FIELD OF THE DISCLOSURE

[0001] The present application is directed to inhibitors of autophagy -related protein-protein interactions. Further, described herein is the use of these inhibitors for treating an autophagy- related disease or disorder, cancer or tumor, a cytokine release syndrome (CRS) or a cytokine storm in a subject.

BACKGROUND

[0002] Autophagy manifests in advanced cancer and acute inflammation as two functional arms of lysosomal degradation of intracellular components and autophagy-dependent secretion of cytokines. It is well established that many types of primary and metastatic solid tumors, depend on the lysosomal-mediated recycling features of autophagy in order to manage the various stress conditions in the tumor microenvironment such as hypoxia and nutrient starvation. The dependence of various tumors on excessive levels of autophagy is termed autophagy addiction. During chemotherapy or targeted cancer therapy, autophagy is upregulated and assists the cancer cells to counteract the drug-induced toxicity caused by these treatments. Additionally, the secretory arm of autophagy that enables leaderless cytokines such as IL-1β to exit the cell without entering the Endoplasmic reticulum (ER) and the Golgi pathways, promotes the cytokine storm in acute inflammation.

[0003] The current available drugs such as chloroquine / hydroxychloroquine, or inhibitors of ULK1 or of Vps34, have multiple off target effects, and are not selective to autophagy.

[0004] In view of the lack of specific autophagy inhibitory drugs, there is a need to develop potent and selective drugs, having minimal off target effects, for the treatment of cancer and acute inflammation, and other autophagy-related diseases or disorders.

SUMMARY OF THE DISCLOSURE

[0005] In some aspects, disclosed herein is an autophagy inhibitor compound represented by the structure of formula (I): wherein, is a single or double bond;

Y is NR ₄ , O or S;

Wi- W ₄ are each independently null, hydrogen,

R ₁ is alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -alkyl-aryl, SO ₂ alkyl, SO ₂ aryl, or - alkyl-O-alkyl;

R ₂ and R ₃ are each independently null, OH, hydrogen, -O-alkyl, halide, amino, or R ₂ and R ₃ are joined together to form a 5 or 6 membered substituted or unsubstituted ring;

R ₄ is H, alkyl or aryl;

R ₅ is hydrogen, alkyl, aryl,

R ₆ is hydrogen, or alkyl;

R ₇ is H, -OH, O-alkyl-aryl, or -S02-alkyl; wherein the alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -alkyl-aryl, -alkyl-O-alkyl are independently substituted or unsubstituted;

X ₁ -X ₇ are each independently N or C;

X ₈ -X ₉ are each independently N, C, CH, O or S; and n is an integer between 0-5; or pharmaceutically acceptable salt thereof.

[0006] In some aspects, disclosed herein autophagy inhibitor compounds represented by Compound 55 or Compound 42, or pharmaceutically acceptable salt thereof: [0007] In some aspects, disclosed herein is an autophagy inhibitor compound represented by the structure of formula (VI): wherein the aryl comprises substituted or unsubstituted aryl; and

Q ₃ -Q ₉ are each independently H, halo or -OH, wherein at least one of Q ₃ -Q ₉ is OH; or pharmaceutically acceptable salt thereof.

[0008] In other embodiments, the aryl of formula VI is a phenyl. In other embodiments, the aryl of formula VI is a naphthyl.

[0009] In some aspects, disclosed herein is an autophagy inhibitor compound represented by the structure of formula (VII): wherein.

Q ₁ is independently H, halo, OH, O-alkyl, alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl; Q ₂ is H, halo, OH, O-alkyl, alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl q is an integer between 1-4; and

Q ₃ -Q ₉ are each independently H , halo or -OH, wherein at least one of Q ₃ -Q ₉ is OH; or pharmaceutically acceptable salt thereof.

[0010] In some aspects, disclosed herein is a compound is represented by Compound 200, 201,

202, 203 or pharmaceutically acceptable salt thereof:

[0011] In some aspects, disclosed herein is a pharmaceutical composition comprising the autophagy inhibitor compounds provided herein, pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0012] In some aspects, disclosed herein is a method of treating an autophagy-related disease or disorder in a subject, comprising the step of administering to the subject a pharmaceutical composition provided herein.

[0013] In some aspects, disclosed herein is a method of treating, suppressing or inhibiting a cancer in a subject, comprising the step of administering to the subject a pharmaceutical composition provided herein. In other aspects, the cancer comprises a solid tumor. In other aspects, the cancer comprises a diffuse cancer.

[0014] In some aspects, disclosed herein is a method of inhibiting autophagic cell death (ACD) in a subject, comprising the step of administering to the subject a pharmaceutical composition provided herein.

[0015] In some aspects, disclosed herein is a method of decreasing or inhibiting cytokine production or secretion in a subject experiencing cytokine release syndrome or cytokine storm or vulnerable to cytokine release syndrome or cytokine storm comprising the step of administering to the subject a pharmaceutical composition provided herein. In other aspects the method comprises reducing production or secretion of one or more autophagy -related cytokines. In other aspects the one or more autophagy related cytokines are selected from IL-1β , IL-6, IL- 18, TNF-α, IFN-y, or TGF-β, or any combination thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1A. ATG12-ATG3 Interaction surface. The crystal structure of human ATG12 (blue, white and red) bound to a short segment of residues 153-165 of ATG3 (cyan blue). Color gradient in ATG12 refers to the electric charge of the surface residue; blue, white and red refer to positive, neutral or negative charges, respectively. On the left, the list of anchoring residues in ATG12 and ATG3 that play major role in ATG12/ATG3 interaction.

[0017] Figure IB. Mutational scanning of ATG12-L1 reveals variants of Atgl2 which fail to interact with ATG3-L2 WT in the PCA platform. Bulky Trp73 and Phe87 residues were replaced with small Ala residue (W73 A and F87A). Positive Lys were replaced with negative Asp (K54D and K72D).

[0018] Figure 2. shows the schematic screen workflow of the Protein fragment Complementation

WT

Assay (PCA). Pre-printed plates with compounds were incubated with ATG12-L1 or with ATG12-L1 ^K54D lysates. Then cell lysates expressing ATG3-L2 were added to the plates, and 24h later, the luminescence was measured. After data analysis, all positive hits passed through hit validation. After exclusion of false positive hits, the remaining compounds were triaged by a medicinal chemist, re-synthesized, and subjected to dose response for determining IC50 in the PCA assay. Positive compounds were then used for cell-based assays to determine inhibitory effects of the compounds on autophagy in viable cells. Positive hits with an IC50 in the range of the assay (20-0.3 μM) were then tested in cell-based disease models. In parallel, active compounds were sent to the Organic Chemistry and Biochemistry (IOCB) team for Structure-activity relationship (SAR) studies and subsequent optimization.

[0019] Figure 3A. Adapting the PCA platform for detecting small compounds which inhibit autophagy-related protein-protein interactions (PPIs). 15 pl of ATG12-L1 WT or ATG12-L1 K54D cell lysates (7 pg/pl) were mixed with 15 pl of ATG3-L2 cell lysates (7 pg/pl). Following 24h incubation, luminescence was measured.

[0020] Figure 3B. Bcl-xL-Ll expressing cell lysate was mixed with ABT-737 10 μM for Ih at 4°C or with the DMSO carrier as a control. Then, Bax-L2 cell lysate was added to the mixture. Following 30 min incubation, luminescence was measured.

[0021] Figure 4A. Cell-based GFP-LC3 puncta assay. Compounds 200 and 42 structures and their calculated IC50 in the PCA system. [0022] Figure 4B. Representative images of HEK293A GFP-LC3 cells tested without and with compounds. DMSO represents the basal steady state levels of autophagy. Torinl + CQ represent autophagy induction as assessed by increased number of puncta area per cell. Compounds images represent cells treated with compounds at 10 μM for 24h, followed by 2h treatment with Torinl + CQ. Scale bar 100 pm.

[0023] Figure 4C. Dose-response curves of Compound 200 and Compound 42 on autophagy, measured by autophagosome area/cell. Cells were treated with the compounds at serial dilutions in the range of 20 - 0.31 μM for 24h, followed by 2h treatment with Torinl + CQ. After nuclei staining using Hoechst, the cells were fixated, and the samples were imaged and analyzed. An average of 2 repeats is shown.

[0024] Figures 5A-5E. Detailed follow up of the effects of compound 200 on autophagy levels in cells. Figure 5A. Structure of compound 200. Figure 5B. Representative images of HEK 293 A GFP-LC3B cells treated without and with 10 μM compound 200 for 24 h. Basal steady state levels of autophagy are observed in DMSO treated cells. 200 nM Torinl + 20 μM CQ were used to induce autophagy in the final 2h of treatment. Scale bar, 20 pm. Figure 5C. Dose-response curve of compound 200 effect on autophagy. Cells were treated with the compound at serial dilutions in the range of 20 - 0.31 μM for 22h, followed by 2h treatment with Torinl + CQ. Data is presented as LC3+ membrane area/cell, mean±SD, n=3 independent biological repeats. Figure 5D-Figure 5E.) Western blots of HEK 293A cells treated with 10 μM compound 200 for 22h, followed by 2h of Torinl + CQ, and blotted with LC3B (Figure 5D) or SQSTMl/p62 (Figure 5E) antibodies, and GAPDH or VCL (vinculin) antibodies, as loading controls.

[0025] Figure 6A. SPR plot of compound 200 binding to recombinant ATG12-Flag. Black arrows represent association (left) and dissociation (right) points. Cycle number represents the order of injection. The 20 μM sample concentration was injected twice to ensure consistency of association levels.

[0026] Figure 6B. Biochemical validation of the recombinant ATG12-Flag used for the SPR assay, purified, and visualized on acrylamide gels by Coomassie blue staining (left panel), Ponceau S (middle panel) and probed with anti-ATG12 antibody (right panel).

[0027] Figure 7A. The structure of Compound 55.

[0028] Figure 7B. Representative dose-response curve in the PCA system (IC50 = 62 μM). Compound 55 retains the inhibitory functions in the PCA lysates and on autophagy in cells while losing its inhibitory effects on CK2.

[0029] Figure 7C. In-silico docking assay of compounds 42 and 55 binding to ATG12 surface. Compound 55 preserve the docking score of Compound 42. [0030] Figure 7D. Representative images of HEK293A GFP-LC3 cells tested with controls and with Compound 55. DMSO represents the basal steady state levels of autophagy. Torinl + CQ image represents activated autophagy control. Compound 55 image represents cells treated with compound 55 at 10 μM for 24h, followed by 2h treatment with Torinl + CQ. Scale bar 100 pm.

[0031] Figure 7E. Dose-response curve of Compound 55 effect on autophagy, measured by autophagosome area/cell. Cells were treated with the Compound at serial dilutions in the range of 20 - 0.31 μM for 24h, followed by 2h treatment with Torinl + CQ. After nuclei staining using Hoechst, the cells were fixated, and the samples were imaged and analyzed. An average of 2 repeats is shown.

[0032] Figure 7F. Representative Western Blot (WB) of Compounds 42 and 55 effect on CK2 activity. HEK293T cells were treated with Compounds 42 or 55 for 24h at 10 μM, followed by lysis and WB, blotting for pAKT S129 (Abeam, abl33458), total AKT (Cells Signaling #2938), and GAPDH (Sigma MAB374). (G) pAKT S129 levels were quantified and compared with total AKT. Data represent average of 3 repetitions. Statistical significance was determined by one-way analysis of variance (ANOVA), *P<0.05.

[0033] Figures 8A-8E. Compound 200 reduces autophagy levels and the growth of autophagy- addicted pancreatic cancer cells. Figure 8A. Western blot showing levels of lipidated and free LC3B in PANCI and NCI-H460 cells. GAPDH was used as a loading control. Figure 8B. Autophagy addicted PANCI and non-autophagy addicted cancer lung NCI-H460 cell lines were treated with 5 μM compound 200, and viability was measured over the course of 4 days by CellTiter-Glo assay. CQ (10 μM) was used as a positive control for autophagy inhibition. Data represent the mean±SD of 3 repetitions, normalized to day 0, time at which drug was added. Statistical significance was determined by two-way analysis of variance (ANOVA) with Tukey’s multiple comparisons test, **P<0.0L, ***P<0.001. Figure 8C. Relative viability of PANCI, HEC-1 A, NCI-H1299 and NCI-H460 cells after 4 days incubation with either DMSO, compound 200 (5 μM, PANCI, NCI-H460 or 10 μM, HEC-1A, NCI-H1299), CQ (10 μM, PANCI, NCI- H460, HEC-1). Note that since NCI-H1299 cells did not respond to CQ, ULK1 inhibitor (10 μM) was used instead as a control for an established autophagy inhibitor. Statistical significance was determined by ordinary one-way ANOVA with Tukey’s multiple comparisons test, **P<0.01; ***P<0.001; ****P<0.0001. Data is presented as growth relative to DMSO treated cells, mean±SD of n=3 (PANCI, H460), n=l 1 (HEC1A) or n=6 (NCI-H1299) biological repeats. Figure 8D RFP-GFP-LC3B PANCI stable cells were treated with compound 200 (10 μM) and CQ (10 μM) for 24 h, followed by fixation and DAPI staining, and imaged by confocal microscopy. Scale bar, 10 pm. Figure 8E Quantification of number of autophagosomes and autolysosomes per cell. The number of autolysosomes was calculated as the number of red dots minus the green dots (autophagosomes). Data was normalized to the number of autolysosomes in the DMSO treated cells, mean±SD, n=3 independent biological repeats. Statistical significance was determined by two-way ANOVA with Sidak’s multiple comparisons test, *P<0.05; ***P<0.001.

[0034] Figure 9. Compound 200 reduces the viability of autophagy-addicted melanoma cells. Autophagy addicted (MM 34) and non-addicted (MM 39) melanoma cell lines were treated with the compounds at 3 concentrations with and without vemurafenib. 48h later, viability was measured using CellTiter-Glo assay. Statistical significance was determined by two-way analysis of variance (ANOVA), **P<0.01; ***P<0.001; ****P<0.0001.

[0035] Figure 10A. Compound 200 reduces IL1β secretion in LPS-treated RAW 264.7 mouse cells. RAW 264.7 cells were treated with LPS (1 pg/ml) combined with Compound 200 (10 μM), HCQ (20 μM), or Dexamethasone (2 pg/ml) for 24h, and levels of ILip in the medium was measured using ELISA procedure. Data represent average of 4 repetitions, and was normalized to LPS-treated cells. Statistical significance was assessed using one-way analysis of variance (ANOVA), ****P<0.0001.

[0036] Figure 10B. Compound 55 reduces ILip secretion in LPS-treated RAW 264.7 mouse cells. RAW 264.7 cells were treated with LPS (1 pg/ml) combined with Compound 55 (10 and 5 μM), HCQ (20 μM), or Dexamethasone (2 pg/ml) for 24h, and levels of ILip in the medium was measured using ELISA procedure. Data represent average of 3 repetitions, and was normalized to LPS-treated cells. Statistical significance was assessed using one-way analysis of variance (ANOVA), *P<0.05; **P<0.01; ****P<0.0001.

[0037] Figure 10C. Compound 200 reduces ILip secretion in LPS-treated human THP-1 cells. THP-1 cells were treated with 0.5 μM PMA for 3 h followed by 0.5 pg/ml LPS combined with DMSO, compound 200 (10 μM), or dexamethasone (2 pg/ml) for 4 h and ILip levels were assayed by ELISA as described in Figure 10A. Data represent mean±SD of 3 biological repetitions, and was normalized to LPS-treated cells. Statistical significance was assessed using one-way analysis of variance (ANOVA) with Tukey's multiple comparisons test, ***P=0.0002; ****P<0.0001.

[0038] Figure 11A. A549 cells treated with Resveratrol (RSV) for 48h at indicated concentrations, followed by lysis and WB, blotting for LC3-I/II and VCL (vinculin) for loading control.

[0039] Figure 11B. A549 cells treated with RSV and DMSO for 48h, followed by viability measurement using CellTiter-Glo assay. Data represent average of 4 repetitions. Statistical significance was determined by the two-tailed unpaired Student t test, ****P<0.0001.

[0040] Figure 11C. A549 cells transfected with either ATG7 or ATG12 siRNAs were treated with RSV (200 μM). After 48h cell viability was assessed using CellTiter-Glo assay and represented as fold-change in siRNA + RSV-treated cells compared with siRNA treated cells. Data represents four replicate experiments, and statistical significance was assessed using one-way analysis of variance (ANOVA), **P<0.01; ***P<0.001.

[0041] Figure 11D. A549 cells treated with Compound 55 and with RSV (100 μM). After 48h cell viability was assessed using CellTiter-Glo assay and represented as fold-change in compound + RSV-treated cells compared to compound only treated cells.

DETAILED DESCRIPTION

[0042] The present subject matter may be understood more readily by reference to the following detailed description which forms a part of this disclosure. It is to be understood that this disclosure is not limited to the specific products, methods, conditions, or parameters described and/or shown herein, and that the terminology used herein is for the purpose of describing particular embodiments by way of example only and is not intended to be limiting of the claimed disclosure. [0043] In some embodiments, provided herein a compound represented by the structure of formula (I): wherein,

- is a single or double bond;

Y is NR ₄ , O or S;

Wi- W ₄ are each independently null, hydrogen, CO ₂ R ₅ , -(CH ₂ ) _n - CO ₂ R ₅ , CN, halide, -(CH ₂ ) _n -

R ₁ is alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -alkyl-aryl, SO ₂ alkyl, SO ₂ aryl, or - alkyl-O-alkyl;

R ₂ and R ₃ are each independently null, OH, hydrogen, -O-alkyl, halide, amino, or R ₂ and R ₃ are joined together to form a 5 or 6 membered substituted or unsubstituted ring;

R ₄ is H, alkyl, or aryl; R ₅ is hydrogen, alkyl, aryl, -(CH ₂ ) _n -O-CO ₂ - R ₇ , -(CH ₂ ) _n -aryl-O-C(=O)- R ₇ , or

R ₆ is hydrogen, or alkyl;

R ₇ is H, -OH, O-alkyl-aryl, or -SO ₂ -alkyl; wherein the alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -alkyl-aryl, -alkyl-O-alkyl are independently substituted or unsubstituted;

X ₁ -X ₇ are each independently N or C;

X ₈ -X ₉ are each independently N, C, CH, O or S; and n is an integer between 0-5.

[0044] In some embodiments, provided herein a compound represented by the structure of formula (II): wherein,

Y is NR ₄ , O or S;

W ₁ -W ₄ are each independently null, hydrogen, CO ₂ R ₅ , -(CH ₂ ) _n - CO ₂ R ₅ , CN, halide, -(CH ₂ ) _n -

R ₁ is alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -alkyl-aryl, SO ₂ alkyl, SO ₂ aryl, or - alkyl-O-alkyl;

R ₂ and R ₃ are each independently null, OH, hydrogen, -O-alkyl, halide, amino, or R ₂ and R ₃ are joined together to form a 5 or 6 membered substituted or unsubstituted ring;

R4 is H, alkyl or aryl; R ₅ is hydrogen, alkyl, aryl, -(CH ₂ ) _n -O-CO ₂ -R ₇ , -(CH ₂ ) _n -aryl-O-C(=O)-R ₇ , or

R ₆ is hydrogen, or alkyl;

R ₇ is H, -OH, O-alkyl-aryl, or - SO ₂ -alkyl; wherein the alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -alkyl-aryl or -alkyl-O-alkyl are independently substituted or unsubstituted;

X1-X ₉ are each independently N or C; and n is an integer between 0-5.

[0045] In some embodiments, provided herein a compound represented by the structure of formula

(III): wherein, is a single or double bond;

Y is NR ₄ , O or S;

W ₁ -W ₄ are each independently null, hydrogen, or CO ₂ R ₅ , -(CH ₂ ) _n -CO ₂ R ₅ , CN, halide, -(CH ₂ ) _n -

OR ₆ , -C(=O)-NH-R ₇ ,

W ₅ -W ₈ are each independently null, hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, or cycloheteroalkyl;

R ₁ is alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -alkyl-aryl, SO ₂ alkyl, SO ₇ aryl, or - alkyl-O-alkyl;

R ₄ is H, alkyl, or aryl; R ₅ is hydrogen, alkyl, aryl, -(CH ₂ ) _n -O-CO ₂ -R ₇ , -(CH ₂ ) _n -aryl-O-C(=O)-R ₇ , or

R ₆ is hydrogen, or alkyl;

R ₇ is H, -OH, O-alkyl-aryl, or -SO ₂ -alkyl; wherein the alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -alkyl-aryl, or -alkyl-O-alkyl are independently substituted or unsubstituted;

X ₁ -X ₇ are each independently N or C;

X ₈ -X ₁₃ are each independently N, C, CH, O or S; n is an integer between 0-5; and

K is 0 or 1.

[0046] In some embodiments, provided herein a compound represented by the structure of formula wherein, is a single or double bond;

Y is NR ₄ , O or S;

W ₁ -W ₄ are each independently null, hydrogen, or CO ₂ R ₅ , -(CH ₂ ) _n -CO ₂ R ₅ , CN, halide, -(CH ₂ ) _n -

OR ₆ , -C(=O)-NH-R ₇ ,

W ₆ -W ₈ are each independently null, hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, or cycloheteroalkyl; R ₁ is alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -alkyl-aryl, SO ₂ alkyl, SO ₂ aryl or - alkyl-O-alkyl;

R4 is H, alkyl, or aryl;

R ₅ is hydrogen, alkyl, aryl, -(CH ₂ ) _n -O-CO ₂ -R ₇ , -(CH ₂ ) _n -aryl-O-C(=O)-R ₇ , or

R ₆ is hydrogen, or alkyl;

R ₇ is H, -OH, O-alkyl-aryl, or -SO ₂ -alkyl; wherein the alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -alkyl-aryl or -alkyl-O-alkyl are independently substituted or unsubstituted;

X ₁ -X ₇ are each independently N or C;

X ₈ -X ₁₃ are each independently N, C, CH, O, or S; and n is an integer between 0-5.

[0047] In some embodiments, provided herein a compound represented by the structure of formula (VA): wherein

W ₁ -W ₃ and W ₄ are each independently a hydrogens or null and

W ₂ is CO ₂ R ₅ , W ₅ -W ₈ are each independently null, hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, cycloheteroalkyl;

R ₅ is H, alkyl, -(CH ₂ ) _n -O-CO ₂ -R ₇ , -(CH ₂ ) _n -aryl-O-C(=O)-R ₇ or

R ₇ is H, -OH, O-alkyl-aryl, or -SO ₂ -alkyl;

X ₁ -X ₇ are each independently N or C;

X ₈ -X ₁₃ are each independently N, C, CH, O, or S; n is an integer between 0-5; and k is 0 or 1.

[0048] In some embodiments, provided herein a compound represented by the structure of formula

(VB): wherein, is a single or double bond;

W ₁ -W ₄ are each independently null, hydrogen, or CO ₂ R ₅ , -(CH ₂ ) _n -CO ₂ R ₅ , CN, halide, -(CH ₂ ) _n -

W ₆ -W ₈ are each independently null, hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, or cycloheteroalkyl; R ₅ is hydrogen, alkyl, aryl, -(CH ₂ ) _n -O-CO2-R ₇ , -(CH ₂ )n-aryl-O-C(=O)-R ₇ , or

R ₆ is hydrogen, or alkyl;

R ₇ is H, -OH, O-alkyl-aryl, or -SO ₂ -alkyl; wherein the alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -alkyl-aryl or -alkyl-O-alkyl are independently substituted or unsubstituted;

X ₁ -X ₇ are each independently N or C;

X ₈ -X ₁₃ are each independently N, C, CH, O, or S; and n is an integer between 0-5.

[0049] In some embodiments, the bond between X ₈ -X ₉ of formula I, III, IV VA or VB is a single bond. In some embodiments bond between X ₈ -X ₉ of formula , III, IV VA or VB is a double bond. In other embodiments, the bond between X ₈ -X ₁₃ of formula III, IV, VA or VB is a single bond. In other embodiments, the bond between X ₈ -X ₁₃ of formula III, IV, VA or VB is a double bond. In other embodiments, the bond between X ₁₂ -X ₁₃ of formula III, IV, VA or VB is a single bond. In other embodiments, the bond between X ₁₂ -X ₁₃ of formula III, IV, VA or VB is a double bond. In other embodiments, the bond between X ₁₁ - X ₁₂ of formula III, IV, VA or VB is a single bond. In other embodiments, the bond between X ₁₀ -X ₁₂ of formula III, IV VA or VB is a double bond. In other embodiments, the bond between X ₁₀ -X ₁₁ of formula III or VA is a single bond. In other embodiments, the bond between X ₁₀ - X ₁₁ of formula III or VA is a doble bond. In other embodiments, the bond between X ₉ -X ₁₁ of formula IV or VB is a single bond. In other embodiments, the bond between X ₉ -X ₁₁ of formula IV or VB is a double bond.

[0050] In some embodiments, Y of formula I, II, III or IV is NR4 wherein R4 is H, alkyl, or aryl. In other embodiments, Y of formula I, II, III or IV is NH. In other embodiments, Y of formula I, II, III or IV is N-alkyl. In other embodiments, Y of formula I, II, III or IV is N-aryl. In some embodiments, Y of formula I, II, III or IV is O. In some embodiments, Y of formula I, II, III or IV is S.

[0051] In some embodiments, Wi- W4 of formula I, II, III, IV, VA or VB are each independently or VB is null (if X2-X7 is nitrogen (N) then W ₁ -W ₄ , respectively is null). In some embodiments, Wi- W4 of formula I, II, III, IV, VA or VB is hydrogen. In some embodiments, Wi- W4 of formula I, II, III, IV, VA or VB is CO ₂ R ₅ . In some embodiments, Wi- W4 of formula I, II, III, IV, VA or VB is -(CH ₂ ) _n -CO ₂ R ₅ . In some embodiments, Wi- W4 of formula I, II, III, IV, VA or VB is CN. In some embodiments, Wi- W4 of formula I, II, III, IV, VA or VB is halide. In some embodiments, Wi- W4 of formula I, II, III, IV, VA or VB is -(CH ₂ ) _n -OR ₆ ,. In some embodiments, Wi- W4 of formula I, II, III, IV, VA or VB is -C(=O)-NH-R ₇ . In some embodiments, Wi- W4 of formula 11,

II, III, IV, VA or VB is In some embodiments, Wi- W4 of formula I, II, III, IV, VA or

VB is In some embodiments, Wi- W4 of formula I, II, III, IV, VA or VB is

. In some embodiments, Wi- W4 of formula I, II, III, IV, VA or VB

[0052] In some embodiments, W ₅ -W ₈ of formula III, IV, VA or VB are each independently null, hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, or cycloheteroalkyl. In some embodiments, W ₅ -W ₈ of formula III, IV, VA or VB is null (if X ₁₀ -X ₁₃ is nitrogen (N) in a double bond, then W ₅ -W ₈ , respectively is null or if X ₁₀ -X ₁₃ is oxygen (O) or sulfur (S) in a single bond, then W ₅ -W ₈ , respectively is null). In some embodiments, W ₅ -W ₈ of formula III, IV, VA or VB is hydrogen. In some embodiments, W ₅ -W ₈ of formula III, IV, VA or VB is alkyl. In some embodiments, W ₅ - W ₈ of formula III, IV, VA or VB is aryl. In some embodiments, W ₅ -W ₈ of formula III, IV, VA or VB is heteroaryl. In some embodiments, W ₅ -W ₈ of formula III, IV, VA or VB is cycloalkyl. In some embodiments, W ₅ -W ₈ of formula III, IV, VA or VB is cycloheteroalkyl.

[0053] In some embodiments the R ₁ of formula I, II, III or IV is alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -alkyl-aryl or -alkyl-O-alkyl. In other embodiments, R ₁ of formula I, II, III or IV is an alkyl. In other embodiments, R ₁ of formula I, II, III or IV is an aryl. In other embodiments,

R ₁ of formula I, II, III or IV is a heteroaryl. In other embodiments, R ₁ of formula I, II, III or IV is a cycloalkyl. In other embodiments, R ₁ of formula I, II, III or IV is a heterocycloalkyl. In other embodiments, R ₁ of formula I, II, III or IV is an -alkyl-aryl. In other embodiments, R ₁ of formula I, II, III or IV is an -alkyl-O-alkyl. In other embodiments, R ₁ of formula I, II, III or IV is SO ₂ alkyl. In other embodiments, R ₁ of formula I, II, III or IV SO ₂ aryl,

[0054] In some embodiments the R ₂ and R ₃ of formula I or II are each independently null, hydrogen, -O-alkyl, halide, amino, or R ₂ and R ₃ are joined together to form a 5 or 6 membered substituted or unsubstituted ring. In other embodiments, R ₂ and R ₃ of formula I or II are each independently null (R2 is null if X9 is nitrogen (N), R ₃ is null if X ₈ is nitrogen (N)). In other embodiments, R ₂ and R ₃ of formula I or II are each independently hydrogen. In other embodiments, R ₂ and R ₃ of formula I or II are each independently OH. In other embodiments, R ₂ and R ₃ of formula I or II are each independently -O-alkyl. In other embodiments, R ₂ and R ₃ of formula I or II are each independently a halide. In other embodiments, R ₂ and R ₃ of formula I or II are each independently an amino. In other embodiments, R ₂ and R ₃ of formula I or II are joined together to form a 5 or 6 membered substituted or unsubstituted ring.

[0055] In some embodiments the R ₅ of CO ₂ R ₅ or -(CH ₂ ) _n -CO ₂ R ₅ of W ₁ -W ₄ of formula I, II, III,

IV or V is H, alkyl, -(CH ₂ ) _n -O-CO ₂ -R ₇ , -(CH ₂ ) _n -aryl-O-C(=O)-R ₇ or wherein n is an integer between 0-5. In some embodiments R ₅ of CO ₂ R ₅ or -(CH ₂ ) _n -CO ₂ R ₅ of W ₁ -W ₄ of formula I, II, III, IV or V is H. In some embodiments R ₅ group of CO ₂ R ₅ or -(CH ₂ ) _n -CO ₂ R ₅ of W ₁ -W ₄ of formula I, II, III, IV or V is alkyl. In some embodiments R ₅ of CO ₂ R ₅ or -(CH ₂ ) _n -CO ₂ R ₅ of Wi- W4 of formula I, II, III, IV or V is -(CH ₂ ) _n -O-CO ₂ -R ₇ wherein n is an integer between 0 -5. In some embodiments R ₅ of CO ₂ R ₅ or -(CH ₂ ) _n -CO ₂ R ₅ of W ₁ -W ₄ of formula I, II, III, IV or V is -(CH ₂ ) _n - aryl-O-C(=O)-R ₇ wherein n is an integer between 0-5. In some embodiments R ₅ group of CO ₂ R ₅ or -(CH ₂ ) _n -CO ₂ R ₅ of W ₁ -W ₄ of formula I, II, III, IV or V is wherein n is an integer between 0-5.

[0056] In some embodiments the R ₆ of -(CH ₂ ) _n -OR ₆ of W ₁ -W ₄ of formula I, II, III or IV wherein n is an integer between 0-5, is hydrogen or alkyl. In other embodiments, R ₆ of -(CH ₂ ) _n -OR ₆ of

W ₁ -W ₄ of formula I, II, III or IV wherein n is an integer between 0-5 is hydrogen. In other embodiments, R ₆ of -(CH ₂ ) _n -OR ₆ of W ₁ -W ₄ of formula I, II, III or IV wherein n is an integer between 0-5 is an alkyl.

[0057] In some embodiments the R ₇ of -C(=O)-NH-R ₇ of Wi- W4 of formula I, II, III or IV or R ₇ of -(CH ₂ ) _n -O-CO2-R ₇ , -(CH ₂ ) _n -aryl-O-C(=O)-R ₇ or defined as an R ₅ is -OH, O-alkyl- aryl, or -SO ₂ -alkyl. In other embodiments, R ₇ is -OH. In other embodiments, R ₇ is O-alkyl-aryl. In other embodiments, R ₇ is -SO ₂ -alkyl-aryl. In other embodiments, R ₇ is -H.

[0058] In some embodiments X ₁ -X ₇ of formula I, II, III, IV, VA or VB are atoms linked by a double bond within a ring, wherein each independently are a nitrogen (N) or a carbon (C). In other embodiments, when X ₁ -X ₇ is a nitrogen the corresponding W ₁ -W ₄ is a null. In other embodiments, X ₁ -X ₇ of formula I, II, III, IV, VA or VB is a nitrogen. In other embodiments, X ₁ -X ₇ of formula I, II, III, IV, VA or VB is a carbon.

[0059] In some embodiments, X ₈ -X ₁₃ of formula I, II, III, IV, VA or VB are atoms linked by a double bond or a single bond within a ring wherein each independently is N, C, CH, O, or S. In some embodiments, when any of X ₈ -X ₁₃ of formula I, II, III, IV, VA or VB is linked by a double bond, then it is not a S or O. In some embodiments, when X ₈ -X ₁₃ of formula I, II, III, IV, VA or VB is linked by a double bond with the ring, then X ₈ -X ₁₃ a N, C. In some embodiments, if X ₈ -X ₁₃ of formula I, II, III, IV, VA or VB is linked by a single bond with the ring, then X ₈ -X ₁₃ a N, CH, O, or S. In other embodiments, X ₈ -X ₁₃ each independently of formula I, II, III, IV, VA or VB is linked by a double bond and is a carbon. In other embodiments, X ₈ -X ₁₃ each independently of formula I, II, III, IV, VA or VB is linked by a double bond and is a nitrogen. In other embodiments,

X ₈ -X ₁₃ each independently of formula I, II, III, IV, VA or VB is linked by a single bond and is a CH. In other embodiments, X ₈ -X ₁₃ each independently of formula I I, II, III, IV, VA or VB is linked by a single bond and is a nitrogen (N). In other embodiments, X ₈ -X ₁₃ each independently of formula I, II, III, IV, VA or VB is linked by a single bond and is an oxygen (O). In other embodiments, X ₈ -X ₁₃ each independently of formula I, II, III, IV, VA or VB is linked by a single bond and is an sulfur (S).

[0060] In some embodiments, provided herein compounds of this invention. In other embodiments, the compounds are autophagy inhibitors.

[0016] In some aspects, disclosed herein is an autophagy inhibitor compound represented by the structure of formula (VI): wherein the aryl comprises substituted or unsubstituted aryl ; and

Q ₃ -Q ₉ are each independently H, halo or -OH, wherein at least one of Q ₃ -Q ₉ is OH; or pharmaceutically acceptable salt thereof.

[0061] In other embodiments, the aryl of formula VI is a phenyl. In other embodiments, the aryl of formula VI is a naphthyl.

[0062] In some aspects, disclosed herein is an autophagy inhibitor compound represented by the structure of formula (VII):

wherein. Q ₁ is independently H, halo, OH, O-alkyl, alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl; Q ₂ is H, halo, OH, O-alkyl, alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl q is an integer between 1-4; and

Q ₃ -Q ₉ are each independently H , halo or -OH, wherein at least one of Q ₃ -Q ₉ is OH; or pharmaceutically acceptable salt thereof.

[0063] In some embodiment, Q ₁ of formula VII is hydrogen (H). In some embodiment, Q ₁ of formula VII is an alkyl. In some embodiment, Q ₁ of formula VII is halo. In some embodiment, Qi of formula VII is OH In some embodiment, Q ₁ of formula VII is O-alkyl. In some embodiment, Q ₁ of formula VII is aryl. In some embodiment, Q ₁ of formula VII is heteroaryl. In some embodiment, Q ₁ of formula VII is cycloalkyl. In some embodiment, Q ₁ of formula VII is heterocycloalkyl. In some embodiment, Q ₂ of formula VII is a hydrogen. In some embodiments Q ₂ of formula VII is an alkyl. In some embodiment, Q ₂ of formula VII is halo. In some embodiment, Q ₂ of formula VII is OH In some embodiment, Q ₁ of formula VII is O-alkyl. In some embodiment, Q ₂ of formula VII is aryl. In some embodiment, Q ₂ of formula VII is heteroaryl. In some embodiment, Q ₂ of formula VII is cycloalkyl. In some embodiment, Q ₂ of formula VII is heterocycloalkyl.

[0064] In some embodiment, Q ₃ -Q ₉ of Formula VI or VII are each independently H or -OH, wherein at least one of Q ₃ -Q ₉ is OH. In other embodiments, Q ₃ -Q ₉ are each independently H, wherein at least one of Q3-Q9 is a hydroxyl (OH). In other embodiments, Q ₃ -Q ₉ are each independently OH. In other embodiments, Q ₃ -Q ₉ are each independently halo. [0065] In some aspects, disclosed herein is a compound of Formula VI represented by Compound 200, 201, 202, 203 or pharmaceutically acceptable salt thereof:

[0066] The term “alkyl” used alone or as part of another group, refers, in one embodiment, to a “C ₁ to C ₁₂ alkyl” and denotes linear and branched, saturated or unsaturated (e.g., alkenyl, alkynyl) groups, the latter only when the number of carbon atoms in the alkyl chain is greater than or equal to two, and can contain mixed structures. Non-limiting examples are alkyl groups containing from 1 to 6 carbon atoms (C ₁ to C ₆ , alkyls), or alkyl groups containing from 1 to 4 carbon atoms (C ₁ to C ₄ alkyls). Examples of saturated alkyl groups include, but are not limited to, methyl, ethyl, n- propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, amyl, tert-amyl and hexyl. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, butenyl and the like. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl and the like. The alkyl group can be unsubstituted or substituted with one or more substituents selected from the group consisting of alkyl, aryl, halogen, haloalkyl, hydroxyl, alkoxy, carbonyl, amido, alkylamido, dialkylamido, cyano, nitro, CO ₂ H, amino, alkylamino, dialkylamino, carboxyl, thio, thioalkyl, C ₁ -C ₅ linear or branched haloalkoxy, CF ₃ , CH ₃ , phenyl, halophenyl, (benzyloxy )phenyl, -CH ₂ CN, NH ₂ , NH- alkyl, N(alkyl) ₂ , -OC(O)CF ₃ , -OCH ₂ Ph, -NHCO-alkyl, -C(O)Ph, C(O)O-alkyl, C(O)H, -C(O)NH ₂ or any combination thereof.

[0067] The term “aryl” used herein alone or as part of another group refers to an aromatic ring system containing from 6-14 ring carbon atoms. The aryl ring can be a monocyclic, bicyclic, tricyclic and the like. Non -limiting examples of aryl groups are phenyl, naphthyl including 1- naphthyl and 2-naphthyl, and the like. The aryl group can be unsubstituted or substituted through available carbon atoms with one or more groups such as halogen, alkyl, haloalkyl, hydroxyl, alkoxy, carbonyl, amido, alkylamido, dialkylamido, cyano, nitro, CO ₂ H, amino, alkylamino, dialkylamino, carboxyl, thio, thioalkyl, C ₁ -C ₅ linear or branched haloalkoxy, CF ₃ , phenyl, halophenyl, (benzyloxy)phenyl, -CH ₂ CN, NH ₂ , NH-alkyl, N(alkyl)2, -OC(O)CF ₃ , -OCH ₂ Ph, - NHCO-alkyl, -C(O)Ph, C(O)O-alkyl, C(O)H, -C(O)NH ₂ or any combination thereof.

[0068] The term “heteroaryl” refers herein to an aromatic ring system containing from 5-14 member ring having at least one heteroatom in the ring. Non-limiting examples of suitable heteroatoms which can be included in the aromatic ring include oxygen, sulfur, phospate and nitrogen. Non-limiting examples of heteroaryl rings include pyridinyl, pyrrolyl, oxazolyl, indolyl, isoindolyl, purinyl, furanyl, thienyl, benzofuranyl, benzothiophenyl, carbazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, quinolyl, isoquinolyl, pyridazyl, pyrimidyl, pyrazyl, etc. The heteroaryl group can be unsubtituted or substituted through available carbon atoms with one or more groups such as halogen, alkyl, haloalkyl, hydroxyl, alkoxy, carbonyl, amido, alkylamido, dialkylamido, cyano, nitro, CO ₂ H, amino, alkylamino, dialkylamino, carboxyl, thio, thioalkyl, C ₁ -C ₅ linear or branched haloalkoxy, CF ₃ , phenyl, halophenyl, (benzyl oxy )phenyl, - CH ₂ CN, NH ₂ , NH-alkyl, N(alkyl) ₂ , -OC(O)CF ₃ , -OCH ₂ Ph, -NHCO-alkyl, -C(O)Ph, C(O)O-alkyl, C(O)H, -C(O)NH ₂ or any combination thereof.

[0069] The term “cycloalkyl” refers herein to a ring structure comprising carbon atoms as ring atoms, which may be either saturated or unsaturated, substituted, or unsubstituted, single or fused. In some embodiments the cycloalkyl is a 3-10 membered ring. In some embodiments the cycloalkyl is a 3-12 membered ring. In some embodiments the cycloalkyl is a 6 membered ring. In some embodiments the cycloalkyl is a 5-7 membered ring. In some embodiments the cycloalkyl is a 3-8 membered ring. In some embodiments, the cycloalkyl group may be unsubstituted or substituted by a halogen, alkyl, haloalkyl, hydroxyl, alkoxy, carbonyl, amido, alkylamido, dialkylamido, cyano, nitro, CO ₂ H, amino, alkylamino, dialkylamino, carboxyl, thio, thioalkyl, Ci- C5 linear or branched haloalkoxy, CF ₃ , phenyl, halophenyl, (benzyloxy)phenyl, -CH ₂ CN, NH ₂ , NH-alkyl, N(alkyl) ₂ , -OC(O)CF ₃ , -OCH ₂ Ph, -NHCO-alkyl, -C(O)Ph, C(O)O-alkyl, C(O)H, - C(O)NH ₂ or any combination thereof. In some embodiments, the cycloalkyl ring may be fused to another saturated or unsaturated cycloalkyl or heterocyclic 3-8 membered ring. In some embodiments, the cycloalkyl ring is a saturated ring. In some embodiments, the cycloalkyl ring is an unsaturated ring. Non limiteing examples of a cycloalkyl group comprise cyclohexyl, cyclohexenyl, cyclopropyl, cyclopropenyl, cyclopentyl, cyclopentenyl, cyclobutyl, cyclobutenyl, cycloctyl, cycloctadienyl (COD), cycloctaene (COE) etc.

[0070] The term “-alkyl-aryl” refers herein to an alkyl group as defined herein substituted by an aryl. A non-limited example is a benzyl (-CH ₂ -PI1).

[0071] The term “-alkyl-O-alkyl” refers herein to an ether group. Non limited examples of an - alkyl-O-alkyl includes diethyl ether, dimethyl ether, methyl-ethyl-ether. [0072] The term "alkoxy" refers to -O-alkyl group wherein the alkyl group as defined above. Alkoxy refers both to linear and to branched alkoxy groups. Nonlimiting examples of alkoxy groups are methoxy, ethoxy, propoxy, iso-propoxy, tert-butoxy.

[0073] The term “5 or 6 membered substituted or unsubstituted ring” refers to a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring as defined herein.

[0074] The term “heterocycloalkyl” used herein alone or as part of another group refers to a cycloalkyl as defined herein having at least one heteroatom such as oxygen, sulfur and/or nitrogen. [0075] The disclosure includes “pharmaceutically acceptable salts” of the compounds described herein, which may be produced, by reaction of a compound described herein with an acid or base. Certain compounds, particularly those possessing acid or basic groups, can also be in the form of a salt, preferably a pharmaceutically acceptable salt. The term "pharmaceutically acceptable salt" refers to those salts that retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable. The salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxylic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, /'/-acetylcysteine and the like. Other salts are known to those of skill in the art and can readily be adapted for use in accordance with the present disclosure.

[0076] Suitable pharmaceutically-acceptable salts of amines of compounds described herein may be prepared from an inorganic acid or from an organic acid. In various embodiments, examples of inorganic salts of amines are bisulfates, borates, bromides, chlorides, hemisulfates, hydrobromates, hydrochlorates, 2-hydroxyethylsulfonates (hydroxyethanesulfonates), iodates, iodides, isothionates, nitrates, persulfates, phosphate, sulfates, sulfamates, sulfanilates, sulfonic acids (alkyl sulfonates, aryl sulfonates, halogen substituted alkylsulfonates, halogen substituted aryl sulfonates), sulfonates and thiocyanates.

[0077] In various embodiments, examples of organic salts of amines may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which are acetates, arginines, aspartates, ascorbates, adipates, anthranilates, algenates, alkane carboxylates, substituted alkane carboxylates, alginates, benzenesulfonates, benzoates, bisulfates, butyrates, bicarbonates, bitartrates, citrates, camphorates, camphorsulfonates, cyclohexylsulfamates, cyclopentanepropionates, calcium edetates, camsylates, carbonates, clavulanates, cinnamates, dicarboxylates, digluconates, dodecyl sulfonates, dihydrochlorides, decanoates, enanthuates, ethanesulfonates, edetates, edisylates, estolates, esylates, fumarates, formates, fluorides, galacturonates gluconates, glutamates, glycolates, glucorate, glucoheptanoates, glycerophosphates, gluceptates, glycollylarsanilates, glutarates, glutamate, heptanoates, hexanoates, hydroxymaleates, hydroxycarboxlic acids, hexylresorcinates, hydroxybenzoates, hydroxynaphthoates, hydrofluorates, lactates, lactobionates, laurates, malates, maleates, methylenebis(beta- oxynaphthoate), malonates, mandelates, mesylates, methane sulfonates, methylbromides, methylnitrates, methylsulfonates, monopotassium maleates, mucates, monocarboxylates, naphthalenesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, napsylates, N- methylglucamines, oxalates, octanoates, oleates, pamoates, phenylacetates, picrates, phenylbenzoates, pivalates, propionates, phthalates, phenyl acetate, pectinates, phenylpropionates, palmitates, pantothenates, polygalacturates, pyruvates, quinates, salicylates, succinates, stearates, sulfanilate, subacetates, tartrates, theophyllineacetates, p-toluenesulfonates (tosylates), trifluoroacetates, terephthalates, tannates, teoclates, trihaloacetates, triethiodide, tricarboxylates, undecanoates and valerates.

[0078] In various embodiments, examples of inorganic salts of carboxylic acids or hydroxyls may be selected from ammonium, alkali metals to include lithium, sodium, potassium, cesium; alkaline earth metals to include calcium, magnesium, aluminium; zinc, barium, cholines, quaternary ammoniums.

[0079] In some embodiments, examples of organic salts of carboxylic acids or hydroxyl may be selected from arginine, organic amines to include aliphatic organic amines, alicyclic organic amines, aromatic organic amines, benzathines, t-butylamines, benethamines (N- benzylphenethylamine), dicyclohexylamines, dimethylamines, diethanolamines, ethanolamines, ethylenediamines, hydrabamines, imidazoles, lysines, methylamines, meglamines, N-methyl-D- glucamines, N,N’-dibenzylethylenediamines, nicotinamides, organic amines, ornithines, pyridines, picolies, piperazines, procain, tris(hydroxymethyl)methylamines, triethylamines, triethanolamines, trimethylamines, tromethamines and ureas.

