Phosphoinositide 3-kinase beta inhibitors and compositions and methods thereof - Patents.com

Abstract

The present invention provides novel phosphoinositide 3-kinase beta selective inhibitors and pharmaceutical compositions thereof, as well as methods for their preparation and use in the treatment of various diseases and conditions, such as solid tumors.

Description

[Technical Field]

[0001] Priority claims and related patent applications This application claims the benefit of priority to U.S. Provisional Application No. 63 / 144,287, filed February 1, 2021, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] The present invention relates generally to pharmaceuticals and methods of treatment. More specifically, the present invention provides novel phosphoinositide 3-kinase beta inhibitors and pharmaceutical compositions thereof, as well as methods for their preparation and use in the treatment of various diseases and conditions, including multiple types of tumors.

[0003] Background of the Invention Phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases that play important regulatory roles in many cellular processes, including cell survival, proliferation, differentiation, motility, and metabolism (Thorpe LM et al., Nat Rev Cancer, 2015, 1, 7-14). Based on their properties and substrate specificity, PI3Ks are divided into three classes: class I, class II, and class III. Class I PI3Ks are further classified into class IA enzymes, which are activated by receptor tyrosine kinases (RTKs), G protein-coupled receptors (GPCRs), and oncoproteins, and class IB enzymes, which are exclusively regulated by GPCRs. Class IA PI3Ks are heterodimers of a p110 catalytic subunit and a p85 regulatory subunit. Three highly homologous p110 catalytic isoforms, p110α, p110β, and p110δ, are encoded by the genes PIK3CA, PIK3CB, and PIK3CD, respectively, and associate with one of five p85 regulatory isoforms: p85α (and its splice variants p55α and p50α, encoded by PIK3R1), p85β (PIK3R2), and p55γ (PIK3R3). Class IB PI3Ks are heterodimers of the p110γ catalytic subunit (encoded by PIK3CG) associated with the regulatory isoforms p101 (PIK3R5) or p87 (p84 or p87PIKAP, encoded by PIK3R6) (Engelman JA et al. Nat Rev Genet, 2006, 7, 606-19). p110α and p110β are ubiquitously expressed, whereas expression of p110δ and p110γ is primarily restricted to leukocytes (OKKenhaug K et al., Nat Rev Immunol, 2003, 3, 317-30).

[0004] In response to ligand stimulation and subsequent activation of RTKs or GPCRs, the p110 catalytic subunit is activated through interaction with its p85 regulatory subunit, using phosphatidylinositol 4,5-bisphosphate (PIP2) as a substrate to generate phosphatidylinositol 3,4,5-triphosphate (PIP3), which then activates AKT-dependent and AKT-independent downstream signaling pathways. The phosphatase and tensin homolog (PTEN) lipid phosphatase removes the 3-phosphate from PtdIns(3,4,5)P3, counteracting PI3K activation (Engelman JA et al. Nat Rev Genet, 2006, 7,606-19).

[0005] Hyperactivation of the PI3K pathway is one of the most common phenomena in human cancers. Aberrant activation of PI3K signaling is primarily caused by somatic loss of PTEN via genetic or epigenetic alterations, RTK activation, or altered PI3K isoforms. These alterations are frequently detected in various tumor types, providing opportunities for pathway-targeted therapy (Parsons R et al., Semin Cell Dev Biol, 2004, 15, 171-6; Janku F et al., Nat Rev Clin Oncol, 2018, 15, 273-291). Significant efforts have been made to develop effective PI3K inhibitors. However, non-isoform-selective pan-PI3K inhibitors have not produced encouraging results due to potential severe toxicity to the immune system, whose function is highly dependent on p110δ and p110β. Recent preclinical studies have shown that different PI3K isoforms play distinct roles in cell signaling and cancer (Jia S et al., Curr Opin Cell Biol, 2009, 2, 199-208), suggesting that inhibitors targeting individual isoforms may achieve greater therapeutic efficacy.

[0006] PTEN deficiency, the most common mechanism causing aberrant PI3K signaling, frequently occurs in multiple human malignancies, including prostate, colon, breast, thyroid, endometrial, renal, melanoma, and leukemia (Michele Milella et al., Front Oncol, 2015, 5, 24). The p110β isoform plays a dominant role in PTEN-deficient tumors through the use of pharmacological agents and genetic models. p110β ablation is sufficient to inhibit tumorigenesis in the prostate, with a concomitant reduction in AKT activation in a mouse prostate tumor model driven by PTEN deficiency (Jia S et al., Nature, 2008, 454, 776-9). Cell culture-based studies have confirmed and extended this finding to other types of human cancer cells (prostate, brain, and breast). Knockdown of p110β inhibits downstream activation of AKT, cell transformation, and growth of these PTEN-deficient cells and tumor xenografts (Wee S et al., Proc Natl Acad Sci USA, 2008, 105, 13057-13062). In mouse models, myeloid tumors caused by PTEN loss depend on p110β through a p110β-Rac positive feedback loop. Disruption of this loop may provide a novel and effective therapeutic strategy for PTEN-deficient leukemia (Yuzugullu H et al., Nat Commun, 2015, 6, 8501).

[0007] It is also noteworthy that amplification or mutation of the PIK3CB gene occurs in multiple types of human cancers, including breast cancer, lung cancer, prostate cancer, esophageal cancer, and glioblastoma. Tumor cells expressing gain-of-function mutations, such as p110β E1051K is sensitive to p110β inhibition (Whale AD et al. Signal Transduct Target Ther, 2017, 2, 17063).

[0008] In addition to tumorigenesis, evidence suggests that p110β plays an important role in various other diseases and physiological processes, including thrombosis, male fertility, and fragile X syndrome. p110β has been proposed as an antithrombotic target based on its ability to inhibit platelet shear activation, stable platelet aggregation, and thrombus formation without causing a significant increase in bleeding (Jackson SP et al., J Thromb Haemost, 2012, 10, 2123-2126). Inactivation of p110β results in specific inhibition of spermatogenesis without affecting the spermatogenic stem cell pool, making it a potential drug target for male contraception (Julie Guillermet-Guibert J et al., PLoS Genet, 2015, 11, el005304). Fragile X syndrome is caused by loss of function of the fragile X mental retardation protein. Preclinical results have demonstrated that p110β plays a critical role in prefrontal cortex (PFC)-dependent cognitive impairment in a mouse model of fragile X syndrome (Gross C et al. Cell Rep. 2015, 11, 681-688). Collectively, these findings suggest that PI3Kβ-specific targeted therapy may be a highly effective treatment for PTEN-deficient tumors and diseases that are highly dependent on PI3Kβ, while simultaneously mitigating the severe toxic effects of pan-PI3K inhibitors. Summary of the Invention [Problem to be solved by the invention]

[0009] PI3Kβ-selective inhibitors are now emerging in clinical practice, but they face immense challenges. For example, research into the PI3Kβ-selective inhibitor SAR260301 (WO2011001114A1) was permanently halted in a phase I clinical trial in lymphoma patients due to lack of sustained pharmacodynamic efficacy. One subject in a phase I clinical trial of AZD6482 (WO2009093972A1) in patients with thrombosis was unable to continue due to itching and a rash at the injection site.

[0010] Therefore, there is an urgent need for novel PI3Kβ inhibitors and treatments for PTEN-deficient cancers and PI3Kβ-dependent diseases that improve clinical efficacy while reducing side effects.

[0011] The present invention provides novel selective PI3Kβ inhibitors that are useful in the treatment of a variety of diseases including cancer, for example, breast cancer, colon cancer, endometrial cancer, kidney cancer, lung cancer, melanoma, prostate cancer, thyroid cancer, and leukemia. [Means for solving the problem]

[0012] In one aspect, the present invention generally relates to a compound of structural formula (I): [ka] a compound having During the ceremony, A represents carbon and B represents oxygen, or A and B each represent nitrogen; W represents -CHR-Q- or -Q-CHR-; where Q represents a bond, O, S, CH or NR', and R and R' are independently hydrogen, C 1~4 Alkyl, or C substituted with -OH or halo 1~4 alkyl; R w represents Ar or a substituted or unsubstituted indoline group, where Ar is a group containing a substituted or unsubstituted 6-membered aromatic or heteroaromatic ring; R 2 is C 1~3 alkyl, CN, CH2OH, CH2F or CONH2; R 1 is H, NH2, OH, CN, CF3, CHO, COC 1~4 Alkyl, CH2C(=O)-NR 1a R 1b , C(=O)-NR 1a R 1b , CH2COOR 1c , N.R. 1d R 1e , C 1~4 Alkyl, OC 1~4 Alkyl, Het, Ar, NR 1h(C=O)R 1i , N.R. 1j (C=O)NR 1k R 1l , N.R. 1j (SO2)R 1m , SO2NR 1n R 1o , [ka] P(O)MeMe, P(O)OMeOMe; where A is carbon, B is oxygen, and R w If Ar, then R 1 are NH2, CN, CHO, COC 1~4 Alkyl, CH2C(=O)-NR 1a R 1b , CH2COOR 1c , N.R. 1d R 1e , O.C. 2~4 Alkyl, Het, NR 1h (C=O)R 1i , N.R. 1j (C=O)NR 1k R 1l , N.R. 1j (SO2)R 1m , SO2NR 1n R 1o , N.R. 1j (C=O)C(CN)C(OH)R 1p , P(O)MeMe, P(O)OMeOMe; when A and B are nitrogen, R w is Ar and R 1 are NH2, CN, CHO, COC 1~4 Alkyl, CH2C(=O)-NR 1a R 1b , CH2COOR 1c , N.R. 1d R 1e , O.C. 2~4 Alkyl, Het, NR 1h (C=O)R 1i , N.R. 1j (C=O)NR 1k R 1l , N.R. 1j (SO2)R 1m , SO2NR 1n R1o , N.R. 1j (C=O)C(CN)C(OH)R 1p , P(O)MeMe, P(O)OMeOMe, C(=O)-NR 1q R 1r where R 1q and R 1r Together, C 1~3 Alkyl and NR 3a R 3b forming a 3-8 membered nitrogen-containing heterocyclyl ring having one or more substituents selected from the group consisting of: where R 1a , R 1b , R 1c , R 1d , R 1e , R 1h , R 1i , R 1j , R 1k , R 1l , R 1m , R 1n , R 1o , R 1p Each of these is independently H, C 1~4 Alkyl, C 3~8 Cycloalkyl, C 3~8 Heterocycloalkyl, or hydroxyl, OMe, CN, fluoro, NR 3a R 3b , C 3~8 Cycloalkyl, C 3~8 C substituted with one or more substituents selected from the group consisting of heterocycloalkyl 1~4 alkyl; R 1a and R 1b , R 1d and R 1e , R 1n and R 1o are arbitrarily combined together, C 1~3 Alkyl and NR 3a R 3b forming a 3-8 membered nitrogen-containing heterocyclyl ring having one or more substituents selected from the group consisting of: C 1~4 Alkyl is unsubstituted or can be OH, F, NR 1d R 1eand is substituted with one or more substituents selected from the group consisting of R 3a and R 3b are each independently H and C 1~4 selected from the group consisting of alkyl; Het is O, S, S(=O) p and N; a substituted heterocyclyl is selected from halo, NR 3a R 3b , C 1~4 having one or two substituents each independently selected from the group consisting of alkyl, OH, OMe, and CN; n represents 0, 1, 2, 3, or 4; and p represents 1 or 2; or a pharmaceutically acceptable form or isotopic derivative thereof.

[0013] In another aspect, the present invention generally relates to pharmaceutical compositions comprising a compound disclosed herein and a pharmaceutically acceptable excipient, carrier, or diluent, effective for treating or ameliorating one or more diseases or disorders in a mammal, including a human.

[0014] In yet another aspect, the present invention generally provides compounds of structural formula (I): [ka] a compound having During the ceremony, A represents carbon and B represents oxygen, or A and B each represent nitrogen; W represents -CHR-Q- or -Q-CHR-; where Q represents a bond, O, S, CH or NR', and R and R' are independently hydrogen, C 1~4 Alkyl, or C substituted with -OH or halo 1~4 alkyl; Rw represents Ar or a substituted or unsubstituted indoline group, where Ar is a group containing a substituted or unsubstituted 6-membered aromatic or heteroaromatic ring; R 2 is C 1~3 alkyl, CN, CH2OH, CH2F or CONH2; R 1 is H, NH2, OH, CN, CF3, CHO, COC 1~4 Alkyl, CH2C(=O)-NR 1a R 1b , C(=O)-NR 1a R 1b , CH2COOR 1c , N.R. 1d R 1e , C 1~4 Alkyl, OC 1~4 Alkyl, Het, Ar, NR 1h (C=O)R 1i , N.R. 1j (C=O)NR 1k R 1l , N.R. 1j (SO2)R 1m , SO2NR 1n R 1o , N.R. 1j (C=O)C(CN)C(OH)R 1p , P(O)MeMe, P(O)OMeOMe; where A is carbon, B is oxygen, and R w If Ar, then R 1 are NH2, CN, CHO, COC 1~4 Alkyl, CH2C(=O)-NR 1a R 1b , CH2COOR 1c , N.R. 1d R 1e , O.C. 2~4 Alkyl, Het, NR 1h (C=O)R 1i , N.R. 1j (C=O)NR 1k R 1l , N.R. 1j (SO2)R 1m , SO2NR 1n R 1o , N.R. 1j(C=O)C(CN)C(OH)R 1p , P(O)MeMe, P(O)OMeOMe; when A and B are nitrogen, R w is Ar and R 1 are NH2, CN, CHO, COC 1~4 Alkyl, CH2C(=O)-NR 1a R 1b , CH2COOR 1c , N.R. 1d R 1e , O.C. 2~4 Alkyl, Het, NR 1h (C=O)R 1i , N.R. 1j (C=O)NR 1k R 1l , N.R. 1j (SO2)R 1m , SO2NR 1n R 1o , N.R. 1j (C=O)C(CN)C(OH)R 1p , P(O)MeMe, P(O)OMeOMe, C(=O)-NR 1q R 1r where R 1q and R 1r Together, C 1~3 Alkyl and NR 3a R 3b forming a 3-8 membered nitrogen-containing heterocyclyl ring having one or more substituents selected from the group consisting of: where R 1a , R 1b , R 1c , R 1d , R 1e , R 1h , R 1i , R 1j , R 1k , R 1l , R 1m , R 1n , R 1o , R 1p Each of these is independently H, C 1~4 Alkyl, C 3~8 Cycloalkyl, C 3~8 Heterocycloalkyl, or hydroxyl, OMe, CN, fluoro, NR 3a R 3b, C 3~8 Cycloalkyl, C 3~8 C substituted with one or more substituents selected from the group consisting of heterocycloalkyl 1~4 alkyl; R 1a and R 1b , R 1d and R 1e , R 1n and R 1o are arbitrarily combined together, C 1~3 Alkyl and NR 3a R 3b forming a 3-8 membered nitrogen-containing heterocyclyl ring having one or more substituents selected from the group consisting of: C 1~4 Alkyl is unsubstituted or can be OH, F, NR 1d R 1e and is substituted with one or more substituents selected from the group consisting of R 3a and R 3b are each independently H and C 1~4 selected from the group consisting of alkyl; Het is O, S, S(=O) p and N; a substituted heterocyclyl is selected from halo, NR 3a R 3b , C 1~4 having one or two substituents each independently selected from the group consisting of alkyl, OH, OMe, and CN; n represents 0, 1, 2, 3, or 4; and p represents 1 or 2; or a pharmaceutically acceptable form or isotopic derivative thereof; and a pharmaceutically acceptable excipient, carrier, or diluent.

[0015] In yet another aspect, the invention generally relates to unit dosage forms comprising the pharmaceutical compositions disclosed herein.

[0016] In yet another aspect, the invention generally relates to a method for treating or ameliorating a disease or disorder, comprising administering to a subject in need thereof a compound of structural formula (I): [ka] a compound having During the ceremony, A represents carbon and B represents oxygen, or A and B each represent nitrogen; W represents -CHR-Q- or -Q-CHR-; where Q represents a bond, O, S, CH or NR', and R and R' are independently hydrogen, C 1~4 Alkyl, or C substituted with -OH or halo 1~4 alkyl; R w represents Ar or a substituted or unsubstituted indoline group, where Ar is a group containing a substituted or unsubstituted 6-membered aromatic or heteroaromatic ring; R 2 is C 1~3 alkyl, CN, CH2OH, CH2F or CONH2; R 1 is H, NH2, OH, CN, CF3, CHO, COC 1~4 Alkyl, CH2C(=O)-NR 1a R 1b , C(=O)-NR 1a R 1b , CH2COOR 1c , N.R. 1d R 1e , C 1~4 Alkyl, OC 1~4 Alkyl, Het, Ar, NR 1h (C=O)R 1i , N.R. 1j (C=O)NR 1k R 1l , N.R. 1j (SO2)R 1m , SO2NR 1n R 1o , N.R. 1j (C=O)C(CN)C(OH)R 1p, P(O)MeMe, P(O)OMeOMe; where A is carbon, B is oxygen, and R w If Ar, then R 1 are NH2, CN, CHO, COC 1~4 Alkyl, CH2C(=O)-NR 1a R 1b , CH2COOR 1c , N.R. 1d R 1e , O.C. 2~4 Alkyl, Het, NR 1h (C=O)R 1i , N.R. 1j (C=O)NR 1k R 1l , N.R. 1j (SO2)R 1m , SO2NR 1n R 1o , N.R. 1j (C=O)C(CN)C(OH)R 1p , P(O)MeMe, P(O)OMeOMe; when A and B are nitrogen, R w is Ar and R 1 are NH2, CN, CHO, COC 1~4 Alkyl, CH2C(=O)-NR 1a R 1b , CH2COOR 1c , N.R. 1d R 1e , O.C. 2~4 Alkyl, Het, NR 1h (C=O)R 1i , N.R. 1j (C=O)NR 1k R 1l , N.R. 1j (SO2)R 1m , SO2NR 1n R 1o , N.R. 1j (C=O)C(CN)C(OH)R 1p , P(O)MeMe, P(O)OMeOMe, C(=O)-NR 1q R 1r where R 1q and R 1r Together, C 1~3 Alkyl and NR 3a R 3bforming a 3-8 membered nitrogen-containing heterocyclyl ring having one or more substituents selected from the group consisting of: where R 1a , R 1b , R 1c , R 1d , R 1e , R 1h , R 1i , R 1j , R 1k , R 1l , R 1m , R 1n , R 1o , R 1p Each of these is independently H, C 1~4 Alkyl, C 3~8 Cycloalkyl, C 3~8 Heterocycloalkyl, or hydroxyl, OMe, CN, fluoro, NR 3a R 3b , C 3~8 Cycloalkyl, C 3~8 C substituted with one or more substituents selected from the group consisting of heterocycloalkyl 1~4 alkyl; R 1a and R 1b , R 1d and R 1e , R 1n and R 1o are arbitrarily combined together, C 1~3 Alkyl and NR 3a R 3b forming a 3-8 membered nitrogen-containing heterocyclyl ring having one or more substituents selected from the group consisting of: C 1~4 Alkyl is unsubstituted or can be OH, F, NR 1d R 1e and is substituted with one or more substituents selected from the group consisting of R 3a and R 3b are each independently H and C 1~4 selected from the group consisting of alkyl; Het is O, S, S(=O) pand N; a substituted heterocyclyl is selected from halo, NR 3a R 3b , C 1~4 having one or two substituents each independently selected from the group consisting of alkyl, OH, OMe, and CN; n represents 0, 1, 2, 3, or 4; and p represents 1 or 2; or a pharmaceutical composition comprising a pharmaceutically acceptable form or isotopic derivative thereof.

[0017] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. General principles of organic chemistry, and specific functional moieties and reactivities are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 2006.

[0018] As used herein, "at least" a particular value is understood to be that value and all values ​​greater than that value.

[0019] The term "comprising," when used to define compositions and methods, is intended to mean that the compositions and methods include the recited elements but do not exclude other elements. The term "consisting essentially of," when used to define compositions and methods, is intended to mean that the compositions and methods include the recited elements and exclude other elements of essential importance to the compositions and methods. For example, "consisting essentially of" refers to the administration of explicitly recited pharmacologically active agents and excludes pharmacologically active agents not explicitly recited. The term "consisting essentially of" does not exclude pharmacologically inactive or inert agents, such as pharmaceutically acceptable excipients, carriers, or diluents. The term "consisting of," when used to define compositions and methods, is intended to mean excluding trace elements and substantial method steps of other components. Embodiments defined by each of these transition terms are within the scope of the present invention.

[0020] Unless otherwise specified or clear from the context, the term "about" as used herein is understood to mean within normal tolerances in the art, for example, within two standard deviations of the mean. "About" can be understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise clear from the context, all numerical values ​​provided herein may be modified by the term "about."

[0021] As used herein, the term "administration" of the disclosed compounds includes delivery of a compound as described herein, or a prodrug or other pharmaceutically acceptable form thereof, to a subject using any suitable formulation or route of administration as discussed herein.

[0022] The terms "disease," "disorder," and "condition" are used interchangeably unless otherwise specified.

[0023] As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of a compound or pharmaceutical composition described herein sufficient to achieve its intended use, including but not limited to, treating a disease, as set forth below.

[0024] In some embodiments, the amount is effective to detectably kill or inhibit the growth or spread of cancer cells, tumor size or number, or other measure of the level, stage, progression, or severity of cancer.

[0025] The therapeutically effective amount may vary depending on the intended use or the subject and disease state to be treated, for example, the desired biological endpoint, the pharmacokinetics of the compound, the disease to be treated, the mode of administration, and the patient's weight and age, and these can be easily determined by those skilled in the art. This term also applies to a dose that will induce a specific response in target cells, such as a reduction in cell migration. The specific dose will vary depending, for example, on the specific compound selected, the type of subject and their age / pre-existing health condition or risk of health condition, the dosing regimen to be followed, the severity of the disease, whether it is used in combination with other drugs, the timing of administration, the tissue to which it is administered, and the physical delivery system by which it is delivered.

[0026] The term "optionally substituted" is understood to mean that a given chemical moiety (e.g., an alkyl group) can (but need not) be attached to other substituents (e.g., heteroatoms). For example, an optionally substituted alkyl group can be a fully saturated alkyl chain (i.e., pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have a substituent other than hydrogen. For example, it can be attached at any point along the chain to a halogen atom, a hydroxyl group, or any other substituent described herein. Thus, the term "optionally substituted" means that a given chemical moiety can include other functional groups, but does not necessarily have to have additional functional groups. Suitable substituents for use in any substitution of the described groups include, but are not limited to, halogen, oxo, CN, -COOH, -CHCN, -O-Ci-C alkyl, Ci-C alkyl, -O-Ci-C alkenyl, -O-Ci-C alkynyl, -Ci-C alkenyl, -Ci-C alkynyl, -OH, -O-P(O)(OH), -OC(O)Ci-C alkyl, -C(O)Ci-C alkyl, -OC(O)O-Ci-C alkyl, NH, NH(Ci-C alkyl), N(Ci-C alkyl), -NHC(O)Ci-C alkyl, -C(O)NHCi-C alkyl, -S(O)-Ci-C alkyl, -S(O)NHCi-C alkyl, and S(O)N(Ci-C alkyl).

[0027] As used herein, "pharmaceutically acceptable forms" of the disclosed compounds include, but are not limited to, pharmaceutically acceptable salts, esters, hydrates, solvates, isomers, prodrugs, and isotopically labeled derivatives of the disclosed compounds. In one embodiment, "pharmaceutically acceptable forms" include, but are not limited to, pharmaceutically acceptable salts, esters, isomers, prodrugs, and isotopically labeled derivatives of the disclosed compounds. In some embodiments, "pharmaceutically acceptable forms" include, but are not limited to, pharmaceutically acceptable salts, esters, stereoisomers, prodrugs, and isotopically labeled derivatives of the disclosed compounds.

[0028] In certain embodiments, the pharmaceutically acceptable form is a pharmaceutically acceptable salt. As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject without undue toxicity, irritation, allergic reaction, etc., and that is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. provide a detailed description of pharmaceutically acceptable salts in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds provided herein include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, besylate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, and the like. Examples of salts that can be used include lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate.In some embodiments, organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, lactic acid, trifluoroacetic 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, and the like.

[0029] The salts can be prepared in situ during the isolation and purification of the disclosed compounds, or separately, such as by reacting the free base or free acid of the parent compound with a suitable base or acid, respectively. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1~4 Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, formed, where appropriate, using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, pharmaceutically acceptable base addition salts can be selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0030] In certain embodiments, the pharmaceutically acceptable form is a pharmaceutically acceptable ester. As used herein, the term "pharmaceutically acceptable ester" refers to a salt that hydrolyzes in vivo and readily decomposes in the human body to yield the parent compound or its salt. Such esters can act as prodrugs, as defined herein. Pharmaceutically acceptable esters include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, aralkyl, and cycloalkyl esters of acidic groups, including, but not limited to, carboxylic acids, phosphoric acids, phosphinic acids, sulfinic acids, sulfonic acids, and boronic acids. Examples of esters include formates, acetates, propionates, butyrates, acrylates, and ethylsuccinates. The esters can be formed using hydroxy or carboxylic acid groups of the parent compound.

[0031] In certain embodiments, the pharmaceutically acceptable form is a "solvate" (e.g., a hydrate). As used herein, the term "solvate" refers to a compound that further comprises a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. The solvate may be a solvate of the disclosed compound or a pharmaceutically acceptable salt thereof. When the solvent is water, the solvate is a "hydrate." Pharmaceutically acceptable solvates and hydrates are complexes that may contain, for example, 1 to about 100, or 1 to about 10, or 1 to about 2, about 3, or about 4 solvent or water molecules. It will be understood that the term "compound" as used herein encompasses the compound and solvates of the compound, as well as mixtures thereof.

