacking the start codon.

A single adenine residue was inserted after nucleotide 48 of exon 7 of SMN2 by site-directed mutagenesis. This minigene construct is referred to as SMN2-A.

SMN2 transcripts derived from minigenes containing exon 6 through 8 and the intervening introns recapitulate the splicing of their endogenous pre-mRNAs (Lorson et al, Proc. Natl. Acad. Sci. U.S.A., 1999, 96 (11), 6307). An SMN2-alternative splicing reporter construct which contains exons 6 through 8 and the intervening introns followed by a luciferase reporter gene was generated. Salient features of this construct are the lack of the start codon in the luciferase gene, inactivation of the termination codon (in the open reading frame that encodes the SMN protein) of exon 7 by insertion of a nucleotide after nucleic acid 48 of exon 7 and addition of a start codon (ATG) immediately upstream of exon 6. A single adenine (SMN2-A) was inserted after nucleic residue 48 of exon 7.

The SMN2 minigene was designed such that the luciferase reporter is in frame with the ATG start codon immediately upstream of exon 6 when exon 7 is present in the mRNA and the luciferase reporter is out of frame with the ATG start codon immediately upstream of exon 6 if exon 7 of SMN2 is removed during splicing of the pre-mRNA. In addition, in the absence of exon 7, the open reading frame that starts from the ATG start codon immediately upstream of exon 6 contains a stop codon in the fragment of exon 8 of SMN. Thus, in the presence of compounds that increase the inclusion of exon 7 of SMN2 into mRNA transcribed from the SMN2 gene, more transcripts containing exon 7 and more functional reporter are produced. A schematic illustration of this description can be found in FIG. 1.

The DNA sequence of the minigene from the SMN2-A construct SEQ ID NO. 21 is provided in FIG. 2a. A picture of the minigene SMN2-A subsequences is shown in FIG. 2b.

Example 2

SMN2 Minigene mRNA Splicing RT-qPCR Assay in Cultured Cells

The reverse transcription-quantitative PCR-based (RT-qPCR) assay is used to quantify the level of the full length SMN2 minigene mRNA containing SMN2 exon 7 in a HEK293H cell line stably transfected with said minigene and treated with a test compound.

Materials

Material                   Source

HEK293H cells              ATCC Catalog No. CRL-1573
Cells-To-Ct lysis buffer   Life Technologies, Inc. (formerly Applied
                           Biosystems) Catalog No.: 4399002
DMEM                       Life Technologies, Inc. (formerly Invitrogen)
                           Catalog No.: 11960-044
96-well flat-bottom plates Becton Dickinson Catalog No.: 353072
RT-PCR Enzyme Mix          Life Technologies, Inc. (formerly Applied
                           Biosystems) part #4388520 (also included in
                           AgPath-ID kit Catalog No.: 4387391)
RT-PCR buffer              Life Technologies, Inc. (formerly Applied
                           Biosystems) part #4388519 (also included in
                           AgPath-ID kit Catalog No.: 4387391)
AgPath-ID One-Step         Life Technologies, Inc. (formerly Applied
RT-PCR kit                 Biosystems) Catalog No.: 4387391
Thermocycler               Life Technologies, Inc. (formerly Applied
                           Biosystems) 7900HT

Protocol. HEK293H cells stably transfected with the SMN2-A minigene construct described above (10,000 cells/well) are seeded in 200 μL of cell culture medium (DMEM plus 10% FBS, with 200 μg/mL hygromycin) in 96-well flat-bottom plates and the plate is immediately swirled to ensure proper dispersal of cells, forming an even monolayer of cells. Cells are allowed to attach for at least 4-6 hours. Test compounds are serially diluted 3.16-fold in 100% DMSO to generate a 7-point concentration curve. A solution of test compound (1 μL, 200× in DMSO) is added to each cell-containing well and the plate is incubated for 24 hours in a cell culture incubator (37° C., 5% CO₂, 100% relative humidity). 2 replicates are prepared for each test compound concentration. The cells are then lysed in Cells-To-Ct lysis buffer and the lysate is stored at −80° C.

Full length SMN2-A minigene and GAPDH mRNA are quantified using the following primers and probes provided in Table 3. Primer SMN Forward A (SEQ ID NO. 1) hybridizes to a nucleotide sequence in exon 7 (nucleotide 22 to nucleotide 40), primer SMN Reverse A (SEQ ID NO. 2) hybridizes to a nucleotide sequence in the coding sequence of Firefly luciferase, SMN Probe A (SEQ ID NO. 3) hybridizes to a nucleotide sequence in exon 7 (nucleotide 50 to nucleotide 54) and exon 8 (nucleotide 1 to nucleotide 21). The combination of these three oligonucleotides detects only SMN1 or SMN2 minigenes (RT-qPCR) and will not detect endogenous SMN1 or SMN2 genes.

TABLE 3
Primers/Probes	Sequence	Source
SMN Forward	SEQ ID NO. 1:	PTC1
Primer A	GAAGGAAGGTGCTCACATT
SMN Reverse	SEQ ID NO. 2:	PTC1
Primer A	TCTTTATGTTTTTGGCGTCTTC
SP N Forward	SEQ ID NO. 3:	PTC1
Probe A	6FAM-
	AAGGAGAAATGCTGGCAT
	AGAGCAGC-TAMRA
hGAPDH Forward	SEQ ID NO. 4:	LTI2
Probe	VIC-CGCCTGGTCACCAGGGCT
	GCT-TAMRA
hGAPDH Forward	SEQ ID NO. 5:	LTI2
Primer	CAACGGATTTGGTCGTATTGG
hGAPDH Reverse	SEQ ID NO. 6:	LTI2
Primer	TGATGGCAACAATATCCACTTT
	ACC
1Primers and probes designed by PTC Therapeutics, Inc.;
2Commercially available from Life Technologies, Inc. (formerly Invitrogen).

The SMN forward and reverse primers are used at final concentrations of 0.4 μM. The SMN probe is used at a final concentration of 0.15 μM. The GAPDH primers are used at final concentrations of 0.2 μM and the probe at 0.15 μM.

The SMN2-minigene GAPDH mix (15 μL total volume) is prepared by combining 7.5 μL of 2×RT-PCR buffer, 0.4 μL of 25×RT-PCR enzyme mix, 0.75 μL of 20×GAPDH primer-probe mix, 4.0075 μL of water, 2 μL of 10-fold diluted cell lysate, 0.06 μL of 100 μM SMN forward primer, 0.06 μL of 100 μM SMN reverse primer, and 0.225 μL of 100 μM SMN probe.

PCR is carried out at the following temperatures for the indicated time: Step 1: 48° C. (15 min); Step 2: 95° C. (10 min); Step 3: 95° C. (15 sec); Step 4: 60° C. (1 min); then repeat Steps 3 and 4 for a total of 40 cycles.

Each reaction mixture contains both SMN2-A minigene and GAPDH primers/probe sets (multiplex design), allowing simultaneous measurement of the levels of two transcripts.

Two SMN spliced products are generated from the SMN2 minigene. The first spliced product containing exon 7, corresponding to full length SMN2 mRNA, is called SMN2mini FL. The second one lacking exon 7 is called SMN2mini Δ7.

The increase of SMN2mini FL mRNA relative to that in cells treated with vehicle control is determined from real-time PCR data using a modified ΔΔCt method (as described in Livak and Schmittgen, Methods, 2001, 25:402-8). The amplification efficiency E is calculated from the slope of the amplification curve for SMN2mini FL and GAPDH individually. The abundances of SMN2mini FL and GAPDH are then calculated as (1+FE)^−Ct, where Ct is the threshold value for each amplicon. The abundance of SMN2mini FL is normalized to GAPDH abundance. The normalized SMN2mini FL abundance from test compound-treated samples is then divided by normalized SMN2mini FL abundance from vehicle-treated cells to determine the level of SMN2 FL mRNA relative to vehicle control.

Results. As seen in FIG. 3, cells treated with Compound 35 (FIG. 3a) and Compound 626 (FIG. 3b) increased SMN2mini FL mRNA at low concentrations. The two test compounds fully restored exon 7 inclusion relative to untreated cells.

For compounds of Formula (I) or a form thereof disclosed herein, Table 4 provides the EC_1.5x for production of full length SMN2 mRNA that was obtained from the 7-point concentration data generated for each test compound according to the procedure of Biological Example 2. The term “EC_1.5x for production of full length SMN2 mRNA” is defined as that concentration of test compound that is effective in increasing the amount of full length SMN2 mRNA to a level 1.5-fold greater relative to that in vehicle-treated cells. An EC_1.5x for production of full length SMN2 mRNA between >3 μM and ≤30 μM is indicated by one star (*), an EC_1.5x between >1 μM and ≤3 μM is indicated by two stars (**), an EC_1.5x between >0.3 μM and ≤1 μM is indicated by three stars (***), an EC_1.5x between >0.1 μM and ≤0.3 μM is indicated by four stars (****) and an EC_1.5x≤0.1 μM is indicated by five stars (*****).

TABLE 4

Cpd EC1.5x


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Example 3

Endogenous SMN2 mRNA RT-qPCR Splicing Assay in Cultured Cells

The reverse transcription-quantitative PCR-based (RT-qPCR) assay is used to quantify the levels of the full length and Δ7 SMN2 mRNAs in primary cells and cell lines containing the SMN2 gene treated with a test compound.

Materials

Material                 Source

SMA Type 1 human cells   GM03813 (Coriell Institute)
Cells-To-Ct lysis buffer Life Technologies, Inc. (formerly Applied
                         Biosystems) Catalog No.: 4399002
DMEM                     Life Technologies, Inc. (formerly Invitrogen)
                         Catalog No.: 11960-044
96-well flat-bottom      Becton Dickinson Catalog #353072
plates
RT-PCR Enzyme Mix        Life Technologies, Inc. (formerly Applied
                         Biosystems) part #4388520 (also included in
                         AgPath-ID kit Catalog No.: 4387391)
RT-PCR buffer            Life Technologies, Inc. (formerly Applied
                         Biosystems) part #4388519 (also included in
                         AgPath-ID kit Catalog No.: 4387391)
AgPath-ID One-Step RT-   Life Technologies, Inc. (formerly Applied
PCR kit                  Biosystems) Catalog No.: 4387391
Thermocycler             Life Technologies, Inc. (formerly Applied
                         Biosystems) 7900HT

Protocol. GM03813 SMA patient cells (5,000 cells/well) are seeded in 200 μL, of cell culture medium (DMEM plus 10% FBS) in 96-well flat-bottom plates and the plate is immediately swirled to ensure proper dispersal of cells, forming an even monolayer of cells. Cells are allowed to attach for at least 4-6 hrs. Test compounds are serially diluted 3.16-fold in 100% DMSO to generate a 7-point concentration curve. A solution of test compound (1 μL, 200× in DMSO) is added to each test well and 1 μL, DMSO is added to each control well. The plate is incubated for 24 hrs in a cell culture incubator (37° C., 5% CO₂, 100% relative humidity). The cells are then lysed in Cells-To-Ct lysis buffer and the lysate is stored at −80° C.

SMN2-specific spliced products and GAPDH mRNA are identified using the following primers and probes in Table 5. Primer SMN FL Forward B (SEQ ID NO. 7) hybridizes to a nucleotide sequence in exon 7 (nucleotide 32 to nucleotide 54) and exon 8 (nucleotide 1 to nucleotide 4), primer SMN Δ7 Forward B (SEQ ID NO. 8) hybridizes to a nucleotide sequence in exon 6 (nucleotide 87 to nucleotide 111) and exon 8 (nucleotide 1 to nucleotide 3), primer SMN Reverse B (SEQ ID NO. 9) hybridizes to a nucleotide sequence in exon 8 (nucleotide 39 to nucleotide 62), probe SMN Probe B (SEQ ID NO. 10) hybridizes to a nucleotide sequence in exon 8 (nucleotide 7 to nucleotide 36). These primers and probe hybridize to nucleotide sequences common to human SMN1 and SMN2 mRNAs. Since the SMA patient cells used in Example 3 contain only the SMN2 gene, RT-qPCR can quantify only SMN2 full-length and Δ7 mRNA.

TABLE 5
Primer/Probe	Sequence	Source
SMN FL Forward	SEQ ID NO. 7:	PTC1
Primer B	GCTCACATTCCTTAAATTAAGG
	AGAAA
SMN Δ7 Forward	SEQ ID NO. 8:	PTC1
Primer B	TGGCTATCATACTGGCTATTAT
	ATGGAA
SMN Reverse	SEQ ID NO. 9:	PTC1
Primer B	TCCAGATCTGTCTGATCGTTTC
	TT
SMN Forward	SEQ ID NO. 10:	PTC1
Probe B	6FAM-
	CTGGCATAGAGCAGCACT
	AAATGACACCAC-TAMRA
hGAPDH Forward	SEQ ID NO. 4:	LTI2
Probe	VIC-CGCCTGGTCACCAGGGCT
	GCT-TAMRA
hGAPDH Forward	SEQ ID NO. 5:	LTI2
Primer	CAACGGATTTGGTCGTATTGG
hGAPDH Reverse	SEQ ID NO. 6:	LTI2
Primer	TGATGGCAACAATATCCACTTT
	ACC
1Primers and probes designed by PTC Therapeutics, Inc.;
2Commercially available from Life Technologies, Inc. (formerly Invitrogen).

The SMN forward and reverse primers are used at final concentrations of 0.4 μM. The SMN probe is used at a final concentration of 0.15 μM. GAPDH primers are used at final concentrations of 0.1 μM and the probe at 0.075 μM. TaqMan gene expression assays were conducted at 20× concentrations with the GAPDH primers and Vic labeled probe provided as a 20× mixture. The One-Step RT-PCR kit was used as the Real-Time PCR Mix.

The SMN-GAPDH mix (10 μL total volume) is prepared by combining 5 μL of 2×RT-PCR buffer, 0.4 μL of 25×RT-PCR enzyme mix, 0.25 μL of 20×GAPDH primer-probe mix, 1.755 μL water, 2.5 μL of cell lysate, 0.04 μL of 100 μM SMN FL or SMN Δ7 forward primer, 0.04 μL of 100 μM SMN reverse primer, and 0.015 μL of 100 μM probe.

PCR is carried out at the following temperatures for indicated time: Step 1: 48° C. (15 min); Step 2: 95° C. (10 min); Step 3: 95° C. (15 sec); Step 4: 60° C. (1 min); then, repeat Steps 3 and 4 for a total of 40 cycles.

Each reaction mixture contains either SMN2 FL and GAPDH or SMN2 Δ7 and GAPDH primers/probe sets (multiplex design), allowing simultaneous measurement of the levels of two transcripts.

The endogenous SMN2 gene gives rise to two alternatively spliced mRNAs. The full length SMN2 mRNA contains exon 7 and termed SMN2 FL. The truncated mRNA lacks exon 7 and termed SMN2 Δ7.

The increase of SMN2 FL and decrease in SMN2 Δ7 mRNAs relative to those in cells treated with vehicle control are determined from real-time PCR data using a modified ΔΔCt method (as described in Livak and Schmittgen, Methods, 2001, 25:402-8). The amplification efficiency E is calculated from the slope of the amplification curve for SMN2 FL, SMN2 Δ7, and GAPDH individually. The abundances of SMN2 FL, SMN2 Δ7, and GAPDH are then calculated as (1+E)^−Ct, where Ct is the threshold value for each amplicon. The abundances of SMN2 FL and SMN2 Δ7 are normalized to GAPDH abundance. The normalized SMN2 FL and SMN2 Δ7 abundances from test compound-treated samples are then divided by normalized SMN2 FL and SMN2 Δ7 abundances, respectively, from vehicle-treated cells to determine the levels of SMN2 FL and SMN2 Δ7 mRNAs relative to vehicle control.

Results. As seen in FIG. 4, cells treated with increasing concentrations of Compound 35 (FIG. 4a) and Compound 626 (FIG. 4b) contain progressively more SMN2 FL mRNA and less SMN2 Δ7 mRNA than those treated with vehicle indicating a correction of SMN2 alternative splicing.

Example 4

Endogenous SMN2 mRNA End-Point Semi-Quantitative RT-PCR Splicing Assay in Cultured Cells

The endpoint reverse transcription-PCR splicing assay is used to visualize and quantify the levels of the full length and Δ7 SMN2 mRNAs in primary cells and cell lines containing the SMN2 gene treated with a test compound.

Materials

Material                   Source

SMA Type 1 human cells     GM03813 (Coriell Institute)
Cells-To-Ct lysis buffer   Life Technologies, Inc. (formerly Applied
                           Biosystems) Catalog No.: 4399002
DMEM                       Life Technologies, Inc. (formerly Invitrogen)
                           Catalog No.: 11960-044
96-well flat-bottom plates Becton Dickinson Catalog No.: 353072
Platinum Tag HiFi DNA      Life Technologies, Inc. (formerly Invitrogen)
Polymerase Super Mix       Catalog No.: 11304-016
iScript RT enzyme kit      BioRad Catalog No.: 170-8890
Ethidium bromide 2%        Life Technologies, Inc. (formerly Invitrogen)
agarose E gels 48-Well     Catalog No.: G8008-02
Double Comb
Gel Documentation System   UVP Gel Doc It 310 Imaging system

Protocol. GM03813 SMA patient cells (5,000 cells/well) are seeded in 200 μL of cell culture medium (DMEM plus 10% FBS) in 96-well flat-bottom plates and the plate is immediately swirled to ensure proper dispersal of cells, forming an even monolayer of cells. Cells are allowed to attach for at least 4-6 hrs. Test compounds are serially diluted 3.16-fold in 100% DMSO to generate a 7-point concentration curve. A solution of test compound (1 μL, 200× in DMSO) is added to each test well and 1 μL DMSO is added to each control well. The plate is incubated for 24 hrs in a cell culture incubator (37° C., 5% CO₂, 100% relative humidity). The cells are then lysed in Cells-To-Ct lysis buffer and the lysate is stored at −80° C.

SMN FL and Δ7 mRNAs are identified using the following primers in Table 6. These primers hybridize to a nucleotide sequence in exon 6 (SMN Forward C, SEQ ID NO. 11) (nucleotide 43 to nucleotide 63) and exon 8 (SMN Reverse C, SEQ ID NO. 12) (nucleotide 51 to nucleotide 73) common to human SMN1 and SMN2 mRNAs. Since the SMA patient cells used in Example 4 contain only the SMN2 gene, RT-PCR can visualize and quantify only SMN2 full-length and SMN2 Δ7 mRNAs.

TABLE 6
Primer	Sequence	Source
SMN Forward C	SEQ ID NO. 11:	PTC1
	GATGCTGATGCTTTGGGAAGT
SMN Reverse C	SEQ ID NO. 12:	PTC1
	CGCTTCACATTCCAGATCTGTC
1Primers designed by PTC Therapeutics, Inc.

To synthesize cDNA, 5 μL of lysate, 4 μL of 5× iScript reaction mix, 1 μL of reverse transcriptase, and 10 μL of water are combined and incubated 5 min at 25° C. followed by 30 min at 42° C., followed by 5 min at 85° C. cDNA solution is stored at −20° C.

To perform endpoint PCR, 5 μL of cDNA, 0.2 μL of 100 μM forward primer, 0.2 μL of 100 μM reverse primer, and 22.5 μL of polymerase super mix are combined in a 96 well semiskirted PCR plate. PCR is carried out at the following temperatures for indicated time: Step 1: 94° C. (2 min), Step 2: 94° C. (30 sec), Step 3: 55° C. (30 sec), Step 4: 68° C. (1 min), then repeat Steps 2 to 4 for a total of 33 cycles, then hold at 4° C.

10 μL of each PCR sample is electrophoretically separated on a 2% agarose E-gel for 14 minutes stained with ds DNA staining reagents (e.g., ethidium bromide) and visualized using a gel imager.

Results. As seen in FIG. 5, cells treated with increasing concentrations of Compound 35 (FIG. 5a) and Compound 626 (FIG. 5b) contain progressively more SMN2 FL mRNA and less SMN2 Δ7 mRNA indicating a correction of SMN2 alternative splicing.

Example 5

SMN2 mRNA RT-qPCR Splicing Assay in Animal Tissues

The reverse transcription-quantitative PCR-based (RT-qPCR) assay is used to quantify the levels of the full length and Δ7 SMN2 mRNAs in tissues from mice treated with test compound.