[0080] In various embodiments, the salts may be formed by conventional means, such as by reacting the free base or free acid form of the product with one or more equivalents of the appropriate acid or base in a solvent or medium in which the salt is insoluble or in a solvent such as water, which is removed in vacuo or by freeze drying or by exchanging the ions of an existing salt for another ion or suitable ion-exchange resin.

[0081] In some embodiments, the present disclosure provides compounds which are useful for inhibiting autophagy. In some embodiments, the present disclosure provides compounds which are useful for inhibiting lysosomal degradation of intracellular components. In some embodiments, the present disclosure provides compounds which are useful for inhibiting autophagy-dependent secretion of cytokines. In some embodiments, the present disclosure provides compounds which are useful for treating cancer. In some embodiments, the present disclosure provides compounds which are useful for decreasing or inhibiting cytokine production or secretion in a subject experiencing cytokine release syndrome (CRS) or cytokine storm. In some embodiments, the present disclosure provides compounds which are useful for inhibiting autophagic cell death (ACD). In some embodiments, the present disclosure provides compounds which are useful for treating autophagy-related diseases or disorders.

[0082] In some embodiments, the compounds described herein comprise autophagy inhibitors. In some embodiments, the compounds described herein are autophagy inhibitors. In some embodiments, the compounds are autophagy inhibitor compounds. In some embodiments, the compounds are inhibitors of autophagy-related protein-protein interactions (PPIs).

[0083] An artisan would appreciate that the term “autophagy -related disease” or an “autophagy- related disorder” refers to a disease or disorder that results from disruption in autophagy or cellular self-digestion. In some embodiments, autophagy-related disease or disorder may present itself as a reduced or increased level of autophagy in asubject (compared to normal autophagy levels in a healthy subject). In some embodiments, autophagy -related diseases or disorders may include, for example, cancer, including metastasis of cancer, and inflammatory diseases (such as those with increased cytokine production or secretion.

Pharmaceutical composition

[0084] Another aspect of the present disclosure relates to a pharmaceutical composition including a pharmaceutically acceptable carrier and a compound according to the embodiments of the present disclosure. The pharmaceutical composition can contain one or more of the aboveidentified compounds.

[0085] The compounds and pharmaceutical compositions described herein may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. For example, the pharmaceutical composition may be administered orally, mucosally, or parentally including intravascularly, intraperitoneally, subcutaneously, intramuscularly, and intrasternally.

[0086] Typically, the pharmaceutical composition described herein will include a compound of the present disclosure or its pharmaceutically acceptable salt, as well as a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" refers to any suitable adjuvants, carriers, excipients, or stabilizers, and can be in solid or liquid form such as, tablets, capsules, powders, solutions, suspensions, or emulsions.

[0087] The solid unit dosage forms can be of the conventional type. The solid form can be a capsule and the like, such as an ordinary gelatin type containing the compounds described herein and a carrier, for example, lubricants and inert fillers such as, lactose, sucrose, or cornstarch. In some embodiments, these compounds are tabulated with conventional tablet bases such as lactose, sucrose, or cornstarch in combination with binders like acacia, cornstarch, or gelatin, disintegrating agents, such as cornstarch, potato starch, or alginic acid, and a lubricant, like stearic acid or magnesium stearate.

[0088] The tablets, capsules, and the like can also contain a binder such as gum tragacanth, acacia, corn starch, or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose, or saccharin. When the dosage unit form is a capsule, it can contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.

[0089] Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets can be coated with shellac, sugar, or both. A syrup can contain, in addition to active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye, and flavoring such as cherry or orange flavor.

[0090] For oral therapeutic administration, these active compounds can be incorporated with excipients and used in the form of tablets, capsules, elixirs, suspensions, syrups, and the like. Such compositions and preparations should contain at least 0.1% of active compound.

[0091] The active compounds of the present disclosure may be orally administered, for example, with an inert diluent, or with an assimilable edible carrier, or they can be enclosed in hard or soft shell capsules, or they can be compressed into tablets, or they can be incorporated directly with the food of the diet.

[0092] The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form should be sterile and should be fluid to the extent that easy syringability exists. It should be stable under the conditions of manufacture and storage and should be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

[0093] The compounds or pharmaceutical compositions of the present disclosure may also be administered in injectable dosages by solution or suspension of these materials in a physiologically acceptable diluent with a pharmaceutical adjuvant, carrier, or excipient. Such adjuvants, carriers and/or excipients include, but are not limited to, sterile liquids, such as water and oils, with or without the addition of a surfactant and other pharmaceutically and physiologically acceptable components. Illustrative oils are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, or mineral oil. In general, water, saline, aqueous dextrose and related sugar solution, and glycols, such as propylene glycol or polyethylene glycol, are preferred liquid carriers, particularly for injectable solutions.

[0094] These active compounds may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Illustrative oils are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, or mineral oil. In general, water, saline, aqueous dextrose and related sugar solution, and glycols such as, propylene glycol or polyethylene glycol, are preferred liquid carriers, particularly for injectable solutions. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

[0095] For use as aerosols, the compounds described herein in solution or suspension may be packaged in a pressurized aerosol container together with suitable propellants, for example, hydrocarbon propellants like propane, butane, or isobutane with conventional adjuvants. The materials described herein also may be administered in a non-pressurized form such as in a nebulizer or atomizer.

[0096] The amounts of compounds that are administered and the dosage regimen for treating a disease or condition with the compositions described herein depends on a variety of factors, including the age, weight, gender, the medical condition of the subject, the type of disease, the severity of the disease, the route and frequency of administration, and the particular compound employed. Thus, the dosage regimen may vary widely, but can be determined routinely using standard methods.

Methods of Use

[0097] In some embodiments, disclosed herein is the use of the compounds and compositions described herein in detail for treating, suppressing, or inhibiting cancer in a subject.

[0098] In some embodiments, disclosed herein is a method of treating, suppressing, or inhibiting a cancer in a subject, comprising the step of administering to the subject a compound or composition, as described herein. In some embodiments, disclosed herein is a method of treating, suppressing, or inhibiting cancer in a subject, comprising the step of administering to the subject one or more compounds described herein.

[0099] In some embodiments, the cancer comprises a solid tumor. In some embodiments, the cancer or tumor comprises a metastasis of a cancer or tumor. In some embodiments, the solid tumor comprises a sarcoma or a carcinoma, a fibrosarcoma, a myxosarcoma, a liposarcoma, a chondrosarcoma, an osteogenic sarcoma, a chordoma, an angiosarcoma, an endotheliosarcoma, a lymphangiosarcoma, a lymphangioendotheliosarcoma, a synovioma, a mesothelioma, an Ewing's tumor, a leiomyosarcoma, a rhabdomyosarcoma, a colon carcinoma, a pancreatic cancer or tumor, a breast cancer or tumor, an ovarian cancer or tumor, a prostate cancer or tumor, a squamous cell carcinoma, a basal cell carcinoma, an adenocarcinoma, a sweat gland carcinoma, a sebaceous gland carcinoma, a papillary carcinoma, a papillary adenocarcinomas, a cystadenocarcinoma, a medullary carcinoma, a bronchogenic carcinoma, a renal cell carcinoma, a hepatoma, a bile duct carcinoma, a choriocarcinoma, a seminoma, an embryonal carcinoma, a Wilm's tumor, a cervical cancer or tumor, a uterine cancer or tumor, a testicular cancer or tumor, a lung carcinoma, a small cell lung carcinoma, a bladder carcinoma, an epithelial carcinoma, a glioma, an astrocytoma, a medulloblastoma, a craniopharyngioma, an ependymoma, a pinealoma, a hemangioblastoma, an acoustic neuroma, an oligodenroglioma, a schwannoma, a meningioma, a melanoma, a neuroblastoma, or a retinoblastoma.

[0100] In some embodiments, a compound or composition as disclosed herein, has a therapeutic and/or prophylactic efficacy against a cancer or a tumor, for example sarcomas and carcinomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, nile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, uterine cancer, testicular cancer, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodenroglioma, schwannoma, meningioma, melanoma, neuroblastoma, and retinoblastoma). In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is melanoma.

[0101] In some embodiments, the cancer comprises a diffuse cancer. In some embodiments, the cancer is widely spread; not localized or confined. In some embodiments, a diffuse cancer may comprise a non-solid tumor. Examples of diffuse cancers include leukemias. Leukemias comprise a cancer that starts in blood-forming tissue, such as the bone marrow, and causes large numbers of abnormal blood cells to be produced and enter the bloodstream. [0102] In some embodiments, a diffuse cancer comprises a B-cell malignancy. In some embodiments, the diffuse cancer comprises leukemia. In some embodiments, the cancer is lymphoma. In some embodiments, the lymphoma is large B-cell lymphoma.

[0103] In some embodiments, the diffuse cancer or tumor comprises a hematological tumor. In some embodiments, hematological tumors are cancer types affecting blood, bone marrow, and lymph nodes. Hematological tumors may derive from either of the two major blood cell lineages: myeloid and lymphoid cell lines. The myeloid cell line normally produces granulocytes, erythrocytes, thrombocytes, macrophages, and masT-cells, whereas the lymphoid cell line produces B, T, NK, and plasma cells. Lymphomas (e.g. Hodgkin's Lymphoma), lymphocytic leukemias, and myeloma are derived from the lymphoid line, while acute and chronic myelogenous leukemia (AML, CML), myelodysplastic syndromes and myeloproliferative diseases are myeloid in origin.

[0104] In some embodiments, a non-solid (diffuse) cancer comprises a hematopoietic malignancy, a blood cell cancer, a leukemia, a myelodysplastic syndrome, a lymphoma, a multiple myeloma (a plasma cell myeloma), an acute lymphoblastic leukemia, an acute myelogenous leukemia, a chronic myelogenous leukemia, a Hodgkin lymphoma, a non-Hodgkin lymphoma, or plasma cell leukemia.

[0105] In some embodiments, the compound or composition as disclosed herein, has therapeutic and/or prophylactic efficacy against diffuse cancers, for example but not limited to leukemias (e.g., acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocyte leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphoma (Hodgkin's disease, non-Hodgkin's disease), Waldenstrom's macroglobulinemia, heavy chain disease.

[0106] In some embodiments, disclosed herein is a method of treating a proliferative disorder, or suppressing or inhibiting a proliferative disorder in a subject, comprising the step of administering to the subject a compound or composition, as described herein.

[0107] In another embodiment, disclosed herein is a method of treating an autophagy -related disease or disorder in a subject, comprising the step of administering to the subject a compound or composition, as described herein. In some embodiments the autophagy-related disease is cancer.

[0108] In another embodiment, disclosed herein is a method of inhibiting autophagic cell death (ACD), comprising the step of administering to a subject a compound or composition, as described herein.

[0109] In some embodiments, the ACD is caused by an infection. In some embodiments, the ACD is caused by a bacterial infection. In some embodiments, the ACD is caused by a viral infection. In some embodiments, the viral infection is an avian H5N1 Influenza virus infection. In some embodiments, avian H5N1 Influenza virus infection causes acute lung injury. In some embodiments, the ACD is caused by acute lung injury as a result of an avian H5N1 Influenza virus infection. In some embodiments, the inhibition of ACD is compared with a subject not administered the compound or composition described herein.

[0110] In some embodiments, disclosed herein is a method of decreasing or inhibiting cytokine production or secretion in a subject experiencing cytokine release syndrome or cytokine storm or vulnerable to cytokine release syndrome or cytokine storm comprising the step of administering to the subject a compound or composition, as described herein.

[0111] In some embodiments, disclosed herein is a method of decreasing or inhibiting cytokine production or secretion in a subject experiencing cytokine release syndrome or cytokine storm or vulnerable to cytokine release syndrome or cytokine storm comprising the step of administering to the subject a compound or composition, as described herein, wherein said administering decreases or inhibits cytokine production or secretion in said subject. In some embodiments, the decrease or inhibition of cytokine production or secretion is compared with a subject experiencing cytokine release syndrome or cytokine storm or vulnerable to cytokine release syndrome or cytokine storm and not administered the compound or composition described herein. In another embodiment, methods for decreasing or inhibiting cytokine production or secretion, decrease or inhibit pro-inflammatory cytokine production or secretion. In another embodiment, methods for decreasing or inhibiting cytokine production or secretion, decrease or inhibit production or secretion of at least one pro-inflammatory cytokine. In another embodiment, methods for decreasing or inhibiting cytokine production or secretion, decrease or inhibit autophagy -related cytokine production or secretion. In another embodiment, methods for decreasing or inhibiting cytokine production or secretion, decrease or inhibit production or secretion of at least one autophagy-related cytokine.

[0112] An artisan would appreciate that the terms “ autophagy-related cytokine” or “autophagy- dependent secretion of cytokines” may encompass cytokines which are associated with autophagy, or with autophagy-related diseases or disorders. In some embodiments, autophagy -related cytokines may include, for example IL-1β, IL-6, IL-18, TNF-α, IFN-y, TGF-β, or CXCL8.

[0113] In some embodiments, the methods described herein decrease or inhibit production or secretion of at least one pro-inflammatory cytokine. In some embodiments, the methods described herein decrease or inhibit production or secretion of at least one autophagy -related cytokine.

[0114] In some embodiments of decreasing or inhibiting cytokine production or secretion, the cytokine is Interleukin- ip (IL-lp). In some embodiments of decreasing or inhibiting cytokine production or secretion, the cytokine is IL-6. In some embodiments of decreasing or inhibiting cytokine production or secretion, the cytokine is IL-18. In some embodiments of decreasing or inhibiting cytokine production or secretion, the cytokine is tumor necrosis factor-a ( TNF-α). In some embodiments of decreasing or inhibiting cytokine production or secretion, the cytokine is interferon-y (IFN-y). In some embodiments of decreasing or inhibiting cytokine production or secretion, the cytokine is transforming growth factor-β (TGF-β). In some embodiments of decreasing or inhibiting cytokine production or secretion, the cytokine is CXCL8. In another embodiment, methods disclosed herein for decreasing or inhibiting cytokine production or secretion, result in reduction or inhibition of production or secretion of cytokines IL-1β, IL-6, IL- 18, TNF-α, IFN-y, TGF-β, or CXCL8, or any combination thereof. In some embodiments, the autophagy related cytokine is selected from IL-1β, IL-6, IL-18, TNF-α, IFN-y, TGF-β, or CXCL8, or any combination thereof.

[0115] In some embodiments, the methods described herein comprise reducing production or secretion of one or more autophagy -related cytokines. In some embodiments, the one or more autophagy related cytokines are selected from IL-1β, IL-6, IL- 18, TNF-α, FN-y, TGF-β, or CXCL8, or any combination thereof.

[0116] A skilled artisan would appreciate that the terms to “reduce”, “decrease” or “inhibit” or grammatical variants thereof may encompass fold decrease or inhibition of, for example, cytokine production or secretion, or a net decrease or inhibition, or percent (%) decrease or inhibition, or may encompass a rate of change of decrease or inhibition of a cytokine production or secretion. [0117] In some embodiments, disclosed herein is a method of inhibiting lysosomal degradation of intracellular components comprising the step of administering to a subject a compound or composition, as described herein. In some embodiments, inhibiting lysosomal degradation of intracellular components is compared with a subject not administered the compound or composition described herein.

[0118] In some embodiments, disclosed herein is a method of inhibiting autophagy-dependent secretion of cytokines comprising the step of administering to a subject a compound or composition, as described herein. In some embodiments, inhibiting autophagy-dependent secretion of cytokines is compared with a subject not administered the compound or composition described herein.

[0119] In some embodiments, methods of use of a compound or composition as described herein, comprises reducing production or secretion of pro-inflammatory cytokines. In some embodiments, methods of use of a compound or composition as described herein, comprises reducing production or secretion of autophagy-related cytokines. In some embodiments, methods of use of a compound or composition as described herein, comprises reducing production or secretion of pro- inflammatory cytokines/chemokines, anti-inflammatory cytokines/chemokines, and autophagy- related cytokines.

[0120] In some embodiments, disclosed herein is a method of decreasing or inhibiting an acute inflammatory response in a subject comprising the step of administering to the subject a compound or composition, as described herein in detail. In some embodiments, the acute inflammatory response is caused by a bacterial infection. In some embodiments, the acute inflammatory response is caused by a viral infection. In some embodiments, the acute inflammatory response comprises cytokine release syndrome. In some embodiments, the acute inflammatory response comprises cytokine storm.

[0121] In some embodiments, methods of use of a compound or composition as described herein, comprise inhibiting autophagy -related protein-protein interactions (PPIs). In some embodiments, methods of use of a compound or composition as described herein, comprise inhibiting autophagy. In some embodiments, methods of use of a compound or composition as described herein, comprise inhibiting lysosomal degradation of intracellular components. In some embodiments, methods of use of a compound or composition as described herein, comprise inhibiting autophagydependent secretion of cytokines.

[0122] In some embodiments, provided herein is a compound wherein the compound is represented by the structure of Formula I, Formula II, Formula III, Formula IV, Formula V, or Formula VI, for use in the treatment of a disease or disorder in a subject in need thereof.

[0123] In some embodiments, provided herein is a pharmaceutical composition comprising a compound wherein the compound is represented by the structure of Formula I, Formula II, Formula III, Formula IV, Formula V, or Formula VI, or any combination thereof, for use in the treatment of a disease or disorder in a subject in need thereof.

[0124] In some embodiments, the disease or disorder is selected from cancer, a proliferative disorder, an autophagy-related disease or disorder, or cytokine release syndrome or cytokine storm. In some embodiments, the disease is cancer. In some embodiments, the disorder is a proliferative disorder. In some embodiments, the disease is an autophagy-related disease. In some embodiments, the disease is a cytokine release syndrome. In some embodiments, the disease is a cytokine storm.

[0125] In some embodiments, the autophagy -related disease comprises autophagy-dependent tumors. In some embodiments, autophagy-dependent tumors display intrinsic or acquired addiction to autophagy. In some embodiments, the autophagy-dependent tumor displays intrinsic addiction to autophagy. In some embodiments, the autophagy-dependent tumor displays acquired addiction to autophagy. In some embodiments, tumors are intrinsically addicted to autophagy due to changes in their metabolism caused by Ras or BRAF oncogenes. In some embodiments, the intrinsically addicted autophagy-dependent tumor is a pancreatic tumor. In some embodiments, the intrinsically addicted autophagy-dependent tumor is a melanoma. In some embodiments, the intrinsically addicted autophagy-dependent tumor is a lung tumor. In some embodiments, the intrinsically addicted autophagy-dependent tumor is a colon tumor. In some embodiments, the intrinsically addicted autophagy-dependent tumor comprises a pancreatic, melanoma, lung, or colon tumor.

[0126] In some embodiments, tumors acquire addiction to autophagy during chemotherapy, targeted therapy, radiotherapy, and immunotherapy, as a mechanism to cope with the stress conditions developing in these regimens. In some embodiments, the acquired addiction autophagydependent tumor comprises a solid tumor.

[0127] In some embodiments, the combination of autophagy inhibition with anti-cancer drug treatment enhances drug cytotoxicity, thus reducing drug -resistant clones and preventing tumor relapse after treatment.

[0128] skilled artisan would appreciate that the term “autophagy-dependent tumor” may encompass tumors which rely on autophagy for tumor promotion and maintenance. In some embodiments, the autophagy-dependent tumor relies on autophagy even under basal conditions for meeting their metabolic demands. In some embodiments, tumors are addicted to autophagy either intrinsically or they acquire such addiction. In some embodiments, tumors with oncogenic mutations depend on autophagy in order to cope with oncogene-induced metabolic stress.

[0129] A skilled artisan would appreciate that the terms “treatment” or “treating” encompass both therapeutic treatment and prophylactic or preventative measures including amelioration of a disease or condition, wherein the object is to prevent or lessen the targeted pathologic condition or disorder as described hereinabove. Thus, in one embodiment, treating may include directly affecting or curing, suppressing, inhibiting, preventing, reducing the severity of, delaying the onset of, reducing symptoms associated with the disease, disorder or condition, or any combination thereof. Thus, in one embodiment, “treating” refers inter alia to delaying progression, expediting remission, inducing remission, augmenting remission, speeding recovery, increasing efficacy of or decreasing resistance to alternative therapeutics, or any combination thereof. In one embodiment, “preventing” refers, inter alia, to delaying the onset of symptoms, preventing relapse to a disease, decreasing the number or frequency of relapse episodes, increasing latency between symptomatic episodes, or any combination thereof. In one embodiment, “suppressing” or “inhibiting”, refers inter alia to reducing the severity of symptoms, reducing the severity of an acute episode, reducing the number of symptoms, reducing the incidence of disease-related symptoms, reducing the latency of symptoms, ameliorating symptoms, reducing secondary symptoms, reducing secondary infections, prolonging patient survival, or any combination thereof. [0130] A skilled artisan would appreciate that the term "subject" may encompass a vertebrate, in some embodiments, to a mammal, and in some embodiments, a human. Subject may also refer, in some embodiments, to domesticated animals such as cows, sheep, horses, cats, dogs and laboratory animals such as mice, rats, gerbils, hamsters, etc. In some embodiments, the subject is a human subject. In some embodiments, the subject is a child. In one embodiment, the child is an infant. In some embodiments, the subject is an adult.

[0131] It should be understood that the disclosure presented herein is not limited to the particular methodologies, protocols and reagents, and examples described herein. The terminology and examples used herein is for the purpose of describing particular embodiments only, for the intent and purpose of providing guidance to the skilled artisan, and is not intended to limit the scope of the disclosure presented herein.

EXAMPLES

[0132] General procedure A (GP-A): SCla (Int. Patent WO 2007125405), corresponding 2- aminoalcohol and EtiN in EtOH were stirred at r.t. for 2 h. EtOH was evaporated in vacuo and solid was suspended in EtOAc. Product was filtered off, washed with H ₂ O and dried in vacuo.

[0133] General procedure B (GP-B): Corresponding compound and Mn02 in anhydrous toluene were stirred at 120 °C for 16 h under Ar atmosphere. Suspension was then filtered and filter cake was washed with EtOAc and MeOH. Solvents from combined filtrate were evaporated in vacuo and product was purified by FCC on silica (cH/EtOAc) and RP FCC on C18 (H ₂ O/ACN).

[0134] General procedure C (GP-C): Corresponding compound and 3 -chloroaniline in EtOH were stirred at 100 °C for 4 h. EtOH was then evaporated in vacuo and solid was suspended in EtOAc. Product was filtered off, washed with H ₂ O and dried in vacuo.

[0135] General procedure D (GP-D): Corresponding compound and LiOH.H ₂ O in H ₂ O/THF were stirred at r.t. for 6 d. Solvents were evaporated in vacuo and solid was dissolved in H ₂ O. pH was adjusted to 2 with AcOH and resulting suspension was diluted with EtOH. Solvents were evaporated in vacuo and product was purified by RP FCC on Cl 8 (H ₂ O/ACN).

[0136] General procedure E (GP-E): Pd ₂ (dba) ₃ and Xantphos in anhydrous toluene was degassed at 0 °C for 5 min and then stirred at 50 °C for 20 min under Ar atmosphere. Then solution degassed at 0 °C for 5 min of corresponding compound and 3 -chloroaniline in anhydrous 1,4- dioxane was added together with CS2CO3. Reaction mixture was stirred at 110 °C for 24 h under Ar atmosphere and the reaction was then quenched with a few drops of saturated aqueous solution of NH4CI. Mixture was partitioned between EtOAc and H ₂ O. Organic fraction was washed with brine, dried over MgSO ₄ and solvents were evaporated in vacuo. Product was purified by FCC on silica (cH/EtOAc) and RP FCC on Cl 8 (H ₂ O/ACN).

[0137] General procedure F (GP-F): Corresponding compound and LiOH.FEO in H ₂ O/THF were stirred at r.t. for 2 h. Solvents were evaporated in vacuo and solid was dissolved in H ₂ O. pH was adjusted to 2 with AcOH and resulting precipitate was filtered off. Filter cake was washed with H ₂ O and dried in vacuo. Product was purified by RP FCC on C18 (H ₂ O/ACN).

[0138] General procedure G (GP-G): Pd ₂ (dba) ₃ and Xantphos in anhydrous THF was degassed at 0 °C for 5 min and then stirred at 50 °C for 30 min under Ar atmosphere. Then solution degassed at 0 °C for 5 min of corresponding compound in anhydrous THF was added and reaction mixture was stirred at r.t. for 10 min under Ar atmosphere. 0.5 M solution of benzylzinc bromide in THF was added and reaction mixture was stirred at 65 °C for 24 h. Reaction was then quenched with a few drops of saturated aqueous solution of NH4CI and solvents were evaporated in vacuo. Product was purified by FCC on silica (cH/EtOAc) and RP FCC on C18 (H ₂ O/ACN).

[0139] General procedure H (GP-H): Corresponding compound and urea was heated at 200 °C for 2 h. Then reaction mixture was allowed to cool to 50 °C and H ₂ O was added. Resulting mixture was sonicated until the homogeneous suspension was reached. Product was filtered off, washed successively with MeOH and CHCl ₃ and dried in vacuo.

[0140] General procedure I (GP-I): Corresponding compound, POCl ₃ and A.A-DMA was stirred at 125 °C for 16 h. Then reaction was quenched by pouring of mixture over ice and resulting suspension was filtered. Product from filter cake was washed out by MeOH and filtrate was evaporated in vacuo. Product was purified by FCC on silica (cH/EtOAc) and RP FCC on Cl 8 (H ₂ O/ACN).

[0141] General procedure J (GP-J): Corresponding compound in 10 M solution of NH ₃ in MeOH was stirred at r.t. for 3 h. Then solvents were evaporated in vacuo and solid was suspended in H ₂ O. Product was filtered off, washed with H ₂ O and dried in vacuo.

[0142] General procedure K (GP-K): Corresponding compound and chloroacetone were stirred at 125 °C for 2 d. Then solvents were evaporated in vacuo and solid was partitioned between saturated aqueous solution of NaHCO ₃ and EtOAc. Organic fraction was washed with brine, dried over MgSO ₄ and solvents were evaporated in vacuo. Product was purified by FCC on silica (cH/EtOAc) and RP FCC on C18 (H ₂ O/ACN).

[0143] General procedure L (GP-L): Corresponding compound, NaN ₃ and NH ₄ CI in DMF were stirred at 125 °C for 16 h. Then solvents were evaporated in vacuo and product was purified by RP FCC on C18 (H ₂ O/ACN). [0144] General procedure M(GP-M): Reaction with POCl ₃ . Appropriate carbonyl derivative (11.406 mmol) was treated with POCl ₃ (50 ml) and heated under reflux until complete dissolution of the starting material, cooled to RT and carefully poured into crushed ice under vigorous stirring. The solids were filtered off, washed with ice-cold water and dried in vacuo to give yellow solid (3.1 g, 94 %). Used as it is without further purification. MS (ESI): m/z = 273.1 [M+H] ⁺ . Reactive, insoluble, no NMR.

[0145] General procedure N (GP-N): Reaction with amine or aniline. The appropriate chloroderivative (1 mmol) in ACN (1 ml) was treated with corresponding amine or aniline (3 mmol) and heated at 100 °C in a sealed vial until complete consumption of the chloro- derivative. The mixture was cooled to RT, ACN was evaporated and directly applied to the RP FC (H ₂ O/ACN + 0.1 FA). The product was evaporated, co-distilled with water and EtOH and dried.

[0146] General procedure O (GP-O): Appropriate methyl or ethyl ester (1 mmol) in EtOH/H ₂ O mixture (3: 1, 10 ml) was treated with NaOH (5M aq. solution) to pH 12 and heated under reflux until complete dissolution of the starting material. The mixture was acidified by IM HC1, the precipitated product was filtered off, washed with water and dried in vacuo.

[0147] General procedure Al (GP-A1): Suzuki cross-coupling and cyclization. a-Haloaniline (1 mmol), boronate (1 mmol), K2CO3 (3 mmol) and Pd(PPh ₃ ) ₂ Cl ₂ (0.05 mmol) in dioxane/water mixture (9: 1, 10 ml) were heated at 105 °C under argon atmosphere for 2 h. The mixture was cooled to RT and the precipitate was filtered off, washed with MeOH/water (2: 1) mixture and dried in vacuo.

[0148] General procedure Bl (GP-B1): Reaction with POCl ₃ . Appropriate carbonyl derivative (1 mmol) was treated with POCl ₃ (2 ml) and heated under reflux until complete dissolution of the starting material, cooled to RT and carefully poured into crushed ice under vigorous stirring. The solids were filtered off, washed with ice-cold water and dried in vacuo. Used as it is without further purification.

[0149] General procedure Cl (GP-C1): Reaction with 3 -chloroaniline. The appropriate chloroderivative (1 mmol) in ACN (1 ml) or NMP (1 ml) was treated with 3 -chloroaniline (3 mmol) and heated at 100 °C in a sealed vial until complete consumption of the chloro- derivative. The mixture was cooled to RT, ACN was evaporated, NMP was diluted with DMSO (1 ml) and directly applied to the RP FC (H ₂ O/ACN + 0.1 FA). The product was evaporated, codistilled with water and EtOH and dried.

[0150] General procedure DI (GP-D1): Appropriate methyl or ethyl ester (1 mmol) in EtOH/H ₂ O mixture (3: 1, 10 ml) was treated with NaOH (5M aq. solution) to pH 12 and heated under reflux until complete dissolution of the starting material. The mixture was acidified by IM HC1, the precipitated product was filtered off, washed with water and dried. [0151] Examples 7-11 disclose synthetic processes for the preparation of the compounds described herein. The above listed General Procedures are referred to as GP-A, GP-B, etc. . .in Examples 7- 11.

Example 1: Design high-throughput screen for detection of inhibitors that target autophagy- related protein-protein interactions (PPIs)

[0152] Goal'. Design a screen for identifying small compounds that specifically inhibit autophagy by targeting a pair of autophagic proteins (ATGs) whose interaction is indispensable for the function of both degradative and secretory arms of autophagy.

[0153] A screen for inhibitors that target autophagy-related protein-protein interactions (PPIs) was designed since inhibitors should be highly specific. Even if each protein in the pair of proteins has another nonrelevant cellular function, by targeting the interface between them, the probability of a common off target effect is reduced by several orders of magnitude. A quantitative and sensitive platform was developed for monitoring PPI, with high signal to noise ratio. This robust platform, named Protein fragment Complementation Assay (PCA), is based on split luciferase reporters, for monitoring multiple PPIs along the autophagic and cell death pathways (Gilad, Yuval, et al. "Discovering protein-protein interactions within the programmed cell death network using a protein-fragment complementation screen." Cell reports 8.3: 909-921, 2014).

[0154] Methods:

[0155] Choosing the pair of proteins (PPI) to be targeted in the screen

[0156] The choice of the ultimate pair of proteins to be targeted in the screen was based on three criteria: (1) indispensability of the chosen PPI for both the degradative and secretory arms of autophagy; (2) PPI have a well-defined function along the molecular pathway that constitute the core machinery of autophagy, without other non-relevant functions; and (3) the solved crystal structure of the interaction interface between the two proteins reveals a promising ‘hotspot’ that is amenable to inhibition by small molecules. These criteria led to the choice of the ATG12/ATG3 pair of proteins as the ultimate target for the compound screens (Figure 1A). In addition, the structural predictions of hotspots at the interaction interface were confirmed by mutational scanning of the ATG12 reporter gene (Figure IB). One of these mutations (ATG12 K54D) was used as a reference for maximal inhibition of ATG12/ATG3 interaction during the high throughput screens.

[0157] Protein fragment Complementation Assay (PCA)

[0158] Figure 2 shows the schematic screen workflow of the PCA. The strategy design was based on a PCA platform for detecting PPI inhibitors in high throughput compound screens. The strategy included mixing of cell lysates of two cells, each derived from transfection of an individual reporter gene (Figure 3A), to allow the detection of PPI inhibitors. Pre-printed plates with

WT compounds (at 10 μM final concentrations) were loaded with ATG12-L1 or with ATG12- L1 ^K54D lysates and allowed to incubate with the compounds for 1 hour at 4°C. Then ATG3-L2 was added to the plates, and 24h later, the luminescence was measured. After data analysis, all positive hits passed through hit validation. After exclusion of false positive hits, the remaining compounds were triaged by a medicinal chemist, re-synthesized, and subjected to dose response for determining IC50 in the PCA assay. Positive compounds were then used for cell-based assays to determine inhibitory effects of the compounds on autophagy in viable cells. Positive hits with an IC50 in the range of the assay (20-0.3 μM) were then tested in cell-based disease models. In parallel, active compounds were sent to the Organic Chemistry and Biochemistry (IOCB) team for Structure-activity relationship (SAR) studies and subsequent optimization.

[0159] Calibration and optimization of the screening platform

[0160] The screening protocol was calibrated and optimized by pre-exposing the cell lysates expressing the ATG12 reporter to the compounds before adding the ATG3 cell lysates, and determining the optimal time length of lysate mixing incubation. A proof of concept showing that the protocol is adequate for detecting small compound inhibitors was done using the well-known ABT-737 compound that successfully and specifically inhibited the luminescence. Cell lysates comprising the target pair, the Bcl-xL/Bax proteins, fused to the luciferase reporters were mixed (Figure 3B). The calibrated platform was then adapted to the high-throughput robotic system of the G- INCPM unit (Weizmann Institute core unit facility).

[0161] Results:

[0162] Screening compound libraries and filtering positive hits

[0163] During phase 1 -41,000 small molecules were screened from six different compound libraries. The positive hits were filtered through a multi-step pipeline (Figure 2). Out of the primary screen, 785 compounds passed the threshold and identified as hits (1.9% hit rate). All hits were then validated in triplicates and triaged for selection by medicinal chemists. Eventually, 24 compounds were chosen and re-synthesized for QC, of which 17 compounds gave a dose response in the PCA assays, displaying IC50 corresponding to 9-40 μM, and further tested in cell-based assays for their function as autophagy inhibitors in viable cells (Figure 4A-C). The autophagy cell-based assay uses HEK 293A cells stably expressing GFP-LC3, the marker for autophagic activity in cells. These cells were treated with the hit compounds in gradient concentrations for 24h, followed by induction of autophagy and quantification of autophagosomes formation under fluorescent microscopy. Altogether, two compounds were identified from phase 1 screen that were active in cells, measured by their capability to inhibit GFP-LC3 puncta formation. The structure of the two active compounds, Compound 200 and Compound 42 is shown in Figure 4A and their IC50 in the cell lysates is documented (Figure 4 B and 4C). In the cell-based assays, these compounds showed dose-response dependent puncta inhibition with IC50 corresponding to 10.96 μM, and 3.9 μM, respectively.

Example 2: The biochemical and cellular functions of compound 200.

[0164] The dose response curve measuring the inhibitory effects of compound 200 on GFP-LC3B positive membrane area/cell is shown in Figures 5A- C. Western blot analysis provided an independent proof for the inhibitory effect of compound 200 on LC3B lipidation; incubation with compound 200 reduced the levels of lipidated LC3B (LC3B-II) relative to the unlipidated form (LC3B-I) upon induction of autophagosomes with Torinl and CQ (Figure 5D). In parallel, accumulation of the autophagy cargo receptor SQSTMl/p62 was enhanced by addition of compound 200 to Torinl/CQ treated cells, as expected for an inhibitor of autophagy (Figure 5E). To prove direct binding of compound 200 to ATG12 protein, purified recombinant ATG12-Flag was prepared (Figure 6B) and used in surface plasmon resonance (SPR) in vitro binding assays, which showed a direct dose-dependent binding between compound 200 and ATG12-Flag; subsequent dissociation excluded covalent binding (Figure 6A).

Example 3: Chemical modification of Compound 42

[0165] Compound 42, from the bioactive compound library, is also known as Silmitasertib (CX- 4945), a known inhibitor of the CK2 (Casein kinase II) protein (Siddiqui-Jain, A. et al. CX-4945, an orally bioavailable selective inhibitor of protein kinase CK2, inhibits prosurvival and angiogenic signaling and exhibits antitumor efficacy. Cancer Res. 70, 10288-10298, 2010). In order to eliminate this off target effect, the IOCB team prepared a derivative (named compound 55, Figure 7A) that lost its inhibitory effects on CK2, yet still retained its function as inhibitor of ATG12/ATG3 interaction in PC A cell lysates (Figure 7B), and its ability to inhibit autophagy in the cell-based experiment. The design of this improved derivative was conducted by comparing the available crystal structure of compound 42 docking within the CK2 catalytic site to its in-silico docking on ATG12 (Figure 7C). The inhibitory effect of compound 55 on autophagy (Figure 7D and E), as well as the loss of CK2 activity (Figure 7F and G), were confirmed experimentally.

Example 4: Assessing compounds activity in cell culture-based Cancer disease model

[0166] Goal: Test the efficacy and specificity of Compound 200 in suppressing the growth of tumor cells that are addicted to autophagy. [0167] Method: two cell culture-based systems were used. In one system, based on the autophagy addicted tumor pancreatic cell line, the stand alone functions was tested (Yang, S. et al. Pancreatic cancers require autophagy for tumor growth. Genes Dev. 25, 717-729, 2011; Guo, J. Y. et al. Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis. Genes Dev. 25, 460-470, 2011). In a second system, consisting of early passage melanoma cell cultures, the combinatorial effects with vemurafenib targeting the BRAFV600E mutation, was measured (Dekel-Bird, N. P. etal. A functional pre-screening platform for identifying points of vulnerability in the cell death map of human melanoma tumors. J Cancer Sci Clin Therap. 2022; 6:39-60).

[0168] Results: Compound 200 inhibited the proliferation of the autophagy addicted pancreatic cell line dispalaying high basal levels of autophagy. The effect was selectiive as the non-addicted H460 cells displaying low basal levels of autophagy were not affected by the compound (Figure 8A,B) This effect could be generalized to additional cancer cell lines with RAS mutations as compound 200 had similar growth restrictive effects on endometrial adenocarcinoma HEC-1A cells, and lung carcinoma NCI-H1299 cells (Figure 8C). To test the inhibitory effects of compound 200 on autophagy flux in PDAC cells, a stable polyclonal population expressing the RFP-GFP-LC3B reporter was generated (Figure 8D). As expected, basal levels of autophagy in these cells were high; many autolysosomes (red-only puncta, the GFP signal is quenched by the low pH within the autolysosome) were observed in the absence of any treatment (Figure 8E). Compound 200 significantly reduced the number of autolysosomes. Treatment with CQ resulted, as expected, in a shift towards increased number of autophagosomes at the expense of autolysosomes, as autophagosomes failed to fuse with lysosomes. Combined treatment with compound 200, however, resulted in a strong reduction in the number of both autophagosomes and autolysosomes observed, with minimal change in their proportions, as expected from an inhibitor of the conjugation steps necessary for autophagosome formation. These findings suggest that compound 200 is effective in reducing the continuous growth of autophagy-addicted tumor cells by suppressing the high basal levels of autophagy flux through inhibition of ATG12-ATG3 interactions.

[0169] In the melanoma system, Compound 200 synergized with the killing effects of vemurafenib, showing selectivity for autophagy-sensitive melanoma cells, reflecting its combinatorial effects with targeted therapy (Figure 9).

Example 5: Assessing compounds ability to inhibit the secretory arm of autophagy [0170] Goal: Test the ability of Compound 200 and Compound 55 to inhibit the secretory arm of autophagy. [0171] Method: RAW 264.7 cells were treated with LPS (1 pg/ml) for inducing cytokine storm, combined with Compound 200 or Compound 55, HCQ (20 μM), or Dexamethasone (2 pg/ml) for 24h, and level of IL1β in the medium, a cytokine secreted after LPS exposure, was measured using ELISA procedure.

[0172] Results: Compound 200 and Compound 55 inhibited IL-1β secretion in LPS treated macrophage cultures (Figure 10A and B) confirming their capability to inhibit the secretory arm of autophagy and possible involvement in the cytokine storm during acute inflammation. Compound 200 also reduced the secretion of IL-1β in LPS treated THP-1 human macrophage-like cells (Figure 10C).

Example 6: Assessing compounds effect on autophagic cell death (ACD)

[0173] Another biological system in which autophagy is involved once it is abnormally over activated is autophagic cell death (ACD), shown to contribute to lung injury in viral infections (Sun, Y. et al. Inhibition of autophagy ameliorates acute lung injury caused by avian influenza A H5N1 infection. Sci. Signal. 5, 1-13, 2012). A model system of autophagic cell death in a lung cell line (Dasari, S. K. et al. Signalome-wide RNAi screen identifies GBA1 as a positive mediator of autophagic cell death. Cell Death Differ. 24, 1288-1302, 2017) is used to examine the compounds.

[0174] Goal: Test the effect of Compound 55 on autophagic cell death (ACD).

[0175] Methods: The following assays were done in the A549 cell line of lung carcinoma epithelial cells:

A549 cells were treated with Resveratrol (RSV) for 48h at various concentrations of: 3.12, 6.25, 12.5, 25, 50, 100, and 200 μM, followed by lysis and WB, blotting for LC3-EII, which are markers for autophagosomes, and VCL (vinculin) for loading control (Figure 11 A)

A549 cells were treated with RSV and DMSO for 48h, followed by viability measurement using CellTiter- Gio assay (Figure 11B).

A549 cells transfected with either ATG7 or ATG12 siRNAs were treated with RSV (200 μM). After 48h cell viability was assessed using CellTiter-Glo assay and represented as fold-change in siRNA + RSV-treated cells compared with siRNA treated cells (Figure 11C)

A549 cells were treated with compound 55 and with RSV (100 μM). After 48h cell viability was assessed using CellTiter-Glo assay and represented as fold-change in compound + RSV-treated cells compared to compound only treated cells (Figure 11D). [0176] Results: Treatment of A549 cells with increasing concentrations of RSV cause an increase of LC3-II levels, which indicate activation of autophagy in cells (Figure 11A). Treatment of A549 cells with RSV causes a reduction in cell viability (Figure 11B). Treatment of A549 cells with either ATG7 or ATG12 siRNAs, two essential genes for autophagic activity, rescued from ACD upon RSV treatment, relative to control non-target siRNA treated with RSV, suggesting that autophagy plays a role in RSV-induced cell death(Figure 11C). Compound 55 was able to rescue RSV-induced cell death, suggesting that compound 55 inhibits autophagy at concentrations of 10 and 20 uM. (Figure 11D).

Example 7: Synthesis of the Imidazo[1,2-c]Quinazoline compounds.

Scheme 1- Reagents and conditions: a) Et ₃ N, EtOH, 20 °C; b) SOCh, CHCl ₃ , 80 °C; c) MnO ₂ . Toluene, 120 °C, Ar atm.; d) 3 -chloroaniline, EtOH, 100 °C; e) LiOH.H ₂ O, H ₂ O, THF, 20 °C

[0177] Methyl 2-chloro-4-((l-hydroxy-3-methylbutan-2-yl)amino)quinazoline- 7- carboxylate (SClb). Prepared from SCla (362 mg, 1.4 mmol), 2-amino-3-methylbutan-l-ol (160 mg, 1.5 mmol) and EtsN (392 pl, 2.8 mmol) in EtOH (5 ml) by GP-A. White solid (391 mg, yield 86 %). MS (ESI): m/z = 324.1 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 8.62 - 8.55 (m, 1H), 8.49 (d, J = 8.6 Hz, 1H), 8.08 (d, J= 1.6 Hz, 1H), 7.99 (dd, J = 8.6, 1.8 Hz, 1H), 4.71 (t, J = 5.6 Hz, 1H), 4.26 - 4.14 (m, 1H), 3.92 (s, 3H), 3.71 - 3.56 (m, 2H), 2.04 (dq, J= 13.8, 6.8 Hz, 1H), 0.93 (dd, J = 16.4, 6.8 Hz, 6H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 165.45, 161.43, 158.00, 150.22, 133.92, 127.80, 124.92, 124.54, 116.50, 60.55, 58.78, 52.71, 28.60, 19.47, 19.22 ppm. HRMS (ESI): m/z calculated for C15H ₁₉ CIN ₃ O ₂ 324.11095, found 324.11080 [M+H] ⁺ .

[0178] FMethyl 2-chloro-4-((2-hydroxy-l-phenylethyl)amino)quinazoline-7-car boxylate (SClc). Prepared from SCla (398 mg, 1.6 mmol), 2-amino-2-phenylethanol (234 mg, 1.7 mmol) and EtsN (431 pl, 3.1 mmol) in EtOH (15 ml) by GP-A. White solid (546 mg, yield 98 %). MS (ESI): m/z = 358.1 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 9.16 (d, J= 8.0 Hz, 1H), 8.66 (d, J = 8.6 Hz, 1H), 8.11 (d, J= 1.7 Hz, 1H), 8.05 (dd, J= 8.6, 1.8 Hz, 1H), 7.49 - 7.42 (m, 2H), 7.38 - 7.30 (m, 2H), 7.30 - 7.21 (m, 1H), 5.47 (td, J= 8.4, 5.0 Hz, 1H), 5.09 (t, J= 5.8 Hz, 1H), 3.92 (s, 3H), 3.94 - 3.83 (m, 1H), 3.82 - 3.72 (m, 1H) ppm. ¹³ C NMR (DMSO-d ₆ ): = 165.39, 160.90, 157.77, 150.16, 139.87, 134.07, 128.33, 127.87, 127.25, 127.08, 125.18, 124.48, 116.39, 64.09, 57.45, 52.72 ppm. HRMS (ESI): m/z calculated for C ₁₈ H ₁₇ CIN ₃ O ₃ 358.09530, found 358.09514 [M+H] ⁺ . [0179] Methyl 2-chloro-4-((l-hydroxy-3-phenylpropan-2-yl)amino)quinazoline -7- carboxylate (SC Id). Prepared from SC la (432 mg, 1.6 mmol), 2-amino-2-phenylpropan-l-ol (279 mg, 1.8 mmol) and EtsN (467 pl, 3.3 mmol) in EtOH (15 ml) by GP-A. White solid (555 mg, yield 89 %). MS (ESI): m/z = 372.1 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 8.67 (d, J= 8.1 Hz, 1H), 8.50 (d, J= 8.7 Hz, 1H), 8.07 (d, J= 1.7 Hz, 1H), 8.00 (dd, J= 8.6, 1.8 Hz, 1H), 7.32 - 7.26 (m, 2H), 7.26 - 7.18 (m, 2H), 7.17 - 7.08 (m, 1H), 4.95 (t, J= 5.7 Hz, 1H), 4.61 - 4.48 (m, 1H), 3.91 (s, 3H), 3.66 - 3.52 (m, 1H), 3.04 - 2.88 (m, 1H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 165.39, 160.88, 157.85, 150.08, 138.93, 133.94, 129.09, 128.16, 127.82, 126.07, 125.06, 124.29, 116.35, 61.87, 55.15, 52.70, 36.15 ppm. HRMS (ESI): m/z calculated for C ₁₉ H ₁₉ CIN ₃ O ₂ 372.11095, found 372.11109 [M+H] ⁺ .

[0180] Methyl 5-chloro-2-isopropyl-2,3-dihydroimidazo[1,2-c]quinazoline-8- carboxylate (SCle).