[0032] In certain embodiments, the pharmaceutically acceptable form is a prodrug. As used herein, the term "prodrug" (or "drug precursor") refers to a compound that is converted in vivo to produce the disclosed compound or a pharmaceutically acceptable form of the compound. A prodrug may be inactive when administered to a subject, but is converted to an active compound in vivo, for example, by hydrolysis (e.g., hydrolysis in the blood). In some cases, a prodrug has improved physical and / or delivery properties compared to the parent compound. A prodrug can increase the bioavailability of the compound when administered to a subject (e.g., by increasing absorption into the blood after oral administration) or can increase delivery to a desired biological compartment (e.g., the brain or lymphatic system) compared to the parent compound. Exemplary prodrugs include derivatives of the disclosed compounds that have enhanced aqueous solubility or active transport across intestinal membranes compared to the parent compound.

[0033] Prodrug compounds often offer advantages such as solubility, tissue compatibility, or delayed release in mammalian organisms (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)). Discussions of prodrugs are provided in Higuchi, T. et al., "Prodrug as Novel Delivery Systems," ACS Symposium Series, Vol. 14, and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference in their entireties. Examples of advantages of prodrugs include, but are not limited to, their physical properties, such as increased water solubility upon parenteral administration at physiological pH, compared to the parent compound. Alternatively, prodrugs may improve absorption from the gastrointestinal tract or improve the stability of drugs during long-term storage.

[0034] As used herein, the term "pharmaceutically acceptable" excipient, carrier, or diluent refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in carrying or transporting the subject agent from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Examples of substances which can function as pharmaceutically acceptable carriers include sugars such as lactose, glucose, sucrose, and the like; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose, cellulose acetate, and the like; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffers; and other non-toxic, compatible substances used in pharmaceutical formulations. Wetting agents, emulsifiers and lubricants such as sodium lauryl sulfate, magnesium stearate, and polyethylene oxide-polypropylene oxide copolymers, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition.

[0035] As used herein, the term "subject" refers to any animal (e.g., mammal) that is to receive a particular treatment, including, but not limited to, humans, non-human primates, rodents, etc. Typically, the terms "subject" and "patient" are used interchangeably herein in reference to a human subject.

[0036] As used herein, the terms "treatment" or "treating" of a disease or disorder refer to a method of alleviating, delaying, or ameliorating such a condition before or after it occurs. Treatment may be directed at one or more effects or symptoms of the disease and / or underlying pathology. Treatment is intended to obtain a beneficial or desired result, including, but not limited to, a curative effect and / or a prophylactic effect. A therapeutic effect refers to the eradication or amelioration of the underlying disorder being treated. A therapeutic benefit is also achieved by eradicating or ameliorating one or more physiological symptoms associated with the underlying disorder, such that an improvement is observed in the patient, although the patient may still suffer from the underlying disorder. For prophylactic benefit, pharmaceutical compounds and / or compositions can be administered to patients at risk of developing a particular disease or who report one or more physiological symptoms of the disease, even though they may not have been diagnosed with the disease. Treatment may be any alleviation, including, but not limited to, complete elimination of the disease or symptoms of the disease, where the degree of such reduction or prevention is at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95%, or 100% as measured by any standard technique, when compared to an equivalent untreated control.

[0037] As used herein, the term "therapeutic benefit" refers to a therapeutic benefit and / or a prophylactic benefit as described herein. A prophylactic benefit includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0038] After their preparation, the compounds of the invention are preferably isolated and purified to obtain compositions containing 95% or more by weight ("substantially pure"), which are then used or formulated as described herein. In certain embodiments, the compounds of the invention are greater than 99% pure.

[0039] Solvates and polymorphs of the compounds of the invention are also contemplated herein. Solvates of the compounds of the invention include, for example, hydrates.

[0040] As used herein, the terms "isolated" or "substantially isolated" molecules (e.g., polypeptides or polynucleotides) refer to molecules that have been engineered to exist in concentrations greater than those found in nature or that have been removed from their natural environment. For example, a subject antibody is isolated, purified, substantially isolated, or substantially purified if at least 10%, 20%, 40%, 50%, 70%, or 90% of the non-subject antibody material with which it is naturally associated has been removed. For example, a polynucleotide or polypeptide naturally present in a living animal is not "isolated," but the same polynucleotide or polypeptide separated from the coexisting materials in its natural state is "isolated." Furthermore, recombinant DNA molecules contained in a vector are considered isolated for purposes of the present invention. Isolated RNA molecules include the products of in vivo or in vitro RNA replication of DNA and RNA molecules. Isolated nucleic acid molecules also include synthetically produced molecules. In addition, vector molecules contained in recombinant host cells are also isolated. Therefore, not all "isolated" molecules need to be "purified."

[0041] As used herein, the term "purified," when used with respect to a molecule, means that the concentration of the purified molecule is increased relative to the molecules with which it is associated in its natural environment or the environment in which it was produced, discovered, or synthesized. Naturally associated molecules include proteins, nucleic acids, lipids, and sugars, but generally do not include water, buffers, or reagents that are added to maintain the integrity of the purified molecule or to facilitate purification. By this definition, a substance may be 5% or more, 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, 95% or more, 98% or more, 99% or more, or 100% pure relative to its contaminants.

[0042] Definitions of specific functional groups and chemical terms are discussed in more detail below. When a range of values ​​is listed, it is intended to include each value and subrange within the range. For example, "C 1~4 "Alkyl" is C1, C2, C3, C4, C 1~3 , C 1~2 , C 2~4 , C 3~4 and C 2~3 is intended to include alkyl groups of the formula:

[0043] As used herein, the term "alkyl" refers to a straight or branched hydrocarbon chain radical, consisting solely of carbon and hydrogen atoms, containing no unsaturation, and having from 1 to 10 carbon atoms (e.g., C 1~10 As used herein, numerical ranges such as "1 to 10" refer to each integer within the specified range. For example, "1 to 10 carbon atoms" means that the alkyl group can be composed of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to 10 carbon atoms, although this definition also encompasses occurrences of the term "alkyl" where no numerical range is specified. In some embodiments, "alkyl" refers to C 1~6The alkyl group may be an alkyl group. In some embodiments, the alkyl group has 1 to 10, 1 to 8, 1 to 6, or 1 to 3 carbon atoms. Representative saturated straight-chain alkyls include, but are not limited to, -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl. Meanwhile, saturated branched alkyls include, but are not limited to, -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, and the like. The alkyl is attached to the parent molecule by a single bond. Unless stated otherwise in the specification, an alkyl group is optionally substituted by one or more substituents, which substituents are independently selected from acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si(R a )3, -OR a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -OC(O)N(R a )2, -C(O)N(R a )2, -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a )2, -N(R a)C(NR a )N(R a )2, -N(R a )S(O) t N(R a )2 (where t is 1 or 2), -P(=O)(R a )(R a ), or -OP(=O)(OR a )2, where R a are each independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, each of which moieties can be optionally substituted as defined herein. In a non-limiting embodiment, the substituted alkyl can be selected from fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, benzyl, and phenethyl.

[0044] Unless otherwise defined, the terms "aromatic" or "aryl" refer to a cyclic aromatic hydrocarbon group having one to two aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl. When containing two aromatic rings (such as bicyclic), the aromatic rings of the aryl group can be joined at a single point (e.g., biphenyl) or fused (e.g., naphthyl). The aryl group may be optionally substituted at any point of attachment with one or more substituents, e.g., 1 to 5 substituents. Exemplary substituents include, but are not limited to, H, halogen, —O—Ci-C alkyl, —Ci-C alkyl, —Ci-C alkenyl, —O—Ci-C alkynyl, —Ci-C alkenyl, —Ci-C alkynyl, —OH, —O—P(O)(OH), —OC(O)Ci-C alkyl, —C(O)Ci-C alkyl, —OC(O)O—Ci-C alkyl, NH, NH(Ci-C alkyl), N(Ci-C alkyl), —S(O)—Ci-C alkyl, —S(O)NHCi-C alkyl, and S(O)N(Ci-C alkyl). The substituents themselves may be optionally substituted. Furthermore, when containing two fused rings, aryl groups as defined herein may have a fully unsaturated ring and a fused unsaturated or partially saturated ring. Exemplary ring systems of these aryl groups include indanyl, indenyl, tetrahydronaphthalenyl, and tetrahydrobenzoannurenyl.

[0045] The term "halogen" or "halo" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0046] Unless otherwise defined, the term "heteroaryl" or "heteroaromatic" as used herein refers to a monocyclic heteroaryl ring or a bicyclic heteroaryl ring. The monocyclic heteroaryl ring is a 5- or 6-membered ring. The 5-membered ring has two double bonds and contains 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S. The 6-membered ring has three double bonds and contains 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S. The bicyclic heteroaryl ring consists of a 5- or 6-membered heteroaryl ring fused to a phenyl group, a 5- or 6-membered heteroaryl ring fused to a cycloalkyl group, a 5- or 6-membered heteroaryl ring fused to a cycloalkenyl group, or a 5- or 6-membered heteroaryl ring fused to another 5- or 6-membered heteroaryl ring. The nitrogen heteroatom contained within the heteroaryl can be optionally oxidized to an N-oxide or optionally protected with a nitrogen protecting group known to those skilled in the art. The heteroaryl is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heteroaryl. Representative examples of heteroaryl include, but are not limited to, benzothienyl, benzoxadiazolyl, cirmolinyl, 5,6-dihydroisoquinolinyl, 7,8-dihydroisoquinolinyl, 5,6-dihydroquinolinyl, 7,8-dihydroquinolinyl, furopyridinyl, furyl, imidazolyl, indazolyl, indolyl, isoxazolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, pyridinium N-oxide, quinolinyl, 5,6,7,8-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydroquinolinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienopyridinyl, thienyl, triazolyl, and triazinyl.

[0047] The term "heteroaryl" or "heteroaromatic" group of the present invention is substituted with 0, 1, 2, 3, or 4 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkylthioalkyl, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, -NZ1Z2, and (NZ1Z2)carbonyl. As used herein, the term "NZ1Z2" refers to two groups, Z1 and Z2, appended to the parent molecular moiety through a nitrogen atom. Z1 and Z2 are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, and formyl. Representative examples of NZ1Z2 include, but are not limited to, amino, methylamino, acetylamino, and acetylmethylamino.

[0048] As used herein, the term "alkoxy" refers to an --O-alkyl radical.

[0049] As used herein, the terms "cycloalkyl" and "carbocyclyl" refer to monocyclic or polycyclic radicals, respectively, that contain only carbon and hydrogen and may be saturated or partially unsaturated. Unless otherwise stated in the specification, the term is intended to include both substituted and unsubstituted cycloalkyl groups. Partially unsaturated cycloalkyl groups can be referred to as "cycloalkenyl" if the carbocyclic ring contains at least one double bond and "cycloalkynyl" if the carbocyclic ring contains at least one triple bond. Cycloalkyl groups include groups having 3 to 13 ring atoms (i.e., C 3~13As used herein, numerical ranges such as "3 to 10" refer to each integer within the specified range. For example, "3 to 13 carbon atoms" means that the cycloalkyl group can consist of 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, etc., up to a maximum of 13 carbon atoms. The term "cycloalkyl" also includes bridged and spiro-fused ring structures that do not contain heteroatoms. The term also includes monocyclic or fused-ring polycyclic (i.e., rings that share adjacent pairs of ring atoms) groups. Polycyclic aryl groups include bicyclic, tricyclic, tetracyclic, etc. In some embodiments, "cycloalkyl" refers to C 3~8 In some embodiments, "cycloalkyl" can be a C 3~5 Illustrative examples of cycloalkyl groups include, but are not limited to, the following moieties: C 3~6 Carbocyclyl groups include, but are not limited to, cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. 3~7 Examples of carbocyclyl groups include norbornyl (C7). 3~8 Examples of carbocyclyl groups include the aforementioned C 3~7 Examples include carbocyclyl groups, as well as cycloheptyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, and the like. 3~13 Examples of carbocyclyl groups include the aforementioned C 3~8carbocyclyl groups, as well as octahydro-1H-indenyl, decahydronaphthalenyl, spiro[4.5]decanyl, etc. Unless stated otherwise in this specification, the radicals independently include acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si(R a )3, -OR a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -OC(O)N(R a )2, -C(O)N(R a )2, -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a )2, -N(R a )C(NR a )N(R a )2, -N(R a )S(O) t N(R a )2(t is 1 or 2), -P(=O)(R a )(R a ), or -OP(=O)(OR a The cycloalkyl group may be optionally substituted with one or more substituents, including 2, where each R aare independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, each of which moieties is optionally substituted as defined herein. The terms "cycloalkenyl" and "cycloalkynyl" mirror the above description of "cycloalkyl," with the prefix "alkyl" replaced by "alkene" or "alkyne," respectively, and the parent "alkenyl" or "alkynyl" terms as defined herein. For example, a cycloalkenyl group can have 3 to 13 ring atoms, e.g., 5 to 8 ring atoms. In some embodiments, a cycloalkynyl group can have 5 to 13 ring atoms.

[0050] As used herein, the term "heterocycloalkyl" refers to a cycloalkyl radical having one or more skeletal atoms selected from atoms other than carbon, e.g., O, N, S, P, or combinations thereof. Unless otherwise stated in the specification, this term is intended to include both substituted and unsubstituted heterocycloalkyl groups. Specific examples of heterocycloalkyl include 2-hydroxyaziridin-1-yl, 3-oxo-1-oxacyclobutan-2-yl, 2,2-dimethyl-tetrahydrofuran-3-yl, 3-carboxy-morpholin-4-yl, 1-cyclopropyl-4-methyl-piperazin-2-yl, 2-pyrrolinyl, 3-pyrrolinyl, dihydro-2H-pyranyl, 1,2,3,4-tetrahydropyridine, 3,4-dihydro-2H-[1,4]oxazine, and the like.

[0051] As used herein, the terms "heterocycle," "heterocyclic," or "heterocyclo" refer to a fully saturated or partially unsaturated cyclic group, e.g., a 3- to 7-membered monocyclic ring, a 7- to 12-membered bicyclic ring, or a 10- to 15-membered tricyclic ring, which have at least one heteroatom in at least one ring, and in which 0, 1, 2, or 3 atoms in each ring may be optionally substituted. Each ring of a heteroatom-containing heterocyclic group may have 1, 2, 3, or 4 heteroatoms selected from nitrogen, oxygen, and / or sulfur atoms, and the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. The heterocyclic group may be attached to any heteroatom or carbon atom in the ring or ring system. DETAILED DESCRIPTION OF THE INVENTION

[0052] The present invention is based, in part, on the discovery of novel PI3Kβ inhibitors, pharmaceutical compositions thereof, and methods for their preparation and use in the treatment of various diseases and conditions, such as cancer (e.g., breast, colon, endometrial, renal, lung, melanoma, prostate, thyroid cancer, and leukemia).

[0053] In one aspect, the present invention generally relates to a compound of structural formula (I): [ka] a compound having During the ceremony, A represents carbon and B represents oxygen, or A and B each represent nitrogen; W represents -CHR-Q- or -Q-CHR-; where Q represents a bond, O, S, CH or NR', and R and R' are independently hydrogen, C 1~4 Alkyl, or C substituted with -OH or halo 1~4 alkyl; R w represents Ar or a substituted or unsubstituted indoline group, where Ar is a group containing a substituted or unsubstituted 6-membered aromatic or heteroaromatic ring; R 2 is C1~3 alkyl, CN, CH2OH, CH2F or CONH2; R 1 is H, NH2, OH, CN, CF3, CHO, COC 1~4 Alkyl, CH2C(=O)-NR 1a R 1b , C(=O)-NR 1a R 1b , CH2COOR 1c , N.R. 1d R 1e , C 1~4 Alkyl, OC 1~4 Alkyl, Het, Ar, NR 1h (C=O)R 1i , N.R. 1j (C=O)NR 1k R 1l , N.R. 1j (SO2)R 1m , SO2NR 1n R 1o , N.R. 1j (C=O)C(CN)C(OH)R 1p , P(O)MeMe, P(O)OMeOMe; where A is carbon, B is oxygen, and R w If Ar, then R 1 are NH2, CN, CHO, COC 1~4 Alkyl, CH2C(=O)-NR 1a R 1b , CH2COOR 1c , N.R. 1d R 1e , O.C. 2~4 Alkyl, Het, NR 1h (C=O)R 1i , N.R. 1j (C=O)NR 1k R 1l , N.R. 1j (SO2)R 1m , SO2NR 1n R 1o , N.R. 1j (C=O)C(CN)C(OH)R 1p , P(O)MeMe, P(O)OMeOMe; when A and B are nitrogen, R w is Ar and R 1 are NH2, CN, CHO, COC1~4 Alkyl, CH2C(=O)-NR 1a R 1b , CH2COOR 1c , N.R. 1d R 1e , O.C. 2~4 Alkyl, Het, NR 1h (C=O)R 1i , N.R. 1j (C=O)NR 1k R 1l , N.R. 1j (SO2)R 1m , SO2NR 1n R 1o , N.R. 1j (C=O)C(CN)C(OH)R 1p , P(O)MeMe, P(O)OMeOMe, C(=O)-NR 1q R 1r where R 1q and R 1r Together, C 1~3 Alkyl and NR 3a R 3b forming a 3-8 membered nitrogen-containing heterocyclyl ring having one or more substituents selected from the group consisting of: where R 1a , R 1b , R 1c , R 1d , R 1e , R 1h , R 1i , R 1j , R 1k , R 1l , R 1m , R 1n , R 1o , R 1p Each of these is independently H, C 1~4 Alkyl, C 3~8 Cycloalkyl, C 3~8 Heterocycloalkyl, or hydroxyl, OMe, CN, fluoro, NR 3a R 3b , C 3~8 Cycloalkyl, C 3~8 C substituted with one or more substituents selected from the group consisting of heterocycloalkyl 1~4 alkyl; R 1aand R 1b , R 1d and R 1e , R 1n and R 1o are arbitrarily combined together, C 1~3 Alkyl and NR 3a R 3b forming a 3-8 membered nitrogen-containing heterocyclyl ring having one or more substituents selected from the group consisting of: C 1~4 Alkyl is unsubstituted or can be OH, F, NR 1d R 1e and is substituted with one or more substituents selected from the group consisting of R 3a and R 3b are each independently H and C 1~4 selected from the group consisting of alkyl; Het is O, S, S(=O) p and N; a substituted heterocyclyl is selected from halo, NR 3a R 3b , C 1~4 having one or two substituents each independently selected from the group consisting of alkyl, OH, OMe, and CN; n represents 0, 1, 2, 3, or 4; and p represents 1 or 2; or a pharmaceutically acceptable form or isotopic derivative thereof.

[0054] In certain embodiments, A is carbon and B is oxygen, as defined by structural formula (Ia): [ka] It has.

[0055] In certain embodiments of Formula (Ia), R w In certain embodiments, W is —CHR 4 -NR 5 - and R4 and R 5 are independently selected from H, methyl, or ethyl.

[0056] In certain embodiments of Formula (Ia), R w is a substituted or unsubstituted indoline group. In certain embodiments, W is —CHR 4 where R 4 is selected from H, methyl or ethyl.

[0057] In certain embodiments, each of A and B is nitrogen, as defined by Structural Formula (Ib): [ka] It has.

[0058] In certain embodiments of Formula (Ib), R w In certain embodiments, W is —CHR 4 -NR 5 - and R 4 and R 5 are independently selected from H, methyl, or ethyl.

[0059] In certain embodiments of Formula (Ib), R w is a substituted or unsubstituted indoline group. In certain embodiments, W is —CHR 4 and R 4 is selected from H, methyl or ethyl.

[0060] In certain embodiments of Formula (I), (Ia) or (Ib), R 4 and R 5 Each of is H.

[0061] In certain embodiments of Formula (I), (Ia) or (Ib), R 4 and R 5 At least one of is methyl or ethyl.

[0062] In certain embodiments of Formula (I), (Ia) or (Ib), said Ar or said indoline group may be selected from the group consisting of halogen, C 1~4 Alkyl, OC 1~4 Substituted with one or more substituents selected from the group consisting of alkyl, CN, CHF2, CF3 and CH2OH.

[0063] In certain embodiments of Formula (I), (Ia), or (Ib), said Ar or said indoline group is substituted with at least one F atom. In certain embodiments (I), (Ia), or (Ib), said Ar or said indoline group is substituted with two F atoms.

[0064] In certain embodiments of Formula (I), (Ia) or (Ib), WR w is the following: [ka] is selected from In the formula, R is independently hydrogen, C 1~4 Alkyl, or C substituted with -OH or halo 1~4 alkyl.

[0065] In certain embodiments of Formula (I), (Ia) or (Ib), n is 0.

[0066] In certain embodiments of Formula (I), (Ia) or (Ib), n is 1.

[0067] In certain embodiments of Formula (I), (Ia) or (Ib), R 2 is C 1~3 In certain embodiments (I), (Ia) or (Ib), R 2 is CH2OH, CN or CONH2.

[0068] In certain embodiments of Formula (I), (Ia) or (Ib), R 1 is C(=O)-NR 1a R 1b where R 1a and R1b each independently represents H and C 1~4 alkyl.

[0069] In certain embodiments of Formula (I), (Ia) or (Ib), R 1 is C(=O)-NR 1q R 1r where R 1q and R 1r Together, C 1~3 Alkyl and NR 3a R 3b and forming a 3-8 membered nitrogen-containing heterocyclyl ring optionally substituted with one or more of:

[0070] In certain embodiments, R 1q and R 1r Together, C 1~3 It forms a 5-membered nitrogen-containing heterocyclyl ring substituted with alkyl.

[0071] In certain embodiments, R 1q and R 1r Together, NR 3a R 3b forming a 5-membered nitrogen-containing heterocyclyl ring substituted with

[0072] In certain embodiments, R 3a and R 3b Each of is methyl.

[0073] In certain embodiments of Formula (I), (Ia) or (Ib), R 1 is optionally substituted with hydroxy, C 1~4 Alkyl, -OC 1~4 Alkyl and NR 1c R 1d is.

[0074] In certain embodiments of Formula (I), (Ia) or (Ib), R 1 is selected from the following: [ka]

[0075] Examples of compounds according to the present invention include, but are not limited to, the following compounds or pharmaceutically acceptable forms or isotopic derivatives thereof: [Table 1] TIFF2024508045000011.tif218167 TIFF2024508045000012.tif217167 TIFF2024508045000013.tif218167 TIFF2024508045000014.tif218167 TIFF2024508045000015.tif219169 TIFF2024508045000016.tif218167 TIFF2024508045000017.tif218167 TIFF2024508045000018.tif218167 TIFF2024508045000019.tif218167 TIFF2024508045000020.tif218167 TIFF2024508045000021.tif218167 TIFF2024508045000022.tif218167 TIFF2024508045000023.tif218167 TIFF2024508045000024.tif162165

[0076] In certain embodiments, the compounds of the present invention have one or more (e.g., one, two, three) deuterium atoms replacing one or more (e.g., one, two, three) hydrogen atoms. In certain embodiments, the compounds of the present invention have one deuterium atom replacing one hydrogen atom.

[0077] In another aspect, the present invention generally relates to pharmaceutical compositions comprising a compound disclosed herein and a pharmaceutically acceptable excipient, carrier, or diluent, effective for treating or ameliorating one or more diseases or disorders in a mammal, including a human.

[0078] In yet another aspect, the present invention generally provides compounds of structural formula (I): [ka] a compound having During the ceremony, A represents carbon and B represents oxygen, or A and B each represent nitrogen; W represents -CHR-Q- or -Q-CHR-; where Q represents a bond, O, S, CH or NR', and R and R' are independently hydrogen, C 1~4 Alkyl, or C substituted with -OH or halo 1~4 alkyl; R w represents Ar or a substituted or unsubstituted indoline group, where Ar is a group containing a substituted or unsubstituted 6-membered aromatic or heteroaromatic ring; R 2 is C 1~3 alkyl, CN, CH2OH, CH2F or CONH2; R 1 is H, NH2, OH, CN, CF3, CHO, COC 1~4 Alkyl, CH2C(=O)-NR 1a R 1b , C(=O)-NR 1a R 1b , CH2COOR 1c , N.R. 1d R 1e , C 1~4 Alkyl, OC 1~4 Alkyl, Het, Ar, NR 1h (C=O)R 1i , N.R. 1j (C=O)NR 1k R 1l , N.R.1j (SO2)R 1m , SO2NR 1n R 1o , N.R. 1j (C=O)C(CN)C(OH)R 1p , P(O)MeMe, P(O)OMeOMe; where A is carbon, B is oxygen, and R w If Ar, then R 1 are NH2, CN, CHO, COC 1~4 Alkyl, CH2C(=O)-NR 1a R 1b , CH2COOR 1c , N.R. 1d R 1e , O.C. 2~4 Alkyl, Het, NR 1h (C=O)R 1i , N.R. 1j (C=O)NR 1k R 1l , N.R. 1j (SO2)R 1m , SO2NR 1n R 1o , N.R. 1j (C=O)C(CN)C(OH)R 1p , P(O)MeMe, P(O)OMeOMe; when A and B are nitrogen, R w is Ar and R 1 are NH2, CN, CHO, COC 1~4 Alkyl, CH2C(=O)-NR 1a R 1b , CH2COOR 1c , N.R. 1d R 1e , O.C. 2~4 Alkyl, Het, NR 1h (C=O)R 1i , N.R. 1j (C=O)NR 1k R 1l , N.R. 1j (SO2)R 1m , SO2NR 1n R 1o , N.R. 1j (C=O)C(CN)C(OH)R 1p , P(O)MeMe, P(O)OMeOMe, C(=O)-NR 1q R1r where R 1q and R 1r Together, C 1~3 Alkyl and NR 3a R 3b forming a 3-8 membered nitrogen-containing heterocyclyl ring having one or more substituents selected from the group consisting of: where R 1a , R 1b , R 1c , R 1d , R 1e , R 1h , R 1i , R 1j , R 1k , R 1l , R 1m , R 1n , R 1o , R 1p Each of these is independently H, C 1~4 Alkyl, C 3~8 Cycloalkyl, C 3~8 Heterocycloalkyl, or hydroxyl, OMe, CN, fluoro, NR 3a R 3b , C 3~8 Cycloalkyl, C 3~8 C substituted with one or more substituents selected from the group consisting of heterocycloalkyl 1~4 alkyl; R 1a and R 1b , R 1d and R 1e , R 1n and R 1o are arbitrarily combined together, C 1~3 Alkyl and NR 3a R 3b forming a 3-8 membered nitrogen-containing heterocyclyl ring having one or more substituents selected from the group consisting of: C 1~4 Alkyl is unsubstituted or can be OH, F, NR 1d R 1e and is substituted with one or more substituents selected from the group consisting of R 3a and R 3b are each independently H and C 1~4selected from the group consisting of alkyl; Het is O, S, S(=O) p and N; a substituted heterocyclyl is selected from halo, NR 3a R 3b , C 1~4 having one or two substituents each independently selected from the group consisting of alkyl, OH, OMe, and CN; n represents 0, 1, 2, 3, or 4; and p represents 1 or 2; or a pharmaceutically acceptable form or isotopic derivative thereof; and a pharmaceutically acceptable excipient, carrier, or diluent.