Materials

Material                     Source

Tissues from C/C-allele      The Jackson Laboratory, strain #008714
SMA mice                     (B6.129-Smn1tm5(Smn1/SMN2)Mrph/J)
Tissues from Δ7 SMA mice     The Jackson Laboratory, strain #005025
                             (FVB.Cg-Tg(SMN2*delta7)4299Ahmb
                             Tg(SMN2)89Ahmb Smn1tm1Msd/J)
RT-PCR Enzyme Mix            Life Technologies, Inc. (formerly Applied
                             Biosystems) part #4388520 (also included
                             in AgPath-ID kit Catalog No.: 4387391)
RT-PCR buffer                Life Technologies, Inc. (formerly Applied
                             Biosystems) part #4388519 (also included
                             in AgPath-ID kit Catalog No.: 4387391)
AgPath-ID One-Step RT-       Life Technologies, Inc. (formerly Applied
PCR kit                      Biosystems) Catalog No.: 4387391
Mouse GAPDH primers          Life Tecimologies, Inc. (formerly Applied
and probes                   Biosystems) Catalog No.: 4352339E
QIAzol Lysis Reagent         Qiagen Catalog No.: 79306
RNeasy Lipid Tissue Mini Kit Qiagen Catalog No.: 74804
5 mm Stainless Steel Bead    Qiagen Catalog No.: 69989
TissueLyzer II               Qiagen Catalog No.: 85300
Thermocycler                 Life Tecimologies, Inc. (formerly Applied
                             Biosystems) 7900HT

Protocol. C/C-allele SMA mice are treated by oral gavage two times per day for 10 days with test compounds resuspended in 0.5% HPMC and 0.1% Tween-80. Tissue samples were collected and snap frozen for RNA purification.

Tissue samples (20-40 mg) are homogenized in QIAzol Lysis Reagent for 2 minutes at 20 Hz in the TissueLyser II using one stainless steel bead. After addition of chloroform, the homogenate is separated into aqueous and organic phases by centrifugation. RNA partitioned to the upper, aqueous phase is extracted and ethanol is added to provide appropriate binding conditions. The sample is then applied to the RNeasy spin column from the RNeasy Mini Kit, where total RNA binds to the membrane. The RNA is eluted in RNase-free water then stored at −20° C. and subsequently analyzed using the TaqMan RT-qPCR on the 7900HT Thermocycler. Total RNA is diluted ten fold and 2.5 μL of the diluted sample is added to the TaqMan RT-qPCR mixture.

SMN2 spliced products are identified using the following primers and probes in Table 7. Primer SMN FL Forward B (SEQ ID NO. 7) hybridizes to a nucleotide sequence in exons 7 and 8, primer SMN Δ7 Forward B (SEQ ID NO. 8) hybridizes to a nucleotide sequence in exons 6 and 8, primer SMN Reverse B (SEQ ID NO. 9) hybridizes to a nucleotide sequence in exon 8, probe SMN Probe B (SEQ ID NO. 10) hybridizes to a nucleotide sequence in exon 8. These primers and probe hybridize to nucleotide sequences common to human SMN1 and SMN2 mRNAs. Since the SMA patient cells used in Example 5 contain only the SMN2 gene, RT-qPCR can quantify only SMN2 full-length and Δ7 mRNAs.

TABLE 7
Primer/Probe	Sequence	Source
SMN FL Forward	SEQ ID NO. 7:	PTC1
Primer B	GCTCACATTCCTTAAATTAAGG
	AGAAA
SMN Δ7 Forward	SEQ ID NO. 8:	PTC1
Primer B	TGGCTATCATACTGGCTATTAT
	ATGGAA
SMN Reverse	SEQ ID NO. 9:	PTC1
Primer B	TCCAGATCTGTCTGATCGTTTC
	TT
SMN Forward	SEQ ID NO. 10:	PTC1
Probe B	6FAM-CTGGCATAGAGCAGCAC
	TAAATGACACCAC-TAMRA
1Primers and probes designed by PTC Therapeutics, Inc.

The SMN forward and reverse primers are used at final concentrations of 0.4 μM. The SMN probe is used at a final concentration of 0.15 μM. The SMN-GAPDH Mix (10 μL total volume) is prepared by combining 5 μL of 2×RT-PCR buffer, 0.4 μL of 25×RT-PCR enzyme mix, 0.5 μL of 20×GAPDH primer-probe mix, 1.505 μL of water, 2.5 μL of RNA solution, 0.04 μL of 100 μM forward primer, 0.04 μL of 100 μM reverse primer, and 0.015 μL of 100 μM SMN probe.

Each PCR cycle was carried out at the following temperatures for indicated time: Step 1: 48° C. (15 min); Step 2: 95° C. (10 min); Step 3: 95° C. (15 sec); Step 4: 60° C. (1 min); then, repeat Steps 3 and 4 for a total of 40 cycles.

Each reaction mixture contains either SMN2 FL and mGAPDH or SMN2 Δ7 and mGAPDH primers/probe sets (multiplex design), allowing simultaneous measurement of the levels of two transcripts.

The increase of SMN2 FL and decrease in SMN2 Δ7 mRNAs relative to those in tissues from animals treated with vehicle control are determined from real-time PCR data using a modified ΔΔCt method (as described in Livak and Schmittgen, Methods, 2001, 25:402-8). The amplification efficiency E is calculated from the slope of the amplification curve for SMN2 FL, SMN2 Δ7, and GAPDH individually. The abundances of SMN2 FL, SMN2 Δ7, and GAPDH are then calculated as (1+E)^−Ct, where Ct is the threshold value for each amplicon. The abundances of SMN2 FL and SMN2 Δ7 are normalized to GAPDH abundance. The normalized SMN2 FL and SMN2 Δ7 abundances from test compound-treated samples are then divided by normalized SMN2 FL and SMN2 Δ7 abundances, respectively, from vehicle-treated cells to determine the levels of SMN2 FL and SMN2 Δ7 mRNAs relative to vehicle control.

Results. As seen in FIG. 6, tissues of animals treated with Compound 35 (FIG. 6a) and Compound 626 (FIG. 6b) contain substantially more SMN2 FL mRNA and less SMN2 Δ7 mRNA than those treated with vehicle indicating a correction of SMN2 alternative splicing.

Example 6

Endogenous SMN2 mRNA End-Point Semi-Quantitative RT-PCR Splicing Assay in Animal Tissues

The endpoint reverse transcription-PCR (RT-PCR) splicing assay is used to quantify the levels of the full length and Δ7 SMN2 mRNAs in tissues from mice treated with test compound.

Materials

Material                Source

Tissues from C/C-allele The Jackson Laboratory, strain #008714
SMA mice                (B6.129-Smn1tm5(Smn1/SMN2)Mrph/J)
Tissues from ΔExon7     The Jackson Laboratory, strain #005025
SMA mice                (FVB.Cg-Tg(SMN2*delta7)4299 Ahmb
                        Tg(SMN2)89Ahmb Smn1tm1Msd/J)
Qiagen RNeasy lipid kit Qiagen Catalog No.: 74804
Platinum Tag HiFi DNA   Life Technologies, Inc. (formerly Invitrogen)
Polymerase Super Mix    Catalog No.: 11304-016
iScript RT enzyme kit   BioRad Catalog No.: 170-8890
Twin.tec 96-Well Semi-  Eppendorf Catalog No.: 951020389
skirted PCR Plate
Ethidium bromide 2%     Life Technologies, Inc. (formerly Invitrogen)
agarose E gels 48-Well  Catalog No.: G8008-02
Double Comb
Gel Documentation       UVP Gel Doc It 310 Imaging system
System

Protocol. C/C-allele SMA mice are treated by oral gavage two times per day for 10 days with test compounds in 0.5% HPMC and 0.1% Tween-80. Tissue samples are collected and snap frozen for RNA purification.

Tissue samples (20-40 mg) are homogenized in QIAzol Lysis Reagent for 2 minutes at 20 Hz in the TissueLyser II using one stainless steel bead. After addition of chloroform, the homogenate is separated into aqueous and organic phases by centrifugation. RNA partitioned to the upper, aqueous phase is extracted and ethanol is added to provide appropriate binding conditions. The sample is then applied to the RNeasy spin column from the RNeasy Mini Kit, where total RNA binds to the membrane. The RNA is eluted in RNase-free water then stored at −20° C.

SMN2 spliced products are identified using the following amplification primers in Table 8. These primers hybridize to a nucleotide sequence in exon 6 (SMN Forward D, SEQ ID NO. 13) (nucleotide 22 to nucleotide 46) and exon 8 (SMN Reverse C, SEQ ID NO. 12) common to human SMN1 and SMN2 mRNAs.

TABLE 8
Primer	Sequence	Source
SMN Forward D	SEQ ID NO. 13:	PTC1
	ATATGTCCAGATTCTCTTGATG
	ATG
SMN Reverse C	SEQ ID NO. 12:	PTC1
	CGCTTCACATTCCAGATCTGTC
1Primers designed by PTC Therapeutics, Inc.

To synthesize cDNA, combine 1 μL of RNA solution (25-50 ng), 4 μL of 5× iScript reaction mix, 1 μL of reverse transcriptase, and 10 μL of water are combined and incubates 25° C. for 5 min followed by 42° C. for 30 min followed by 85° C. for 5 min. cDNA solution is stored at −20° C.

To perform endpoint PCR, 5 μL of cDNA, 0.2 μL of 100 μM forward primer, 0.2 μL of 100 μM reverse primer, and 22.5 μL of polymerase super mix are combined in a 96 well semiskirted PCR plate. PCR is carried out at the following temperatures for indicated time: Step 1: 94° C. (2 min), Step 2: 94° C. (30 sec), Step 3: 55° C. (30 sec), Step 4: 68° C. (1 min), then repeat Steps 2 to 4 for a total of 33 cycles, then hold at 4° C.

10 μL of each PCR sample is electrophoretically separated on a 2% agarose E-gel for 14 minutes, stained with ds DNA staining reagents (e.g., ethidium bromide) and visualized using a gel imager.

Results. As seen in FIG. 7, tissues from mice treated with increasing concentrations of Compound 35 (FIGS. 7a) and Compound 626 (FIG. 7b) contain progressively more SMN2 FL mRNA and less SMN2 Δ7 mRNA indicating a correction of SMN2 alternative splicing.

Example 7

Smn Protein Assay in Cultured Cells

The SMN HTRF (homogeneous time resolved fluorescence) assay is used to quantify the level of Smn protein in SMA patient fibroblast cells treated with test compounds. The results of the assay are shown in Table 9.

Materials

Material                    Source

SMA Type 1 human cells      GM03813 (Coriell Institute)
Protease inhibitor cocktail Roche Applied Science Catalog No.:
                            11836145001
Anti-SMN d2                 Blue cap Cisbio Catalog No.: 63IDC002-
                            SMN
Anti-SMN kryptate           Red cap Cisbio Catalog No.: 63IDC002-
                            SMN
SMN reconstitution buffer   Cisbio Catalog No.: 63IDC002-SMN-Buffer
DMEM                        Life Technologies, Inc. (formerly Invitrogen)
                            Catalog No.: 11960-044
RIPA Lysis Buffer           20 mM Tris-HCl pH 7.5, 150 mM NaCl, 1 mM
                            EDTA, 1% NP-40, 1% Sodium deoxycholate
Diluent Buffer              20 mM Tris-HCl pH 7.5, 150 mM NaCl
Envision Plate Reader       Perkin Elmer Model No.: 2103

Protocol. Cells are thawed and cultured in DMEM-10% FBS for 72 hours. Cells are trypsinized, counted and resuspended to a concentration of 25,000 cells/mL in DMEM-10% FBS. The cell suspensions are plated at 5,000 cells per well in a 96 well microtiter plate and incubated for 3 to 5 hours. To provide a control signal, three (3) wells in the 96 well plate do not receive cells and, thus, serve as Blank control wells. Test compounds are serially diluted 3.16-fold in 100% DMSO to generate a 7-point concentration curve. 1 μL of test compound solution is transferred to cell-containing wells and cells are incubated for 48 hours in a cell culture incubator (37° C., 5% CO₂, 100% relative humidity). Triplicate samples are set up for each test compound concentration. After 48 hours, the supernatant is removed from the wells and 25 μL of the RIPA lysis buffer, containing protease inhibitors, is added to the wells and incubated with shaking at room temperature for 1 hour. 25 μL of the diluent is added and then 35 μL of the resulting lysate is transferred to a 384-well plate, where each well contains 5 μL of the antibody solution (1:100 dilution of anti-SMN d2 and anti-SMN kryptate in SMN reconstitution buffer). The plate is centrifuged for 1 minute to bring the solution to the bottom of the wells, then incubated overnight at room temperature. Fluorescence for each well of the plate at 665 nm and 620 nm is measured on an EnVision multilabel plate reader (Perkin-Elmer).

The normalized fluorescence signal is calculated for each sample, Blank and vehicle control well by dividing the signal at 665 nm by the signal at 620 nm. Normalizing the signal accounts for possible fluorescence quenching due to the matrix effect of the lysate. The ΔF value (a measurement of Smn protein abundance) for each sample well is calculated by subtracting the normalized average fluorescence for the Blank control wells from the normalized fluorescence for each sample well and then dividing this difference by the normalized average fluorescence for the Blank control wells. The resulting ΔF value for each sample well represents the Smn protein abundance from test compound-treated samples. The ΔF value for each sample well is divided by the ΔF value for the vehicle control wells to calculate the fold increase in Smn protein abundance relative to the vehicle control.

Results. As seen in FIG. 8, SMA Type 1 patient fibroblast cells treated with Compound 35 (FIG. 8a) and Compound 626 (FIG. 8b) show a dose dependent increase in Smn protein expression as measured by the SMN HTRF assay.

For compounds of Formula (I) or a form thereof disclosed herein, Table 9 provides the EC_1.5x for Smn protein expression that was obtained from the 7-point concentration data generated for each test compound according to the procedure of Biological Example 7. The term “EC_1.5x for Smn protein expression” is defined as that concentration of test compound that is effective in producing 1.5 times the amount of Smn protein in a SMA patient fibroblast cell compared to the amount produced from the DMSO vehicle control. An EC_1.5x for Smn protein expression between >3 μM and ≤10 μM is indicated by one star (*), an EC_1.5x between >1 and ≤3 μM is indicated by two stars (**), an EC_1.5x between >0.3 μM and ≤1 μM is indicated by three stars (***) and an EC_1.5x≤0.3 μM is indicated by four stars (****).

TABLE 9

Cpd EC1.5x


39  *
51  ****
58  ***
72  ***
81  *
83  **
84  **
87  **
88  **
89  ***
95  ****
96  *
97  *
98  **
105 ***
107 ***
108 ***
109 *
117 ***
118 ****
120 ****
123 ***
128 *
133 *
134 **
142 ***
148 **
150 *
152 **
161 *
162 ***
169 **
186 **
188 *
193 *
198 *
203 ***
212 ***
227 *
231 *
243 *
246 **
248 **
250 **
271 *
294 **
295 ***
302 ***
303 *
304 **
307 *
311 **
335 **
338 *
345 *
353 **
354 **
355 ***
373 ***
383 **
404 **
417 ****
418 ***
420 ****
421 ****
424 ****
425 **
438 **
443 ***
450 **
454 *
455 ***
456 **
459 *
460 *
462 **
471 ***
476 ****
477 ****
482 ****
483 **
493 ****
507 ****
515 ****
516 ****
517 ****
518 ****
519 ****
527 ****
530 ****
533 ****
536 ****
537 ****
550 ****
551 ****
552 ****
554 ****
555 ****
556 ***
558 ***
560 ****
561 ****
562 ****
563 ****
564 ****
566 ****
567 ****
568 ****
569 ****
570 ****
572 ***
573 ****
584 ****
586 ****
587 ****
588 ****
589 ****
590 ****
591 ****
592 ****
593 ****
594 ****
597 ****
600 ****
601 ****
605 ****
606 ****
607 ***
608 ****
609 ****
611 **
614 ****
615 ****
618 ****
619 ****
620 ****
621 ****
622 ****
623 ***
625 ***
626 ****
627 ****
628 ****
632 ****
634 ****
635 ****
638 ****
640 ****
643 ****
644 ****
645 ****
646 ****
647 ****
648 ****
649 ***
650 ***
651 ****
652 ****
654 ****
655 ****
656 ****
657 ****
658 ****
659 ****
660 ***
661 ****
662 **
664 ****
665 ****
666 ****
667 ****
668 ****
669 ****
670 ****
671 ****
672 ****
673 ****
674 ****
675 **
676 ****
677 ****
678 ****
679 ****
680 ****
681 ****
682 **
683 ****
684 ****
685 ****
686 ****
687 **
688 ****
690 ***
691 ****
692 ****
693 ***
694 ****
696 ****
697 ***
699 ***
700 ****
704 ****
706 ***
707 ***
709 ***
711 **
713 ****
716 **
718 ****
723 ****
725 ***
726 ***
727 **
729 **
732 ****
734 ****
735 ***
736 ****
737 ****
738 ****
739 ****
740 ****
741 ****
742 ****
743 ****
745 ****
746 ****
747 ****
748 ****
749 ****
750 ****
752 ***
753 **
757 **
761 ****
762 ***
763 ****
767 ****
768 ****
770 ****
772 ****
773 ****
774 ****
775 ****
778 ****
779 ****
780 ****
782 ****
785 **
786 ****
787 ***
788 ****
791 **
792 ****
793 ****
794 ****
795 ****
796 ***
797 ****
798 ***
799 ****
800 ****
801 ****
802 ****
804 ****
805 ****
806 ****
807 ****
808 ****
809 **
810 **
811 ***
813 ****
814 ****
815 ****
816 ***
821 ****
822 ****
823 **
824 ****
825 ****
826 ****
827 ****
828 ***
829 ****
830 ****
833 ****
834 ****
835 ***
836 ***
837 ****
838 ****
839 ***
841 ****
842 ****
843 ****
844 ***
846 ***
848 ***
849 ***
852 ****
854 ****
855 ****
856 ****
857 ****
858 ****
859 ***
860 **
861 ***
862 ***
863 ***
864 ****
865 **
866 ***
867 ****
868 ****
869 ****
870 ****
871 ****
872 ***
873 ***
874 ****
875 ****
876 ****
877 ***
878 ***
879 ****
880 ****
881 ****
882 ****
883 ****
884 ****
885 ***
886 ***
887 ****
888 ****
889 ****
890 ****
891 ***
892 ****
893 ****
894 ***
895 ****
896 ****
897 ****
898 ****
899 ****
900 ****
901 ****
902 ****
903 ***
904 ***
905 **
906 ****
907 ****
908 ***
909 ****
910 ****
911 ****
912 ****
913 ****
914 ****
915 ***
916 ***
917 ****
918 ***
919 ****
920 ****
921 ****
922 ***
923 ***
924 ****
925 **
926 ****
929 **
930 ****
931 ***
932 ****
935 ***
936 ****
937 ****
938 ****
939 ****
941 **
942 **
943 ****
944 ***
945 ****
946 ****
947 ****
949 ****
950 **
951 **
952 ****
953 ****
954 ****
956 **
957 ***
958 ****
959 ***
960 **
961 ****
962 ****
965 ****
966 ****
967 ****
968 ****
969 ****
970 ***
971 ****
972 *
976 **
981 **
982 ****
983 ****
984 ****
985 ****
986 ****

For compounds of Formula (I) or a form thereof disclosed herein, Table 10 provides the maximum fold (Fold) increase of Smn protein that was obtained from the 7-point concentration data generated for each test compound according to the procedure of Biological Example 7. A maximum fold increase of ≤1.2 is indicated by one star (*), a fold increase between >1.2 and ≤1.35 is indicated by two stars (**), a fold increase between >1.35 and ≤1.5 is indicated by three stars (***), a fold increase between >1.5 and ≤1.65 is indicated by four stars (****) and a fold increase >1.65 is indicated by five stars (*****).