[0181] SClb (244 mg, 0.8 mmol) and SOCl ₂ (15.0 ml, 205.7 mmol) in CHCl ₃ (15.0 ml) were stirred at 80 °C for 16 h. Solvents were then evaporated in vacuo and solid was dissolved in DCM. Resulting solution was washed successively with saturated aqueous solution of NaHCO ₂ and brine. Organic fraction was evaporated in vacuo and product was purified by FCC on silica (DCM/MeOH) to give a white solid (224 mg, yield 97 %). MS (ESI): m/z = 306.1 [M+H] ⁺ . ¹ H NMR (CDCl ₃ ): 5 = 8.08 (dd, , J= 1.6, 0.6 Hz, 1H), 8.04 (dd, J = 8.2, 0.6 Hz, 1H), 7.93 (dd, J = 8.2, 1.6 Hz, 1H), 4.23 - 4.10 (m, 2H), 3.93 (s, 3H), 3.94 - 3.82 (m, 1H), 2.00 - 1.87 (m, 1H), 1.06 (d, J= 6.7 Hz, 3H), 0.97 (d, J= 6.7 Hz, 3H) ppm. ¹³ C NMR (CDCl ₃ ): δ = 166.11, 152.63, 146.65, 143.48, 134.74, 128.08, 127.35, 126.03, 121.04, 71.04, 52.68, 51.79, 33.51, 18.83, 18.07 ppm. HRMS (ESI): m/z calculated for C15H17CIN ₃ O ₂ 306.10038, found 306.10024 [M+H] ⁺ .

[0182] Methyl 5-chloro-2-phenyl-2,3-dihydroimidazo[1,2-c]quinazoline-8-car boxylate (SClf). SClc (229 mg, 0.6 mmol) and SOCl ₂ (15.0 ml, 205.7 mmol) in CHCl ₃ (15.0 ml) were stirred at 80 °C for 16 h. Solvents were evaporated in vacuo and solid was suspended in DCM. Product was filtered off and dried in vacuo to give white solid (176 mg, yield 81 %). MS (ESI): m/z = 340.1 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 8.79 (d, J= 8.4 Hz, 1H), 8.27 (d, J= 1.6 Hz, 1H), 8.23 (dd, J= 8.4, 1.6 Hz, 1H), 7.70 - 7.61 (m, 2H), 7.53 - 7.40 (m, 3H), 5.78 (dd, J= 11.5, 9.0 Hz, 1H), 5.18 (t, J= 11.6 Hz, 1H), 4.48 (dd, J = 11.6, 9.0 Hz, 1H), 3.96 (s, 3H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 164.71, 157.46, 147.68, 142.55, 138.16, 137.40, 129.07, 128.92, 128.21, 127.82, 127.77 (br), 114.84, 60.29, 57.06, 53.13 ppm. HRMS (ESI): m/z calculated for C ₁₈ H ₁₅ CIN ₃ O ₃ 340.08473, found 340.08460 [M+H] ⁺ . [0183] Methyl 2-benzyl-5-chloro-2,3-dihydroimidazo [1,2-c] quinazoline-8-carboxylate

(SClg). SCld (499 mg, 1.3 mmol) and SOCl ₂ (31.5 ml, 431.2 mmol) in CHCl ₃ (31.5 ml) were stirred at 80 °C for 16 h. Solvents were then evaporated in vacuo and solid was suspended in DCM. Product was filtered off and purified by FCC on silica (DCM + 5 % MeOH) and RP FCC on C18 (H ₂ O/ACN) to give a white solid (373 mg, yield 79 %). MS (ESI): m/z = 354.1 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 7.98 (d, J= 8.1 Hz, 1H), 7.88 (dd, J= 8.2, 1.7 Hz, 1H), 7.82 (d, J= 1.6 Hz, 1H), 7.40 - 7.26 (m, 4H), 7.26 - 7.17 (m, 1H), 4.64 - 4.52 (m, 1H), 4.17 (t, J = 10.5 Hz, 1H), 3.95 - 3.84 (m, 1H), 3.89 (s, 3H), 3.06 (dd, J = 13.6, 6.2 Hz, 1H), 2.83 (dd, J = 13.6, 7.7 Hz, 1H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 165.29, 151.89, 146.35, 143.79, 138.01, 133.98, 129.34, 128.31, 126.68, 126.64, 126.33, 125.96, 120.86, 65.52, 53.27, 52.65, 41.46 ppm. HRMS (ESI): m/z calculated for C ₁₉ H ₁₇ CIN ₃ O ₂ 354.10038, found 354.10055 [M+H] ⁺ .

[0184] Methyl 5-chloro-2-isopropylimidazo[1,2-c]quinazoline-8-carboxylate (SClh). Prepared from SCle (210 mg, 0.7 mmol) and MnO ₂ (1.2 g, 13.7 mmol) in toluene (10 ml) by GP- B. White solid (66 mg, yield 32 %). MS (ESI): m/z = 304.1 [M+H] ⁺ . ¹ H NMR (CDCl ₃ ): 6 = 8.56 (d, J= 0.6 Hz, 1H), 8.55 (br d, 1H), 8.25 (dd, J= 8.4, 1.6 Hz, 1H), 7.53 (d, J= 1.0 Hz, 1H), 3.99 (s, 3H), 3.18 (hept, J= 6.9 Hz, 1H), 1.41 (d, J= 6.9 Hz, 6H) ppm. ¹³ C NMR (CDCl ₃ ): 6 = 166.29,

154.74, 143.34, 140.49, 135.55, 131.72, 129.60, 128.76, 123.26, 121.26, 108.60, 52.71, 28.71, 22.34 ppm. HRMS (ESI): m/z calculated for C ₁₅ H ₁₅ CIN ₃ O ₂ 304.08473, found 304.08488 [M+H] ⁺ . [0185] Methyl 5-chloro-2-phenylimidazo[1,2-c]quinazoline-8-carboxylate (Compound 69). Prepared from SCli (157 mg, 0.5 mmol) and MnO ₂ (803 mg, 9.2 mmol) in toluene (7.5 ml) by GP-B. White solid (77 mg, yield 49 %). MS (ESI): m/z = 338.1 [M+H] ⁺ . ¹ H NMR (CDCl ₃ ): 6 = 8.62 (dd, J= 8.3, 0.6 Hz, 1H), 8.56 (dd, J= 1.6, 0.6 Hz, 1H), 8.28 (dd, J= 8.4, 1.6 Hz, 1H), 8.02 (s, 1H), 8.04 - 8.00 (m, 2H), 7.53 - 7.44 (m, 2H), 7.44 - 7.35 (m, 1H), 3.99 (s, 3H) ppm. ¹³ CNMR (CDCl ₃ ): δ = 166.19, 146.18, 143.90, 140.61, 135.36, 132.36, 132.01, 129.67, 129.07, 129.05, 128.95, 126.42, 123.46, 121.26, 108.83, 52.74 ppm. HRMS (ESI): m/z calculated for C ₁₈ H ₁₃ CIN ₃ O ₂ 338.06908, found 338.06892 [M+H] ⁺ .

[0186] Methyl 2-benzyl-5-chloroimidazo[1,2-c]quinazoline-8-carboxylate (SClj). Prepared from SClg (148 mg, 0.4 mmol) and MnO ₂ (726 mg, 8.4 mmol) in toluene (7.5 ml) by GP-B. Yellow solid (25 mg, yield 17 %). MS (ESI): m/z = 352.1 [M+H] ⁺ . ¹ H NMR (CDCl ₃ ): δ = 8.56 (s, 1H), 8.56 - 8.53 (m, 1H), 8.26 (dd, J= 8.3, 1.7 Hz, 1H), 7.42 - 7.38 (m, 1H), 7.38 - 7.33 (m, 4H), 7.31 - 7.26 (m, 1H), 4.22 (d, J= 1.0 Hz, 2H), 3.99 (s, 3H) ppm. ¹³ C NMR (CDCl ₃ ): δ = 166.20,

147.74, 143.59, 140.56, 138.44, 135.38, 131.97, 129.64, 129.16, 128.94, 128.89, 126.92, 123.28, 121.06, 111.07, 52.74, 35.55 ppm. HRMS (ESI): m/z calculated for C ₁₉ H ₁₅ CIN ₃ O ₂ 352.08473, found 352.08457 [M+H] ⁺ . [0187] Methyl 5-((3-chlorophenyl)amino)-2-isopropylimidazo[1,2-c]quinazoli ne-8- carboxylate (Compound 67). Prepared from SClh (57 mg, 0.2 mmol) and 3 -chloroaniline (59 pl, 0.6 mmol) in EtOH (5 ml) by GP-C. White solid (73 mg, yield 98 %). MS (ESI): m/z = 395.1 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 10.37 (s, 1H), 8.88 (s, 1H), 8.68 (d, J= 8.4 Hz, 1H), 8.13 (br s, 1H), 8.11 (d, J= 1.6 Hz, 1H), 8.01 (d, J= 8.4 Hz, 1H), 7.96 (dd, J= 8.4, 1.7 Hz, 1H), 7.47 (t, J = 8.1 Hz, 1H), 7.23 (dd, J= 7.9, 2.1 Hz, 1H), 3.92 (s, 3H), 3.22 (hept, J= 7.0 Hz, 1H), 1.43 (d, J = 6.9 Hz, 6H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 165.49, 145.83, 143.15, 142.24, 141.39, 139.82, 132.89, 132.55, 130.37, 126.66, 124.38, 123.83, 123.63, 120.75, 119.73, 114.76, 108.97, 52.63, 26.17, 21.56 ppm. HRMS (ESI): m/z calculated for C ₂₁ H ₂₀ CIN ₄ O ₂ 395.12693, found 395.12673 [M+H] ⁺ .

[0188] Methyl 5-((3-chlorophenyl)amino)-2-phenylimidazo[1,2-c]quinazoline- 8-carboxylate (Compound 69). Prepared from SCli (57 mg, 0.2 mmol) and 3 -chloroaniline (53 pl, 0.6 mmol) in EtOH (5 ml) by GP-C. Ochre solid (62 mg, yield 86 %). MS (ESI): m/z = 429.1 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 10.11 (s, 1H), 9.31 (s, 1H), 8.48 (d, J= 8.3 Hz, 1H), 8.19 (t, J= 2.1 Hz, 1H), 8.08 (d, J= 1.6 Hz, 1H), 8.07 - 7.98 (m, 3H), 7.91 (dd, J= 8.3, 1.7 Hz, 1H), 7.53 (t, J= 7.6 Hz, 2H), 7.46 (t, J= 8.1 Hz, 1H), 7.44 - 7.38 (m, 1H), 7.20 (dd, J= 8.0, 2.2 Hz, 1H), 3.89 (s, 3H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 165.77, 142.97, 142.41, 141.22, 140.38, 140.20, 132.90, 131.84, 131.02, 130.32, 129.03, 128.53, 126.49, 125.60, 124.27, 123.20, 123.02, 120.50, 119.48, 117.87, 108.98, 52.43 ppm. HRMS (ESI): m/z calculated for C ₂₄ H ₁₈ CIN ₄ O ₂ 429.11128, found 429.11148 [M+H] ⁺ .

[0189] Methyl 2-benzyl-5-((3-chlorophenyl)amino)imidazo[1,2-c]quinazoline- 8-carboxylate (Compound 100a). Prepared from SClj (84 mg, 0.2 mmol) and 3 -chloroaniline (58 pl, 0.6 mmol) in EtOH (5 ml) by GP-C. Dark ochre solid (81 mg, yield 99 %). MS (ESI): m/z = 443.1 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 10.19 (s, 1H), 8.59 (s, 1H), 8.53 (d, J= 8.3 Hz, 1H), 8.13 (d, J= 1.6 Hz, 1H), 8.07 (t, J= 2.1 Hz, 1H), 8.00 - 7.91 (m, 2H), 7.48 - 7.40 (m, 3H), 7.40 - 7.34 (m, 2H), 7.31 - 7.25 (m, 1H), 7.24 - 7.18 (m, 1H), 4.26 (s, 1H), 3.91 (s, 3H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 165.63, 141.88, 141.84, 140.83, 140.02, 138.46, 137.94, 132.90, 132.10, 130.39, 128.97, 128.67, 126.76, 126.61, 124.43, 123.57, 123.41, 120.85, 119.85, 115.85, 110.64, 52.59, 32.5 ppm. HRMS (ESI): m/z calculated for C25H ₂ 0CIN ₄ O ₂ 443.12693, found 443.12678 [M+H] ⁺ .

[0190] 5-((3-chlorophenyl)amino)-2-isopropylimidazo [1 ,2-c] quinazoline-8-carboxylic acid (Compound 68). Prepared from SClj (43 mg, 0.1 mmol) and LiOH.H ₂ O (14 mg, 0.3 mmol) in H ₂ O/THF (1 :4 ml) by GP-D. White solid (28 mg, yield 67 %). MS (ESI): m/z = 381.1 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 13.15 (s, 1H), 9.63 (s, 1H), 8.31 (d, J = 8.3 Hz, 1H), 8.27 - 8.23 (m, 1H), 8.15 (t, J = 2.1 Hz, 1H), 8.12 (d, J = 1.6 Hz, 1H), 7.94 (ddd, J= 8.3, 2.1, 0.9 Hz, 1H), 7.91 (dd, J= 8.3, 1.7 Hz, 1H), 7.46 (t, J= 8.1 Hz, 1H), 7.19 (ddd, J= 8.0, 2.1, 0.9 Hz, 1H), 3.15 - 3.02 (m, 1H), 1.37 (d, J= 6.8 Hz, 6H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 167.08, 152.51, 142.71, 140.81, 140.40, 140.35, 132.91, 131.69, 130.34, 126.86, 124.48, 122.99, 122.32, 120.43, 119.36, 118.74, 106.80, 27.87, 22.14 ppm. HRMS (ESI): m/z calculated for C ₂₀ H ₁₈ CIN ₄ O ₂ 381.11128, found 381.11148 [M+H] ⁺ .

[0191] 5-((3-chlorophenyl)amino)-2-phenylimidazo [1,2-c] quinazoline-8-carboxylic acid

(Compound 70). Prepared from Compound 69 (51 mg, 0.1 mmol) and LiOH.H ₂ O (15 mg, 0.4 mmol) in H ₂ O/THF (1 :3 ml) by GP-D. Light yellow solid (21 mg, yield 42 %). MS (ESI): m/z = 415.1 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 10.50 (s, 1H), 9.19 (s, 1H), 8.36 (s, 1H), 8.28 (d, J= 8.1 Hz, 1H), 8.22 (d, J= 1.4 Hz, 1H), 8.12 - 7.98 (m, 4H), 7.47 (t, J= 6.5 Hz, 2H), 7.44 (t, J= 8.1 Hz, 1H), 7.38 - 7.30 (m, 1H), 7.15 (dd, J= 7.9, 2.2 Hz, 1H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 168.95, 144.33, 143.22, 142.04, 141.48, 141.12, 139.98, 133.39, 132.94, 130.19, 128.88, 127.87, 126.39, 125.66, 125.49, 122.36, 121.08, 120.23, 119.19, 116.00, 108.02 ppm. HRMS (ESI): m/z calculated for C ₂₃ H ₁₆ CIN ₄ O ₂ 415.09563, found 415.09578 [M+H] ⁺ .

[0192] 2-benzyl-5-((3-chlorophenyl)amino)imidazo [1,2-c] quinazoline-8-carboxylic acid (Compound 100b). Compound 100a (50 mg, 0.1 mmol) and LiOH.H ₂ O (14 mg, 0.3 mmol) in H ₂ O/THF (1 :3 ml) were stirred at r.t. for 6 d. Solvents were evaporated in vacuo and solid was dissolved in H ₂ O. pH was adjusted to 2 with AcOH and resulting suspension was filtered. Product was filtered off, filter cake was washed with H ₂ O and dried in vacuo to give a light-yellow solid (37 mg, yield 76 %). MS (ESI): m/z = 429.1 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 13.15 (s, 1H), 9.65 (s, 1H), 8.31 (d, J= 8.2 Hz, 1H), 8.15 (s, 1H), 8.13 - 8.09 (m, 2H), 7.94 - 7.87 (m, 2H), 7.44 (t, J= 8.1 Hz, 1H), 7.41 - 7.32 (m, 4H), 7.28 - 7.22 (m, 1H), 7.18 (dd, J= 7.9, 2.1 Hz, 1H), 4.16 (s, 2H) ppm. ^{I 3} C NMR (DMSO-d ₆ ): δ = 167.02, 145.77, 142.97, 140.85, 140.40, 140.32, 139.31, 132.86, 131.69, 130.28, 128.99, 128.50, 126.84, 126.32, 124.50, 123.02, 122.36, 120.54, 119.49, 118.69, 109.13, 34.77 ppm. HRMS (ESI): m/z calculated for C ₂₄ H ₁₈ CIN ₄ O ₂ 429.11128, found 429.11143 [M+H] ⁺ .

Scheme 2- Reagents and conditions: a) NH3, MeOH, 20 °C; b) 100 °C (R = H); c) 125 °C (R= Me); d) 3 -chloroaniline, Pd ₂ (dba) ₃ , Xantphos, Cs2CO3, 1,4-dioxane, Toluene, 110 °C, Ar atm. (R = H); e) 3- chloroaniline, EtOH, 100 °C (R = Me); f) LiOH.H ₂ O, H ₂ O, THF, 20 °C; g) NH4C1, DIPEA, HATU, DMF, 20 °C

[0193] Methyl 4-amino-2-chloroquinazoline-7-carboxylate (SC2a). Prepared from SCla (1.0 g, 3.9 mmol) in 10 M solution of NH3 in MeOH (48.8 ml, 487.7 mmol) by GP-J. White solid (904 mg, yield 97 %). MS (ESI): m/z = 238.0 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 8.54 (d, J= 7.1 Hz, 2H), 8.34 (d, J= 8.6 Hz, 1H), 8.08 (d, J= 1.7 Hz, 1H), 7.95 (dd, J= 8.5, 1.7 Hz, 1H), 3.92 (s, 3H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 165.86, 163.89, 158.47, 151.04, 134.72, 128.27, 125.44, 125.28,

116.26, 53.18 ppm. HRMS (ESI): m/z calculated for C ₁₀ H ₉ CIN ₃ O ₂ 238.03778, found 238.03789 [M+H] ⁺ .

[0194] Methyl 5-chloroimidazo[1,2-c]quinazoline-8-carboxylate (SC2b). SC2a (103 mg, 0.4 mmol) and chloroacetaldehyde (16.6 ml, 130.5 mmol) were stirred at 100 °C for 1 h. Reaction was then quenched with EtOH and solvents were evaporated in vacuo. Product was purified by FCC on silica (cH/MeOH) and RP FCC on Cl 8 (H ₂ O/ACN) to white ochre solid (47 mg, yield 41 %). MS (ESI): m/z = 262.0 [M+H] ⁺ . ¹ H NMR (CDCl ₃ ): δ = 8.59 (d, J= 1.6 Hz, 1H), 8.57 (d, J= 8.4 Hz, 1H), 8.30 (dd, J= 8.4, 1.6 Hz, 1H), 7.83 (d, J= 1.5 Hz, 1H), 7.71 (d, J= 1.5 Hz, 1H), 4.00 (s, 3H) ppm. ¹³ C NMR (CDCl ₃ ): δ = 166.15, 143.93, 140.56, 135.66, 133.55, 132.15, 129.68, 129.21,

123.27, 121.51, 113.97, 52.78 ppm. HRMS (ESI): m/z calculated for C ₁₂ H ₉ CIN ₃ O ₂ 262.03778, found 262.03774 [M+H] ⁺ .

[0195] Methyl 5-chloro-2-methylimidazo[1,2-c]quinazoline-8-carboxylate (SC2c). Prepared from SC2a (344 mg, 1.5 mmol) and chloroacetone (17.3 ml, 217.3 mmol) by GP-K. Ochre solid (276 mg, yield 53 %). MS (ESI): m/z = 276.1 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 8.55 (dd, J = 1.7, 0.6 Hz, 1H), 8.51 (dd, J= 8.3, 0.6 Hz, 1H), 8.25 (dd, J= 8.4, 1.6 Hz, 1H), 7.56 (q, J= 1.0 Hz, 1H), 3.99 (s, 3H), 2.53 (d, J= 1.1 Hz, 3H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 166.22, 143.87, 143.37, 140.49, 135.26, 131.81, 129.63, 128.89, 123.05, 120.99, 110.65, 52.72, 14.47 ppm. HRMS (ESI): m/z calculated for C ₁₃ H ₁₁ CIN ₃ O ₂ 276.05343, found 276.05338 [M+H] ⁺ .

[0196] Methyl 5-((3-chlorophenyl)amino)imidazo [1 ,2-c] quinazoline-8-carboxylate

(Compound 58). Prepared from SC2b (53 mg, 0.2 mmol) and 3 -chloroaniline (20 pl, 0.2 mmol) in toluene (5 ml), 1,4-dioxane (7.5 ml) with Pd ₂ (dba) ₃ (9 mg, 10 pmol) and Xantphos (11 mg, 20 pmol) and CS2CO3 (88 mg, 0.3 mmol) by GP-E. White solid (10 mg, yield 15 %). MS (ESI): m/z = 353.1 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 9.75 (s, 1H), 8.49 (s, 1H), 8.32 (d, J = 8.3 Hz, 1H), 8.15 - 8.06 (m, 2H), 7.99 - 7.85 (m, 2H), 7.71 (s, 1H), 7.46 (t, J= 8.1 Hz, 1H), 7.20 (ddd, J= 8.1, 2.1, 0.9 Hz, 1H), 3.90 (s, 3H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 165.88, 143.07, 140.84, 140.60, 140.25, 132.91, 132.58, 130.45, 130.34, 126.63, 124.23, 123.15, 122.50, 120.66, 119.63, 119.30, 112.41, 52.36 ppm. HRMS (ESI): m/z calculated for C ₁₈ H ₁₄ CIN ₄ O ₂ 353.07998, found 353.08011 [M+H] ⁺ .

[0197] Methyl 5-((3-chlorophenyl)amino)-2-methylimidazo [1 ,2-c] quinazoline-8-carboxylate (Compound 60). Prepared from SC2c (213 mg, 0.8 mmol) and 3 -chloroaniline (245 pl, 2.3 mmol) in EtOH (20 ml) by GP-C. Light yellow solid (255 mg, yield 90 %). MS (ESI): m/z = 367.1 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 9.59 (s, 1H), 8.25 (d, J = 8.3 Hz, 1H), 8.18 (s, 1H), 8.10 (s, 1H), 8.06 (d, J= 1.6 Hz, 1H), 7.92 (d, J= 8.3 Hz, 1H), 7.86 (dd, J= 8.3, 1.7 Hz, 1H), 7.44 (t, J= 8.1 Hz, 1H), 7.18 (ddd, J= 7.9, 2.0, 0.9 Hz, 1H), 3.9O (s, 3H), 2.41 (s, 3H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 165.89, 142.48, 141.79, 140.69, 140.38, 140.17, 132.89, 130.25, 130.16, 126.61, 124.02, 122.94, 122.31, 120.42, 119.37, 118.80, 108.82, 52.30, 14.11 ppm. HRMS (ESI): m/z calculated for C ₁₉ H ₁₆ CIN ₄ O ₂ 367.09563, found 367.09557 [M+H] ⁺ .

[0198] 5-((3-chlorophenyl)amino)imidazo[1,2-c]quinazoline-8-carboxy lic acid (Compound 59). Prepared from Compound 58 (10 mg, 28 pmol) and LiOH. _H2 O (4 mg, 85 pmol) in H ₂ O/THF (1 :3 ml) by GP-D. White solid (8 mg, yield 85 %). MS (ESI): m/z = 337.0 [M-H]’. ¹ H NMR (DMSO-d ₆ ): δ = 9.93 (s, 1H), 8.62 (s, 1H), 8.32 (d, J= 8.2 Hz, 1H), 8.21 (s, 1H), 8.15 (d, J= 1.6 Hz, 1H), 8.04 - 7.89 (m, 2H), 7.70 (s, 1H), 7.46 (t, J= 8.1 Hz, 1H), 7.19 (ddd, J= 8.0, 2.1, 0.9 Hz, 1H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 167.81, 143.45, 140.87, 140.47, 140.42, 134.40, 132.91, 132.37, 130.32, 126.72, 124.89, 123.01, 122.03, 120.60, 119.56, 118.45, 112.43 ppm. HRMS (ESI): m/z calculated for C ₁₇ H ₁₀ CIN ₄ O ₂ 337.04978, found 337.04973 [M-H]'.

[0199] 5-((3-chlorophenyl)amino)-2-methylimidazo [1 ,2-c] quinazoline-8-carboxylic acid (Compound 61). Prepared from Compound 60 (150 mg, 0.4 mmol) and LiOH.H ₂ O (8 mg, 1.2 mmol) in H ₂ O/THF (5: 15 ml) by GP-F. White solid (131 mg, yield 91 %). MS (ESI): m/z = 351.1 [M-H]'. ¹ H NMR (DMSO-d ₆ ): δ = 13.18 (s, 1H), 9.67 (s, 1H), 8.30 - 8.22 (m, 2H), 8.18 (s, 1H), 8.13 (s, 1H), 7.98 - 7.89 (m, 2H), 7.45 (t, J= 8.1 Hz, 1H), 7.18 (dd, J= 7.9, 2.1 Hz, 1H), 2.43 (s, 3H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 167.69, 142.84, 141.65, 140.75, 140.49, 140.09, 133.20, 132.90, 130.29, 126.76, 124.66, 122.89, 121.99, 120.37, 119.33, 118.21, 108.70, 14.15 ppm. HRMS (ESI): m/z calculated for C ₁₈ H ₁₂ CIN ₄ O ₂ 351.06543, found 351.06538 [M-H]'.

[0200] 5-((3-chlorophenyl)amino)-2-methylimidazo[1,2-c]quinazoline- 8-carboxamide

(Compound 98b). Compound 61 (23 mg, 66 μmol)4Cl (7 mg, 132 pmol), DIPEA (46 pl, 263 pmol) and HATU (38 mg, 99 pmol) in DMF (0.5 ml) was stirred at r.t. for 2 h. Then reaction mixture was diluted with EtOAc and organic layer was washed with saturated aqueous solution of NaHCCE and brine. Organic fraction was dried over MgSO ₄ and solvents were evaporated in vacuo. Product was purified by RP FCC on C18 (H ₂ O/ACN) to give white solid (19 mg, yield 83 %). MS (ESI): m/z = 352.1 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 9.58 (s, 1H), 8.26 (d, J = 8.3 Hz, 1H), 8.20 (br s, 2H), 8.18 - 8.12 (m, 2H), 7.95 - 7.85 (m, 2H), 7.48 (s, 1H), 7.45 (t, J = 8.1 Hz, 1H), 7.19 (ddd, J= 8.0, 2.1, 0.9 Hz, 1H), 2.43 (d, J = 0.9 Hz, 3H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 167.47, 142.92, 141.60, 140.84, 140.44, 140.16, 135.25, 132.96, 130.31, 124.91, 123.41, 123.05, 121.87, 120.59, 119.52, 117.50, 108.51, 14.15 ppm. HRMS (ESI): m/z calculated for C ₁₈ H ₁₅ CIN5O 352.09596, found 352.09602 [M+H] ⁺ .

Scheme 3- Reagents and conditions: a) Mel, K2CO3, DMF, 20 °C; b) CuCN, DMF, 140 °C; c) urea, 200 °C; d) POC13, N,N-DMA, 125°C; e) NH3, MeOH, 20 °C; f) chloroacetone, 125 °C; g) 3 -chloroaniline, EtOH, 100 °C; h) NaN3, NH4C1, DMF, 125 °C; i) NH ₂ OH.HC1, NaHCO3, H2O, EtOH, 100 °C; j) DBU, CDI, ACN, 20 °C

[0201] Methyl 2-amino-4-bromobenzoate (SC3a). K2CO3 (14.1 g, 101.9 mmol) and Mel (6.3 ml, 101.9 mmol) were added to a solution of 2-amino-4-bromobenzoic acid (11.0 g, 50.9 mmol) in anhydrous DMF (130 ml) and reaction mixture was stirred at r.t. for 16 h. Then resulting mixture was filtered and solvent from filtrate was evaporated in vacuo. The solid was partitioned between H ₂ O and EtOAc. Organic fraction was washed with brine, dried over MgSO ₄ and solvents were evaporated in vacuo. Product was purified by FCC on silica (cH/EtOAc) and RP FCC on Cl 8 (H ₂ O/ACN) to give a light-yellow solid (9.2 g, yield 78 %). MS (ESI): m/z = 230.0 [M+H] ⁺ . ³ H NMR (DMSO-d ₆ ): δ = 7.69 (d, J= 8.6 Hz, 1H), 6.84 (d, J= 1.9 Hz, 1H), 6.75 (dd, J= 8.6, 1.9 Hz, 1H), 5.78 (s, 2H), 3.86 (s, 3H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 168.23, 151.34, 132.74, 128.85, 119.68, 119.14, 109.77, 51.82 ppm. HRMS (ESI): m/z calculated for C ₈ H ₉ BrNO ₂ 299.98112, found 299.98082 [M+H] ⁺ .

[0202] Methyl 2-amino-4-cyanobenzoate (SC3b). SC3a (5.4 g, 23.5 mmol) and CuCN (8.4 g, 94.1 mmol) in anhydrous DMF (200 ml) was degassed for 30 min at 0 °C and then stirred at 140 °C for 48 h under Ar atmosphere. Solvent was then evaporated in vacuo and solid was suspended in 10% aqueous solution of KCN (250 ml). Mixture was partitioned between H ₂ O and EtOAc. Organic fraction was washed with brine, dried over MgSO ₄ and solvents were evaporated in vacuo. Product was purified by FCC on silica (cH/EtOAc) to give yellow solid (3.7 g, yield 89 %). MS (ESI): m/z = 177.1 [M+H] ⁺ . ¹ H NMR (CDCl ₃ ): δ = 7.92 (d, J= 8.2 Hz, 1H), 6.94 (dd, J= 1.5, 0.5 Hz, 1H), 6.86 (dd, J = 8.2, 1.6 Hz, 1H), 5.94 (s, 2H), 3.90 (s, 3H) ppm. ¹³ C NMR (CDCl ₃ ): 6 = 167.57, 150.14, 132.33, 120.21, 118.69, 118.35, 117.21, 113.91, 52.22 ppm. HRMS (El): m/z calculated for C ₉ H ₈ N ₂ O ₂ 176.0580, found 176.0581 [M] ⁺ .

[0203] 2,4-dioxo-l,2,3,4-tetrahydroquinazoline-7-carbonitrile (SC3c). Prepared from SC3b (2.0 g, 11.4 mmol) and urea (1.7 g, 28.5 mmol) by GP-H. Yellow-orange solid (1.8 g, yield 86 %). MS (ESI): m/z = 188.0 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 11.19 (s, 2H), 8.01 (d, J= 8.0 Hz, 1H), 7.56 (dd, J= 8.1, 1.5 Hz, 1H), 7.48 (s, 1H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 161.89, 149.97, 141.08, 128.35, 124.95, 119.21, 117.77, 117.75, 116.51 ppm. HRMS (El): m/z calculated for C ₉ H5N ₃ O ₂ 187.0376, found 187.0377 [M] ⁺ .

[0204] 2,4-dichloroquinazoline-7-carbonitrile (SC3d). Prepared from SC3c (1.8 g, 9.9 mmol), POCl ₃ (22.6 ml, 246.4 mmol) and A.A-DMA (1.0 ml, 7.9 mmol) by GP-I. White solid (912 mg, yield 41 %). MS (ESI): m/z = 224.0 [M+H] ⁺ . ¹ H NMR (CDCl ₃ ): δ = 8.40 (dd, J= 8.6, 0.7 Hz, 1H), 8.35 (dd, J= 1.5, 0.8 Hz, 1H), 7.90 (dd, J = 8.6, 1.5 Hz, 1H) ppm. ¹³ C NMR (CDCl ₃ ): δ = 164.70, 157.28, 151.59, 133.54, 130.17, 127.81, 124.11, 119.76, 116.80 ppm. HRMS (El): m/z calculated for C ₉ H ₃ CI ₂ N ₃ 222.9699, found 222.9699 [M] ⁺ .

[0205] 4-amino-2-chloroquinazoline-7-carbonitrile (SC3e). Prepared from SC3d (502 mg, 2.2 mmol) in 10 M solution of NH3 in MeOH (28.0 ml, 280.1 mmol) by GP-J. White solid (446 mg, yield 97 %). MS (ESI): m/z = 205.0 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 8.66 (s, 2H), 8.38 (d, J = 8.5 Hz, 1H), 8.15 (d, J = 1.6 Hz, 1H), 7.87 (dd, J = 8.5, 1.7 Hz, 1H) ppm. ¹³ C NMR (DMSO-d ₆ ): □ = 163.37, 158.54, 150.27, 131.76, 127.38, 125.61, 117.85, 116.16, 115.67 ppm. HRMS (ESI): m/z calculated for C ₉ H ₆ CIN ₄ 205.02755, found 205.02740 [M+H] ⁺ .

[0206] 5-chloro-2-methylimidazo[1,2-c]quinazoline-8-carbonitrile (SC3f). Prepared from SC3e (483 mg, 2.4 mmol) and chloroacetone (28.2 ml, 354.2 mmol) by GP-K. White solid (240 mg, yield 42 %). MS (ESI): m/z = 243.0 [M+H] ⁺ . ¹ H NMR (CDCl ₃ ): δ = 8.55 (dd, J = 8.3, 0.6 Hz, 1H), 8.18 (dd, J= 1.5, 0.6 Hz, 1H), 7.83 (dd, J= 8.3, 1.5 Hz, 1H), 7.60 (q, J = 1.0 Hz, 1H), 2.54 (d, J= 1.1 Hz, 3H) ppm. ¹³ C NMR (CDCl ₃ ): δ = 144.46, 142.62, 140.29, 136.34, 132.40, 130.58, 124.10, 120.92, 118.03, 113.69, 111.05, 14.47 ppm. HRMS (ESI): m/z calculated for C ₁₂ H ₈ CIN ₄ 243.04320, found 243.04304 [M+H] ⁺ .

[0207] 5-((3-chlorophenyl)amino)-2-methylimidazo[1,2-c]quinazoline- 8-carbonitrile

(Compound 72). Prepared from SC3f (199 mg, 0.8 mmol) and 3 -chloroaniline (261 pl, 2.5 mmol) in EtOH (22 ml) by GP-C. Brown solid (271 mg, yield 99 %). MS (ESI): m/z = 334.1 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 9.67 (s, 1H), 8.28 (d, J= 8.2 Hz, 1H), 8.23 (s, 1H), 8.06 (t, J= 2.1 Hz, 1H), 7.99 (d, J= 1.6 Hz, 1H), 7.90 (dd, J= 8.3, 1.3 Hz, 1H), 7.69 (dd, J= 8.2, 1.6 Hz, 1H), 7.43 (t, J= 8.1 Hz, 1H), 7.20 (ddd, J= 8.0, 2.1, 0.9 Hz, 1H), 2.43 (s, 3H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 142.10 (overlap of two signals), 140.82, 140.63, 140.02, 132.93, 130.26, 129.87, 126.35, 123.32, 123.06, 120.75, 119.68, 118.73, 118.62, 111.59, 109.14, 14.09 ppm. HRMS (ESI): m/z calculated for C ₁₈ H ₁₃ C1N ₅ 334.08540, found 334.08521 [M+H] ⁺ .

[0208] N-(3-chlorophenyl)-2-methyl-8-(1H-tetrazol-5-yl)imidazo[1,2- c]quinazolin-5-amine (Compound 88(b)). Prepared from Compound 72 (56 mg, 0.2 mmol), NaN ₃ (164 mg, 2.5 mmol) and NH4CI (180 mg, 3.4 mmol) in DMF (2.5 ml) by GP-L. Light yellow solid (22 mg, yield 35 %). MS (ESI): m/z = 377.1 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 16.92 (s, 1H), 9.65 (s, 1H), 8.37 (d, J= 8.3 Hz, 1H), 8.24 (d, J= 1.7 Hz, 1H), 8.21 (s, 1H), 8.13 (s, 1H), 8.04 (dd, J= 8.3, 1.7 Hz, 1H), 7.88 (d, J= 8.3 Hz, 1H), 7.46 (t, J= 8.1 Hz, 1H), 7.21 (dd, J= 7.9, 2.1 Hz, 1H), 2.43 (s, 3H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 155.14, 142.55, 141.49, 141.15, 140.37, 140.24, 132.95, 130.31, 125.13, 123.90, 123.24 (2C), 122.46, 120.74, 119.68, 116.91, 108.80, 13.90 ppm. HRMS (ESI): m/z calculated for C ₁₈ H ₁₄ C1N ₈ 377.10245, found 377.10225 [M+H] ⁺ .

[0209] 5-((3-chlorophenyl)amino)-N-hydroxy-2-methylimidazo[1,2-c]qu inazoline-8- carboximidamide (SC3g). Solution stirred at r.t. for 15 min of NH ₂ OH.HCI (25 mg, 0.4 mmol) and NaHCO ₃ (46 mg, 0.5 mmol) in H ₂ O (0.5 ml) was added to a solution of Compound 72 (61 mg, 0.2 mmol) in EtOH (1 ml). Reaction mixture was stirred at 100 °C for 16 h. Then solvents were evaporated in vacuo and solid was suspended in H ₂ O. Product was filtered off, washed with H ₂ O and dried in vacuo to give white solid (54 mg, yield 80 %). MS (ESI): m/z = 367.1 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 9.82 (s, 1H), 9.53 (s, 1H), 8.20 (d, J= 4.5 Hz, 1H), 8.17 (br s, 2H), 7.94 (d, J= 1.7 Hz, 1H), 7.91 (dd, J= 8.1, 2.1 Hz, 1H), 7.76 (dd, J= 8.4, 1.7 Hz, 1H), 7.45 (t, J= 8.1 Hz, 1H), 7.18 (dd, J= 7.9, 2.2 Hz, 1H), 5.97 (s, 2H), 2.43 (s, 3H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 150.44, 143.20, 141.37, 141.03, 140.55, 139.94, 134.54, 132.95, 130.28, 122.89, 122.28, 121.70, 121.64, 120.42, 119.34, 115.76, 108.13, 14.16 ppm. HRMS (ESI): m/z calculated for C ₁₈ H ₁₆ C1N ₆ O 367.10686, found 367.10669 [M+H] ⁺ .

[0210] 3-(5-((3-chlorophenyl)amino)-2-methylimidazo[1,2-c]quinazoli n-8-yl)-l,2,4- oxadiazol-5(4H)-one (Compound 88c). SC3g (39 mg, 106 pmol), DBU (64 pl, 427 pmol) and CDI (19 mg, 117 pmol) in CAN (1 ml) was stirred at r.t. for 3 d. Then reaction mixture was diluted with DCM and organic fraction was washed with H ₂ O. Organic layer was dried over MgSO ₄ and solvents were evaporated in vacuo. Product was purified by RP FCC on C18 (H ₂ O + 0.1 % TFA/CAN + 0.1 % TFA) to give light yellow solid (33 mg, yield 78 %). MS (ESI): m/z = 393.1 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 13.04 (s, 1H), 9.64 (s, 1H), 8.30 (d, J = 8.4 Hz, 1H), 8.21 (s, 1H), 8.14 (d, J= 3.9 Hz, 1H), 8.01 (d, J= 1.6 Hz, 1H), 7.85 (d, J= 7.8 Hz, 1H), 7.77 (dd, J= 8.3, 1.7 Hz, 1H), 7.45 (t, J= 8.1 Hz, 1H), 7.21 (ddd, J= 8.0, 2.1, 0.9 Hz, 1H), 2.43 (d, J= 1.0 Hz, 3H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 159.84, 157.09, 142.44, 141.49, 141.23, 140.46, 140.18, 132.95, 130.26, 124.10, 123.67, 123.27, 123.02, 120.88, 120.78, 119.68, 117.63, 108.86, 13.96 ppm. HRMS (ESI): m/z calculated for C ₁₉ H ₁₄ CIN ₆ O ₂ 393.08613, found 393.08590 [M+H] ⁺

Scheme 4- Reagents and conditions: a) NH3, MeOH, 20 °C; b) chloroacetone, 125 °C; c) 3- chloroaniline, EtOH, 100 °C; d) diethyl phosphite, DIPEA, Pd(OAc)2, dppf, ACN, 90 °C; e) TMSBr, DCM, 20 °C

[0211] 7-bromo-2-chloroquinazolin-4-amine (SC4b). Prepared from SC4a (918 mg, 3.3 mmol) in 10 M solution of NH ₃ in MeOH (41.3 ml, 412.8 mmol) by GP-J. White solid (829 mg, yield 97 %). MS (ESI): m/z = 257.9 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 8.46 (s, 2H), 8.17 (d, J = 8.7 Hz, 1H), 7.83 (d, J = 1.9 Hz, 1H), 7.69 (dd, J = 8.8, 2.0 Hz, 1H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 163.47, 158.04, 151.88, 128.98, 128.61, 127.55, 125.98, 112.00 ppm. HRMS (ESI): m/z calculated for C ₈ H ₆ BrClN ₃ 257.94281, found 257.94302 [M+H] ⁺ .

[0212] 8-bromo-5-chloro-2-methylimidazo[1,2-c]quinazoline (SC4c). Prepared from SC4b (829 mg, 3.2 mmol) and chloroacetone (38.3 ml, 481.0 mmol) by GP-K. Light yellow solid (561 mg, yield 59 %). MS (ESI): m/z = 296.0 [M+H] ⁺ . ¹ H NMR (CDCl ₃ ): δ = 8.33 (d, J= 8.6 Hz, 1H), 8.03 (d, J= 1.9 Hz, 1H), 7.74 (dd, J= 8.6, 1.9 Hz, 1H), 7.52 (q, J= 1.1 Hz, 1H), 2.51 (d, J= 1.0 Hz, 3H) ppm. ¹³ C NMR (CDCl ₃ ): δ = 143.61, 143.47, 141.75, 135.53, 132.01, 130.35, 124.28, 124.21, 116.78, 110.18, 14.43 ppm. HRMS (ESI): m/z calculated for C _{1 1} H ₈ BrClN ₃ 295.95846, found 295.95872 [M+H] ⁺ .

[0213 ] 8-bromo-N-(3-chlorophenyl)-2-methylimidazo [1 ,2-c] quinazolin-5-amine (SC4d).

Prepared from SC4c (676 mg, 2.3 mmol) and 3 -chloroaniline (724 pl, 6.8 mmol) in EtOH (60 ml) by GP-C. White solid (858 mg, yield 97 %). MS (ESI): m/z = 387.0 [M+H] ⁺ . ¹ H NMR (DMSO- d ₆ ): δ = 10.47 (s, 1H), 8.82 (s, 1H), 8.46 (d, J= 8.6 Hz, 1H), 8.10 (s, 1H), 7.99 (d, J= 8.3 Hz, 1H), 7.91 (d, J= 1.9 Hz, 1H), 7.72 (dd, J= 8.6, 1.9 Hz, 1H), 7.45 (t, J= 8.1 Hz, 1H), 7.23 (dd, J= 8.0, 2.1 Hz, 1H), 2.53 (d, J = 1.0 Hz, 3H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 143.81, 141.37, 139.84, 139.66, 134.17, 132.91, 130.36, 128.14, 128.06, 126.02, 124.83, 123.81, 121.00, 119.99, 110.37, 110.18, 11.18 ppm. HRMS (ESI): m/z calculated for C ₁₇ H ₁₃ BrClN ₄ 387.00066, found 387.00050 [M+H] ⁺ . [0214] Diethyl (5-((3-chlorophenyl)amino)-2-methylimidazo [1,2-c] quinazolin-8- yl)phosphonate (SC4e). SC4d (105 mg, 270 pmol) in anhydrous CAN (3 ml) was degassed at 0 °C for 5 min and then diethyl phosphite (42 pl, 323 pmol), DIPEA (59 pl, 337 pmol), Pd(Oac)2 (3 mg, 13 pmol) and dppf (7 mg, 13 pmol) were added. Reaction mixture was stirred at 90 °C for 2 d under Ar atmosphere. Then solvent was evaporated in vacuo and product was purified by FCC on silica (EtOAc/MeOH) and RP FCC on C18 (H ₂ O + 0.1 % FA/CAN + 0.1 % FA) to give dark brown solid (91 mg, yield 76 %). MS (ESI): m/z = 445.1 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 9.67 (s, 1H), 8.35 (dd, J= 8.0, 4.5 Hz, 1H), 8.25 (d, J= 1.2 Hz, 1H), 8.13 (t, J= 2.1 Hz, 1H), 7.95 (dd, J = 7.9, 1.5 Hz, 1H), 7.90 (dd, J= 14.9, 1.3 Hz, 1H), 7.65 (ddd, J= 11.9, 8.0, 1.4 Hz, 1H), 7.47 (t, J= 8.1 Hz, 1H), 7.20 (ddd, J= 8.0, 2.1, 0.9 Hz, 1H), 4.07 (dqd, J= 8.5, 7.0, 5.1 Hz, 4H), 2.44 (s, 3H), 1.25 (t, J= 7.0 Hz, 6H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 142.57, 141.78, 140.64 (d, J= 19.0 Hz, C-13), 140.41, 140.26, 132.88, 130.35, 129.39 (d, J = 185.7 Hz), 129.10 (d, J = 10.2 Hz), 125.81 (d, J = 9.4 Hz), 123.12, 122.57 (d, J = 15.8 Hz), 120.56, 119.55, 118.32 (d, J = 3.3 Hz), 108.83, 61.91, 61.86, 16.23, 16.17, 14.12 ppm. ³¹ P NMR (DMSO-d ₆ ): δ = 20.04 ppm. HRMS (ESI): m/z calculated for C21H ₂ 3CIN4O3P 445.11908, found 445.11884 [M+H] ⁺ .