[0079] In certain embodiments, the pharmaceutical composition is suitable for oral administration.

[0080] In certain embodiments, the pharmaceutical composition is useful for treating or alleviating cancer.

[0081] In certain embodiments, the pharmaceutical composition is useful for treating or alleviating breast cancer, colon cancer, endometrial cancer, kidney cancer, lung cancer, melanoma, prostate cancer, thyroid cancer, or leukemia.

[0082] In yet another aspect, the invention generally relates to unit dosage forms comprising the pharmaceutical compositions disclosed herein.

[0083] In certain embodiments, the unit dosage form is suitable for oral administration.

[0084] In certain embodiments, the unit dosage form is a tablet or capsule.

[0085] In certain embodiments, the unit dosage form is suitable for intravenous administration.

[0086] In certain embodiments, the unit dosage form is in the form of a liquid formulation.

[0087] In yet another aspect, the invention generally relates to a method for treating or ameliorating a disease or disorder, comprising administering to a subject in need thereof a compound of structural formula (I): [ka] a compound having During the ceremony, A represents carbon and B represents oxygen, or A and B each represent nitrogen; W represents -CHR-Q- or -Q-CHR-; where Q represents a bond, O, S, CH or NR', and R and R' are independently hydrogen, C 1~4 Alkyl, or C substituted with -OH or halo 1~4 alkyl; R w represents Ar or a substituted or unsubstituted indoline group, where Ar is a group containing a substituted or unsubstituted 6-membered aromatic or heteroaromatic ring; R 2 is C 1~3 alkyl, CN, CH2OH, CH2F or CONH2; R 1 is H, NH2, OH, CN, CF3, CHO, COC 1~4 Alkyl, CH2C(=O)-NR 1a R 1b , C(=O)-NR 1a R 1b , CH2COOR 1c , N.R. 1d R 1e , C 1~4 Alkyl, OC 1~4 Alkyl, Het, Ar, NR 1h (C=O)R 1i , N.R. 1j (C=O)NR 1k R 1l , N.R. 1j (SO2)R 1m , SO2NR 1n R1o , N.R. 1j (C=O)C(CN)C(OH)R 1p , P(O)MeMe, P(O)OMeOMe; where A is carbon, B is oxygen, and R w If Ar, then R 1 are NH2, CN, CHO, COC 1~4 Alkyl, CH2C(=O)-NR 1a R 1b , CH2COOR 1c , N.R. 1d R 1e , O.C. 2~4 Alkyl, Het, NR 1h (C=O)R 1i , N.R. 1j (C=O)NR 1k R 1l , N.R. 1j (SO2)R 1m , SO2NR 1n R 1o , N.R. 1j (C=O)C(CN)C(OH)R 1p , P(O)MeMe, P(O)OMeOMe; when A and B are nitrogen, R w is Ar and R 1 are NH2, CN, CHO, COC 1~4 Alkyl, CH2C(=O)-NR 1a R 1b , CH2COOR 1c , N.R. 1d R 1e , O.C. 2~4 Alkyl, Het, NR 1h (C=O)R 1i , N.R. 1j (C=O)NR 1k R 1l , N.R. 1j (SO2)R 1m , SO2NR 1n R 1o , N.R. 1j (C=O)C(CN)C(OH)R 1p , P(O)MeMe, P(O)OMeOMe, C(=O)-NR 1q R 1r where R 1q and R 1rTogether, C 1~3 Alkyl and NR 3a R 3b forming a 3-8 membered nitrogen-containing heterocyclyl ring having one or more substituents selected from the group consisting of: where R 1a , R 1b , R 1c , R 1d , R 1e , R 1h , R 1i , R 1j , R 1k , R 1l , R 1m , R 1n , R 1o , R 1p Each of these is independently H, C 1~4 Alkyl, C 3~8 Cycloalkyl, C 3~8 Heterocycloalkyl, or hydroxyl, OMe, CN, fluoro, NR 3a R 3b , C 3~8 Cycloalkyl, C 3~8 C substituted with one or more substituents selected from the group consisting of heterocycloalkyl 1~4 alkyl; R 1a and R 1b , R 1d and R 1e , R 1n and R 1o are arbitrarily combined together, C 1~3 Alkyl and NR 3a R 3b forming a 3-8 membered nitrogen-containing heterocyclyl ring having one or more substituents selected from the group consisting of: C 1~4 Alkyl is unsubstituted or can be OH, F, NR 1d R 1e and is substituted with one or more substituents selected from the group consisting of R 3a and R 3b are each independently H and C 1~4 selected from the group consisting of alkyl; Het is O, S, S(=O) pand N; a substituted heterocyclyl is selected from halo, NR 3a R 3b , C 1~4 having one or two substituents each independently selected from the group consisting of alkyl, OH, OMe, and CN; n represents 0, 1, 2, 3, or 4; and p represents 1 or 2; or a pharmaceutical composition comprising a pharmaceutically acceptable form or isotopic derivative thereof.

[0088] In certain embodiments, the cancer that can be treated is selected from breast cancer, colon cancer, endometrial cancer, kidney cancer, lung cancer, melanoma, prostate cancer, thyroid cancer, and leukemia. Other PTEN-deficient neoplasms can also be treated with the compounds and pharmaceutical compositions of the present invention, such as brain (glioma), glioblastoma, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, colorectal cancer, Wilms' tumor, Ewing's sarcoma, rhabdomyosarcoma, ependymoma, medulloblastoma, head and neck cancer, liver cancer, squamous cell carcinoma, myeloid leukemia, and leukemia. It can treat cancer, ovarian cancer, pancreatic cancer, sarcoma cancer, osteosarcoma, giant cell tumor of bone, lymphoblastic T-cell, malignant lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, lymphoblastic T-cell lymphoma, Burkitt's lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial carcinoma, vulvar cancer, cervical cancer, kidney cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular carcinoma, gastric cancer, nasopharyngeal cancer, buccal cancer, oral cancer, gastrointestinal stromal tumor, testicular cancer, etc.

[0089] In yet another aspect, the invention generally relates to the use of a compound disclosed herein and a pharmaceutically acceptable excipient, carrier, or diluent in the preparation of a medicament for treating a disease or disorder.

[0090] In certain embodiments, the disease or disorder is cancer or a related disease or disorder.

[0091] In certain embodiments, said treatable cancer is selected from breast cancer, colon cancer, endometrial cancer, kidney cancer, lung cancer, melanoma, prostate cancer, thyroid cancer and leukemia.

[0092] In certain embodiments, the medicament is for oral administration.

[0093] In certain embodiments, the medicament is for intravenous administration.

[0094] Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention is intended to encompass within its scope all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, and mixtures thereof, are intended to be included in the present invention.

[0095] Isomeric mixtures containing any of a variety of isomeric ratios can be utilized in accordance with the present invention. For example, when only two isomers are combined, mixtures containing isomeric ratios of 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0 are contemplated by the present invention. Those skilled in the art will readily appreciate that similar ratios are contemplated for more complex isomeric mixtures.

[0096] For example, if a particular enantiomer of a compound of the present invention is desired, that enantiomer can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary is cleaved to provide the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group such as amino, or an acidic functional group such as carboxyl, diastereomeric salts can be formed with an appropriate optically active acid or base, and the formed diastereomers then resolved by fractional crystallization or chromatographic methods well known in the art, resulting in recovery of the pure enantiomers.

[0097] Isotopically labeled compound is also within the scope of the present disclosure.As used herein, " isotope-labeled compound " refers to the compound disclosed herein, including its pharmaceutical salts and prodrugs, each as described herein, wherein one or more atoms are replaced with the atom that has different atomic mass or mass number from the atomic mass or mass number that is usually found in nature.The examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example, 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36 Examples include Cl.

[0098] By isotopically labeling the compounds of the present disclosure, the compounds may be useful in drug and / or substrate tissue distribution assays. 3 H) labeled compounds and carbon-14( 14 C) labeled compounds are particularly preferred due to their ease of preparation and detectability. 2Substitution with heavier isotopes, such as H, may confer certain therapeutic advantages. This may be preferable in some circumstances due to greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements. The isotopically labeled compounds disclosed herein, including pharmaceutical salts, esters, and prodrugs thereof, may be prepared by any means known in the art.

[0099] Furthermore, the normally abundant hydrogen ( 1 Substitution of hydrogen (H) with heavier isotopes, such as deuterium, can confer certain therapeutic advantages, resulting, for example, from improved absorption, distribution, metabolism, and / or excretion (ADME) properties, creating drugs with improved efficacy, safety, and / or tolerability. 12 C 13 C may also be advantageously substituted (see WO2007 / 005643, WO2007 / 005644, WO2007 / 016361, and WO2007 / 016431).

[0100] Stereoisomers (e.g., cis and trans isomers) and all optical isomers (e.g., R and S enantiomers) of the compounds of the present disclosure, as well as racemates, diastereomers and other mixtures of such isomers, are within the scope of the present disclosure.

[0101] Following their preparation, the compounds of the invention are preferably isolated and purified to provide compositions containing 95% or more by weight ("substantially pure"), which are then used or formulated as described herein. In certain embodiments, the compounds of the invention are greater than 99% pure.

[0102] Solvates and polymorphs of the compounds of the invention are also contemplated herein. Solvates of the compounds of the invention include, for example, hydrates.

[0103] Any suitable route of administration can be used, e.g., parenteral, intravenous, subcutaneous, intramuscular, intracardiac, intravenous, intraperitoneal, rectal, or oral administration. The most appropriate means of administration for a particular patient will depend on the nature and severity of the disease or condition being treated, or the nature of the therapy being used, and the nature of the active compound.

[0104] Compositions for parenteral injection include pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions immediately before use.Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol), carboxymethylcellulose and their suitable mixtures, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate.Proper fluidity can be maintained, for example, by using coating materials such as lecithin, maintaining the required particle size in the case of dispersions, and using surfactants.

[0105] These compositions may also contain auxiliary agents such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol sorbic acid, etc. It may also be desirable to include isotonic agents such as sugars, sodium chloride, etc. Prolonged absorption of injectable pharmaceutical forms can be brought about by the inclusion of agents that delay absorption, such as aluminum monostearate and gelatin.

[0106] The compounds of the present invention can also be administered in the form of liposomes. As known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals dispersed in an aqueous medium. Any non-toxic, physiologically acceptable, and metabolizable lipid capable of forming liposomes can be used. The compositions of the present invention in liposome form can contain stabilizers, preservatives, excipients, etc., in addition to the compounds of the present invention. Preferred lipids are natural and synthetic phospholipids and phosphatidylcholines (lecithins). Methods for forming liposomes are known in the art. See, for example, Prescott, ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, NY (1976), p. 33 et seq.

[0107] The total daily dose of the compositions of the invention administered to a human or other mammalian host in single or divided doses may be, for example, from 0.0001 to 300 mg / kg body weight, more usually from 1 to 300 mg / kg body weight per day, which can be administered twice daily.

[0108] The solid dosage form for oral administration includes capsule, tablet, pill, powder and granule.In such solid dosage form, the compound described herein or its derivatives are mixed with at least one conventional excipient (or carrier) that does not show pharmacological action, such as sodium citrate or dicalcium phosphate, or (i) filler or extender, such as starch, lactose, sucrose, glucose, mannitol and silicic acid, (ii) binder, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia, (iii) moisturizer, such as glycerol, (iv) disintegrant, such as agar, calcium carbonate, The solids may be mixed with: potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (v) solution retarders, such as paraffin; (vi) absorption enhancers, such as quaternary ammonium compounds; (vii) wetting agents, such as cetyl alcohol and glycerol monostearate; (viii) adsorbents, such as kaolin and bentonite; and (ix) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. For capsules, tablets, and pills, the dosage form may also contain buffering agents. Solid compositions of a similar type may also be used as fillers for soft and hard-filled gelatin capsules, using excipients such as lactose, milk sugar, and high molecular weight polyethylene glycols. Solid dosage forms, such as tablets, dragees, capsules, pills, and granules, can be prepared with coatings and shells, such as enteric coatings and other coatings known in the art.

[0109] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, fatty acid esters of sorbitan, or mixtures of these substances. In addition to such inert diluents, the compositions may also contain additional agents such as wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, or fragrances.

[0110] The materials, compositions, and components disclosed herein can be used in, can be used in conjunction with, can be used in preparation for, or are products of, the disclosed methods and compositions. When combinations, subsets, interactions, groups, etc. of these materials are disclosed, it is understood that although specific reference to the various individual and collective combinations and permutations of these compounds may not be explicitly disclosed, each is specifically contemplated and described herein. For example, when a method is disclosed and discussed, and multiple modifications that can be made to multiple molecules included in the method are discussed, unless specifically stated to the contrary, all combinations and permutations of the method and possible modifications are specifically contemplated. Likewise, any subset or combination of these is specifically contemplated and disclosed. This concept applies to all aspects of the present disclosure, including, but not limited to, steps in methods using the disclosed compositions. Thus, when there are various additional steps that can be performed, it is understood that each of these additional steps can be performed with any particular method step or combination of method steps of the disclosed method, and that each such combination or subset of combinations should be considered specifically contemplated and disclosed. [Example]

[0111] The following examples are presented for the purpose of illustrating the present invention, but are not intended to limit the scope or spirit of the present invention.

[0112] The compounds of the present invention (including those specifically disclosed hereinabove and below) can be prepared as described in the following schemes. For example, the compounds of formula (I) can be prepared as described in the following schemes, and it is known to those skilled in the art to prepare fragments and combinations thereof. Although the present invention has been described in detail with preferred embodiments, those skilled in the art will understand that modifications, variations, and equivalent substitutions made to the present invention within the scope of the present invention belong to the protection of the present invention. [Table 2] [ka]

[0113] General procedure for preparing compounds of Scheme 1 Preparation of 1-(5-bromo-2-hydroxy-3-iodophenyl)ethanone (Step 1 in Scheme 1) [ka] To a solution of 1-(5-bromo-2-hydroxyphenyl)ethanone (40 g, 186.01 mmol, 1 equiv.) in AcOH (400 mL) was added NIS (50.22 g, 223.21 mmol, 1.2 equiv.) at 25° C., and the reaction mixture was stirred at 120° C. for 12 hours. HPLC and LCMS showed that 1-(5-bromo-2-hydroxyphenyl)ethanone was completely consumed. The mixture was cooled to room temperature and poured into ice water (400 mL). A brown precipitate formed. The collected solid was triturated with EtOH (100 mL) at 25° C. for 30 minutes. The compound 1-(5-bromo-2-hydroxy-3-iodo-phenyl)ethanone (45 g, 131.99 mmol, 70.96% yield) was obtained as a yellow solid. 1 H NMR (CDCl3,400MHz) δ 13.08(s,1H), 8.07(d,J=2.4Hz,1H), 7.86(d,J=2.4Hz,1H), 2.66(s,3H).

[0114] Preparation of 1-(5-bromo-2-hydroxy-3-iodophenyl)-3-morpholinopropane-1,3-dione (Step 2 of Scheme 1) [ka] To a solution of 1-(5-bromo-2-hydroxy-3-iodo-phenyl)ethanone (45 g, 131.99 mmol, 1 equiv.) in THF (400 mL), LiHMDS (1 M, 422.36 mL, 3.2 equiv.) was added dropwise at −65° C. under N , and the reaction mixture was then stirred at 0° C. for 1 hour. The mixture was recooled to −65° C., and morpholine-4-carbonyl chloride (21.72 g, 145.19 mmol, 16.97 mL, 1.1 equiv.) was added dropwise at −65° C. The mixture was stirred at 25° C. for 12 hours. LCMS indicated that 1-(5-bromo-2-hydroxy-3-iodo-phenyl)ethanone was completely consumed. The mixture was cooled to 0° C. and adjusted to pH 7 with 2 M HCl. The aqueous phase was extracted with ethyl acetate (200 mL × 3). The combined organic phase was washed with brine (150 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude material was triturated with MTBE (200 mL) at 25° C. for 30 minutes. 1-(5-Bromo-2-hydroxy-3-iodo-phenyl)-3-morpholino-propane-1,3-dione (57 g, 125.54 mmol, 95.11% yield) was obtained as a yellow solid. 1 H NMR (DMSO-d6,400MHz) δ 8.06(s,1H), 7.96(s,1H), 4.32(s,2H), 3.59~3.55(m,4H), 3.45~3.37(m,4H).

[0115] Preparation of 6-bromo-8-iodo-2-morpholino-4H-chromen-4-one (Step 3 of Scheme 1) [ka] To a solution of 1-(5-bromo-2-hydroxy-3-iodo-phenyl)-3-morpholino-propane-1,3-dione (44 g, 96.90 mmol, 1 equiv.) in DCM (440 mL) was added TfO (109.36 g, 387.62 mmol, 63.95 mL, 4 equiv.) dropwise at 0 °C. The resulting mixture was stirred at 25 °C under N for 12 h. TLC (petroleum ether:ethyl acetate = 0:1, R f= 0.4), indicating that 1-(5-bromo-2-hydroxy-3-iodo-phenyl)-3-morpholino-propane-1,3-dione was completely consumed. The reaction mixture was cooled to 0 °C, MeOH (200 mL) was added, and the mixture was stirred at 25 °C for 1 h. The mixture was concentrated, and the residue was adjusted to pH = 7 with saturated NaHCO3. The aqueous phase was extracted with DCM (200 mL × 3). The combined organic phase was washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate to ethyl acetate:MeOH = 50 / 1 to 4:1). 6-Bromo-8-iodo-2-morpholino-chromen-4-one (11.6 g, 26.60 mmol, 27.45% yield) was obtained as a yellow solid. 1 H NMR (DMSO-d6,400MHz) δ 8.29(d,J=2.4Hz,1H), 7.95(d,J=2.4Hz,1H), 5.59(s,1H), 3.81~3.72(m,4H), 3.62~3.57(m,4H).

[0116] Preparation of 6-bromo-2-morpholino-8-vinyl-4H-chromen-4-one (Step 4 in Scheme 1) [ka] To a mixture of 6-bromo-8-iodo-2-morpholino-chromen-4-one (8.4 g, 19.26 mmol, 1 equiv.) and potassium trifluoro(vinyl)boranide (2.84 g, 21.19 mmol, 1.1 equiv.) in dioxane (80 mL) was added a solution of Pd(dppf)Cl (704.79 mg, 963.22 μmol, 0.05 equiv.) and KCO (5.32 g, 38.53 mmol, 2 equiv.) in HO (10 mL) under N at 25 °C. The resulting mixture was stirred at 60 °C for 4 h. LCMS showed that 6-bromo-8-iodo-2-morpholino-chromen-4-one was completely consumed. After filtration, the filtrate was concentrated. The residue was dissolved in EtOAc (50 mL) and HO (80 mL). The organic phase was separated, and the aqueous phase was extracted with EtOAc (50 mL × 2). The combined organic phase was washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude product was triturated with MTBE (30 mL) at 25 °C for 30 minutes. The compound 6-bromo-2-morpholino-8-vinyl-chromen-4-one (6.9 g, crude) was obtained as a yellow solid. 1 H NMR(DMSO-d6,400MHz) δ 8.09(d,J=2.4Hz,1H), 7.90(d,J=2.4Hz,1H), 7.12(q,J=11.2Hz,1H), 6.13( d,J=17.6Hz,1H), 5.60~5.55(m,2H), 3.77~3.69(m,4H), 3.55~3.49(m,4H).

[0117] Preparation of 6-bromo-2-morpholino-4-oxo-4H-chromene-8-carbaldehyde (Step 5 of Scheme 1) [ka] To a solution of 6-bromo-2-morpholino-8-vinyl-chromen-4-one (6.3 g, 18.74 mmol, 1 equiv.) in THF (50 mL) and HO (10 mL), KOsO 2HO (345.25 mg, 937.00 μmol, 0.05 equiv.) was added at 25 °C, and the reaction mixture was stirred at 25 °C for 30 min. NaIO (12.02 g, 56.22 mmol, 3.12 mL, 3 equiv.) was added in portions to the resulting mixture at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. TLC (petroleum ether: EtOAc = 0:1, R f =0.23), indicating that 6-bromo-2-morpholino-8-vinyl-chromen-4-one was completely consumed. The mixture was quenched with water (100 mL) and extracted with ethyl acetate (80 mL × 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate to EtOAc:MeOH = 30:1 to 4:1). Compound 6-bromo-2-morpholino-4-oxo-chromene-8-carbaldehyde (5.2 g, 15.38 mmol, 82.06% yield) was obtained as a yellow solid. 1 H NMR (DMSO-d6,400MHz) δ 10.33(s,1H), 8.24~8.21(m,2H), 5.66(s,1H), 3.72~3.75(m,4H), 3.61~3.63(m,4H).

[0118] Preparation of 6-bromo-8-(((3,5-difluorophenyl)amino)methyl)-2-morpholino-4H-chromen-4-one (Step 6 of Scheme 1) [ka] To a mixture of 6-bromo-2-morpholino-4-oxo-chromene-8-carbaldehyde (5.2 g, 15.38 mmol, 1 equiv.) and 3,5-difluoroaniline (3.97 g, 30.76 mmol, 2 equiv.) in CHCN (2 mL) was added EtSiH (10.73 g, 92.27 mmol, 14.74 mL, 6 equiv.) and TFA (7.01 g, 61.51 mmol, 4.55 mL, 4 equiv.) at 25 °C. The reaction mixture was stirred at 25 °C for 12 h. LCMS showed that 6-bromo-2-morpholino-4-oxo-chromene-8-carbaldehyde was completely consumed. The mixture was adjusted to pH = 7 with saturated NaHCO at 0 °C. The mixture was extracted with ethyl acetate (80 mL × 3). The combined organic phase was washed with brine (80 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 0:1). The compound 6-bromo-8-[(3,5-difluoroanilino)methyl]-2-morpholino-chromen-4-one (1.8 g, 3.99 mmol, 25.94% yield) was obtained as a yellow solid. 1 H NMR(DMSO-d6,400MHz) δ 7.89(d,J=2.4Hz,1H), 7.64(d,J=2.4Hz,1H), 6.34~6.28(m,3H), 5.59(s,1H), 4.53(d,J=6.0Hz,2H), 3.72~3.67(m,4H), 3.53~3.50(m,4H).

[0119] Preparation of the final compound of Scheme 1 (Step 7 of Scheme 1) [ka] 6-Bromo-8-(((3,5-difluorophenyl)amino)methyl)-2-morpholino-4H-chromen-4-one (332.40 μmol, 1 equiv.), R'NHR" (997.21 μmol to 1.662 mmol, 3 equiv. to 5 equiv.), Pd2(dba)3 (33.24 μmol to 66.48 μmol, 0.1 equiv. to 0.2 equiv.), XPhos (49.86 μmol to 99.72 μmol, 0.1 equiv.) in dioxane (4.5 mL / mmol to 9.0 mL / mmol). A mixture of Cs2CO3 (997.21 μmol, 2.66 mmol, 3 equiv. to 8 equiv.) and Cs2CO3 (997.21 μmol, 2.66 mmol, 3 equiv. to 8 equiv.) was stirred at 100 °C under N2 for 10 to 12 h. HPLC and LCMS indicated the reaction was complete. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in EtOAc and washed with water. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: Phenomenex Gemini-NX 80 × 30 mm × 3 μm or Phenomenex luna C18 80 × 40 mm × 3 μm; mobile phase: [water (10 mM NH4HCO3)-MeCN]; B%: 30% to 45%, 10 min or [water (0.04% HCl)-MeCN]; B%: 20% to 50%, 7 min). The aqueous solution was lyophilized to give the desired product.

[0120] compound 1 Preparation of 8-(((3,5-difluorophenyl)amino)methyl)-2,6-dimorpholino-4H-chromen-4-one (Step 7 of Scheme 1) [ka] A mixture of 6-bromo-8-(((3,5-difluorophenyl)amino)methyl)-2-morpholino-4H-chromen-4-one (150 mg, 332.40 μmol, 1 equiv.), morpholine (86.88 mg, 997.21 μmol, 87.75 μL, 3 equiv.), Pd(dba) (30.44 mg, 33.24 μmol, 0.1 equiv.), XPhos (23.77 mg, 49.86 μmol, 0.15 equiv.), and CsCO (324.91 mg, 997.21 μmol, 3 equiv.) in dioxane (3 mL) was stirred at 100 °C under N for 10 h. TLC (petroleum ether: EtOAc = 0:1, R f =0.2) and LCMS indicated that the reaction was complete. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in EtOAc (5 mL) and washed with water (2 mL × 2). The combined organic layers were washed with brine (2 mL × 1), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: Phenomenex Gemini-NX 80 × 30 mm × 3 μm; mobile phase: [water (10 mM NH4HCO3)-MeCN]; B%: 30% to 45%, 10 min). The eluent was removed by lyophilization. Compound 8-(((3,5-difluorophenyl)amino)methyl)-2,6-dimorpholino-4H-chromen-4-one (26.3 mg, 57.49 μmol, 17.30% yield) was obtained as a white solid. 1 H NMR(DMSO-d6,400MHz) δ 7.30(d,J=2.8Hz,1H), 7.23(d,J=2.8Hz,1H), 6.75(t,J=2.8Hz,1H), 6.31~6.25(m,3H), 5.50(s,1H), 4.45( t,J=5.2Hz,2H), 3.74(t,J=4.4Hz,4H), 3.66(t,J=4.4Hz,4H), 3.46(t,J=4.4Hz,4H), 3.09(t,J=4.4Hz,4H). HPLC: 97.61% (220nm), 99.42% (254nm). MS(ESI): Mass calculation value. C 24 H 25 For F2N3O4, 457.18 m / z found 458.2 [M+H] + .