TABLE 10

Cpd Fold


1   *
2   *
3   *
4   *
5   *
6   *
7   *
8   *
9   *
10  *
12  *
13  **
14  ***
15  *
16  **
17  **
18  *
19  *
20  *
22  *
23  *
24  *
25  *
26  *
27  *
28  *
29  **
30  *
31  *
34  **
35  *
36  *
37  **
39  ***
40  **
41  *
42  *
43  *
45  *
47  **
49  *
50  *
51  *****
52  *
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54  *
55  *
56  *
57  **
58  ****
59  **
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62  *
63  **
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67  *
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69  *
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72  ***
73  **
75  *
76  *
78  ***
79  ***
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81  ***
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83  ****
84  ***
85  *
86  *
87  ****
88  ***
89  ****
90  ***
91  **
92  ***
93  **
94  ***
95  ****
96  ***
97  ***
98  ***
99  *
100 **
101 **
103 **
104 ***
105 ****
106 *
107 ****
108 ****
109 ***
110 **
111 **
112 *
114 **
115 ***
116 **
117 ****
118 *****
119 **
120 ****
121 ***
122 *
123 ***
124 **
125 *
126 *
128 ***
129 **
130 *
131 ***
132 *
133 ***
134 ***
135 **
136 **
137 ***
138 **
139 ***
140 **
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142 ****
143 ***
144 *
145 **
146 *
147 *
148 *****
149 ***
150 ***
151 *
152 ***
153 ***
154 *
155 *
156 **
157 *
158 **
159 ***
160 *
161 ***
162 ***
163 *
164 *
165 **
166 **
167 **
168 *
169 ***
170 **
171 *
172 *
173 **
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175 *
176 *
177 *
178 *
179 ***
180 *
181 **
182 **
183 **
184 ***
185 *
186 ***
187 **
188 ***
189 **
190 **
191 **
192 **
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194 *
195 *
196 *
197 **
198 ****
199 **
200 *
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202 **
203 ****
204 ***
205 ***
206 **
207 **
208 *
209 *
210 *
211 *
212 ****
213 ***
214 **
215 *
216 ***
217 ***
218 **
219 *
220 **
221 *
222 *
223 *
224 *
225 ***
226 *
227 ***
228 **
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230 ***
231 **
232 *
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234 *
235 *
236 *
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238 *
239 *
240 *
241 *
242 ***
243 **
244 *
245 **
246 ***
247 **
248 **
249 **
250 ***
251 *
252 **
253 *
254 *
255 *
256 *
257 *
258 *
259 *
260 *
261 **
262 **
263 *
264 *
265 *
266 *
267 *
268 *
269 *
270 **
271 ****
272 **
273
274 **
275 *
276 *
277 *
278 *
279 *
280 ***
281 **
282 *
283 *
284 *
285 *
286 *
287 *
288 *
289 *
290 *
291 *
292 ***
293 *
294 **
295 ****
296 ***
297 *
298 *
299 *
300 *
301 *
302 ***
303 ***
304 ***
305 **
306 ***
307 ***
308 **
309 **
310 **
311 ***
312 **
313 *
314 *
315 *
316 **
317 *
318 *
319 **
320 *
321 **
322 **
323 **
324 ***
325 *
326 **
327 **
328 *
329 *
330 *
331 *
332 *
333 *
334 *
335 ***
336 *
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338 **
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340 *
341 *
342 **
343 *
344 **
345 ***
346 **
347 *
348 *
349 *
350 *
351 *
352 *
353 ****
354 ***
355 ****
356 **
357 ***
358 ***
359 *
360 *
361 **
362 **
363 **
364 *
365 *
366 **
367 ***
368 **
369 **
370 *
371 *
372 **
373 ****
374 *
375 **
376 *
377 *
378 **
379 ***
380 **
381 *
382 *
383 ****
384 *
385 *
386 *
387 *
388 **
389 ***
390 ***
391 **
392 **
393 ***
394 *
395 *
396 **
397 *
398 *
399 *
400 *
401 *
402 *
403 *
404 ****
405 **
406 *
407 *
408 *
409 *
410 *
411 *
412 *
413 *
414 *
415 *
416 **
417 ***
418 ****
419 **
420 ****
421 ***
422 **
423 *
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425 ***
426 ***
427 ***
428 *
429 *
430 *
431 *
432 **
433 *
434 **
435 *
436 *
437 **
438 ***
439 **
440 *
441 ***
442 **
443 ****
444 *
445 *
446 *
447 *
448 *
449 *
450 ***
451 ***
452 *
453 *
454 ***
455 ****
456 ****
457 **
458 ***
459 ***
460 ***
461 *
462 ***
463 *
464 ***
465 *
466 *
467 *
468 **
469 **
470 *
471 ****
472 *
473 **
474 *
475 *
476 *****
477 *****
478 *
479 *
480 *
481 *
482 ****
483 ***
484 *
485 *
486 *
487 *
488 *
489 *
490 *
491 **
492 *
493 *****
494 *
495 *
496 *
497 *
498 *
499 *
500 *
501 **
502 *
503 *
504 *
505 *
506 **
507 ****
508 **
509 *
510 *
511 *
512 *
513 *
514 *
515 *****
516 *****
517 *****
518 *****
519 *****
520 **
521 **
522 *
523 **
524 *
525 ***
526 ***
527 ****
528 **
529 *
530 ****
531 **
532 *
533 ****
534 ***
535 *
536 *****
537 *****
538 *
539 *
540 *
541 *
542 *
543 *
544 **
545 ***
546 *
547 *
548 *
549 **
550 ****
551 ***
552 ****
553 *
554 *****
555 ****
556 ***
557 ***
558 ****
559 ***
560 ****
561 ****
562 ****
563 *****
564 *****
565 *
566 ****
567 *****
568 *****
569 *****
570 *****
571 **
572 ****
573 ****
574 *
575 *
576 *
577 **
578 *
579 *
580 *
581 *
582 **
583 **
584 *****
585 ***
586 ***
587 ****
588 *****
589 *****
590 *****
591 *****
592 *****
593 *****
594 *****
595 **
596 **
597 ****
598 ***
599 ***
600 *****
601 *****
602 *
603 *
604 *
605 *****
606 *****
607 ***
608 *****
609 *****
610 **
611 ****
612 **
613 **
614 *****
615 ****
616 **
617 ***
618 ****
619 ****
620 ****
621 *****
622 ****
623 ***
624 ***
625 ***
626 ****
627 *****
628 ****
629 *
630 *
631 *
632 *****
633 ***
634 *****
635 ****
636 **
638 ****
639 *
640 ****
641 *
642 **
643 ****
644 *****
645 *****
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648 *****
649 *****
650 ****
651 ***
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653 ***
654 ****
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656 *****
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660 *****
661 *****
662 ***
663 ***
664 *****
665 *****
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669 *****
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672 ****
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680 ****
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686 *****
687 ***
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695 ***
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698 *
699 *****
700 *****
701 **
702 *
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705 ***
706 ****
707 ****
708 **
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710 **
711 ***
712 **
713 ***
714 *
715 **
716 ****
717 ***
718 ****
719 **
720 **
721 *
722 *
723 *****
724 *
725 ***
726 ****
727 ***
728 *
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730 ***
731 ***
732 ***
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744 **
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750 *****
751 **
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753 ***
754 ***
755 ***
756 ***
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758 *
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760 ***
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764 **
765 *
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767 *****
768 ****
769 **
770 ****
771 *
772 *****
773 ****
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775 ****
776 **
777 *
778 *****
779 *****
780 ****
781 **
782 ****
783 ***
784 **
785 ****
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787 ***
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789 ***
790 **
791 ***
792 ****
793 ****
794 ****
795 ****
796 ****
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799 ****
800 *****
801 ****
802 ****
803 ***
804 *****
805 *****
806 *****
807 *****
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812 ***
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814 *****
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817 **
818 *
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820 **
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830 *****
831 *
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840 *
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844 ****
845 *
846 *****
847 **
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850 **
851 ***
852 ****
853 *
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855 *****
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857 *****
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863 *****
864 *****
865 ****
866 ***
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869 *****
870 ****
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875 ****
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900 *****
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925 ***
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927 **
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930 *****
931 ****
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933 *
934 **
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936 *****
937 *****
938 *****
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940 *
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950 ***
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955 ***
956 *****
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959 ***
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961 ***
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963 ***
964 **
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966 ****
967 ****
968 *****
969 ****
970 *****
971 *****
972 ***
973 *
974 **
975 ***
976 ***
977 *
978 **
979 **
980 ***
981 ****
982 *****
983 *****
984 *****
985 *****
986 *****

Example 8

Gems Count (Smn-dependent Nuclear Speckle Count) Assay

The level of Smn protein directly correlates with the amount of nuclear foci, also known as gems, produced upon staining the cell with a fluorescently labeled anti-Smn antibody (Liu and Dreyfuss, EMBO J., 1996, 15:3555). Gems are multi-protein complexes whose formation is nucleated by the Smn protein and the gems count assay is used to evaluate the level of Smn protein in the cell. As described herein, the gems count assay is used to quantify the level of Smn protein in SMA patient fibroblast cells treated with a test compound.

Materials

Material                       Source

SMA Type 1 human cells         GM03813 (Coriell Institute)
Primary Antibody-mouse anti-   Sigma Catalog No.: S2944
SMN clone 2B1
Secondary Antibody-anti-mouse  Life Technologies, Inc. (formerly
Alexa Fluor 555                Invitrogen) Catalog No.: A21422
Bovine Serum Albumin (BSA)     Sigma Catalog No.: A3294
4% Paraformaldehyde            Electron Microscopy Sciences
                               Catalog No.: 15710
Bortezomib                     LC Labs, Catalog No.: B-1408
0.05% Triton X-100             Sigma Catalog No.: 93443-100 mL
Mounting medium-ProLong Gold   Life Technologies, Inc. (formerly
Antifade Reagent with DAPI     Invitrogen) Catalog Nos.: P7481 and
                               P36935
22 × 22 #1 sterile Cover slips Fisher Catalog No.: 12-548-B
DMEM                           Life Technologies, Inc. (formerly
                               Invitrogen) Catalog No.: 11960-044
PBS                            Life Technologies, Inc. (formerly
                               Invitrogen) Catalog No.: 10010-031
Clear-coat nail polish         Revlon brand Catalog No.: 1271-76
Zeiss Axovert 135 Fluorescence Zeiss
microscope

Protocol: Cells are thawed and incubated in DMEM-10% FBS for 72 hours, then trypsinized, counted and resuspended to 100,000 cells/mL in DMEM-10% FBS. 2 mL of the cell suspension is plated in a 6-well cell culture plate with a sterile cover slip and incubated for 3 to 5 hours. Test compounds are serially diluted 3.16-fold in 100% DMSO to generate a 7-point dilution curve. 10 μL of test compound solution is added to each cell-containing well and incubated for 48 hours in a cell culture incubator (37° C., 5% CO₂, 100% relative humidity). Duplicates are set up for each test compound concentration. Cells containing DMSO at a final concentration of 0.5% are used as controls.

Cell culture medium is aspirated from the wells containing cover slips and gently washed three times with cold PBS. The cells are fixed by incubation for 20 minutes at room temperature while in paraformaldehyde. The cells are then washed two times with cold PBS followed by incubation for 5 minutes at room temperature with 0.05% Triton X-100 in PBS to permeabilize the cells. After the fixed cells are washed three times with cold PBS, they are blocked with 10% FBS for 1 hour. 60 μL of primary antibody diluted 1:1000 in blocking buffer is added and the mixture is incubated for one hour at room temperature. The cells are washed three times with PBS and 60 μL of secondary antibody diluted 1:5000 in blocking buffer is added, then the mixture is incubated for one hour at room temperature. The cover slips are mounted onto the slides with the aid of mounting medium and allowed to dry overnight. Nail polish is applied to the sides of the cover slip and the slides are stored, protected from light. A Zeiss Axovert 135 with a 63× Plan-Apochromat, NA=1.4 objective is used for immunofluorescence detection and counting. The number of gems is counted per ≥150 nuclei and % activation is calculated using DMSO and 10 nM bortezomib as controls. For each test compound, the cells are examined at all wavelengths to identify test compounds with inherent fluorescence.

Results. As seen in FIG. 9, SMA Type 1 patient cells treated with Compound 35 (FIG. 9a) and Compound 626 (FIG. 9b) contain progressively more gems relative to cells treated with DMSO.

Example 9

Smn Protein Assay in Human Motor Neurons

Smn immunofluorescent confocal microscopy is used to quantify the level of Smn protein in human motor neurons treated with test compounds.

Protocol. Human motor neurons derived from SMA iPS cells (Ebert et al., Nature, 2009, 457:2770; and, Rubin et al., BMC Biology, 2011, 9:42) are treated with test compound at various concentrations for 72 hours. The level of Smn protein in the cell nucleus is quantified using Smn immunostaining and confocal fluorescence microscopy essentially as described in Makhortova et al., Nature Chemical Biology, 2011, 7:544. The level of Smn protein in compound-treated samples is normalized to that in vehicle-treated samples and plotted as a function of the compound concentration.

Results. As seen in FIG. 10, human motor neurons treated for 72 hours with increasing concentrations of Compound 35 (FIG. 10a) and Compound 626 (FIG. 10b) contain progressively more Smn protein in the nucleus.

Example 10

Smn Protein Assay in Animal Tissues

This Smn protein assay compares tissues from test compound treated mice with those from DMSO vehicle treated mice to determine the increase in levels of Smn protein produced from the human SMN2 gene.

Materials

Material                        Source

Tissues from C/C-allele SMA     The Jackson Laboratory, strain #008714
mice                            (B6.129-smn1tm5(Smn1/SMN2)Mrph/J)
Tissues from Δ7 SMA mice        The Jackson Laboratory, strain #005025
                                (FVB.Cg-Tg(SMN2*delta7)4299 Ahmb
                                Tg(SMN2)89Ahmb Smn1tm1Msd/J)
Protease inhibitor cocktail     Roche Applied Science Catalog No.:
                                11836145001
Anti-SMN d2                     Blue cap Cisbio Catalog No.:
                                63IDC002-SMN
Anti-SMN kryptate               Red cap Cisbio Catalog No.: 63IDC002-
                                SMN
SMN reconstitution buffer       Cisbio Catalog No.: 63IDC002-SMN-
                                Buffer
RIPA Lysis Buffer               20 mM Tris-HCl pH 7.5, 150 mM NaCl,
                                1 mM EDTA, 1% NP-40, 1% Sodium
                                deoxycholate
Diluent Buffer                  20 mM Tris-HCl pH 7.5, 150 mM NaCl
BCA protein assay kit           Pierce Catalog No.: 23225
White 384 well plate            Nunc Catalog No.: 351190
Polypropylene V-bottom plate    Falcon Catalog No.: 165195
Clear 96 well polystyrene plate Nunc Catalog No.: 442404
5 mm Stainless Steel Beads      Qiagen Catalog No.: 69989
Safe-Lock Tubes 2.0 mL          Eppendorf Catalog No.: 022363352
Twin.tec 96-Well Semiskirted    Eppendorf Catalog No.: 951020389
PCR Plate
TissueLyzer II                  Qiagen Catalog No.: 85300
Envision Plate Reader           Perkin Elmer Model No.: 2103

Protocol. The tissue samples in Safe-Lock tubes are weighed and the volume of RIPA buffer containing the protease inhibitor cocktail is added based on the weight to volume ratios for each type of tissue: Brain (50 mg/mL), Muscle (50 mg/mL) and Spinal Cord (25 mg/mL).

Tissues are homogenized using the TissueLyzer by bead milling. 5 mm stainless steel beads are added to the sample and shaken vigorously for 5 minutes at 30 Hz in the TissueLyzer. The samples are then centrifuged for 20 minutes at 14,000×g in a microcentrifuge and the homogenates transferred to the PCR plate. The homogenates are diluted in RIPA buffer to approximately 1 mg/mL for HTRF and approximately 0.5 mg/mL for total protein measurement using the BCA protein assay. For the SMN HTRF assay, 35 μL of the tissue homogenate is transferred to a 384-well plate containing 5 μL of the antibody solution (1:100 dilution of each of the anti-SMNd2 and anti-SMN Kryptate in reconstitution buffer). To provide a control signal, three (3) wells in the plate contain only RIPA Lysis Buffer and, thus, serve as Blank control wells. The plate is centrifuged for 1 minute to bring the solution to the bottom of the wells and then incubated overnight at room temperature. Fluorescence for each well of the plate at 665 nm and 620 nm is measured on an EnVision multilabel plate reader (Perkin-Elmer). The total protein in the tissue homogenate is measured using the BCA assay according to the manufacturer's protocol.

The normalized fluorescence signal is calculated for each sample, Blank and vehicle control well by dividing the signal at 665 nm by the signal at 620 nm. Normalizing the signal accounts for possible fluorescence quenching due to the matrix effect of the tissue homogenate. The ΔF value (a measurement of Smn protein abundance) for each tissue sample well is calculated by subtracting the normalized average fluorescence for the Blank control wells from the normalized fluorescence for each tissue sample well and then dividing this difference by the normalized average fluorescence for the Blank control wells. The ΔF value for each tissue sample well is divided by the total protein quantity (determined using the BCA assay) for that tissue sample. The change in Smn protein abundance for each tissue sample relative to the vehicle control is calculated as the percent difference in the ΔF value of the tissue sample in the presence of the test compound and the averaged ΔF value of the vehicle control signal divided by the averaged ΔF value of the vehicle control signal.

Example 11

Smn Protein Assay in Tissues of Adult C/C-Allele SMA Mice

The tissues for use in the assay for Smn protein in adult C/C-allele SMA mice are prepared as described in Example 10. The assay assesses whether treatment of C/C-allele SMA mice with a test compound for 10 days increases levels of Smn protein produced from the SMN2 gene.

Materials

Material          Source

Tissues from C/   The Jackson Laboratory, strain #008714 (B6.129-
C-allele SMA mice Smn1tm5(Smn1/SMN2)Mrph/J)

Protocol. C/C-allele SMA mice are dosed twice a day orally (in 0.5% hydroxypropylmethyl cellulose (HPMC) with 0.1% Tween-80) with a test compound at 10 mg/kg for 10 days. Age-matched heterozygous mice are dosed with vehicle for use as a control. Tissues are collected for analysis of protein levels according to Example 10.

Results. As seen in FIG. 11, total protein normalized Smn level was increased in target tissues (Brain: FIG. 11a; Spinal cord: FIG. 11b; and Muscle: FIG. 11c) of adult C/C-allele SMA mice treated with Compound 35 and Compound 626 relative to the vehicle group. The dashed line in each Figure represents the average increase in normalized Smn levels of heterozygous mice relative to those in the knock out vehicle group. Test compound treatment in the C/C-allele SMA mice increased the Smn protein levels in the target tissues above those observed in the corresponding tissues of the heterozygous mice.

Example 12

Smn Protein in Tissues of Neonatal Δ7 SMA Mice

The assay for Smn protein in neonatal SMA mice tissues is used to determine whether treatment with a test compound increases Smn protein levels produced from the SMN2 gene.

Materials

Material        Source

Tissues from Δ7 The Jackson Laboratory, strain #005025 (FVB.Cg-
SMA mice        Tg(SMN2*delta7)4299Ahmb Tg(SMN2)89Ahmb
                Smn1tm1Msd/J)

Protocol. SMA Δ7 homozygous knockout mice are dosed once a day (QD) intraperitoneally (IP) with a test compound or vehicle (100% DMSO) from postnatal day (PND) 3 to day 9. Tissues are collected for analysis of protein levels according to Example 10.

Results. As seen in FIG. 12, total protein normalized Smn level was dose dependently increased in target tissues (Brain: FIG. 12a and FIG. 12b; Spinal cord: FIG. 12c and FIG. 12d; and Muscle: FIG. 12e and FIG. 12f) of neonatal SMA Δ7 homozygous knockout mice treated with Compound 35 and Compound 626, respectively. The dashed line and grey zone in each Figure represent the average and standard deviation of the total protein normalized Smn levels in heterozygous mice.

Example 13

Body Weight of Neonatal Δ7 SMA Mice

The change in body weight of neonatal SMA mice is used to determine whether treatment with a test compound improves body weight.

Materials

Material            Source

Tissues from ΔExon7 The Jackson Laboratory, strain #005025
SMA mice            (FVB.Cg-Tg(SMN2*delta7)4299Ahmb
                    Tg(SMN2)89Ahmb Smn1tm1Msd/J)

Protocol. SMA Δ7 homozygous knockout mice are dosed intraperitoneally (IP) with test compound or vehicle (100% DMSO) once per day (QD) from postnatal day (PND) 3 until the dose regimen is switched to an oral dose twice per day (BID) in 0.5% hydroxypropylmethyl cellulose (HPMC) with 0.1% Tween-80 at a dose 3.16-fold higher than the dose used for IP. Body weights of SMA Δ7 mice treated with test compound or vehicle and age matched heterozygous mice are recorded every day.

Results. As seen in FIG. 13, body weight of neonatal SMA Δ7 homozygous knockout mice treated with Compound 35, dosed IP QD from PND 3 to day 24, then orally BID from day 25 until study end (FIG. 13a) and Compound 626, dosed IP QD from PND 3 to day 30, then orally BID from day 31 until study end (FIG. 12b) improved compared to vehicle treated mice.

Example 14

Righting Reflex in Neonatal Δ7 SMA Mice

The functional change in righting reflex of neonatal SMA mice is used to determine whether treatment with a test compound improves righting reflex.

Materials

Material            Source

Tissues from ΔExon7 The Jackson Laboratory, strain #005025
SMA mice            (FVB.Cg-Tg(SMN2*delta7)4299Alumb
                    Tg(SMN2)89Ahmb Smn1tm1Msd/J)

Protocol. SMA Δ7 homozygous knockout mice are dosed intraperitoneally (IP) with test compound or vehicle (100% DMSO) once per day (QD) from postnatal day (PND) 3 until the dose regimen is switched to an oral dose twice per day (BID) in 0.5% hydroxypropylmethyl cellulose (HPMC) with 0.1% Tween-80 at a dose 3.16-fold higher than the dose used for IP. The righting reflex time is measured as the time taken by a mouse to flip over onto its feet after being laid on its back. Righting reflex is measured five times for each mouse (allowing a maximal time of 30 sec for each try) with 5 minutes between each measurement. The righting reflex time for SMA Δ7 homozygous knockout mice treated with test compound or vehicle and age-matched heterozygous mice is measured on PND 10, 14 and 18 and plotted.