[0215] (5-((3-chlorophenyl)amino)-2-methylimidazo[1,2-c]quinazolin- 8-yl)phosphonic acid (Compound 88d). TMSBr (129 pl, 1.0 mmol) was added dropwise to a solution of SC4e (45 mg, 0.1 mmol) in DCM (2.5 ml). Reaction mixture was stirred at r.t. for 3 d under Ar atmosphere. Then solvent was evaporated in vacuo and solid was dissolved in MeOH/H ₂ O mixture (9: 1). Mixture was stirred at r.t. for 1 h, then solvents were evaporated in vacuo and solid was suspended in H ₂ O. Product was filtered off, washed with H ₂ O and dried in vacuo to give light red solid (35 mg, yield 90 %). MS (ESI): m/z = 387.0 [M-H]'. ¹ H NMR (DMSO-d ₆ ): δ = 9.61 (s, 1H), 8.28 (dd, J= 8.1, 4.0 Hz, 1H), 8.22 (s, 1H), 8.18 (s, 1H), 7.94 - 7.86 (m, 2H), 7.66 (dd, J= 11.7, 8.0 Hz, 1H), 7.46 (t, J= 8.1 Hz, 1H), 7.19 (dd, J = 7.9, 2.1 Hz, 1H), 2.43 (s, 3H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 142.89, 141.45, 140.44, 140.27 (d, J= 24.4 Hz), 140.12, 135.54 (d, J= 179.7 Hz), 132.93, 130.36, 128.10 (d, J = 9.9 Hz), 125.82 (d, J = 8.9 Hz), 122.97, 121.93 (d, J= 15.2 Hz), 120.40, 119.36, 117.08 (d, J = 2.8 Hz), 108.53, 14.10 ppm. ³¹ P NMR (DMSO-d ₆ ): δ = 14.54 ppm. HRMS (ESI): m/z calculated for C ₁₇ H13CIN4O3P 387.04193, found 387.04170 [M-H]'. Scheme 5- Reagents and conditions: a) urea, 200 °C; b) POCl ₃ , N,N-DMA, 125°C; c) NH3, MeOH, 20 °C; d) chloroacetone, 125 °C; e) 3 -chloroaniline, EtOH, 100 °C; f) NabE, NH4CI, DMF, 125 °C; g) H ₂ SO4, MeOH, 100 °C; h) LiOH.H ₂ O, H ₂ O, THF, 20 °C

[0216] 2,4-dioxo-l,2,3,4-tetrahydroquinazoline-6-carbonitrile (SC5b). Prepared from SC5a (3.2 g, 18.0 mmol) and urea (2.7 g, 45.0 mmol) by GP-H. Yellow solid (2.4 g, yield 71 %). MS (ESI): m/z = 188.0 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 11.53 (s, 2H), 8.24 (d, J= 2.0 Hz, 1H), 8.01 (dd, J = 8.6, 2.0 Hz, 1H), 7.26 (d, J= 8.5 Hz, 1H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 161.50, 150.02, 144.11, 137.63, 132.08, 118.27, 116.65, 115.05, 104.54 ppm. HRMS (ESI): m/z calculated for C ₉ H ₆ N ₃ O ₂ 188.04545, found 188.04542 [M+H] ⁺ .

[0217] 2,4-dichloroquinazoline-6-carbonitrile (SC5c). Prepared from SC5b (1.0 g, 5.4 mmol), POCl ₃ (12.3 ml, 134.0 mmol) and N,N-DMA (272 pl, 2.1 mmol) by GP-I. White solid (632 mg, yield 53 %). MS (ESI): m/z = 224.0 [M+H] ⁺ . ¹ H NMR (CDCl ₃ ): δ = 8.59 (dd, J= 1.5, 1.0 Hz, 1H), 8.11 - 8.02 (m, 2H) ppm. ¹³ C NMR (CDCl ₃ ): δ = 164.68, 158.28, 153.48, 136.85, 132.25, 129.89, 122.29, 117.08, 113.33 ppm. HRMS (El): m/z calculated for C ₉ H ₃ CI ₂ N ₃ 222.9709, found 222.9697 [M] ⁺ .

[0218] 4-amino-2-chloroquinazoline-6-carbonitrile (SC5d). Prepared from SC5c (519 mg, 2.3 mmol) in 10 M solution of NH ₃ in MeOH (29.0 ml, 289.5 mmol) by GP-J. White solid (431 mg, yield 91 %). MS (ESI): m/z = 205.0 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 8.81 (d, J= 1.9 Hz, 1H), 8.71 (s, 1H), 8.64 (s, 1H), 8.11 (dd, J= 8.7, 1.8 Hz, 1H), 7.71 (d, J= 8.7 Hz, 1H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 163.25, 159.81, 152.94, 135.21, 130.58, 127.91, 118.36, 113.06, 107.86 ppm. HRMS (ESI): m/z calculated for C ₉ H ₆ CIN ₄ 205.02755, found 205.02742 [M+H] ⁺ .

[0219] 5-chloro-2-methylimidazo[1,2-c]quinazoline-9-carbonitrile (SC5e). Prepared from SC5d (392 mg, 1.9 mmol) and chloroacetone (22.9 ml, 287.1 mmol) by GP-K. Light yellow solid (252 mg, yield 54 %). MS (ESI): m/z = 243.0 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 8.86 (d, J= 1.8 Hz, 1H), 8.05 (dd, J= 8.6, 1.9 Hz, 1H), 7.91 (q, J= 1.1 Hz, 1H), 7.61 (d, J= 8.6 Hz, 1H), 2.41 (d, J= 1.2 Hz, 3H) ppm. ^{I 3} C NMR (DMSO-d ₆ ): δ = 143.97, 141.08, 139.63, 136.78, 135.29, 128.84, 118.59, 117.92, 112.21, 110.28, 106.33, 12.15 ppm. HRMS (ESI): m/z calculated for C ₁₂ H ₈ CIN ₄ 243.04320, found 243.04308 [M+H] ⁺ .

[0220] 5-((3-chlorophenyl)amino)-2-methylimidazo[1,2-c]quinazoline- 9-carbonitrile (SC5f). Prepared from SC5e (209 mg, 0.9 mmol) and 3 -chloroaniline (274 pl, 2.6 mmol) in EtOH (25 ml) by GP-C. Light yellow solid (231 mg, yield 80 %). MS (ESI): m/z = 334.1 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 10.57 (s, 1H), 8.91 (s, 1H), 8.76 (s, 1H), 8.09 (s, 1H), 8.02 (d, J = 8.6 Hz, 1H), 7.93 (d, J = 8.2 Hz, 1H), 7.74 (d, J = 8.6 Hz, 1H), 7.46 (t, J= 8.1 Hz, 1H), 7.26 (d, J= 7.4 Hz, 1H), 2.52 (s, 3H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 145.47, 141.44, 141.38, 139.90, 136.33, 134.45, 133.40, 130.84, 128.66, 127.33, 124.63, 121.93, 120.86, 118.93, 112.73, 110.87, 106.99, 12.20 ppm. HRMS (ESI): m/z calculated for C ₁₈ H ₁₃ C1N ₅ 334.08540, found 334.08527 [M+H] ⁺ .

[0221] N-(3-chlorophenyl)-2-methyl-9-(1H-tetrazol-5-yl)imidazo[1,2- c]quinazolin-5-amine (Compound 89b). Prepared from SC5f (59 mg, 0.2 mmol), NaN ₃ (744 mg, 2.7 mmol) and NH4CI (190 mg, 3.6 mmol) in DMF (2.5 ml) by GP-L. Light yellow solid (14 mg, yield 21 %). MS (ESI): m/z = 377.1 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 16.79 (s, 1H), 9.70 (s, 1H), 8.93 (d, J = 2.1 Hz, 1H), 8.25 - 8.17 (m, 2H,8), 8.15 - 8.09 (m, 1H), 7.89 (d, J= 8.1 Hz, 1H), 7.75 (d, J= 8.6 Hz, 1H), 7.45 (t, J= 8.1 Hz, 1H), 7.21 (dd, J= 8.0, 2.1 Hz, 1H), 2.43 (s, 3H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 155.51, 142.99, 142.83, 141.20, 140.68, 140.19, 132.96, 130.33, 127.99, 126.67, 123.31, 120.88, 120.82, 119.75 (overlap of two signals), 115.71, 108.56, 13.96 ppm. HRMS (ESI): m/z calculated for C ₁₈ H ₁₄ C1N ₈ 377.10245, found 377.10224 [M+H] ⁺ .

[0222] Methyl 2,4-dioxo-l,2,3,4-tetrahydroquinazoline-6-carboxylate (SC5g). Concentrated H ₂ SO4 (1.0 ml, 18.0 mmol) was added dropwise to a suspension of SC5b (79 mg, 0.4 mmol) in anhydrous MeOH (5 ml). Reaction mixture was stirred at 100 °C for 16 h in a pressure test tube. Then reaction was diluted with H ₂ O, pH was adjusted to 7 with solid NaHCO ₃ and product was filtered off. Filter cake was dried in vacuo to give light ochre solid (79 mg, yield 85 %). MS (ESI): m/z = 221.1 [M+H] ⁺ . ¹ HNMR (DMSO-d ₆ ): δ = 11.50 (s, 2H), 8.41 (d, J= 2.0 Hz, 1H), 8.14 (dd, J= 8.5, 2.1 Hz, 1H), 7.23 (d, J= 8.6 Hz, 1H), 3.85 (s, 3H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 165.19, 162.24, 150.19, 144.35, 135.12, 128.71, 123.35, 115.84, 114.31, 52.23 ppm. HRMS (ESI): m/z calculated for C ₁₀ H ₉ N ₂ O ₄ 221.05568, found 221.05577 [M+H] ⁺ .

[0223] Methyl 2,4-dichloroquinazoline-6-carboxylate (SC5h). Prepared from SC5g (705 mg, 3.2 mmol), POC1 ₃ (7.3 ml, 80.1 mmol) and N,N- DMA (162 pl, 1.3 mmol) by GP-I. White solid (289 mg, yield 35 %). MS (ESI): m/z = 257.0 [M+H] ⁺ . ¹ H NMR (CDC1 ₃ ): δ = 8.96 (dd, J= 1.9, 0.6 Hz, 1H), 8.57 (dd, J= 8.8, 1.8 Hz, 1H), 8.05 (dd, J= 8.8, 0.6 Hz, 1H), 4.04 (s, 3H) ppm. ¹³ C NMR (CDC1 ₃ ): δ = 165.48, 165.23, 157.33, 154.28, 135.83, 130.87, 128.91, 128.63, 122.07, 53.12 ppm. HRMS (El): m/z calculated for C ₁₀ H ₆ CI ₂ N ₂ O ₂ 255.9801, found 255.9797 [M] ⁺ .

[0224] Methyl 4-amino-2-chloroquinazoline-6-carboxylate (SC5i). Prepared from SC5h (259 mg, 1.0 mmol) in 10 M solution of NH ₃ in MeOH (12.6 ml, 125.8 mmol) by GP-J. White solid (190 mg, yield 80 %). MS (ESI): m/z = 238.0 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 8.96 (d, J= 1.9 Hz, 1H), 8.79 (s, 1H), 8.53 (s, 1H), 8.23 (dd, J= 8.7, 1.9 Hz, 1H), 7.66 (d, J= 8.7 Hz, 1H), 3.91 (s, 3H) ppm. ^{I 3} C NMR (DMSO-d ₆ ): δ = 165.43, 164.05, 159.22, 153.55, 133.21, 126.99, 126.83, 126.67, 112.65, 52.42 ppm. HRMS (ESI): m/z calculated for C ₁₀ H ₉ CIN ₃ O ₂ 238.03778, found 238.03800 [M+H] ⁺ .

[0225] Methyl 5-chloro-2-methylimidazo[1,2-c]quinazoline-9-carboxylate (SC5j). Prepared from SC5i (159 mg, 0.7 mmol) and chloroacetone (8.0 ml, 100.6 mmol) by GP-K. Light brown solid (62 mg, yield 34 %). MS (ESI): m/z = 276.1 [M+H] ⁺ . ¹ H NMR (CDCl ₃ ): δ = 9.19 (dd, J = 1.9, 0.6 Hz, 1H), 8.30 (dd, J= 8.6, 2.0 Hz, 1H), 7.91 (dd, J = 8.6, 0.6 Hz, 1H), 7.54 (q, J= 1.1 Hz, 1H), 3.98 (s, 3H), 2.53 (d, J = 1.1 Hz, 3H) ppm. ¹³ C NMR (CDCl ₃ ): δ = 166.05, 143.71, 143.47, 143.43, 136.36, 130.95, 130.17, 127.92, 125.32, 117.54, 110.26, 52.63, 14.37 ppm. HRMS (ESI): m/z calculated for C ₁₃ H11CIN ₃ O ₂ 276.05343, found 276.05356 [M+H] ⁺ .

[0226] Methyl 5-((3-chlorophenyl)amino)-2-methylimidazo[1,2-c]quinazoline- 9-carboxylate (Compound 86b). Prepared from SC5j (52 mg, 0.2 mmol) and 3 -chloroaniline (59 pl, 0.6 mmol) in EtOH (10 ml) by GP-C. Light brown solid (54 mg, yield 79 %). MS (ESI): m/z = 367.1 [M+H] ⁺ . 1H NMR (DMSO-d ₆ ): δ = δ 9.74 (s, 1H), 8.74 (s, 1H), 8.20 (s, 1H), 8.12 (s, 1H), 8.04 (d, J = 8.7 Hz, 1H), 7.88 (d, J= 8.0 Hz, 1H), 7.60 (d, J = 8.6 Hz, 1H), 7.44 (t, J= 8.1 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 3.89 (s, 3H), 2.41 (s, 3H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 165.68, 144.55, 142.78, 141.01, 140.87, 139.99, 132.92, 130.28, 129.80, 125.78, 124.84, 123.78, 123.40, 120.91, 119.82, 114.78, 108.52, 52.20, 13.86 ppm. HRMS (ESI): m/z calculated for C ₁₉ H ₁₆ CIN ₄ O ₂ 367.09563, found 367.09546 [M+H] ⁺ .

[0227] 5-((3-chlorophenyl)amino)-2-methylimidazo[1,2-c]quinazoline- 9-carboxylic acid (Compound 86a). Prepared from Compound 86b (31 mg, 86 pmol) and LiOH.^O (11 mg, 257 pmol) in H ₂ O/THF (1 :3 ml) after 6 d by GP-F. Brown solid (27 mg, yield 90 %). MS (ESI): m/z = 351.1 [M-H]'. ¹ H NMR (DMSO-d ₆ ): δ = 12.60 (s, 1H), 9.53 (s, 1H), 8.82 (s, 1H), 8.14 (s, 1H), 8.11 - 8.04 (m, 1H), 7.88 (br s, 1H), 7.63 (d, J= 8.6 Hz, 1H), 7.43 (t, J = 8.1 Hz, 1H), 7.19 (dd, J = 8.0, 2.1 Hz, 1H), 2.44 (s, 3H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 166.33, 143.97, 142.84, 141.18, 140.72, 139.86, 132.67, 129.78, 129.53, 126.07, 125.21, 123.54, 122.96, 120.77, 119.59, 114.92, 107.88, 13.60 ppm. HRMS (ESI): m/z calculated for C ₁₈ H12CIN ₄ O ₂ 351.06543, found 351.06524 [M-H]'.

Scheme 6- Reagents and conditions: a) TEA, EtOH, RT; b) i) SOC12, CHC13, reflux; b) Mn02, toluene, reflux; c) 3 -chloroaniline, EtOH, 80 °C; d) NaOH, EtOH, H ₂ O, 80 °C. [0228] Methyl 2-chloro-4-((l-hydroxybutan-2-yl)amino)quinazoline-7-carboxy late (SC6a). Compound SCla (200 mg, 0.78 mmol) in dry dioxane (4 ml) was treated with TEA (0.22 ml, 1.56 mmol) and 2-amino-l -butanol (0.088 ml, 0.934 mmol) and the resulting mixture was stirred at RT for 30 min. The reaction mixture was diluted with CHCl ₃ , washed with water and dried over MgSO ₄ . White solid, 210 mg (87%). MS (ESI): m/z = 310.2 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 8.53 (dd, 1H, J= 8.7, 0.6 Hz); 8.50 (d, 1H, J = 8.5 Hz); 8.08 (dd, 1H, J= 1.7, 0.5 Hz); 7.99 (dd, 1H, J= 8.6, 1.8 Hz); 4.79 (t, 1H, J = 5.7 Hz); 4.27 (m, 1H); 3.92 (s, 3H); 3.54 (m, 2H); 1.75 (m, 1H); 1.60 (m, 1H); 0.90 (t, 3H, J = 7.4 Hz) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 165.40; 161.19; 157.99; 150.15; 133.89; 127.79; 124.92; 124.39; 116.44; 62.19; 54.82; 52.66; 23.25; 10.58 ppm. HRMS (ESI): m/z calculated for C ₁₄ H ₁₇ CIN ₃ O ₂ 310.09530, found 310.09552.

[0229] Methyl 2-chloro-4-((2-hydroxypropyl)amino)quinazoline-7-carboxylate (SC6b). Compound SCla (200 mg, 0.78 mmol) in dry dioxane (4 ml) was treated with TEA (0.22 ml, 1.56 mmol) and l-amino-2-propanol (0.072 ml, 0.934 mmol) and the resulting mixture was stirred at RT for 30 min. Crystalline solid was filtered off, washed with small amount of cold EtOH and dried in vacuo. White solid, 207 mg (90%). MS (ESI): m/z = 296.2 [M+H] ⁺ . ¹ H NMR (DMSO- d ₆ ): δ = 8.96 (t, 1H, J= 5.6 Hz); 8.44 (dd, 1H, J= 8.7, 0.6 Hz); 8.07 (dd, 1H, J= 1.7, 0.5 Hz); 7.97 (dd, 1H, J= 8.6, 1.7 Hz); 4.89 (d, 1H, J= 4.8 Hz); 3.98 (m, 1H); 3.92 (s, 3H); 3.45 (m, 2H); 1.12 (d, 3H, J = 6.3 Hz) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 165.37; 160.98; 157.90; 150.01; 133.88; 127.76; 125.03; 124.26; 116.46; 63.97; 52.66; 48.76; 21.25 ppm. HRMS (ESI): m/z calculated for C ₁₃ H ₁₅ CIN ₃ O ₃ 296.07965, found 296.07979.

[0230] Methyl 5-chloro-2-ethylimidazo[1,2-c]quinazoline-8-carboxylate (SC6c). Compound SC6a (200 mg, 0.65 mmol) in CHCl ₃ (10 ml) was treated with SOCl ₂ (5 ml) and the mixture was heated under reflux for 5 hrs, volatiles were removed under reduced pressure, the residue in DCM was washed with sat. NaHCCE and water, dried over MgSCE. The crude product was codistilled with toluene, dissolved in toluene (5 ml) and treated with MnO ₂ (536 mg, 6.2 mmol) under argon atmosphere and heated at 120 °C for 24 hrs. FC (c-hex/EtOAc/MeOH) afforded white solid (70 mg, 39%). MS (ESI): m/z = 290.1 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 8.41 (dd, 1H, J = 8.3, 0.6 Hz); 8.27 (dd, 1H, J= 1.6, 0.6 Hz); 8.14 (dd, 1H, J = 8.4, 1.7 Hz); 7.90 (t, 1H, J= 1.0 Hz); 3.93 (s, 3H); 2.80 (dq, 2H, J = 7.5, 1.0 Hz); 1.32 (t, 3H, J= 7.5 Hz) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 165.34; 148.88; 142.20; 139.72; 135.59; 130.66; 128.18; 128.05; 122.91; 120.70; 110.45; 52.58; 21.51; 13.10 ppm. HRMS (ESI): m/z calculated for C ₁₄ H ₁₃ CIN ₃ O ₂ 290.06908, found 290.06860.

[0231] Methyl 5-chloro-3-methylimidazo[1,2-c]quinazoline-8-carboxylate (SC6d). Compound SC6b (180 mg, 0.61 mmol) in CHCl ₃ (10 ml) was treated with SOCl ₂ (5 ml) and the mixture was heated under reflux for 12 hrs, volatiles were removed under reduced pressure, the residue in DCM was washed with sat. NaHCO ₃ and water, dried over MgSO ₄ . The crude product was codistilled with toluene, dissolved in toluene (5 ml) and treated with MnO ₂ (282 mg, 3.2 mmol) under argon atmosphere and heated at 120 °C for 24 hrs. FC (c-hex/EtOAc/MeOH) afforded white poorly soluble solid (70 mg, 40%). MS (ESI): m/z = 276.2 [M+H] ⁺ . ³ H NMR (DMSO-d ₆ ): δ = 8.37 (d, 1H, J= 8.2 Hz); 8.20 (d, 1H, J= 1.7 Hz); 8.11 (dd, 1H, J= 8.3, 1.6 Hz); 7.48 (s, 1H); 3.92 (s, 3H); 2.76 (s, 3H) ppm.

[0232] Methyl 5-((3-chlorophenyl)amino)-2-ethylimidazo[1,2-c]quinazoline-8 -carboxylate (Compound 24). Prepared from SC6c by GP-C (white solid, yield 91%). MS (ESI): m/z = 381.3 [M+H] ⁺ . ¹ HNMR(DMS0-d ₆ ): δ = 9.59 (bs, 1H); 8.26 (d, 1H, J= 8.2 Hz); 8.21 (bs, 1H); 8.10 (bs, 1H); 8.07 (d, 1H, J= 1.6 Hz); 7.93 (bs, 1H, J = 6.5 Hz); 7.87 (dd, 1H, J = 8.3, 1.7 Hz); 7.45 (t, 1H, J= 8.1 Hz); 7.18 (ddd, 1H, J= 8.0, 2.1, 0.9 Hz); 3.90 (s, 3H); 2.79 (qd, 2H, J= 13, 3.5 Hz); 1.34 (t, 3H, J = 1.5 Hz) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 165.90; 147.98; 142.49; 140.73; 140.30; 132.88; 130.28; 130.18; 126.59; 124.02; 122.95; 122.37; 120.42; 119.37; 118.89; 107.81; 52.30; 21.67; 13.04 ppm. HRMS (ESI): m/z calculated for C ₂₀ H ₁₈ CIN ₄ O ₂ 381.11128, found 381.11114.

[0233 ] Methyl 5-((3-chlorophenyl)amino)-3-methylimidazo [1 ,2-c] quinazoline-8-carboxylate (Compound 25). Prepared from SC6d by GP-C, white solid, yield 80%. MS (ESI): m/z = 367.3 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 9.58 (s, 1H); 8.28 (d, 1H, J= 8.3 Hz); 8.20 (d, 1H, J = 0.8 Hz); 8.11 (t, 1H, J = 2.0 Hz); 8.08 (d, 1H, J= 1.6 Hz); 7.93 (ddd, 1H, J= 8.3, 2.1, 1.0 Hz); 7.88 (dd, 1H, J = 8.3, 1.7 Hz); 7.45 (t, 1H, J = 8.1 Hz); 7.19 (ddd, 1H, J= 7.9, 2.1, 0.9 Hz); 3.90 (s, 3H); 2.43 (d, 3H, J= 0.8 Hz) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 165.93; 142.55; 141.86; 140.74; 140.30; 140.24; 132.89; 130.32; 130.23; 126.65; 124.14; 123.04; 122.39; 120.44; 119.41; 118.89; 108.83; 52.36; 14.14 ppm. HRMS (ESI): m/z calculated for C ₁₉ H ₁₆ CIN ₄ O ₂ 367.09563, found 367.09550.

[0234] 5-((3-Chlorophenyl)amino)-2-ethylimidazo[1,2-c]quinazoline-8 -carboxylic acid (Compound 26). Prepared from Compound 24 by GP-D, white solid, yield 68%. MS (ESI): m/z = 367.3 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 13.17 (bs, 1H); 9.62 (s, 1H); 8.30 (d, 1H, J= 8.3 Hz); 8.25 (s, 1H); 8.15 (t, 1H, J= 2.1 Hz); 8.12 (d, 1H, J = 1.6 Hz); 7.92 (m, 2H); 7.46 (t, 1H, J= 8.1 Hz); 7.19 (ddd, 1H, J = 8.0, 2.1, 0.9 Hz); 2.81 (q, 2H, J = 7.5 Hz); 1.34 (t, 3H, J= 7.5 Hz) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 167.02; 147.90; 142.70; 140.81; 140.37; 140.27; 132.91; 131.59; 130.34; 126.86; 124.47; 123.00; 122.29; 120.42; 119.36; 118.68; 107.77; 21.68; 13.11 ppm. HRMS (ESI): m/z calculated for C ₁₉ H ₁₆ CIN ₄ O ₂ 367.09563, found 367.09543.

[0235] 5-((3-Chlorophenyl)amino)-3-methylimidazo[1,2-c]quinazoline- 8-carboxylic acid (Compound 27). Prepared from Compound 25 by GP-D, white solid, yield 62%. MS (ESI): m/z = 353.3 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 9.91 (bs, 1H); 8.33 (bd, 1H); 8.26 (bs, 1H); 8.20 (d, 1H, J= 8.1 Hz); 8.14 (d, 1H, J= 1.5 Hz); 8.00 (bd, 1H, J= 8.5 Hz); 7.93 (m, 1H); 7.44 (t, 1H, J= 8.1 Hz); 7.16 (m, 1H); 2.41 (bd, 3H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 168.45; 143.22; 141.28; 140.86; 140.72; 139.82; 138.05; 132.90; 130.24; 126.41; 125.14; 122.60; 121.30; 120.22; 119.18; 116.91; 108.57; 14.16 ppm. HRMS (ESI): m/z calculated for C ₁₈ H ₁₄ CIN ₄ O ₂ 353.07998, found 353.08007.

Scheme 7- Reagents and conditions: a) Amine, MeCN, 80 °C; b) NaOH, water/EtOH, RT.

Table 1 : Compounds prepared according to Scheme 7

[0236] Methyl 5-((3-chlorophenyl)(methyl)amino)-2-methylimidazo [1,2-c] quinazoline-8- carboxylate (Compound 104a(La)) Prepared from SC2c and 3-chloro-N-methylaniline by GP- N, off-white solid, yield 54 %. MS (ESI): m/z = 381.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 8.36 (dd, J= 8.3, 0.6 Hz, 1H), 8.25 (dd, J= 1.7, 0.6 Hz, 1H), 8.01 (dd, J= 8.3, 1.7 Hz, 1H), 7.40 (t, J= 2.1 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.29 (ddd, J = 8.0, 2.0, 1.0 Hz, 1H), 7.07 (ddd, J = 8.1, 2.2, 1.0 Hz, 1H), 6.63 (q, J= 0.9 Hz, 1H), 3.92 (s, 3H), 3.59 (s, 3H), 2.23 (d, J= 1.0 Hz, 3H). ¹³ C NMR (101 MHz, DMSO) δ 165.83, 149.54, 146.30, 143.56, 143.39, 141.63, 140.52, 134.05, 131.16, 130.83, 130.23, 127.49, 125.31, 125.23, 123.10, 122.54, 121.81, 119.71, 111.32, 110.92, 110.50, 52.41, 41.53, 13.89. HRMS (ESI): m/z calculated for C ₂₀ H ₁₈ O ₂ N ₄ CI 381.11128, found 381.11133.

[0237] Methyl 5-ethoxy-2-methylimidazo[1,2-c]quinazoline-8-carboxylate ( Compound 105a(Lb)) Prepared from SC2c and ethanol by GP-N, off-white solid, yield 58 %. MS (ESI): m/z = 286.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 8.32 (d, J= 8.2 Hz, 1H), 8.17 (d, J= 1.8 Hz, 1H), 8.02 - 7.95 (m, 1H), 7.71 - 7.65 (m, 1H), 4.75 - 4.66 (m, 3H), 3.91 (s, 3H), 2.39 (d, J = 1.1 Hz, 3H), 1.48 (t, J = 7.1 Hz, 3H). ¹³ C NMR (101 MHz, DMSO) δ 165.75, 146.09, 142.97, 142.40, 140.40, 130.35, 127.12, 125.25, 122.61, 119.56, 108.51, 64.91, 52.42, 14.12, 13.96. HRMS (ESI): m/z calculated for C ₁₅ H ₁₆ O ₃ N ₃ 286.11862, found 286.11871. [0238] Methyl 2-methyl-5-((3-(trifluoromethyl)phenyl)amino)imidazo[1,2-c]q uinazoline-8- carboxylate (Compound 106a(Lc)) Prepared from SC2c and 3-(trifluoromethyl)aniline by GP-

N, off-white solid, yield 68 %. MS (ESI): m/z = 401.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 9.68 (s, 1H), 8.32 (d, J= 12.0 Hz, 2H), 8.25 (d, J = 8.3 Hz, 1H), 8.18 (s, 1H), 8.04 (dd, J= 1.6,

O.5 Hz, 1H), 7.86 (dd, J= 8.3, 1.7 Hz, 1H), 7.70 - 7.61 (m, 1H), 7.47 (ddt, J = 7.7, 1.7, 0.9 Hz, 1H), 3.89 (s, 3H), 2.42 (d, J= 1.0 Hz, 3H). ¹³ C NMR (101 MHz, DMSO) 6 165.87, 142.50, 141.84, 140.61, 140.19, 139.64, 130.18, 129.83, 126.58, 124.41, 124.13, 122.32, 119.49, 118.87, 117.02, 108.75, 66.34, 52.30, 14.09. HRMS (ESI): m/z calculated for C ₂₀ H ₁₆ O ₂ N ₄ F ₃ 401.12199, found 401.12203.

[0239] Methyl 5-((3-fluorophenyl)amino)-2-methylimidazo[1,2-c]quinazoline- 8-carboxylate (Compound 107a(Ld)) Prepared from SC2c and 3-fluoroaniline by GP-N, off-white solid, yield 50 %. MS (ESI): m/z = 351.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 9.57 (s, 1H), 8.25 (dd, J=

8.2, 0.6 Hz, 1H), 8.20 (d, J= 1.1 Hz, 1H), 8.07 (dd, J= 1.7, 0.6 Hz, 1H), 7.97 (dt, J = 12.0, 2.3 Hz, 1H), 7.86 (dd, J= 8.3, 1.7 Hz, 1H), 7.72 (ddd, J= 8.3, 2.0, 0.9 Hz, 1H), 7.44 (td, J= 8.3, 6.9 Hz, 1H), 6.95 (tdd, J= 8.5, 2.6, 0.9 Hz, 1H), 3.90 (s, 3H), 2.42 (d, J= 0.9 Hz, 3H). ¹³ C NMR (101 MHz, DMSO) δ 165.90, 163.28, 160.88, 142.51, 141.80, 140.70, 140.63, 140.52, 140.17, 130.17, 130.09, 126.67, 124.07, 122.30, 118.82, 109.84, 109.63, 108.79, 107.82, 107.56, 66.35, 52.29, 14.09. HRMS (ESI): m/z calculated for C ₁₉ H ₁₆ O ₂ N ₄ F 351.12518, found 351.12513.

[0240] Methyl 5-((3-methoxyphenyl)amino)-2-methylimidazo[1,2-c]quinazoline -8- carboxylate (Compound 108a(Le)) Prepared from SC2c and 3 -methoxy aniline by GP-N, off- white solid, yield 56 %. MS (ESI): m/z = 363.1 [M+H] ⁺ . ¹ H NMR (500 MHz, 80 °C, DMSO) δ 8.64 (s, 1H), 8.54 (d, J= 8.3 Hz, 1H), 8.15 (d, J= 1.7 Hz, 1H), 7.95 (dd, J= 8.3, 1.7 Hz, 1H), 7.63 (t, J= 2.2 Hz, 1H), 7.56 (dd, J= 8.0, 2.1 Hz, 1H), 7.34 (t, J = 8.2 Hz, 1H), 6.77 (dd, J = 8.2, 2.5 Hz, 1H), 3.93 (s, 3H), 3.83 (s, 3H), 2.55 - 2.51 (m, 3H). ¹³ C NMR (126 MHz, 80 °C, DMSO) δ 166.25, 160.24, 142.68, 142.16, 140.76, 140.21, 132.78, 129.90, 127.12, 124.65, 123.79, 114.62, 110.20, 108.45, 55.80, 52.87, 12.65. HRMS (ESI): m/z calculated for C ₂₀ H ₁₉ O ₃ N ₄ 363.14517, found 363.14524.

[0241 ] Methyl 5-((4-chlorophenyl)amino)-2-methylimidazo [1,2-c] quinazoline-8-carboxylate (Compound 109a(Lf)) Prepared from SC2c and 4-chloroaniline by GP-N, off-white solid, yield 86 %. MS (ESI): m/z = 367.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 9.54 (s, 1H), 8.24 (d, J = 8.3 Hz, 1H), 8.19 (d, J= 2.0 Hz, 1H), 8.06 (q, J= 0.9 Hz, 1H), 8.01 - 7.95 (m, 2H), 7.84 (dd, J=

8.3, 1.7 Hz, 1H), 7.51 - 7.43 (m, 2H), 3.89 (s, 43), 2.42 (d, J= 0.9 Hz, 3H). ¹³ C NMR (101 MHz, DMSO) δ 165.91, 142.49, 141.69, 140.84, 140.31, 137.72, 137.62, 130.15, 128.50, 127.09, 126.64, 123.91, 122.67, 122.55, 122.31, 118.72, 108.80, 52.30, 14.08. HRMS (ESI): m/z calculated for C ₁₉ H ₁₆ O ₂ N ₄ CI 367.09563, found 367.09558. [0242] Methyl 5-((3-cyanophenyl)amino)-2-methylimidazo[1,2-c]quinazoline-8 -carboxylate (Compound 110a(Lg)) Prepared from SC2c and 3 -aminobenzonitrile by GP-N, off-white solid, yield 44 %. MS (ESI): m/z = 358.2 [M+H] ⁺ . ¹ H NMR (600 MHz, 80 °C, DMSO) δ 9.61 (s, 1H), 8.38 (s, 1H), 8.31 (d, J= 8.3 Hz, 1H), 8.29 - 8.24 (m, 1H), 8.18 (s, 2H), 8.14 (dd, J= 1.6, 0.5 Hz, 1H), 7.94 - 7.89 (m, 1H), 7.66 - 7.60 (m, 2H), 7.55 (dt, J= 7.7, 1.3 Hz, 1H), 3.93 (s, 3H), 2.45 (s, 3H). ¹³ C NMR (151 MHz, 80 °C, DMSO) δ 166.15, 142.90, 142.25, 140.94, 140.52, 140.07, 130.76, 130.19, 126.99, 126.93, 125.85, 124.49, 124.11, 122.55, 119.26, 111.83, 108.93, 52.32, 14.18. HRMS (ESI): m/z calculated for C ₂₀ H ₁₆ O2N5 358.12985, found 358.12989.

[0243] Methyl 5-((2-chloropyridin-4-yl)amino)-2-methylimidazo [1,2-c] quinazoline-8- carboxylate (Compound llla(Lh)) Prepared from SC2c and 2-chloropyridin-4-amine by GP- N, off-white solid, yield 12 %. MS (ESI): m/z = 368.1 [M+H] ⁺ . ¹ H NMR (600 MHz, 80 °C, DMSO) δ 9.83 (s, 1H), 8.33 (t, J= 6.7 Hz, 2H), 8.22 - 8.15 (m, 2H), 8.14 - 8.10 (m, 1H), 8.03 - 7.94 (m, 2H), 3.94 (s, 3H), 2.45 (s, 3H). ¹³ C NMR (151 MHz, 80 °C, DMSO) δ 166.05, 151.04, 148.75, 142.87, 142.37, 140.37, 139.60, 130.84, 127.25, 125.22, 122.60, 119.46, 113.82, 113.64, 109.08, 52.38, 14.16. HRMS (ESI): m/z calculated for C ₁₈ H ₁₅ O2N5CI 368.09088, found 368.09057.

[0244] Methyl 5-(((1R,4R)-4-aminocyclohexyl)amino)-2-methylimidazo[1,2-c]q uinazoline-8- carboxylate (Compound 112a(Li)) Prepared from SC2c and (1R,4R)-cyclohexane-l,4-diamine by GP-N, off-white solid, yield 35 %. MS (ESI): m/z = 354.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 8.20 (dd, J= 8.2, 0.5 Hz, 1H), 8.04 - 7.98 (m, 2H), 7.76 (dd, J= 8.2, 1.7 Hz, 1H), 7.45 (d, J= 7.6 Hz, 1H), 3.89 (s, 3H), 2.37 (d, J = 1.0 Hz, 3H), 2.13 - 1.76 (m, 4H), 1.53 - 1.14 (m, 4H). ¹³ C NMR (101 MHz, DMSO) δ 166.11, 142.73, 142.42, 142.23, 141.51, 130.00, 126.09, 122.31 (d, J= 13.0 Hz), 117.87, 108.29, 52.20, 49.83 (d, J= 2.2 Hz), 34.93, 30.90, 14.07. HRMS (ESI): m/z calculated for C ₁₉ H ₂ 4O2N5 354.19245, found 354.19216.

[0245] Methyl 5-(adamantan-l-ylamino)-2-methylimidazo[1,2-c]quinazoline-8- carboxylate (Compound 113a(Lj)) Prepared from SC2c and adamantan-1 -amine by GP-N, off-white solid, yield 71 %. MS (ESI): m/z = 391.2 [M+H] ⁺ . ¹ H NMR (500 MHz, 80 °C, DMSO) δ 8.23 (d, J = 8.2 Hz, 1H), 8.13 - 8.04 (m, 2H), 7.80 (dd, J = 8.2, 1.7 Hz, 1H), 6.55 (s, 1H), 3.91 (s, 4H), 2.39 (d, J= 1.0 Hz, 3H), 2.33 (d, J= 2.9 Hz, 7H), 2.15 (p, J = 3.2 Hz, 4H), 1.75 (qt, J= 12.2, 3.2 Hz, 7H). ¹³ C NMR (126 MHz, 80 °C, DMSO) δ 165.83, 142.11, 141.41, 141.29, 140.90, 129.85, 126.00, 122.34, 121.80, 117.67, 108.40, 52.78, 51.66, 40.76, 35.87, 28.86, 13.56. HRMS (ESI): m/z calculated for C23H ₂ 7O ₂ N ₄ 391.21285, found 391.21265.

[0246] Methyl 5-(tert-butylamino)-2-methylimidazo[1,2-c]quinazoline-8-carb oxylate (Compound 114a(Lk)) Prepared from SC2c and 2-methylpropan-2-amine by GP-N, off-white solid, yield 54 %. MS (ESI): m/z = 313.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 8.20 (dd, J = 8.2, 0.6 Hz, 1H), 8.13 (q, J= 1.0 Hz, 1H), 8.05 (dd, J = 1.7, 0.6 Hz, 1H), 7.78 (dt, J= 8.2, 1.6 Hz, 1H), 6.89 (s, 1H), 3.89 (d, J= 1.1 Hz, 3H), 2.38 (d, J= 1.0 Hz, 3H), 1.59 (s, 9H). ¹³ C NMR (101 MHz, CDCl ₃ ) 6 167.28, 143.72, 142.20, 141.65, 130.88, 127.69, 123.64, 122.34, 117.77, 106.66, 52.23, 28.81, 13.62. HRMS (ESI): m/z calculated for C ₁₇ H ₂ 1O ₂ N ₄ 313.16590, found 313.16569.

[0247] Methyl 5-(cyclohexylamino)-2-methylimidazo[1,2-c]quinazoline-8-carb oxylate (Compound 115a(Ll)) Prepared from SC2c and cyclohexanamine by GP-N, off-white solid, yield 65 %. MS (ESI): m/z = 339.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 6 8.38 (dd, J= 8.3, 0.6 Hz, 1H), 8.32 (dd, J= 1.6, 0.6 Hz, 1H), 7.93 (dd, J= 8.3, 1.7 Hz, 1H), 7.26 (d, J= 1.1 Hz, 1H), 3.96 (s, 3H), 2.47 (d, J= 1.0 Hz, 3H), 2.21 (dd, J= 12.8, 3.7 Hz, 2H), 1.81 (dt, J= 13.6, 3.5 Hz, 2H), 1.71 (dt, J = 12.9, 3.7 Hz, 1H), 1.58 - 1.42 (m, 2H), 1.39 - 1.16 (m, 4H). ¹³ C NMR (101 MHz, CDCl ₃ ) 6 167.21, 144.14, 142.84, 142.59, 141.99, 131.20, 127.61, 123.92, 122.70, 118.46, 105.94, 52.37, 50.63, 33.35, 25.79, 25.11, 14.33. HRMS (ESI): m/z calculated for C ₁₉ H _{2 3} O ₂ N ₄ 339.18155, found 339.18133.

[0248] Methyl 5-((3-chlorobenzyl)amino)-2-methylimidazo[1,2-c]quinazoline- 8-carboxylate (Compound 116a(Lm)) Prepared from SC2c and (3-chlorophenyl)methanamine by GP-N, off- white solid, yield 52 %. MS (ESI): m/z = 381.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 8.45 (t, J = 5.8 Hz, 1H), 8.23 (d, J= 8.3 Hz, 1H), 8.00 (d, J= 1.6 Hz, 1H), 7.97 - 7.89 (m, 1H), 7.79 (dd, J = 8.2, 1.7 Hz, 1H), 7.51 (d, J= 1.9 Hz, 1H), 7.44 - 7.29 (m, 2H), 4.80 (d, J= 5.7 Hz, 2H), 3.88 (s, 3H), 2.39 (d, J= 1.0 Hz, 3H). ¹³ C NMR (101 MHz, DMSO) δ 166.06, 143.34, 142.47, 141.94, 141.84, 141.81, 133.01, 130.25, 130.11, 127.29, 126.95, 126.19, 126.15, 122.80, 122.36, 118.13, 108.15, 66.35, 59.75, 52.25, 43.57, 14.10. HRMS (ESI): m/z calculated for C ₂₀ H ₁₈ O ₂ N ₄ CI 381.11128, found 381.11095.

[0249] Methyl 5-((4-chlorobenzyl)amino)-2-methylimidazo[1,2-c]quinazoline- 8-carboxylate (Compound 117a(Ln)) Prepared from SC2c and (4-chlorophenyl)methanamine by GP-N, off- white solid, yield 43 %. MS (ESI): m/z = 381.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 8.44 (t, J = 5.8 Hz, 1H), 8.21 (d, J= 8.3 Hz, 1H), 7.98 (d, J = 1.6 Hz, 1H), 7.93 (d, J= 1.1 Hz, 1H), 7.77 (dd, J= 8.2, 1.7 Hz, 1H), 7.51 - 7.42 (m, 2H), 7.38 (d, J= 8.5 Hz, 2H), 4.77 (d, J= 5.7 Hz, 2H), 3.87 (s, 3H), 2.38 (d, J = 1.0 Hz, 3H). ¹³ C NMR (101 MHz, DMSO) δ 166.52, 143.78, 142.93, 142.43, 142.29, 138.72, 131.99, 130.54, 129.83, 128.74, 126.62, 123.20, 122.78, 118.55, 108.57, 52.70, 43.91, 14.57. HRMS (ESI): m/z calculated for C ₂₀ H ₁₈ O ₂ N ₄ CI 381.11128, found 381.11095.

[0250] Methyl 5-(cyclopentylamino)-2-methylimidazo[1,2-c]quinazoline-8-car boxylate (Compound 118a(Lo)) Prepared from SC2c and cyclopentanamine by GP-N, off-white solid, yield 73 %. MS (ESI): m/z = 325.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 8.21 (dd, J= 8.3, 0.5 Hz, 1H), 8.07 - 8.01 (m, 2H), 7.77 (dd, J= 8.2, 1.7 Hz, 1H), 7.51 (d, J= 6.7 Hz, 1H), 4.51 (h, J= 6.7 Hz, 1H), 3.89 (s, 3H), 2.38 (d, J= 1.0 Hz, 3H), 2.14 - 2.01 (m, 2H), 1.83 - 1.55 (m, 6H). ¹³ C NMR (101 MHz, DMSO) δ 166.11, 143.07, 142.36, 141.48, 130.00, 126.18, 122.44, 122.26, 117.92, 108.38, 52.82, 52.21, 30.66, 23.66, 14.07. HRMS (ESI): m/z calculated for C ₁₈ H ₂ 1O ₂ N ₄ 325.16590, found 325.16587.

[0251] Methyl 2-methyl-5-((3-(trifluoromethoxy)phenyl)amino)imidazo[1,2-c] quinazoline- 8-carboxylate (Compound 119a(Lp)) Prepared from SC2c and 3-(trifluoromethoxy)aniline by GP-N, off-white solid, yield 31 %. MS (ESI): m/z = 417.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 9.66 (s, 1H), 8.25 (d, J= 8.3 Hz, 1H), 8.19 (s, 1H), 8.12 (s, 1H), 8.06 (d, J= 1.6 Hz, 1H), 7.96 (d, J= 8.3 Hz, 1H), 7.87 (dd, J= 8.2, 1.7 Hz, 1H), 7.54 (t, J= 8.2 Hz, 1H), 7.11 (ddt, J= 8.2, 2.3, 1.0 Hz, 1H), 3.89 (s, 3 H), 2.42 (d, J= 0.9 Hz, 3H). ¹³ C NMR (101 MHz, DMSO) δ 166.34, 148.89, 142.16, 141.13, 140.96, 140.60, 130.75, 127.08, 124.62, 122.81, 119.92, 115.72, 113.41, 109.30, 52.79, 14.50. HRMS (ESI): m/z calculated for C ₂₀ H ₁₆ 0 ₃ N ₄ F ₃ 417.11690, found 417.11600.

[0252] Methyl 2-methyl-5-((4-(trifluoromethyl)phenyl)amino)imidazo[1,2-c]q uinazoline-8- carboxylate (Compound 120a(Lq)) Prepared from SC2c and 4-(trifluoromethyl)aniline by GP- N, off-white solid, yield 39 %. MS (ESI): m/z = 401.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 9.71 (s, 1H), 8.24 (d, J= 8.3 Hz, 1H), 8.22 - 8.19 (m, 2H), 8.18 (s, 1H), 8.09 (d, J= 1.6 Hz, 1H), 7.86 (dd, J= 8.2, 1.7 Hz, 1H), 7.76 (d, J= 8.6 Hz, 2H), 3.89 (s, 3H), 2.41 (s, 3H). ¹³ C NMR (101 MHz, DMSO) δ 165.85, 142.55, 142.49, 141.80, 140.51, 139.96, 130.12, 126.77, 125.82 (d, J = 3.7 Hz), 124.23, 122.28, 120.55, 118.91, 108.87, 52.27, 14.08. HRMS (ESI): m/z calculated for C ₂₀ H ₁₆ 02N ₄ F ₃ 401.12199, found 401.12180.

[0253] Methyl 5-((3-bromophenyl)amino)-2-methylimidazo[1,2-c]quinazoline-8 -carboxylate (Compound 121a(Lr)) Prepared from SC2c and 3 -bromoaniline by GP-N, off-white solid, yield 64 %. MS (ESI): m/z = 411.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 9.51 (s, 1H), 8.26 - 8.20 (m, 2H), 8.16 (s, 1H), 8.03 (d, J= 1.6 Hz, 1H), 7.99 (d, J= 8.3 Hz, 1H), 7.85 (dd, J= 8.2, 1.7 Hz, 1H), 7.38 (t, J = 8.0 Hz, 1H), 7.31 (ddd, J = 8.0, 1.9, 1.0 Hz, 1H), 3.89 (s, 3H), 2.41 (s, 3H). ¹³ C NMR (101 MHz, DMSO) δ 165.88, 142.48, 141.76, 140.69, 140.40, 140.14, 130.57, 130.19, 126.59, 125.87, 124.08, 123.24, 122.33, 119.74, 118.80, 108.77, 52.31, 14.08. HRMS (ESI): m/z calculated for C ₁₉ H ₁₆ O ₂ N ₄ Br 411.04511, found 411.04497.