[0121] compound 2 8-(((3,5-difluorophenyl)amino)methyl)-6-(dimethylamino)-2-morpholino-4H-chromen-4-one was prepared according to the procedure described in Scheme 1, Step 7. [ka] The desired compound (22.2 mg, 48.48 μmol, 10.94% yield, 98.69% purity, HCl) was obtained as a yellow solid. 1 H NMR (DMSO-d6,400MHz) δ 7.20~7.09(m,2H), 6.33~6.21(m,3H), 5.65(s,1H), 4.47(s,2H), 3.71~3.59(m,8H), 2.92(s,6H). HPLC: 98.69% (220nm), 98.47% (254nm). MS(ESI): Mass calculation value. C 22 H 23 For F2N3O3, 415.17 m / z, actual value 416.2 [M+H] + .

[0122] compound 3 Preparation of 8-(((3,5-difluorophenyl)amino)methyl)-2-morpholino-4-oxo-4H-chromene-6-carbonitrile (Step 7 of Scheme 1) [ka] To a solution of 6-bromo-8-[(3,5-difluoroanilino)methyl]-2-morpholino-chromen-4-one (0.1 g, 221.60 μmol, 1 equiv.) in DMA (1 mL) was added Zn(CN) (78.07 mg, 664.80 μmol, 42.20 μL, 3.0 equiv.), DPPF (19.66 mg, 35.46 μmol, 0.16 equiv.), and Pd(dba) (16.23 mg, 17.73 μmol, 0.08 equiv.) under N at 25 °C. The resulting mixture was stirred at 170 °C for 2 h. LCMS and HPLC indicated that 6-bromo-8-[(3,5-difluoroanilino)methyl]-2-morpholino-chromen-4-one was completely consumed. The reaction mixture was filtered. The filtrate was purified by preparative HPLC (column: Welch Xtimate C18 150 × 25 mm × 5 μm; mobile phase: [water (0.04% HCl)-MeCN]; B%: 25% to 45%, 8 min). The eluent was removed by lyophilization. The compound 8-[(3,5-difluoroanilino)methyl]-2-morpholino-4-oxo-chromene-6-carbonitrile (27.5 mg, 69.20 μmol, 31.23% yield) was obtained as a white solid. 1 H NMR(DMSO-d6,400MHz) δ 8.20(d,J=2.4Hz,1H), 7.86(d,J=2.4Hz,1H), 6.94~6.79(m,1H), 6.37~6.2 2(m,3H), 5.65(s,1H), 4.56(s,2H), 3.75~3.67(m,4H), 3.56~3.49(m,4H). HPLC: 96.81% (220nm), 99.10% (254nm). MS(ESI): Mass calculation value. C 21 H 17 For F2N3O3, 397.12 m / z, actual value 398.1 [M+H] + .

[0123] compound 4 Preparation of 8-(((3,5-difluorophenyl)amino)methyl)-6-ethoxy-2-morpholino-4H-chromen-4-one (Step 7 of Scheme 1) [ka] To a mixture of 6-bromo-8-[(3,5-difluoroanilino)methyl]-2-morpholino-chromen-4-one (0.15 g, 332.40 μmol, 1 equiv.) and EtONa (67.86 mg, 997.21 μmol, 3 equiv.) in EtOH (0.3 mL) and toluene (0.2 mL), ditert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (28.23 mg, 66.48 μmol, 0.2 equiv.), Pd(OAc) (7.46 mg, 33.24 μmol, 0.1 equiv.), and CsCO (162.45 mg, 498.60 μmol, 1.5 equiv.) were added under N at 25 °C. The resulting mixture was stirred at 100 °C for 12 h. LCMS and HPLC showed that 6-bromo-8-[(3,5-difluoroanilino)methyl]-2-morpholino-chromen-4-one was completely consumed. The reaction mixture was filtered, and the filtrate was concentrated. The resulting residue was purified by preparative HPLC (column: Xtimate C18 100 × 30 mm × 3 μm; mobile phase: [water (0.04% HCl)-MeCN]; B%: 30% to 60%, 8 min). The solvent was removed by lyophilization. The compound 8-[(3,5-difluoroanilino)methyl]-6-ethoxy-2-morpholino-chromen-4-one (4.9 mg, 11.77 μmol, yield 3.54%) was obtained as a white solid. 1 H NMR(DMSO-d6,400MHz) δ 7.24(d,J=2.4Hz,1H), 7.09(d,J=2.4Hz,1H), 6.40~6.21(m,3H), 5.61(s,1H), 4.51(s,2 H), 4.04(q,J=8.0Hz,2H), 3.69~3.67(m,4H), 3.52~3.50(m,4H), 1.31(t,J=6.8Hz,3H). HPLC: 93.72% (220nm), 96.88% (254nm). MS(ESI): Mass calculation value. C 22 H 22 For F2O4N2, 416.15 m / z, actual value 417.1 [M+H] + .

[0124] compound 5 Preparation of 8-(((3,5-difluorophenyl)amino)methyl)-6-ethynyl-2-morpholino-4H-chromen-4-one (Step 7 of Scheme 1) Preparation of 8-(((3,5-difluorophenyl)amino)methyl)-2-morpholino-6-((trimethylsilyl)ethynyl)-4H-chromen-4-one [ka] To a mixture of 6-bromo-8-[(3,5-difluoroanilino)methyl]-2-morpholino-chromen-4-one (0.18 g, 398.88 μmol, 1 equiv.) and ethynyl(trimethyl)silane (195.89 mg, 1.99 mmol, 276.29 μL, 5 equiv.) in MeCN (3 mL), [2-(2-aminophenyl)phenyl]-chloro-palladium tritert-butylphosphane (20.44 mg, 39.89 μmol, 0.1 equiv.) and N-cyclohexyl-N-methyl-cyclohexanamine (233.75 mg, 1.20 mmol, 253.80 μL, 3 equiv.) were added under N at 25 °C. The reaction mixture was stirred at 80 °C for 12 h. LCMS showed that 6-bromo-8-[(3,5-difluoroanilino)methyl]-2-morpholino-chromen-4-one was completely consumed. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The compound 8-[(3,5-difluoroanilino)methyl]-2-morpholino-6-(2-trimethylsilylethynyl)chromen-4-one (0.18 g, crude) was obtained as a yellow solid. MS (ESI): Mass calculated. 25 H 26 For F2O3N2Si, 468.57 m / z, actual value 469.0 [M+H] + .

[0125] Preparation of 8-(((3,5-difluorophenyl)amino)methyl)-6-ethynyl-2-morpholino-4H-chromen-4-one [ka] To a solution of 8-[(3,5-difluoroanilino)methyl]-2-morpholino-6-(2-trimethylsilylethynyl)chromen-4-one (0.17 g, 362.81 μmol, 1 equiv.) in MeOH (2 mL) was added K2CO3 (100.28 mg, 725.62 μmol, 2 equiv.) at 25 °C, and the resulting mixture was stirred at 25 °C for 1 h. LCMS and HPLC showed that 8-[(3,5-difluoroanilino)methyl]-2-morpholino-6-(2-trimethylsilylethynyl)chromen-4-one was completely consumed. The mixture was cooled to 0 °C and adjusted to pH = 7 with 2 M HCl. The aqueous phase was extracted with ethyl acetate (15 mL × 3). The combined organic phase was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by preparative HPLC (column: Xtimate C18 100 × 30 mm × 3 μm; mobile phase: [water (0.04% HCl)-MeCN]; B%: 30% to 60%, 6 min). The eluent was removed by lyophilization. The compound 8-[(3,5-difluoroanilino)methyl]-6-ethynyl-2-morpholino-chromen-4-one (8.3 mg, 18.78 μmol, yield 5.18%, purity 97.94%, HCl) was obtained as a white solid. 1 H NMR(DMSO-d6,400MHZ) δ 7.85(d,J=2.0Hz,1H), 7.56(d,J=2.0Hz,1H), 6.88(s,1H), 6.35~6.21(m,3H), 5.59(s,1H), 4.52(s,2H), 4.23(s,1H), 3.71~3.66(m,4H), 3.53~3.51(m,4H). HPLC: 97.94% (220nm), 99.62% (254nm). MS(ESI): Mass calculation value. C 22 H 18 For F2O3N2, 396.13 m / z, actual value 397.1 [M+H] + .

[0126] compound 6 Preparation of 6-cyclopropyl-8-(((3,5-difluorophenyl)amino)methyl)-2-morpholino-4H-chromen-4-one (Step 7 of Scheme 1) [ka] To a mixture of 6-bromo-8-[(3,5-difluoroanilino)methyl]-2-morpholino-chromen-4-one (0.2 g, 443.20 μmol, 1 equiv.) and cyclopropylboronic acid (304.56 mg, 3.55 mmol, 8 equiv.) in dioxane (10 mL) and HO (2 mL), PCy (12.43 mg, 44.32 μmol, 14.37 μL, 0.1 equiv.), KPO (188.15 mg, 886.41 μmol, 2 equiv.), and Pd(OAc) (4.98 mg, 22.16 μmol, 0.05 equiv.) were added under N at 25 °C. The resulting mixture was stirred at 90 °C for 12 h. LCMS showed that 6-bromo-8-[(3,5-difluoroanilino)methyl]-2-morpholino-chromen-4-one was completely consumed. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75 × 30 mm × 3 μm; mobile phase: [water (0.05% NH3H2O ​​+ 10 mM NH4HCO3)-MeCN]; B%: 35% to 60%, 8 min). The solvent was concentrated, and the resulting product was further purified by preparative HPLC (column: Phenomenex Luna C18 80 × 40 mm × 3 μm; mobile phase: [water (0.04% HCl)-MeCN]; B%: 42% to 52%, 7 min). The solvent was removed by lyophilization. The compound 6-cyclopropyl-8-[(3,5-difluoroanilino)methyl]-2-morpholino-chromen-4-one (7.2 mg, 16.84 μmol, yield 3.80%, purity 96.49%) was obtained as a white solid. 1 H NMR(DMSO-d6,400MHz) δ 7.51(d,J=2.0Hz,1H), 7.31(d,J=2.0Hz,1H), 6.36~6.22(m,3H), 5.60(s,1H), 4.47(s,2H), 3. 68~3.66(m,4H), 3.53~3.48(m,4H), 2.03~1.96(m,1H), 0.98~0.96(m,2H), 0.66~0.58(m,2H). HPLC: 98.24% (220nm), 100% (254nm). MS(ESI): Mass calculation value. C 23 H22 For F2O3N2, 412.16 m / z, actual value 413.1 [M+H] + .

[0127] compound 7 Preparation of 3-(8-(((3,5-difluorophenyl)amino)methyl)-2-morpholino-4-oxo-4H-chromen-6-yl)-1,1-dimethylurea (Step 7 of Scheme 1) [ka] To a mixture of 6-bromo-8-[(3,5-difluoroanilino)methyl]-2-morpholino-chromen-4-one (0.2 g, 443.20 μmol, 1 equiv.) and 1,1-dimethylurea (78.10 mg, 886.41 μmol, 2 equiv.) in dioxane (3 mL), CsCO (288.81 mg, 886.41 μmol, 2 equiv.) and BrettPhos Pd G (40.18 mg, 44.32 μmol, 0.1 equiv.) were added under N at 25 °C. The resulting mixture was stirred at 100 °C for 12 h. LCMS and HPLC indicated that 6-bromo-8-[(3,5-difluoroanilino)methyl]-2-morpholino-chromen-4-one was completely consumed. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by preparative HPLC (column: Welch Xtimate C18 150 × 25 mm × 5 μm; mobile phase: [water (0.04% HCl)-MeCN]; B%: 20% to 40%, 8 min). The compound 3-[8-[(3,5-difluoroanilino)methyl]-2-morpholino-4-oxo-chromen-6-yl]-1,1-dimethyl-urea (8.7 mg, 17.13 μmol, yield 3.86%, purity 97.43%, HCl) was obtained as a white solid. 1H NMR(DMSO-d6,400MHz) δ 8.50(s,1H), 7.93(d,J=2.4Hz,1H), 7.76(d,J=2.4Hz,1H), 6.86(s,1H), 6.26~6.24( m,3H), 5.50(s,1H), 4.46(s,2H), 3.69~3.67(m,4H), 3.50~3.48(m,4H), 2.91(s,6H). HPLC: 97.42% (220nm), 99.13% (254nm). MS(ESI): Mass calculation value. C 22 H 24 For F2O4N4, 458.18 m / z, actual value 459.2 [M+H] + .

[0128] compound 8 Preparation of N-(8-(((3,5-difluorophenyl)amino)methyl)-2-morpholino-4-oxo-4H-chromen-6-yl)acetamide (Step 7 of Scheme 1) [ka] A mixture of 6-bromo-8-(((3,5-difluorophenyl)amino)methyl)-2-morpholino-4H-chromen-4-one (0.15 g, 332.40 μmol, 1 equiv.), acetamide (58.90 mg, 997.21 μmol, 3 equiv.), CuI (12.66 mg, 66.48 μmol, 0.2 equiv.), N1,N2-dimethylethane-1,2-diamine (5.86 mg, 66.48 μmol, 7.16 μL, 0.2 equiv.), and Cs2CO3 (324.91 mg, 997.21 μmol, 3 equiv.) in dioxane (3 mL) was stirred at 100 °C under N2 for 10 h. LCMS showed the reaction was complete. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: Phenomenex Luna C18 80 × 40 mm × 3 μm; mobile phase: [water (0.04% HCl)-MeCN]; B%: 19% to 49%, 7 min). The eluent was removed by lyophilization. The compound N-(8-(((3,5-difluorophenyl)amino)methyl)-2-morpholino-4-oxo-4H-chromen-6-yl)acetamide (42.8 mg, 91.87 μmol, yield 27.64%, HCl) was obtained as a white solid. 1 H NMR(DMSO-d6,400MHz) δ 10.13(s,1H), 8.20(d,J=2.4Hz,1H), 7.65(d,J=2.0Hz,1H), 6.93(s,1H), 6.26~6.23(m,3 H), 5.61(s,1H), 4.51(s,2H), 3.70(t,J=4.4Hz,4H), 3.52(t,J=4.4Hz,4H), 2.02(s,3H). HPLC: 94.83% (220nm), 97.01% (254nm). MS(ESI): Mass calculation value. C 22 H 21 For F2N3O4, 429.15 m / z, actual value 430.2 [M+H] + . [ka]

[0129] General procedure for preparing compounds of Scheme 2 Preparation of 6-bromo-4-hydroxy-8-iodo-2H-chromene-2-thione (Step 1 of Scheme 2) [ka] To a solution of 1-(5-bromo-2-hydroxy-3-iodo-phenyl)ethanone (42 g, 123.19 mmol, 1.0 equiv) in THF (500 mL) was added NaHMDS (1 M, 431.16 mL, 3.5 equiv) under N at −65° C. The resulting mixture was stirred at 0° C. for 1 h, then cooled to −65° C., and CS (15.01 g, 197.10 mmol, 11.91 mL, 1.6 equiv) was added dropwise. The mixture was stirred at 25° C. for 12 h. LCMS showed that the reaction was complete. The reaction mixture was poured into ice water (1000 mL), and concentrated HCl was slowly added to adjust the pH to approximately 4. The organic layer was separated, and the aqueous phase was extracted with EtOAc (500 mL × 3). The combined organic layers were washed with brine (300 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure. The crude product was triturated with DCM (300 mL) at 25 °C for 30 minutes. Compound 6-bromo-4-hydroxy-8-iodo-chromene-2-thione (80 g, 208.88 mmol, 56.52% yield) was obtained as a yellow solid. 1 H NMR (DMSO-d6,400MHz) δ 8.33(d,J=2.4Hz,1H), 7.94(d,J=2.4Hz,1H), 6.55(s,1H).

[0130] Preparation of 6-bromo-2-(ethylthio)-8-iodo-4H-chromen-4-one (Step 2 of Scheme 2) [ka] To a solution of 6-bromo-4-hydroxy-8-iodo-chromene-2-thione (70 g, 182.77 mmol, 1.0 equiv) in acetone (100 mL) was added K2CO3 (30.31 g, 219.32 mmol, 1.2 equiv) and EtI (99.77 g, 639.69 mmol, 51.16 mL, 3.5 equiv) at 25 °C. The resulting mixture was stirred at 65 °C for 3 h. LCMS showed the reaction was completely consumed. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc (300 mL) and washed with 0.05 N HCl until pH = 7. The combined organic layers were washed with brine (100 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was triturated with EtOAc (120 mL) at 25 °C for 30 min. The compound 6-bromo-2-ethylsulfanyl-8-iodo-chromen-4-one (60 g, 145.97 mmol, 79.86% yield) was obtained as a yellow solid. 1 H NMR (DMSO-d6,400MHz) δ 8.40(d,J=2.4Hz,1H), 8.01(d,J=2.4Hz,1H), 6.45(s,1H), 3.29~3.26(m,2H), 1.39(t,J=7.2Hz,3H).

[0131] Preparation of 6-bromo-8-iodo-2-morpholino-4H-chromen-4-one (Step 3 of Scheme 2) [ka] To a solution of 6-bromo-2-ethylsulfanyl-8-iodo-chromen-4-one (50 g, 121.64 mmol, 1.0 equiv.) in CH3CN (300 mL) was added morpholine (31.79 g, 364.92 mmol, 32.11 mL, 3 equiv.) at 25 °C, and the reaction mixture was stirred at 100 °C for 12 hours. LCMS showed the reactant was completely consumed. The mixture was concentrated under reduced pressure at 45 °C. The crude product was triturated with petroleum ether (200 mL × 2) at 25 °C for 30 minutes. The compound 6-bromo-8-iodo-2-morpholino-chromen-4-one (49 g, 112.38 mmol, 92.38% yield) was obtained as a yellow solid. 1H NMR (DMSO-d6,400MHz) δ 8.29(d,J=2.4Hz,1H), 7.95(d,J=2.4Hz,1H), 5.59(s,1H), 3.78~3.73(m,4H), 3.63~3.60(m,4H).

[0132] Preparation of 6-bromo-2-morpholino-8-vinyl-4H-chromen-4-one (Step 4 of Scheme 2) [ka] To a mixture of 6-bromo-8-iodo-2-morpholino-chromen-4-one (5 g, 11.47 mmol, 1.0 equiv.) and potassium trifluoro(vinyl)boranide (1.69 g, 12.61 mmol, 1.1 equiv.) in dioxane (60 mL) and HO (10 mL), KCO (3.17 g, 22.93 mmol, 2.0 equiv.) and Pd(dppf)Cl (419.52 mg, 573.34 μmol, 0.05 equiv.) were added under N at 25 °C. The resulting mixture was stirred at 70 °C for 4 h. LCMS indicated the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated. The residue was dissolved in EtOAc (80 mL) and HO (80 mL). The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (50 mL × 2). The combined organic phase was washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude product was triturated with MTBE (50 mL) at 25° C. for 30 minutes. The compound 6-bromo-2-morpholino-8-vinyl-chromen-4-one (3.8 g, 11.30 mmol, 98.58% yield) was obtained as a yellow solid. 1 H NMR(DMSO-d6,400MHz) δ 8.08(d,J=2.4Hz,1H), 7.90(d,J=2.4Hz,1H), 7.11(dd,J=11.2Hz,17.6Hz,1H), 6 .12(d,J=17.6Hz,1H), 5.60~5.55(m,2H), 3.73~3.71(m,4H), 3.55~3.51(m,4H).

[0133] Preparation of 6-bromo-8-(1-bromoethyl)-2-morpholino-4H-chromen-4-one (Step 5 of Scheme 2) [ka] A solution of 6-bromo-2-morpholino-8-vinyl-chromen-4-one (3.8 g, 11.30 mmol, 1.0 equiv) in HBr (40 mL, 48%) was stirred at 100° C. for 12 hours. LCMS showed the reaction was complete. Some yellow solid was formed. After filtration, the compound 6-bromo-8-(1-bromoethyl)-2-morpholino-chromen-4-one (3.8 g, 9.11 mmol, 80.60% yield) was obtained as a yellow solid. 1 H NMR (DMSO-d6,400MHz) δ 7.99(d,J=2.4Hz,1H), 7.85(d,J=2.4Hz,1H), 5.85(s,1H), 5.63~5.61(m,1H), 3.76~3.71(m,8H), 1.39(d,J=6.4Hz,3H).

[0134] Preparation of 6-bromo-8-(1-((3,5-difluorophenyl)amino)ethyl)-2-morpholino-4H-chromen-4-one (Step 6 of Scheme 2) [ka] A mixture of 6-bromo-8-(1-bromoethyl)-2-morpholino-chromen-4-one (3.8 g, 9.11 mmol, 1.0 equiv.) and 3,5-difluoroaniline (4.71 g, 36.44 mmol, 4.0 equiv.) in DMA (40 mL) was stirred at 50° C. for 12 hours. LCMS showed the reaction was complete. The mixture was poured into water (100 mL) and extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with brine (40 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The resulting residue was purified by flash chromatography (Biotage; 40 g SepaFlash® silica flash column, eluent: petroleum ether / ethyl acetate to ethyl acetate:MeOH=40:1 to 4:1). The compound 6-bromo-8-[1-(3,5-difluoroanilino)ethyl]-2-morpholino-chromen-4-one (1.6 g, 3.44 mmol, 37.74% yield) was obtained as a yellow solid. 1 H NMR(DMSO-d6,400MHz) δ 7.87(d,J=2.4Hz,1H), 7.64(d,J=2.4Hz,1H), 6.94(d,J=6.8Hz,1H), 6.26(t,J=9.6Hz,1H), 6.16(d,J=2 .0Hz,2H), 5.60(s,1H), 5.03~4.92(m,1H), 3.76~3.70(m,4H), 3.58~3.51(m,4H), 1.49(d,J=6.8Hz,3H).

[0135] Preparation of the final compound of Scheme 2 (Step 7 of Scheme 2) [ka] Method A: To a mixture of 6-bromo-8-[1-(3,5-difluoroanilino)ethyl]-2-morpholino-chromen-4-one (279.40 μmol, 1.0 equiv.) and R'NHR" (838.20 μmol, 1.40 mmol, 3 equiv. to 5 equiv.) in dioxane (5 mL / mmol to 14 mL / mmol), CuI (111.76 μmol to 558.80 μmol, 0.4 equiv. to 2.0 equiv.), N,N'-dimethylethane-1,2-diamine (55.88 μmol to 139.70 μmol, 0.2 equiv. to 0.5 equiv.), and CsCO (838.19 μmol, 3.0 equiv.) were added under N at 25 °C. The resulting mixture was stirred at 100 °C for 10 to 48 h.

[0136] Method B: To a mixture of 6-bromo-8-[1-(3,5-difluoroanilino)ethyl]-2-morpholino-chromen-4-one (279.40 μmol, 1.0 equiv.) and R'NHR" (838.20 μmol, 1.40 mmol, 3 equiv., 5 equiv.) in dioxane (5 mL / mmol–14 mL / mmol), [2-(2-aminophenyl)phenylmethylsulfonyloxy-palladium dicyclohexyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane (27.94 μmol, 0.1 equiv.) and CsCO (838.19 μmol, 3.0 equiv.) were added under N at 25 °C. The resulting mixture was stirred at 100 °C for 10–48 h.

[0137] Workup: LCMS showed that the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated. The resulting residue was purified by preparative HPLC (column: Welch Xtimate C18 100 × 25 mm × 3 μm or Waters Xbridge BEH C18 100 × 30 mm × 10 μm; mobile phase: [water (0.05% HCl)-MeCN]; B%: 25% to 55%, 8 min or [water (10 mM NH4HCO3)-MeCN]; B%: 35% to 45%, 8 min). The eluate was lyophilized to give the desired product.

[0138] compound 9 Preparation of N-(8-(1-((3,5-difluorophenyl)amino)ethyl)-2-morpholino-4-oxo-4H-chromen-6-yl)-N-methylacetamide using Method B (Step 7 of Scheme 2) [ka] To a mixture of 6-bromo-8-[1-(3,5-difluoroanilino)ethyl]-2-morpholino-chromen-4-one (150 mg, 322.38 μmol, 1.0 equiv.) and N-methylacetamide (117.82 mg, 1.61 mmol, 123.11 μL, 5.0 equiv.) in dioxane (3 mL), [2-(2-aminophenyl)phenylmethylsulfonyloxy-palladium dicyclohexyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane (29.22 mg, 32.24 μmol, 0.1 equiv.) and CsCO (210.08 mg, 644.76 μmol, 2.0 equiv.) were added under N at 25 °C. The resulting mixture was stirred at 100 °C for 12 h. LCMS showed that the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated. The resulting residue was purified by preparative HPLC (column: Welch Xtimate C18 100 × 25 mm × 3 μm; mobile phase: [water (0.05% HCl)-MeCN]; B%: 25% to 55%, 8 min). The eluent was removed by lyophilization. The resulting product was further purified by preparative HPLC (column: Waters Xbridge BEH C18 100 × 30 mm × 10 μm; mobile phase: [water (NH4HCO3)-MeCN]; B%: 15% to 40%, 8 min). The eluent was removed by lyophilization. The compound N-[8-[1-(3,5-difluoroanilino)ethyl]-2-morpholino-4-oxo-chromen-6-yl]-N-methyl-acetamide (26.4 mg, 57.44 μmol, 17.82% yield, 99.54% purity) was obtained as a white solid. 1H NMR(DMSO-d6,400MHz) δ 7.67(d,J=2.4Hz,1H), 7.41~7.39(m,1H), 6.87(d,J=7.2Hz,1H), 6.28~6.13(m,3H), 5.59(s,1H), 4.99 ~4.97(m,1H), 3.74~3.72(m,4H), 3.57~3.64(m,4H), 3.16(s,3H), 2.52(s,3H), 1.53(d,J=6.4Hz,3H). HPLC: 99.55% (220nm), 100% (254nm). MS(ESI): Mass calculation value. C 24 H 25 For F2O4N3, 457.18 m / z, actual value 458.2 [M+H] + .