Results. As seen in FIG. 14, the righting reflex of neonatal SMA Δ7 homozygous knockout mice treated with Compound 35, dosed IP QD from PND 3 to day 24, then orally BID from day 25 until study end, improved compared to vehicle treated mice. The righting time of the compound treated neonatal SMA Δ7 homozygous knockout mice was similar to that of the age matched heterozygous mice on postnatal day 18.

Example 15

Survival of Neonatal Δ7 SMA Mice

The change in the number of surviving mice over time is used to determine whether treatment with a test compound improves survival.

Materials

Material        Source

Tissues from Δ7 The Jackson Laboratory, strain #005025
SMA mice        (FVB.Cg-Tg(SMN2*delta7)4299Alumb
                Tg(SMN2)89Ahmb Smn1tm1Msd/J)

Protocol. SMA Δ7 homozygous knockout mice are dosed intraperitoneally (IP) with test compound or vehicle (100% DMSO) once per day (QD) from postnatal day (PND) 3 until the dose regimen is switched to an oral dose twice per day (BID) in 0.5% hydroxypropylmethyl cellulose (HPMC) with 0.1% Tween-80 at a dose 3.16-fold higher than the dose used for IP. The number of surviving mice in each group is recorded every day and plotted as a percent of total number of mice. Tissues of SMA Δ7 and age-matched heterozygous mice are collected for the measurement of Smn protein levels and processed as detailed in Example 10. The total protein normalized Smn protein levels measured in the tissues are plotted as a percent of those in the age-matched heterozygous mice tissues, with the heterozygous levels represented as 100 percent. The level of Smn protein in the test compound treated mice tissue relative to that in heterozygous mice tissue is indicated as a percent value above each bar in the graph.

Results. As seen in FIG. 15, survival of neonatal SMA Δ7 homozygous knockout mice treated with Compound 35 (FIG. 15a) dosed IP QD from PND 3 to day 24, then orally BID from day 25 until study end, and Compound 626 (FIG. 15b) dosed IP QD from PND 3 to day 30, then orally BID from day 31 until study end, improved compared to vehicle treated mice.

Results. As seen in FIG. 16, Smn protein levels in target tissues (brain, FIG. 16a, and muscle, FIG. 16b) of SMA Δ7 homozygous knockout mice after treatment with Compound 35 and Compound 626 from postnatal day 3 until necropsy was measured and plotted relative to vehicle treated and age-matched heterozygous mice. As seen in FIGS. 16a and FIG. 16b, none of the vehicle treated SMA Δ7 homozygous knockout mice survived past day 22.

Without regard to whether a document cited herein was specifically and individually indicated as being incorporated by reference, all documents referred to herein are incorporated by reference into the present application for any and all purposes to the same extent as if each individual reference was fully set forth herein.

Although certain embodiments have been described in detail above, those having ordinary skill in the art will clearly understand that many modifications are possible in the embodiments without departing from the teachings thereof. All such modifications are intended to be encompassed within the claims as described herein.

Claims

1. A compound selected from formula (Ia) :

2. The compound of claim 1, wherein the salt form is a chloride, hydrochloride, dihydrochloride, hydrobromide, acetate or trifluoroacetate salt.

3. A compound, wherein the compound is selected from:

7-(piperazin-1-yl)-3-[4-(trifluoromethyl)-1,3-benzoxazol-2-yl]-2H-chromen-2-one;

7-(piperazin-1-yl)-3-[7-(trifluoromethyl)-1,3-benzoxazol-2-yl]-2H-chromen-2-one;

2-oxo-N-phenyl-7-(piperazin-1-yl)-2H-chromene-3-carboxamide;

3-(1,3-benzothiazol-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(4-chloro-1,3-benzothiazol-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(7-chloro-1,3-benzothiazol-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(4-chloro-1,3-benzothiazol-2-yl)-7-(piperazin-1-ylmethyl)-2H-chromen-2-one;

3-(1,3-benzothiazol-2-yl)-7-[(propan-2-ylamino)methyl]-2H-chromen-2-one;

7-[(propan-2-ylamino)methyl]-3-[4-(trifluoromethyl)-1,3-benzothiazol-2-yl]-2H-chromen-2-one;

3-(4-chloro-1,3-benzothiazol-2-yl)-7-[(propan-2-ylamino)methyl]-2H-chromen-2-one;

7-(4-methylpiperazin-1-yl)-3-[3-(trifluoromethyl)phenyl]-2H-chromen-2-one;

7-(piperazin-1-yl)-3-(pyridin-3-yl)-2H-chromen-2-one;

3-(1,3-benzothiazol-2-yl)-7-[(dimethylamino)methyl]-2H-chromen-2-one;

3-(4-chloro-1,3-benzothiazol-2-yl)-7-[(dimethylamino)methyl]-2H-chromen-2-one;

3-(1,3-benzothiazol-2-yl)-7-[4-(propan-2-yl)piperazin-1-yl]-2H-chromen-2-one;

3-(1,3-benzothiazol-2-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

3-(4-chloro-1,3-benzothiazol-2-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

3-(4-chloro-1,3-benzothiazol-2-yl)-7-(piperidin-4-yl)-2H-chromen-2-one;

3-(5-fluoro-1,3-benzoxazol-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(1,3-benzoxazol-2-yl)-7-(piperidin-4-yloxy)-2H-chromen-2-one;

3-(4-methyl-1,3-benzoxazol-2-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

3-(4-methyl-1,3-benzoxazol-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(1,3-benzoxazol-2-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2H-chromen-2-one;

3-(1,3-benzothiazol-2-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2H-chromen-2-one;

3-(4-chloro-1,3-benzothiazol-2-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2H-chromen-2-one;

3-(3-fluorophenyl)-7-(piperazin-1-yl)-2H-chromen-2-one;

7-(piperazin-1-yl)-3-(pyridin-4-yl)-2H-chromen-2-one;

3-(4-chloro-1,3-benzothiazol-2-yl)-7-[(4-methylpiperazin-1-yl)carbonyl]-2H-chromen-2-one;

7-(piperazin-1-yl)-3-(1H-pyrazol-5-yl)-2H-chromen-2-one;

7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-oxo-N-phenyl-2H-chromene-3-carboxamide;

7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-(4-methyl-1,3-benzoxazol-2-yl)-2H-chromen-2-one;

7-(piperazin-1-yl)-3-(pyridin-2-ylamino)-2H-chromen-2-one;

7-(piperazin-1-yl)-3-(pyrimidin-2-ylamino)-2H-chromen-2-one;

3-(imidazo[1,2-a]pyridin-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(4-chloro-1,3-benzothiazol-2-yl)-7-[2-(propan-2-ylamino)ethyl]-2H-chromen-2-one;

3-(4-chloro-1,3-benzothiazol-2-yl)-7-[3-(propan-2-ylamino)propyl]-2H-chromen-2-one;

3-(4-methyl-1,3-thiazol-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(1-methyl-1H-pyrazol-3-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-(4-fluoro-1,3-benzoxazol-2-yl)-2H-chromen-2-one;

3-(4-fluoro-1,3-benzoxazol-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(1,3-benzothiazol-2-yl)-2-oxo-2H-chromen-7-yl piperazine-1-carboxylate;

3-(4-chloro-1,3-benzothiazol-2-yl)-2-oxo-2H-chromen-7-yl piperazine-1-carboxylate;

benzyl 4-[3-(1-methyl-1H-benzimidazol-2-yl)-2-oxo-2H-chromen-7-yl]piperazine-1-carboxylate;

3-(8-methylimidazo[1,2-a]pyridin-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

7-(4-methylpiperazin-1-yl)-3-(4-phenyl-1,3-thiazol-2-yl)-2H-chromen-2-one;

3-(1,3-benzothiazol-2-yl)-7-(piperidin-4-yloxy)-2H-chromen-2-one;

3-(1,3-benzoxazol-2-yl)-7-(4-methyl-1,4-diazepan-1-yl)-2H-chromen-2-one;

3-(1,3-benzoxazol-2-yl)-7-[3-(dimethylamino)pyrrolidin-1-yl]-2H-chromen-2-one;

3-(1,3-benzoxazol-2-yl)-7-{[2-(dimethylamino)ethyl](methyl)amino}-2H-chromen-2-one;

3-(5-phenyl-1,2,4-oxadiazol-3-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(6-methylimidazo[1,2-a]pyridin-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

7-(piperazin-1-yl)-3-(pyridin-3-ylamino)-2H-chromen-2-one;

7-(4-methylpiperazin-1-yl)-3-[4-(trifluoromethyl)-1,3-thiazol-2-yl]-2H-chromen-2-one

3-(1,3-benzothiazol-2-yl)-7-[(3S)-pyrrolidin-3-yloxy]-2H-chromen-2-one

3-(1,3-benzothiazol-2-yl)-7-[(3R)-pyrrolidin-3-yloxy]-2H-chromen-2-one

3-(1,3-benzothiazol-2-yl)-7-[(2S)-pyrrolidin-2-ylmethoxy]-2H-chromen-2-one

3-(1,3-benzothiazol-2-yl)-7-[(diethylamino)methyl]-2H-chromen-2-one

3-(4-chloro-1,3-benzothiazol-2-yl)-7-[(diethylamino)methyl]-2H-chromen-2-one

3-(1,3-benzothiazol-2-yl)-7-(piperidin-1-ylmethyl)-2H-chromen-2-one

3-(4-chloro-1,3-benzothiazol-2-yl)-7-(piperidin-1-ylmethyl)-2H-chromen-2-one

3-[(3-methylpyridin-2-yl)amino]-7-(piperazin-1-yl)-2H-chromen-2-one

3-[(4-methylpyridin-2-yl)amino]-7-(piperazin-1-yl)-2H-chromen-2-one

3-[(5-methylpyridin-2-yl)amino]-7-(piperazin-1-yl)-2H-chromen-2-one

3-[(6-methylpyridin-2-yl)amino]-7-(piperazin-1-yl)-2H-chromen-2-one

3-[(5-chloropyridin-2-yl)amino]-7-(piperazin-1-yl)-2H-chromen-2-one

7-(piperazin-1-yl)-3-(pyridin-3-ylamino)-2H-chromen-2-one

3-(4-iodo-1,3-benzoxazol-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(4-chloro-1,3-benzoxazol-2-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

3-(4-chloro-1,3-benzoxazol-2-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2H-chromen-2-one;

3-(4-chloro-1,3-benzoxazol-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(6-chloroimidazo[1,2-a]pyridin-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(imidazo[1,2-a]pyridin-2-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

7-(4-methylpiperazin-1-yl)-3-(1-methyl-1H-pyrazol-3-yl)-2H-chromen-2-one;

7-(4-methylpiperazin-1-yl)-3-(1-phenyl-1H-pyrazol-3-yl)-2H-chromen-2-one;

3-(phenylamino)-7-(piperazin-1-yl)-2H-chromen-2-one;

7-(piperazin-1-yl)-3-[4-(trifluoromethyl)pyridin-2-yl]-2H-chromen-2-one;

3-(3-methoxyphenyl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(1,3-benzothiazol-2-yl)-7-[(methylamino)methyl]-2H-chromen-2-one;

3-(1,3-benzothiazol-2-yl)-7-{[(2-hydroxyethyl)(methyl)amino]methyl}-2H-chromen-2-one;

3-(4-methyl-1H-pyrazol-3-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(6-methylimidazo[1,2-a]pyridin-2-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

3-(6-methylimidazo[1,2-a]pyridin-2-yl)-7-[4-(propan-2-yl)piperazin-1-yl]-2H-chromen-2-one;

3-(8-chloroimidazo[1,2-a]pyridin-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(8-methylimidazo[1,2-a]pyridin-2-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

3-(1,3-benzoxazol-2-yl)-7-(2,5-diazabicyclo[2.2.1]hept-2-yl)-2H-chromen-2-one;

3-(1,3-benzoxazol-2-yl)-7-(2,5-dimethylpiperazin-1-yl)-2H-chromen-2-one;

3-(imidazo[1,2-a]pyrimidin-2-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

3-(imidazo[2,1-b][1,3]thiazol-6-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(imidazo[1,2-a]pyrimidin-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

7-(piperazin-1-yl)-3-[6-(trifluoromethyl)pyridin-2-yl]-2H-chromen-2-one;

3-(1H-indazol-5-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(6-chloroimidazo[1,2-a]pyridin-2-yl)-7-(4-methyl-1,4-diazepan-1-yl)-2H-chromen-2-one;

3-(6-chloroimidazo[1,2-a]pyridin-2-yl)-7-[(2R,5S)-2,5-dimethylpiperazin-1-yl]-2H-chromen-2-one;

3-(6-chloroimidazo[1,2-a]pyridin-2-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

7-(4-ethylpiperazin-1-yl)-3-(6-methylimidazo[1,2-a]pyridin-2-yl)-2H-chromen-2-one;

3-(2-methylimidazo[2,1-b][1,3]thiazol-6-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(2-methylimidazo[2,1-b][1,3]thiazol-6-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

3-(3-methylimidazo[2,1-b][1,3]thiazol-6-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(1,3-benzothiazol-2-yl)-7-{[(1,3-dihydroxypropan-2-yl)amino]methyl}-2H-chromen-2-one;

7-(4-ethylpiperazin-1-yl)-3-(8-methylimidazo[1,2-a]pyridin-2-yl)-2H-chromen-2-one;

3-(8-methylimidazo[1,2-a]pyridin-2-yl)-7-(4-propylpiperazin-1-yl)-2H-chromen-2-one;

7-[4-(2-hydroxyethyl)piperazin-1-yl]-3-(8-methylimidazo[1,2-a]pyridin-2-yl)-2H-chromen-2-one;

3-(6-fluoroimidazo[1,2-a]pyridin-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(6-chloroimidazo[1,2-a]pyridin-2-yl)-7-[4-(2-hydroxyethyl)piperazin-1-yl]-2H-chromen-2-one;

3-(6-chloroimidazo[1,2-a]pyridin-2-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2H-chromen-2-one;

tert-butyl {(3S)-1-[3-(6-chloroimidazo[1,2-a]pyridin-2-yl)-2-oxo-2H-chromen-7-yl]pyrrolidin-3-yl}carbamate;

7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-(imidazo[1,2-a]pyrimidin-2-yl)-2H-chromen-2-one;

7-(4-ethylpiperazin-1-yl)-3-(imidazo[1,2-a]pyrimidin-2-yl)-2H-chromen-2-one;

3-(imidazo[1,2-a]pyrimidin-2-yl)-7-(4-propylpiperazin-1-yl)-2H-chromen-2-one;

3-([1,3]oxazolo[4,5-b]pyridin-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

7-(4-methylpiperazin-1-yl)-3-([1,3]oxazolo[4,5-b]pyridin-2-yl)-2H-chromen-2-one;

3-(6-chloroimidazo[1,2-a]pyridin-2-yl)-4-methyl-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(5-chloropyridin-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

7-(piperazin-1-yl)-3-[7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]-2H-chromen-2-one;

7-(4-methylpiperazin-1-yl)-3-[7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]-2H-chromen-2-one;

7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-[7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]-2H-chromen-2-one;

3-(imidazo[2,1-b][1,3]thiazol-6-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

3-(imidazo[1,2-a]pyrimidin-2-yl)-7-(4-methyl-1,4-diazepan-1-yl)-2H-chromen-2-one;

3-(8-chloroimidazo[1,2-a]pyridin-2-yl)-7-(4-propylpiperazin-1-yl)-2H-chromen-2-one;

3-(8-chloroimidazo[1,2-a]pyridin-2-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2H-chromen-2-one;

3-(8-chloroimidazo[1,2-a]pyridin-2-yl)-7-[4-(2-hydroxyethyl)piperazin-1-yl]-2H-chromen-2-one;

3-(8-chloroimidazo[1,2-a]pyridin-2-yl)-7-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-2H-chromen-2-one;

3-(7-chloroimidazo[1,2-a]pyridin-2-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2H-chromen-2-one;

7-(piperazin-1-yl)-3-[2-(trifluoromethyl)pyridin-3-yl]-2H-chromen-2-one;

7-(4-methylpiperazin-1-yl)-3-[2-(trifluoromethyl)pyridin-3-yl]-2H-chromen-2-one;

3-(3-fluoropyridin-4-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(1,3-benzothiazol-2-yl)-7-{[(3R)-1-ethylpyrrolidin-3-yl]oxy}-2H-chromen-2-one;

3-(imidazo[1,2-b]pyridazin-2-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

7-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-3-(imidazo[1,2-a]pyrimidin-2-yl)-2H-chromen-2-one;

7-{[2-(dimethylamino)ethyl](methyl)amino}-3-(imidazo[1,2-a]pyrimidin-2-yl)-2H-chromen-2-one;

3-(7-methylimidazo[1,2-a]pyridin-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(5-methylimidazo[1,2-a]pyridin-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-(7-methylimidazo[1,2-a]pyridin-2-yl)-2H-chromen-2-one;

3-(7-methylimidazo[1,2-a]pyridin-2-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

3-(5-methylimidazo[1,2-a]pyridin-2-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-(8-methylimidazo[1,2-a]pyridin-2-yl)-2H-chromen-2-one;

3-(8-chloroimidazo[1,2-a]pyridin-2-yl)-7-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]-2H-chromen-2-one;

3-(6-fluoroimidazo[1,2-a]pyridin-2-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-(imidazo[1,2-a]pyridin-2-yl)-2H-chromen-2-one;

3-(imidazo[1,2-a]pyridin-2-yl)-7-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]-2H-chromen-2-one;

3-(3-methylimidazo[2,1-b][1,3]thiazol-6-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

7-(4-methyl-1,4-diazepan-1-yl)-3-(6-methylimidazo[1,2-a]pyridin-2-yl)-2H-chromen-2-one;

3-(1,3-benzothiazol-2-yl)-7-[1-(dimethylamino)ethyl]-2H-chromen-2-one;

3-(1,3-benzothiazol-2-yl)-7-[1-(propan-2-ylamino)ethyl]-2H-chromen-2-one;

3-(1,3-benzothiazol-2-yl)-7-(4-methyl-1,4-diazepan-1-yl)-2H-chromen-2-one;

3-(1,3-benzothiazol-2-yl)-7-{[2-(dimethylamino)ethyl](methyl)amino}-2H-chromen-2-one;

3-(1,3-benzothiazol-2-yl)-4-methyl-7-(piperazin-1-yl)-2H-chromen-2-one;

7-{[(2-hydroxyethyl)(methyl)amino]methyl}-3-(6-methylimidazo[1,2-a]pyridin-2-yl)-2H-chromen-2-one;

3-(8-fluoroimidazo[1,2-a]pyridin-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(8-fluoroimidazo[1,2-a]pyridin-2-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

7-(4-ethylpiperazin-1-yl)-3-(2-methylimidazo[2,1-b][1,3]thiazol-6-yl)-2H-chromen-2-one;

7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-(2-methylimidazo[2,1-b][1,3]thiazol-6-yl)-2H-chromen-2-one;

7-(4-methyl-1,4-diazepan-1-yl)-3-(2-methylimidazo[2,1-b][1,3]thiazol-6-yl)-2H-chromen-2-one;

7-[3-(dimethylamino)pyrrolidin-1-yl]-3-(2-methylimidazo[2,1-b][1,3]thiazol-6-yl)-2H-chromen-2-one;

8-fluoro-7-(piperazin-1-yl)-3-(pyridin-2-yl)-2H-chromen-2-one;

8-fluoro-3-(6-methylimidazo[1,2-a]pyridin-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(1,3-benzothiazol-2-yl)-6-fluoro-7-(piperazin-1-yl)-2H-chromen-2-one;

6-fluoro-3-(6-methylimidazo[1,2-a]pyridin-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(1,3-benzoxazol-2-yl)-5-fluoro-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(1,3-benzothiazol-2-yl)-5-fluoro-7-(piperazin-1-yl)-2H-chromen-2-one;

5-fluoro-7-(piperazin-1-yl)-3-(pyridin-2-yl)-2H-chromen-2-one;

5-fluoro-3-(6-methylimidazo[1,2-a]pyridin-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(6-methylpyridin-3-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

7-(4-methylpiperazin-1-yl)-3-(6-methylpyridin-3-yl)-2H-chromen-2-one;

3-(2-methoxypyridin-4-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

7-[(2R,5S)-2,5-dimethylpiperazin-1-yl]-3-(8-methylimidazo[1,2-a]pyridin-2-yl)-2H-chromen-2-one;

7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-(imidazo[2,1-b][1,3]thiazol-6-yl)-2H-chromen-2-one;

3-[7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]-7-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]-2H-chromen-2-one;

3-(imidazo[1,2-a]pyrimidin-2-yl)-7-[(3R)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(imidazo[1,2-a]pyrimidin-2-yl)-7-[(3S)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

7-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-3-(6-methylimidazo[1,2-a]pyridin-2-yl)-2H-chromen-2-one;

7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-(6-methylimidazo[1,2-a]pyridin-2-yl)-2H-chromen-2-one;

7-{[2-(dimethylamino)ethyl](methyl)amino}-3-(6-methylimidazo[1,2-a]pyridin-2-yl)-2H-chromen-2-one;