[0254] Methyl 5-((3-iodophenyl)amino)-2-methylimidazo[1,2-c]quinazoline-8- carboxylate (Compound 122a(Ls)) Prepared from SC2c and 3 -iodoaniline by GP-N, off-white solid, yield 23%. MS (ESI): m/z = 459.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 9.50 (s, 1H), 8.33 (s, 1H), 8.26 (d, J= 8.2 Hz, 1H), 8.19 (s, 1H), 8.06 (d, J= 1.6 Hz, 1H), 7.87 (dd, J= 8.2, 1.6 Hz, 1H), 7.49 (ddd, J= 7.8, 1.7, 0.9 Hz, 1H), 7.23 (t, J= 8.0 Hz, 1H), 3.90 (s, 3H), 2.42 (s, 3H). ¹³ C NMR (101 MHz, DMSO) δ 166.38, 142.96, 142.17, 141.27, 140.66, 132.30, 131.14, 130.72, 129.65, 127.07, 124.52, 122.84, 120.78, 119.23, 94.67, 52.81, 14.55. HRMS (ESI): m/z calculated for C ₁₉ H ₁₆ O2N4459.03125, found 459.03101. [0255] Methyl 2-methyl-5-((tetrahydro-2H-pyran-4-yl)amino)imidazo[1,2-c]qu inazoline-8- carboxylate (Compound 123a(Lt)) Prepared from SC2c and tetrahydro-2H-pyran-4-amine by GP-N, off-white solid, yield 73 %. MS (ESI): m/z = 341.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) 5 8.21 (d, J= 8.3 Hz, 1H), 8.02 (dd, J= 8.8, 1.3 Hz, 2H), 7.78 (dd, J= 8.2, 1.7 Hz, 1H), 7.55 (d, J = 7.3 Hz, 1H), 4.40 - 4.26 (m, 1H), 3.95 (ddd, J= 11.9, 4.6, 2.0 Hz, 2H), 3.89 (s, 3H), 3.48 (td, J = 11.8, 2.0 Hz, 2H), 2.39 (d, J= 1.0 Hz, 3H), 2.00 (ddd, J= 12.4, 4.4, 2.0 Hz, 2H), 1.66 (qd, J = 12.0, 4.5 Hz, 2H). ¹³ C NMR (101 MHz, DMSO) δ 166.07, 142.55, 142.41, 142.10, 141.49, 130.06, 126.14, 122.58, 122.29, 117.89, 108.31, 66.21, 52.22, 47.59, 32.36, 14.03. HRMS (ESI): m/z calculated for C ₁₈ H ₂₁ O ₃ N ₄ 341.16082, found 341.16077.

[0256] Methyl 2-methyl-5-(m-tolylamino)imidazo[1,2-c]quinazoline-8-carboxy late

(Compound 124a(Lu)) Prepared from SC2c and m-toluidine by GP-N, off-white solid, yield 95 %. MS (ESI): m/z = 347.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 9.38 (s, 1H), 8.29 - 8.20 (m, 2H), 8.06 (d, J= 1.6 Hz, 1H), 7.85 (dd, J= 8.2, 1.7 Hz, 1H), 7.81 - 7.75 (m, 1H), 7.67 (d, J= 2.1 Hz, 1H), 7.31 (t, J= 7.8 Hz, 1H), 6.97 (ddt, J= 7.5, 1.8, 0.9 Hz, 1H), 3.89 (s, 3H), 2.42 (d, J= 1.0 Hz, 3H), 2.37 (s, 3H). ¹³ C NMR (101 MHz, DMSO) δ 165.98, 142.56, 141.71, 141.13, 140.66, 138.53, 137.80, 130.15, 128.50, 126.58, 124.33, 123.67, 122.31, 121.96, 118.71, 108.77, 52.28,

21.25, 14.12. HRMS (ESI): m/z calculated for C ₂₀ H ₁₉ O ₂ N ₄ 347.15025, found 347.15021.

[0257] Methyl 5-((3-isopropylphenyl)amino)-2-methylimidazo[1,2-c]quinazoli ne-8- carboxylate (Compound 125a(Lv)) Prepared from SC2c and 3-isopropylaniline by GP-N, off- white solid, yield 87 %. MS (ESI): m/z = 375.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 9.41 (s, 1H), 8.29 - 8.21 (m, 2H), 8.04 (dd, J= 1.7, 0.6 Hz, 1H), 7.88 - 7.80 (m, 2H), 7.73 (t, J= 1.9 Hz, 1H), 7.35 (t, J= 7.9 Hz, 1H), 7.07 - 7.00 (m, 1H), 3.89 (s, 3H), 2.94 (hept, J= 6.9 Hz, 1H), 2.43 (d, J = 1.0 Hz, 3H), 1.27 (d, J = 6.9 Hz, 6H). ¹³ C NMR (101 MHz, DMSO) δ 165.96, 148.81, 142.55, 141.70, 141.14, 140.69, 138.56, 130.17, 128.51, 126.51, 123.64, 122.31, 121.75, 119.37, 119.13, 118.68, 108.76, 52.29, 33.47, 23.89, 14.11. HRMS (ESI): m/z calculated for C ₂₂ H ₂₃ O ₂ N ₄ 375.18155, found 375.18150.

[0258] Methyl 5-((3-(tert-butyl)phenyl)amino)-2-methylimidazo[1,2-c]quinaz oline-8- carboxylate (Compound 126a(Lw)) Prepared from SC2c and 3-(tert-butyl)aniline by GP-N, off- white solid, yield 72 %. MS (ESI): m/z = 389.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 9.42 (s, 1H), 8.30 - 8.22 (m, 2H), 8.05 (dd, J= 1.6, 0.6 Hz, 1H), 7.91 (t, J = 2.0 Hz, 1H), 7.85 (ddd, J = 8.1, 3.5, 2.0 Hz, 2H), 7.36 (t, J = 7.9 Hz, 1H), 7.18 (ddd, J = 7.8, 1.9, 1.0 Hz, 1H), 3.89 (s, 3H), 2.43 (d, J= 0.9 Hz, 4H), 1.35 (s, 9H). ¹³ C NMR (101 MHz, DMSO) δ 166.44, 151.59, 143.04, 142.20, 141.64, 141.21, 138.81, 130.68, 128.74, 126.97, 124.13, 122.81, 120.98, 119.19, 118.99,

109.25, 52.79, 35.00, 31.63, 14.60. HRMS (ESI): m/z calculated for C ₂₃ H ₂ 5O ₂ N ₄ 389.19720, found 389.19703. [0259] Methyl 5-((2-chlorophenyl)amino)-2-methylimidazo[1,2-c]quinazoline- 8-carboxylate (Compound 127a(Lx)) Prepared from SC2c and 2-chloroaniline by GP-N, off-white solid, yield 56 %. MS (ESI): m/z = 367.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 9.60 (s, 1H), 8.28 (s, 1H), 8.13 (s, 1H), 7.87 (d, J= 19.7 Hz, 2H), 7.66 (d, 32.2 Hz, 1H), 7.43 (d, J= 32.4 Hz, 2H), 7.15

(s, 1H), 3.85 (s, 3H), 2.44 (s, 3H). Poor solubility, no ¹³ C NMR. HRMS (ESI): m/z calculated for C ₁₉ H ₁₆ O ₂ N ₄ CI 367.09563, found 367.09589.

[0260] Methyl 5-((3-acetamidophenyl)amino)-2-methylimidazo[1,2-c]quinazoli ne-8- carboxylate (Compound 128a(Ly)) Prepared from SC2c and 7V-(3-aminophenyl)acetamide by GP-N, off-white solid, yield 21 %. MS (ESI): m/z = 390.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 10.03 (s, 1H), 9.51 (s, 1H), 8.34 - 8.27 (m, 3H), 8.16 (s, 1H), 7.89 (d, J = 8.3 Hz, 1H), 7.63 (s, 1H), 7.33 (d, J= 4.7 Hz, 2H), 3.90 (s, 3H), 2.43 (s, 3H), 2.09 (s, 3H). ¹³ C NMR (101 MHz, DMSO) 8 168.86, 166.51, 143.07, 142.21, 141.61, 141.12, 140.09, 139.43, 130.68, 129.17, 127.27, 124.30, 122.83, 119.26, 116.74, 114.83, 112.61, 109.42, 52.80, 24.61, 14.61. HRMS (ESI): m/z calculated for C ₁₉ H ₁₆ O ₂ N ₄ CI 390.15607, found 390.15629.

[0261] 5-((3-Chlorophenyl)(methyl)amino)-2-methylimidazo[1,2-c]quin azoline-8-carboxylic acid (Compound 104b (Ma)) Prepared from Compound 104a (La) by GP-O, off-white solid, yield 74 %. ¹ H NMR (400 MHz, DMSO) δ 13.20 (s, 1H), 8.35 (d, J= 8.3 Hz, 1H), 8.25 (d, J= 1.5 Hz, 1H), 8.01 (dd, J= 8.3, 1.7 Hz, 1H), 7.40 - 7.38 (m, 1H), 7.36 (d, J= 8.1 Hz, 1H), 7.28 (ddd, J= 8.1, 2.1, 1.0 Hz, 1H), 7.05 (ddd, J = 8.0, 2.2, 1.0 Hz, 1H), 6.64 (d, J= 1.1 Hz, 1H), 3.58 (s, 3H), 2.23 (d, J= 1.0 Hz, 3H). ¹³ C NMR (101 MHz, DMSO) δ 167.38, 146.88, 143.99, 143.96, 142.07, 141.01, 134.54, 131.63, 128.12, 126.16, 125.59, 123.43, 122.83, 122.14, 119.98, 110.87, 41.96, 14.40. HRMS (ESI): m/z calculated for C ₁₉ H ₁₆ O ₂ N ₄ CI 367.09563, found 367.09569.

[0262] 5-Ethoxy-2-methylimidazo[1,2-c]quinazoline-8-carboxylic acid ( Compound 105b(Mb) Prepared from Compound 105a(Lb) by GP-O, off-white solid, yield 16 %. MS (ESI): m/z = 272.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 8.32 (d, J= 8.2 Hz, 1H), 8.17 (d, J= 1.8 Hz, 1H), 8.02 - 7.95 (m, 1H), 7.71 - 7.65 (m, 1H), 4.75 - 4.66 (m, 3H), 3.91 (s, 3H), 1.48 (t, J= 7.1 Hz, 3H). ¹³ C NMR (101 MHZ, DMSO) δ 165.75, 146.09, 142.97, 142.40, 140.40, 130.35, 127.12, 125.25, 122.61, 119.56, 108.51, 64.91, 52.42, 14.12. HRMS (ESI): m/z calculated for C ₁₅ H ₁₃ O ₃ N ₄ 272.10324, found 272.10312.

[0263] 2-Methyl-5-((3-(trifluoromethyl)phenyl)amino)imidazo[1,2-c]q uinazoline-8- carboxylic acid (Compound 106b(Mc) Prepared from Compound 106a (Lc) by GP-O, off- white solid, yield 54 %. MS (ESI): m/z = 387.1 [M+H] ^{+ 1} H NMR (400 MHz, DMSO) δ 9.98 (s, 1H), 8.39 (s, 2H), 8.32 (t, J= 7.2 Hz, 2H), 8.09 (d, J= 1.5 Hz, 1H), 7.92 (dd, J= 8.3, 1.6 Hz, 1H), 7.66 (t, J = 8.0 Hz, 1H), 7.48 (ddt, J = 7.7, 1.7, 0.8 Hz, 1H), 2.46 (s, 3H). ¹³ C NMR (101 MHz, DMSO) δ 167.28, 142.65, 141.54, 140.42, 132.82, 130.33, 129.94, 129.63, 126.05, 125.10, 125.05, 123.34, 122.98, 120.17, 120.13, 117.65, 109.84, 13.74. HRMS (ESI): m/z calculated for C ₁₉ H ₁₄ O2N ₄ F ₃ 387.10634, found 387.10646.

[0264] 5-((3-Fluorophenyl)amino)-2-methylimidazo[1,2-c]quinazoline- 8-carboxylic acid ( Compound 107b(Md)) Prepared from Compound 107a(Ld) by GP-O, off-white solid, yield 65%. MS (ESI): m/z = 337.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 13.13 (s, 1H), 9.59 (s, 1H), 8.28 (d, J= 8.2 Hz, 1H), 8.21 (s, 1H), 8.13 (t, J= 1.4 Hz, 1H), 8.01 - 7.95 (m, 1H), 7.90 (dt, J = 8.3, 1.3 Hz, 1H), 7.77 - 7.70 (m, 1H), 7.45 (tdd, J = 8.2, 6.8, 1.1 Hz, 1H), 7.00 - 6.91 (m, 1H), 2.43 (s, 3H). ¹³ C NMR (101 MHz, DMSO) δ 167.48, 163.77, 161.38, 143.16, 142.21, 141.24, 141.17, 141.06, 140.62, 132.03, 130.69, 130.59, 127.37, 124.92, 122.66, 119.08, 117.14, 117.11, 110.31, 110.10, 109.21, 108.31, 108.05, 14.59. HRMS (ESI): m/z calculated for C ₁₈ H ₁₄ O ₂ N ₄ F 337.10953, found 337.10961.

[0265] 5-((3-Methoxyphenyl)amino)-2-methylimidazo[1,2-c]quinazoline -8-carboxylic acid ( Compound 108b(Me)) Prepared from Compound 108a(Le) by GP-O, off-white solid, yield 66 %. MS (ESI): m/z = 349.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 13.13 (s, 1H), 9.44 (s, 1H), 8.31 - 8.23 (m, 2H), 8.10 (d, J= 1.6 Hz, 1H), 7.92 - 7.85 (m, 1H), 7.67 (s, 1H), 7.54 (d, J= 8.1 Hz, 1H), 7.33 (t, J = 8.1 Hz, 1H), 6.73 (dd, J = 8.2, 2.5 Hz, 1H), 3.82 (s, 3H), 2.44 (s, 3H). ¹³ C NMR (101 MHz, DMSO) δ 167.50, 159.95, 143.14, 142.02, 141.53, 140.89, 140.40, 132.05, 129.88, 127.26, 124.67, 122.68, 118.90, 113.94, 109.31, 107.55, 55.55, 14.56. HRMS (ESI): m/z calculated for C ₁₉ HI ₇ O ₃ N ₄ 349.12952, found 349.12957.

[0266] 5-((4-Chlorophenyl)amino)-2-methylimidazo[1,2-c]quinazoline- 8-carboxylic acid ( Compound 109b(Mf)) Prepared from Compound 109a(Lf) by GP-O, off-white solid, yield 35 %. MS (ESI): m/z = 353.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 10.18 (s, 1H), 8.68 (s, 1H), 8.46 (d, J= 8.3 Hz, 1H), 8.14 (d, J= 1.6 Hz, 1H), 8.05 (d, J= 8.4 Hz, 2H), 7.93 (dd, J= 8.4, 1.6 Hz, 1H), 7.52 - 7.44 (m, 2H) , 2.50 (s, 3H). ¹³ C NMR (101 MHz, DMSO) δ 167.17, 142.15, 140.40, 138.02, 133.62, 129.00, 127.94, 124.96, 123.44, 110.58, 12.81. HRMS (ESI): m/z calculated for C ₁₈ H ₁₄ O ₂ N ₄ C1 353.07998, found 353.08002.

[0267] 5-((3-Cyanophenyl)amino)-2-methylimidazo[1,2-c]quinazoline-8 -carboxylic acid ( Compound 110b (Mg) Prepared from Compound 110a(Lg) by GP-O, off-white solid, yield 47 %. MS (ESI): m/z = 344.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 9.78 (s, 1H), 8.44 (s, 1H), 8.26 (d, J= 7.7 Hz, 2H), 8.20 (s, 1H), 8.12 (s, 1H), 7.90 (d, J= 8.3 Hz, 1H), 7.66 - 7.53 (m, 2H), 2.42 (s, 3H). ¹³ C NMR (101 MHz, DMSO) δ 167.59, 143.18, 142.25, 141.06, 140.51, 140.31, 132.40, 130.53, 127.37, 127.10, 125.90, 125.08, 124.07, 122.61, 119.35, 119.05, 111.88, 109.20, 66.82, 14.58. HRMS (ESI): m/z calculated for C ₁₉ HI ₄ O ₂ N ₅ 344.11420, found 344.11389.

[0268] 5-((2-Chloropyridin-4-yl)amino)-2-methylimidazo[1,2-c]quinaz oline-8-carboxylic acid ( Compound lllb(Mh) Prepared from Compound llla(Lh) by GP-O, off-white solid, yield 21 %. MS (ESI): m/z = 354.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 10.02 (s, 1H), 8.31 (d, J= 5.7 Hz, 1H), 8.27 (d, J= 8.2 Hz, 1H), 8.22 (s, 1H), 8.19 (s, 1H), 8.17 - 8.14 (m, 1H), 8.02 (d, J= 5.7 Hz, 1H), 7.93 (d, J= 8.4 Hz, 1H), 2.41 (s, 3H). ¹³ C NMR (101 MHz, DMSO) δ 167.33, 151.19, 150.48, 149.01, 143.06, 142.22, 140.49, 139.67, 132.14, 127.63, 125.76, 122.70, 119.19, 113.95, 113.68, 109.46, 14.50. HRMS (ESI): m/z calculated for C ₁₇ H ₁₃ O ₂ N ₅ CI 354.07523, found 354.07506.

[0269] 5-(((1R,4R)-4-aminocyclohexyl)amino)-2-methylimidazo[1,2-c]q uinazoline-8- carboxylic acid ( Compound 112b(Mi)) Prepared from Compound 112a(Li) by GP-O, off- white solid, yield 90%. MS (ESI): m/z = 341.3 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO) δ 8.42 - 8.36 (m, 2H), 8.26 (s, 1H), 8.12 (s, 1H), 8.05 (dd, J= 18.0, 5.3 Hz, 2H), 7.90 (d, J= 8.4 Hz, 1H), 4.09 (s, 1H), 3.09 (s, 1H), 2.54 (s, 5H), 2.11 (d, J= 42.7 Hz, 5H), 1.55 (q, J= 6.8 Hz, 5H), 1.23 (d, J= 11.2 Hz, 2H).°C NMR (126 MHz, DMSO) δ 167.08, 143.83, 142.27, 141.58, 135.37, 134.53, 126.73, 124.05, 123.66, 113.36, 110.32, 50.11, 48.98, 29.90, 29.62. HRMS (ESI): m/z calculated for C ₁₈ H ₂₂ O ₂ N ₅ 340.17680, found 340.17652.

[0270] 5-(adamantan-l-ylamino)-2-methylimidazo[1,2-c]quinazoline-8- carboxylic acid ( Compound 113b(Mj)) Prepared from Compound 113a(Lj) by GP-O, off-white solid, yield 86 %. MS (ESI): m/z = 377.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 8.19 (d, J= 8.2 Hz, 1H), 8.14 (s, 1H), 8.05 (d, J= 1.6 Hz, 1H), 7.79 (dd, J= 8.2, 1.6 Hz, 1H), 6.72 (s, 1H), 2.37 (s, 4H), 2.34 - 2.29 (m, 6H), 2.13 (s, 3H), 1.72 (q, J = 12.5 Hz, 6H). ¹³ C NMR (101 MHz, DMSO) δ 167.96, 143.04, 142.02, 141.50, 132.62, 126.94, 123.58, 122.35, 117.87, 109.18, 53.42, 41.37, 36.61, 29.55, 14.54. HRMS (ESI): m/z calculated for C ₂₂ H ₂ 5O ₂ N ₄ 377.19720, found 377.19704.

[0271] 5-(tert-butylamino)-2-methylimidazo[1,2-c]quinazoline-8-carb oxylic acid ( Compound 114b(Mk)) Prepared from Compound 114a(Lk) by GP-O, off-white solid, yield 36 %. MS (ESI): m/z = 299.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 13.06 (s, 1H), 8.21 (d, J= 8.2 Hz, 1H), 8.13 (d, J= 1.1 Hz, 1H), 8.06 (d, J= 1.6 Hz, 1H), 7.85 - 7.76 (m, 1H), 6.87 (s, 1H), 2.38 (d, J= 0.9 Hz, 3H), 1.59 (s, 9H). ¹³ C NMR (101 MHz, DMSO) δ 167.65, 142.90, 142.48, 142.14, 141.44, 131.78, 127.03, 123.53, 122.54, 118.01, 109.26, 52.83, 29.18, 14.47. HRMS (ESI): m/z calculated for C16H ₁₉ O ₂ N ₄ 299.15025, found 299.15016.

[0272] 5-(cyclohexylamino)-2-methylimidazo[1,2-c]quinazoline-8-carb oxylic acid ( Compound 115b(Ml)) Prepared from Compound 115a(Ll) by GP-O, off-white solid, yield 74 %. MS (ESI): m/z = 325.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 8.20 (d, J= 8.2 Hz, 1H), 8.03 (dd, J= 6.6, 1.4 Hz, 2H), 7.78 (dd, J= 8.2, 1.6 Hz, 1H), 7.45 (d, J= 7.6 Hz, 1H), 2.39 (d, J= 1.0 Hz, 3H), 2.08 - 2.02 (m, 2H), 1.80 (d, J= 6.9 Hz, 2H), 1.67 (d, J= 12.9 Hz, 1H), 1.40 (t, J= 9.4 Hz, 4H), 1.21 (s, 1H). ¹³ C NMR (101 MHz, DMSO) δ 167.63, 142.99, 132.00, 126.71, 123.26, 122.64, 108.81, 50.63, 32.78, 25.82, 25.46, 14.36. HRMS (ESI): m/z calculated for C ₁₈ H ₂ 1O ₂ N ₄ 325.16590, found 325.16577.

[0273] 5-((3-Chlorobenzyl)amino)-2-methylimidazo[1,2-c]quinazoline- 8-carboxylic acid ( Compound 116b(Mm) Prepared from Compound 116a(Lm) by GP-O, off-white solid, yield 83 %. MS (ESI): m/z = 367.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 8.43 (t, J= 5.8 Hz, 1H), 8.22 (dd, J= 8.2, 0.5 Hz, 1H), 8.01 (dd, J= 1.7, 0.5 Hz, 1H), 7.95 (dd, J= 1.7, 0.8 Hz, 1H), 7.85 - 7.77 (m, 1H), 7.52 (t, J= 1.9 Hz, 1H), 7.46 - 7.28 (m, 3H), 4.80 (d, J= 5.7 Hz, 2H), 2.40 (s, 3H). ¹³ C NMR (101 MHz, DMSO) δ 167.13, 143.25, 142.61, 141.93, 141.85, 141.75, 132.99, 131.41, 130.24, 127.33, 126.93, 126.22, 123.13, 122.17, 117.87, 108.05, 43.58, 14.12. HRMS (ESI): m/z calculated for C ₁₉ H ₁₆ O ₂ N ₄ CI 367.09563, found 367.09536.

[0274] 5-((4-Chlorobenzyl)amino)-2-methylimidazo[1,2-c]quinazoline- 8-carboxylic acid ( Compound 117b(Mn) Prepared from Compound 117a(Ln) by GP-O, off-white solid, yield 73 %. MS (ESI): m/z = 367.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 8.57 (d, J= 6.1 Hz, 1H), 8.24 (d, J= 8.2 Hz, 1H), 8.01 (dt, J= 1.7, 0.8 Hz, 2H), 7.81 (dd, J= 8.3, 1.6 Hz, 1H), 7.52 - 7.44 (m, 2H), 7.42 - 7.35 (m, 2H), 4.78 (d, J= 5.6 Hz, 2H), 2.41 (d, J= 0.9 Hz, 3H). ¹³ C NMR (101 MHz, DMSO) δ 167.52, 143.61, 142.85, 142.69, 138.67, 132.28, 132.01, 129.91, 128.75, 126.82, 123.65, 122.79, 108.78, 43.96, 14.16. HRMS (ESI): m/z calculated for C ₁₉ H ₁₆ O ₂ N ₄ CI 367.09563, found 367.09547.

[0275] 2-Methyl-5-((tetrahydro-2Z/-pyran-4-yl)amino)imidazo[1,2-c]q uinazoline-8- carboxylic acid (Compound 123b(Mt)) Prepared from Compound 123a(Lt) by GP-O, off-white solid, yield 54 %. MS (ESI): m/z = 327.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 8.19 - 8.14 (m, 1H), 8.11 - 8.05 (m, 2H), 7.82 (dd, J= 8.1, 1.5 Hz, 1H), 7.69 (d, J= 7.4 Hz, 1H), 4.38 - 4.26 (m, 1H), 3.98 - 3.89 (m, 2H), 3.46 (td, J= 11.8, 2.0 Hz, 2H), 2.36 (s, 3H), 2.01 - 1.93 (m, 2H), 1.74 (qd, J= 12.0, 4.5 Hz, 2H). ¹³ C NMR (101 MHz, DMSO) δ 170.24, 142.64, 142.51, 141.25, 126.38, 124.22, 121.39, 116.14, 108.55, 66.79, 47.96, 32.84, 14.59. HRMS (ESI): m/z calculated for C ₁₇ H ₁₉ O ₃ N ₄ 327.14517, found 327.14531.

[0276] 5-(Cyclopentylamino)-2-methylimidazo[1,2-c]quinazoline-8-car boxylic acid ( Compound 118b(Mo)) Prepared from Compound 118a(Lo) by GP-O, off-white solid, yield 76 %. MS (ESI): m/z = 311.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 8.42 - 8.35 (m, 2H), 8.07 (d, J= 1.6 Hz, 1H), 7.83 (dd, J= 8.3, 1.6 Hz, 1H), 4.53 (p, J= 6.6 Hz, 1H), 2.45 (d, J= 1.0 Hz, 3H), 2.13 - 2.01 (m, 2H), 1.82 - 1.57 (m, 6H). ¹³ C NMR (101 MHz, DMSO) δ 166.84, 142.99, 142.47, 141.45, 132.99, 126.25, 123.10, 122.91, 109.51, 53.19, 31.91, 23.72, 12.28. HRMS (ESI): m/z calculated for C ₁₇ H ₁₉ O ₂ N ₄ 311.15025, found 311.15021.

[0277] 2-Methyl-5-((3-(trifluoromethoxy)phenyl)amino)imidazo[1,2-c] quinazoline-8- carboxylic acid (Compound 119b (Mp)) Prepared from Compound 119a(Lp) by GP-O, off- white solid, yield 34%. MS (ESI): m/z = 403.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 9.70 (s, 1H), 8.29 (d, J= 8.3 Hz, 1H), 8.25 - 8.20 (m, 1H), 8.20 - 8.17 (m, 1H), 8.12 (dd, J= 1.6, 0.6 Hz, 1H), 7.55 (t, J= 8.2 Hz, 1H), 7.11 (ddt, J= 8.2, 2.4, 1.0 Hz, 1H), 2.46 - 2.41 (m, 3H). ¹³ C NMR (101 MHz, DMSO) δ 167.01, 148.42, 142.71, 141.77, 140.69, 140.57, 140.13, 131.71, 130.27,

126.81, 124.55, 122.20, 121.48, 119.43, 118.93, 118.64, 115.23, 112.93, 108.74, 14.11. HRMS (ESI): m/z calculated for C ₁₉ H ₁₄ O ₃ N ₄ F ₃ 403.10125, found 403.10116.

[0278] 2-Methyl-5-((4-(trifluoromethyl)phenyl)amino)imidazo[1,2-c]q uinazoline-8- carboxylic acid (Compound 120b(Mq)) Prepared from Compound 120a(Lq) by GP-O, off- white solid, yield 73 %. MS (ESI): m/z = 387.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 9.78 (s, 1H), 8.31 - 8.14 (m, 5H), 7.91 (dd, J= 8.2, 1.6 Hz, 1H), 7.77 (d, J= 8.5 Hz, 2H), 2.43 (s, 3H). ¹³ C NMR (101 MHz, DMSO) δ 167.05, 142.69, 141.73, 140.59, 139.94, 131.80, 127.03, 125.86, 124.65, 123.22, 122.90, 122.14, 120.56, 118.65, 108.83, 14.10. HRMS (ESI): m/z calculated for C ₁₉ H ₁₄ O2N ₄ F ₃ 387.10634, found 387.10628.

[0279] 5-((3-Bromophenyl)amino)-2-methylimidazo[1,2-c]quinazoline-8 -carboxylic acid ( Compound 121b(Mr)) Prepared from Compound 121a(Lr) by GP-O, off-white solid, yield 79%. MS (ESI): m/z = 397.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 9.57 (s, 1H), 8.27 (dt, J = 5.7, 1.7 Hz, 2H), 8.20 (s, 1H), 8.11 (d, J= 1.6 Hz, 1H), 7.99 (d, J= 8.1 Hz, 1H), 7.90 (dt, J= 8.2, 1.8 Hz, 1H), 7.39 (td, J= 8.1, 1.6 Hz, 1H), 7.31 (ddt, J= 8.1, 2.6, 1.2 Hz, 1H), 2.43 (s, 3H). ¹³ C NMR (101 MHz, DMSO) δ 167.02, 142.69, 141.76, 140.74, 140.50, 140.13, 131.64, 130.59,

126.82, 125.84, 124.46, 123.25, 122.20, 121.30, 119.73, 118.60, 108.71, 14.12. HRMS (ESI): m/z calculated for C ₁₈ H ₁₄ O ₂ N ₄ Br 397.02946, found 397.02930.

[0280] 5-((3-Iodophenyl)amino)-2-methylimidazo[1,2-c]quinazoline-8- carboxylic acid ( Compound 122b(Ms)) Prepared from Compound 122a(Ls) by GP-O, off-white solid, yield 19%. MS (ESI): m/z = 445.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 13.16 (s, 1H), 9.52 (s, 1H), 8.42 - 8.36 (m, 1H), 8.29 (d, J = 8.2 Hz, 1H), 8.21 (s, 1H), 8.11 (d, J = 1.6 Hz, 1H), 8.06 (d, J = 8.2 Hz, 1H), 7.90 (dd, J= 8.2, 1.7 Hz, 1H), 7.49 (d, J= 7.8 Hz, 1H), 7.24 (t, J= 8.0 Hz, 1H), 2.43 (s, 3H). ¹³ C NMR (101 MHz, DMSO) δ 167.48, 143.17, 142.25, 141.28, 140.75, 140.63, 132.25, 132.03, 131.15, 129.64, 127.29, 124.89, 122.70, 119.10, 109.19, 94.67, 14.62. HRMS (ESI): m/z calculated for C ₁₈ H ₁₄ O ₂ N ₄ I 445.01560, found 445.01523.

[0281] 2-Methyl-5-(m-tolylamino)imidazo[1,2-c]quinazoline-8-carboxy lic acid ( Compound 124b (Mu) Prepared from Compound 124a(Lu) by GP-O, off-white solid, yield 91 %. MS (ESI): m/z = 333.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 13.12 (s, 1H), 9.38 (s, 1H), 8.32 - 8.21 (m, 2H), 8.09 (d, J= 1.6 Hz, 1H), 7.88 (dd, J= 8.2, 1.6 Hz, 1H), 7.81 - 7.74 (m, 1H), 7.71 (d, J= 2.0 Hz, 1H), 7.31 (t, J = 7.8 Hz, 1H), 6.97 (ddt, J = 7.5, 1.8, 0.9 Hz, 1H), 2.43 (d, J= 1.0 Hz, 3H), 2.37 (s, 3H). ¹³ C NMR (101 MHz, DMSO) δ 167.56, 143.20, 142.14, 141.63, 141.08, 139.09, 138.28, 132.02, 128.96, 127.25, 124.76, 124.51, 122.62, 122.41, 119.14, 118.94, 109.16, 21.73, 14.63. HRMS (ESI): m/z calculated for C ₁₉ H17O ₂ N ₄ 333.13460, found 333.13437.

[0282] 5-((3-Isopropylphenyl)amino)-2-methylimidazo[1,2-c]quinazoli ne-8-carboxylic acid ( Compound 125b(Mv)) Prepared from Compound 125a(Lv) by GP-O, off-white solid, yield 72 %. MS (ESI): m/z = 361.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 9.42 (s, 1H), 8.28 (d, J = 8.2 Hz, 1H), 8.25 (d, J= 1.2 Hz, 1H), 8.08 (d, J= 1.6 Hz, 1H), 7.88 (dd, J= 8.3, 1.6 Hz, 1H), 7.81 (ddd, J= 8.0, 2.2, 1.0 Hz, 1H), 7.78 (t, J= 1.9 Hz, 1H), 7.34 (t, J= 7.8 Hz, 1H), 7.03 (dt, J= 7.8, 1.4 Hz, 1H), 2.94 (hept, J = 6.9 Hz, 1H), 2.44 (d, J= 1.0 Hz, 3H), 1.27 (d, J= 6.9 Hz, 6H). ¹³ C NMR (101 MHz, DMSO) δ 167.08, 148.81, 142.73, 141.66, 141.16, 140.63, 138.64, 131.59, 128.50, 126.71, 124.03, 122.15, 121.72, 119.33, 119.06, 118.46, 108.67, 33.48, 23.90, 14.14. HRMS (ESI): m/z calculated for C ₂₁ H ₂ 1O ₂ N ₄ 361.16590, found 361.16571.

[0283] 5-((3-(tert-Butyl)phenyl)amino)-2-methylimidazo[1,2-c]quinaz oline-8-carboxylic acid ( Compound 126b(Mw)) Prepared from Compound 126a(Lw) by GP-O, off-white solid, yield 62 %. MS (ESI): m/z = 375.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 13.11 (s, 1H), 9.44 (s, 1H), 8.29 (d, J= 8.2 Hz, 1H), 8.27 (d, J= 1.2 Hz, 1H), 8.08 (d, J= 1.7 Hz, 1H), 7.97 (t, J= 2.0 Hz, 1H), 7.88 (dd, J= 8.2, 1.6 Hz, 1H), 7.82 (ddd, J= 8.1, 2.2, 1.0 Hz, 1H), 7.36 (t, J= 7.9 Hz, 1H), 7.18 (ddd, J= 7.8, 2.0, 1.0 Hz, 1H), 2.46 - 2.42 (m, 3H), 1.35 (s, 9H). ¹³ C NMR (101 MHz, DMSO) δ 167.04, 151.11, 142.72, 141.65, 141.18, 140.66, 138.40, 131.53, 128.24, 126.68, 124.03, 122.18, 120.44, 118.64, 118.51, 118.49, 108.71, 34.53, 31.16, 14.14. HRMS (ESI): m/z calculated for C ₂₂ H ₂₃ O ₂ N ₄ 375.18155, found 375.18134.

[0284] 5-((2-Chlorophenyl)amino)-2-methylimidazo[1,2-c]quinazoline- 8-carboxylic acid ( Compound 127b(Mx)) Prepared from Compound 127a(Lx) by GP-O, off-white solid, yield 54 %. MS (ESI): m/z = 353.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 9.69 (s, 1H), 8.15 (s, 2H), 7.95 (s, 1H), 7.82 (s, 1H), 7.57 (s, 1H), 7.42 (s, 1H), 7.31 (s, 2H), 2.41 (s, 3H). ¹³ C NMR (101 MHz, DMSO) δ 167.53, 145.37, 144.61, 138.82, 135.42, 131.42, 130.01, 129.87, 128.53, 125.41, 125.13, 123.91, 123.84, 122.52, 122.00, 109.13, 14.02. HRMS (ESI): m/z calculated for C ₁₈ H14O ₂ N ₄ CI 353.07998, found 353.08014.

[0285] 5-((3-Acetamidophenyl)amino)-2-methylimidazo[1,2-c]quinazoli ne-8-carboxylic acid ( Compound 128b(My)) Prepared from Compound 128a(Ly) by GP-O, off-white solid, yield 39 %. MS (ESI): m/z = 376.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 13.13 (s, 1H), 10.03 (s, 1H), 9.52 (s, 1H), 8.34 (d, J= 20.0 Hz, 2H), 8.29 (d, J= 8.3 Hz, 2H), 8.18 (d, J= 1.6 Hz, 1H), 7.90 (dd, J= 8.2, 1.6 Hz, 1H), 7.61 (s, 1H), 7.38 - 7.28 (m, 2H), 2.44 (s, 3H), 2.09 (s, 3H). ¹³ C NMR (101 MHz, DMSO) δ 168.38, 142.66, 141.31, 140.47, 139.66, 139.02, 131.61, 128.69, 127.01, 124.17, 122.21, 118.30, 116.18, 114.31, 112.07, 108.95, 24.14, 14.02. HRMS (ESI): m/z calculated for C ₂₀ H ₁₈ O ₃ N ₅ 376.14042, found 376.14035.

Scheme 8- Reagents and conditions: a) Chloroacetone, reflux; b) ethyl chloroformate, n-BuLi, THF, -78 °C; c) 3-chloroaniline, ACN, 90 °C ; d) NaOH, water/EtOH, RT.

[0286] 7-Bromo-5-chloro-2-methylimidazo[1,2-c]quinazoline (SC8a) Ring closure. 8-Bromo- 2-chloroquinazolin-4-amine (1.934 mmol) was refluxed in chloroacetone (37.678 mmol) for 16 h. The mixture was cooled to RT and concentrated in vacuo. The mixture was diluted with EtOAc, then washed with water. Aqueous phase was repeatedly back extracted with EtOAc. Collected organic fractions were dried over MgSO ₄ and dried in vacuo. Purified by FC (c-hex/EtOAc) to give off-white solid (346 mg, 60 %). MS (ESI): m/z = 296.0 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.45 (dd, J = 8.0, 1.3 Hz, 1H), 7.95 (dt, J = 7.7, 1.0 Hz, 1H), 7.53 (q, J= 1.0 Hz, 1H), 7.51 - 7.44 (m, 1H), 2.52 (s, 3H). ¹³ C NMR (101 MHz, CDCl ₃ ) 6 143.70, 138.88, 134.33, 129.24, 122.65, 122.42, 110.20, 14.41. HRMS (ESI): m/z calculated for CuH ₈ N ₃ BrCl 295.95846, found 295.95850.

[0287] Ethyl 5-chloro-2-methylimidazo[1,2-c]quinazoline-7-carboxylate (SC8b) Ethyl ester attachment. SC8a (0.727 mmol) in freshly distilled THF (10 ml) under argon atmosphere at -78 °C. n-BuLi (0.799 mmol) was added dropwise to the mixture of SC8a. The mixture was stirred for 15 min. Ethyl chloroformate (7.267 mmol) in THF (10 ml) under argon atmosphere at -78 °C in a separate flask. The mixture of SC8a///-BuLi was added to the mixture of ethyl chloroformate dropwise. Stirred for 1 h at - 78 °C, then allowed to warm up to RT. The reaction was quenched with saturated aqueous solution of NH4CI. The mixture was diluted with EtOAc, then washed with water. Aqueous phase was repeatedly back extracted with EtOAc. Collected organic fractions were dried over MgSO ₄ and dried in vacuo. Purified by FC (c-hex/EtOAc) to give off-white solid (40 mg, 19 %). MS (ESI): m/z = 290.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 8.50 (dd, J= 8.0, 1.5 Hz, 1H), 7.94 (dd, J= 7.4, 1.5 Hz, 1H), 7.90 (q, J = 0.9 Hz, 1H), 7.77 (dd, J= 8.0, 7.4 Hz, 1H), 4.41 (q, J= 7.1 Hz, 2H), 2.43 (s, 3H), 1.36 (t, J= 7.1 Hz, 3H). ¹³ C NMR (101 MHz, DMSO) δ 166.35, 142.52, 137.11, 135.15, 130.61, 129.66, 128.09, 124.98, 118.04, 110.95, 61.26, 14.14, 13.97.

[0288] Ethyl 5-((3-chlorophenyl)amino)-2-methylimidazo[1,2-c]quinazoline- 7-carboxylate (SC8c) Prepared from SC8b and 3-chloroaniline by GP-B, off-white solid, yield 74 %. MS (ESI): m/z = 381.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 9.63 (s, 1H), 8.35 (q, J= 1.8 Hz, 1H), 8.28 - 8.18 (m, 1H), 8.02 - 7.93 (m, 1H), 7.79 (dd, J= 7.4, 1.6 Hz, 1H), 7.47 - 7.42 (m, 1H), 7.40 (t, J = 8.1 Hz, 1H), 7.16 (ddd, J = 8.0, 2.1, 0.9 Hz, 1H), 4.42 (q, J= 7.1 Hz, 2H), 2.42 (d, J = 0.9 Hz, 3H), 1.30 (t, J = 7.1 Hz, 3H). ¹³ C NMR (101 MHz, DMSO) δ 167.44, 142.86, 141.31, 140.37, 139.54, 138.61, 133.07, 129.93, 129.30, 128.76, 124.60, 123.66, 122.85, 119.88, 118.72, 116.18, 108.33, 61.01, 14.09. HRMS (ESI): m/z calculated for C ₂₀ H ₁₈ O ₂ N ₄ CI 381.11128, found 381.11110.

[0289] 5-((3-Chlorophenyl)amino)-2-methylimidazo[1,2-c]quinazoline- 7-carboxylic acid (Compound 103) Prepared from SC8c by GP-C, off-white solid, yield 79 %. MS (ESI): m/z = 353.2 [M+H] ⁺ . ¹ H NMR (600 MHz, 90 °C, TFA, DMSO) δ 8.46 - 8.41 (m, 1H), 8.20 (d, J= 7.6 Hz, 1H), 8.06 (s, 1H), 7.64 (s, 1H), 7.57 - 7.42 (m, 2H), 7.33 (d, J= 7.6 Hz, 1H), 2.44 (s, 3H). ¹³ C NMR (151 MHz, DMSO) δ 166.21, 141.61, 133.33, 131.84, 130.34, 126.37, 124.73, 123.17, 122.99, 121.91, 108.53. HRMS (ESI): m/z calculated for C ₁₈ H ₁₄ O ₂ N ₄ CI 353.07998, found 353.07981.

Example 8: Synthesis of the benzo-naphthyridin Compounds

Scheme 9- Reagents and conditions: a) KOAc, B2pin, Pd(dppf)Cl.DCM, DMF, 105 °C; b) K2CO3,

Pd(PPh ₃ )2Cl ₂ , 1,4-dioxane, H ₂ O, 105 °C; c) POCl ₃ , reflux; d) 3 -chloroaniline, ACN, 90 °C; e) see Table .

Table 2: Compounds prepared according to Scheme 9.

[0290] Methyl 3-amino-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzo ate (SC9b). Methyl 3-amino-4-bromobenzoate (5g, 21.7 mmol), KO Ac (6.4 g, 65.2 mmol), bis(pinacolato)diboron (6.6 g, 26 mmol) and Pd(dppf)Cl.DCM (0.89 g, 1.1 mmol) in DMF (50 ml) were heated at 105 °C for 2 h under argon atmosphere. The mixture was cooled to RT, diluted with EtOAc and washed with sat. NH4CI and dried over MgSO ₄ . FC (c-hex/EtOAc/MeOH) gave white solid (6 g, 99%).

[0291] 3-Amino-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzo nitrile (SC9c). SC9a (1.7 g, 8.6 mmol), KO Ac (2.54 g, 25.9 mmol), bis(pinacolato)diboron (2.6 g, 10.4 mmol) and Pd(dppf)Cl.DCM (0.35 g, 0.43 mmol) in DMF (25 ml) were heated at 105 °C for 90 min under argon atmosphere. Cooled to RT, diluted with EtOAc and washed with sat. NH ₄ Cl and dried over MgSO ₄ . Solvent was evaporated and the residue was used without further purification. White solid, 1.7 g (80%). MS (ESI): m/z = 163.3 [M+H] ⁺ (free boronic acid).

[0292] Methyl 5-oxo-5,6-dihydrobenzo[h][l,6]naphthyridine-8-carboxylate (SC9d). Prepared from SC9b and methyl 2-bromonicotinate by GP-A1, white solid, yield 78%. MS (ESI): m/z = 255.2 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 11.97 (bs, 1H); 9.06 (dd, 1H, J= 4.6, 1.8 Hz); 8.65 (d, 1H, J= 8.3 Hz); 8.60 (dd, 1H, J= 8.0, 1.9 Hz); 7.95 (d, 1H, J= 1.6 Hz); 7.78 (dd, 1H, J = 8.3, 1.7 Hz); 7.71 (dd, 1H, J= 8.0, 4.6 Hz) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 165.70; 160.96; 154.25; 149.67; 138.05; 135.83; 131.47; 124.56; 124.29; 122.40, 122.34, 122.19; 117.11; 52.46 ppm. HRMS (ESI): m/z calculated for C ₁₄ H ₁ 1N ₂ O ₃ 255.07642, found 255.07637.

[0293] 5-Oxo-5,6-dihydrobenzo[h][l,6]naphthyridine-8-carbonitrile (SC9e). Prepared from SC9c and methyl 2-bromonicotinate by GP-A1, off-white solid, yield 63%. MS (ESI): m/z = 222.1 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 9.08 (dd, 1H, J= 4.6, 1.8 Hz); 8.67 (m, 1H); 8.60 (dd, 1H, J= 8.0, 1.8 Hz); 7.75 (dd, 1H, J= 8.0, 4.6 Hz); 7.65 (m, 2H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 160.64; 154.41; 149.12; 137.93; 135.84; 125.26; 125.04; 124.73; 122.37; 122.35; 119.59; 118.39; 112.79 ppm. HRMS (ESI): m/z calculated for C ₁₃ H ₈ N ₃ O 222.06619, found 222.06627.

[0294] Methyl 5-((3-chlorophenyl)amino)benzo[h] [l,6]naphthyridine-8-carboxylate

(Compound 9). Compound SC9d was converted to the corresponding chloro- derivative by GP- B1 (white poorly soluble solid, yield 60%, MS (ESI): m/z = 273.2 [M+H] ⁺ ) and without further purification converted by GP-C1 to Compound 9 (white solid, yield 80%). MS (ESI): m/z = 364.3 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 9.62 (s, 1H); 9.18 (dd, 1H, J= 4.4, 1.5 Hz); 9.07 (dd, 1H, J= 8.5, 1.6 Hz); 8.87 (d, 1H, J= 8.4 Hz); 8.26 (t, 1H, J= 2.1 Hz); 8.20 (d, 1H, J= 1.6 Hz); 8.06 (m, 1H); 7.94 (dd, 1H, J = 8.4, 1.7 Hz); 7.88 (dd, 1H, J = 8.4, 4.4 Hz); 7.43 (t, 1H, J= 8.1 Hz); 7.12 (dd, 1H, J= 8.0, 2.1, 0.9 Hz); 3.93 (s, 3H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ= 166.18; 153.29; 151.23; 148.39; 144.75; 142.01; 132.74; 132.48; 131.12; 130.09; 127.67; 125.48; 123.88; 123.64; 123.32; 122.03; 120.02; 119.05; 115.45 ppm. HRMS (ESI): m/z calculated for C ₂₀ H ₁₅ ClN ₃ O ₂ 364.08473, found 364.08462.

[0295] 5-[(3-Chlorophenyl)amino]benzo[h][l,6]naphthyridine-8-carbon itrile (SC9f). First, chloro- derivative was prepared from SC9e by GP-B1 (off white solid, yield 78%, MS (ESI): m/z = 240.1 [M+H] ⁺ ), which was further converted by GP-C1 to compound SC9f (white solid, yield 90%). MS (ESI): m/z = 331.2 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 9.70 (bs, 1H); 9.20 (dd, 1H, J= 4.4, 1.5 Hz); 9.09 (dd, 1H, J= 8.4, 1.6 Hz); 8.89 (d, 1H, J= 8.3 Hz); 8.21 (m, 1H); 8.10 (d, 1H, J = 1.6 Hz); 8.06 (d, 1H, J= 8.0, 2.3 Hz); 7.90 (dd, 1H, J= 8.4, 4.4 Hz); 7.75 (dd, 1H, J= 8.2, 1.7 Hz); 7.41 (t, 1H, J= 8.1 Hz); 7.14 (ddd, 1H, J= 8.3, 2.2, 1.0 Hz) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 153.47; 151.68; 148.00; 144.75; 141.71; 132.76; 132.56; 130.87; 130.04; 125.45; 125.36; 124.61; 124.00; 122.33; 120.30; 119.31; 118.75; 115.64; 112.64 ppm. HRMS (ESI): m/z calculated for C ₁₉ H12CIN4 331.07450, found 331.07456.