[0139] compound 10 4-(8-(1-((3,5-difluorophenyl)amino)ethyl)-2-morpholino-4-oxo-4H-chromen-6-yl)morpholin-3-one was prepared following the procedure described in Scheme 2, Step 7 using Method A. [ka] Method A was used to obtain the desired compound (52.5 mg, 102.01 μmol, 36.51% yield, 94.33% purity) as a white solid. 1 H NMR(DMSO-d6,400MHz) δ 7.78(d,J=2.4Hz,1H), 7.65(d,J=2.4Hz,1H), 6.89(s,1H), 6.28~6.06(m,3H), 5.58(s,1H), 4.98~4.96 (m,1H), 4.18(s,2H), 3.98~3.93(m,2H), 3.76~3.64(m,6H), 3.57~3.51(m,4H), 1.49(d,J=6.8Hz,3H). HPLC: 94.33% (220nm), 99.63% (254nm). MS(ESI): Mass calculation value. C 25 H 25 For F2N5O3, 485.18 m / z, actual value 486.1 [M+H] + .

[0140] compound 11 N-(8-(1-((3,5-difluorophenyl)amino)ethyl)-2-morpholino-4-oxo-4H-chromen-6-yl)propionamide was prepared following the procedure described in Scheme 2, Step 7 using Method A. [ka] Method A was used to obtain the desired compound (3.2 mg, 7.00 μmol, 2.50% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6) δ 10.02(s,1H), 8.13(d,J=2.8Hz,1H), 7.76(d,J=2.8Hz,1H), 7.01~6.99(m,1H), 6.23~6.07(m,3H), 5.54(s,1H), 4.94 ~4.92(m,1H), 3.73~3.71(m,4H), 3.54~3.51(m,4H), 2.50~2.27(m,2H), 1.49(d,J=6.8Hz,3H), 1.06(t,J=7.6Hz,3H). LCMS: 94.64% (220nm), 98.87% (254nm). MS(ESI): Mass calculation value. C 24 H 25 For F2N3O4, 457.18 m / z, actual value 458.1 [M+H] + .

[0141] compound 12 N-(8-(1-((3,5-difluorophenyl)amino)ethyl)-2-morpholino-4-oxo-4H-chromen-6-yl)cyclopentanecarboxamide was prepared following the procedure described in Scheme 2, Step 7 using Method A. [ka] Method A was used to obtain the desired compound (30.6 mg, 59.09 μmol, 21.15% yield, 96.08% purity) as a pale yellow solid. 1H NMR (DMSO-d6, 400 MHz) δ 10.01(s,1H), 8.12(d,J=2.4Hz,1H), 7.78(d,J=2.4Hz,1H), 6.97(d,J=5. 6Hz,1H), 6.20(t,J=9.6Hz,1H), 6.11~6.08(m,2H), 5.50(s,1H), 4.93~4. 90(m,1H), 3.71(t,J=4.8Hz,4H), 3.53~3.49(m,4H), 2.74~2.70(m,1H), 1 .80~2.07(m,2H), 1.70~1.66(m,4H), 1.52(s,2H), 1.47(d,J=6.8Hz,3H). LCMS: 96.08% (220nm), 99.64% (254nm). MS(ESI): Mass calculation value. C 27 H 29 For F2N3O4, 497.21 m / z, actual value 498.2 [M+H] + .

[0142] compound 13 N-(8-(1-((3,5-difluorophenyl)amino)ethyl)-2-morpholino-4-oxo-4H-chromen-6-yl)methanesulfonamide was prepared following the procedure described in Scheme 2, Step 7 using Method A. [ka] Method A was used to obtain the desired compound (12.5 mg, 29.49 μmol, 20.15% yield, 97.30% purity) as a white solid. 1 H NMR(DMSO-d6,400MHz) δ 9.86(s,1H), 7.62(d,J=2.4Hz,1H), 7.43(d,J=2.8Hz,1H), 6.98(d,J=6.4Hz,1H), 6.24~6.19(m,1H), 6.12~6.09(m,2 H), 5.56(s,1H), 4.94(t,J=6.4Hz,1H), 3.71(t,J=4.8Hz,4H), 3.55~3.30(m,4H), 2.85(s,3H), 1.49(d,J=6.8Hz,3H). LCMS: 98.01% (220nm), 100.00% (254nm). MS(ESI): Mass calculation value. C 22 H 23For F2N3O5S, 479.13 m / z, actual value 480.1 [M+H] + .

[0143] compound 14 2-(8-(1-((3,5-difluorophenyl)amino)ethyl)-2-morpholino-4-oxo-4H-chromen-6-yl)guanidine was prepared following the procedure described in Scheme 2, Step 7 using Method A. [ka] Method A was used to obtain the desired compound (48.3 mg, 106.45 μmol, 24.76% yield, 97.73% purity) as a yellow solid. 1 H NMR(DMSO-d6,400MHz) δ 9.99(s,1H), 7.62(d,J=2.4Hz,1H), 7.57(s,4H), 7.38(s,1H), 6.25~6.13(m,3H), 5.71( s,1H), 4.98~4.95(m,1H), 3.78~3.73(m,4H), 3.69~3.63(m,4H), 1.50(d,J=6.8Hz,3H). LCMS: 97.73% (220nm), 98.13% (254nm). MS(ESI): Mass calculation value. C 22 H 23 For F2N5O3, 443.18 m / z, actual value 444.1 [M+H] + . [ka]

[0144] compound 15 Preparation of 8-(1-((3,5-difluorophenyl)amino)ethyl)-6-hydroxy-2-morpholino-4H-chromen-4-one (Steps 1-2 of Scheme 3) Preparation of 8-(1-((3,5-difluorophenyl)amino)ethyl)-2-morpholino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4H-chromen-4-one (Step 1 of Scheme 3) [ka] A mixture of 6-bromo-8-[1-(3,5-difluoroanilino)ethyl]-2-morpholino-chromen-4-one (0.3 g, 644.76 μmol, 1 equiv.), BPD (491.19 mg, 1.93 mmol, 3 equiv.), Pd(dppf)Cl (47.18 mg, 64.48 μmol, 0.1 equiv.), and AcOK (189.83 mg, 1.93 mmol, 3 equiv.) in dioxane (3 mL) was degassed and purged with N three times, then the mixture was stirred at 100° C. under a N atmosphere for 15 h. LCMS indicated the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. The compound 8-[1-(3,5-difluoroanilino)ethyl]-2-morpholino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chromen-4-one (1.170 g, crude) was obtained as a brown oil. 1 H NMR(DMSO-d6,400MHz) δ 8.18(s,1H), 7.85(s,1H), 7.04(d,J=6.8Hz,1H), 6.24(t,J=9.6Hz,1H), 6.13(d,J=10.4Hz,2H), 5.56(s,1H) ), 4.99(t,J=6.4Hz,1H), 3.74(t,J=4.4Hz,4H), 3.55(t,J=5.2Hz,4H), 1.48(d,J=6.8Hz,3H), 1.29(s,12H).

[0145] Preparation of 8-(1-((3,5-difluorophenyl)amino)ethyl)-6-hydroxy-2-morpholino-4H-chromen-4-one (Step 2 of Scheme 3) [ka] To a solution of 8-[1-(3,5-difluoroanilino)ethyl]-2-morpholino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chromen-4-one (1.1 g, 2.15 mmol, 1 equiv.) in THF (20 mL) and HO (20 mL) was added 3-oxidedioxaborolane sodium tetrahydrate (5.82 g, 37.84 mmol, 7.28 mL, 17.62 equiv.). The resulting mixture was stirred at 20 °C for 2 h. LCMS and HPLC showed that 8-[1-(3,5-difluoroanilino)ethyl]-2-morpholino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chromen-4-one was completely consumed. The reaction mixture was partitioned between EtOAc (45 mL) and HO (15 mL). The aqueous phase was separated and then extracted with EtOAc (10 mL × 3). The organic phase was washed with brine (10 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (Column: Waters Xbridge BEH C18 100 × 30 mm × 10 μm; Mobile phase: [water (10 mM NHHCO)-MeCN]; B%: 25% to 50%, 8 min). The eluent was removed by lyophilization. Compound 8-[1-(3,5-difluoroanilino)ethyl]-6-hydroxy-2-morpholino-chromen-4-one (56.5 mg, 140.41 μmol, yield 40.36%, purity 100.00%) was obtained as a white solid. 1 H NMR(DMSO-d6,400MHz) δ 9.74(s,1H), 7.13(d,J=2.8Hz,1H), 7.00(d,J=2.8Hz,1H), 6.95(s,1H), 6.24(t,J=6.8Hz,1H), 6.12(d,J=9.2 Hz,2H), 5.60(s,1H), 4.92(d,J=6.4Hz,1H), 3.74(t,J=4.4Hz,4H), 3.58~3.53(m,4H), 1.48(d,J=6.4Hz,3H). LCMS: 100.00%(220nm), 100.00%(254nm). MS(ESI): Mass calculation value. C 21 H 20 For F2N2O4, 402.14 m / z, actual value 403.1 [M+H] + . [ka]

[0146] General procedure for preparing compounds of Scheme 4 Preparation of 8-(1-((3,5-difluorophenyl)amino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-sulfonyl fluoride (Step 1 of Scheme 4) [ka] To a mixture of 6-bromo-8-[1-(3,5-difluoroanilino)ethyl]-2-morpholino-chromen-4-one (1 g, 2.15 mmol, 1.0 equiv.) and 1,4-diazoniabicyclo[2.2.2]octane-1,4-disulfinate (568.10 mg, 2.36 mmol, 1.1 equiv.) in i-PrOH (15 mL) was added EtN (652.43 mg, 6.45 mmol, 897.43 μL, 3.0 equiv.) and 4-di-tert-butylphosphanyl-N,N-dimethylaniline dichloropalladium (152.18 mg, 214.92 μmol, 152.18 μL, 0.1 equiv.) under N at 25 °C. The resulting mixture was stirred at 85 °C for 12 h and then cooled to 25 °C. To the above reaction mixture was added NFSI (1.02 g, 3.22 mmol, 1.5 equiv.), and the resulting mixture was stirred at 25 °C for 1 h. LCMS revealed approximately 20% of 8-(1-((3,5-difluorophenyl)amino)ethyl)-2-morpholino-4H-chromen-4-one and approximately 65% ​​of the desired compound. The reaction mixture was filtered, and the filtrate was concentrated. The resulting residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate to EtOAc:MeOH = 40:1 to 4:1). The solvent was concentrated. Compound 8-[1-(3,5-difluoroanilino)ethyl]-2-morpholino-4-oxo-chromene-6-sulfonyl fluoride (0.48 g, 1.02 mmol, 11.92% yield) was obtained as a yellow solid. 1H NMR(DMSO-d6,400MHz) δ 8.38(d,J=2.4Hz,1H), 8.09(d,J=2.4Hz,1H), 7.04(d,J=6.8Hz,1H), 6.33~6.11(m,3H), 5. 75(s,1H), 5.11~4.98(m,1H), 3.77~3.72(m,4H), 3.65~3.54(m,4H), 1.54(d,J=6.8Hz,3H).

[0147] Preparation of Compounds of Scheme 4 (Step 2 of Scheme 4) [ka] To a mixture of 8-[1-(3,5-difluoroanilino)ethyl]-2-morpholino-4-oxochromene-6-sulfonyl fluoride (156.90 μmol, 1.0 equiv.) and R1NHR2 (0.31 mmol, 2.0 equiv., HCl or free base) in MeCN (6 mL / mmol–12 mL / mmol), DIEA (0.47 mmol, 390.42 μL, 3.0 equiv.) was added dropwise at room temperature. The resulting mixture was stirred at 80°C for 12 hours. HPLC and LCMS showed that 8-[1-(3,5-difluoroanilino)ethyl]-2-morpholino-4-oxochromene-6-sulfonyl fluoride was completely consumed. The mixture was quenched with water (5 mL) and extracted with ethyl acetate (5 mL × 3). The combined organic phase was washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by preparative HPLC (column: Phenomenex Luna C18 80 × 40 mm × 3 μm or Phenomenex Gemim-NX C18 75 × 30 mm × 3 μm or Waters Xbridge BEH C18 10 × 30 mm × 10 μm; mobile phase: [water (0.04% HCl)-MeCN]; B%: 32% to 54%, 7 min) or [water (10 mM NH4HCO3)-MeCN]; B%: 25% to 45%, 8 min) or [water (10 mM NH4HCO3)-MeCN]; B%: 30% to 60%, 10 min). The aqueous solution was lyophilized to give the desired product.

[0148] compound 16 Preparation of 8-(1-((3,5-difluorophenyl)amino)ethyl)-N-methyl-2-morpholino-4-oxo-4H-chromene-6-sulfonamide (Step 2 of Scheme 4) [ka] To a mixture of 8-[1-(3,5-difluoroanilino)ethyl]-2-morpholino-4-oxo-chromene-6-sulfonyl fluoride (0.31 g, 661.76 μmol, 1 equiv.) and methanamine (89.36 mg, 1.32 mmol, 2 equiv., HCl) in CHCN (5 mL) was added DIEA (256.58 mg, 1.99 mmol, 345.80 μL, 3 equiv.) at 25 °C. The resulting mixture was stirred at 80 °C for 12 h. HPLC and LCMS showed that 8-[1-(3,5-difluoroanilino)ethyl]-2-morpholino-4-oxo-chromene-6-sulfonyl fluoride was completely consumed. The mixture was quenched with water (20 mL), and the aqueous phase was extracted with ethyl acetate (15 mL × 3). The combined organic phase was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by preparative HPLC (column: Phenomenex Gemini-NX 80 × 40 mm × 3 μm; mobile phase: [water (10 mM NH4HCO3)-MeCN]; B%: 20% to 50%, 8 min). The eluent was removed by lyophilization. Compound 8-[1-(3,5-difluoroanilino)ethyl]-N-methyl-2-morpholino-4-oxo-chromene-6-sulfonamide (118.9 mg, 247.97 μmol, 37.47% yield, 100% purity) was obtained as a white solid. 1H NMR(400MHz,DMSO-d6) δ 8.20(d,J=2.4Hz,1H), 7.86(d,J=2.4Hz,1H), 7.49~7.51(m,1H), 7.05(d,J=6.8Hz,1H), 6.25~6.14(m,3H), 5.66 (s,1H), 5.03~5.00(m,1H), 3.74~3.72(m,4H), 3.60~3.53(m,4H), 2.22(d,J=4.8Hz,3H), 1.53(d,J=6.4Hz,3H). LCMS: 100.00%(220nm), 100.00%(254nm). MS(ESI): Mass calculation value. C 22 H 23 For F2N3O5S, 479.13 m / z, actual value 480.1 [M+H] + .

[0149] compound 17 6-((3-aminoazetidin-1-yl)sulfonyl)-8-(1-((3,5-difluorophenyl)amino)ethyl)-2-morpholino-4H-chromen-4-one was prepared according to the procedure described in Scheme 4, Step 2. [ka] The desired compound (18.8 mg, 33.96 μmol, 11.71% yield, 94.02% purity) was obtained as a white solid. 1 H NMR(400MHz,DMSO-d6) δ 8.10(d,J=2.4Hz,1H), 7.80(d,J=2.0Hz,1H), 7.08(d,J=6.8Hz,1H), 6.24~6.18(m,3H), 5.70(s,1H), 5.09~5.02(m,1H) , 3.78~3.72(m,4H), 3.63~3.56(m,5H), 3.31~3.24(m,2H), 3.05~3.02(m,1H), 2.90~2.87(m,1H), 1.55(d,J=6.8Hz,3H). LCMS: 94.02% (220nm), 94.50% (254nm). MS(ESI): Mass calculation value. C 24 H 26 For F2N4O5S, 520.16 m / z, actual value 521.2 [M+H] + .

[0150] compound 18 Preparation of 8-(1-((3,5-difluorophenyl)amino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-sulfonic acid (Step 3 of Scheme 4) [ka] To a solution of 8-[1-(3,5-difluoroanilino)ethyl]-2-morpholino-4-oxochromene-6-sulfonyl fluoride (120 mg, 256.17 μmol, 1.0 equiv.) in MeOH (10 mL) was added ammonia formate (484.58 mg, 7.68 mmol, 30 equiv.). The resulting mixture was stirred at 50° C. for 4 hours. LCMS and HPLC indicated that 8-[1-(3,5-difluoroanilino)ethyl]-2-morpholino-4-oxochromene-6-sulfonyl fluoride was completely consumed. The mixture was concentrated in vacuo. The resulting residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100 × 25 mm × 5 μm; mobile phase: [water (10 mM NH4HCO3)-MeCN]; B%: 15% to 45%, 10 min). The eluent was removed by lyophilization. Compound 8-[1-(3,5-difluoroanilino)ethyl]-2-morpholino-4-oxo-chromene-6-sulfonic acid (30 mg, 64.58 μmol, yield 24.71%, purity 99.58%) was obtained as a white solid. 1 H NMR(400MHz,D2O) δ 8.20(d,J=2.0Hz,1H), 7.95(d,J=2.0Hz,1H), 6.09~6.03(m,3H), 5.63(s,1H), 4 .85~4.83(m,1H), 3.79~3.78(m,4H), 3.58~3.57(m,4H), 1.48(d,J=6.8Hz,3H). LCMS: 99.58% (220nm), 100.00% (254nm). MS(ESI): Mass calculation value. C 21 H 20 For F2N2O6S, 466.10 m / z, actual value 467.1 [M+H] + . [ka]

[0151] General procedure for preparing compounds of Scheme 5 Preparation of tert-butyl (8-(1-((3,5-difluorophenyl)amino)ethyl)-2-morpholino-4-oxo-4H-chromen-6-yl)carbamate (Step 1 of Scheme 5) [ka] A mixture of 6-bromo-8-[1-(3,5-difluoroamino)ethyl]-2-morpholino-chromen-4-one (1 g, 2.15 mmol, 1 equiv.), tert-butyl carbamate (755.31 mg, 6.45 mmol, 5.76 μL, 3 equiv.), CuI (409.32 mg, 2.15 mmol, 1 equiv.), N,N'-dimethylethane-1,2-diamine (56.84 mg, 644.76 μmol, 69.40 μL, 0.3 equiv.), and CsCO (2.10 g, 6.45 mmol, 3 equiv.) in dioxane (10 mL) was degassed and purged with N three times. The mixture was then stirred at 100 °C under a N atmosphere for 10 h. TLC (petroleum ether:ethyl acetate = 1:1, R f =0.25), LCMS, and HPLC indicated the reaction was complete. The mixture was quenched with water (10 mL), and the aqueous phase was extracted with ethyl acetate (15 mL × 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography (Biotage; 12 g SepaFlash® silica flash column, eluent: 0-100% ethyl acetate gradient @ 60 mL / min). The eluent was removed under reduced pressure. The compound tert-butyl N-[8-[1-(3,5-difluoroanilino)ethyl]-2-morpholino-4-oxo-chromen-6-yl]carbamate (0.55 g, 1.10 mmol, 51.03% yield) was obtained as a pale yellow solid. 1H NMR(DMSO-d6,400MHz) δ 9.52(s,1H), 7.95(s,1H), 7.65(d,J=2.8Hz,1H), 6.96(d,J=6.4Hz,1H), 6.23~6.08(m,3H), 5.51 (s,1H), 4.90(t,J=6.0Hz,1H), 3.71(t,J=4.8Hz,4H), 3.50(t,J=4.8Hz,4H), 1.45~1.49(m,12H).

[0152] compound 19 Preparation of 6-amino-8-(1-((3,5-difluorophenyl)amino)ethyl)-2-morpholino-4H-chromen-4-one (Step 2 of Scheme 5) [ka] To a solution of tert-butyl N-[8-[1-(3,5-difluoroanilino)ethyl]-2-morpholino-4-oxochromen-6-yl]carbamate (0.66 g, 1.28 mmol, 1 equiv.) in EtOAc (2 mL) was added HCl / EtOAc (4 M, 6.69 mL, 24.39 equiv.). The resulting mixture was stirred at 25 °C for 6 hours. LCMS showed the reaction was complete. A pale yellow precipitate formed. After filtration, the solid was collected and dried. The compound 6-amino-8-[1-(3,5-difluoroanilino)ethyl]-2-morpholino-chromen-4-one (471 mg, 1.08 mmol, 98.09% yield, HCl) was obtained as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6) δ 7.62(s,1H), 7.38(s,1H), 7.08(s,1H), 6.30~5.97(m,3H), 5.71(s,1H), 4.9 6~4.94(m,1H), 3.78~3.76(m,4H), 3.57~3.54(m,4H), 1.49(d,J=9.6Hz,3H). HPLC: 95.08% (220nm), 96.94% (254nm). MS(ESI): Mass calculation value. C 21 H 21 For F2N3O3, 401.16 m / z, actual value 402.1 [M+H] + .

[0153] Preparation of Compounds of Scheme 5 (Step 3 of Scheme 5) [ka] To a solution of 6-amino-8-[1-(3,5-difluoroanilino)ethyl]-2-morpholino-chromen-4-one (274.06 μmol, 1 equiv., HCl) in pyridine (5 mL / mmol) or AcOH (10 mL / mmol) was added MeS-amine (1.37 mmol, 5 equiv.). Alternatively, to a mixture of 6-amino-8-[1-(3,5-difluoroanilino)ethyl]-2-morpholino-chromen-4-one (124.56 μmol, 1.0 equiv.), 2-cyanoacetic acid (373.69 μmol, 3.0 equiv.), and DIEA (622.81 μmol, 108.48 μL, 5.0 equiv.) in THF (15 mL / mmol) was added T3P (448.42 μmol, 266.69 μL, 50% purity, 3.6 equiv.) dropwise at 0°C. The resulting mixture was then stirred at 25°C to 150°C for 4 to 15 hours. HPLC and LCMS indicated the reaction was complete. The mixture was filtered, and the filtrate was concentrated in vacuo, or the mixture was basified to pH = 7 with saturated NaOH and NaHCO3. A precipitate formed and was collected by filtration. The resulting residue or filter cake was purified by preparative HPLC (column: Welch Xtimate C18 100 × 25 mm × 3 μm or Phenomenex Luna C18 80 × 40 mm × 3 μm; mobile phase: [water (0.05% HCl)-MeCN]; B%: 15% to 30% for 8 min or [water (0.04% HCl)-MeCN]; B%: 27% to 42% for 5.5 min or [water (0.04% HCl)-MeCN]; B%: 23% to 47% for 7 min). The eluent was removed by lyophilization.

[0154] compound 20 Preparation of 8-(1-((3,5-difluorophenyl)amino)ethyl)-6-((4,5-dihydro-1H-imidazol-2-yl)amino)-2-morpholino-4H-chromen-4-one (Step 3 of Scheme 5) [ka] To a solution of 6-amino-8-[1-(3,5-difluoroanilino)ethyl]-2-morpholino-chromen-4-one (120 mg, 274.06 μmol, 1 equiv., HCl) in pyridine (1.5 mL) was added 2-methylsulfanyl-4,5-dihydro-1H-imidazole hydroiodide (334.48 mg, 1.37 mmol, 5 equiv.). The resulting mixture was stirred at 150°C for 15 hours. HPLC and LCMS indicated the reaction was complete. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Xtimate C18 100 × 25 mm × 3 μm; mobile phase: [water (0.05% HCl)-MeCN]; B%: 15% to 30%, 8 min). The eluent was removed by lyophilization. The compound 8-(1-((3,5-difluorophenyl)amino)ethyl)-6-((4,5-dihydro-1H-imidazol-2-yl)amino)-2-morpholino-4H-chromen-4-one (13.7 mg, 26.34 μmol, yield 9.61%, purity 97.28%, HCl) was obtained. 1 H NMR(DMSO-d6,400MHz) δ 10.64(s,1H), 8.40(s,2H), 7.67(d,J=2.8Hz,1H), 7.39(d,J=2.4Hz,1H), 6.23(t,J=9.6Hz,1H), 6.15~6 .13(m,2H), 5.66(s,1H), 5.0~4.95(m,1H), 3.75~3.72(m,8H), 3.58~3.56(m,4H), 1.51(d,J=6.8Hz,3H). LCMS: 97.28% (220nm), 98.00% (254nm). MS(ESI): Mass calculation value. C 24 H 25 For O3N5F, 469.19 m / z, actual value 470.2 [M+H] + .

[0155] compound 21 8-(1-((3,5-difluorophenyl)amino)ethyl)-6-((4,4-dimethyl-4,5-dihydrooxazol-2-yl)amino)-2-morpholino-4H-chromen-4-one was prepared according to the procedure described in Scheme 5, Step 3. [ka] The desired compound (4.7 mg, 9.43 μmol, 4.13% yield, 90.56% purity) was obtained as a yellow solid. 1 H NMR(DMSO-d6,400MHz) δ 7.82(s,1H), 7.49(s,1H), 6.23(s,1H), 6.16(d,J=9.2Hz,2H), 5.67(s,1H), 4.98(s,1 H), 4.56(s,2H), 3.73(s,4H), 3.60~3.57(m,4H), 1.51(d,J=4.8Hz,3H), 1.41(s,6H). LCMS: 90.56% (220nm), 88.11% (254nm). MS(ESI): Mass calculation value. C 26 H 28 For F2N4O4, 498.21 m / z, actual value 499.2 [M+H] + .

[0156] compound 22 2-Cyano-N-(8-(1-((3,5-difluorophenyl)amino)ethyl)-2-morpholino-4-oxo-4H-chromen-6-yl)acetamide was prepared following the procedure described in Scheme 5, Step 3. [ka] The desired compound (14.0 mg, 29.42 μmol, 23.62% yield, 98.45% purity) was obtained as a white solid. 1H NMR(400MHz,DMSO-d6) δ 10.46(s,1H), 8.11(d,J=2.8Hz,1H), 7.66(d,J=2.8Hz,1H), 7.00(s,1H), 6.21(t,J=9.6Hz,1H), 6.10(d,J=9.6Hz, 2H), 5.58(s,1H), 4.93(d,J=6.8Hz,1H), 3.86(s,2H), 3.73~3.71(m,4H), 3.64~3.53(m,4H), 1.49(d,J=6.5Hz,3H). LCMS: 98.45% (220nm), 98.82% (254nm). MS(ESI): Mass calculation value. C 24 H 22 For F2N4O4, 468.16 m / z, actual value 469.1 [M+H] + .