7-(1,4-diazepan-1-yl)-3-(6-methylimidazo[1,2-a]pyridin-2-yl)-2H-chromen-2-one;

tert-butyl {(3S)-1-[3-(6-methylimidazo[1,2-a]pyridin-2-yl)-2-oxo-2H-chromen-7-yl]pyrrolidin-3-yl}carbamate;

7-(4-ethylpiperazin-1-yl)-3-(3-methylimidazo[2,1-b][1,3]thiazol-6-yl)-2H-chromen-2-one;

7-(4-methyl-1,4-diazepan-1-yl)-3-(3-methylimidazo[2,1-b][1,3]thiazol-6-yl)-2H-chromen-2-one;

3-(2-chloropyridin-4-yl)-7-(piperazin-1-yl)-2H-chromen-2-one; 3-(imidazo[1,2-a]pyrimidin-2-yl)-7-[methyl(1-methylpyrrolidin-3-yl)amino]-2H-chromen-2-one;

7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-(3-methylimidazo[2,1-b][1,3]thiazol-6-yl)-2H-chromen-2-one;

3-(8-chloroimidazo[1,2-a]pyridin-2-yl)-7-[(3R)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(8-chloroimidazo[1,2-a]pyridin-2-yl)-7-[(3S)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(3-methylimidazo[2,1-b][1,3]thiazol-6-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

7-(1,4-diazepan-1-yl)-3-(imidazo[1,2-a]pyrimidin-2-yl)-2H-chromen-2-one;

7-(piperazin-1-yl)-3-(pyrazolo[1,5-a]pyridin-2-yl)-2H-chromen-2-one;

7-(4-methylpiperazin-1-yl)-3-(pyrazolo[1,5-a]pyridin-2-yl)-2H-chromen-2-one;

7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-(pyrazolo[1,5-a]pyridin-2-yl)-2H-chromen-2-one;

7-[4-(2-hydroxyethyl)piperazin-1-yl]-3-(pyrazolo[1,5-a]pyridin-2-yl)-2H-chromen-2-one;

7-(2,5-diazabicyclo[2.2.2]oct-2-yl)-3-(pyrazolo[1,5-a]pyridin-2-yl)-2H-chromen-2-one;

7-(1,4-diazepan-1-yl)-3-(pyrazolo[1,5-a]pyridin-2-yl)-2H-chromen-2-one;

7-(4-methyl-1,4-diazepan-1-yl)-3-(pyrazolo[1,5-a]pyridin-2-yl)-2H-chromen-2-one;

7-(4-ethylpiperazin-1-yl)-3-(pyrazolo[1,5-a]pyridin-2-yl)-2H-chromen-2-one;

7-(4-propylpiperazin-1-yl)-3-(pyrazolo[1,5-a]pyridin-2-yl)-2H-chromen-2-one;

7-[4-(propan-2-yl)piperazin-1-yl]-3-(pyrazolo[1,5-a]pyridin-2-yl)-2H-chromen-2-one;

3-(imidazo[1,2-a]pyrimidin-2-yl)-7-(piperidin-4-yloxy)-2H-chromen-2-one;

7-[(dimethylamino)methyl]-3-(imidazo[2,1-b][1,3]thiazol-6-yl)-2H-chromen-2-one;

3-(imidazo[2,1-b][1,3]thiazol-6-yl)-7-[(propan-2-ylamino)methyl]-2H-chromen-2-one;

7-[3-(dimethylamino)piperidin-1-yl]-3-(6-methylimidazo[1,2-a]pyridin-2-yl)-2H-chromen-2-one;

7-(4-ethylpiperazin-1-yl)-3-(imidazo[2,1-b][1,3]thiazol-6-yl)-2H-chromen-2-one;

7-{[2-(dimethylamino)ethyl](methyl)amino}-3-(imidazo[2,1-b][1,3]thiazol-6-yl)-2H-chromen-2-one;

3-(imidazo[2,1-b][1,3]thiazol-6-yl)-7-(4-methyl-1,4-diazepan-1-yl)-2H-chromen-2-one;

3-(imidazo[2,1-b][1,3]thiazol-6-yl)-7-[(3R)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(imidazo[2,1-b][1,3]thiazol-6-yl)-7-[(3S)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

7-(1,4-diazepan-1-yl)-3-(imidazo[2,1-b][1,3]thiazol-6-yl)-2H-chromen-2-one;

3-(6-methylimidazo[1,2-a]pyridin-2-yl)-7-(4-propylpiperazin-1-yl)-2H-chromen-2-one;

2-[7-(4-methylpiperazin-1-yl)-2-oxo-2H-chromen-3-yl]imidazo[1,2-a]pyridine-6-carbonitrile;

7-(piperazin-1-yl)-3-[8-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]-2H-chromen-2-one;

7-(4-methylpiperazin-1-yl)-3-[8-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]-2H-chromen-2-one;

7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-[8-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]-2H-chromen-2-one;

3-(8-chloroimidazo[1,2-a]pyridin-2-yl)-7-(1,4-diazepan-1-yl)-2H-chromen-2-one;

3-(7-methylimidazo[1,2-a]pyridin-2-yl)-7-[(3S)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(7-methylimidazo[1,2-a]pyridin-2-yl)-7-[(3R)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

7-(3,3-dimethylpiperazin-1-yl)-3-(7-methylimidazo[1,2-a]pyridin-2-yl)-2H-chromen-2-one;

7-(1,4-diazepan-1-yl)-3-(7-methylimidazo[1,2-a]pyridin-2-yl)-2H-chromen-2-one;

7-(4-methyl-1,4-diazepan-1-yl)-3-(7-methylimidazo[1,2-a]pyridin-2-yl)-2H-chromen-2-one;

3-(6-methoxypyridin-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

7-(4-aminopiperidin-1-yl)-3-(6-methylimidazo[1,2-a]pyridin-2-yl)-2H-chromen-2-one;

3-(6-methylimidazo[1,2-a]pyridin-2-yl)-7-[(3R)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(6-methylimidazo[1,2-a]pyridin-2-yl)-7-[methyl(pyridin-3-ylmethyl)amino]-2H-chromen-2-one;

7-(3,3-dimethylpiperazin-1-yl)-3-(6-methylimidazo[1,2-a]pyridin-2-yl)-2H-chromen-2-one;

3-(7-methylimidazo[1,2-a]pyrimidin-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(7-methylimidazo[1,2-a]pyrimidin-2-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-(7-methylimidazo[1,2-a]pyrimidin-2-yl)-2H-chromen-2-one;

7-{[2-(dimethylamino)ethyl](methyl)amino}-3-(7-methylimidazo[1,2-a]pyrimidin-2-yl)-2H-chromen-2-one;

7-(4-methyl-1,4-diazepan-1-yl)-3-(7-methylimidazo[1,2-a]pyridin-2-yl)-2H-chromen-2-one

3-(7-methylimidazo[1,2-a]pyrimidin-2-yl)-7-[(3R)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(7-methylimidazo[1,2-a]pyrimidin-2-yl)-7-[(3S)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

7-(1,4-diazepan-1-yl)-3-(7-methylimidazo[1,2-a]pyrimidin-2-yl)-2H-chromen-2-one;

3-(2-methylimidazo[2,1-b][1,3]thiazol-6-yl)-7-[(3R)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(2-methylimidazo[2,1-b][1,3]thiazol-6-yl)-7-[(3S)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

7-(1,4-diazepan-1-yl)-3-(2-methylimidazo[2,1-b][1,3]thiazol-6-yl)-2H-chromen-2-one;

3-(4-methoxypyridin-3-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(4-chloropyridin-3-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-[4-(trifluoromethyl)-1,3-thiazol-2-yl]-2H-chromen-2-one;

7-(1,4-diazepan-1-yl)-3-[4-(trifluoromethyl)-1,3-thiazol-2-yl]-2H-chromen-2-one;

7-(4-methyl-1,4-diazepan-1-yl)-3-[4-(trifluoromethyl)-1,3-thiazol-2-yl]-2H-chromen-2-one;

7-[(3S)-3-methylpiperazin-1-yl]-3-[4-(trifluoromethyl)-1,3-thiazol-2-yl]-2H-chromen-2-one;

7-[(3R)-3-methylpiperazin-1-yl]-3-[4-(trifluoromethyl)-1,3-thiazol-2-yl]-2H-chromen-2-one;

3-(6-methylimidazo[1,2-a]pyrimidin-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(6-methylimidazo[1,2-a]pyrimidin-2-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-(6-methylimidazo[1,2-a]pyrimidin-2-yl)-2H-chromen-2-one;

3-(8-cyclopropylimidazo[1,2-a]pyridin-2-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

3-(8-bromoimidazo[1,2-a]pyridin-2-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

7-(4-methyl-1,4-diazepan-1-yl)-3-(8-methylimidazo[1,2-a]pyridin-2-yl)-2H-chromen-2-one;

3-(8-methylimidazo[1,2-a]pyridin-2-yl)-7-[(3R)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(8-methylimidazo[1,2-a]pyridin-2-yl)-7-[(3S)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(8-chloroimidazo[1,2-a]pyridin-2-yl)-7-(3,3-dimethylpiperazin-1-yl)-2H-chromen-2-one;

7-(4-methyl-1,4-diazepan-1-yl)-3-(6-methylimidazo[1,2-a]pyrimidin-2-yl)-2H-chromen-2-one;

7-{[(1-hydroxypropan-2-yl)amino]methyl}-3-(6-methylimidazo[1,2-a]pyridin-2-yl)-2H-chromen-2-one;

7-[(4-hydroxypiperidin-1-yl)methyl]-3-(6-methylimidazo[1,2-a]pyridin-2-yl)-2H-chromen-2-one;

7-[(3-hydroxypyrrolidin-1-yl)methyl]-3-(6-methylimidazo[1,2-a]pyridin-2-yl)-2H-chromen-2-one;

5-fluoro-7-(piperazin-1-yl)-3-[4-(trifluoromethyl)-1,3-benzoxazol-2-yl]-2H-chromen-2-one;

3-(6-methylimidazo[1,2-a]pyridin-2-yl)-7-(octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2H-chromen-2-one;

3-(2-ethoxypyridin-3-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(6-methoxypyridin-2-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

3-(1-methyl-1H-indol-3-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(1-methyl-1H-indol-3-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyridin-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyridin-2-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyridin-2-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2H-chromen-2-one;

3-(6-chloro-8-methylimidazo[1,2-a]pyridin-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(6-chloro-8-methylimidazo[1,2-a]pyridin-2-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

3-(6-chloro-8-methylimidazo[1,2-a]pyridin-2-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2H-chromen-2-one;

7-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-3-[4-(trifluoromethyl)-1,3-thiazol-2-yl]-2H-chromen-2-one;

7-[(3R)-3-methylpiperazin-1-yl]-3-[7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]-2H-chromen-2-one;

7-[(3S)-3-methylpiperazin-1-yl]-3-[7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]-2H-chromen-2-one;

7-(3,3-dimethylpiperazin-1-yl)-3-[7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]-2H-chromen-2-one;

3-(4-chloro-1,3-benzothiazol-2-yl)-7-{[(1-hydroxypropan-2-yl)amino]methyl}-2H-chromen-2-one;

3-(4-chloro-1,3-benzothiazol-2-yl)-7-{[(2-hydroxyethyl)(methyl)amino]methyl}-2H-chromen-2-one;

3-(4-chloro-1,3-benzothiazol-2-yl)-7-[(3-hydroxypyrrolidin-1-yl)methyl]-2H-chromen-2-one;

3-(4-chloro-1,3-benzothiazol-2-yl)-7-[(4-hydroxypiperidin-1-yl)methyl]-2H-chromen-2-one;

3-(2-methylpyrimidin-4-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

7-(1,4-diazepan-1-yl)-3-[7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]-2H-chromen-2-one;

7-(4-methyl-1,4-diazepan-1-yl)-3-[7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]-2H-chromen-2-one;

7-[(2R,5S)-2,5-dimethylpiperazin-1-yl]-3-[7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]-2H-chromen-2-one;

3-(2-cyclopropylpyrimidin-4-yl)-7-(piperazin-1-yl)-2H-chromen-2-one; 7-(piperazin-1-yl)-3-[2-(propan-2-yl)pyrimidin-4-yl]-2H-chromen-2-one;

3-(8-chloroimidazo[1,2-a]pyridin-2-yl)-7-(4-methyl-1,4-diazepan-1-yl)-2H-chromen-2-one;

7-(1,4-diazepan-1-yl)-3-(8-methylimidazo[1,2-a]pyridin-2-yl)-2H-chromen-2-one;

3-(6-methylimidazo[1,2-a]pyridin-2-yl)-7-[methyl(1-methylpiperidin-4-yl)amino]-2H-chromen-2-one;

7-[(3S)-3-methylpiperazin-1-yl]-3-(4-methyl-1,3-thiazol-2-yl)-2H-chromen-2-one;

7-(1,4-diazepan-1-yl)-3-(4-methyl-1,3-thiazol-2-yl)-2H-chromen-2-one;

7-(4-methyl-1,4-diazepan-1-yl)-3-(4-methyl-1,3-thiazol-2-yl)-2H-chromen-2-one;

7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-(4-methyl-1,3-thiazol-2-yl)-2H-chromen-2-one;

3-(7-ethylimidazo[1,2-a]pyridin-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(7-ethylimidazo[1,2-a]pyridin-2-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-(7-ethylimidazo[1,2-a]pyridin-2-yl)-2H-chromen-2-one;

3-(3,5-difluorophenyl)-5-fluoro-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(3,5-difluorophenyl)-7-(piperazin-1-yl)-2H-chromen-2-one;

5-fluoro-3-(4-fluoro-1,3-benzoxazol-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

7-(4-methyl-1,4-diazepan-1-yl)-3-[8-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]-2H-chromen-2-one;

3-(6-fluoroimidazo[1,2-a]pyridin-2-yl)-7-(4-methyl-1,4-diazepan-1-yl)-2H-chromen-2-one;

3-(8-fluoroimidazo[1,2-a]pyridin-2-yl)-7-(4-methyl-1,4-diazepan-1-yl)-2H-chromen-2-one;

3-(8-chloroimidazo[1,2-a]pyridin-2-yl)-7-[(3R)-3,4-dimethylpiperazin-1-yl]-2H-chromen-2-one;

7-(4-methylpiperazin-1-yl)-3-(2-methylpyrimidin-4-yl)-2H-chromen-2-one;

3-(2-cyclopropylpyrimidin-4-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

7-[(2S,5R)-2,5-dimethylpiperazin-1-yl]-3-(4-methyl-1,3-thiazol-2-yl)-2H-chromen-2-one;

7-[(3R)-3-methylpiperazin-1-yl]-3-(4-methyl-1,3-thiazol-2-yl)-2H-chromen-2-one;

7-(3,3-dimethylpiperazin-1-yl)-3-(4-methyl-1,3-thiazol-2-yl)-2H-chromen-2-one;

3-(5-methylpyrazolo[1,5-a]pyridin-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

7-(4-methylpiperazin-1-yl)-3-(5-methylpyrazolo[1,5-a]pyridin-2-yl)-2H-chromen-2-one;

7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-(5-methylpyrazolo[1,5-a]pyridin-2-yl)-2H-chromen-2-one;

7-(3,3-dimethylpiperazin-1-yl)-3-(5-methylpyrazolo[1,5-a]pyridin-2-yl)-2H-chromen-2-one;

7-[(3R)-3-methylpiperazin-1-yl]-3-(5-methylpyrazolo[1,5-a]pyridin-2-yl)-2H-chromen-2-one;

7-(4-ethylpiperazin-1-yl)-3-(5-methylpyrazolo[1,5-a]pyridin-2-yl)-2H-chromen-2-one;

3-(5-methylpyrazolo[1,5-a]pyridin-2-yl)-7-(4-propylpiperazin-1-yl)-2H-chromen-2-one;

7-(1,4-diazepan-1-yl)-3-(5-methylpyrazolo[1,5-a]pyridin-2-yl)-2H-chromen-2-one;

7-(4-methyl-1,4-diazepan-1-yl)-3-(5-methylpyrazolo[1,5-a]pyridin-2-yl)-2H-chromen-2-one;

5-fluoro-3-(imidazo[2,1-b][1,3]thiazol-6-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

5-fluoro-3-(imidazo[1,2-a]pyrimidin-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(1H-benzimidazol-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

7-(piperazin-1-yl)-3-(9H-purin-8-yl)-2H-chromen-2-one;

7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-(6-methoxypyridin-2-yl)-2H-chromen-2-one;

3-(3,4-dimethoxyphenyl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(3,4-dimethoxyphenyl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

3-(4-methylthiophen-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

7-(piperazin-1-yl)-3-(thiophen-3-yl)-2H-chromen-2-one;

7-(4-methylpiperazin-1-yl)-3-(thiophen-3-yl)-2H-chromen-2-one;

3-(imidazo[1,2-a]pyrimidin-2-yl)-7-[(3R)-pyrrolidin-3-yloxy]-2H-chromen-2-one;

3-(7-methylimidazo[1,2-a]pyrimidin-2-yl)-7-[(3R)-pyrrolidin-3-yloxy]-2H-chromen-2-one;

3-(7-methylimidazo[1,2-a]pyridin-2-yl)-7-[(3R)-pyrrolidin-3-yloxy]-2H-chromen-2-one;

3-(imidazo[2,1-b][1,3]thiazol-6-yl)-7-[(3R)-pyrrolidin-3-yloxy]-2H-chromen-2-one;

3-(2-methylimidazo[2,1-b][1,3]thiazol-6-yl)-7-[(3R)-pyrrolidin-3-yloxy]-2H-chromen-2-one;

3-(6-methylimidazo[1,2-a]pyridin-2-yl)-7-[(3R)-pyrrolidin-3-yloxy]-2H-chromen-2-one;

3-(6-methylimidazo[1,2-a]pyrimidin-2-yl)-7-[(3R)-pyrrolidin-3-yloxy]-2H-chromen-2-one;

3-(6-fluoro-8-methylimidazo[1,2-a]pyridin-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(6-fluoro-8-methylimidazo[1,2-a]pyridin-2-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

3-(6-fluoro-8-methylimidazo[1,2-a]pyridin-2-yl)-7-(4-methyl-1,4-diazepan-1-yl)-2H-chromen-2-one;

7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-(6-fluoro-8-methylimidazo[1,2-a]pyridin-2-yl)-2H-chromen-2-one;

3-(8-ethyl-6-methylimidazo[1,2-a]pyridin-2-yl)-7-(4-methyl-1,4-diazepan-1-yl)-2H-chromen-2-one;

3-(7-ethylimidazo[1,2-a]pyridin-2-yl)-7-(4-methyl-1,4-diazepan-1-yl)-2H-chromen-2-one;

3-(8-ethyl-6-methylimidazo[1,2-a]pyridin-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

5-fluoro-3-(imidazo[1,2-a]pyrimidin-2-yl)-7-(4-methyl-1,4-diazepan-1-yl)-2H-chromen-2-one;

7-(1,4-diazepan-1-yl)-5-fluoro-3-(imidazo[1,2-a]pyrimidin-2-yl)-2H-chromen-2-one;

3-(6-chloroimidazo[1,2-a]pyrimidin-2-yl)-7-(4-methyl-1,4-diazepan-1-yl)-2H-chromen-2-one;

7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-(8-fluoroimidazo[1,2-a]pyridin-2-yl)-2H-chromen-2-one;

3-(8-chloroimidazo[1,2-a]pyridin-2-yl)-7-[(3S)-3,4-dimethylpiperazin-1-yl]-2H-chromen-2-one;

3-(8-ethyl-6-methylimidazo[1,2-a]pyridin-2-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-(8-ethyl-6-methylimidazo[1,2-a]pyridin-2-yl)-2H-chromen-2-one;

3-(8-chloro-6-methylimidazo[1,2-a]pyridin-2-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2H-chromen-2-one;

3-(8-chloro-6-methylimidazo[1,2-a]pyridin-2-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

3-(8-chloro-6-methylimidazo[1,2-a]pyridin-2-yl)-7-(4-methyl-1,4-diazepan-1-yl)-2H-chromen-2-one;

7-{[(2-hydroxyethyl)(methyl)amino]methyl}-3-(imidazo[2,1-b][1,3]thiazol-6-yl)-2H-chromen-2-one;

7-[(4-hydroxypiperidin-1-yl)methyl]-3-(imidazo[2,1-b][1,3]thiazol-6-yl)-2H-chromen-2-one;

3-(6-chloroimidazo[1,2-a]pyrimidin-2-yl)-7-[4-(2-hydroxyethyl)piperazin-1-yl]-2H-chromen-2-one;

3-(6-chloroimidazo[1,2-a]pyrimidin-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(6-chloroimidazo[1,2-a]pyrimidin-2-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2H-chromen-2-one;

3-(6-chloroimidazo[1,2-a]pyrimidin-2-yl)-7-[(3R)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