[0296] 5- [(3-Chlorophenyl)amino] benzo [h] [1,6] naphthyridine-8-carboxylic acid

(Compound 10). Prepared from Compound 9 by GP-D1 (white solid, yield 73%). MS (ESI): m/z = 350.3 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 13.19 (bs, 1H); 9.67 (bs, 1H); 9.20 (dd, 1H, J = 4.4, 1.5 Hz); 9.09 (dd, 1H, J= 8.3, 1.6 Hz); 8.89 (d, 1H, J= 8.4 Hz); 8.29 (m, 1H); 8.25 (d, 1H, J= 1.6 Hz); 8.05 (dd, 1H, J= 8.2, 2.2 Hz); 7.97 (dd, 1H, J= 8.4, 1.7 Hz); 7.88 (dd, 1H, J= 8.4, 4.4 Hz); 7.44 (t, 1H, J= 8.1 Hz); 7.13 (m, 1H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 167.28; 153.36; 151.16; 148.53; 144.61; 142.03; 132.80; 132.56; 132.46; 130.13; 127.72; 125.22; 123.74; 123.59; 122.10; 120.10; 119.12; 115.44 ppm. HRMS (ESI): m/z calculated for C ₁₉ H11CIN ₃ O ₂ 348.05453, found 348.05449.

[0297] 5-[5-[(3-Chlorophenyl)amino]benzo [h][1,6]85aphthyridine-8-yl]-1,3,4-oxadiazol-

2(3H)-one (Compound 96a). Compound 10 (60 mg, 0.17 mmol) in THF (6 ml) was treated with CDI (42 mg, 0.26 mmol) and the resulting mixture was stirred at RT for 2 h, NH ₂ NH ₂ .H ₂ O (128 pl, 2.6 mmol) was added and the resulting mixture was stirred at RT overnight, diluted with DCM and washed with water, aqueous phase was repeatedly back extracted with DCM. Collected organic fractions were dried over MgSCE and evaporated. The residue in CAN (6 ml) was treated with TEA (96 pl, 0.69 mmol) and CDI (42 mg, 0.26 mmol), to the resulting suspension was added DMF (1 ml) to improve solubility and the solution was stirred at RT overnight, evaporated and purified by RP FC (H ₂ O/CAN + 0.1% FA) to give an orange solid (43 mg, 65%). MS (ESI): m/z = 390.2 [M+H] ⁺ . ¹ HNMR (DMSO-d ₆ ): δ = 12.71 (s, 1H); 9.64 (bs, 1H); 9.16 (dd, 1H, J= 4.4, 1.5 Hz); 9.06 (dd, 1H, J= 8.4, 1.6 Hz); 8.87 (d, 1H, J = 8.4 Hz); 8.25 (m, 1H); 8.07 (bd, 1H, J = 7.9 Hz); 7.94 (d, 1H, J= 1.7 Hz); 7.84 (dd, 1H, J= 8.4, 4.4 Hz); 7.80 (dd, J = 8.4, 1.8 Hz); 7.43 (t, 1H, J = 8.1 Hz); 7.12 (ddd, 1H, J = 8.0, 2.1, 0.9 Hz) ppm. ¹³ C NMR (DMSO-d ₆ ): δ =154.44; 153.66; 153.33; 151.33; 148.40; 144.91; 141.92; 132.76; 132.48; 130.10; 125.51; 124.47; 123.96; 123.38; 123.05; 122.11; 120.10; 119.71; 119.11; 115.15 ppm. HRMS (ESI): m/z calculated for C ₂₀ H ₁₃ CIN ₅ O ₂ 390.07523, found 390.07531.

[0298] 4-Acetoxybenzyl 5-[(3-chlorophenyl)amino]benzo[h] [l,6]naphthyridine-8- carboxylate (Compound 23). Compound 10 (100 mg, 0.29 mmol), 4-acetoxybenzyl alcohol (51 pl, 0.36 mmol) and PI13P (93.7 mg, 0.36 mmol) in dry dioxane were heated at 60 °C and DIAD (70 pl, 0.36 mmol) was added dropwise, the resulting mixture was heated at 60 °C for 5 min, cooled to RT, evaporated and purified by FC (c-hex/EtOAc/MeOH) and repurified by RP FC (H ₂ O/ACN) to give white solid (90 mg, 63%). MS (ESI): m/z = 498.3 [M+H] ⁺ . ¹ H NMR (DMSO- d ₆ ): δ = 9.62 (s, 1H); 9.18 (dd, 1H, J= 4.4, 1.5 Hz); 9.07 (dd, 1H, J= 8.6, 1.5 Hz); 8.89 (d, 1H, J = 8.4 Hz); 8.24 (m, 2H); 8.05 (ddd, 1H, J= 8.3, 2.1, 0.9 Hz); 7.98 (dd, 1H, J= 8.4, 1.8 Hz); 7.87 (dd, 1H, J= 8.4, 4.4 Hz); 7.57 (m, 2H); 7.42 (t, 1H, J= 8.1 Hz); 7.20 (m, 2H); 7.12 (ddd, 1H, J= 8.0, 2.2, 0.9 Hz); 5.43 (s, 2H); 2.28 (2, 3H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 169.17; 165.53; 153.27; 151.24; 150.34; 148.37; 144.78; 141.96; 133.61; 132.72; 132.46; 131.04; 130.06; 129.43; 127.78; 125.61; 123.94; 123.64; 123.35; 122.03; 121.99; 120.08; 119.09; 115.47; 65.92; 20.83 ppm. HRMS (ESI): m/z calculated for C ₂₈ H ₂₁ CIN ₃ O ₄ 498.12151, found 498.12157.

[0299] [(Isopropoxycarbonyl)oxy] methyl 5-[(3- chlorophenyl)amino]benzo[h][l,6]naphthyridine-8-carboxylate (Compound 21). Compound 10 (100 mg, 0.29 mmol) in ACN (5 ml) was treated with Bu4NH ⁺ OH" (IM in MeOH, 0.29 mmol), the volatiles were evaporated and the residue was codistilled with dry ACN (3 x 5 ml), dissolved in dry ACN (5 ml) and treated with isopropyl iodomethyl carbonate (POC-I, 10 eq.) and stirred at RT overnight. K ₂ CO ₃ (2 eq.) and further portion of POC-I (10 eq.) were added and the resulting mixture was stirred at RT for 4 h, quenched with water (5 ml) and directly purified by RP FC (H ₂ O/ACN) to give Compound 21 (25 mg, 19%) as a white solid. MS (ESI): m/z = 466.3 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 9.68 (s, 1H); 9.22 (dd, 1H, J = 4.4, 1.5 Hz); 9.11 (dd, 1H, J = 8.5, 1.6 Hz); 8.94 (d, 1H, J= 8.4 Hz); 8.25 (m, 2H); 8.06 (ddd, 1H, J= 8.0, 2.1, 1.0 Hz); 7.99 (dd, 1H, J= 8.4, 1.8 Hz); 7.92 (dd, 1H, J = 8.4, 4.4 Hz); 7.45 (t, 1H, J= 8.1 Hz); 7.14 (ddd, 1H, J = 7.9, 2.1, 0.9 Hz); 6.02 (s, 2H); 4.86 (hept, 1H, J= 6.3 Hz); 1.26 (d, 6H, J= 6.3 Hz) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 164.47; 153.44; 152.82; 151.45; 148.32; 144.82; 141.93; 132.75; 132.59; 130.14; 129.90; 128.15; 126.15; 124.21; 123.90; 123.50; 122.17; 120.15; 119.18; 115.68; 82.65; 72.80; 21.35 ppm. HRMS (ESI): m/z calculated for C ₂₄ H ₂₁ CIN ₃ O ₅ 466.11642, found 466.11658.

[0300] (5-Methyl-2-oxo-l,3-dioxol-4-yl)methyl 5-|(3- chlorophenyl)amino]benzo[h][l,6]naphthyridine-8-carboxylate (Compound 22). Compound 10 (100 mg, 0.29 mmol) in DMF (2.5 ml) was treated with K2CO3 (79 mg, 0.57 mmol) and 4- chloromethyl-5-methyl-l,3-dioxol-2-one (63.7 mg, 0.43 mmol) and the mixture was heated at 45 °C for 2 h, diluted with EtOAc, washed with water and dried over Na2SO4. Purification by RP FC (H ₂ O/ACN) gave white solid (70 mg, 53%). MS (ESI): m/z = 462.2 [M+H] ⁺ . ¹ H NMR (DMSO- d ₆ ): δ = 9.64 (s, 1H); 9.19 (dd, 1H, J= 4.4, 1.5 Hz); 9.08 (dd, 1H, J= 8.6, 1.6 Hz); 8.91 (d, 1H, J = 8.4 Hz); 8.22 (m, 2H); 8.06 (ddd, 1H, J= 8.3, 2.1, 0.9 Hz); 7.97 (dd, 1H, J= 8.4, 1.8 Hz); 7.89 (dd, 1H, J = 8.4, 4.4 Hz); 7.44 (t, 1H, J= 8.1 Hz); 7.13 (ddd, 1H, J= 8.1, 2.2, 1.0 Hz); 5.30 (s, 2H); 2.07 (s, 3H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 165.25; 153.36; 151.94; 151.35; 148.35; 144.79; 141.76; 140.43; 133.38; 132.74; 132.53; 130.50; 130.12; 127.92; 125.80; 124.02; 123.76; 123.42; 122.11; 120.13; 119.17; 115.56; 54.74; 8.97 ppm. HRMS (ESI): m/z calculated for C24H17CIN3O5 462.08512, found 462.08518.

[0301] N-(3-ChlorophenyI )-8-( 1H-tetrarazol-5-yI)benzo [h] [1,6] naphthyridin-5-amine

(Compound 96b). Compound SC9f (80 mg, 0.24 mmol), NH4CI (233 mg, 4.4 mmol) and NaNi (157 mg, 2.4 mmol) in DMF (1 ml) were heated at 100 °C overnight, diluted with DMF (1 ml) and directly applied to the RP FC (H ₂ O/CAN) to give Compound 96b (white solid, 55 mg, 61%). MS (ESI): m/z = 374.2 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 9.64 (bs, 1H); 9.18 (dd, 1H, J = 4.4, 1.5 Hz); 9.09 (dd, 1H, J= 8.4, 1.6 Hz); 8.95 (d, 1H, J= 8.4 Hz); 8.38 (m, 1H); 8.33 (m, 1H); 8.13 (dd, 1H, J= 8.13, 1.7 Hz); 8.06 (dd, 1H, J= 8.3, 1.7 Hz); 7.85 (dd, 1H, J = 8.4, 4.4 Hz); 7.44 (t, 1H, J = 8.1 Hz); 7.13 (ddd, 1H, J= 7.9, 2.1, 0.9 Hz) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 156.66; 153.24; 151.20; 148.73; 145.39; 142.15; 132.78; 132.48; 130.04; 128.17; 124.36; 124.29; 123.17; 123.08; 121.96; 121.91; 120.06; 119.06; 114.95 ppm. HRMS (ESI): m/z calculated for C ₁₉ H ₁₃ CIN ₇ 374.09155, found 374.09173.

[0302] 5- [(3-Chlorophenyl)amino] benzo [h] [1,6] naphthyridine-8-carboxamide (Compound 97). Compound SC9f (80 mg, 0.24 mmol) in dry toluene (2 ml) and tBuOH (1 ml) mixture was treated with t-BuOK (82 mg, 0.73 mmol) under argon atmosphere, the mixture was heated at 100 °C for 2 h. The reaction mixture was diluted with EtOH and neutralized with IM HC1, evaporated and purified by RP FC (H ₂ O/CAN + 0.1% FA). White solid, yield 50 mg (60%). MS (ESI): m/z =

349.2 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 9.65 (bs, 1H); 9.20 (dd, 1H, J= 4.4, 1.5 Hz); 9.10 (dd, 1H, J= 8.4, 1.6 Hz); 8.87 (d, 1H, J= 8.3 Hz); 8.29 (m, 1H); 8.26 (m, 2H); 8.06 (dd, 1H, J= 8.2,

2.2 Hz); 7.95 (dd, 1H, J= 8.4, 1.8 Hz); 7.88 (dd, 1H, J= 8.4, 4.4 Hz); 7.50 (bs, 1H); 7.43 (t, 1H, J= 8.1 Hz); 1.13 (ddd, 1H, J= 8.0, 2.1, 0.9 Hz) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 167.74; 153.26; 151.04; 148.69; 144.71; 142.14; 136.13; 132.81; 132.53; 130.06; 125.78; 124.01; 123.26; 122.66; 122.00; 120.10; 119.10; 115.12 ppm. HRMS (ESI): m/z calculated for C ₁₉ H ₁₄ CIN ₄ O 349.08507, found 349.08510.

[0303] 3-[5-((3-Chlorophenyl)amino)benzo[h][l,6]87aphthyridine-8-yl ]-l,2,4-oxadiazol-

5(4H)-one (Compound 96c). Hydroxylamine hydrochloride (33.6 mg, 0.48 mmol) in water (1 ml) was treated with NaHCO ₃ (61 mg, 0.73 mmol) and the mixture was stirred at RT for 30 min, the resulting solution was added to the solution of SC9f (80 mg, 0.24 mmol) in EtOH (1 ml) and the mixture was heated at 100 °C overnight, evaporated and the residue in EtOAc was washed with water, dried over MgSO ₄ and evaporated. The residue in ACN (2 ml) was treated with DBU (0.145 ml, 0.97 mmol) and CDI (47 mg, 0.29 mmol) and the mixture was stirred at RT overnight. Second portion of DBU (0.075 ml, 0.48 mmol) and CDI (24 mg, 0.25 mmol) were added and the mixture was stirred at RT for 1 h, diluted with DCM, washed with water and purified by RP FC (H ₂ O/ACN + 0.1% FA) to give a yellow solid (50 mg, 53%). MS (ESI): m/z = 390.2 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 13.14 (bs, 1H); 9.69 (bs, 1H); 9.20 (dd, 1H, J= 4.4, 1.5 Hz); 9.10 (dd, 1H, J = 8.4, 1.6 Hz); 8.93 (d, 1H, J= 8.7 Hz); 8.30 (t, 1H, J= 2.1 Hz); 8.17 (dd, 1H, J= 1.9, 0.5 Hz); 8.01 (ddd, 1H, J= 8.4, 2.1, 1.0 Hz); 7.90 (dd, 1H, J = 8.4, 4.4 Hz); 7.87 (dd, 1H, J= 8.4, 1.8 Hz); 7.43 (t, 1H, J= 8.1 Hz); 7.15 (ddd, 1H, J = 8.0, 2.1, 0.9 Hz) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 159.91; 157.30; 153.42; 151.51; 148.39; 145.15; 141.49; 132.81; 132.57; 130.02; 124.89; 124.71; 124.55; 124.46; 123.59; 122.22; 120.29; 120.16; 119.26; 115.30 ppm. HRMS (ESI): m/z calculated for C ₂₀ H ₁₃ CIN ₅ O ₂ 390.07523, found 390.07542.

Scheme 10- Reagents and conditions: a) nBuLi, TMP, THF, -50 to 0 °C; b) K2CO3, Pd(PPh3)2C12, 1,4- dioxane, H ₂ O, 105 °C; c) POC13, reflux; d) 3 -chloroaniline, ACN, 90 °C; e) NaOH, EtOH, H ₂ O, 80 °C.

[0304] Ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate (SClOa). LTMP (IM in THF, 13.5 mmol) was added dropwise to the mixture of ethyl nicotinate (1.2 ml, 9 mmol) and 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (3.7 ml, 18 mmol) in THF (15 ml) at - 50 °C, the resulting mixture was slowly warmed to 0 °C and stirred at that temperature for 1 h. The reaction was quenched with sat. NH ₄ CI, diluted with EtOAc, washed with water and dried over MgSO ₄ . The crude product (brown oil, 1.7 g, 97%) was used without further purification in the next step. ¹ H NMR. (CDCl ₃ ): δ = 9.14 (s, 1H); 8.71 (d, 1H, J= 4.9 Hz); 7.44 (dd, 1H, J= 4.9, 1.0 Hz); 4.46 (q, 2H, J= 7.1 Hz); 1.42 (s, 12H); 1.38 (t, 3H, J= 7.1 Hz) ppm.

[0305] Methyl 5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridine-8-carboxylate (SClOb). Prepared from methyl 3-amino-4-bromobenzoate and SClOa by GP-A1. White solid, yield 42%. MS (ESI): m/z = 255.2 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 9.43 (d, 1H, J= 0.9 Hz); 8.85 (d, 1H, J= 5.6 Hz); 8.47 (d, 1H, J= 8.4 Hz); 8.36 (dd, 1H, J= 5.6, 0.9 Hz); 7.92 (d, 1H, J= 1.8 Hz); 7.66 (dd, 1H, J = 8.4, 1.8 Hz); 3.89 (s, 3H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 165.97; 162.62; 150.71; 150.48; 142.83; 139.63; 131.39; 124.36; 121.06; 120.44; 120.15; 119.46; 116.18; 52.35 ppm. HRMS (ESI): m/z calculated for C ₁₄ H ₁ 1O3N2 255.07642, found 255.07632.

[0306] Methyl 5-((3-chlorophenyl)amino)benzo[c] [2,7]naphthyridine-8-carboxylate (Compound 6). Compound SClOb was converted by GP-B1 to the corresponding chloroanalogue (white poorly soluble solid, yield 70%, MS (ESI): m/z = 273.2 [M+H] ⁺ ), which was directly converted by GP-C to the desired Compound 6 (white poorly soluble solid, yield 50%). MS (ESI): m/z = 364.3 [M+H] ⁺ .

[0307] 5-((3-Chlorophenyl)amino)benzo[c] [2,7]naphthyridine-8-carboxylic acid

(Compound 5). Compound 6 was converted to Compound 5 by GP-D1 (white solid, yield 52%). MS (ESI): m/z = 350.3 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 9.98 (s, 1H); 9.80 (bs, 1H); 8.96 (d, 1H, J= 5.6 Hz); 8.65 - 8.63 (m, 2H); 8.35 (s, 1H); 8.24 (s, 1H); 8.09 (d, 1H, J= 8.3 Hz); 7.98 (d, 1H, J= 8.3 Hz); 7.43 (t, 1H, J= 8.1 Hz); 7.11 (d, 1H, J= 8.0 Hz) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 167.85; 150.48; 149.32; 147.82; 144.48; 142.17; 138.46; 132.75; 130.07; 127.93; 124.39; 123.14; 121.87; 120.93; 119.99; 119.03; 116.33; 114.64 ppm. HRMS (ESI): m/z calculated for C ₁₉ H ₁₁ CIN ₃ O ₂ 348.05453, found 348.05422.

Scheme 11- Reagents and conditions: a) Bis(pinacolato)diboron, Pd(dppf)C12.CH ₂ C12, AcOK, DMF, 105 C; b) Methyl 3 -bromoisonicotinate, K2CO3, Pd(PPh3)2C12, 1,4-dioxane, H ₂ O, 105 °C; c) POC13, reflux.

Scheme ll(cont.)- Reagents and conditions: a) Amine, MeCN, 100 °C; b) Phenol, NaH, DMF, 105 °C; c) NaOH, water/EtOH, RT.

Table 3: Compounds prepared according to Scheme 11

[0308] Methyl 3-amino-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzo ate (SClla) Borylation. Methyl 3-amino-4-bromobenzoate (21.733 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'- bi(l,3,2-dioxaborolane) (26.080 mmol), Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (1.087 mmol) and AcOK (65.200 mmol) in DMF (50 ml, were heated at 105 °C under argon atmosphere for 3 h. The mixture was cooled to RT and diluted with EtOAc , then washed with water. Aqueous phase was repeatedly back extracted with EtOAc. Collected organic fractions were dried over MgSO ₄ and dried in vacuo Purified by FC (c-hex/EtOAc) to give yellow solid (5.9 g, 99 %). MS (ESI): m/z = 278.2 [M+H] ⁺ . ¹ H NMR (401 MHz, CDCl ₃ ) δ 7.64 (dd, J= 7.7, 0.5 Hz, 1H), 7.30 - 7.22 (m, 2H), 4.84 (s, 2H), 3.87 (s, 3H), 1.33 (s, 12H). ¹³ C NMR (101 MHz, CDCl ₃ ) 6 167.46, 153.58, 136.96, 133.77, 132.63, 117.41, 115.54, 84.00, 52.16, 25.13.

[0309] Methyl 5-oxo-5,6-dihydrobenzo[c][2,6]naphthyridine-8-carboxylate (SCI lb) Suzuki cross-coupling and cyclization. SClla (18.042 mmol), methyl 3-bromoisonicotinate (19.859 mmol), K ₂ CO ₃ (54.126 mmol) and Pd(PPh ₃ ) ₂ Cl ₂ (0.902 mmol) in dioxane/water mixture (9: 1, 10 ml) were heated at 105 °C under argon atmosphere for 2 h. The mixture was cooled to RT and the precipitate was filtered off, washed with MeOH/water (2: 1) mixture and dried in vacuo to give yellow solid (3.2 g, 69 %). MS (ESI): m/z = 255.2 [M+H] ⁺ . Insoluble, no NMR.

[0310] Methyl 5-chlorobenzo[c][2,6]naphthyridine-8-carboxylate (SCllc), prepared from SCI lb according to GP-M.

[0311] Methyl 5-(3-chlorophenoxy)benzo [c] [2,6] naphthyridine-8-carboxylate (Compound 28b (Xa)) Reaction with 3 -chlorophenol. SCllc (0.550 mmol), 3 -chlorophenol (1.100 mmol) and NaH (1.1 mmol) in DMF (2 ml) were heated at 100 °C for 5 h. The mixture was cooled to RT and solvent was removed in vacuo. The material was applied to the RP FC (H ₂ O/ACN + 0.1 FA). The product was evaporated, codistilled with water and EtOH and dried to give white solid (0.092 mmol, 17 %). MS (ESI): m/z = 365.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO-d6) δ 10.24 (s, 1H), 9.05 (d, J= 5.4 Hz, 1H), 8.98 (d, J= 8.5 Hz, 1H), 8.34 (d, J= 5.4 Hz, 1H), 8.19 (d, J= 1.5 Hz, 1H), 8.14 (dd, J= 8.5, 1.7 Hz, 1H), 7.60 - 7.53 (m, 2H), 7.48 - 7.39 (m, 1H), 3.92 (s, 3H). ¹³ C NMR (101 MHz, DMSO-d6) δ 165.64, 153.31, 148.04, 147.48, 141.69, 133.50, 131.08, 130.63, 128.77, 128.00, 125.80, 124.45, 123.99, 123.44, 122.53, 121.17, 117.11, 52.49. HRMS (ESI): m/z calculated for C ₂₀ H ₁₄ O ₃ N ₂ CI 365.06875, found 365.06849.

[0312] Methyl 5-(phenylamino)benzo[c][2,6]naphthyridine-8-carboxylate (29b(Xb)) Prepared from SCllc and aniline by GP-N, off-white solid, yield 39 %. MS (ESI): m/z = 330.2 [M+H] ⁺ . ¹ H NMR (401 MHz, DMSO) δ 10.15 (s, 1H), 9.54 (s, 1H), 8.97 (d, J= 5.6 Hz, 1H), 8.79 (d, J= 8.5 Hz, 1H), 8.62 (d, J = 5.7 Hz, 1H), 8.27 (s, 1H), 8.14 - 8.07 (m, 2H), 7.98 (d, J= 8.1 Hz, 1H), 7.46 - 7.38 (m, 2H), 7.09 (t, J= 13 Hz, 1H). ¹³ C NMR (101 MHz, DMSO) δ 166.95, 150.16, 147.66, 147.19, 143.64, 140.42, 130.55, 128.44, 127.15, 123.91, 122.63, 122.05, 122.03, 122.00, 120.98, 116.45, 55.84, 29.60. HRMS (ESI): m/z calculated for C ₂₀ H ₁₆ O ₂ N ₃ 330.12370, found 330.12353.

[0313] Methyl 5-(pyridin-3-ylamino)benzo[c][2,6]naphthyridine-8-carboxylat e (34b (Xc)) Prepared from SCllc and 3 -aminopyridine by GP-N, off-white solid, yield 84 %. MS (ESI): m/z = 331.2 [M+H] ⁺ . ¹ H NMR (401 MHz, DMSO) δ 10.53 (d, J= 1.0 Hz, 1H), 9.32 (d, J= 8.7 Hz, 1H), 9.06 (d, J= 5.6 Hz, 1H), 8.71 (d, J= 1.7 Hz, 1H), 8.67 - 8.58 (m, 2H), 8.46 (dd, J= 8.6, 1.8 Hz, 1H), 8.10 - 8.03 (m, 1H), 7.99 (ddd, J= 8.8, 2.4, 1.1 Hz, 1H), 7.82 (dd, J= 5.7, 0.9 Hz, 1H), 3.98 (s, 3H). ¹³ C NMR (101 MHz, DMSO) δ 165.31, 158.98, 151.53, 148.65, 148.44, 141.23, 131.58, 131.35, 131.03, 130.36, 129.67, 128.16, 128.10, 127.77, 126.95, 125.11, 124.00, 116.85, 52.84. HRMS (ESI): m/z calculated for C ₁₉ H ₁₅ O ₂ N ₄ 331.11895, found 331.11879.

[0314] Methyl 5-((furan-2-ylmethyl)amino)benzo [c] [2,6] naphthyridine-8-carboxylate

(44b(Xd)) Prepared from SCllc and furan-2-ylmethanamine by GP-N, off-white solid, yield 67 %. MS (ESI): m/z = 278.2 [M+H] ⁺ . ¹ H NMR (401 MHz, DMSO) δ 10.03 (s, 1H), 9.15 (s, 1H), 8.92 (d, J= 5.6 Hz, 1H), 8.69 (d, J = 8.5 Hz, 1H), 8.41 - 8.34 (m, 1H), 8.21 (d, J= 1.7 Hz, 1H), 7.83 (dd, J= 8.4, 1.8 Hz, 1H), 7.63 (dd, J= 1.8, 0.9 Hz, 1H), 6.50 - 6.40 (m, 2H), 4.91 - 4.85 (m, 2H), 3.91 (s, 3H). ¹³ C NMR (101 MHz, DMSO) δ 165.83, 152.04, 151.37, 147.45, 147.34, 142.41, 130,62, 130.53, 126.47,125.43, 124.31, 123.13, 122.99, 121.46, 116.88, 110.63, 107.96, 52.39, 38.02. HRMS (ESI): m/z calculated for C ₁₉ H ₁₆ O ₃ N ₃ 334.11862, found 334.11836.

[0315] Methyl 5-(isobutylamino)benzo[c][2,6]naphthyridine-8-carboxylate (36b(Xe)) Prepared from SCllc and 2-methylpropan-l -amine by GP-N, off-white solid, yield 97 %. MS (ESI): m/z = 310.3 [M+H] ⁺ . ¹ H NMR (401 MHz, DMSO) δ 10.07 (s, 1H), 9.92 (s, 1H), 9.02 (d, J = 5.6 Hz, 1H), 8.78 (d, J= 8.6 Hz, 1H), 8.60 - 8.52 (m, 1H), 8.48 (d, J= 1.7 Hz, 1H), 7.92 (dd, J = 8.4, 1.7 Hz, 1H), 3.93 (s, 3H), 3.55 (t, J= 6.3 Hz, 2H), 2.20 (dh, J= 13.6, 7.4 Hz, 1H), 1.03 (d, J = 6.6 Hz, 6H). ¹³ C NMR (101 MHz, DMSO) δ 165.35, 151.71, 148.73, 147.75, 131.05, 125.84 , 125.01, 124.59, 123.54, 122.89, 121.02, 119.98, 117.57, 52.60, 49.60, 26.89, 20.12. HRMS (ESI): m/z calculated for C ₁₈ H ₂₀ O ₂ N ₃ 310.15500, found 310.15489. [0316] Methyl 5-((2-methoxyethyl)amino)benzo[c] [2,6]naphthyridine-8-carboxylate (37b(Xf)) Prepared from SCllc and 2-methoxyethan-l -amine by GP-N, off-white solid, yield 83 %. MS (ESI): m/z = 312.2 [M+H] ⁺ . ¹ H NMR (401 MHz, DMSO) δ 9.99 (s, 1H), 9.19 (s, 1H), 8.92 (d, J= 5.6 Hz, 1H), 8.67 (d, J= 8.5 Hz, 1H), 8.37 (d, J= 5.6 Hz, 1H), 8.22 (s, 1H), 7.80 (dd, J= 8.4, 1.7 Hz, 1H), 3.91 (s, 3H), 3.84 (q, J= 4.9 Hz, 2H), 3.69 (t, J= 5.6 Hz, 2H), 3.33 (s, 3H). ¹³ C NMR (101 MHz, DMSO) δ 165.61, 152.08, 148.06, 147.54, 130.57, 126.04, 124.36, 123.43, 123.05, 122.51, 121.10, 117.50, 116.94, 69.59, 58.15, 52.42, 41.56. HRMS (ESI): m/z calculated for C ₁₇ H ₁₈ O3N3 312.13427, found 312.13423.

[0317] Methyl 5-((3-fluorophenyl)amino)benzo [c] [2,6] naphthyridine-8-carboxylate

(38b(Xg)) Prepared from SCllc and 3 -fluoroaniline by GP-N, off-white solid, yield 90 %. MS (ESI): m/z = 348.2 [M+H] ⁺ . ¹ H NMR (401 MHz, DMSO) δ 10.05 (s, 1H), 9.63 (s, 1H), 8.96 (d, J = 5.7 Hz, 1H), 8.71 (d, J= 8.5 Hz, 1H), 8.55 (dd, J = 5.7, 0.8 Hz, 1H), 8.12 (d, J= 1.7 Hz, 1H), 8.08 (dt, J= 12.3, 2.3 Hz, 1H), 7.86 (dd, J= 8.5, 1.8 Hz, 1H), 7.81 (ddd, J= 8.3, 2.1, 0.9 Hz, 1H), 7.42 (td, J = 8.3, 7.0 Hz, 1H), 6.91 (tdd, J= 8.5, 2.6, 0.9 Hz, 1H), 3.91 (s, 3H). ¹³ C NMR (101 MHz, DMSO) δ 165.90, 163.31, 160.92, 149.97, 147.10, 146.66, 130.45, 129.87, 127.79, 126.87, 124.40, 123.76, 122.75, 122.29, 116.80, 116.58, 113.86, 109.06, 107.62, 52.34. HRMS (ESI): m/z calculated for C ₂₀ H ₁₅ O ₂ N ₃ F 348.11428, found 348.11409.

[0318] Methyl 5-(( 1 H-p razol-4-yl)amino)benzo [c] [2,6] naphthyridine-8-carboxylate

(39b(Xh)) Prepared from SCllc and 1H-pyrazol-4-amine by GP-N, off-white solid, yield 67 %. MS (ESI): m/z = 320.2 [M+H] ⁺ . ¹ H NMR (401 MHz, DMSO) δ 10.25 (s, 1H), 10.10 (s, 1H), 8.99 (d, J= 5.7 Hz, 1H), 8.74 (d, J = 8.5 Hz, 1H), 8.54 (dd, J = 5.7, 0.8 Hz, 1H), 8.31 (d, J= 1.8 Hz, 1H), 8.20 (s, 2H), 7.86 (dd, J= 8.4, 1.8 Hz, 1H), 3.92 (s, 3H). ¹³ C NMR (101 MHz, DMSO) δ 165.97, 149.72, 147.08, 146.76, 131.91, 130.68, 127.74, 126.58, 126.53, 126.40, 124.68, 123.60, 123.26, 122.97, 121.64, 116.96, 52.39. HRMS (ESI): m/z calculated for C ₁₇ H ₁₄ O ₂ N ₅ 320.11420, found 320.11397.

[0319] 5-(Phenylamino)benzo[c][2,6]naphthyridine-8-carboxylic acid (29a (Yb)) Prepared from 29b(Xb)) by GP-O, off-white solid, yield 38 %. MS (ESI): m/z = 316.2 [M+H] ⁺ . ¹ H NMR (401 MHz, DMSO) δ 10.15 (s, 1H), 9.54 (s, 1H), 8.97 (d, J= 5.6 Hz, 1H), 8.79 (d, J = 8.5 Hz, 1H), 8.62 (d, J = 5.7 Hz, 1H), 8.27 (s, 1H), 8.14 - 8.07 (m, 2H), 7.98 (d, J= 8.1 Hz, 1H), 7.46 - 7.38 (m, 2H), 7.09 (t, J = 7.3 Hz, 1H). ¹³ C NMR (101 MHz, DMSO) δ 166.95, 150.16, 147.66, 147.19, 143.64, 140.42, 130.55, 128.44, 127.15, 123.91, 122.63, 122.05, 122.03, 122.00, 120.98, 116.45, 55.84, 29.60. HRMS (ESI): m/z calculated for C ₁₉ H ₁₄ O ₂ N ₃ 316.10805, found 316.10777.

[0320] 5-(3-Chlorophenoxy)benzo[c][2,6]naphthyridine-8-carboxylic acid (28a Ya) Prepared from 28b-Xa by GP-O, off-white solid, yield 86 %. MS (ESI): m/z = 351.1 [M+H] ⁺ . ¹ H NMR (401 MHz, DMSO) δ 10.28 (s, 1H), 9.03 (d, J= 5.4 Hz, 1H), 8.97 (d, J= 8.2 Hz, 1H), 8.33 (dd, J = 5.5, 0.9 Hz, 1H), 8.15 (s, 1H), 8.12 (d, J= 1.7 Hz, 1H), 7.62 (t, J= 2.1 Hz, 1H), 7.57 (t, J= 8.1 Hz, 1H), 7.47 - 7.41 (m, 2H). ¹³ C NMR (101 MHz, DMSO) δ 167.11, 157.46, 153.44, 147.93, 147.58, 146.15, 141.72, 133.44, 131.03, 128.67, 128.25, 126.42, 125.64, 123.58, 123.43, 122.74, 122.51, 121.16, 116.90. HRMS (ESI): m/z calculated for C ₁₉ H12O3N2CI 351.05310, found 351.05318.

[0321] 5-((3-Fluorophenyl)amino)benzo[c][2,6]naphthyridine-8-carbox ylic acid (38a-Yg) Prepared from 38b-Xg by GP-O, off-white solid, yield 99 %. MS (ESI): m/z = 334.2 [M+H] ⁺ . ¹ H NMR (401 MHz, DMSO) δ 13.20 (s, 1H), 10.14 (s, 1H), 9.97 (s, 1H), 8.96 (d, J = 5.7 Hz, 1H), 8.82 (dd, J= 7.2, 5.8 Hz, 2H, H4), 8.23 (d, J= 1.7 Hz, 1H), 8.19 (dt, J = 12.4, 2.4 Hz, 1H), 7.95 (td, J = 8.1, 1.9 Hz, 2H), 7.42 (td, J = 8.2, 7.0 Hz, 1H), 6.89 (td, J = 8.4, 2.6 Hz, 1H). ¹³ C NMR (101 MHz, DMSO) δ 167.07, 162.08 (d, J = 240.1 Hz), 150.15, 147.21, 146.80, 143.17, 142.14 (d, J= 11.3 Hz), 131.80, 129.85 (d, J= 9.5 Hz), 128.10, 127.03, 124.38, 124.13, 122.67, 122.18, 117.17, 116.69, 109.00 (d, J= 21.1 Hz), 107.52 (d, J = 26.5 Hz). HRMS (ESI): m/z calculated for C ₁₉ H ₁₃ O ₂ N ₃ F 334.09863, found 334.09834.

[0322] 5-(Isobutylamino)benzo[c][2,6]naphthyridine-8-carboxylic acid (36a-Ye) Prepared from 36b-Xe by GP-O, off-white solid, yield 15 %. MS (ESI): m/z = 296.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 10.10 (s, 1H), 8.97 (d, J = 5.4 Hz, 1H), 8.80 (d, J= 8.5 Hz, 1H), 7.93 (d, J = 8.2 Hz, 1H), 3.66 (s, 3H), 2.22 (dt, J = 13.7, 6.9 Hz, 1H), 1.01 (d, J = 6.7 Hz, 6H). ¹³ C NMR (101 MHz, DMSO) δ 167.36, 158.23, 149.62, 146.27, 146.11, 132.12, 132.05, 125.29, 124.79, 124.14, 121.55, 119.36, 50.52, 27.94, 20.43. HRMS (ESI): m/z calculated for C ₁₇ H ₁₈ O ₂ N ₃ 296.13935, found 296.13917.

[0323] 5-((2-Methoxyethyl)amino)benzo[c][2,6]naphthyridine-8-carbox ylic acid (37a- Yf) Prepared from 37b-Xf by GP-O, off-white solid, yield 26 %. MS (ESI): m/z = 298.1 [M+H] ⁺ . ¹ H NMR (401 MHz, DMSO) δ 10.08 - 10.03 (m, 1H), 8.87 (d, J= 5.6 Hz, 1H), 8.73 (d, J= 8.5 Hz, 1H), 8.41 (dd, J= 5.6, 0.8 Hz, 1H), 8.24 (t, J= 5.4 Hz, 1H), 8.13 (d, J= 1.7 Hz, 1H), 7.81 (dd, J = 8.4, 1.8 Hz, 1H), 3.78 (q, J= 5.7 Hz, 2H), 3.70 - 3.62 (m, 2H), 3.37 (s, 3H). ¹³ C NMR (101 MHz, DMSO) δ 167.33, 152.81, 147.53, 147.40, 144.83, 131.48, 127.67, 126.75, 123.95, 122.49, 122.31, 121.32, 116.48, 70.10, 57.99. HRMS (ESI): m/z calculated for C ₁₆ H ₁₆ O ₃ N ₃ 298.11862, found 298.11840.

[0324] 5-(( lZ/-pyrazol-4-yl)amino)benzo[c][2,6]naphthyridine-8-carboxyl ic acid (39a- Yh) Prepared from 39b-Xh by GP-O, off-white solid, yield 41 %. MS (ESI): m/z = 306.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 10.11 (s, 1H), 9.88 (s, 1H), 8.96 (d, J= 5.6 Hz, 1H), 8.78 (d, J= 8.5 Hz, 1H), 8.49 (dd, J = 5.8, 0.8 Hz, 1H), 8.31 (d, J= 1.7 Hz, 1H), 8.22 (s, 2H), 7.89 (dd, J = 8.4, 1.8 Hz, 1H). ¹³ C NMR (101 MHz, DMSO) δ 167.30, 149.27, 147.68, 147.51, 144.54, 131.61, 128.00, 126.79, 124.00, 123.04, 122.48, 121.66, 116.12. HRMS (ESI): m/z calculated for C16H12O2N5 306.09855, found 306.09831.

Example 10: Synthesis of Compounds of this invention

Preparation of Compound 2 and Compound 4

Scheme 12- Reagents and conditions: a) K2CO3, Pd(PPh3)2C12, 1,4-dioxane, H ₂ O, 105 °C; b) POC13, reflux; c) 3 -chloroaniline, ACN, 90 °C; d) NaOH, EtOH, H ₂ O, 80 °C; e) NaN3, NH4C1, DMF, 100 °C.

[0325] Methyl 6-oxo-5,6-dihydrophenanthridine-3-carboxylate (SC12a). Prepared from methyl 3-amino-4-bromobenzoate and methyl 2-(4,4,5,5,-tetramethyl-l,3,2-dioxaborolan-2- yl)benzoate according to the GP-A1, white solid, yield 75%. MS (ESI): m/z = 254.2 [M+H] ⁺ . ³ H NMR (DMSO-d ₆ ): δ = 11.80 (bs, 1H); 8.54 (m, 1H); 8.49 (d, 1H, J= 8.3 Hz); 8.34 (ddd, 1H, J= 7.9, 1.5, 0.5 Hz); 7.98 (dd, 1H, J= 1.7, 0.4 Hz); 7.89 (dd, 1H, J= 8.2, 7.2, 1.5 Hz); 7.76 (dd, 1H, J = 8.4, 1.7 Hz); 7.71 (ddd, 1H, J = 8.1, 7.2, 1.0 Hz); 3.89 (s, 3H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 165.68; 160.70; 136.48; 133.23; 133.02; 129.99; 129.11; 127.55; 126.35; 123.77; 123.37; 122.23; 121.38; 117.05; 52.36 ppm. HRMS (ESI): m/z calculated for C ₁₅ H ₁₂ NO ₃ 254.08117, found 254.08107.

[0326] 3-Amino-4-bromobenzonitrile (SC9a). 4-Bromo-3 -nitrobenzonitrile (1g, 4.4 mmol) in EtOH (10 ml) was treated with SnCl ₂ (4.17 g, 22 mmol) and heated under reflux for 90 min. The mixture was cooled down, diluted with EtOAc poured to crushed ice, basified with sat. NaHCCE and the thick precipitate was filtered off and washed with EtOAc. The filtrate was washed with brine, dried over MgSO ₄ and evaporated. The crude product was used without further purification. White solid (0.74g, 85%).

[0327] 6-Oxo-5,6-dihydrophenanthridine-3-carbonitrile (SC12b). Prepared from SC9a and methyl 2-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate ¹ according to the GP-A1, white solid, yield 88%. MS (ESI): m/z = 221.2 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 8.57 (d, 1H, J= 8.1 Hz); 8.56 (d, 1H, J= 8.4 Hz); 8.34 (dd, 1H, J= 7.9, 1.4 Hz); 7.89 (ddd, 1H, J= 8.4, 7.2, 1.5 Hz); 7.73 (ddd, 1H, J= 8.0, 7.1, 1.0 Hz); 7.68 (d, 1H, J= 1.7 Hz); 7.61 (dd, 1H, J= 8.3, 1.7 Hz) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 161.14; 137.73; 132.90; 129.43; 127.56; 126.55; 124.65; 124.37; 123.47; 121.58; 120.25; 118.65; 111.12 ppm. HRMS (ESI): m/z calculated for C14H9N2O 221.07094, found 221.07080.

[0328] Methyl 6-[(3-chlorophenyl)amino]phenanthridine-3-carboxylate (Compound 1). Compound SC12a was converted to the corresponding chloro derivative by GP-B1. White solid, yield 95%. MS (ESI): m/z = 272.2 [M+H] ⁺ . The crude product was converted by GP-C1 to the desired Compound 1 (white solid, 86%). MS (ESI): m/z = 363.3 [M+H] ⁺ . ¹ H NMR (DMSO-cf): δ = 9.54 (s, 1H); 8.80 (d, 1H, J= 8.2 Hz); 8.68 (m, 2H); 8.28 (d, 1H, J= 2.6 Hz); 8.22 (d, 1H, J= 1.8 Hz); 8.12 - 8.05 (m, 1H); 7.98 - 7.85 (m, 3H); 7.43 (t, 1H, J= 8.1 Hz); 7.11 (dd, 1H, J= 7.8, 2.1 Hz); 3.92 (s, 3H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 166.20; 151.34; 142.81; 142.32; 132.73; 132.69; 131.32; 130.01; 129.70; 128.77; 128.06; 124.65; 124.10; 123.62; 123.18; 123.11; 121.76; 120.09; 119.85; 119.15; 52.28 ppm. HRMS (ESI): m/z calculated for C21H ₁₆ CIN ₂ O ₂ 363.08948, found 363.08899.

[0329] 6-[(3-Chlorophenyl)amino]phenanthridine-3-carbonitrile ( Compound 3). Compound SC12b was converted to the corresponding chloro- derivative by GP-B1. White solid, yield 96%. MS (ESI): m/z = 239.2 [M+H] ⁺ . The crude product was converted by GP-C1 to the desired Compound 3 (white solid, 92%). MS (ESI): m/z = 330.4 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 9.68 (s, 1H); 8.82 (d, 1H, J = 8.2 Hz); 8.73 (d, 2H, J = 8.2 Hz); 8.22 (d, 1H, J = 2.6 Hz); 8.10 - 8.08 (m, 1H); 8.07 (m, 1H); 7.98 (t, 1H, J= 7.6 Hz); 7.90 (t, 1H, J= 7.6 Hz); 7.75 (m, 1H); 7.41 (t, 1H, J= 8.1 Hz); 7.13 (d, 1H, J= 8.0 Hz) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 151.79; 142.65; 141.92; 132.75; 132.41; 131.63; 130.91; 130.03; 129.23; 125.38; 124.58; 124.25; 124.11; 123.77; 122.22; 120.53; 119.93; 119.56; 118.84; 111.18 ppm. HRMS (ESI): m/z calculated for C ₂₀ H ₁₃ CIN ₃ 330.07925, found 330.07929.

[0330] 6-[(3-Chlorophenyl)amino]phenanthridine-3-carboxylic acid (Compound 2). Prepared from Compound 1 by GP-D1, white solid, yield 68%. MS (ESI): m/z = 349.3 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 13.13 (br s); 9.57 (br s, 1H); 8.83 (d, 1H, J= 8.2 Hz); 8.70 (m, 2H); 8.32 (br s, 1H); 8.25 (br, 1H); 8.08 (d, 1H, J= 8.3 Hz); 7.99 - 7.86 (m, 3H); 7.43 (t, 1H, J= 8.1 Hz); 7.11 (d, 1H, J= 7.8) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 167.30; 151.26; 142.69; 142.33; 132.87; 132.73; 131.38; 130.99; 130.05; 128.69; 128.19; 124.35; 124.15; 123.63; 123.58; 122.96; 121.78; 120.11; 119.81; 119.16 ppm. HRMS (ESI): m/z calculated for C ₂₀ H ₁₂ CIN ₂ O ₂ 347.05928, found 347.05922.

[0331] N-(3-Chlorophenyl)-3-(tetrazol-5-yl)phenanthridin-6-amine (Compound 4). Compound 3 (80 mg, 0.24 mmol), NH4CI (234 mg, 4.4 mmol) and NaNi (237 mg, 3.6 mmol) in DMF (1 ml) were heated at 120 °C for 2 h, cooled to RT, diluted with DMSO (1 ml) and directly applied to the RP FC (H ₂ O/ACN, 0 - 100 %), the poorly soluble product was finally eluted with 0.1% TFA in ACN. White solid, 47 mg (52%). MS (ESI): m/z = 373.3 [M+H] ⁺ . ¹ H NMR (DMSO- d ₆ ): δ= 9.82 (bs); 8.86 (dd, 1H, J = 13, 1.2 Hz); 8.82 (d, 1H, J = 8.6 Hz); 8.73 (dd, 1H, J = 8.3, 1.2 Hz); 8.43 (d, 1H, J= 1.8 Hz); 8.26 (t, 1H, J= 2.1 Hz); 8.10 (dd, 1H, J= 8.4, 1.8 Hz); 8.01 (m, 2H); 7.90 (ddd, 1H, J= 8.3, 7.0, 1.2 Hz); 7.47 (t, 1H, J= 8.1 Hz); 7.19 (m, 1H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 151.66; 141.78; 133.00; 132.95; 131.90; 130.25; 128.71; 124.43; 124.09; 123.53; 122.95; 121.85; 121.47; 120.82; 120.18; 119.58 ppm. HRMS (ESI): m/z calculated for C ₂₀ H14CIN6 373.09630, found 373.09617.