[0157] compound 23 (Z)-2-cyano-N-(8-(1-((3,5-difluorophenyl)amino)ethyl)-2-morpholino-4-oxo-4H-chromen-6-yl)-3-hydroxybut-2-enamide was prepared according to the procedure described in Scheme 5, Step 3. [ka] The desired compound (5.8 mg, 10.03 μmol, 6.71% yield, 94.59% purity, HCl) was obtained as a yellow solid. 1 H NMR(DMSO-d6,400MHz) δ 8.12(d,J=2.4Hz,1H), 7.67(d,J=2.4Hz,1H), 6.27~6.07(m,3H), 5.73(s,1H), 5.02~4 .84(m,1H), 3.77~3.70(m,4H), 3.67~3.62(m,4H), 2.19(s,3H), 1.49(d,J=6.8Hz,3H). HPLC: 94.60% (220nm), 92.11% (254nm). MS(ESI): Mass calculation value. C 26 H 24 For F2N4O5, 510.17 m / z, actual value 511.1 [M+H] + . [ka]

[0158] compound 24 Preparation of 2-(8-(1-((3,5-difluorophenyl)amino)ethyl)-2-morpholino-4-oxo-4H-chromen-6-yl)-N,N-dimethylacetamide (Steps 1-3 of Scheme 6) compound 25 Preparation of methyl 2-(8-(1-((3,5-difluorophenyl)amino)ethyl)-2-morpholino-4-oxo-4H-chromen-6-yl)acetate (Step 1 of Scheme 6) [ka] A mixture of 6-bromo-8-[1-(3,5-difluoroanilino)ethyl]-2-morpholino-chromen-4-one (1 g, 2.15 mmol, 1 equiv.), dimethylpropanedioate (1.87 g, 14.18 mmol, 1.63 mL, 6.6 equiv.), tri-tert-butylphosphonium tetrafluoroborate (124.71 mg, 429.84 μmol, 0.2 equiv.), KPO (1.28 g, 6.02 mmol, 2.8 equiv.), 18-crown-6 (284.03 mg, 1.07 mmol, 0.5 equiv.), and Pd(dba) (196.81 mg, 214.92 μmol, 0.1 equiv.) was degassed and purged with N three times, and then the mixture was stirred at 160 °C under N for 6 h. TLC (petroleum ether: ethyl acetate = 0:1, R f=0.44), LCMS, and HPLC indicated the reaction was complete. The reaction mixture was filtered, and the filter cake was washed with ethyl acetate (10 mL × 6). The combined filtrates were concentrated in vacuo. The residue was quenched with water (100 mL) and then extracted with ethyl acetate (15 mL × 3). The combined organic phases were washed with brine (10 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography (Biotage; 20 g SepaFlash® silica flash column, eluent: 0-100% ethyl acetate, 0-40% MeOH / ethyl acetate gradient @ 60 mL / min). The eluent was removed under reduced pressure to give 804 mg of methyl 2-[8-[1-(3,5-difluoroanilino)ethyl]-2-morpholino-4-oxo-chromen-6-yl]acetate. 30 mg of the crude product was further purified by preparative HPLC (column: Welch Xtimate C18 100 × 25 mm × 3 μm; mobile phase: [water (0.05% HCl)-MeCN]; B%: 30% to 45%, 8 min). The compound 2-[8-[1-(3,5-difluoroanilino)ethyl]-2-morpholino-4-oxo-chromen-6-yl]methyl acetate (10.7 mg, 22.37 μmol, yield 1.04%, purity 95.83%) was obtained as a yellow solid. 1 H NMR(DMSO-d6,400MHz) δ 7.74(d,J=2.0Hz,1H), 7.49(d,J=2.0Hz,1H), 6.23~6.18(m,1H), 6.14(t,J=1.6Hz,2H),5. 73(s,1H), 4.98~4.93(m,1H), 3.75~3.71(m,6H), 3.70~3.59(m,7H), 1.50(d,J=6.8Hz,3H). LCMS: 95.83% (220nm), 96.03% (254nm). MS(ESI): Mass calculation value. C 24 H 24 For F2N2O5, 458.17 m / z, actual value 459.1 [M+H] + .

[0159] compound 26 Preparation of 2-(8-(1-((3,5-difluorophenyl)amino)ethyl)-2-morpholino-4-oxo-4H-chromen-6-yl)acetic acid (Step 2 of Scheme 6) [ka] A solution of methyl 2-[8-[1-(3,5-difluoroanilino)ethyl]-2-morpholino-4-oxo-chromen-6-yl]acetate (0.1 g, 218.12 μmol, 1 equiv.) in HCl (12 M, 0.15 mL, 8.25 equiv.) was stirred at 80° C. for 1 h. LCMS showed that methyl 2-[8-[1-(3,5-difluoroanilino)ethyl]-2-morpholino-4-oxo-chromen-6-yl]acetate was completely consumed. The resulting mixture was basified with saturated NaOH (0.5 mL) to pH=5. The resulting precipitate (150 mg) was collected by filtration. 20 mg of the precipitate was further purified by preparative HPLC (column: Welch Xtimate C18 100 × 25 mm × 3 μm; mobile phase: [water (0.05% HCl)-MeCN]; B%: 25% to 40%, 8 min). The eluent was removed by lyophilization. The compound 2-[8-[1-(3,5-difluoroanilino)ethyl]-2-morpholino-4-oxo-chromen-6-yl]acetic acid (2.4 mg, 5.33 μmol, yield 2.44%, purity 98.64%) was obtained as a white solid. 1 H NMR(DMSO-d6,400MHz) δ 7.72(d,J=2.0Hz,1H), 7.48(d,J=2.0Hz,1H), 6.92(s,1H), 6.22~6.18(m,1H), 6.14~6.08(m,2H), 5.64(s,1H) ), 4.96~4.95(m,1H), 3.74(t,J=4.4Hz,4H), 3.63(d,J=3.2Hz,2H), 3.56~3.53(m,4H), 1.50(d,J=6.8Hz,3H). LCMS: 98.64% (220nm), 99.38% (254nm). MS(ESI): Mass calculation value. C 23 H 22 For F2N2O5, 444.15 m / z, actual value 445.1 [M+H] + .

[0160] Preparation of 2-(8-(1-((3,5-difluorophenyl)amino)ethyl)-2-morpholino-4-oxo-4H-chromen-6-yl)-N,N-dimethylacetamide (Step 3 of Scheme 6) [ka] To a solution of 2-[8-[1-(3,5-difluoroanilino)ethyl]-2-morpholino-4-oxochromen-6-yl]acetic acid (130 mg, 270.33 μmol, 1 equiv., HCl), DIEA (279.51 mg, 2.16 mmol, 376.70 μL, 8 equiv.), and N-methylmethanamine hydrochloride (132.27 mg, 1.62 mmol, 6 equiv.) in THF (1.5 mL) was added T3P (344.06 mg, 540.67 μmol, 321.55 μL, 50% purity, 2 equiv.) dropwise at 0° C. After the addition, the resulting mixture was stirred at 25° C. for 2 h. LCMS and HPLC showed that 2-[8-[1-(3,5-difluoroanilino)ethyl]-2-morpholino-4-oxo-chromen-6-yl]acetic acid was completely consumed. The reaction mixture was quenched by adding water (0.5 mL). The mixture was directly purified by preparative HPLC (column: Waters Xbridge BEH C18 100 × 25 mm × 5 μm; mobile phase: [water (10 mM NH4HCO3)-MeCN]; B%: 25% to 50%, 10 min). The eluent was removed by lyophilization. The compound 2-[8-[1-(3,5-difluoroanilino)ethyl]-2-morpholino-4-oxo-chromen-6-yl]-N,N-dimethyl-acetamide (10.4 mg, 21.88 μmol, yield 8.09%, purity 99.18%) was obtained as a white solid. 1H NMR(DMSO-d6,400MHz) δ 7.66(d,J=2.0Hz,1H), 7.36(d,J=2.0Hz,1H), 6.94(d,J=6.4Hz,1H), 6.23~6.18(m,1H), 6.11(dd,J=2.0Hz,10.4Hz,2H), 5.5 4(s,1H), 4.97~4.91(m,1H), 3.76(s,4H), 3.72(s,2H), 3.57~3.51(m,4H), 2.84(s,3H), 2.74(s,3H), 1.50(d,J=6.8Hz, 3H). LCMS: 99.18% (220nm), 100.00% (254nm). MS(ESI): Mass calculation value. C 25 H 27 For F2N3O4, 471.20 m / z, actual value 472.2 [M+H] + . [ka]

[0161] General procedure for preparing compounds of Scheme 7 Preparation of methyl 3-acetyl-4-hydroxybenzoate (Step 1 of Scheme 7) [ka] A mixture of 1-(5-bromo-2-hydroxy-phenyl)ethanone (10 g, 46.50 mmol, 1 equiv.), Pd(dppf)Cl (1.70 g, 2.33 mmol, 0.05 equiv.) and TEA (9.41 g, 93.00 mmol, 12.95 mL, 2 equiv.) in MeOH (300 mL) was stirred at 80 °C under CO (50 psi.) for 15 h. TLC (petroleum ether: EtOAc = 5:1, R f=0.45) and LCMS indicated the reaction was complete. After filtration, the filtrate was removed under reduced pressure. The residue was dissolved in EtOAc (100 mL) and washed with 0.5 N HCl to pH = 7, followed by brine (50 mL × 3). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (Biotage®; 40 g SepaFlash® silica flash column, eluent: 0-16% ethyl acetate / petroleum ether gradient @ 80 mL / min). The eluent was removed under reduced pressure. The compound, methyl 3-acetyl-4-hydroxybenzoate (9 g, 46.35 mmol, 99.67% yield), was obtained as a brown needle-like solid. 1 H NMR (DMSO-d6,400MHz) δ 12.20(s,1H), 8.36(s,1H), 8.03(d,J=8.4Hz,1H), 7.07(d,J=8.8Hz,1H), 3.84(s,3H), 2.67(s,3H).

[0162] Preparation of methyl 3-acetyl-5-bromo-4-hydroxybenzoate (Step 2 of Scheme 7) [ka] To a mixture of methyl 3-acetyl-4-hydroxybenzoate (37 g, 190.54 mmol, 1 equiv.) and pyridine (60.29 g, 762.17 mmol, 61.52 mL, 4 equiv.) in DCM (400 mL), Br2 (33.50 g, 209.60 mmol, 10.80 mL, 1.1 equiv.) was added dropwise at 0 °C. The resulting mixture was then stirred at 20 °C under N2 for 3 h. TLC (petroleum ether: EtOAc = 5:1, R f=0.45), which indicated the reaction was complete. The mixture was poured into ice water (300 mL) and slowly adjusted to pH=4 with 2N HCl. The organic layer was separated, and the aqueous layer was extracted with DCM (300 mL×2). The combined organic layers were washed with brine (300 mL×5), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was triturated with petroleum ether (200 mL). The solid was collected after filtration. The compound methyl 3-acetyl-5-bromo-4-hydroxybenzoate (48.5 g, 177.60 mmol, 93.21% yield) was obtained as a brown solid. 1 H NMR (DMSO-d6,400MHz) δ 13.28(s,1H), 8.44(d,J=2.0Hz,1H), 8.31(d,J=2.0Hz,1H), 3.87(s,3H), 2.76(s,3H).

[0163] Preparation of methyl 8-bromo-4-hydroxy-2-thioxo-2H-chromene-6-carboxylate (Step 3 of Scheme 7) [ka] To a solution of methyl 3-acetyl-5-bromo-4-hydroxybenzoate (40 g, 146.48 mmol, 1 equiv.) in THF (200 mL) was added NaHMDS (1 M, 512.67 mL, 3.5 equiv.) dropwise at -50 °C. The resulting mixture was then stirred at -5 °C to 0 °C for 1 h under N2. CS2 (17.84 g, 234.36 mmol, 14.16 mL, 1.6 equiv.) was then added dropwise at -50 °C, and the resulting mixture was stirred at 20 °C under N2 for 12 h. TLC (petroleum ether: EtOAc = 0:1, R f=0.2) and LCMS showed that the reaction was nearly complete. The mixture was poured into ice water (1 L) and slowly adjusted to pH=4 with concentrated HCl. The organic layer was separated, and the aqueous layer was extracted with EtOAc (400 mL×3). The combined organic layers were washed with brine (200 mL×5), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was triturated with DCM (100 mL). The solid was collected after filtration. Compound methyl 8-bromo-4-hydroxy-2-thioxo-chromene-6-carboxylate (28.5 g, 67.73 mmol, yield 46.24%, purity 74.89%) was obtained as a yellow solid. 1 H NMR (DMSO-d6,400MHz) δ 8.36(d,J=2.0Hz,1H), 8.32(d,J=2.0Hz,1H), 6.63(s,1H), 3.91(s,3H).

[0164] Preparation of methyl 8-bromo-2-(ethylthio)-4-oxo-4H-chromene-6-carboxylate (Step 4 of Scheme 7) [ka] To a solution of methyl 8-bromo-4-hydroxy-2-thioxo-chromene-6-carboxylate (28.5 g, 90.44 mmol, 1 equiv.) and EtI (49.37 g, 316.53 mmol, 25.32 mL, 3.5 equiv.) in acetone (600 mL) was added KCO (15.00 g, 108.52 mmol, 25.55 mL, 1.20 equiv.). The resulting mixture was stirred at 65 °C for 2 h. TLC (petroleum ether: EtOAc = 5:1, R f =0.2) and LCMS showed that the reaction was nearly complete. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc (300 mL) and washed with 0.05 N HCl until pH = 7. The combined organic layers were washed with brine (100 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was triturated with EtOAc (20 mL). The solid was collected after filtration. Compound methyl 8-bromo-2-ethylsulfanyl-4-oxo-chromene-6-carboxylate (25 g, 72.85 mmol, 80.55% yield) was obtained as a brown solid.1 H NMR (DMSO-d6,400MHz) δ 8.44(d,J=2.0Hz,1H), 8.42(d,J=2.0Hz,1H), 6.51(s,1H), 3.92(s,3H), 3.26(q,J=7.2Hz,2H), 1.40(t,J=7.2Hz,3H).

[0165] Preparation of methyl 8-acetyl-2-(ethylthio)-4-oxo-4H-chromene-6-carboxylate (Step 5 of Scheme 7) [ka] A mixture of methyl 8-bromo-2-ethylsulfanyl-4-oxo-chromene-6-carboxylate (10 g, 29.14 mmol, 1 equiv.), tributyl(1-ethoxyvinyl)stannane (13.33 g, 36.91 mmol, 12.46 mL, 1.27 equiv.), and Pd(PPh3)2Cl2 (1.02 g, 1.46 mmol, 0.05 equiv.) in dioxane (150 mL) was stirred at 100 °C under N2 for 3 h. TLC (petroleum ether: EtOAc = 4:1, R f =0.2) and LCMS showed that the reaction was complete. The mixture was cooled to room temperature, and 17.48 mL of 2N HCl was added, and the resulting mixture was stirred at 20 °C for 1 hour. The organic solvent was removed under reduced pressure. The aqueous layer was adjusted to pH = 7 with saturated NaHCO3 and extracted with DCM (100 mL × 3). The combined organic layers were washed with brine (100 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was triturated with petroleum ether and MTBE (v:v = 10:1, 110 mL × 2). The solid was collected after filtration. Compound methyl 8-acetyl-2-ethylsulfanyl-4-oxo-chromene-6-carboxylate (8 g, 26.12 mmol, 89.63% yield) was obtained as a brown solid. 1 H NMR(DMSO-d6,400MHz) δ 8.64(d,J=2.0Hz,1H), 8.53(d,J=2.4Hz,1H), 6.52(s,1H), 3.93(s,3H), 3.22(q,J=7.2Hz,2H), 2.72(s,3H), 1.36(t,J=7.2Hz,3H).

[0166] Preparation of methyl 2-(ethylthio)-8-(1-hydroxyethyl)-4-oxo-4H-chromene-6-carboxylate (Step 6 of Scheme 7) [ka] To a solution of methyl 8-acetyl-2-ethylsulfanyl-4-oxo-chromene-6-carboxylate (7 g, 22.85 mmol, 1 equiv.) in MeOH (70 mL) and AcOH (41.17 g, 685.53 mmol, 39.21 mL, 30 equiv.), NaBHCN (2.87 g, 45.70 mmol, 2 equiv.) was added portionwise at 20° C., and the resulting mixture was stirred at 20° C. for 2 h. TLC (petroleum ether: EtOAc = 2:1, R f =0.2) and LCMS indicated the reaction was complete. The mixture was quenched with ice water (100 mL) at 0 °C, and the organic solvent was removed under reduced pressure. Some yellow solid formed. After filtration, this solid (2 g) was collected. The filtrate was extracted with EtOAc (100 mL × 3). The combined organic layers were washed with saturated NaHCO to pH = 7, additionally with brine (50 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was triturated with EtOAc (30 mL). A solid (3.2 g) was collected after filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by flash silica gel chromatography (Biotage®; 20 g SepaFlash® silica flash column, eluent 0-7% DCM and EtOAc gradient @ 80 mL / min). The eluent was removed under reduced pressure. The compound methyl 2-ethylsulfanyl-8-(1-hydroxyethyl)-4-oxo-chromene-6-carboxylate (5.2 g, 16.86 mmol, yield 73.80%) was obtained as a brown solid. 1H NMR(DMSO-d6,400MHz)δ 8.44(d,J=2.4Hz,1H), 8.40(d,J=2.0Hz,1H), 6.45(s,1H), 5.64(d,J=4.8Hz,1H), 5.24(t,J= 6.0Hz,1H), 3.92(s,3H), 3.23(q,J=7.2Hz,2H), 1.40(d,J=6.0Hz,3H), 1.37(t,J=7.2Hz,3H).

[0167] Preparation of methyl 8-(1-bromoethyl)-2-(ethylthio)-4-oxo-4H-chromene-6-carboxylate (Step 7 of Scheme 7) [ka] To a solution of methyl 2-ethylsulfanyl-8-(1-hydroxyethyl)-4-oxo-chromene-6-carboxylate (4 g, 12.97 mmol, 1 equiv.) in DCM (100 mL), PPh (5.10 g, 19.46 mmol, 1.5 equiv.) and CBr (6.45 g, 19.46 mmol, 1.5 equiv.) were added portionwise with stirring at 0 °C. The resulting mixture was then stirred at 20 °C under N for 2 h. TLC (petroleum ether:ethyl acetate = 1:1, R f =0.8), indicated the detection of one major new spot with the desired lower polarity. The mixture was concentrated under reduced pressure at 20 °C. The resulting residue was purified by flash silica gel chromatography (Biotage®; 120 g SepaFlash® silica flash column, eluting with a 0-20% ethyl acetate / petroleum ether gradient at 100 mL / min). The eluent was removed under reduced pressure. Methyl 8-(1-bromoethyl)-2-ethylsulfanyl-4-oxo-chromene-6-carboxylate (3.5 g, 9.43 mmol, 72.68% yield) was obtained as a yellow solid. 1H NMR(DMSO-d6,400MHz) δ 8.49(d,J=2.0Hz,1H), 8.40(d,J=1.2Hz,1H), 6.51(s,1H), 5.88(t,J=6.8Hz,1H), 3.92(s,3H), 3.27(q,J=7.2Hz,2H), 2.12(d,J=7.2Hz,3H), 1.39(t,J=7.2Hz,3H).

[0168] Preparation of methyl 8-(1-((3,5-difluorophenyl)amino)ethyl)-2-(ethylthio)-4-oxo-4H-chromene-6-carboxylate (Step 8 of Scheme 7) [ka] A mixture of methyl 8-(1-bromoethyl)-2-ethylsulfanyl-4-oxo-chromene-6-carboxylate (2 g, 5.39 mmol, 1 equiv.) and 3,5-difluoroaniline (1.25 g, 9.70 mmol, 1.8 equiv.) in DMA (20 mL) was stirred at 50° C. for 16 h. TLC (petroleum ether:ethyl acetate=2:1, R f =0.3), indicated the detection of one major new spot with greater polarity. The resulting mixture was cooled to 20 °C. The residue was poured into ice-water (w / w = 1 / 1, 100 mL) and stirred for 5 min. The aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with brine (30 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography (Biotage®; 40 g SepaFlash® silica flash column, eluent: 0–20% ethyl acetate / petroleum ether gradient @ 100 mL / min). 8-[1-(3,5-difluoroanilino)ethyl]-2-ethylsulfanyl-4-oxo-chromene-6-carboxylate (1.4 g, 3.34 mmol, 61.96% yield) was obtained as a yellow solid. 1H NMR(DMSO-d6,400MHz) δ 8.43(d,J=2.0Hz,1H), 8.19(d,J=2.0Hz,1H), 7.09(d,J=6.8Hz,1H), 6.49(s,1H), 6.23(t,J=9.6Hz,1H), 6.14(dd,J=2.0H z,J=14.0Hz,2H), 4.98(t,J=6.4Hz,1H), 3.86(s,3H), 3.25(q,J=7.2Hz,2H), 1.52(d,J=6.8Hz,3H), 1.38(t,J=7.2Hz,3H).

[0169] Preparation of methyl 8-(1-((3,5-difluorophenyl)amino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylate (Step 9 of Scheme 7) [ka] A solution of methyl 8-[1-(3,5-difluoroanilino)ethyl]-2-ethylsulfanyl-4-oxo-chromene-6-carboxylate (0.6 g, 1.43 mmol, 1 equiv.) and morpholine (498.49 mg, 5.72 mmol, 503.53 μL, 4 equiv.) in MeCN (5 mL) was stirred at 80° C. for 10 h. Morpholine (249.25 mg, 2.86 mmol, 251.76 μL, 4 equiv.) was added, and the resulting mixture was stirred at 80° C. for 10 h. TLC (petroleum ether: EtOAc = 0:1, R f =0.15) and LCMS showed that the reaction was nearly complete. The solvent was removed under reduced pressure. The residue was triturated with EtOAc (10 mL). The resulting solid was collected. Compound 8-[1-(3,5-difluoroanilino)ethyl]-2-morpholino-4-oxo-chromene-6-carboxylate methyl ester (0.47 g, 1.06 mmol, 73.93% yield) was obtained as a yellow solid. 1H NMR(DMSO-d6,400MHz) δ 8.39(d,J=2.4Hz,1H), 8.10(d,J=2.0Hz,1H), 7.07(d,J=6.8Hz,1H), 6.22(t,J=4.0Hz,1H), 6.14(dd,J=2.0Hz,J=10.4Hz, 2H), 5.63(s,1H), 5.00(t,J=6.8Hz,1H), 3.86(s,3H), 3.75(t,J=4.4Hz,4H), 3.58(t,J=4.8Hz,4H), 1.50(d,J=6.4Hz,3H).

[0170] Preparation of 8-(1-((3,5-difluorophenyl)amino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (Step 10 of Scheme 7) [ka] A solution of methyl 8-[1-(3,5-difluoroanilino)ethyl]-2-morpholino-4-oxo-chromene-6-carboxylate (0.24 g, 540.02 μmol, 1 equiv.) in HCl (12 M, 4.50 mL, 100 equiv.) was stirred at 80° C. for 1 h. TLC (petroleum ether: EtOAc = 0:1, R f =0.05) and LCMS showed that the reaction was complete. Some white solid formed. The solid was collected after filtration and concentrated under reduced pressure. This solid was used in the next step without further purification. The compound 8-[1-(3,5-difluoroanilino)ethyl]-2-morpholino-4-oxo-chromene-6-carboxylic acid (0.2 g, 464.68 μmol, 86.05% yield) was obtained as a pink solid. 1 H NMR(DMSO-d6,400MHz) δ 8.37(d,J=2.4Hz,1H), 8.11(d,J=2.4Hz,1H), 6.21(t,J=4.4Hz,1H), 6.15(dd,J=2.4Hz,J=10.4Hz,2H), 5.77(s,1H), 5.00(q,J=6.4Hz,1H), 3.75(t,J=4.8Hz,4H), 3.61(t,J=3.6Hz,4H), 1.50(d,J=6.8Hz,3H).

[0171] Preparation of Compound (Step 11 in Scheme 7) [ka] To a mixture of 8-[1-(3,5-difluoroanilino)ethyl]-2-morpholino-4-oxochromene-6-carboxylic acid, R'NHR" (255.57 μmol to 697.02 μmol, 1.1 equiv to 3 equiv) and DIEA (1.16 mmol, 202.35 μL, 5 equiv) in THF (6 mL / mmol to 12 mL / mmol) and DMF (2 mL / mmol), T3P (302.04 μmol, 50% purity, 1.3 equiv) was added dropwise at 0 °C, and the resulting mixture was stirred at 20 °C for 2 to 3 h. HPLC and LCMS indicated the reaction was complete. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: Phenomenex Gemini-NX Purification was performed using a 80 x 40 mm x 3 μm column or a Phenomenex Gemini-NX 80 x 30 mm x 3 μm column or a Phenomenex Gemini-NX C18 80 x 30 mm x 5 μm column or a Waters Xbridge BEH C18 100 x 25 mm x 5 μm column; mobile phase: [water (10 mM NH4HCO3)-MeCN]; B%: 15% to 45% for 8 min; mobile phase: [water (10 mM NH4HCO3)-MeCN]; B%: 25% to 50% for 10 min; or mobile phase: [water (10 mM NH4HCO3)-MeCN]; B%: 25% to 55% for 8 min]. The aqueous solution was lyophilized to give the desired product.