5-fluoro-3-(imidazo[1,2-a]pyrimidin-2-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-5-fluoro-3-(imidazo[1,2-a]pyrimidin-2-yl)-2H-chromen-2-one;

3-(8-fluoro-6-methylimidazo[1,2-a]pyridin-2-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-(8-fluoro-6-methylimidazo[1,2-a]pyridin-2-yl)-2H-chromen-2-one;

3-(8-fluoro-6-methylimidazo[1,2-a]pyridin-2-yl)-7-(4-methyl-1,4-diazepan-1-yl)-2H-chromen-2-one;

3-(8-fluoro-6-methylimidazo[1,2-a]pyridin-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

7-(1,4-diazepan-1-yl)-3-(8-fluoroimidazo[1,2-a]pyridin-2-yl)-2H-chromen-2-one;

3-(8-ethylimidazo[1,2-a]pyridin-2-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

3-(6-methoxypyridin-2-yl)-7-(4-methyl-1,4-diazepan-1-yl)-2H-chromen-2-one;

7-(4-ethylpiperazin-1-yl)-3-(6-methoxypyridin-2-yl)-2H-chromen-2-one;

3-(6-methoxypyridin-2-yl)-7-[(3R)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(6-methoxypyridin-2-yl)-7-[(3S)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

7-(piperazin-1-yl)-3-(thiophen-2-yl)-2H-chromen-2-one;

7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-(thiophen-2-yl)-2H-chromen-2-one;

3-(3,5-difluorophenyl)-5-fluoro-7-(4-methyl-1,4-diazepan-1-yl)-2H-chromen-2-one;

5-fluoro-3-(4-fluoro-1,3-benzoxazol-2-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-5-fluoro-3-(4-fluoro-1,3-benzoxazol-2-yl)-2H-chromen-2-one;

7-(1,4-diazepan-1-yl)-5-fluoro-3-(4-fluoro-1,3-benzoxazol-2-yl)-2H-chromen-2-one;

5-fluoro-3-(4-fluoro-1,3-benzoxazol-2-yl)-7-(4-methyl-1,4-diazepan-1-yl)-2H-chromen-2-one;

3-(1H-benzimidazol-2-yl)-5-fluoro-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

3-(1H-benzimidazol-2-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-5-fluoro-2H-chromen-2-one;

5-fluoro-3-(imidazo[2,1-b][1,3]thiazol-6-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

5-fluoro-3-(imidazo[2,1-b][1,3]thiazol-6-yl)-7-(4-methyl-1,4-diazepan-1-yl)-2H-chromen-2-one;

3-(1H-benzimidazol-2-yl)-7-(1,4-diazepan-1-yl)-5-fluoro-2H-chromen-2-one;

3-(1H-benzimidazol-2-yl)-5-fluoro-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(6-chloroimidazo[1,2-a]pyrimidin-2-yl)-7-[(3S)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

7-[(1-benzylpyrrolidin-3-yl)(methyl)amino]-3-(7-methylimidazo[1,2-a]pyrimidin-2-yl)-2H-chromen-2-one;

7-(1,4-diazepan-1-yl)-3-(6-methylimidazo[1,2-a]pyrimidin-2-yl)-2H-chromen-2-one;

7-[(3S)-3,4-dimethylpiperazin-1-yl]-3-(7-methylimidazo[1,2-a]pyridin-2-yl)-2H-chromen-2-one;

3-(6-fluoropyridin-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(6-ethoxypyridin-2-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

3-(3,4-dimethoxyphenyl)-7-[(3R)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(3,4-dimethoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(3,4-dimethoxyphenyl)-7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2H-chromen-2-one;

7-(piperazin-1-yl)-3-[6-(propan-2-yloxy)pyridin-2-yl]-2H-chromen-2-one;

7-(piperazin-1-yl)-3-[6-(pyrrolidin-1-yl)pyridin-2-yl]-2H-chromen-2-one;

7-(1,4-diazepan-1-yl)-3-(3,5-dimethoxyphenyl)-2H-chromen-2-one;

3-(8-chloroimidazo[1,2-a]pyridin-2-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-5-fluoro-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyridin-2-yl)-7-(4-methyl-1,4-diazepan-1-yl)-2H-chromen-2-one;

3-(8-chloroimidazo[1,2-a]pyridin-2-yl)-5-fluoro-7-[(3R)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-5-fluoro-3-[7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]-2H-chromen-2-one;

3-(8-chloroimidazo[1,2-a]pyridin-2-yl)-5-fluoro-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(8-chloroimidazo[1,2-a]pyridin-2-yl)-5-fluoro-7-[(3S)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(4-methyl-1H-benzimidazol-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(5-fluoro-1H-benzimidazol-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(1H-benzimidazol-2-yl)-7-[(dimethylamino)methyl]-2H-chromen-2-one;

5-fluoro-7-(hydroxymethyl)-3-(imidazo[2,1-b][1,3]thiazol-6-yl)-2H-chromen-2-one;

3-[8-(methylsulfanyl)imidazo[1,2-a]pyrazin-2-yl]-7-(piperazin-1-yl)-2H-chromen-2-one;

7-(4-methylpiperazin-1-yl)-3-[8-(methylsulfanyl)imidazo[1,2-a]pyrazin-2-yl]-2H-chromen-2-one;

7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-[8-(methylsulfanyl)imidazo[1,2-a]pyrazin-2-yl]-2H-chromen-2-one;

7-(4-methyl-1,4-diazepan-1-yl)-3-[8-(methylsulfanyl)imidazo[1,2-a]pyrazin-2-yl]-2H-chromen-2-one;

3-(8-methoxyimidazo[1,2-a]pyridin-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(8-methoxyimidazo[1,2-a]pyridin-2-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

3-(3,4-dimethoxyphenyl)-5-fluoro-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(3,4-dimethoxyphenyl)-5-fluoro-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

3-(3,4-dimethoxyphenyl)-5-fluoro-7-(4-methyl-1,4-diazepan-1-yl)-2H-chromen-2-one;

3-(1-benzothiophen-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(1-benzothiophen-2-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2H-chromen-2-one;

3-(1-benzothiophen-2-yl)-7-[(3R)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(1-benzothiophen-2-yl)-7-[(3S)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(3,5-dimethoxyphenyl)-7-(4-methyl-1,4-diazepan-1-yl)-2H-chromen-2-one;

3-(3,5-dimethoxyphenyl)-7-[(3R)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(3,5-dimethoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-[6-(cyclobutyloxy)pyridin-2-yl]-7-(piperazin-1-yl)-2H-chromen-2-one;

3-[6-(cyclobutyloxy)pyridin-2-yl]-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

3-(3,4-dimethoxyphenyl)-5-fluoro-7-[(3R)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-(imidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-(8-methoxyimidazo[1,2-a]pyridin-2-yl)-2H-chromen-2-one;

3-(8-methoxyimidazo[1,2-a]pyridin-2-yl)-7-(4-methyl-1,4-diazepan-1-yl)-2H-chromen-2-one;

3-(8-fluoro-6-methylimidazo[1,2-a]pyridin-2-yl)-7-[(3R)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(8-fluoro-6-methylimidazo[1,2-a]pyridin-2-yl)-7-[(3S)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

5-fluoro-3-(imidazo[1,2-a]pyridin-2-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

5-fluoro-3-(8-methylimidazo[1,2-a]pyridin-2-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

5-fluoro-3-(7-methylimidazo[1,2-a]pyridin-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyridin-2-yl)-7-[(3S)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

7-(3,3-dimethylpiperazin-1-yl)-3-(8-fluoro-6-methylimidazo[1,2-a]pyridin-2-yl)-2H-chromen-2-one;

7-(1,4-diazepan-1-yl)-3-(8-fluoro-6-methylimidazo[1,2-a]pyridin-2-yl)-2H-chromen-2-one;

3-(2-ethylimidazo[2,1-b][1,3]thiazol-6-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-(2-ethylimidazo[2,1-b][1,3]thiazol-6-yl)-2H-chromen-2-one;

7-(1,4-diazepan-1-yl)-3-(2-ethylimidazo[2,1-b][1,3]thiazol-6-yl)-2H-chromen-2-one;

3-(2-ethylimidazo[2,1-b][1,3]thiazol-6-yl)-7-(4-methyl-1,4-diazepan-1-yl)-2H-chromen-2-one;

7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-(7-methoxyimidazo[1,2-a]pyridin-2-yl)-2H-chromen-2-one;

7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-[1-(pyridin-2-yl)-1H-imidazol-4-yl]-2H-chromen-2-one;

3-(7-methoxyimidazo[1,2-a]pyridin-2-yl)-7-[(3S)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(7-methoxyimidazo[1,2-a]pyridin-2-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

3-(7-methoxyimidazo[1,2-a]pyridin-2-yl)-7-(4-methyl-1,4-diazepan-1-yl)-2H-chromen-2-one;

7-[(1R,5S,6s)-6-(dimethylamino)-3-azabicyclo[3.1.0]hex-3-yl]-3-(imidazo[2,1-b][1,3]thiazol-6-yl)-2H-chromen-2-one;

7-(1,4-diazabicyclo[3.2.2]non-4-yl)-3-(imidazo[2,1-b][1,3]thiazol-6-yl)-2H-chromen-2-one;

7-[(1R,5S,6s)-6-(dimethylamino)-3-azabicyclo[3.1.0]hex-3-yl]-3-(imidazo[1,2-a]pyrimidin-2-yl)-2H-chromen-2-one;

7-(1,4-diazabicyclo[3.2.2]non-4-yl)-3-(imidazo[1,2-a]pyrimidin-2-yl)-2H-chromen-2-one;

3-(2-methylimidazo[2,1-b][1,3,4]thiadiazol-6-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(2-methylimidazo[2,1-b][1,3,4]thiadiazol-6-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-(2-methylimidazo[2,1-b][1,3,4]thiadiazol-6-yl)-2H-chromen-2-one;

7-[(3S)-3-methylpiperazin-1-yl]-3-(pyridin-2-yl)-2H-chromen-2-one;

3-[6-(methylsulfanyl)pyridin-2-yl]-7-(piperazin-1-yl)-2H-chromen-2-one;

7-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-3-(3,4-dimethoxyphenyl)-5-fluoro-2H-chromen-2-one;

3-(4-methoxyphenyl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(4-methoxyphenyl)-7-[(3R)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(4-methoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

7-(1,4-diazepan-1-yl)-3-(2-methylimidazo[2,1-b][1,3,4]thiadiazol-6-yl)-2H-chromen-2-one;

7-(4-methyl-1,4-diazepan-1-yl)-3-(2-methylimidazo[2,1-b][1,3,4]thiadiazol-6-yl)-2H-chromen-2-one;

7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-(1-phenyl-1H-imidazol-4-yl)-2H-chromen-2-one;

7-(4-methyl-1,4-diazepan-1-yl)-3-[2-methyl-1-(pyridin-2-yl)-1H-imidazol-4-yl]-2H-chromen-2-one;

7-(1,4-diazepan-1-yl)-3-(imidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

3-(imidazo[1,2-a]pyrazin-2-yl)-7-(4-methyl-1,4-diazepan-1-yl)-2H-chromen-2-one;

3-(imidazo[1,2-a]pyrazin-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(imidazo[1,2-a]pyrazin-2-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

3-(imidazo[1,2-c]pyrimidin-2-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-(imidazo[1,2-c]pyrimidin-2-yl)-2H-chromen-2-one;

3-(imidazo[1,2-c]pyrimidin-2-yl)-7-(4-methyl-1,4-diazepan-1-yl)-2H-chromen-2-one;

7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-(quinoxalin-2-yl)-2H-chromen-2-one;

3-(6-methylimidazo[1,2-a]pyrimidin-2-yl)-7-[(3S)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(6-methylimidazo[1,2-a]pyrimidin-2-yl)-7-[(3R)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(3,4-dimethoxyphenyl)-5-fluoro-7-[(3S)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(2,4-dimethoxyphenyl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(2,4-dimethoxyphenyl)-7-[(3R)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(2,4-dimethoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

5-fluoro-3-(6-methoxypyridin-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

5-fluoro-3-(6-methoxypyridin-2-yl)-7-[(3S)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

7-{[2-(dimethylamino)ethyl]amino}-3-(7-methylimidazo[1,2-a]pyridin-2-yl)-2H-chromen-2-one;

7-[(3S)-3,4-dimethylpiperazin-1-yl]-3-(8-fluoro-6-methylimidazo[1,2-a]pyridin-2-yl)-2H-chromen-2-one;

3-(3,4-dimethoxyphenyl)-7-[(2S)-2-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(2-chloroimidazo[2,1-b][1,3]thiazol-6-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2H-chromen-2-one;

3-(7-methylimidazo[1,2-a]pyridin-2-yl)-7-[(1-methylpiperidin-4-yl)amino]-2H-chromen-2-one;

7-{[3-(dimethylamino)propyl]amino}-3-(7-methylimidazo[1,2-a]pyridin-2-yl)-2H-chromen-2-one;

7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-(6-methylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

7-(1,4-diazepan-1-yl)-3-(6-methylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

3-(2-chloroimidazo[2,1-b][1,3]thiazol-6-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

3-(2-chloroimidazo[2,1-b][1,3]thiazol-6-yl)-7-(4-methyl-1,4-diazepan-1-yl)-2H-chromen-2-one;

3-(6-fluoroimidazo[1,2-a]pyrimidin-2-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

3-(6-fluoroimidazo[1,2-a]pyrimidin-2-yl)-7-[(3R)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(2-methylimidazo[2,1-b][1,3,4]thiadiazol-6-yl)-7-[(3S)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(2-methylimidazo[2,1-b][1,3,4]thiadiazol-6-yl)-7-[(3R)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(3-chloro-4-fluorophenyl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(3-chloro-4-fluorophenyl)-7-[(3S)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(1,3-benzodioxol-5-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(1,3-benzodioxol-5-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2H-chromen-2-one;

3-(1,3-benzodioxol-5-yl)-7-[(3R)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(1,3-benzodioxol-5-yl)-7-[(3S)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

7-[(3S)-3-methylpiperazin-1-yl]-3-[3-(trifluoromethyl)phenyl]-2H-chromen-2-one;

7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-(6-fluoroimidazo[1,2-a]pyrimidin-2-yl)-2H-chromen-2-one;

3-(6-fluoroimidazo[1,2-a]pyrimidin-2-yl)-7-[(3S)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

7-(4-methyl-1,4-diazepan-1-yl)-3-(6-methylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

3-(2-chloroimidazo[2,1-b][1,3]thiazol-6-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(7-methylimidazo[1,2-a]pyridin-2-yl)-7-(piperidin-4-ylamino)-2H-chromen-2-one;

3-(7-methylimidazo[1,2-a]pyridin-2-yl)-7-[(3R)-pyrrolidin-3-ylamino]-2H-chromen-2-one;

3-(6-cyclopropyl-8-fluoroimidazo[1,2-a]pyridin-2-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2H-chromen-2-one;

3-(6-cyclopropyl-8-fluoroimidazo[1,2-a]pyridin-2-yl)-7-[(3S)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(6-cyclopropyl-8-fluoroimidazo[1,2-a]pyridin-2-yl)-7-(4-methyl-1,4-diazepan-1-yl)-2H-chromen-2-one;

3-(6-cyclopropyl-8-fluoroimidazo[1,2-a]pyridin-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

7-(1,4-diazabicyclo[3.2.2]non-4-yl)-3-(8-fluoroimidazo[1,2-a]pyridin-2-yl)-2H-chromen-2-one;

3-(6-fluoroimidazo[1,2-a]pyrimidin-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(6-cyclopropyl-8-fluoroimidazo[1,2-a]pyridin-2-yl)-7-[(3R)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(6-cyclopropyl-8-fluoroimidazo[1,2-a]pyridin-2-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

7-(1,4-diazabicyclo[3.2.2]non-4-yl)-3-(8-methylimidazo[1,2-a]pyridin-2-yl)-2H-chromen-2-one;

7-(3,8-diazabicyclo[3.2.1]oct-3-yl)-3-(8-fluoroimidazo[1,2-a]pyridin-2-yl)-2H-chromen-2-one;

7-(3,3-dimethylpiperazin-1-yl)-3-(8-fluoroimidazo[1,2-a]pyridin-2-yl)-2H-chromen-2-one;

7-(3,3-dimethylpiperazin-1-yl)-3-(6-fluoroimidazo[1,2-a]pyridin-2-yl)-2H-chromen-2-one;

3-(3-chlorophenyl)-7-[(3S)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(2-chloro-4-fluorophenyl)-7-[(3S)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(3-methylphenyl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(3-methylphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(2,3-dihydro-1,4-benzodioxin-6-yl)-7-[(3S)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(2,3-dihydro-1,4-benzodioxin-6-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2H-chromen-2-one;

7-(1,4-diazepan-1-yl)-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-(4-methyl-1,4-diazepan-1-yl)-2H-chromen-2-one;

3-(6,8-difluoroimidazo[1,2-a]pyridin-2-yl)-7-(4-methyl-1,4-diazepan-1-yl)-2H-chromen-2-one;

7-(1,4-diazabicyclo[3.2.2]non-4-yl)-3-(7-methylimidazo[1,2-a]pyridin-2-yl)-2H-chromen-2-one;

3-(6,8-difluoroimidazo[1,2-a]pyridin-2-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

3-(6,8-difluoroimidazo[1,2-a]pyridin-2-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2H-chromen-2-one;

3-(6,8-difluoroimidazo[1,2-a]pyridin-2-yl)-7-[(3S)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(8-fluoroimidazo[1,2-a]pyridin-2-yl)-7-[(3S)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(8-chloroimidazo[1,2-a]pyridin-2-yl)-7-(3,8-diazabicyclo[3.2.1]oct-3-yl)-2H-chromen-2-one;

3-(8-chloroimidazo[1,2-a]pyridin-2-yl)-7-(2,5-diazabicyclo[2.2.2]oct-2-yl)-2H-chromen-2-one;

3-(8-fluoroimidazo[1,2-a]pyridin-2-yl)-7-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-2H-chromen-2-one;

3-(indolizin-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(8-fluoroimidazo[1,2-a]pyridin-2-yl)-7-[(3R)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(8-fluoroimidazo[1,2-a]pyridin-2-yl)-7-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-2H-chromen-2-one;

3-(6,8-difluoroimidazo[1,2-a]pyridin-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

7-[(3R)-3,4-dimethylpiperazin-1-yl]-3-(8-fluoro-6-methylimidazo[1,2-a]pyridin-2-yl)-2H-chromen-2-one;

7-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-3-(7-methylimidazo[1,2-a]pyridin-2-yl)-2H-chromen-2-one;

7-[(1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl]-3-(7-methylimidazo[1,2-a]pyridin-2-yl)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(3R)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(3S)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(3,5-difluoro-2-methoxyphenyl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(3,5-difluoro-2-methoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(3,5-difluoro-2-methoxyphenyl)-7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2H-chromen-2-one;

3-(4-methoxy-3-methylphenyl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(4-methoxy-3-methylphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-(4-methoxy-3-methylphenyl)-2H-chromen-2-one;

3-(3-fluoro-4-methoxyphenyl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(3-fluoro-4-methoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(2,3-difluorophenyl)-7-[(3S)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-[6-(dimethylamino)pyridin-3-yl]-7-(piperazin-1-yl)-2H-chromen-2-one;

3-[6-(dimethylamino)pyridin-3-yl]-7-[(3S)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

7-[(3S)-3-methylpiperazin-1-yl]-3-(pyridin-4-yl)-2H-chromen-2-one;

7-(1,4-diazepan-1-yl)-5-fluoro-3-(6-methylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

3-(8-methylimidazo[1,2-a]pyrazin-2-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-(8-methylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-(indolizin-2-yl)-2H-chromen-2-one;

7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-(1-methylpyrrolo[1,2-a]pyrazin-7-yl)-2H-chromen-2-one;

3-(1-methylpyrrolo[1,2-a]pyrazin-7-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

7-(4-methyl-1,4-diazepan-1-yl)-3-(1-methylpyrrolo[1,2-a]pyrazin-7-yl)-2H-chromen-2-one;

7-(4-methylpiperazin-1-yl)-3-(1-methylpyrrolo[1,2-a]pyrazin-7-yl)-2H-chromen-2-one;

7-(4-methyl-1,4-diazepan-1-yl)-3-(8-methylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

3-(8-methylimidazo[1,2-a]pyrazin-2-yl)-7-[(3R)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(8-fluoro-6-methylimidazo[1,2-a]pyridin-2-yl)-7-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-2H-chromen-2-one;

7-(1,4-diazabicyclo[3.2.2]non-4-yl)-3-(8-fluoro-6-methylimidazo[1,2-a]pyridin-2-yl)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-(piperidin-4-ylamino)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(3S)-pyrrolidin-3-ylamino]-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(3R)-pyrrolidin-3-ylamino]-2H-chromen-2-one;

3-(indolizin-2-yl)-7-[(3S)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

7-[(3S)-3-methylpiperazin-1-yl]-3-(1-methylpyrrolo[1,2-a]pyrazin-7-yl)-2H-chromen-2-one;