Scheme 13- Reagents and conditions: a) B2pin2, KOAc, Pd(dppf)C12.DCM, DMF, 105 °C; b) K2CO3, Pd(PPh3)2C12, 1,4-dioxane, H ₂ O, 105 °C; c) POC13, reflux; d) 3 -chloroaniline, ACN, 90 °C; e) NaOH, EtOH, H ₂ O, 80 °C.

Table 4: Compounds prepared according to Scheme 13

[0332] Methyl 5-oxo-5,6-dihydrobenzo[f][l,7]naphthyridine-8-carboxylate (Xb). Ethyl 3- chloropicolinate (536 mg, 2.89 mmol), SC9b (800 mg, 2.89 mmol), Cs ₂ CO ₃ (2.82 g, 8.66 mmol) and Pd(dppf)Cl.DCM (118 mg, 0.14 mmol) in dioxane/water mixture (9: 1, 30 ml) were heated at 105 °C for 3h, poured to ice cold sat. NH4CI and DCM, repeatedly extracted with DCM, dried over MgSO ₄ and purified by FC (EtOAc/EtOH 10 - 30%), pale brown solid (340 mg, 41%). MS (ESI): m/z = 255.3 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 12.04 (s, 1H); 8.98 (dd, 1H, J= 8.4, 1.6 Hz); 8.94 (dd, 1H, J = 4.4, 1.5 Hz); 8.50 (d, 1H, J= 8.5 Hz); 7.98 (d, 1H, J= 1.7 Hz); 7.87 (dd, 1H, J= 8.4, 4.4 Hz); 7.77 (dd, 1H, J= 8.4, 1.7 Hz); 3.89 (s, 3H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 165.62; 159.34; 151.11; 142.28; 136.4; 132.13; 130.63; 129.96; 127.23; 124.31; 122.19; 120.36; 116.88; 52.48 ppm. HRMS (ESI): m/z calculated for C ₁₄ H ₁ 1N2O3 255.07642, found 255.07627.

[0333] Methyl 5-((3-chlorophenyl)amino)benzo[f] [l,7]naphthyridine-8-carboxylate

(Compound 15-Yb). Compound Xb was converted by GP-B1 to the corresponding Cl-derivative (dark violet solid, yield 70%, MS (ESI): m/z = 272.3 [M+H] ⁺ ) and directly converted by GP-C1 to the Compound 15-Yb (yield 63%, violet solid). MS (ESI): m/z = 364.3 [M+H] ⁺ . ³ H NMR (DMSO-d ₆ ): δ = 10.02 (s, 1H); 9.17 (dd, 1H, J= 8.6, 1.5 Hz); 9.07 (dd, 1H, J= 4.4, 1.5 Hz); 8.63 (d, 1H, J= 8.4 Hz); 8.52 (t, 1H, J= 2.1 Hz); 8.22 (d, 1H, J= 1.7 Hz); 8.17 (ddd, 1H, J= 8.3, 2.1, 0.9 Hz); 7.97 (dd, 1H, J= 8.3, 4.4 Hz); 7.90 (dd, 1H, J = 8.4, 1.8 Hz); 7.41 (t, 1H, J= 8.1 Hz); 7.10 (ddd, 1H, J= 7.9, 2.1, 0.9 Hz); 3.93 (s, 3H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 166.10; 151.00; 150.35; 142.84; 141.48; 135.00; 132.95; 132.45; 130.42; 130.16; 128.03; 127.42; 126.59; 123.70; 123.64; 123.25; 121.84; 119.14; 118.32; 52.39 ppm. HRMS (ESI): m/z calculated for C ₂₀ H ₁₅ CIN ₃ O ₂ 364.08473, found 364.08517.

[0334] 5-((3-Chlorophenyl)amino)benzo[f|[l,7]naphthyridine-8-carbox ylic acid (Compound 16-Zb). Prepared from Compound 15-Yb by GP-D1, yield 74%, off-white solid. MS (ESI): m/z = 350.3 [M+H] ⁺ . ¹ HNMR (DMSO-d ₆ ): δ = 13.19 (bs, 1H); 10.05 (s, 1H); 9.22 (d, 1H, J= 7.8 Hz); 9.08 (d, 1H, J= 4.3 Hz); 8.66 (d, 1H, J = 8.4 Hz); 8.58 (t, 1H, J = 2.2 Hz); 8.28 (d, 1H, J= 1.7 Hz); 8.19 (dd, 1H, J= 8.3, 2.1 Hz); 8.00 (dd, 1H, J= 8.3, 4.4 Hz); 7.94 (dd, 1H, J= 8.4, 1.8 Hz); 7.41 (t, 1H, J= 8.1 Hz); 7.10 (dd, 1H, J= 7.9, 2.1 Hz) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 167.19; 150.93; 150.23; 142.83; 141.55; 134.97; 132.94; 132.43; 131.71; 130.13; 128.23; 127.54; 126.57; 123.60; 123.52; 123.34; 121.77; 119.12; 118.31 ppm. NEG-HRMS (ESI): m/z calculated for C ₁₉ H ₁₁ CIN ₃ O ₂ 348.05453, found 348.05445.

[0335] Ethyl 5-bromo-l-methyl-1H-pyrazole-4-carboxylate (SC13b). Ethyl 1-methyl-1H- pyrazole-4-carboxylate (1.4 g, 9 mmol) in dry THF (25 ml) was treated with TMPMgCl-LiCl (IM, 11.1 ml, 11 mmol) at -30 °C under argon atmosphere and the mixture was allowed to warm to 0 °C, cooled back to -50 °C and 1,2-dibromotetrachloroethane (3.9 g, 12 mmol) in dry THF (10 ml) was slowly added. The resulting mixture was left to warm to RT, quenched with sat. NH4CI, diluted with EtOAc and washed with sat. NH4CI and water, dried over MgSCE. FC (c-hex/EtOAc + 10% MeOH) gave 1.4 g (66%) of crystalline solid. MS (ESI): m/z = 233.6 [M+H] ⁺ . ¹ H NMR (CDCl ₃ ): δ = 7.92 (s, 1H); 4.30 (q, 2H, J= 7.1 Hz); 3.90 (s, 3H); 1.35 (t, 3H, J= 7.1 Hz) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 161.89; 142.06; 118.09; 113.98; 60.50; 38.14; 14.41 ppm.

[0336] Methyl l-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]quinoline-7-car boxylate (Xc). Prepared from SC13b and SC9b by GP-A1. Reaction mixture was diluted with EtOAc and washed with water, organic fraction was dried over MgSO ₄ and evaporated. The residue in AcOH (5 ml) was heated at 60 °C for Ih. The precipitated product was filtered, washed with water and dried. White poorly soluble solid, yield 44%. MS (ESI): m/z = 258.2 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 11.56 (s, 1H); 8.25 (d, 1H, J= 8.5 Hz); 8.10 (s, 1H); 8.02 (d, 1H, J= 1.8 Hz); 7.74 (dd, J= 8.5, 1.7 Hz); 4.36 (s, 3H); 3.89 (s, 3H) ppm. HRMS (ESI): m/z calculated for C13H12N3O3 258.08732, found 258.08735.

[0337] Methyl 4-((3-chlorophenyl)amino)-l-methyl-1H-pyrazolo [4,3-c] quinoline-7- carboxylate (Compound 75b-Yc). Compound Xc was converted by GP-B1 to the corresponding Cl-derivative (white solid, yield 84%, MS (ESI): m/z = 276.1 [M+H] ⁺ ) and directly converted by GP-C1 to the Compound 75b-Yc (yield 80%, white poorly soluble solid). MS (ESI): m/z = 367.2 [M+H] ⁺ . ¹ H NMR (100 °C, DMSO-d ₆ ): δ = 8.69 (s, 1H); 8.47 (d, 1H, J= 8.6 Hz); 8.45 (d, 1H, J = 1.7 Hz); 8.13 (t, 1H, J= 2.1 Hz); 7.97 (dd, 1H, J= 8.5, 1.8 Hz); 7.91 (d, 1H, J= 8.0 Hz); 7.47 (t, 1H, J = 8.1 Hz); 7.23 (d, 1H, J = 7.9 Hz); 4.47 (s, 3H); 3.95 (s, 3H) ppm. ¹³ C NMR (100 °C, DMSO-d ₆ ): δ = 165.37; 148.19; 141.36; 139.89; 138.69; 133.25; 132.91; 129.97; 129.69; 125.28; 123.25; 122.96; 122.25; 121.07; 119.89; 116.07; 109.62; 51.74; 39.5 ppm. HRMS (ESI): m/z calculated for C ₁₉ H ₁₆ CIN ₄ O ₂ 367.09563, found 367.09568.

[0338] 4-((3-Chlorophenyl)amino)-l-methyl-1H-pyrazolo[4,3-c]quinoli ne-7-carboxylic acid (Compound 75a-Zc). Prepared from Compound 75b-Yc by GP-D1, yield 78%, white poorly soluble solid. MS (ESI): m/z = 353.1 [M+H] ⁺ . ¹ H NMR (70 °C, DMSO-d ₆ ): δ = 8.78 (s, 1H); 8.52 - 8.46 (m, 2H); 8.06 (bs, 1H); 8.01 (dd, 1H, J= 8.5, 1.7 Hz); 7.85 - 7.80 (m, 1H); 7.52 (t, 1H, J= 8.1 Hz); 7.35 - 7.29 (m, 1H); 4.49 (s, 3H) ppm. ¹³ C NMR (70 °C, DMSO-d ₆ ): δ = 166.27; 148.13; 140.0; 138.97; 138.85; 134.22; 133.29; 131.36; 130.53; 124.61; 124.6; 123.98; 122.62; 122.34; 121.18; 115.61; 109.31; 40.04 ppm. HRMS (ESI): m/z calculated for C ₁₈ H ₁₄ CIN ₄ O ₂ 353.07998, found 353.08011.

[0339] Methyl 4-oxo-4,5-dihydrothiazolo[4,5-c]quinoline-7-carboxylate (Xd). Prepared from SC9b and methyl 5-bromothiazole-4-carboxylate by GP-A1. Orange solid, yield 89%. MS (ESI): m/z = 261.2 [M+H] ⁺ . ¹ HNMR (DMS0-d ₆ ): δ = 12.12 (bs, 1H); 9.40 (s, 1H); 8.06 (d, 1H, J= 1.6 Hz); 7.96 (d, 1H, J= 8.2 Hz); 7.74 (dd, 1H, J= 8.2, 1.6 Hz); 3.89 (s, 3H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 165.60; 156.98; 155.9; 145.55; 140.97; 136.83; 130.26; 126.03; 122.27; 118.47; 117.46; 52.50 ppm. HRMS (ESI): m/z calculated for C12H9N2O3S 261.03284, found 261.03280.

[0340] Methyl 4-((3-chlorophenyl)amino)thiazolo[4,5-c]quinoline-7-carboxyl ate

(Compound 8-Yd). Compound Xd was converted by GP-B1 to the corresponding Cl-derivative (grey solid, yield 97%, MS (ESI): m/z = 279.2 [M+H] ⁺ ), which was directly converted by GP-C1 to the Compound 8 (white solid, 90%). MS (ESI): m/z = 370.3 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 9.91 (s, 1H); 9.63 (s, 1H); 8.46 (t, 1H, J= 2.1 Hz); 8.34 (d, 1H, J= 1.6 Hz); 8.21 (ddd, 1H, J= 8.3, 2.1, 0.9 Hz); 8.10 (d, 1H, J= 8.3 Hz); 7.89 (dd, 1H, J= 8.3, 1.7 Hz); 7.41 (t, 1H, J= 8.1 Hz); 7.09 (ddd, 1H, J= 8.0, 2.2, 0.9 Hz); 3.93 (s, 3H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 166.04; 157.08; 148.58; 143.11; 141.78; 139.74; 138.85; 132.81; 130.08; 130.02; 128.44; 125.60; 123.27; 122.79; 121.79; 119.32; 118.44; 52.42 ppm. HRMS (ESI): m/z calculated for C ₁₈ H ₁₃ CIN ₃ O ₂ S 370.04115, found 370.04127.

[0341] 4-((3-Chlorophenyl)amino)thiazolo[4,5-c]quinoline-7-carboxyl ic acid (Compound 7- Zd). Prepared from Compound 8-Yd by GP-D1, white solid, yield 73%. MS (ESI): m/z = 356.3 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 9.93 (s, 1H); 9.65 (s, 1H); 8.51 (t, 1H, J = 2.1 Hz); 8.38 (d, 1H, J= 1.6 Hz); 8.22 (dd, 1H, J= 8.1, 1.9 Hz); 8.12 (d, 1H, J= 8.3 Hz); 7.92 (dd, 1H, J= 8.3, 1.7 Hz) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 167.15; 157.20; 148.55; 143.21; 141.89; 139.67; 138.97; 132.82; 131.37; 130.10; 125.48; 123.69; 122.58; 121.73; 119.28; 118.42 ppm. NEG-HRMS (ESI): m/z calculated for C ₁₇ H ₉ CIN ₃ O ₂ S 354.01095, found 354.01088.

[0342] Methyl 4-oxo-4,5-dihydrothieno[3,2-c]quinoline-7-carboxylate (Xe). Prepared by GP- A1 from SC9b and ethyl 2 -bromothiophene-3 -carboxylate, pale grey solid, yield 75%. MS (ESI): m/z = 260.3 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 8.03 (d, 1H, J= 1.6 Hz); 7.92 (d, 1H, J= 8.2 Hz); 7.86 (d, 1H, J= 5.2 Hz); 7.71 (dd, 1H, J= 8.2, 1.6 Hz); 7.61 (d, 1H, J= 5.2 Hz); 3.89 (s, 3H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 165.79; 158.89; 144.20; 137.26; 132.79; 129.39; 128.24; 125.57; 123.67; 121.94; 119.88; 118.05; 52.38 ppm. HRMS (ESI): m/z calculated for C ₁₃ H ₁₀ NO ₃ S 260.03759, found 260.03750.

[0343] Methyl 4-((3-chlorophenyl)amino)thieno[3,2-c]quinoline-7-carboxylat e (Compound 13-Ye). Compound Xe was converted by GP-B1 to corresponding Cl-derivative (off-white solid, 51%, MS (ESI): m/z = 278.2 [M+H] ⁺ ), which was directly converted to Compound 13-Ye by GP- Cl, yellow solid, 92%. MS (ESI): m/z = 369.3 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 9.69 (bs, 1H, NH); 8.35 (d, 1H, J= 1.7 Hz); 8.27 (t, 1H, J= 2.1 Hz); 8.23 (d, 1H, J= 5.4 Hz); 8.11 (m, 2H); 8.05 (ddd, 1H, J= 8.3, 2.2, 0.9 Hz); 7.90 (dd, 1H, J= 8.3, 1.7 Hz); 7.45 (t, 1H, J= 8.1 Hz); 7.16 (ddd, 1H, J = 8.0, 2.2, 0.9 Hz); 3.92 (s, 3H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 166.07; 149.35; 144.72; 141.52; 132.98; 130.36; 129.51; 129.14; 127.64; 126.25; 123.56; 123.52; 123.44; 123.07; 122.44; 120.13; 119.16; 52.39 ppm. HRMS (ESI): m/z calculated for C ₁₉ H14CIN ₂ O ₂ S 369.04590, found 369.04575.

[0344] 4-((3-Chlorophenyl)amino)thieno[3,2-c]quinoline-7-carboxylic acid (Compound 14- Ze). Prepared from Compound 13-Ye by GP-D1, yellow solid, yield 61%. MS (ESI): m/z = 355.3 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 10.50 (bs, 1H); 8.44 (bs, 1H); 8.41 (bs, 1H, J= 5.4 Hz); 8.14 - 8.18 (m, 3H); 7.94 (m, 2H); 7.50 (t, 1H, J = 8.1 Hz); 7.27 (bs, 1H, J = 8.0 Hz) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 166.87; 149.02; 145.67; 140.53; 133.32; 131.19; 130.74; 129.69; 126.27; 125.82; 124.49; 124.84; 123.76; 123.61 (2C); 122.62; 121.87 ppm. NEG-HRMS (ESI): m/z calculated for C ₁₈ H ₁₀ CIN ₂ O ₂ S 353.01570, found 353.01550. [0345] Methyl 4-oxo-4,5-dihydrothieno[2,3-c]quinoline-7-carboxylate (Xf). Prepared by GP- A1 from SC9b and ethyl 3-bromothiophene-2-carboxylate, pale yellow solid, yield 80%. MS (ESI): m/z = 260.3 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 12.60 (bs, 1H); 8.28 (d, 1H, J = 8.3 Hz); 8.23 (d, 1H, J= 5.2 Hz); 8.12 (d, 1H, J= 52 Hz); 8.07 (d, 1H, J= 1.6 Hz); 7.79 (dd, 1H, J= 8.3, 1.6 Hz); 3.89 (s, 3H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 165.75; 157.64; 142.14; 137.20; 134.75; 131.96; 129.43; 124.65; 123.87; 122.25; 120.24; 117.23; 52.41 ppm. HRMS (ESI): m/z calculated for C ₁₃ H ₁₀ NO ₃ S 260.03759, found 260.03742.

[0346] Methyl 4-((3-chlorophenyl)amino)thieno[2,3-c]quinoline-7-carboxylat e (Compound 12-Yf). Compound Xf was converted by GP-B1 to corresponding Cl-derivative (off-white solid, 98%, MS (ESI): m/z = 278.2 [M+H] ⁺ ), which was directly converted to Compound 12-Yf by GP- Cl, off-white solid, 86%. MS (ESI): m/z = 369.3 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 8.46 (d, 1H, J= 8.4 Hz); 8.38 (d, 1H, J= 1.7 Hz); 8.35 - 8.27 (m, 2H); 8.21 (t, 1H, J= 2.1 Hz); 8.00 (ddd, 1H, J = 8.3, 2.2, 1.0 Hz); 7.94 (dd, 1H, J = 8.4, 1.7 Hz); 7.44 (t, 1H, J= 8.1 Hz); 7.15 (ddd, 1H, J = 8.0, 2.1, 0.9 Hz); 3.92 (s, 3H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 166.19; 148.87; 143.14; 142.06; 141.56; 133.34; 132.93; 130.28; 129.27; 127.23; 125.07; 124.32; 123.90; 123.28; 123.19; 122.51; 120.52; 119.54; 52.36 ppm. HRMS (ESI): m/z calculated for C ₁₉ H ₁₄ CIN ₂ O ₂ S 369.04590, found 369.04625.

[0347] 4-((3-Chlorophenyl)amino)thieno[2,3-c]quinoline-7-carboxylic acid (Compound 11- Zf). Prepared from Compound 12-Yf by GP-D1, off-white solid, yield 73%. MS (ESI): m/z = 355.3 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 9.51 (bs, 1H); 8.45 (d, 1H, J= 8.4 Hz); 8.36 (d, 1H, J= 1.8 Hz); 8.26 - 8.30 (m, 3H); 8.05 (dd, 1H, J = 8.3, 2.1 Hz); 7.94 (dd, 1H, J= 8.4, 1.9 Hz); 7.40 (t, 1H, J= 8.1 Hz); 7.09 (dd, 1H, J= 7.9, 2.1 Hz) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 167.42; 148.79; 143.38; 142.97; 142.30; 132.77; 132.42; 130.33; 130.09; 128.36; 125.05; 124.02; 123.97; 123.28; 123.21; 121.64; 119.66; 118.70 ppm. NEG-HRMS (ESI): m/z calculated for C ₁₈ H ₁₀ CIN ₂ O ₂ S 353.01570, found 353.01542.

[0348] Methyl 4-bromo-l-methyl-1H-imidazole-5-carboxylate (SC13d). Methyl 4-bromo-1H- imidazole-5-carboxylate (1.4 g, 6.8 mmol) in DMF (20 ml) was treated with K2CO3 (1.4 g, 10.24 mmol) and CH3I (0.51 ml, 8.2 mmol) was added dropwise, the resulting mixture was stirred at RT overnight. The mixture was diluted with EtOAc and washed with sat. NH4CI and water and dried over MgSO ₄ . Purification by FC (c-hex/EtOAc) afforded compound SC13d as a major product, white solid 460 mg (31%). MS (ESI): m/z = 218.9 [M+H] ⁺ . ¹ HNMR(DMSO-d ₆ ): δ = 7.44 (d, 1H, J= 0.7 Hz); 3.90 (s, 3H); 3.89 (d, 3H, J= 0.7 Hz) ppm. ¹³ C NMR (DMSO-d ₆ ): δ =160.15; 141.21; 124.25; 120.99; 51.89; 35.85 ppm.

[0349] Methyl 3-methyl-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]quinoline-7-carb oxylate (Xg).

Prepared by GP-A1 from SC9b and SC13d, off-white solid, yield 46%. MS (ESI): m/z = 258.1 [M+H] ⁺ . ¹ HNMR DMSO^): δ = 11.85 (bs, 1H); 8.28 (s, 1H); 8.12 (d, 1H, J= 8.2 Hz); 8.05 (d, 1H, J= 1.6 Hz); 7.79 (dd, 1H, J= 8.2, 1.6 Hz); 4.07 (s, 3H); 3.88 (s, 3H) ppm. ¹³ C NMR (DMSO- d ₆ ) δ = 165.95; 155.57; 145.55; 143.54; 136.04; 128.39; 122.34; 121.90; 121.69; 119.95; 117.03; 52.32; 33.17 ppm. HRMS (ESI): m/z calculated for C13H12N3O3 258.08732, found 258.08742.

[0350] 4-((3-Chlorophenyl)amino)-3-methyl-3H-imidazo[4,5-c]quinolin e-7-carboxylic acid (Compound 30a-Zg). Compound Xg was converted by GP-B1 to corresponding Cl-derivative (off-white solid, 98%, MS (ESI): m/z = 276.2 [M+H] ⁺ ), which was directly converted to 3- chlorophenylamino derivative by GP-C1, however, mixture of product and deprotected product was observed. Thus, the mixture was diluted with EtOH and water and treated with 5M NaOH to pH 12, heated at 80 °C until complete removal of methyl ester. The mixture was acidified by IM HC1, precipitated products were filtered off and discarded. Mother liquor was evaporated and purified by RP FC (H ₂ O/ACN + 0.1% FA) to afford desired Compound 30a-Zg (yield 32%, white solid). MS (ESI): m/z = 353.2 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 13.01 (bs, 1H); 8.64 (s, 1H); 8.40 (s, 1H); 8.31 - 8.34 (m, 2H); 7.94 - 7.98 (m, 2H); 7.80 (dd, 1H, J= 8.3, 2.1 Hz); 7.40 (t, 1H, J= 8.1 Hz); 7.07 (dd, 1H, J= 8.1, 2.1 Hz); 4.28 (s, 3H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 167.54; 146.40; 145.45; 143.78; 142.49; 141.85; 132.83; 130.13; 129.25; 128.52; 123.62; 123.55; 121.35; 121.20; 120.59; 119.33; 118.44; 33.93 ppm. HRMS (ESI): m/z calculated for C ₁₈ H14CIN ₄ O ₂ 353.07998, found 353.07991.

[0351] Methyl 3-methyl-4-oxo-4,5-dihydro-3H-pyrazolo[3,4-c]quinoline-7-car boxylate (Xh). Prepared by GP-A1 from SC9b and methyl 4-iodo-l-methyl-1H-pyrazole-5-carboxylate, off- white solid, yield 58%. MS (ESI): m/z = 258.2 [M+H] ⁺ . ¹ HNMR (DMSO-d ₆ ): δ = 11.84 (bs, 1H); 8.44 (s, 1H); 8.07 (d, 1H, J= 8.0 Hz); 7.98 (d, 1H, J= 1.7 Hz); 7.74 (dd, 1H, J= 8.3, 1.6 Hz); 4.29 (s, 3H); 3.87 (s, 3H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 165.98; 155.03; 136.99; 132.93; 127.79; 123.37; 122.27; 119.34; 117.72; 52.26; 38.19 ppm. HRMS (ESI): m/z calculated for C ₁₃ H ₁₂ N ₃ O ₃ 258.08732, found 258.08747.

[0352] Methyl 4-((3-chlorophenyl)amino)-3-methyl-3H-pyrazolo [3,4-c] quinoline-7- carboxylate (Compound 73b- Yh). Compound Xh was converted to 2-C1 derivative by GP-B (off-white solid, 97%, MS (ESI): m/z = 276.2 [M+H] ⁺ ), which was directly converted to Compound 73b- Yh by GP-C1, off-white solid, 79%. MS (ESI): m/z = 367.2 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): tautomer a: δ = 8.81 (s, 1H); 8.65 (s, 1H); 8.27 (dd, 1H, J= 8.3 Hz); 8.25 (d, 1H, J= 1.6 Hz); 7.96 (t, 1H, J= 2.1 Hz); 7.95 - 7.90 (m, 1H); 7.83 (ddd, J= 8.2, 2.1, 0.9 Hz); 7.46 - 7.35 (m, 1H); 7.15 - 7.08 (m, 1H); 4.49 (s, 3H); 3.90 (s, 3H) ppm; tautomer b: 10.07 (s, 1H); 8.34 (s, 1H); 8.14 (d, 1H, J= 1.6 Hz); 7.95 - 7.90 (m, 1H); 7.62 (dd, 1H, J= 8.1, 1.7 Hz); 7.46 - 7.35 (m, 1H); 7.15 - 7.08 (m, 1H); 7.02 (t, 1H, J= 2.0 Hz); 6.93 (ddd, 1H, J= 7.9, 2.0, 1.0 Hz); 4.34 (s, 3H); 3.82 (s, 3H) ppm. ¹³ C NMR (DMSO-d ₆ ): tautomer a: δ = 166.3; 142.80; 141.97; 140.86; 132.81; 132.50; 130.14; 127.97; 127.90; 127.73; 124.73; 123.96; 123.37; 123.12; 121.89; 119.89; 118.99; 52.20; 39.9 ppm; tautomer b: 166.01; 150.20; 140.65; 135.92; 133.80; 132.73; 131.07; 130.55; 127.59; 122.82; 122.37; 122.05; 121.60; 120.57; 114.99; 119.34; 117.00; 52.06; 39.6 ppm. HRMS (ESI): m/z calculated for C ₁₉ H ₁₆ CIN ₄ O ₂ 367.09563, found 367.09568.

[0353] 4-((3-Chlorophenyl)amino)-3-methyl-3H-pyrazolo[3,4-c]quinoli ne-7-carboxylic acid (Compound 73a-Zh). Prepared from Compound 73b- Yh by GP-D1, off-white solid, yield 85%. MS (ESI), m/z = 353.25 [M+H] ⁺ . ¹ H NMR (DMF-d ₇ ): tautomer a: δ = 8.90 (s, 1H); 8.72 (s, 1H); 8.46 - 8.42 (m, 1H); 8.38 (d, 1H, J= 8.2 Hz); 8.20 - 8.15 (m, 1H); 8.07 - 8.03 (m, 1H); 7.92 (dd, 1H, J= 8.3, 2.1 Hz); 7.46 (t, 1H, J= 8.1 Hz); 7.15 (dd, 1H, J= 7.8, 2.1 Hz); 4.65 (s, 3H) ppm; tautomer b: 10.37 (s, 1H); 8.46 - 8.42 (m, 1H); 8.31 - 8.25 (m, 1H); 8.07 - 8.03 (m, 1H); 7.75 (d, 1H, J= 8.1 Hz); 7.41 (t, 1H, J = 8.2 Hz); 7.14 - 7.11 (m, 2H); 7.03 (d, 1H, J = 8.0 Hz); 4.43 (s, 3H) ppm. ¹³ C NMR (DMF-d ₇ ): tautomer a: δ = 167.89; 143.44; 142.78; 141.76; 133.59; 132.68; 130.35; 129.68; 128.82; 128.53; 125.68; 124.81; 123.84; 123.18; 122.31; 120.54; 117.61; 39.78 ppm; tautomer b: 167.54; 151.14; 141.49; 136.73; 134.54; 132.92; 131.30; 131.25; 129.83; 123.00; 122.90; 122.46; 122.12; 120.98; 120.98; 119.76; 117.61; 39.53 ppm. HRMS (ESI): m/z calculated for C ₁₈ H ₁₄ CIN ₄ O ₂ 353.07998, found 353.08008.

[0354] Methyl 3-methyl-4-oxo-4,5-dihydrothieno[3,4-c]quinoline-7-carboxyla te (Xi). Compound SC9b and ethyl 2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)thiophene-3 -carboxylate ⁴ were converted to Xi by GP-A1, yield 49%, white solid. MS (ESI): m/z = 274.2 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 11.14 (s, 1H); 8.20 (s, 1H); 8.11 (d, 1H, J = 8.2 Hz); 7.83 (d, 1H, J= 1.7 Hz); 7.65 (dd, 1H, J= 8.2, 1.7 Hz); 3.86 (s, 3H); 2.91 (s, 3H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 165.78; 159.42; 147.51; 136.34; 135.81; 128.92; 124.91; 124.01; 122.35; 120.82; 116.67; 116.21; 52.26; 15.05 ppm. HRMS (ESI): m/z calculated for C ₁₄ H ₁₂ NO ₃ S 274.05324, found 274.05347.

[0355] Methyl 4-((3-chlorophenyl)amino)-3-methylthieno [3,4-c] quinoline-7-carboxylate

(Compound 74a-Yi). Compound Xi was converted by GP-B1 to corresponding Cl-derivative (off-white solid, 96%, MS (ESI): m/z = 292.1 [M+H] ⁺ ), which was directly converted to Compound 74a-Yi by GP-C1, off-white solid, 62%. MS (ESI): m/z = 383.2 [M+H] ⁺ . ¹ H NMR (DMF-d ₇ , -30 °C): tautomer a: δ = 8.61 (s, 1H); 8.57 (s, 1H); 8.46 (d, J= 8.0 Hz); 8.30 (s, 1H); 8.17 (s, 1H); 7.97 (d, 1H, J= 8.2 Hz); 7.90 (d, 1H, J= 8.2 Hz); 7.49 (t, 1H, J= 8.1 Hz); 7.19 (d, 1H, J= 8.0 Hz); 3.96 (s, 3H); 3.29 (s, 3H) ppm; tautomer b: δ = 9.92 (s, 1H); 8.34 (s, 1H); 8.22 (d, 1H, J= 8.2 Hz); 8.18 (s, 1H); 7.64 (d, 1H, J= 8.2 Hz); 7.42 (t, 1H, J= 7.9 Hz); 7.13 (d, 1H, J = 7.8 Hz); 7.10 (s, 1H); 7.00 (d, 1H, J= 7.8 Hz); 3.87 (s, 3H); 2.95 (s, 3H) ppm. ¹³ C NMR (DMF- d ₇ , -30 °C): tautomer a: δ = 166.92; 145.99; 143.32; 142.72; 139.69; 138.59; 133.63; 130.60; 129.49; 128.05; 126.01; 124.45; 124.08; 123.25; 122.41; 120.63; 119.72; 115.68; 52.40; 15.86 ppm; tautomer b: δ = 166.61; 152.01; 150.55; 145.07; 137.63; 135.84; 134.53; 131.43; 129.65; 125.67; 124.27; 122.41; 122.30; 121.54; 121.12; 117.63; 115.77; 52.48; 16.89 ppm. HRMS (ESI): m/z calculated for C ₂₀ H ₁₆ CIN ₂ O ₂ S 383.06155, found 383.06143.

[0356] 4-((3-Chlorophenyl)amino)-3-methylthieno[3,4-c]quinoline-7-c arboxylic acid (Compound 74b-Zi). Prepared from Compound 74a-Yi by GP-D1, off-white solid, yield 90%. MS (ESI) m/z = 369.2 [M+H] ⁺ . ¹ HNMR (DMSO-d ₆ , 75 °C): δ = 8.30 (s, 1H); 8.19 (d, 1H, J= 8.1 Hz); 8.11 (d, 1H, J= 1.7 Hz); 7.77 (dd, 1H, J= 8.2, 1.7 Hz); 7.69 (bs, 1H); 7.51 (bs, 1H); 7.43 (t, 1H, J= 8.0 Hz); 7.20 - 7.14 (m, 1H); 3.08 (s, 3H) ppm. ¹³ C NMR (DMSO-d ₆ , 75 °C): δ = 166.62; 148.16; 143.2; 142.1; 136.27; 133.05; 130.15; 130.10; 123.49; 123.05 (2C); 122.68; 122.39; 121.41; 120.33; 116.36; 115.00; 114.05; 15.82 ppm. HRMS (ESI): m/z calculated for C ₁₉ H ₁₄ CIN ₂ O ₂ S 369.04590, found 369.04605.

[0357] Methyl 3-methyl-4-oxo-4,5-dihydroisothiazolo[4,5-c]quinoline-7-carb oxylate (Xj). Prepared from SC9b and ethyl 5-iodo-3-methylisothiazole-4-carboxylate by GP-A1, orange poorly soluble solid, yield 80%. MS (ESI): m/z = 275.2 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 7.96 (d, 1H, J= 1.7 Hz); 7.90 (d, 1H, J= 8.2 Hz); 7.60 (dd, 1H, J= 8.2, 1.7 Hz); 3.88 (s, 3H); 2.77 (s, 3H) ppm. HRMS (ESI): m/z calculated for C ₁₃ H ₁₁ N ₂ O ₃ S 275.04849, found 275.04854.

[0358] Methyl 4-((3-chlorophenyl)amino)-3-methylisothiazolo [4,5-c] quinoline-7- carboxylate (Compound 31-Yj). Compound Xj was converted directly to Cl-derivative by GP- B1 (brown solid, yield 68%, MS (ESI): m/z = 293.1 [M+H] ⁺ ) and subsequent conversion by GP- C1 using CAN as a solvent afforded Compound 31-Yj, off-white solid, yield 87%, MS (ESI): m/z = 384.2 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 8.50 (s, 1H); 8.23 (d, 1H, J= 1.6 Hz); 8.14 (d, 1H, J= 8.3 Hz); 8.02 (t, 1H, J= 2.1 Hz); 7.87 (dd, 1H, J = 8.3, 1.7 Hz); 7.86 (ddd, 1H, J= 8.2, 2.1, 0.9 Hz); 7.43 (t, 1H, J= 8.1 Hz); 7.14 (ddd, 1H, J= 7.9, 2.1, 0.9 Hz); 3.91 (s, 3H); 3.07 (s, 3H) ppm. ^{I 3} C NMR (DMSO-d ₆ ): δ = 165.80; 163.33; 162.30; 149.90; 143.32; 141.56; 132.82; 131.49; 130.13; 128.27; 125.22; 123.61; 122.21; 121.66; 121.24; 120.05; 119.17; 52.48; 20.96 ppm. HRMS (ESI): m/z calculated for C ₁₉ H ₁₅ CIN ₃ O ₂ S 384.05680, found 384.05697.

[0359] 4-((3-Chlorophenyl)amino)-3-methylisothiazolo[4,5-c]quinolin e-7-carboxylic acid (Compound 32-Zj). Prepared from Compound 31-Zj by GP-D1, off-white solid, yield 90%. MS (ESI): m/z = 370.2 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 13.32 (bs, 1H); 8.52 (s, 1H); 8.27 (d, 1H, J = 1.7 Hz); 8.14 (d, 1H, J = 8.3 Hz); 8.05 (t, 1H, J= 2.1 Hz); 7.90 (dd, 1H, J= 8.3, 1.7 Hz); 7.86 (dd, 1H, J= 7.5, 1.8 Hz); 7.42 (t, 1H, J= 8.1 Hz); 7.13 (dd, 1H, J= 7.7, 2.0 Hz); 3.08 (s, 3H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 166.92; 163.35; 162.40; 149.82; 143.38; 141.67; 132.94; 132.84; 130.12; 128.42; 125.02; 124.03; 122.12; 121.62; 121.04; 119.99; 119.11; 20.98 ppm. HRMS (ESI): m/z calculated for C ₁₈ H ₁₃ CIN ₃ O ₂ S 370.04115, found 370.04120.

Scheme 14- Reagents and conditions: a) i) TEA, EtOH, RT; ii) SOC12, CHC13, reflux; b) 3 -chloroaniline, EtOH, 80 °C; c) NaOH, EtOH, H ₂ O, 80 °C.

[0360] Methyl 5-chloro-2,3-dihydroimidazo[1,2-c]quinazoline-8-carboxylate (SC14a). SCla (300 mg, 1.7 mmol) in dry EtOH (3 ml) was treated with TEA (0.325 ml, 2.3 mmol) and ethanolamine (0.085 ml, 1.4 mmol) at RT and the mixture was stirred at RT for 30 min, diluted with DCM, washed with IM HC1 and water and dried over MgSO ₄ and evaporated. The crude product was dissolved in CHCl ₃ (6 ml) and treated with SOCl ₂ (3 ml) and heated under reflux for 2 h. Volatiles were evaporated and the residue in DCM was washed with sat. NaHCO ₃ , water and dried over MgSO ₄ . FC (c-hex/EtOAc/MeOH) afforded pale yellow foam, yield 85%. MS (ESI): m/z = 264.11 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 7.94 (d, 1H, J= 8.1 Hz); 7.85 (dd, 1H, J= 8.1, 1.7 Hz); 7.81 (d, 1H, J= 1.7 Hz); 4.18 (t, 2H, J= 9.3 Hz); 3.88 (s, 3H) ppm. ¹³ C NMR (DMSO- d ₆ ): δ = 165.30; 152.47; 146.37; 144.06; 133.83; 126.59; 126.56; 125.79; 121.18; 52.89; 52.61; 48.95 ppm. HRMS (ESI): m/z calculated for C ₁₂ H ₁₁ CIN ₃ O ₂ 264.05343, found 264.05347.

[0361] Methyl 6-chloro-3,4-dihydro-2H-pyrimido[1,2-c]quinazoline-9-carboxy late (SC14b). SCla (300 mg, 1.7 mmol) in dry EtOH (3 ml) was treated with TEA (0.325 ml, 2.3 mmol) and 3- amino-1 -propanol (0.098 ml, 1.3 mmol) atRT 30 min. Crystalline product was filtered off, washed with small amount of EtOH and dried. Dissolved in CHCl ₃ (5 ml) and treated with SOCl ₂ (3 ml) and heated under reflux for 24 h, evaporated, dissolved in DCM and washed with sat. NaHCOs and water, dried over MgSO ₄ and evaporated. FC (c-hex/EtOAc/MeOH), white solid, yield 60%. MS (ESI): m/z = 278.1 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 8.08 (d, 1H, J= 8.3 Hz); 7.81 (dd, 1H, J = 8.3, 1.7 Hz); 7.75 (d, 1H, J = 1.7 Hz); 4.01 (t, 2H, J= 6.0 Hz); 3.87 (s, 3H); 3.52 (t, 2H, J = 5.5 Hz); 1.89 (m, 2H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 165.44; 146.69; 144.01; 143.20; 132.76; 126.50; 126.32; 125.17; 125.36; 52.50; 46.92; 43.70; 19.93 ppm. HRMS (ESI): m/z calculated for C ₁₃ H ₁₃ CIN ₃ O ₂ 278.06908, found 278.06905. [0362] Methyl 5-((3-chlorophenyl)amino)-2,3-dihydroimidazo [1 ,2-c] quinazoline-8- carboxylate (Compound 17). Prepared from SC14a by GP-C1, white solid, yield 90%. MS (ESI): m/z = 355.2 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 8.57 (s, 1H); 7.96 (t, 1H, J= 2.1 Hz); 7.85 (d, 1H, J= 8.1 Hz); 7.78 (m, 1H); 7.65 (d, 1H, J= 1.7 Hz); 7.57 (dd, 1H, J= 8.1, 1.7 Hz); 7.36 (t, 1H, J= 8.1 Hz); 7.10 (m, 1H); 4.10 (m, 2H); 4.04 (m, 2H); 3.86 (s, 3H) ppm. ¹³ C NMR (DMSO- d ₆ ) δ = 165.85; 153.53; 148.00; 147.12; 140.73; 133.27; 132.59; 129.97; 125.44; 125.41; 122.43; 121.66; 120.67; 119.63; 119.19; 53.47; 52.35; 45.84 ppm. HRMS (ESI): m/z calculated for C ₁₈ H ₁₆ CIN ₄ O ₂ 355.09563, found 355.095569.

[0363] Methyl 6-((3-chlorophenyl)amino)-3,4-dihydro-2H-pyrimido [1 ,2-c] quinazoline-9- carboxylate (Compound 19). Prepared from SC14b by GP-C1, white solid, yield 83%. MS (ESI): m/z = 369.2 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 9.74 (bs, 1H); 8.71 (d, 1H, J= 8.9 Hz); 7.85 - 7.82 (m, 3H); 7.73 (d, 1H, J= 8.1 Hz); 7.44 (t, 1H, J= 8.1 Hz); 7.22 (dd, 1H, J= 8.2, 2.1, 1.0 Hz); 4.31 (t, 2H, J= 6.0 Hz); 3.90 (s, 3H); 3.62 (t, 2H, J= 5.6 Hz); 2.22 (m, 2H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 165.11; 153.41; 146.56; 146.16; 140.16; 135.87; 132.64; 130.16; 126.70; 125.38; 123.86; 123.51; 122.29; 121.27; 114.22; 52.79; 45.26; 38.43; 17.61 ppm. HRMS (ESI): m/z calculated for C ₁₉ H ₁₈ CIN ₄ O ₂ 369.11128, found 369.11105.

[0364] 5-((3-Chlorophenyl)amino)-2,3-dihydroimidazo[1,2-c]quinazoli ne-8-carboxylic acid (Compound 18). Prepared from Compound 17 by GP-D, white solid, yield 78%. MS (ESI): m/z = 341.2 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 8.62 (bs, 1H); 7.98 (bs, 1H); 7.84 (d, 1H, J= 8.2 Hz); 7.76 (bs, 1H); 7.69 (bs, 1H); 7.58 (dd, 1H, J= 8.1, 1.6 Hz); 7.35 (t, 1H, J= 8.1 Hz); 7.09 (m, 1H); 4.11 (bm, 2H); 4.03 (m, 2H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 166.96; 153.56; 147.91; 140.74; 135.10; 132.67; 130.03; 125.25 (2C); 122.71; 122.30; 120.51; 119.54; 118.46; 56.04; 45.83 ppm. HRMS (ESI): m/z calculated for C ₁₇ H ₁₄ CIN ₄ O ₂ 341.07998, found 341.08003.

[0365] 6-((3-Chlorophenyl)amino)-3,4-dihydro-2H-pyrimido[1,2-c]quin azoline-9- carboxylic acid (Compound 20). Prepared from Compound 19 by GP-D1, white solid, yield 78%. MS (ESI): m/z = 355.3 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 8.05 (d, 1H, J= 8.3 Hz); 7.70 (bs, 1H); 7.56 (d, 1H, J= 8.2 Hz); 7.34 (t, 1H, J= 7.9 Hz); 7.08 (m, 1H); 7.70 - 7.06 (b, 2H); 3.97 (t, 2H, J= 6.1 Hz); 3.54 (t, 2H, J= 5.4 Hz); 1.94 (m, 2H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 167.04; 146.44; 135.36; 132.88; 130.18; 124.74; 122.59; 122.13; 121.81; 120.82; 43.00; 42.72; 19.71 ppm. HRMS (ESI): m/z calculated for C ₁₈ H ₁₆ CIN ₄ O ₂ 355.09563, found 355.09554.

Scheme 15- Reagents and conditions: a) i) PPh3, DIAD, dioxane, RT; ii) 3 -chlorophenyl isocyanate, THF, RT; iii) NH3, RT; b) POC13, 105 °C; c) i) D,L-alaninol, TEA, dioxane, RT; ii) SOC12, CHCH, reflux; iii) K2CO3, ACN, 80 °C; d) Mn02, toluene, reflux; e) Zn(CN)2, Zn dust, Pd ₂ (dba) ₃ , dppf, DMF, 120 °C; f) NaOH, H ₂ O, EtOH, 80 °C.

[0366] 7-Bromo-2-((3-chlorophenyl)amino)pyrido[3,2-d]pyrimidin-4(3H )-one (SC15b). Methyl 3-amino-5-bromopicolinate (3g, 13 mmol) and Ph ₃ P (5.1 g, 19 mmol) in dry dioxane (20 ml) were treated with DIAD (4.6 ml, 23 mmol) at RT and the mixture was stirred at RT overnight. Reaction mixture was diluted with EtOAc, washed with water and dried over MgSO ₄ . Crude product was dissolved in dry THF (300 ml) under argon atmosphere and treated with 3- chlorophenyl isocyanate (3.9 ml, 32.5 mmol) dropwise. The resulting mixture was stirred at RT for 2 hrs and NH3 was bubbled through the mixture for 2 min, the mixture was sealed and stirred at RT overnight. Precipitated solids were filtered off, washed with THF and EtOAc and dried. White solid, yield 4.57 g (42%). MS (ESI): m/z = 351.2 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 8.54 (d, 1H, J= 2.1 Hz); 8.18 (t, 1H, J= 2.1 Hz); 8.07 (d, 1H, J= 2.1 Hz); 7.84 (ddd, 1H, J= 8.2, 2.1, 0.9 Hz); 7.35 (t, 1H, J= 8.1 Hz); 7.05 (ddd, 1H, J= 8.0, 2.1, 0.9 Hz) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 165.13; 152.51; 148.32; 145.01; 141.59; 134.48; 134.42; 133.01; 130.15; 123.87; 121.48; 118.55; 117.76 ppm. HRMS (ESI): m/z calculated for C ₁₃ H ₈ BrClN ₄ ONa 372.94622, found 372.94634.

[0367] 8-Bromo-N-(3-chlorophenyl)-2-methyl-2,3-dihydroimidazo [1 ,2-c] pyrido [2,3- e]pyrimidin-5-amine (SC15d). Compound SC15b (1 g, 2.8 mmol) was suspended in POCl ₃ (25 ml) and heated at 105 °C for 1 hr. POCl ₃ was evaporated and the residue in DCM was washed with NaHCOs, water and dried over MgSO ₄ . The chloro- derivative (MS (ESI): m/z = 369.1 [M+H] ⁺ ) was dissolved in dry dioxane (30 ml) and treated with TEA (0.78 ml, 5.6 mmol) and DL-alaninol (0.27 ml, 3.4 mmol) and stirred at RT for Ih, evaporated and the residue in CHCl ₃ was washed with water and dried over MgSO ₄ . The crude product in CHCl ₃ (10 ml) was treated with SOCl ₂ and refluxed for 12 h. Volatiles were evaporated and the residue in CHCl ₃ was washed with NaHCO ₂ and water and dried over MgSO ₄ . The crude chloro- derivative in dry ACN was cyclized by addition of K ₂ CO ₃ (20 mg) and heating at 80 °C for 6 h. Purification by FC (c- hex/EtOAc/acetone/EtOH/H ₂ O) gave SC15d (overall yield 25%). MS (ESI): m/z = 390.2 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 8.68 (bs, 1H); 8.35 (d, 1H, J= 2.1 Hz); 7.86 (bs, 1H); 7.75 (d, 1H, J= 2.1 Hz); 7.71 (bs, 1H, J= 7.4 Hz); 7.34 (t, 1H, J= 8.1 Hz); 7.11 (d, 1H, J= 7.5 Hz); 4.36 (m, 1H); 4.24 (t, 1H, J= 10.2 Hz); 3.70 (t, 1H, J= 8.9 Hz); 1.30 (d, 3H, J= 6.6 Hz) ppm. ¹³ C NMR (DMSO- d ₆ ): δ= 147.42; 144.59; 140.30; 133.50; 132.62; 129.44; 123.06; 122.85; 121.22; 120.16; 60.85; 52.52; 22.33 ppm. HRMS (ESI): m/z calculated for Ci ₆ H ₁₄ ClN ₅ Br 390.01143, found 390.01143.