[0172] compound 27 Preparation of 8-(1-((3,5-difluorophenyl)amino)ethyl)-6-(3-(dimethylamino)pyrrolidine-1-carbonyl)-2-morpholino-4H-chromen-4-one (Step 11 of Scheme 7) [ka] To a mixture of 8-[1-(3,5-difluoroanilino)ethyl]-2-morpholino-4-oxochromene-6-carboxylic acid (0.1 g, 232.34 μmol, 1 equiv.), N,N-dimethylpyrrolidin-3-amine (34.49 mg, 302.04 μmol, 1.3 equiv.), and DIEA (150.14 mg, 1.16 mmol, 202.35 μL, 5 equiv.) in THF (3 mL) and DMF (0.5 mL), T3P (192.21 mg, 302.04 μmol, 179.63 μL, 50% purity, 1.3 equiv.) was added dropwise at 0° C., and the resulting mixture was stirred at 20° C. for 3 h. HPLC and LCMS indicated the reaction was complete. The mixture was extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (20 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (Phenomenex Gemini-NX 80 × 40 mm × 3 μm column; mobile phase: [water (10 mM NH4HCO3)-MeCN]; B%: 15% to 45%, 8 min). The eluent was lyophilized to dryness. The compound 8-[1-(3,5-difluoroanilino)ethyl]-6-[3-(dimethylamino)pyrrolidine-1-carbonyl]-2-morpholino-chromen-4-one (46.1 mg, 84.44 μmol, 36.34% yield, 96.45% purity) was obtained as a white solid. 1 H NMR(DMSO-d6,400MHz) δ 7.91(d,J=4.8Hz,1H), 7.63(d,J=12.0Hz,1H), 6.99~6.94(m,1H), 6.22~6.14(m,3H), 5.59(s,1H), 5.01(t,J=2.4Hz,1H), 3.74(t,J =4.4Hz,4H), 3.58~3.50(m,5H), 3.38~3.10(m,3H), 2.68~2.60(m,1H), 2.30~1.80(m,7H), 1.68~1.52(m,1H), 1.49(d,J=5.6Hz,3H). HPLC: 96.45% (220nm), 100% (254nm). MS(ESI): Mass calculation value. C 28 H 32 For F2N4O4, 526.24 m / z, actual value 527.3 [M+H] + .

[0173] compound 28 8-(1-((3,5-difluorophenyl)amino)ethyl)-6-(2,2-dioxide-2-thia-6-azaspiro[3.3]heptane-6-carbonyl)-2-morpholino-4H-chromen-4-one was prepared according to the procedure described in Scheme 7, step 11. [ka] The desired compound (52.3 mg, 89.94 μmol, 48.39% yield, 96.23% purity) was obtained as a yellow solid. 1 H NMR(DMSO-d6,400MHz) δ 8.02(d,J=2.4Hz,1H), 8.84(d,J=2.0Hz,1H), 7.03(d,J=6.8Hz,1H), 6.22(t,J=7.2Hz,1H), 6.16(dd,J=2.0Hz,J=7.2Hz,2H) , 5.63(s,1H), 5.01(t,J=6.4Hz,1H), 4.53~4.26(m,8H), 3.74(t,J=4.8Hz,4H), 3.59(t,J=4.8Hz,4H), 1.50(d,J=6.4Hz,3H). HPLC: 96.23% (220nm), 99.02% (254nm). MS(ESI): Mass calculation value. C 27 H 27 For F2N3O6S, 559.16 m / z, actual value 560.2 [M+H] + .

[0174] compound 29 8-(1-((3,5-difluorophenyl)amino)ethyl)-6-((R)-3-(dimethylamino)pyrrolidine-1-carbonyl)-2-morpholino-4H-chromen-4-one was prepared according to the procedure described in Scheme 7, step 11. [ka] The desired compound (103.1 mg, 191.84 μmol, 48.57% yield, 97.98% purity) was obtained as a white solid. 1H NMR(DMSO-d6,400MHz) δ 7.91(s,1H), 7.66(d,J=11.6Hz,1H), 6.99~6.92(m,1H), 6.16~6.14(m,3H), 5.59(s,1H), 5.05~4.98(m,1H), 3.73(t,J=4.4Hz,4H), 3.58~3.52(m,5H), 3.19~2.99(m,3H), 2.68~2.60(m,1H), 2.16(s,3H), 2.01~1.93(m,4H), 1.71~1.66(m,1H), 1.51(d,J=6.4Hz,3H). HPLC: 97.98% (220nm), 100% (254nm). MS(ESI): Mass calculation value. C 28 H 32 For F2N4O4, 526.24 m / z, actual value 527.3 [M+H] + .

[0175] compound 30 8-(1-((3,5-difluorophenyl)amino)ethyl)-6-((S)-3-(dimethylamino)pyrrolidine-1-carbonyl)-2-morpholino-4H-chromen-4-one was prepared according to the procedure described in Scheme 7, step 11. [ka] The desired compound (116.3 mg, 215.45 μmol, 54.55% yield, 97.55% purity) was obtained as a white solid. 1 H NMR(DMSO-d6,400MHz) δ 7.91(d,J=4.8Hz,1H), 7.65(d,J=11.6Hz,1H), 6.98~6.96(m,1H), 6.22~6.14(m,3H), 5.59(s,1H), 5.00(t,J=3.6Hz,1H), 3.73(t,J=4.4Hz) ,4H), 3.58~3.52(m,5H), 3.28~2.92(m,3H), 2.69~2.60(m,1H), 2.15(s,3H), 1.93~1.80(m,4H), 1.68~1.63(m,1H), 1.49(d,J=5.6Hz,3H). HPLC: 97.55% (220nm), 99.72% (254nm). MS(ESI): Mass calculation value. C 28 H 32For F2N4O4, 526.24 m / z, actual value 527.3 [M+H] + . [ka]

[0176] compound 31 Preparation of 8-(1-((3,5-difluorophenyl)amino)propyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (Steps 1-3 of Scheme 8) Preparation of 8-(1-hydroxypropyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (Step 1 of Scheme 8) [ka] To a mixture of 8-formyl-N,N-dimethyl-2-morpholino-4-oxo-chromene-6-carboxamide (0.3 g, 908.17 μmol, 1 equiv.) in THF (4 mL), EtMgBr (3 M, 605.45 μL, 2 equiv.) was added dropwise under N at 0° C., and the resulting mixture was stirred at 0° C. for 2 h. The mixture was then stirred at 20° C. for 3 h. After that, EtMgBr (3 M, 302.72 μL, 1 equiv.) was added dropwise, and the resulting mixture was stirred at 0° C. for 2 h. TLC (EtOAc:MeOH=20:1, R f=0.15), HPLC and LCMS indicated the reaction was nearly complete. The resulting mixture was quenched with saturated NH4Cl (5 mL) and brought to pH = 7 with 1N HCl at 0 °C. The aqueous layer was extracted with DCM:i-PrOH (v:v = 3:1, 40 mL × 3). The combined organic layers were washed with brine (5 mL × 1), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (Biotage®; 4 g SepaFlash® silica flash column, eluent: 0-20% MeOH / ethyl acetate gradient @ 30 mL / min). The eluent was removed under reduced pressure. A mixture of compounds 8-(1-hydroxypropyl)-N,N-dimethyl-2-morpholino-4-oxo-chromene-6-carboxamide (0.1 g, crude) and 8-(hydroxymethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide was obtained as a yellow solid. 1 H NMR(DMSO-d6,400MHz) δ 7.79(s,1H), 7.72(s,1H), 5.56(s,1H), 5.44(d,J=4.4Hz,1H), 5.04~5.00(m,1H), 3.74(t,J=4.8H z,4H), 3.54(t,J=8.4Hz,4H), 2.99(s,3H), 2.94(s,3H), 1.80~1.64(m,2H), 0.87(t,J=7.2Hz,3H). MS(ESI): Mass calculation value. C 19 H 24 For N2O5, 360.17 m / z, actual value 360.2 [M+H] + .

[0177] Preparation of 8-(1-bromopropyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (Step 2 of Scheme 8) [ka] To a mixture of 8-(1-hydroxypropyl)-N,N-dimethyl-2-morpholino-4-oxo-chromene-6-carboxamide (0.1 g, 277.47 μmol, 1 equiv.) and 8-(hydroxymethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (277.47 μmol, 1 equiv.) in DCE (1 mL) was added PBr (150.22 mg, 554.93 μmol, 52.71 μL, 2 equiv.) dropwise at 0° C., and the resulting mixture was stirred at 50° C. for 2 h. TLC (ethyl acetate:MeOH = 15:1, R f =0.56), HPLC and LCMS indicated the reaction was complete. The mixture was quenched with ice water (2 mL) at 0 °C and adjusted to pH = 7 with saturated NaHCO3. The aqueous layer was extracted with DCM (15 mL × 3). The combined organic layers were washed with brine (10 mL × 1), dried over Na2SO4, filtered, and concentrated under reduced pressure. A mixture of compound 8-(1-bromopropyl)-N,N-dimethyl-2-morpholino-4-oxo-chromene-6-carboxamide (90 mg, 212.62 μmol, 76.63% yield) and 8-(bromomethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide was obtained as a brown solid. 1 H NMR(DMSO-d6,400MHz) δ 7.88(s,1H), 7.86(s,1H), 5.75(s,1H), 5.64~5.60(m,1H), 3.75(t,J=4.8Hz,4H), 3.60 (t,J=8.4Hz,4H), 3.00(s,3H), 2.93(s,3H), 2.36~2.32(m,2H), 0.99(t,J=7.2Hz,3H). MS(ESI): Mass calculation value. C 19 H 23 For BrN2O4, 422.08 m / z, observed value 423.1 [M+H] + .

[0178] Preparation of 8-(1-((3,5-difluorophenyl)amino)propyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (Step 3 of Scheme 8) [ka] A mixture of 8-(bromomethyl)-N,N-dimethyl-2-morpholino-4-oxo-chromene-6-carboxamide (84.04 mg, 212.62 μmol, 1 equiv.), 8-(1-bromopropyl)-N,N-dimethyl-2-morpholino-4-oxo-chromene-6-carboxamide (90.00 mg, 212.62 μmol, 1 equiv.), and 3,5-difluoroaniline (109.80 mg, 850.46 μmol, 4 equiv.) in DMA (1 mL) was stirred at 50° C. for 10 h. LCMS and HPLC showed the reaction was nearly complete. The reaction mixture was purified by preparative HPLC (column: Welch Xtimate C18 100 × 25 mm × 3 μm; mobile phase: [water (0.05% HCl)-MeCN]; B%: 20% to 40%, 8 min). The solvent was removed by lyophilization. Compound 8-[1-(3,5-difluoroanilino)propyl]-N,N-dimethyl-2-morpholino-4-oxo-chromene-6-carboxamide (13.8 mg, 29.20 μmol, yield 13.73%, purity 99.76%) was obtained as a yellow solid. 1 H NMR(DMSO-d6,400MHz) δ 7.80(d,J=2.0Hz,1H), 7.55(d,J=2.0Hz,1H), 6.93~6.90(m,1H), 6.23~6.15(m,3H), 5.66(s,1H), 4.82(t,J=6.0Hz,1 H), 3.76(t,J=4.8Hz,4H), 3.61(t,J=8.4Hz,4H), 2.95(s,3H), 2.74(s,3H), 1.89~1.78(m,2H), 0.96(t,J=7.2Hz,3H). HPLC: 99.76% (220nm), 99.78% (254nm). MS(ESI): Mass calculation value. C 25 H 27 For F2N3O4, 471.20 m / z, actual value 472.2 [M+H] + . [ka]

[0179] General procedure for preparing compounds of Scheme 9 Preparation of methyl 8-bromo-2-morpholino-4-oxo-4H-chromene-6-carboxylate (Step 1 of Scheme 9) [ka] A solution of methyl 8-bromo-2-ethylsulfanyl-4-oxo-chromene-6-carboxylate (2 g, 5.83 mmol, 1 equiv.) and morpholine (2.03 g, 23.31 mmol, 2.05 mL, 4 equiv.) in MeCN (30 mL) was stirred at 80° C. for 5 h. TLC (petroleum ether: EtOAc = 1:1, R f =0.15) and LCMS showed that the reaction was nearly complete. The solvent was removed under reduced pressure. The residue was triturated with EtOAc (30 mL). The solid was collected. The compound methyl 8-bromo-2-morpholino-4-oxo-chromene-6-carboxylate (1.5 g, 4.07 mmol, 69.91% yield) was obtained as an off-white solid. 1 H NMR (DMSO-d6,400MHz) δ 8.41(s,1H), 8.33(s,1H), 5.63(s,1H), 3.90(s,3H), 3.75(t,J=5.2Hz,4H), 3.59(t,J=4.8Hz,4H).

[0180] Preparation of methyl 2-morpholino-4-oxo-8-vinyl-4H-chromene-6-carboxylate (Step 2 of Scheme 9) [ka] A mixture of methyl 8-bromo-2-morpholino-4-oxo-chromene-6-carboxylate (3.9 g, 10.59 mmol, 1 equiv.), Pd(dppf)Cl (775.08 mg, 1.06 mmol, 0.1 equiv.), KCO (2.93 g, 21.19 mmol, 2 equiv.), and potassium trifluoro(vinyl)borohydride (2.13 g, 15.89 mmol, 1.5 equiv.) in dioxane (50 mL) and HO (5 mL) was stirred at 100 °C under N for 5 h. TLC (petroleum ether: EtOAc = 0:1, R f=0.18) and LCMS showed that the reaction was nearly complete. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in EtOAc (100 mL) and water (100 mL). Some off-white solid was present. This solid (2.2 g) was collected after filtration. The filtrate was extracted with EtOAc (30 mL × 2). The combined organic layers were washed with brine (20 mL × 1), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was triturated with EtOAc (30 mL) to give 0.3 g of product. The compound methyl 2-morpholino-4-oxo-8-vinyl-chromene-6-carboxylate (2.5 g, 7.93 mmol, 74.85% yield) was obtained as a white solid. 1 H NMR(DMSO-d6,400MHz) δ 8.41(d,J=2.0Hz,1H), 8.33(d,J=2.4Hz,1H), 7.18(dd,J=6.0Hz,J=11.6Hz,1H), 6.08(d,J= 17.2Hz,1H), 5.61~5.58(m,2H), 3.91(s,3H), 3.74(t,J=4.4Hz,4H), 3.55(t,J=4.8Hz,4H).

[0181] Preparation of 2-morpholino-4-oxo-8-vinyl-4H-chromene-6-carboxylic acid (Step 3 of Scheme 9) [ka] A solution of methyl 2-morpholino-4-oxo-8-vinyl-chromene-6-carboxylate (4 g, 12.69 mmol, 1.0 equiv.) and LiOH·HO (1.60 g, 38.06 mmol, 3.0 equiv.) in THF (20 mL) and HO (20 mL) was stirred at 25 °C for 2 h. LCMS showed the reaction was complete. The resulting mixture was adjusted to pH = 4 with 2 M HCl. A yellow precipitate formed. The filter cake was collected after filtration. The compound 2-morpholino-4-oxo-8-vinyl-chromene-6-carboxylic acid (3.49 g, 11.58 mmol, 91.31% yield) was obtained as a yellow solid. 1H NMR(DMSO-d6,400MHz) δ 8.40(d,J=1.8Hz,1H), 8.33(d,J=1.8Hz,1H), 7.19(dd,J=11.2Hz,17.6Hz,1H), 6 .07(d,J=17.6Hz,1H), 5.61~5.55(m,2H), 3.72~3.75(m,4H), 3.57~3.53(m,4H).

[0182] Preparation of N,N-dimethyl-2-morpholino-4-oxo-8-vinyl-4H-chromene-6-carboxamide (Step 4 of Scheme 9) [ka] To a mixture of 2-morpholino-4-oxo-8-vinyl-chromene-6-carboxylic acid (1.4 g, 4.65 mmol, 1.0 equiv.) and N-methylmethanamine (1.14 g, 13.95 mmol, 1.28 mL, 3.0 equiv., HCl) in THF (30 mL), DIEA (3.00 g, 23.25 mmol, 4.05 mL, 5.0 equiv.) and T3P (2.22 g, 6.98 mmol, 2.07 mL, 1.5 equiv.) were added dropwise at 0 °C. The resulting mixture was stirred at 25 °C for 12 h. The mixture was adjusted to pH = 6 with 2 M HCl. The mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The compound N,N-dimethyl-2-morpholino-4-oxo-8-vinyl-chromene-6-carboxamide (1.7 g, crude) was obtained as a yellow solid. 1 H NMR(DMSO-d6,400MHz) δ 7.93(d,J=2.0Hz,1H), 7.82(d,J=2.0Hz,1H), 7.18(dd,J=11.2Hz,17.6Hz,1H), 6.09(d,J= 17.6Hz,1H), 5.62~5.50(m,2H), 3.77~3.72(m,4H), 3.58~3.51(m,4H), 3.06~2.92(m,6H).

[0183] Preparation of 8-formyl-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (Step 5 of Scheme 9) [ka] To a solution of N,N-dimethyl-2-morpholino-4-oxo-8-vinyl-chromene-6-carboxamide (1.7 g, 5.18 mmol, 1.0 equiv) in THF (15 mL) and HO (10 mL) was added OsO (0.25 g, 983.37 μmol, 51.02 μL, 0.19 equiv) at 25 °C. NaIO (3.32 g, 15.53 mmol, 860.64 μL, 3.0 equiv) was then added portionwise at 0 °C, and the resulting mixture was stirred at 0 °C for 30 min. The mixture was quenched with water (50 mL) and then extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with HO (30 mL × 2) and brine (30 mL × 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The compound 8-formyl-N,N-dimethyl-2-morpholino-4-oxo-chromene-6-carboxamide (1.2 g, 3.63 mmol, 70.17% yield) was obtained as a yellow solid. 1 H NMR (DMSO-d6,400MHz) δ 10.41(s,1H), 8.16(dd,J=2.0Hz,14.8Hz,2H), 5.66(s,1H), 3.77~3.72(m,4H), 3.66~3.60(m,4H), 3.08~2.96(m,6H).

[0184] Preparation of Compounds of Scheme 9 (Step 6 of Scheme 9) [ka] To a mixture of 8-formyl-N,N-dimethyl-2-morpholino-4-oxo-chromene-6-carboxamide (3.63 mmol, 1.0 equiv.) and indoline (3.63 mmol–7.27 mmol, 1.0 equiv.–2.0 equiv.) in MeOH (5 mL / mmol–7 mL / mmol), AcOH (108.98 mmol, 30 equiv.) was added at 25°C, and the resulting mixture was stirred at 25°C for 1 h. NaBH3CN (3.63 mmol–7.27 mmol, 1.0 equiv.–2.0 equiv.) was then added at 0°C, and the reaction mixture was stirred at 25°C for 1–2 h. The mixture was cooled to 0°C and adjusted to pH 6 with saturated NaHCO3. The mixture was extracted with ethyl acetate. The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography (Biotage; 20 g SepaFlash® silica flash column, eluting with a 0–20% MeOH / ethyl acetate gradient at 50 mL / min) or preparative HPLC (column: Phenomenex luna C18 80 × 40 mm × 3 μm or Waters Xbridge BEH C18 100 × 30 mm × 10 μm; mobile phase: [water (0.04% HCl)-MeCN]; B%: 34%–54% for 7 min or [water (0.04% HCl)-MeCN]; B%: 38%–52% for 7 min or [water (10 mM NH4HCO3)-MeCN]; B%: 20%–50% for 10 min or [water (10 mM NH4HCO3)-MeCN]; B%: 30%–50% for 8 min). The solvent was concentrated under reduced pressure or the aqueous solution was lyophilized to give the desired product.

[0185] compound 32 Preparation of 8-((4,6-difluoroindolin-1-yl)methyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (Step 6 of Scheme 9) [ka] To a mixture of 8-formyl-N,N-dimethyl-2-morpholino-4-oxo-chromene-6-carboxamide (1.2 g, 3.63 mmol, 1.0 equiv.) and 4,6-difluoroindoline (1.13 g, 7.27 mmol, 2.0 equiv.) in MeOH (20 mL), AcOH (6.54 g, 108.98 mmol, 6.23 mL, 30 equiv.) was added at 25 °C, and the resulting mixture was stirred at 25 °C for 1 h. NaBHCN (456.57 mg, 7.27 mmol, 2 equiv.) was then added at 0 °C, and the reaction mixture was stirred at 25 °C for 1 h. The mixture was cooled to 0 °C and adjusted to pH = 6 with saturated NaHCO. The mixture was extracted with ethyl acetate (80 mL × 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography (Biotage; 20 g SepaFlash® silica flash column, eluting with a 0-20% MeOH / ethyl acetate gradient at 50 mL / min). The solvent was concentrated. The resulting material was triturated with MTBE and CH3CN (v:v = 20:1, 30 mL) at 25 °C for 30 min. Compound 8-[(4,6-difluoroindolin-1-yl)methyl]-N,N-dimethyl-2-morpholino-4-oxo-chromene-6-carboxamide (1.2 g, 2.52 mmol, 69.38% yield, 98.6% purity) was obtained as a white solid. 1 H NMR(DMSO-d6,400MHz) δ 7.84(d,J=1.6Hz,1H), 7.59(d,J=1.6Hz,1H), 6.47~6.23(m,2H), 5.59(s,1H), 4.63(s,2H) , 3.72~3.66(m,4H), 3.56~3.51(m,4H), 3.48~3.45(m,2H), 3.01~2.94(m,5H), 2.89(s,3H). HPLC: 98.66% (220nm), 98.16% (254nm). MS(ESI): Mass calculation value. C 25 H 25 For F2O4N3, 469.18 m / z, actual value 470.2 [M+H] + .

[0186] compound 33 8-((4-Fluoro-2-methylindolin-1-yl)methyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide was prepared according to the procedure described in Scheme 9, Step 6. [ka] The desired compound (28.3 mg, 58.07 μmol, 19.18% yield, 95.52% purity) was obtained as a white solid. 1 H NMR(DMSO-d6,400MHz) δ 7.82(d,J=2.0Hz,1H), 7.52(d,J=2.0Hz,1H), 6.98~6.94(m,1H), 6.38(t,J=8.4Hz,1H), 6.10(d,J=8.0Hz,1H), 5.64(s,1H), 4.59(d,J= 6.8Hz,2H), 3.90~3.87(m,1H), 3.72~3.69(m,4H), 3.54(d,J=4.4Hz,4H), 3.31~3.27(m,2H), 2.96~2.82(m,6H), 1.25(d,J=6.0Hz,3H). MS: 95.52% (220nm), 95.90% (254nm). MS(ESI): Mass calculation value. C 26 H 28 For FN3O4, 465.21 m / z, actual value 466.2 [M+H] + .

[0187] compound 34 8-((4,6-Difluoro-3,3-dimethylindolin-1-yl)methyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide was prepared according to the procedure described in Scheme 9, step 6. [ka] The desired compound (33.1 mg, 65.63 μmol, 24.09% yield, 98.65% purity) was obtained as a white solid. 1H NMR(DMSO-d6,400MHz) δ 7.86(d,J=2.0Hz,1H), 7.56(s,1H), 6.41(d,J=10.8Hz,1H), 6.31(t,J=10.4Hz,1H), 5.59(s,1H), 4.64(s ,2H), 3.67(d,J=5.2Hz,4H), 3.53(d,J=5.2Hz,4H), 3.21(s,2H), 2.97(s,3H), 2.91(s,3H), 1.32(s,6H). HPLC: 98.65% (220nm), 99.03% (254nm). MS(ESI): Mass calculation value. C 27 H 29 For F2N3O4, 497.21 m / z, actual value 498.2 [M+H] + .

[0188] compound 35 8-((4-hydroxyindolin-1-yl)methyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide was prepared according to the procedure described in Scheme 9, Step 6. [ka] The desired compound (36.4 mg, 80.98 μmol, 26.75% yield, 100% purity) was obtained as a grey solid. 1 H NMR(DMSO-d6,400MHz) δ 9.10(s,1H), 7.84(d,J=2.0Hz,1H), 7.63(d,J=2.0Hz,1H), 6.84(t,J=8.0Hz,1H), 6.15(dd,J=8.0Hz,10.0Hz,2H), 5.60(s,1 H), 4.50(s,2H), 3.69(t,J=4.4Hz,4H), 3.54(t,J=4.8Hz,4H), 3.31(s,2H), 2.98(s,3H), 2.90(s,3H), 2.84(t,J=8.0Hz,2H). MS: 100.00% (220nm), 98.43% (254nm). MS(ESI): Mass calculation value. C 25 H 27 For N3O5, 449.20 m / z, actual value 450.2 [M+H] + .

[0189] compound 36 8-((7-chloroindolin-1-yl)methyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide was prepared according to the procedure described in Scheme 9, Step 6. [ka] The desired compound (2.1 mg, 4.31 μmol, 1.42% yield, 96.01% purity) was obtained as a white solid. 1 H NMR(400MHz,DMSO-d6) δ 7.83(d,J=2Hz,1H), 7.63(d,J=2Hz,1H), 7.10~6.97(m,2H), 6.66(t,J=7.6Hz,1H), 5.58(s,1H), 4.97(s, 2H), 3.71~3.69(m,4H), 3.55~3.51(m,4H), 3.50~3.46(m,2H), 3.03(t,J=8.6Hz,2H), 2.98~2.82(m,6H). LCMS: 96.01% (220nm), 95.47% (254nm). MS(ESI): Mass calculation value. C 25 H 26 For CIN3O4, 467.1 m / z, actual value 468.1 [M+H] + . [ka]

[0190] General procedure for preparing compounds of Scheme 10 Preparation of 8-bromo-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (Step 1 of Scheme 10) [ka] A solution of methyl 8-bromo-2-morpholino-4-oxo-chromene-6-carboxylate (2 g, 5.43 mmol, 1 equiv.) and LiOH HO (683.80 mg, 16.30 mmol, 3 equiv.) in HO (10 mL) and THF (5 mL) was stirred at 20 °C for 1 h. TLC (petroleum ether: EtOAc = 0:1, R f= 0) and LCMS showed that the reaction was complete. The resulting mixture was immediately brought to pH = 4 with 2N HCl at 0 °C, and the organic solvent was removed under reduced pressure. Some off-white solid formed. This solid was collected after filtration and dried under reduced pressure. The compound 8-bromo-2-morpholino-4-oxo-chromene-6-carboxylic acid (1.82 g, 5.14 mmol, 94.60% yield) was obtained as an off-white solid. 1 H NMR (DMSO-d6,400MHz) δ 8.42(d,J=2.0Hz,1H), 8.33(d,J=2.0Hz,1H), 5.64(s,1H), 3.75(t,J=4.4Hz,4H), 3.60(t,J=5.6Hz,4H).