3-(6-methylimidazo[1,2-a]pyrazin-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(6-methylimidazo[1,2-a]pyrazin-2-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

3-(6-methylimidazo[1,2-a]pyrazin-2-yl)-7-[(3S)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(6-methylimidazo[1,2-a]pyrazin-2-yl)-7-[(3R)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(8-methylimidazo[1,2-a]pyrazin-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

7-(1,4-diazepan-1-yl)-3-(8-methylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

3-(8-methylimidazo[1,2-a]pyrazin-2-yl)-7-[(3S)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(3-methoxy-4-methylphenyl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(3-methoxy-4-methylphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(4-fluoro-3-methoxyphenyl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(4-fluoro-3-methoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(8-fluoroimidazo[1,2-a]pyridin-2-yl)-7-(octahydro-2H-pyrido[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

7-(piperazin-1-yl)-3-(pyrrolo[1,2-a]pyrimidin-7-yl)-2H-chromen-2-one;

7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-(pyrrolo[1,2-a]pyrimidin-7-yl)-2H-chromen-2-one;

3-(7-methylimidazo[1,2-a]pyridin-2-yl)-7-[(3S)-pyrrolidin-3-ylamino]-2H-chromen-2-one;

3-(8-fluoro-6-methylimidazo[1,2-a]pyridin-2-yl)-7-[(3S)-pyrrolidin-3-ylamino]-2H-chromen-2-one;

3-(8-fluoro-6-methylimidazo[1,2-a]pyridin-2-yl)-7-[(3R)-pyrrolidin-3-ylamino]-2H-chromen-2-one;

7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-(3-methylpyrrolo[1,2-a]pyrazin-7-yl)-2H-chromen-2-one;

7-[(3S)-3,4-dimethylpiperazin-1-yl]-3-(8-fluoroimidazo[1,2-a]pyridin-2-yl)-2H-chromen-2-one;

7-[(3R)-3-methylpiperazin-1-yl]-3-(1-methylpyrrolo[1,2-a]pyrazin-7-yl)-2H-chromen-2-one;

7-(1,4-diazepan-1-yl)-3-(1-methylpyrrolo[1,2-a]pyrazin-7-yl)-2H-chromen-2-one;

3-(3-methylpyrrolo[1,2-a]pyrazin-7-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

7-(4-methyl-1,4-diazepan-1-yl)-3-(3-methylpyrrolo[1,2-a]pyrazin-7-yl)-2H-chromen-2-one;

7-(4-methylpiperazin-1-yl)-3-(3-methylpyrrolo[1,2-a]pyrazin-7-yl)-2H-chromen-2-one;

5-fluoro-7-(4-methyl-1,4-diazepan-1-yl)-3-(6-methylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

5-fluoro-3-(6-methylimidazo[1,2-a]pyrazin-2-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

5-fluoro-3-(6-methylimidazo[1,2-a]pyrazin-2-yl)-7-[(3S)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(6-methylimidazo[1,2-a]pyrazin-2-yl)-7-[(3R)-pyrrolidin-3-yloxy]-2H-chromen-2-one;

7-(5,8-diazaspiro[3.5]non-8-yl)-3-(7-methylimidazo[1,2-a]pyridin-2-yl)-2H-chromen-2-one;

7-(6,9-diazaspiro[4.5]dec-9-yl)-3-(7-methylimidazo[1,2-a]pyridin-2-yl)-2H-chromen-2-one;

7-(2,5-diazabicyclo[2.2.2]oct-2-yl)-3-(7-methylimidazo[1,2-a]pyridin-2-yl)-2H-chromen-2-one;

7-(5,8-diazaspiro[3.5]non-8-yl)-3-(8-fluoro-6-methylimidazo[1,2-a]pyridin-2-yl)-2H-chromen-2-one;

7-(6,9-diazaspiro[4.5]dec-9-yl)-3-(8-fluoro-6-methylimidazo[1,2-a]pyridin-2-yl)-2H-chromen-2-one;

7-(2,5-diazabicyclo[2.2.2]oct-2-yl)-3-(8-fluoro-6-methylimidazo[1,2-a]pyridin-2-yl)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(3R)-pyrrolidin-3-yloxy]-2H-chromen-2-one;

3-(1-benzofuran-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(1-benzofuran-2-yl)-7-[(3S)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(1-benzofuran-2-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(3R)-3,4-dimethylpiperazin-1-yl]-2H-chromen-2-one;

7-(1,4-diazepan-1-yl)-3-[6-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyrazin-2-yl]-2H-chromen-2-one;

7-(1,4-diazepan-1-yl)-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-5-fluoro-2H-chromen-2-one;

7-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-3-(6-methylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

3-(8-methylimidazo[1,2-a]pyrazin-2-yl)-7-[(3R)-pyrrolidin-3-yloxy]-2H-chromen-2-one;

3-(8-fluoro-6-methylimidazo[1,2-a]pyridin-2-yl)-7-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-2H-chromen-2-one;

3-(8-fluoro-6-methylimidazo[1,2-a]pyridin-2-yl)-7-(octahydro-2H-pyrido[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

3-(8-fluoro-6-methylimidazo[1,2-a]pyridin-2-yl)-7-(8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-5-fluoro-7-(4-methyl-1,4-diazepan-1-yl)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[methyl(1-methylpyrrolidin-3-yl)amino]-2H-chromen-2-one;

7-[(1-benzylpyrrolidin-3-yl)(methyl)amino]-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-(6-methylimidazo[1,2-b]pyridazin-2-yl)-2H-chromen-2-one;

7-(4-ethyl-1,4-diazepan-1-yl)-3-(6-methylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

7-(azetidin-3-ylamino)-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-{methyl[(3S)-pyrrolidin-3-yl]amino}-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-(4-ethylpiperazin-1-yl)-2H-chromen-2-one;

7-(4-ethylpiperazin-1-yl)-3-(6-methylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

7-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-3-(6-methylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

3-(6-methylimidazo[1,2-b]pyridazin-2-yl)-7-[(3S)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

7-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-3-(6-methylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(3S)-4-ethyl-3-methylpiperazin-1-yl]-2H-chromen-2-one;

7-[(3S)-4-ethyl-3-methylpiperazin-1-yl]-3-(6-methylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

7-[(3R)-3,4-dimethylpiperazin-1-yl]-3-(6-methylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

7-[(3S)-3-methylpiperazin-1-yl]-3-(thieno[3,2-c]pyridin-2-yl)-2H-chromen-2-one;

7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-(thieno[3,2-c]pyridin-2-yl)-2H-chromen-2-one;

7-(1,4-diazepan-1-yl)-3-(6-methylimidazo[1,2-b]pyridazin-2-yl)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-(octahydro-2H-pyrido[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-2H-chromen-2-one;

3-(6-methylimidazo[1,2-a]pyrazin-2-yl)-7-(octahydro-2H-pyrido[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

7-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-3-(1-methylpyrrolo[1,2-a]pyrazin-7-yl)-2H-chromen-2-one;

7-[(3R)-3-methylpiperazin-1-yl]-3-(3-methylpyrrolo[1,2-a]pyrazin-7-yl)-2H-chromen-2-one;

7-(1,4-diazepan-1-yl)-3-(3-methylpyrrolo[1,2-a]pyrazin-7-yl)-2H-chromen-2-one;

7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-(2-methylpyrrolo[1,2-b]pyridazin-6-yl)-2H-chromen-2-one;

7-(4-ethylpiperazin-1-yl)-3-(3-methylpyrrolo[1,2-a]pyrazin-7-yl)-2H-chromen-2-one;

3-(2-methylpyrrolo[1,2-b]pyridazin-6-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

7-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-3-(1-methylpyrrolo[1,2-a]pyrazin-7-yl)-2H-chromen-2-one;

7-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-3-(3-methylpyrrolo[1,2-a]pyrazin-7-yl)-2H-chromen-2-one;

3-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-2H-chromen-2-one;

3-(3-methylpyrrolo[1,2-a]pyrazin-7-yl)-7-(octahydro-2H-pyrido[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

7-[(3S)-3-methylpiperazin-1-yl]-3-(3-methylpyrrolo[1,2-a]pyrazin-7-yl)-2H-chromen-2-one;

7-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

7-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-3-(2-methylimidazo[1,2-a]pyrimidin-6-yl)-2H-chromen-2-one;

3-(2-methylimidazo[1,2-a]pyrimidin-6-yl)-7-[(3R)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

7-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-3-(2-methylimidazo[1,2-a]pyridin-6-yl)-2H-chromen-2-one;

3-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3R)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

7-(4-methyl-1,4-diazepan-1-yl)-3-(2-methylimidazo[1,2-a]pyridin-6-yl)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[4-(2-hydroxyethyl)piperazin-1-yl]-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-{methyl[(3S)-1-methylpyrrolidin-3-yl]amino}-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-{[(3S)-1-methylpyrrolidin-3-yl]amino}-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(4aR,7aR)-1-methyloctahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-2H-chromen-2-one;

7-[(3S)-3,4-dimethylpiperazin-1-yl]-5-fluoro-3-(6-methylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

7-[(3R)-3,4-dimethylpiperazin-1-yl]-3-(2-methylimidazo[1,2-a]pyrimidin-6-yl)-2H-chromen-2-one;

7-[(3R)-3,4-dimethylpiperazin-1-yl]-3-(2-methylimidazo[1,2-a]pyridin-6-yl)-2H-chromen-2-one;

7-(4-methyl-1,4-diazepan-1-yl)-3-(2-methylimidazo[1,2-a]pyrimidin-6-yl)-2H-chromen-2-one;

7-(1,4-diazepan-1-yl)-3-(2-methylimidazo[1,2-a]pyridin-6-yl)-2H-chromen-2-one;

3-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3S)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-(3-ethylpiperazin-1-yl)-2H-chromen-2-one;

7-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-3-(3-methylpyrrolo[1,2-a]pyrazin-7-yl)-2H-chromen-2-one;

7-(4-ethyl-1,4-diazepan-1-yl)-3-(3-methylpyrrolo[1,2-a]pyrazin-7-yl)-2H-chromen-2-one;

3-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-7-[(3R)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-7-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-2H-chromen-2-one;

3-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-7-(4-ethyl-1,4-diazepan-1-yl)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(3S)-3,4-dimethylpiperazin-1-yl]-2H-chromen-2-one;

3-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-7-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-2H-chromen-2-one;

3-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-7-(4-ethylpiperazin-1-yl)-2H-chromen-2-one;

7-[(3S)-3,4-dimethylpiperazin-1-yl]-3-(2-methylimidazo[1,2-a]pyridin-6-yl)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-(3-ethyl-4-methylpiperazin-1-yl)-2H-chromen-2-one;

3-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(3R)-4-ethyl-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-7-[(3S)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-7-(4-methyl-1,4-diazepan-1-yl)-2H-chromen-2-one;

7-(1,4-diazepan-1-yl)-3-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-2H-chromen-2-one;

3-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-7-(octahydro-2H-pyrido[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

7-[4-(2-hydroxyethyl)piperazin-1-yl]-3-(3-methylpyrrolo[1,2-a]pyrazin-7-yl)-2H-chromen-2-one;

3-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-7-[4-(2-hydroxyethyl)piperazin-1-yl]-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl]-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(3aS,6aS)-5-methylhexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl]-2H-chromen-2-one;

7-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

7-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

3-(3-methylpyrrolo[1,2-a]pyrazin-7-yl)-7-[4-(propan-2-yl)piperazin-1-yl]-2H-chromen-2-one;

7-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-3-(3-methylpyrrolo[1,2-a]pyrazin-7-yl)-2H-chromen-2-one;

3-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-7-[(3S)-4-ethyl-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(2-methyl-1,3-benzoxazol-6-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]-2H-chromen-2-one;

7-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-3-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-2H-chromen-2-one;

3-(5-methylfuro[3,2-b]pyridin-2-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

3-(6-chloro-8-methylimidazo[1,2-a]pyrazin-2-yl)-7-[(3R)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-{methyl[(3R)-pyrrolidin-3-yl]amino}-2H-chromen-2-one;

7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-(6-methyl-8-nitroimidazo[1,2-a]pyridin-2-yl)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-{[(3-exo)-9-methyl-9-azabicyclo[3.3.1]non-3-yl]amino}-2H-chromen-2-one;

3-(6-methyl-8-nitroimidazo[1,2-a]pyridin-2-yl)-7-[(3S)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(3aR,6aR)-1-methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]-2H-chromen-2-one;

3-(2,4-dimethylthieno[2,3-d]pyrimidin-6-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(3aS,6aS)-1-methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-{methyl[(3R)-1-methylpyrrolidin-3-yl]amino}-2H-chromen-2-one;

7-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-3-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-2H-chromen-2-one;

3-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-7-[4-(propan-2-yl)piperazin-1-yl]-2H-chromen-2-one;

3-(6-chloro-8-methylimidazo[1,2-a]pyrazin-2-yl)-7-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-2H-chromen-2-one;

3-(6-chloro-8-methylimidazo[1,2-a]pyrazin-2-yl)-7-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-2H-chromen-2-one;

3-(6-chloro-8-methylimidazo[1,2-a]pyrazin-2-yl)-7-(4-methyl-1,4-diazepan-1-yl)-2H-chromen-2-one;

3-(6-chloro-8-methylimidazo[1,2-a]pyrazin-2-yl)-7-[(3S)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

7-(4-aminopiperidin-1-yl)-3-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-2H-chromen-2-one;

7-[4-(dimethylamino)piperidin-1-yl]-3-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-2H-chromen-2-one;

7-[4-(dimethylamino)piperidin-1-yl]-3-(3-methylpyrrolo[1,2-a]pyrazin-7-yl)-2H-chromen-2-one;

7-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-3-(2-methylimidazo[1,2-a]pyridin-6-yl)-2H-chromen-2-one;

7-[(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-3-(6-methylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

3-(6-methylimidazo[1,2-a]pyrazin-2-yl)-7-[(4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-2H-chromen-2-one;

7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-(5-methylfuro[3,2-b]pyridin-2-yl)-2H-chromen-2-one;

7-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-3-(5-methylfuro[3,2-b]pyridin-2-yl)-2H-chromen-2-one;

7-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-3-(5-methylfuro[3,2-b]pyridin-2-yl)-2H-chromen-2-one;

3-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

tert-butyl {(3S)-1-[3-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-2-oxo-2H-chromen-7-yl]pyrrolidin-3-yl}carbamate;

3-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-7-[(3S)-3-(propan-2-ylamino)pyrrolidin-1-yl]-2H-chromen-2-one;

3-(6-chloro-8-methylimidazo[1,2-a]pyrazin-2-yl)-7-[(3R)-3,4-dimethylpiperazin-1-yl]-2H-chromen-2-one;

3-(6-chloro-8-methylimidazo[1,2-a]pyrazin-2-yl)-7-[(3S)-3,4-dimethylpiperazin-1-yl]-2H-chromen-2-one;

3-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-7-{[(1R,5S)-9-methyl-9-azabicyclo[3.3.1]non-3-yl]amino}-2H-chromen-2-one;

3-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-7-[(3 aS,6aS)-1-methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-{[(3R)-1-methylpyrrolidin-3-yl]amino}-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-{[(3R)-1-ethylpyrrolidin-3-yl]amino}-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-{[(3R)-1-(2-hydroxyethyl)pyrrolidin-3-yl]amino}-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-{[(3R)-1-(propan-2-yl)pyrrolidin-3-yl]amino}-2H-chromen-2-one;

7-[(3R,4R)-3-(dimethylamino)-4-hydroxypyrrolidin-1-yl]-3-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-2H-chromen-2-one;

7-[3-(diethylamino)pyrrolidin-1-yl]-3-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-(3,3-dimethylpiperazin-1-yl)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-(3,3,4-trimethylpiperazin-1-yl)-2H-chromen-2-one;

7-[(3S,4S)-3-(dimethylamino)-4-hydroxypyrrolidin-1-yl]-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(3′S,4′S)-4′-hydroxy-1,3′-bipyrrolidin-1′-yl]-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(3aR,6aS)-5-(2-hydroxyethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-(piperidin-4-yl)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(3aR,6aS)-5-(propan-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-2H-chromen-2-one;

7-(2,5-diazabicyclo[2.2.1]hept-2-yl)-3-(3-methylpyrrolo[1,2-a]pyrazin-7-yl)-2H-chromen-2-one;

3-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-(4-ethylpiperazin-1-yl)-5-fluoro-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(3aR,6aS)-5-ethylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-(1-methylpiperidin-4-yl)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-(1-ethylpiperidin-4-yl)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[1-(2-hydroxyethyl)piperidin-4-yl]-2H-chromen-2-one;

3-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-7-[(3′R,4′R)-4′-hydroxy-1,3′-bipyrrolidin-1′-yl]-2H-chromen-2-one;

7-(4-cyclopropylpiperazin-1-yl)-3-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-2H-chromen-2-one;

3-(3-methylpyrrolo[1,2-a]pyrazin-7-yl)-7-[4-(propan-2-yl)-1,4-diazepan-1-yl]-2H-chromen-2-one;

3-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-7-[4-(propan-2-yl)-1,4-diazepan-1-yl]-2H-chromen-2-one;

3-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-7-[(3aR,6aR)-1-methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]-2H-chromen-2-one;

3-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-7-[(3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-2H-chromen-2-one;

3-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-7-[3-(morpholin-4-yl)pyrrolidin-1-yl]-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(7R,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-2H-chromen-2-one;

7-[(3R)-3,4-dimethylpiperazin-1-yl]-3-(8-methoxy-6-methylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

7-[(3R)-3,4-dimethylpiperazin-1-yl]-3-(8-hydroxy-6-methylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

7-[(1R,5S,6s)-6-(dimethylamino)-3-azabicyclo[3.1.0]hex-3-yl]-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

7-(4-cyclopropylpiperazin-1-yl)-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

3-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

3-(6-chloro-8-methylimidazo[1,2-a]pyrazin-2-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

3-(6-chloro-8-methylimidazo[1,2-a]pyrazin-2-yl)-7-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-2H-chromen-2-one;

3-(6-chloro-8-methylimidazo[1,2-a]pyrazin-2-yl)-7-(4-ethylpiperazin-1-yl)-2H-chromen-2-one;

3-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-7-[(7R,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-2H-chromen-2-one;

3-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-7-[(3S)-3-methyl-4-(propan-2-yl)piperazin-1-yl]-2H-chromen-2-one;

3-(2-methyl-1,3-benzothiazol-6-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

3-(2-methyl-1,3-benzothiazol-6-yl)-7-[(3S)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

7-(1,4-diazepan-1-yl)-3-(2-methyl-1,3-benzothiazol-6-yl)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(3S)-3-ethylpiperazin-1-yl]-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[1-(propan-2-yl)piperidin-4-yl]-2H-chromen-2-one;

3-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-[4-(2-hydroxyethyl)piperazin-1-yl]-2H-chromen-2-one;

3-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-(4-methyl-1,4-diazepan-1-yl)-2H-chromen-2-one;

7-[(3S)-3,4-dimethylpiperazin-1-yl]-3-(2-methyl-1,3-benzothiazol-6-yl)-2H-chromen-2-one;

7-[(3S)-4-ethyl-3-methylpiperazin-1-yl]-3-(2-methyl-1,3-benzothiazol-6-yl)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(3S)-3-ethyl-4-methylpiperazin-1-yl]-2H-chromen-2-one;

7-[(3S)-3,4-diethylpiperazin-1-yl]-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

3-(6-chloro-8-methylimidazo[1,2-a]pyrazin-2-yl)-7-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(4aR,7aR)-1-methyloctahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-2H-chromen-2-one;

7-(2,5-diazabicyclo[2.2.1]hept-2-yl)-3-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-2H-chromen-2-one;

7-[4-(aminomethyl)piperidin-1-yl]-3-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(4aR,7aR)-1-(2-hydroxyethyl)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(4aR,7aR)-1-ethyloctahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-2H-chromen-2-one;

3-(6-chloro-8-methylimidazo[1,2-a]pyrazin-2-yl)-7-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]-2H-chromen-2-one;

3-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-(4-ethylpiperazin-1-yl)-2H-chromen-2-one;

3-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-[4-(propan-2-yl)piperazin-1-yl]-2H-chromen-2-one;

3-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-7-{4-[(propan-2-ylamino)methyl]piperidin-1-yl}-2H-chromen-2-one;

3-(6-chloro-8-methylimidazo[1,2-a]pyrazin-2-yl)-7-[(1S,4S)-5-ethyl-2,5-diazabicyclo[2.2.1]hept-2-yl]-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[4-(propan-2-yl)piperazin-1-yl]-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(1S,4S)-5-ethyl-2,5-diazabicyclo[2.2.1]hept-2-yl]-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(4aS,7aS)-1-methyloctahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(4aS,7aS)-1-(2-hydroxyethyl)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-2H-chromen-2-one;