[0368] 8-Bromo-N-(3-chlorophenyl)-2-methylimidazo[1,2-c]pyrido[2,3- e]pyrimidin-5- amine (SC15e). Compound SC15d (260 mg, 0.7 mmol) in toluene was treated with MnO ₂ (579 mg, 6.7 mmol) and heated under reflux for 12 hrs. FC (c-hex/EtOAc/EtOH) afforded 140 mg (54%) of white solid. MS (ESI): m/z = 388.3 [M+H] ⁺ . ¹ HNMR(DMSO-d ₆ ): δ = 9.70 (s, 1H); 8.67 (d, 1H, J= 2.1 Hz); 8.20 (m, 2H); 8.03 (t, 1H, J= 2.1 Hz); 7.88 (dd, 1H, J= 8.1, 2.1 Hz); 7.43 (t, 1H, J = 8.1 Hz); 7.20 (dd, 1H, J = 7.9, 2.1 Hz); 2.43 (s, 3H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 146.67; 142.48; 142.16; 140.57; 139.91; 138.28; 134.52; 132.93; 132.33; 130.31; 123.52; 120.96; 119.91; 119.68; 109.03; 14.18 ppm. HRMS (ESI): m/z calculated for C ₁₆ H ₁₂ ClN ₅ Br 387.99591, found 387.99603.

[0369] 5-((3-Chlorophenyl)amino)-2-methylimidazo[1,2-c]pyrido[2,3-e ]pyrimidine-8- carbonitrile (SC15f). Compound SC15e (100 mg, 0.26 mmol), Zn(CN) ₂ (19.6 mg, 0.17 mmol), Zn dust (2 mg, 0.03 mmol), Pd ₂ (dba) ₂ (11.8 mg, 0.013 mmol), dppf (14.3 mg, 0.026 mmol) in dry DMF (4 ml) were heated at 120 °C under argon atmosphere for 4 hrs. FC (c-hex/EtOAc/MeOH) afforded white solid (35 mg, 40%). MS (ESI): m/z = 335.3 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 9.85 (s, 1H); 8.94 (d, 1H, J= 1.9 Hz); 8.51 (d, 1H, J= 1.9 Hz); 8.31 (s, 1H); 8.04 (m, 1H); 7.87 (d, 1H, J= 8.2 Hz); 7.45 (t, 1H, J= 8.1 Hz); 7.23 (dd, 1H, J= 8.2, 2.1 Hz); 2.47 (s, 3H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 147.48; 142.77; 141.85; 140.78; 139.73; 136.88; 136.25; 135.59; 132.99; 130.35; 123.77; 121.15; 120.07; 116.92; 110.00; 108.65; 14.12 ppm. HRMS (ESI): m/z calculated for C ₁₇ H ₁₂ C1N ₆ 335.08065, found 335.08077.

[0370] 5-((3-Chlorophenyl)amino)-2-methylimidazo [1 ,2-c] pyrido [2,3-e]pyrimidine-8- carboxylic acid (Compound 79a) and 5-((3-Chlorophenyl)amino)-2-methylimidazo[l,2- c] pyrido [2, 3-e]pyrimidine-8-carboxamide (Compound 99). Compound SC15f (20 mg, 0.06 mmol) in EtOH/H ₂ O mixture (2: 1, 3 ml) was treated with 5M NaOH to pH12 and heated at 80 °C for 2h, mixture was cooled to RT and neutralized with IM HC1 and purified by RP FC (H ₂ O/ACN + 0.1% FA). Compounds Compound 79a(5 mg, 24%) and Compound 99 (8 mg, 38%) were isolated. [0371] Compound 79a: MS (ESI): m/z = 354.3 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 9.78 (s, 1H); 9.08 (d, 1H, J= 1.9 Hz); 8.34 (d, 1H, J= 1.9 Hz); 8.30 (s, 1H); 8.11 (t, 1H, J= 2.1 Hz); 7.96 (m, 1H); 7.46 (t, 1H, J= 8.1 Hz); 7.22 (ddd, 1H, J= 8.0, 2.1, 0.9 Hz); 2.47 (s, 3H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 166.06; 146.45; 142.51; 142.39; 140.42; 140.06; 136.61; 135.98; 133.69; 132.94; 130.41; 126.78; 123.44; 120.79; 119.77; 109.62; 14.20 ppm. HRMS (ESI): m/z calculated for C ₁₇ H ₁₃ CIN ₅ O ₂ 354.07523, found 354.07536.

[0372] Compound 99: MS (ESI): m/z = 353.3 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 10.22 (bs, 1H); 9.10 (d, 1H, J= 2.0 Hz); 8.63 (s, 1H); 8.47 (d, 1H, J= 2.0 Hz); 8.40 (bs, 1H); 8.17 (t, 1H, J= 2.1 Hz); 7.96 (m, 1H); 7.73 (bs, 1H); 7.46 (t, 1H, J= 8.1 Hz); 7.23 (ddd, 1H, J= 8.0, 2.1, 0.9 Hz); 2.48 (s, 3H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 165.93; 145.85; 142.10; 140.32; 140.04; 137.17; 133.73; 132.92; 131.89; 130.53; 130.39; 123.61; 121.12; 120.08; 110.24; 13.37 ppm. HRMS (ESI): m/z calculated for C ₁₇ H ₁₄ CIN ₆ O 353.09121, found 353.09135.

Example 11 Preparation of Quinazoline and Quinoline based Compounds

SC1a R = Bn (SC16a) R = Bn (52) R = Bn (53)

OMe (SC16b) OMe (56) OMe (57) NH ₂ (SC16c) NH ₂ (101a)

Scheme 16- Reagents and conditions: a) BnZnBr, Pd ₂ (dba) ₃ , Xantphos, 1,4-dioxane, Toluene, 65 °C, Ar atm. (R = Bn); b) Na, MeOH, 20 °C, Ar atm. (R = OMe); c) NH3, MeOH, 20 °C (R = NH ₂ ); d) 3- chloroaniline, Pd ₂ (dba) ₃ , Xantphos, Cs2CO3, 1,4-dioxane, Toluene, 110 °C, Ar atm. (R = Bn or OMe); e) 3 -chloroaniline, NMP, 90 °C (R = NH ₂ ); f) LiOH.H ₂ O, H ₂ O, THF, 20 °C

[0373] Methyl 4-benzyl-2-chloroquinazoline-7-carboxylate (SC16a). Prepared from SCla (257 mg, 1.0 mmol) in THF (10 ml), 0.5 M solution of benzylzinc bromide in THF (2 ml, 1 mmol) and THF (15 ml) with Pd ₂ (dba) ₃ (46 mg, 50 pmol) and Xantphos (58 mg, 100 pmol) by GP-G. Orange brown solid (155 mg, yield 50 %). MS (ESI): m/z = 313.1 [M+H] ⁺ . ¹ H NMR (CDCl ₃ ): 6 = 8.63 (dd, J= 1.6, 0.7 Hz, 1H), 8.19 (dd, J= 8.7, 0.8 Hz, 1H), 8.15 (dd, J= 8.7, 1.6 Hz, 1H), 7.33 - 7.27 (m, 4H), 7.25 - 7.20 (m, 1H), 4.63 (s, 2H), 3.99 (s, 3H) ppm. ¹³ C NMR (CDCl ₃ ): δ = 173.54, 165.64, 157.89, 152.05, 136.62, 135.78, 130.62, 129.10, 128.86, 127.67, 127.36, 126.04, 124.36, 53.05, 41.62 ppm. HRMS (ESI): m/z calculated for C ₁₇ H ₁₄ CIN ₂ O ₂ 313.07383, found 313.07388 [M+H] ⁺ .

[0374] Methyl 2-chloro-4-methoxyquinazoline-7-carboxylate (SC16b). Na (16 mg, 0.7 mmol) in anhydrous MeOH (20 ml) was stirred at r.t. for 15 min, then SCla (278 mg, 0.7 mmol) was added and reaction mixture was stirred at r.t. for 1 h under Ar atmosphere. Reaction was quenched with H ₂ O and pH of resulting solution was adjusted to 7 with 1 M aqueous solution of HC1. Solvents were evaporated in vacuo and solid was partitioned between brine and EtOAc. Organic fraction was dried over MgSO ₄ and solvents were evaporated in vacuo. Product was purified by FCC on silica (cH/EtOAc) to give white solid (136 mg, yield 77 %). MS (ESI): m/z = 253.0 [M+H] ⁺ . ³ HNMR (CDCl ₃ ): δ = 8.52 (dd, J= 1.6, 0.7 Hz, 1H), 8.18 (dd, J= 8.5, 0.7 Hz, 1H), 8.14 (dd, J= 8.5, 1.5 Hz, 1H), 4.24 (s, 3H), 3.99 (s, 3H) ppm. ¹³ C NMR (CDCl ₃ ): 5 = 168.48, 165.95, 157.08, 151.88, 135.79, 129.14, 127.15, 124.33, 117.51, 55.70, 52.95 ppm. HRMS (ESI): m/z calculated for C ₁₁ H ₁₀ CIN2O3 253.03745, found 253.03740 [M+H] ⁺ .

[0375] Methyl 4-benzyl-2-((3-chlorophenyl)amino)quinazoline-7-carboxylate (Compound 52). Prepared from SC16a (90 mg, 0.3 mmol) and 3 -chloroaniline (31 pl, 0.3 mmol) in toluene (2.5 ml), 1,4-dioxane (5 ml) with Pd ₂ (dba) ₃ (13 mg, 14 pmol) and Xantphos (17 mg, 29 pmol) and CS2CO3 (132 mg, 0.4 mmol) by GP-E. Yellow solid (21 mg, yield 17 %). MS (ESI): m/z = 404.1 [M+H] ⁺ . ¹ H NMR (CDCl ₃ ): 5 = 8.44 (dd, J= 1.7, 0.6 Hz, 1H), 8.05 (t, J= 2.1 Hz, 1H), 8.02 (dd, J = 8.6, 0.6 Hz, 1H), 7.87 (dd, J = 8.6, 1.7 Hz, 1H), 7.58 (ddd, J = 8.3, 2.2, 1.0 Hz, 1H), 7.35 (s, 1H), 7.33 - 7.29 (m, 4H), 7.29 - 7.21 (m, 2H), 7.03 (ddd, J= 8.0, 2.0, 0.9 Hz, 1H), 4.51 (s, 2H), 3.99 (s, 3H) ppm. ¹³ C NMR (CDCl ₃ ): δ = 171.26, 166.51, 156.30, 151.65, 140.84, 137.19, 134.92, 134.75, 130.01, 129.54, 129.05, 128.94, 127.07, 125.71, 123.67, 122.56, 122.08, 118.79, 116.91, 52.74, 41.18 ppm. HRMS (ESI): m/z calculated for C ₂₃ H ₁₉ CIN ₃ O ₂ 404.11603, found 404.11617 [M+H] ⁺ .

[0376] Methyl 2-((3-chlorophenyl)amino)-4-methoxyquinazoline-7-carboxylate (Compound 56). Prepared from SC16b (101 mg, 0.4 mmol) and 3 -chloroaniline (42 pl, 0.4 mmol) in toluene (4 ml), 1,4-dioxane (7.5 ml) with Pd ₂ (dba) ₃ (18 mg, 20 pmol) and Xantphos (23 mg, 40 pmol) and CS2CO3 (183 mg, 0.6 mmol) by GP-E. Ochre solid (74 mg, yield 54 %). MS (ESI): m/z = 344.1 [M+H] ⁺ . ¹ H NMR (CDCl ₃ ): δ = 8.34 (dd, J= 1.6, 0.7 Hz, 1H), 8.05 (t, J= 2.1 Hz, 1H), 8.03 (dd, J= 8.4, 0.6 Hz, 1H), 7.86 (dd, J= 8.4, 1.6 Hz, 1H), 7.55 (ddd, J= 8.2, 2.2, 0.9 Hz, 1H), 7.26 (t, J = 8.1 Hz, 1H), 7.13 (s, 1H), 7.02 (ddd, J= 8.0, 2.0, 0.9 Hz, 1H), 4.14 (s, 3H), 3.98 (s, 3H) ppm. ¹³ C NMR (CDCl ₃ ): δ = 167.71, 166.75, 156.07, 152.26, 140.95, 135.00, 134.72, 129.96, 127.92, 124.11, 123.22, 122.46, 119.07, 117.05, 115.71, 54.68, 52.67 ppm. HRMS (ESI): m/z calculated for C ₁₇ H ₁₅ CIN ₃ O ₂ 344.07965, found 344.07960 [M+H] ⁺ .

[0377] Methyl 4-amino-2-((3-chlorophenyl)amino)quinazoline-7-carboxylate (Compound 101a). SC16c (305 mg, 1.2 mmol) and 3 -chloroaniline (272 pl, 2.6 mmol) in NMP (3 ml) was stirred at 90 °C for 4 h. Reaction mixture was then diluted with EtOAc and product was filtered off. Filter cake was washed with EtOAc and H ₂ O and dried in vacuo to give yellow solid (413 mg, yield 98 %). MS (ESI): m/z = 329.1 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 10.71 (s, 1H), 9.56 (s, 1H), 9.41 (s, 1H), 8.46 (d, J= 8.5 Hz, 1H), 8.09 (d, J= 1.6 Hz, 1H), 7.91 (dd, J = 8.5, 1.6 Hz, 1H), 7.82 (t, J= 2.1 Hz, 1H), 7.57 (ddd, J= 8.2, 2.2, 1.0 Hz, 1H), 7.45 (t, J= 8.1 Hz, 1H), 7.27 (ddd, J = 7.9, 2.1, 1.0 Hz, 1H), 3.94 (s, 3H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 164.85, 162.65, 152.26, 139.67, 138.51, 135.29, 133.35, 130.66, 125.81, 124.64, 124.06, 121.75, 120.69, 118.58, 112.95, 52.93 ppm. HRMS (ESI): m/z calculated for C ₁₆ H ₁₄ CIN ₄ O ₂ 329.07998, found 329.08002 [M+H] ⁺ . [0378] 4-benzyl-2-((3-chlorophenyl)amino)quinazoline-7-carboxylic acid (Compound 53). Prepared from Compound 52 (15 mg, 33 pmol) and LiOH.H ₂ O (4 mg, 100 pmol) in H ₂ O/THF (1 :3 ml) by GP-F. Orange solid (11 mg, yield 84 %). MS (ESI): m/z = 388.1 [M-H]'. ¹ H NMR (DMSO-d ₆ ): δ = 10.20 (s, 1H), 8.29 (d, J= 8.6 Hz, 1H), 8.21 - 8.15 (m, 2H), 7.90 (dd, J= 8.2, 2.0 Hz, 1H), 7.80 (dd, J= 8.5, 1.7 Hz, 1H), 7.38 (d, J= 7.2 Hz, 2H), 7.36 - 7.26 (m, 3H), 7.21 (t, J = 7.3 Hz, 1H), 7.02 (dd, J= 7.9, 2.1 Hz, 1H), 4.59 (s, 2H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 171.48, 166.75, 156.44, 151.00, 142.02, 137.70, 135.86, 133.00, 130.23, 128.85, 128.72, 127.83, 126.68, 126.64, 123.08, 121.20, 121.18, 118.02, 117.23, 40.02 ppm. HRMS (ESI): m/z calculated for C ₂₂ H ₁₅ CIN ₃ O ₂ 388.08583, found 388.08578 [M-H]'.

[0379] 2-((3-chlorophenyl)amino)-4-methoxyquinazoline-7-carboxylic acid (Compound 57). Prepared from Compound 56 (24 mg, 62 pmol) and LiOH.H ₂ O (8 mg, 185 pmol) in H ₂ O/THF (1 :3 ml) by GP-F. White solid (19 mg, yield 92 %). MS (ESI): m/z = 330.1 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 9.77 (s, 1H), 8.29 (t, J= 2.1 Hz, 1H), 8.08 (s, 1H), 7.91 - 7.81 (m, 3H), 7.31 (t, J = 8.1 Hz, 1H), 6.98 (ddd, J= 8.0, 2.2, 0.9 Hz, 1H), 4.13 (s, 3H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 168.90, 166.91, 155.51, 151.88, 145.63, 142.52, 132.94, 130.03, 125.48, 124.54, 122.05, 120.59, 117.94, 117.07, 112.34, 54.25 ppm. HRMS (ESI): m/z calculated for C ₁₆ H ₁₃ C1N ₃ O ₃ 330.06400, found 330.06394 [M+H] ⁺ .

Scheme 17- Reagents and conditions: a) 3 -chloroaniline, Pd ₂ (dba) ₃ , Xantphos, Cs2CO3, 1,4-dioxane, Toluene, 110 °C, Ar atm.; b) LiOH.H ₂ O, H ₂ O, THF, 20 °C; c) o -benzylhydroxylamine hydrochloride, EDC.HC1, HOBt, Et3N, DMF, 20 °C; d) BBr3, DCM, 0 °C; e) methansulfonamide, EDC.HC1, DMAP, DCM, 20 °C [0380] Methyl 2-((3-chlorophenyl)amino)quinazoline-7-carboxylate (Compound 50). Prepared from SC17a (515 mg, 2.3 mmol) and 3 -chloroaniline (0.3 ml, 2.3 mmol) in toluene (25 ml), 1,4-dioxane (50 ml) with Pd2(dba) ₃ (106 mg, 0.1 mmol) and Xantphos (134 mg, 0.2 mmol) and CS ₂ CO ₃ (1.1 g, 3.2 mmol) by GP-E. Yellow solid (509 mg, yield 70 %). MS (ESI): m/z = 314.1 [M+H] ⁺ . ³ HNMR (CDC1 ₃ ): δ = 9.16 (d, J= 0.9 Hz, 1H), 8.46 (dt, J= 1.5, 0.7 Hz, 1H), 8.07 (t, J= 2.1 Hz, 1H), 7.96 (dd, J = 8.3, 1.5 Hz, 1H), 7.80 (dd, J = 8.4, 0.7 Hz, 1H), 7.60 (ddd, J = 8.2, 2.2, 0.9 Hz, 1H), 7.58 (s, 1H), 7.29 (t, J= 8.1 Hz, 1H), 7.06 (ddd, J= 7.9, 2.0, 0.9 Hz, 1H), 4.01 (s, 3H) ppm. ¹³ C NMR (CDCl ₃ ): δ = 166.50, 162.21, 156.81, 151.02, 140.58, 135.61, 134.81, 130.05, 128.83, 127.82, 123.99, 122.91, 122.87, 119.06, 117.16, 52.83 ppm. HRMS (ESI): m/z calculated for C ₁₆ H ₁₃ CIN ₃ O ₂ 314.06908, found 314.06927 [M+H] ⁺ .

[0381] 2-((3-chlorophenyl)amino)quinazoline-7-carboxylic acid (Compound 55). Prepared from Compound 50 (203 mg, 0.7 mmol) and LiOH.H ₂ O (82 mg, 1.9 mmol) in H ₂ O/THF (20:60 ml) by GP-F. Yellow solid (191 mg, yield 98 %). MS (ESI): m/z = 298.0 [M-H]'. ¹ H NMR (DMSO-d ₆ ): δ = 13.47 (s, 1H), 10.26 (s, 1H), 9.45 (s, 1H), 8.23 - 8.17 (m, 2H), 8.05 (d, J= 8.3 Hz, 1H), 7.93 (dd, J= 8.2, 2.1 Hz, 1H), 7.87 (dd, J= 8.3, 1.6 Hz, 1H), 7.36 (t, J= 8.1 Hz, 1H), 7.04 (dd, J= 7.7, 2.0 Hz, 1H), 1.20 (s, 1H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ= 166.79, 162.70, 157.00, 150.11, 141.86, 136.07, 133.01, 130.24, 128.55, 127.16, 123.22, 122.30, 121.31, 118.03, 117.24 ppm. HRMS (ESI): m/z calculated for C ₁₅ H ₉ CIN ₃ O ₂ 298.03888, found 298.03882 [M-H]'. N- (benzyloxy)-2-((3-chlorophenyl)amino)quinazoline-7-carboxami de (Compound 62). Compound 55 (32 mg, 106 pmol), EDC.HC1 (20 mg, 106 pmol) and HOBt (14 mg, 106 pmol) in DMF (5 ml) were stirred at r.t. for 1 h and then Et ₃ N (30 pl, 213 pmol) and o-benzylhydroxylamine hydrochloride (20 mg, 128 pmol) were added. Reaction mixture was stirred at r.t. for 16 h and then diluted with EtOAc. Product was filtered off, filter cake was washed with EtOAc and H ₂ O and dried in vacuo to give light yellow solid (36 mg, yield 84 %). MS (ESI): m/z = 405.1 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 12.10 (s, 1H), 10.25 (s, 1H), 9.42 (s, 1H), 8.25 (t, J= 2.1 Hz, 1H), 8.03 (d, J= 8.3 Hz, 1H), 8.01 (d, J= 1.6 Hz, 1H), 7.89 (ddd, J= 8.3, 2.1, 0.9 Hz, 1H), 7.72 (dd, J= 8.3, 1.6 Hz, 1H), 7.49 (dd, J = 7.9, 1.7 Hz, 2H), 7.42 (t, J = 7.0 Hz, 2H), 7.40 - 7.33 (m, 2H), 7.05 (ddd, J = 7.9, 2.1, 0.9 Hz, 1H), 4.99 (s, 2H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 163.58, 162.56, 157.00, 150.06, 141.89, 137.67, 135.86, 133.04, 130.19, 129.03, 128.47, 128.36, 124.41, 122.07, 121.63, 121.31, 117.97, 117.22, 77.05 ppm. HRMS (ESI): m/z calculated for C ₂₂ H ₁₈ CIN ₄ O ₂ 405.11128, found 405.11143 [M+H] ⁺ .

[0382] 2-((3-chlorophenyl)amino)-N-hydroxyquinazoline-7-carboxamide (Compound 63). 1 M solution of BBr ₃ in DCM (589 pl, 0.6 mmol) was added dropwise to a suspension of Compound 62 (48 mg, 0.1 mmol) in anhydrous DCM (5 ml) at -15 °C under Ar atmosphere. Reaction mixture was stirred at 0 °C for 2 h and then reaction was quenched with MeOH. The solvents were evaporated in vacuo and solid was dissolved in DCM. Saturated aqueous solution of NaHCO, was added and resulting suspension was filtered. Product from filter cake was washed out by MeOH, solvent from filtrate was evaporated in vacuo and product was purified by RP FCC on Cl 8 (H ₂ O/CAN) to give light yellow solid (18 mg, yield 47 %). MS (ESI): m/z = 315.1 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 10.21 (s, 1H), 9.39 (s, 1H), 8.25 (t, J= 2.1 Hz, 1H), 8.04 (d, J= 1.5 Hz, 1H), 8.00 (d, J= 8.3 Hz, 1H), 7.89 (ddd, J= 8.4, 2.2, 0.9 Hz, 1H), 7.74 (dd, J= 8.3, 1.6 Hz, 1H), 7.36 (t, J = 8.1 Hz, 1H), 7.04 (ddd, J = 8.0, 2.1, 0.9 Hz, 1H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 163.03, 162.44, 156.98, 150.19, 141.96, 138.42, 133.05, 130.19, 128.28, 124.02, 121.99, 121.41, 121.24, 117.99, 117.21 ppm. HRMS (ESI): m/z calculated for C ₁₅ H ₁₂ CIN ₄ O ₂ 315.06433, found 315.06463 [M+H] ⁺ .

[0383 ] 2-((3-chlorophenyl)amino)-N-(methylsulfonyl)quinazoline-7-ca rboxamide

(Compound 64). Compound 55 (29 mg, 98 pmol), EDC.HC1 (28 mg, 147 pmol), DMAP (27 mg, 221 pmol) and methanesulfonamide (14 mg, 147 pmol) in DCM (5 ml) were stirred at r.t. for 5 h. Reaction mixture was evaporated in vacuo and product was purified by RP FCC on C18 (H ₂ O/CAN) and FCC on silica (EtOAc/MeOH) to give yellow solid (31 mg, yield 84 %). MS (ESI): m/z = 375.0 [M-H]'. ¹ H NMR (DMSO-d ₆ ): δ = 12.49 (s, 1H), 10.25 (s, 1H), 9.43 (d, J= 0.7 Hz, 1H), 8.30 - 8.27 (m, 1H), 8.26 (t, J= 2.1 Hz, 1H), 8.02 (d, J= 8.3 Hz, 1H), 7.97 - 7.90 (m, 1H), 7.85 (dd, J= 8.4, 1.6 Hz, 1H), 7.37 (t, J= 8.1 Hz, 1H), 7.05 (ddd, J= 8.0, 2.2, 0.9 Hz, 1H), 3.31 (s, 3H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 167.32, 162.44, 156.91, 150.05, 141.99, 140.24, 133.02, 130.19, 127.88, 126.01, 122.99, 121.79, 121.18, 117.90, 117.13, 40.86 ppm. HRMS (ESI): m/z calculated for C ₁₆ H ₁₂ CIN ₄ O ₃ S 375.03241, found 375.03226 [M-H]'. Scheme 18- Reagents and conditions: a) malonic acid, 145 °C; b) KN(SiMe3)2, THF, -78 °C, Ar atm., H ₂ SO4, MeOH, reflux; c) POC13, N,N-DMA, 125 °C; d) BnZnBr, Pd ₂ (dba) ₃ , Xantphos, Cs2CO3, 1,4- dioxane, Toluene, 65 °C, Ar atm.; e) 3 -chloroaniline, Pd ₂ (dba) ₃ , Xantphos, Cs2CO3, 1,4-dioxane, Toluene, 110 °C, Ar atm.; f) LiOH.H ₂ O, H ₂ O, THF, 20 °C (R = COOH); g) LiAlH4, THF, -15 °C (R = CH ₂ OH)

[0384] Dimethyl 2-acetamidoterephthalate (SC18a). Dimethyl 2-aminoterephthalate (2.6 g, 12.5 mmol) and malonic acid (9.4 g, 90.8 mmol) was heated at 145 °C for 24 h. Reaction mixture was then dissolved in CHCh, resulting suspension was filtrate and filtrate was evaporated in vacuo. Product was purified by FCC on silica (cH/EtOAc) and RP FCC on C 18 (H ₂ O/CAN) to give brown solid (2.8 g, yield 92 %). MS (ESI): m/z = 252.1 [M+H] ⁺ . ¹ H NMR (CDCl ₃ ): δ = 10.98 (s, 1H), 9.30 (d, J = 1.6 Hz, 1H), 8.08 (dd, J = 8.3, 0.5 Hz, 1H), 7.72 (dd, J = 8.3, 1.7 Hz, 1H), 3.95 (s, 3H), 3.93 (s, 3H), 2.25 (s, 3H) ppm. ¹³ C NMR (CDCl ₃ ): δ = 169.20, 168.26, 166.28, 141.62, 135.51, 130.94, 123.28, 121.49, 118.17, 52.81, 52.67, 25.58 ppm. HRMS (ESI): m/z calculated for C ₁₂ H ₁₄ NO ₅ 252.08665, found 252.08651 [M+H] ⁺ .

[0385] Methyl 2,4-dihydroxyquinoline-7-carboxylate (SC18b). 0.5 M solution of KN(SiMe3)2 in toluene (66.6 ml, 33.3 mmol) was added dropwise to a solution of SC18a (2.8 g, 11.1 mmol) in anhydrous THF (200 ml) at -78 °C under Ar atmosphere. Reaction mixture was stirred at -78 °C for 1 h and then was allowed to warm to r.t. and stirred for an additional 20 h. Reaction was quenched with H ₂ O. Aqueous layer was washed with EtOAc, cooled down to 10 °C and pH was adjusted to 3 with 5 M aqueous solution of HC1. Resulting precipitate was collected by filtration, washed with EtOAc and dried in vacuo. Dry solid was suspended in anhydrous MeOH (250 ml), concentrated H ₂ SO4 (2.5 ml, 46.9 mmol) was added and reaction mixture was refluxed for 16 h. Then pH was adjusted to 7 with solid NaHCO ₃ and solvent was evaporated in vacuo. Solid was suspended in H ₂ O and pH was adjusted to 3 with 5 M aqueous solution of HC1. Product was filtered off, filter cake was washed with EtOAc and dried in vacuo to give yellow solid (2.0 g, yield 83 %). MS (ESI): m/z = 220.1 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 11.66 (s, 1H), 11.40 (s, 1H), 7.89 (s, 1H), 7.88 (d, J= 7.0 Hz, 1H), 7.66 (dd, J = 8.3, 1.7 Hz, 1H), 5.86 (s, 1H), 3.88 (s, 3H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 165.77, 163.45, 161.77, 138.96, 131.22, 123.30, 121.02, 118.41, 116.17, 100.20, 52.45 ppm. HRMS (ESI): m/z calculated for C ₁₁ H ₁₀ NO4 220.06043, found 220.06036 [M+H] ⁺ .

[0386] Methyl 2,4-dichloroquinoline-7-carboxylate (SC18c). SC18b (1.0 g, 4.7 mmol), POCl ₃ (21.4 ml, 0.2 mol) andN,N- DMA (473 pl, 3.7 mmol) was stirred at 125 °C for 16 h. Then reaction was quenched by pouring of mixture over ice. Mixture was diluted with EtOAc and organic layer was washed with brine. Organic fraction was dried over MgSO ₄ and solvents were evaporated in vacuo. Product was purified by FCC on silica (cH/EtOAc) and RP FCC on C18 (H ₂ O/CAN) to give white solid (980 mg, yield 82 %). MS (ESI): m/z = 256.0 [M+H] ⁺ . ¹ H NMR (CDCl ₃ ): 6 = 8.72 (dd, J = 1.4, 0.8 Hz, 1H), 8.29 - 8.19 (m, 2H), 7.59 (s, 1H), 4.01 (s, 3H) ppm. ¹³ C NMR (CDCl ₃ ): 6 = 166.11, 151.06, 147.78, 144.47, 133.07, 131.38, 127.73, 127.55, 124.80, 123.82, 52.89 ppm. HRMS (ESI): m/z calculated for C ₁₁ H ₈ C ₁₂ NO ₂ 255.99266, found 255.99258 [M+H] ⁺ . [0387] Methyl 4-benzyl-2-chloroquinoline-7-carboxylate (SC18d). Prepared from SC18c (269 mg, 1.1 mmol) in THF (10 ml), 0.5 M solution of benzylzinc bromide in THF (2.1 ml, 1.1 mmol) and THF (15 ml) with Pd ₂ (dba) ₃ (48 mg, 53 pmol) and Xantphos (61 mg, 105 pmol) by GP-G. Light yellow solid (250 mg, yield 76 %). MS (ESI): m/z = 312.1 [M+H] ⁺ . ¹ H NMR (CDCl ₃ ): δ = 8.82 (dd, J= 1.6, 0.7 Hz, 1H), 8.22 (dd, J= 8.7, 0.7 Hz, 1H), 8.17 (dd, J= 8.7, 1.6 Hz, 1H), 7.39 (s, 1H), 7.36 - 7.30 (m, 4H), 7.30 - 7.23 (m, 1H), 4.32 (s, 2H), 4.01 (s, 3H) ppm. ¹³ C NMR (CDCl ₃ ): 6 = 166.62, 162.43, 148.21, 142.92, 138.30, 132.07, 131.98, 129.37, 128.99, 127.66, 127.04, 126.57, 124.55, 123.26, 52.70, 45.45 ppm. HRMS (ESI): m/z calculated for C ₁₈ H ₁₅ CINO2 312.07858, found 312.07848 [M+H] ⁺ .

[0388] Methyl 4-benzyl-2-((3-chlorophenyl)amino)quinoline-7-carboxylate (Compound 54). Prepared from SC18d (122 mg, 0.4 mmol) and 3 -chloroaniline (41 pl, 0.4 mmol) in toluene (4 ml), 1,4-dioxane (7.5 ml) with Pd ₂ (dba) ₃ (18 mg, 19 pmol) and Xantphos (23 mg, 39 pmol) and Cs ₂ CO ₃ (178 mg, 0.5 mmol) by GP-E. Light yellow solid (101 mg, yield 65 %). MS (ESI): m/z = 403.1 [M+H] ⁺ . ¹ H NMR (CDCl ₃ ): 6 = 8.75 (dd, J= 1.7, 0.5 Hz, 1H), 8.04 (dd, J = 8.7, 1.7 Hz, 1H), 7.88 (dd, J= 8.7, 0.6 Hz, 1H), 7.31 - 7.27 (m, 4H), 7.25 (t, 1H, J= 8.1 Hz), 7.24 - 7.18 (m, 1H), 7.15 (t, J= 2.0 Hz, 1H), 7.09 (ddd, J= 8.0, 2.0, 1.0 Hz, 1H), 7.02 (ddd, J= 8.1, 2.2, 1.0 Hz, 1H), 6.98 (s, 1H), 6.65 (s, 1H), 4.21 (s, 2H), 3.98 (s, 3H) ppm. ¹³ C NMR (CDCl ₃ ): δ = 166.93, 163.15, 148.50, 146.54, 141.33, 139.16, 135.37, 132.40, 131.18, 130.75, 129.20, 128.80, 126.69, 124.74, 124.29, 121.57, 121.49, 120.12, 119.55, 104.93, 52.57, 45.78 ppm. HRMS (ESI): m/z calculated for C24H ₂ 0CIN2O2 403.12078, found 403.12054 [M+H] ⁺ .

[0389] 4-benzyl-2-((3-chlorophenyl)amino)quinoline-7-carboxylic acid (Compound 51). Prepared from Compound 54 (16 mg, 35 pmol) and LiOH.H ₂ O (4 mg, 104 pmol) in H ₂ O/THF (1 :3 ml) by GP-F. Ochre solid (13 mg, yield 98 %). MS (ESI): m/z = 389.1 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): 6 = 9.16 (s, 1H), 8.40 (d, J= 1.7 Hz, 1H), 8.35 (d, J= 8.7 Hz, 1H), 7.96 (dd, J= 8.7, 1.7 Hz, 1H), 7.35 (t, J= 8.0 Hz, 1H), 7.32 - 7.25 (m, 5H), 7.23 (dd, J = 7.8, 2.1 Hz, 1H), 7.19 (ddd, J= 8.6, 5.8, 2.2 Hz, 1H), 7.10 (dd, J= 7.9, 2.0 Hz, 1H), 7.03 (s, 1H), 4.13 (s, 2H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 167.78, 162.32, 148.19, 146.83, 142.57, 139.58, 133.71, 133.62, 130.88, 130.33, 128.96, 128.47, 126.24, 124.08, 122.59, 122.28, 121.04, 120.37, 119.23, 103.81, 44.56 ppm. HRMS (ESI): m/z calculated for C23H18CIN2O2 389.10513, found 389.10501 [M+H] ⁺ . [0390] (4-benzyl-2-((3-chlorophenyl)amino)quinolin-7-yl)methanol (Compound 49).1 M solution of LiA1Hj in THF (126 pl, 126 pmol) was added dropwise to a solution of Compound 54 (25 mg, 63 pmol) in anhydrous THF (5 ml) at -15 °C under Ar atmosphere and reaction mixture was stirred at -15 °C for 2 h. Reaction was quenched by saturated aqueous solution of sodium potassium tartrate and EtOAc. Organic layer was washed with saturated aqueous solution of NH4CI and brine, dried over MgSO ₄ and solvents were evaporated in vacuo. Product was purified by FCC on silica (cH/EtOAc) and RP FCC on C18 (H ₂ O/ACN) to give light yellow solid (13 mg, yield 57 %). MS (ESI): m/z = 375.1 [M+H] ⁺ . ¹ HNMR (DMSO-d ₆ ): δ = 8.99 (s, 1H), 8.21 (d, J= 8.6 Hz, 1H), 7.80 (d, J= 1.6 Hz, 1H), 7.45 (dd, J= 8.7, 1.8 Hz, 1H), 7.34 (t, J= 8.0 Hz, 1H), 7.30 - 7.26 (m, 4H), 7.25 (dd, J= 3.0, 1.4 Hz, 1H), 7.21 (ddd, J= 9.4, 2.8, 1.7 Hz, 1H), 7.19 - 7.15 (m, 1H), 7.07 (ddd, J= 7.9, 2.1, 0.9 Hz, 1H), 6.96 (s, 1H), 5.38 (t, J= 5.8 Hz, 1H), 4.69 (d, J= 5.3 Hz, 2H), 4.10 (s, 2H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 161.36, 148.72, 146.66, 144.20, 142.82, 139.80, 133.58, 130.82, 128.89, 128.41, 126.14, 125.32, 123.35, 122.22, 121.73, 120.05, 118.93, 117.70, 102.75, 62.64, 44.61 ppm. HRMS (ESI): m/z calculated for C23H ₂ 0CIN2O 375.12587, found 375.12576 [M+H] ⁺ .

Scheme 19- Reagents and conditions: a) 3 -chloroaniline, Pd ₂ (dba) ₃ , Xantphos, Cs2CO3, 1,4-dioxane, Toluene, 110 °C, Ar atm.; b) LiOH.H ₂ O, H ₂ O, THF, 20 °C

[0391] Ethyl 2-((3-chlorophenyl)amino)quinoline-7-carboxylate (Compound 47). Prepared from SC19a (114 mg, 0.5 mmol) and 3 -chloroaniline (51 pl, 0.5 mmol) in toluene (2.5 ml), 1,4- di oxane (5 ml) with Pd ₂ (dba) ₃ (22 mg, 24 pmol) and Xantphos (28 mg, 48 pmol) and CS2CO3 (221 mg, 0.7 mmol) by GP-E. Light yellow solid (59 mg, yield 38 %). MS (ESI): m/z = 327.1 [M+H] ⁺ . 1H NMR (CDCl ₃ ): δ = 8.52 (dt, J= 1.6, 0.7 Hz, 1H), 7.96 (dd, J= 8.9, 0.9 Hz, 1H), 7.94 (dd, J= 8.3, 1.7 Hz, 1H), 7.82 (t, J= 2.1 Hz, 1H), 7.69 (d, J= 8.3 Hz, 1H), 7.55 (ddd, J= 8.2, 2.2, 1.0 Hz, 1H), 7.29 (t, J= 8.1 Hz, 1H), 7.06 (ddd, J = 7.9, 2.0, 1.0 Hz, 1H), 6.97 (d, J = 8.8 Hz, 1H), 6.82 (s, 1H), 4.45 (q, J= 7.2 Hz, 2H), 1.45 (t, J= 7.1 Hz, 3H) ppm. ¹³ C NMR (CDCl ₃ ): δ = 166.83, 154.11, 147.01, 141.35, 137.60, 134.89, 131.74, 130.26, 129.39, 127.67, 126.96, 123.44, 123.02, 119.81, 117.94, 114.42, 61.41, 14.51 ppm. HRMS (ESI): m/z calculated for C ₁₈ H ₁₆ CIN ₂ O ₂ 327.08948, found 327.08963 [M+H] ⁺ . [0392] 2-((3-chlorophenyl)amino)quinoline-7-carboxylic acid (Compound 48). Prepared from Compound 47 (12 mg, 38 pmol) and LiOH.H ₂ O (5 mg, 114 pmol) in H ₂ O/THF (1 :3 ml) by GP-F. Yellow solid (11 mg, yield 99 %). MS (ESI): m/z = 299.1 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): 5 = 13.11 (s, 1H), 9.78 (s, 1H), 8.35 (t, J= 2.2 Hz, 1H), 8.26 (s, 1H), 8.17 (d, J= 8.9 Hz, 1H), 7.91 - 7.75 (m, 3H), 7.37 (t, J= 8.1 Hz, 1H), 7.16 (d, J = 8.9 Hz, 1H), 7.02 (dd, J= 7.9, 2.1 Hz, 1H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 167.39, 154.44, 146.10, 142.61, 136.97, 133.07, 131.55, 130.31, 128.05, 127.98, 126.36, 122.66, 120.79, 117.71, 116.88, 116.25 ppm. HRMS (ESI): m/z calculated for C16H12CIN ₂ O ₂ 299.05818, found 299.05806 [M+H] ⁺ .

Scheme 20- Reagents and conditions: a) 3 -chloroaniline, NMP, 90 °C

[0393] 7-chloro-N-(3-chlorophenyl)quinazolin-2-amine (Compound 65). SC20a (45 mg, 0.2 mmol) and 3 -chloroaniline (48 μl, 0.5 mmol) in NMP (1 ml) was stirred at 90 °C for 16 h. Product was purified by RP FCC on C18 (H ₂ O/ACN) and FCC on silica (cH/EtOAc) to give light ochre solid (39 mg, yield 60 %). MS (ESI): m/z = 290.0 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 10.22 (s, 1H), 9.36 (d, J= 0.8 Hz, 1H), 8.14 (t, J= 2.0 Hz, 1H), 7.98 (dd, J= 8.6, 0.5 Hz, 1H), 7.91 (ddd, J = 8.3, 2.1, 0.9 Hz, 1H), 7.74 (dt, J= 1.6, 0.5 Hz, 1H), 7.44 (dd, J= 8.5, 2.0 Hz, 1H), 7.35 (t, J = 8.1 Hz, 1H), 7.04 (ddd, J= 7.9, 2.1, 1.0 Hz, 1H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 162.36, 157.08, 151.19, 141.76, 139.40, 132.99, 130.17, 129.99, 124.43, 124.41, 121.37, 119.05, 118.13, 117.30 ppm. HRMS (ESI): m/z calculated for C ₁₄ H ₁₀ Cl ₂ N3 290.02463, found 290.02448 [M+H] ⁺ .

Example 12: Preparation of Sulfonamide Compounds 200 , 201, 202 and 203.

200

[0394] General procedure: 4-Amino-l-naphtol hydrochloride (1434 mg, 7.3 mmol) in pyridine (36 ml) was treated with substituted benzenesulfonyl/naphtalenesulfonyl chloride (7.3 mmol) dropwise and stirred for 4 hours at RT. Volatiles were evaporated, the residue was dissolved with EtOAc and washed with IM HC1 and water and dried over MgSO ₄ .

[0395] N-(4-Hydroxynaphthalen-l-yl)-2,4-dimethylbenzenesulfonamide (Compound 200). Crystallized from EtOH, off-white solid, yield 70%. MS (ESI): m/z = 328.3 [M+H] ⁺ . ³ H NMR (DMSO-d ₆ ): δ = 10.23 (s, 1H); 9.69 (s, 1H); 8.08 (m, 1H); 7.94 (m, 1H); 7.49 (d, 1H, J= 8.0 Hz); 7.46 - 7.38 (m, 2H); 7.16 (dd, 1H, J= 1.6, 0.8 Hz); 7.04 (m, 1H); 6.79 (dd, 1H, J= 8.1 Hz); 6.67 (d, 1H, J= 8.1 Hz); 2.50 (s, 3H,); 2.28 (s, 3H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 152.42; 142.60; 136.58; 135.74; 132.89; 131.83; 129.16; 126.57; 126.16; 125.56; 124.83;124.76; 123.22; 123.01; 122.05; 107.20; 20.69; 19.99 ppm.

[0396] 4-Fluoro-N-(4-hydroxynaphthalen-l-yl)-2-methylbenzenesulfona mide (Compound 201). FC (cHex/EtOAc/MeOH), freeze dried from dioxane, white foam, yield 55%. MS (ESI): m/z = 332.0 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 10.29 (s, 1H); 9.87 (s, 1H); 8.08 (m, 1H); 7.88 (m, 1H); 7.62 (dd, 1H, J= 8.8, 5.9 Hz); 7.42 (m, 2H); 7.25 (dd, 1H, J= 10.1, 2.7 Hz); 7.07 (td, 1H, J = 8.6, 2.8 Hz); 6.81 (d, 1H, J= 8.1 Hz); 6.70 (d, 1H, J= 8.1 Hz); 2.52 (s, 3H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 163.80 (d, J= 250.8 Hz); 152.69; 140.55 (d, J= 9.4 Hz); 134.87 (d, J= 2.9 Hz); 132.01 (d, J= 9.7 Hz); 131.87; 126.21 (d, J= 12.4 Hz); 124.83; 123.04; 122.60; 122.13; 119.00 (d, J= 22.2 Hz); 113.01 (d, J= 21.9 Hz); 107.26; 20.14 ppm.

[0397] N-(4-Hydroxynaphthalen-l-yl)naphthalene-l-sulfonamide (Compound 202). FC (cHex/EtOAc/MeOH), freeze dried from dioxane, white foam, yield 51%. MS (ESI): m/z = 350.1 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 10.22 (s, 1H); 10.11 (s, 1H); 8.81 (dd, J = 8.5, 1.3 Hz, 1H); 8.16 (d, J= 8.3 Hz, 1H); 8.10 - 8.04 (m, 1H); 8.04 - 7.98 (m, 1H); 7.89 (dd, J= 7.3, 1.2 Hz, 1H); 7.80 - 7.74 (m, 1H); 7.74 - 7.63 (m, 2H); 7.47 (dd, J = 8.2, 7.3 Hz, 1H); 7.32 (ddd, J = 8.3, 6.8, 1.2 Hz, 1H); 7.19 (ddd, J= 8.3, 6.8, 1.3 Hz, 1H); 6.73 (d, J= 8.1 Hz, 1H); 6.61 (d, J= 8.1 Hz, 1H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 152.52; 135.39; 133.93; 133.76; 131.65; 129.25; 128.97; 127.79; 127.77; 126.81; 125.97; 125.76; 124.86; 124.75; 124.70; 124.38; 123.02; 122.75; 122.01; 107.15. [0398] N-(4-Hydroxynaphthalen-l-yl)-2,4,6-trimethylbenzenesulfonami de (Compound 203). FC (cHex/EtOAc/ MeOH), freeze dried from dioxane, white foam, yield 43%. MS (ESI): m/z = 342.0 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ): δ = 10.26 (s, 1H); 9.61 (s, 1H); 8.12 - 8.03 (m, 1H); 7.96 - 7.87 (m, 1H); 7.47 - 7.35 (m, 2H); 6.92 (s, 2H); 6.78 (d, J = 8.1 Hz, 1H); 6.68 (d, J= 8.1 Hz, 1H); 2.31 (s, 6H); 2.21 (s, 3H) ppm. ¹³ C NMR (DMSO-d ₆ ): δ = 152.60; 141.37; 138.49; 134.72; 132.10; 131.47; 126.19; 126.13; 124.81; 124.77; 123.31; 122.73; 122.04; 107.20; 22.69; 20.39 ppm.