7-[(3R,5S)-4-ethyl-3,5-dimethylpiperazin-1-yl]-3-(6-methylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

7-(4-cyclopropylpiperazin-1-yl)-3-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-2H-chromen-2-one;

3-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-[4-(2-methoxyethyl)piperazin-1-yl]-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[1-(2-hydroxyethyl)-1,2,3,6-tetrahydropyridin-4-yl]-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(4aS,7aS)-1-ethyloctahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-2H-chromen-2-one;

3-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-[(3S)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-[(3S)-3,4-dimethylpiperazin-1-yl]-2H-chromen-2-one;

3-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-[(3R)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-[(3R)-3,4-dimethylpiperazin-1-yl]-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(3S)-3-(propan-2-yl)piperazin-1-yl]-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(3S)-4-methyl-3-(propan-2-yl)piperazin-1-yl]-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(3S)-4-ethyl-3-(propan-2-yl)piperazin-1-yl]-2H-chromen-2-one;

7-(4-cyclopropylpiperazin-1-yl)-3-(6-methylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

7-(4-tert-butylpiperazin-1-yl)-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

3-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-7-[(3R)-3-methyl-4-(propan-2-yl)piperazin-1-yl]-2H-chromen-2-one;

7-(4-cyclobutylpiperazin-1-yl)-3-(1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl)-2H-chromen-2-one;

3-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-(4-propylpiperazin-1-yl)-2H-chromen-2-one;

7-[4-(cyclopropylmethyl)piperazin-1-yl]-3-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-2H-chromen-2-one;

3-(4,6-dimethylthieno[3,2-c]pyridin-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

7-(2-methylimidazo[1,2-a]pyridin-6-yl)-3-(piperazin-1-yl)-2H-chromen-2-one;

3-(4,6-dimethylthieno[3,2-c]pyridin-2-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

3-(4,6-dimethylthieno[3,2-c]pyridin-2-yl)-7-[4-(2-methoxyethyl)piperazin-1-yl]-2H-chromen-2-one;

7-(1-cyclobutylpiperidin-4-yl)-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

7-(4-cyclobutylpiperazin-1-yl)-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[4-(oxetan-3-yl)piperazin-1-yl]-2H-chromen-2-one;

3-(8-ethyl-6-methylimidazo[1,2-a]pyrazin-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperidin-4-yl)-2H-chromen-2-one;

3-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-(1-methylpiperidin-4-yl)-2H-chromen-2-one;

7-(1-ethylpiperidin-4-yl)-3-(2-methylimidazo[1,2-a]pyridin-6-yl)-2H-chromen-2-one;

3-(2-methylimidazo[1,2-a]pyridin-6-yl)-7-[1-(oxetan-3-yl)piperidin-4-yl]-2H-chromen-2-one;

7-[1-(2-hydroxyethyl)piperidin-4-yl]-3-(2-methylimidazo[1,2-a]pyridin-6-yl)-2H-chromen-2-one;

3-(8-ethyl-6-methylimidazo[1,2-a]pyrazin-2-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

3-(4,6-dimethylfuro[3,2-c]pyridin-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(4,6-dimethylfuro[3,2-c]pyridin-2-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

3-(6-methylimidazo[1,2-a]pyrazin-2-yl)-7-[4-(propan-2-yl)piperazin-1-yl]-2H-chromen-2-one;

3-(2-methylimidazo[1,2-a]pyrimidin-6-yl)-7-(piperidin-4-yl)-2H-chromen-2-one;

3-(2-methylimidazo[1,2-a]pyrimidin-6-yl)-7-(1-methylpiperidin-4-yl)-2H-chromen-2-one;

7-(1-ethylpiperidin-4-yl)-3-(2-methylimidazo[1,2-a]pyrimidin-6-yl)-2H-chromen-2-one;

7-[4-(2-hydroxyethyl)piperazin-1-yl]-3-(6-methylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

7-(4-cyclobutylpiperazin-1-yl)-3-(6-methylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

3-(6-methylimidazo[1,2-a]pyrazin-2-yl)-7-[4-(oxetan-3-yl)piperazin-1-yl]-2H-chromen-2-one;

3-(4,6-dimethylfuro[3,2-c]pyridin-2-yl)-7-[4-(propan-2-yl)piperazin-1-yl]-2H-chromen-2-one;

3-(6-methylimidazo[1,2-a]pyrazin-2-yl)-7-(1-methylpiperidin-4-yl)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-(1-propylpiperidin-4-yl)-2H-chromen-2-one;

7-[1-(2-hydroxyethyl)piperidin-4-yl]-3-(6-methylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

7-(1-ethylpiperidin-4-yl)-3-(6-methylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

3-[2-methyl-3-(1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl]-7-(1,2,3,6-tetrahydropyridin-4-yl)-2H-chromen-2-one;

7-[(dimethylamino)methyl]-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-(piperidin-1-ylmethyl)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-(piperazin-1-ylmethyl)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(4-methylpiperazin-1-yl)methyl]-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(propan-2-ylamino)methyl]-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-(1H-imidazol-1-ylmethyl)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-(4-ethyl-3-methylpiperazin-1-yl)-2H-chromen-2-one;

3-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-ethylpiperidin-4-yl)-2H-chromen-2-one;

7-(1-cyclopropylpiperidin-4-yl)-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[1-(oxetan-3-yl)piperidin-4-yl]-2H-chromen-2-one;

3-(2-methyl-2H-indazol-5-yl)-7-(piperidin-4-yl)-2H-chromen-2-one;

7-[3-(dimethylamino)propyl]-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[3-(propan-2-ylamino)propyl]-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[3-(piperazin-1-yl)propyl]-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[3-(4-methylpiperazin-1-yl)propyl]-2H-chromen-2-one;

7-[1-(2-hydroxyethyl)piperidin-4-yl]-3-(2-methyl-2H-indazol-5-yl)-2H-chromen-2-one;

3-(2-methyl-2H-indazol-5-yl)-7-(1-methylpiperidin-4-yl)-2H-chromen-2-one;

7-(1-ethylpiperidin-4-yl)-3-(2-methyl-2H-indazol-5-yl)-2H-chromen-2-one;

7-[2-(dimethylamino)ethyl]-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[2-(propan-2-ylamino)ethyl]-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[2-(piperazin-1-yl)ethyl]-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(1-methylpiperidin-4-yl)oxy]-2H-chromen-2-one;

3-(6-methylimidazo[1,2-a]pyrazin-2-yl)-7-(piperidin-4-yl)-2H-chromen-2-one;

7-(1-cyclobutylpiperidin-4-yl)-3-(6-methylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-{2-[(2-hydroxyethyl)amino]ethyl}-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-{2-[(2-hydroxyethyl)(methyl)amino]ethyl}-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-{2-[(1-hydroxypropan-2-yl)amino]ethyl}-2H-chromen-2-one;

7-{2-[(1,3-dihydroxypropan-2-yl)amino]ethyl}-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-{2-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]ethyl}-2H-chromen-2-one;

7-{2-[bis(2-hydroxyethyl)amino]ethyl}-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

7-[2-(dimethylamino)ethoxy]-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[2-(propan-2-ylamino)ethoxy]-2H-chromen-2-one;

3-(6-methylimidazo[1,2-a]pyrazin-2-yl)-7-[1-(oxetan-3-yl)piperidin-4-yl]-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-{3-[(2-hydroxyethyl)amino]propyl}-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-{3-[(2-hydroxyethyl)(methyl)amino]propyl}-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-{3-[(1-hydroxypropan-2-yl)amino]propyl}-2H-chromen-2-one;

7-{3-[(1,3-dihydroxypropan-2-yl)amino]propyl}-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-{3-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]propyl}-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[3-(morpholin-4-yl)propyl]-2H-chromen-2-one;

7-{3-[bis(2-hydroxyethyl)amino]propyl}-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[2-(morpholin-4-yl)ethyl]-2H-chromen-2-one;

3-(6-methylimidazo[1,2-a]pyrazin-2-yl)-7-(1-propylpiperidin-4-yl)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(3S)-4-(2-hydroxyethyl)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-{[(3R)-1-methylpyrrolidin-3-yl]oxy}-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-{[(3R)-1-ethylpyrrolidin-3-yl]oxy}-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-{[(3R)-1-(propan-2-yl)pyrrolidin-3-yl]oxy}-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-{[(3R)-1-(2-hydroxyethyl)pyrrolidin-3-yl]oxy}-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-{[(3R)-1-(1-hydroxypropan-2-yl)pyrrolidin-3-yl]oxy}-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(3S)-4-(2-fluoroethyl)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

7-[2-(diethylamino)ethoxy]-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

7-{2-[bis(2-hydroxyethyl)amino]ethoxy}-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-(piperidin-4-yloxy)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(1-ethylpiperidin-4-yl)oxy]-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-{[1-(2-hydroxyethyl)piperidin-4-yl]oxy}-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(3S)-4-(3-fluoropropyl)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-{[1-(propan-2-yl)piperidin-4-yl]oxy}-2H-chromen-2-one;

7-[4-(dimethylamino)butyl]-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-{4-[(2-hydroxyethyl)(methyl)amino]butyl}-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-{4-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]butyl}-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[4-(piperazin-1-yl)butyl]-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[1-(3-fluoropropyl)piperidin-4-yl]-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(3S)-4-(3-hydroxypropyl)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

7-[3-(dimethylamino)propyl]-3-(2-methylimidazo[1,2-a]pyridin-6-yl)-2H-chromen-2-one;

7-[3-(dimethylamino)propyl]-3-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2H-chromen-2-one;

7-[3-(dimethylamino)propyl]-3-(8-ethyl-2-methylimidazo[1,2-a]pyridin-6-yl)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[2-(methylamino)ethyl]-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[3-(methylamino)propyl]-2H-chromen-2-one;

3-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[3-(methylamino)propyl]-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[1-(2-methylpropyl)piperidin-4-yl]-2H-chromen-2-one;

7-{[1-(1,3-dihydroxypropan-2-yl)piperidin-4-yl]oxy}-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

3-(6-methylimidazo[1,2-a]pyrazin-2-yl)-7-[1-(2-methylpropyl)piperidin-4-yl]-2H-chromen-2-one;

7-[1-(3-fluoropropyl)piperidin-4-yl]-3-(6-methylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[2-(pyrrolidin-1-yl)ethoxy]-2H-chromen-2-one;

7-(4-aminopiperidin-1-yl)-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

7-(4-amino-4-methylpiperidin-1-yl)-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

7-[4-(dimethylamino)piperidin-1-yl]-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

7-[4-(diethylamino)piperidin-1-yl]-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[4-(propan-2-ylamino)piperidin-1-yl]-2H-chromen-2-one;

7-[4-(cyclobutylamino)piperidin-1-yl]-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-{4-[(1-hydroxypropan-2-yl)amino]piperidin-1-yl}-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[3-(ethylamino)propyl]-2H-chromen-2-one;

7-(3-aminopropyl)-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

7-{4-[bis(2-hydroxyethyl)amino]piperidin-1-yl}-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

7-{4-[(1,3-dihydroxypropan-2-yl)amino]piperidin-1-yl}-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[2-(ethylamino)ethoxy]-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-{3-[(2-methoxyethyl)amino]propyl}-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-{3-[(tetrahydrofuran-2-ylmethyl)amino]propyl}-2H-chromen-2-one;

7-[3-(benzylamino)propyl]-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-{3-[(thiophen-3-ylmethyl)amino]propyl}-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-{3-[(pyridin-2-ylmethyl)amino]propyl}-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-{3-[(pyridin-4-ylmethyl)amino]propyl}-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-{2-[ethyl(methyl)amino]ethoxy}-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-{2-[ethyl(2-hydroxyethyl)amino]ethoxy}-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[3-(tetrahydrofuran-3-ylamino)propyl]-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-{2-[(3R)-3-hydroxypyrrolidin-1-yl]ethoxy}-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[3-(2-methylpiperidin-1-yl)azetidin-1-yl]-2H-chromen-2-one;

7-[3-(dimethylamino)azetidin-1-yl]-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

7-[3-(diethylamino)azetidin-1-yl]-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

7-(2,7-diazaspiro[4.4]non-2-yl)-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-(2-{[(2R)-1-hydroxypropan-2-yl]amino}ethoxy)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-(2-{[(2S)-1-hydroxypropan-2-yl]amino}ethoxy)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(2R)-pyrrolidin-2-ylmethoxy]-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)-2H-chromen-2-one;

7-[(3R)-3-(aminomethyl)pyrrolidin-1-yl]-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[3-(piperidin-1-yl)azetidin-1-yl]-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[4-(methylamino)butyl]-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[2-(piperidin-1-yl)ethoxy]-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-{2-[(3S)-3-hydroxypyrrolidin-1-yl]ethoxy}-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-{2-[(1-hydroxy-2-methylpropan-2-yl)amino]ethoxy}-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[2-(morpholin-4-yl)ethoxy]-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[2-(4-hydroxypiperidin-1-yl)ethoxy]-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-(1-ethyl-4-fluoropiperidin-4-yl)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-{2-[(2-hydroxyethyl)amino]ethoxy}-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-{2-[(2-methoxyethyl)amino]ethoxy}-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-{2-[(2-hydroxypropyl)amino]ethoxy}-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[4-(2-hydroxy-2-methylpropyl)piperazin-1-yl]-2H-chromen-2-one;

7-[3-(aminomethyl)azetidin-1-yl]-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

7-[(3S)-3-(aminomethyl)pyrrolidin-1-yl]-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

7-{(3R)-3-[(dimethylamino)methyl]pyrrolidin-1-yl}-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

7-{3-[(dimethylamino)methyl]azetidin-1-yl}-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

7-{(3S)-3-[(dimethylamino)methyl]pyrrolidin-1-yl}-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

7-[2-(diethylamino)ethyl]-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

7-[3-(diethylamino)propyl]-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

7-[4-(diethylamino)butyl]-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

7-(2,6-diazaspiro[3.3]hept-2-yl)-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-(6-methyl-2,6-diazaspiro[3.3]hept-2-yl)-2H-chromen-2-one;

2-[3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2-oxo-2H-chromen-7-yl]hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one;

1-[3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2-oxo-2H-chromen-7-yl]piperidine-4-carbonitrile;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-(4-hydroxypiperidin-1-yl)-2H-chromen-2-one;

7-(2,7-diazaspiro[3.5]non-7-yl)-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

7-(6-amino-2-azaspiro[3.3]hept-2-yl)-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one;

3-(imidazo[1,2-a]pyridin-6-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

7-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-3-(imidazo[1,2-a]pyridin-6-yl)-2H-chromen-2-one;

3-(imidazo[1,2-a]pyridin-6-yl)-7-(piperazin-1-yl)-2H-chromen-2-one;

3-(imidazo[1,2-a]pyridin-6-yl)-7-[(3S)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

3-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(4-methylpiperazin-1-yl)-2H-chromen-2-one;

3-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-2H-chromen-2-one;

3-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-[(3S)-3-methylpiperazin-1-yl]-2H-chromen-2-one;

7-(2,6-diazaspiro[3.3]hept-2-yl)-3-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2H-chromen-2-one; and

3-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-(piperazin-1-yl)-2H-chromen-2-one,

or a salt, isotopologue, stereoisomer, racemate, enantiomer, diastereomer or tautomer thereof.

4. The compound of claim 3, wherein the compound is selected from:

7-(piperazin-1-yl)-3-[4-(trifluoromethyl)-1,3-benzoxazol-2-yl]-2H-chromen-2-one trifluoroacetate;

7-(piperazin-1-yl)-3-[4-(trifluoromethyl)-1,3-benzoxazol-2-yl]-2H-chromen-2-one hydrochloride;

7-(piperazin-1-yl)-3-[7-(trifluoromethyl)-1,3-benzoxazol-2-yl]-2H-chromen-2-one trifluoroacetate;

7-(piperazin-1-yl)-3-[7-(trifluoromethyl)-1,3-benzoxazol-2-yl]-2H-chromen-2-one hydrochloride;

2-oxo-N-phenyl-7-(piperazin-1-yl)-2H-chromene-3-carboxamide trifluoroacetate;

3-(1,3-benzothiazol-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one hydrochloride;

3-(4-chloro-1,3-benzothiazol-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one hydrochloride;

3-(7-chloro-1,3-benzothiazol-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one hydrochloride;

3-(4-chloro-1,3-benzothiazol-2-yl)-7-(piperidin-4-yl)-2H-chromen-2-one hydrochloride;

3-(5-fluoro-1,3-benzoxazol-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one hydrochloride;

3-(4-methyl-1,3-benzoxazol-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one hydrochloride;

3-(4-fluoro-1,3-benzoxazol-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one hydrochloride;

7-(piperazin-1-yl)-3-[4-(trifluoromethyl)-1,3-thiazol-2-yl]-2H-chromen-2-one trifluoroacetate;

7-(piperazin-1-yl)-3-[4-(trifluoromethyl)-1,3-thiazol-2-yl]-2H-chromen-2-one hydrochloride;

7-(4-methylpiperazin-1-yl)-3-[4-(trifluoromethyl)-1,3-thiazol-2-yl]-2H-chromen-2-one trifluoroacetate;

3-(4-iodo-1,3-benzoxazol-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one hydrochloride;

3-(4-chloro-1,3-benzoxazol-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one hydrochloride;

3-([1,3]oxazolo[4,5-b]pyridin-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one hydrochloride;

7-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-3-(imidazo[1,2-a]pyrimidin-2-yl)-2H-chromen-2-one hydrochloride (1:3);

3-(3-methylimidazo[2,1-b][1,3]thiazol-6-yl)-7-(piperazin-1-yl)-2H-chromen-2-one hydrochloride (1:3);

7-(1,4-diazepan-1-yl)-3-(imidazo[1,2-a]pyrimidin-2-yl)-2H-chromen-2-one hydrochloride;

3-(imidazo[1,2-a]pyrimidin-2-yl)-7-(piperidin-4-yloxy)-2H-chromen-2-one hydrochloride;

3-(2-methylpyrimidin-4-yl)-7-(piperazin-1-yl)-2H-chromen-2-one hydrochloride;

3-(2-cyclopropylpyrimidin-4-yl)-7-(piperazin-1-yl)-2H-chromen-2-one hydrochloride;

7-(piperazin-1-yl)-3-[2-(propan-2-yl)pyrimidin-4-yl]-2H-chromen-2-one hydrochloride;

3-(imidazo[1,2-a]pyrimidin-2-yl)-7-[(3R)-pyrrolidin-3-yloxy]-2H-chromen-2-one hydrochloride (1:2);

3-(7-methylimidazo[1,2-a]pyrimidin-2-yl)-7-[(3R)-pyrrolidin-3-yloxy]-2H-chromen-2-one hydrochloride (1:2);

3-(7-methylimidazo[1,2-a]pyridin-2-yl)-7-[(3R)-pyrrolidin-3-yloxy]-2H-chromen-2-one hydrochloride (1:2);

3-(imidazo[2,1-b][1,3]thiazol-6-yl)-7-[(3R)-pyrrolidin-3-yloxy]-2H-chromen-2-one hydrochloride (1:2);

3-(2-methylimidazo[2,1-b][1,3]thiazol-6-yl)-7-[(3R)-pyrrolidin-3-yloxy]-2H-chromen-2-one hydrochloride (1:2);

3-(6-methylimidazo[1,2-a]pyridin-2-yl)-7-[(3R)-pyrrolidin-3-yloxy]-2H-chromen-2-one hydrochloride (1:2);

3-(6-methylimidazo[1,2-a]pyrimidin-2-yl)-7-[(3R)-pyrrolidin-3-yloxy]-2H-chromen-2-one hydrochloride (1:2);

7-[(1-benzylpyrrolidin-3-yl)(methyl)amino]-3-(7-methylimidazo[1,2-a]pyrimidin-2-yl)-2H-chromen-2-one acetate;

7-[(3R)-3,4-dimethylpiperazin-1-yl]-3-(8-methoxy-6-methylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one acetate (1:2);

7-[(3R)-3,4-dimethylpiperazin-1-yl]-3-(8-hydroxy-6-methylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one acetate;

7-[(3S)-3,4-dimethylpiperazin-1-yl]-3-(2-methyl-1,3-benzothiazol-6-yl)-2H-chromen-2-one acetate (2:1);

7-[(3S)-4-ethyl-3-methylpiperazin-1-yl]-3-(2-methyl-1,3-benzothiazol-6-yl)-2H-chromen-2-one acetate;

3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-[(3S)-3-ethyl-4-methylpiperazin-1-yl]-2H-chromen-2-one acetate; and

7-[(3S)-3,4-diethylpiperazin-1-yl]-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one acetate (1:2),

or a free base, stereoisomer, racemate, enantiomer, diastereomer or tautomer thereof.

5. A pharmaceutical composition comprising an effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier, excipient or diluent.

6. A compound selected from formula (Ia):

7. The compound of claim 6, wherein the salt form is a chloride, hydrochloride, dihydrochloride, hydrobromide, acetate or trifluoroacetate salt.