[0191] Preparation of 8-bromo-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (Step 2 of Scheme 10) [ka] To a mixture of 8-bromo-2-morpholino-4-oxo-chromene-6-carboxylic acid (1.8 g, 5.08 mmol, 1 equiv.), DIEA (3.94 g, 30.50 mmol, 5.31 mL, 6 equiv.), and N-methylmethanamine (1.24 g, 15.25 mmol, 1.40 mL, 3 equiv., HCl) in DMF (10 mL) was added HATU (2.51 g, 6.61 mmol, 1.3 equiv.) in portions. The resulting mixture was stirred at 20 °C for 1 h. TLC (petroleum ether: EtOAc = 0:1, R f=0.12), HPLC and LCMS indicated the reaction was nearly complete. The mixture was poured into ice water (30 mL), which resulted in the formation of some off-white solid. The solid (0.5 g, off-white solid) was collected after filtration. The aqueous layer was extracted with EtOAc (10 mL × 5). The combined organic layers were washed with brine (5 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. This solid was used in the next step without further purification. The resulting residue was purified by flash silica gel chromatography (Biotage®; 20 g SepaFlash® silica flash column, eluent: 0-15% methanol / ethyl acetate @ 50 mL / min). The eluent was removed under reduced pressure (0.7 g, brown solid). Compound 8-bromo-N,N-dimethyl-2-morpholino-4-oxo-chromene-6-carboxamide (1.2 g, 3.15 mmol, 61.93% yield) was obtained as a brown solid. 1 H NMR(DMSO-d6,400MHz) δ 7.99(d,J=2.0Hz,1H), 7.86(d,J=2.0Hz,1H), 5.62(s,1H), 3.75(t,J=4.8Hz,4H), 3.59(t,J=4.4Hz,4H), 2.99(s,3H), 2.93(s,3H).

[0192] Preparation of N,N-dimethyl-2-morpholino-4-oxo-8-vinyl-4H-chromene-6-carboxamide (Step 3 of Scheme 10) [ka] A mixture of potassium trifluoro(vinyl)borohydride (843.28 mg, 6.30 mmol, 1.5 equiv.), Pd(dppf)Cl (307.10 mg, 419.70 μmol, 0.1 equiv.), KCO (1.16 g, 8.39 mmol, 2 equiv.), and 9-bromo-N,N-dimethyl-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxamide (1.6 g, 4.20 mmol, 1 equiv.) in dioxane (15 mL) and HO (1.5 mL) was stirred at 100 °C under N for 5 h. TLC (EtOAc:MeOH = 20:1, Rf =0.13) and LCMS showed the reaction was complete. DCM (20 mL) was added and filtered. The organic layer was separated, and the aqueous layer was extracted with DCM (10 mL × 3). The combined organic layers were washed with brine (5 mL × 1), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was triturated with petroleum ether (50 mL) and EtOAc (5 mL) and then dried under reduced pressure. The compound N,N-dimethyl-2-morpholino-4-oxo-9-vinyl-pyrido[1,2-a]pyrimidine-7-carboxamide (1.3 g, 3.96 mmol, 94.33% yield) was obtained as a brown solid. 1 H NMR(DMSO-d6,400MHz) δ 7.94(s,1H), 7.82(d,J=4.4Hz,1H), 7.18(dd,J=6.4Hz,11.2Hz,1H), 6.10(d,J=17.2Hz,1H), 5.59(s, 1H), 5.56(d,J=10.2Hz,1H), 4.04(t,J=6.8Hz,4H), 3.56(t,J=4.8Hz,4H), 3.01(s,3H), 2.94(s,3H).

[0193] Preparation of 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (Step 4 of Scheme 10) [ka] A mixture of N,N-dimethyl-2-morpholino-4-oxo-8-vinyl-chromene-6-carboxamide (0.3 g, 913.63 μmol, 1 equiv.) in HBr (7.70 g, 45.68 mmol, 5.17 mL, 48% purity, 50 equiv.) was stirred at 90 °C for 1 h. TLC (petroleum ether: EtOAc = 0:1, R f=0.5) and LCMS showed that the reaction was complete. Some brown solid formed. This solid was collected after filtration. The filtrate was adjusted to pH=7 with saturated Na2CO3 and then extracted with DCM (10 mL × 3). The combined organic layers were washed with brine (5 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. Compound 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-chromene-6-carboxamide (0.27 g, 659.71 μmol, 72.21% yield) was obtained as a brown solid. 1 H NMR(DMSO-d6,400MHz) δ 7.89(d,J=4.4Hz,2H), 5.75(q,J=6.4Hz,1H), 5.63(s,1H), 3.75(t,J=4.8Hz, 4H), 3.62(t,J=4.4Hz,4H), 3.00(s,3H), 2.94(s,3H), 2.10(d,J=6.8Hz,3H).

[0194] Preparation of Compounds of Scheme 10 (Step 5 of Scheme 10) [ka] A solution of 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-chromene-6-carboxamide (293.20 μmol, 1 equiv.), indoline (439.80 μmol, 1.5 equiv.), and DIEA (0.88 mmol–1.47 mmol, 3 equiv.–5 equiv.) in DMA (7 mL / mmol) was stirred at 50° C. for 10 h. LCMS and HPLC indicated the reaction was complete. The resulting mixture was quenched with ice-water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: Phenomenex Luna C18 100 × 30 mm × 5 μm or Phenomenex Luna C18 80 × 40 mm × 3 μm; mobile phase: [water (0.04% HCl)-MeCN]; B%: 30% to 60%, 10 min or [water (0.04% HCl)-MeCN]; B%: 40% to 60%, 7 min). The eluent was adjusted to pH = 7 with saturated NaHCO3 and extracted with EtOAc (15 mL × 3). The combined organic layer was washed with brine (10 mL × 1), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was further purified by preparative TLC (EtOAc:MeOH = 20:1). The product was dried by lyophilization to give the desired product.

[0195] compound 37 Preparation of 8-(1-(4,6-difluoroindolin-1-yl)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (Step 5 of Scheme 10) [ka] A solution of 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-chromene-6-carboxamide (0.12 g, 293.20 μmol, 1 equiv.), 4,6-difluoroindoline (68.23 mg, 439.80 μmol, 1.5 equiv.), and DIEA (189.47 mg, 1.47 mmol, 255.35 μL, 5 equiv.) in DMA (2 mL) was stirred at 50° C. for 10 h. LCMS and HPLC indicated the reaction was complete. The resulting mixture was quenched with ice-water (5 mL) and extracted with EtOAc (5 mL × 3). The combined organic layers were washed with brine (2 mL × 1), dried over NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: Phenomenex Luna Cl8 100 × 30 mm × 5 μm; mobile phase: [water (0.04% HCl)-MeCN]; B%: 30% to 60%, 10 min). The eluent was adjusted to pH = 7 with saturated NaHCO3 and extracted with EtOAc (15 mL × 3). The combined organic layers were washed with brine (10 mL × 1), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was further purified by preparative TLC (EtOAc:MeOH = 20:1). The product was dried under lyophilization. Compound 8-[1-(4,6-difluoroindolin-1-yl)ethyl]-N,N-dimethyl-2-morpholino-4-oxo-chromene-6-carboxamide (3.1 mg, 6.11 μmol, yield 2.08%, purity 95.29%) was obtained as a white solid. 1 H NMR(DMSO-d6,400MHz) δ 8.07(d,J=1.6Hz,1H), 7.80(s,1H), 6.17~6.08(m,2H), 5.65(s,1H), 5.38(q,J=6.0Hz,1H), 3.66(t,J=5.6Hz,4H ), 3.55(t,J=4.4Hz,4H), 3.30~3.24(m,2H), 3.13(s,3H), 3.01(s,3H), 3.01~2.88(m,2H), 1.31(d,J=7.2Hz,3H). HPLC: 95.29% (220nm), 94.27% (254nm). MS(ESI): Mass calculation value. C 26 H 27 For F2N3O4, 483.20 m / z, actual value 484.1 [M+H] +.

[0196] compound 38 8-(1-(4,6-Difluoro-2-methylindolin-1-yl)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide was prepared according to the procedure described in Scheme 10, Step 5. [ka] The desired compound (5.8 mg, 10.95 μmol, 3.73% yield, 93.91% purity) was obtained as a white solid. 1 H NMR (DMSO-d6, 400 MHz) δ 8.09 and 8.08 (d, J = 2.0 Hz, 2H), 7.86 and 7.84 (d, J = 1.6 Hz, 2H), 6.31–6.07 (m, 4H), 5.65 and 5.62 (s, 2H), 5.45–5.21 (m, 2H), 4.12–4.07 (m, 1H), 3.68–3.34 (m, 10H), 3.30–3.40 (m, 1H). 3.13(m,1H), 3.13(d,J=8.8Hz,6H), 3.03(d,J=8.8Hz,6H), 2.56~2.15(m,2H), 1.73( d,J=7.2Hz,3H), 1.63(d,J=7.2Hz,3H), 1.14(d,J=6.4Hz,3H), 0.75(d,J=6.0Hz,3H). HPLC: 93.91% (220nm), 92.44% (254nm). MS(ESI): Mass calculation value. C 27 H 29 For F2N3O4, 497.21 m / z, actual value 498.2 [M+H] + . [ka]

[0197] General procedure for preparing compounds of Scheme 11 Preparation of methyl 8-formyl-2-morpholino-4-oxo-4H-chromene-6-carboxylate (Step 1 of Scheme 11) [ka] To a solution of methyl 2-morpholino-4-oxo-8-vinyl-chromene-6-carboxylate (10 g, 31.71 mmol, 1.0 equiv.) in THF (80 mL) and HO (20 mL) was added OsO (0.25 g, 983.37 μmol, 51.02 μL, 3.10 equiv. to 2 equiv.). NaIO (20.35 g, 95.14 mmol, 5.27 mL, 3.0 equiv.) was then added portionwise to the resulting mixture at 0 °C, and the reaction mixture was stirred at 0 °C for 0.5 h. LCMS indicated the reaction was complete. The mixture was quenched with water (80 mL) and extracted with ethyl acetate (60 mL × 3). The combined organic phase was washed with HO (30 mL × 2) and brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The compound methyl 8-formyl-2-morpholino-4-oxo-chromene-6-carboxylate (9 g, 28.36 mmol, yield 89.44%) was obtained as a yellow solid. 1 H NMR(DMSO-d6,400MHz) δ 10.39(s,1H), 8.63(d,J=2.0Hz,1H), 8.55(d,J=2.0Hz,1H), 5.64(s,1H), 3.84(s,3H), 3.75~3.73(m,4H), 3.64~3.62(m,4H).

[0198] Preparation of methyl 8-((4,6-difluoroindolin-1-yl)methyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylate (Step 2 of Scheme 11) [ka] To a mixture of methyl 8-formyl-2-morpholino-4-oxochromene-6-carboxylate (5 g, 15.76 mmol, 1.0 equiv.) and 4,6-difluoroindoline (3.42 g, 22.06 mmol, 1.4 equiv.) in MeOH (40 mL) was added AcOH (28.39 g, 472.75 mmol, 27.04 mL, 30 equiv.) at 25 °C, and the resulting mixture was stirred at 25 °C for 1 h. NaBHCN (1.98 g, 31.52 mmol, 2.0 equiv.) was then added in portions at 0 °C. The resulting mixture was then stirred at 25 °C for 1 h. LCMS showed that the reaction was complete. The mixture was cooled to 0 °C and adjusted to pH = 7 with saturated NaHCO. The organic solvent was removed under reduced pressure at 45 °C. The aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give the compound methyl 8-[(4,6-difluoroindolin-1-yl)methyl]-2-morpholino-4-oxo-chromene-6-carboxylate (5.7 g, 12.49 mmol, 79.25% yield) as a yellow solid. 1 H NMR(DMSO-d6,400MHz) δ 8.41(s,1H), 8.07(s,1H), 6.44~6.42(m,1H), 6.32~6.30(m,1H), 5.59(s,1H), 4.62(s,2H) , 3.85(s,3H), 3.70~3.66(m,4H), 3.53~3.49(m,4H), 3.46~3.44(m,2H), 2.96~2.94(m,2H).

[0199] Preparation of 8-((4,6-difluoroindolin-1-yl)methyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (Step 3 of Scheme 11) [ka] To a solution of methyl 8-[(4,6-difluoroindolin-1-yl)methyl]-2-morpholino-4-oxo-chromene-6-carboxylate (5.5 g, 12.05 mmol, 1.0 equiv.) in THF (40 mL) was added a solution of LiOH·HO (2.02 g, 48.20 mmol, 4.0 equiv.) in HO (40 mL). The reaction mixture was stirred at 25 °C for 2 h. LCMS showed the reaction was complete. The mixture was adjusted to pH = 4 with 2 M HCl, and some off-white precipitate formed. After filtration, the filter cake was collected. The filtrate was concentrated under reduced pressure at 45 °C to remove the organic solvent. The aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The compound 8-[(4,6-difluoroindolin-1-yl)methyl]-2-morpholino-4-oxo-chromene-6-carboxylic acid (2 g, 4.52 mmol, 37.51% yield) was obtained as an off-white solid. 1 H NMR(DMSO-d6,400MHz) δ 8.42(d,J=2.0Hz,1H), 8.08(d,J=2.0Hz,1H), 6.48~6.28(m,2H), 5.60(s,1H), 4.64(s,2 H), 3.71~3.65(m,4H), 3.56~3.53(m,4H), 3.47(t,J=8.4Hz,2H), 2.97(t,J=8.4Hz,2H).

[0200] Preparation of Compounds of Scheme 11 (Step 4 of Scheme 11) [ka] To a mixture of 8-[(4,6-difluoroindolin-1-yl)methyl]-2-morpholino-4-oxo-chromene-6-carboxylic acid (4.48 mmol, 1.0 equiv.) and R'NHR" (5.82 mmol to 13.44 mmol, 1.3 equiv. to 3.0 equiv.) in THF (5 mL / mmol to 10 mL / mmol), DIEA (22.40 mmol to 38.56 mmol, 5.0 equiv. to 7.5 equiv.) was added. eq) and T3P (6.72 mmol to 10.07 mmol, 50% purity, 1.5 eq to 2.25 eq) were added dropwise under N2 at 0°C. The resulting mixture was then stirred at 25°C for 2 to 72 hours. LCMS showed that 8-[(4,6-difluoroindolin-1-yl)methyl]-2-morpholino-4-oxo-chromene-6-carboxylic acid was completely consumed. The mixture was diluted with 2M The pH was adjusted to 7 with HCl. A white precipitate formed. After filtration, the filter cake was triturated twice with MTBE and CH3CN (v:v=20:1) at 25°C for 30 minutes. Alternatively, the reaction mixture was quenched by adding it to ice water. The resulting mixture was filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by preparative HPLC (column: Welch Xtimate C18 100 x 25 mm x 3 μm or Waters Xbridge Prep OBD C18 150 x 40 mm x 10 μm or Phenomenex luna C18 80 × 40 mm × 3 μm; Mobile phase: [water (0.05% HCl)-MeCN]; B%: 15% to 35% for 8 min or [water (0.04% HCl)-MeCN]; B%: 45% to 55% for 7 min or [water (0.04% HCl)-MeCN]; B%: 18% to 55% for 7 min or [water (10 mM NH4HCO3)-MeCN]; B%: 25% to 55% for 8 min]. The aqueous solution was lyophilized to give the desired product.

[0201] compound 39 8-((4,6-difluoroindolin-1-yl)methyl)-N-(2-(dimethylamino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxamide was prepared according to the procedure described in Scheme 11, Step 4. [ka] The desired compound (23.7 mg, 45.38 μmol, 28.68% yield, 98% purity) was obtained as a pale yellow solid. 1 H NMR(DMSO-d6,400MHz) δ 9.09(s,1H), 8.45(s,1H), 8.15(s,1H), 6.44~6.31(m,2H), 5.73(s,1H), 4.64(s,2H), 3.69~3.65( m,4H), 3.64~3.55(m,2H), 3.56~3.49(m,4H), 3.48(m,2H), 3.26(s,2H), 2.97(s,2H), 2.81(s,6H). MS: 98.15% (220nm), 100.00% (254nm). MS(ESI): Mass calculation value. C 27 H 30 For F2N4O4, 512.22 m / z, actual value 513.2 [M+H] + .

[0202] compound 40 8-((4,6-difluoroindolin-1-yl)methyl)-N-(2-(dimethylamino)ethyl)-N-methyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide was prepared according to the procedure described in Scheme 11, Step 4. [ka] The desired compound (16.7 mg, 31.48 μmol, 19.90% yield, 99.26% purity) was obtained as a yellow solid. 1 H NMR(400MHz,DMSO-d6) δ 8.01(s,1H), 7.82(s,1H), 6.43(d,J=9.6Hz,1H), 6.32(t,J=8.0Hz,1H), 5.79(s,1H), 4.63(s,2H), 3.81~3.79(m,2H), 3.69~3.66(m,4H), 3.58~3.55(m,4H), 3.51(t,J=8.4Hz,2H), 3.35~2.33(m,2H), 2.98~2.93(m,5H), 2.85~2.83(m,6H). LCMS: 99.26% (220nm), 99.76% (254nm). MS(ESI): Mass calculation value. C 28 H32 For F2N4O4, 526.24 m / z, actual value 527.2 [M+H] + .

[0203] compound 41 8-((4,6-Difluoroindolin-1-yl)methyl)-6-(morpholine-4-carbonyl)-2-morpholino-4H-chromen-4-one was prepared according to the procedure described in Scheme 11, Step 4. [ka] The desired compound (18.2 mg, 32.47 μmol, 20.52% yield, 91.26% purity) was obtained as a yellow solid. 1 H NMR(DMSO-d6,400MHz) δ 7.85(s,1H), 7.57(s,1H), 6.50~6.20(m,2H), 5.60(s,1H), 4.64(s,2H), 3.70 ~3.66(m,4H), 3.57~3.40(m,12H), 3.30~3.26(m,2H), 2.98(t,J=8.4Hz,2H). HPLC: 91.27% (220nm), 100% (254nm). MS(ESI): Mass calculation value. C 27 H 27 For F2O5N3, 511.19 m / z, actual value 512.2 [M+H] + .

[0204] compound 42 8-((4,6-Difluoroindolin-1-yl)methyl)-2-morpholino-6-(pyrrolidine-1-carbonyl)-4H-chromen-4-one was prepared according to the procedure described in Scheme 11, Step 4. [ka] The desired compound (22.6 mg, 44.90 μmol, 24.83% yield, 98.45% purity) was obtained as a white solid. 1H NMR(400MHz,DMSO-d6) δ 7.97(d,J=2.0Hz,1H), 7.70(d,J=2.0Hz,1H), 6.44(d,J=2.0Hz,1H), 6.35(t,J=2.0Hz,1H), 5.61(s,1H), 4. 64(s,2H), 3.71~3.65(m,4H), 3.54~3.51(m,4H), 3.34~3.32(m,2H), 2.97~2.94(m,2H), 1.89~1.76(m,4H). LCMS: 98.45% (220nm), 100.00% (254nm). MS(ESI): Mass calculation value. C 27 H 27 For F2N3O4, 495.20 m / z, actual value 496.20 [M+H] + .

[0205] compound 43 8-((4,6-Difluoroindolin-1-yl)methyl)-6-(3-(dimethylamino)pyrrolidine-1-carbonyl)-2-morpholino-4H-chromen-4-one was prepared according to the procedure described in Scheme 11, Step 4. [ka] The desired compound (44 mg, 80.75 μmol, 44.65% yield, 98.84% purity) was obtained as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.86(s,1H), 8.01(s,1H), 7.73(s,1H), 6.44(d,J=10.4Hz,1H), 6.31(t ,J=10.0Hz,1H), 5.63(s,1H), 4.65(s,2H), 3.69~3.68(m,2H), 3.67~3.6 5(m,4H), 3.56~3.53(m,4H), 3.49~3.47(m,2H), 2.99~2.97(m,2H), 2.88 ~2.66(m,6H), 2.64~2.62(m,2H), 2.18~2.16(m,1H), 1.72~1.46(m,2H). HPLC: 98.85% (220nm), 99.79% (254nm). MS(ESI): Mass calculation value. C 29 H 32 For F2N4O4, 538.24 m / z, actual value 539.2 [M+H]+ .

[0206] compound 44 8-((4,6-difluoroindolin-1-yl)methyl)-6-(4-methylpiperazine-1-carbonyl)-2-morpholino-4H-chromen-4-one was prepared according to the procedure described in Scheme 11, Step 4. [ka] The desired compound (23.2 mg, 43.01 μmol, 23.78% yield, 97.24% purity) was obtained as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.09(s,1H), 7.93(d,J=2.0Hz,1H), 7.64(d,J=2.0Hz,1H), 6.44(d,J=1.6Hz,1H), 6.36(t,J=1.6Hz,1H), 5.65(s,1H), 4.64(s,2H), 4.04~4.00 (m,4H), 3.71~3.67(m,4H), 3.57~3.53(m,4H), 3.48~3.46(m,2H), 3.37( s,2H), 2.99~2.95(m,2H), 2.97(t,J=8.4Hz,2H), 2.74(d,J=4.4Hz,3H). LCMS: 97.25% (220nm), 100.00% (254nm). MS(ESI): Mass calculation value. C 28 H 30 For F2N4O4, 524.22 m / z, actual value 525.2 [M+H] + .

[0207] compound 45 6-(Azetidine-1-carbonyl)-8-((4,6-difluoroindolin-1-yl)methyl)-2-morpholino-4H-chromen-4-one was prepared according to the procedure described in Scheme 11, Step 4. [ka] The desired compound (12.4 mg, 25.49 μmol, 14.09% yield, 98-96% purity) was obtained as a white solid. 1H NMR(DMSO-d6,400MHz) δ 8.07(d,J=2.0Hz,1H), 7.77(d,J=2.0Hz,1H), 6.44(d,J=9.6Hz,1H), 6.32(t,J=9.6Hz,1H), 5.60(s,1H), 4.65(s,2H), 4.24(t,J=7.2H) z,2H), 4.04(t,J=7.6Hz,2H), 3.72~3.64(m,4H), 3.56~3.51(m,4H), 3.49~3.44(m,2H), 2.97(t,J=8.4Hz,2H), 2.25(t,J=7.8Hz,2H). HPLC: 98.96% (220nm), 100% (254nm). MS(ESI): Mass calculation value. C 26 H 25 For F2O4N3, 481.18 m / z, actual value 482.1 [M+H] + .

[0208] compound 46 8-((4,6-Difluoroindolin-1-yl)methyl)-6-(3-(dimethylamino)azetidine-1-carbonyl)-2-morpholino-4H-chromen-4-one was prepared following the procedure described in Scheme 11, Step 4. [ka] The desired compound (18.1 mg, 34.40 μmol, 19.02% yield, 99.70% purity) was obtained as a white solid. 1 H NMR(DMSO-d6,400MHz) δ 8.09(s,1H), 7.73(s,1H), 6.43(d,J=10.0Hz,1H), 6.31(t,J=9.2Hz,1H), 5.60(s,1H), 4.66(s,2H), 4.17(s,1H), 4.05(t,J=8.0Hz,1H), 3. 93(s,1H), 3.81(s,1H), 3.69(s,4H), 3.53(t,J=6.0Hz,4H), 3.38~3.34(m,2H), 3.07(t,J=4.8Hz,1H), 3.00(t,J=7.2Hz,2H), 2.05(s,6H). LCMS: 99.70% (220nm), 100.00% (254nm). MS(ESI): Mass calculation value. C 28 H 30For F2N4O4, 524.22 m / z, actual value 525.2 [M+H] + . [ka]

[0209] compound 47 Preparation of 9-(1-((3,5-difluorophenyl)amino)ethyl)-7-((4,4-dimethyl-4,5-dihydrooxazol-2-yl)amino)-2-morpholino-4H-pyrido[1,2-a]pyrimidin-4-one (Steps 1-8 of Scheme 12) Preparation of 7-bromo-2-hydroxy-9-iodo-4H-pyrido[1,2-a]pyrimidin-4-one (Step 1 of Scheme 12) [ka] To a mixture of 5-bromo-3-iodo-pyridin-2-amine (40 g, 133.82 mmol, 1 equiv.) in DCE (500 mL) was added propanedioyl dichloride (20.75 g, 147.20 mmol, 14.31 mL, 1.1 equiv.) dropwise under N at 0° C. The resulting mixture was then stirred at 20° C. for 1 hour and then at 50° C. for 9 hours. The mixture was then stirred at 70° C. for 10 hours. The mixture was then stirred at 75° C. for 4 hours. TLC (petroleum ether:ethyl acetate=2:1), HPLC, and LCMS indicated that approximately 15% of 5-bromo-3-iodo-pyridin-2-amine remained, and LCMS indicated approximately 55% of the desired amine remained. Some yellow solid formed, and the yellow precipitate was collected by filtration. The compound 7-bromo-2-hydroxy-9-iodo-pyrido[1,2-a]pyrimidin-4-one (49 g, 133.54 mmol, 99.79% yield) was obtained as a yellow solid. 1 H NMR (DMSO-d6,400MHz) δ 9.11(d,J=2.0Hz,1H), 8.67(d,J=2.0Hz,1H), 5.53(s,1H).

[0210] Preparation of 7-bromo-9-iodo-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl methanesulfonate (Step 2 of Scheme 12) [ka] To a mixture of 7-bromo-2-hydroxy-9-iodo-pyrido[1,2-a]pyrimidin-4-one (10 g, 27.25 mmol, 1 equiv.) and EtN (5.52 g, 54.51 mmol, 7.59 mL, 2 equiv.) in DCM (80 mL) was added MsCl (6.5 g, 56.74 mmol, 4.39 mL, 2.08 equiv.) dropwise under N at 0° C. The resulting mixture was stirred at 25° C. for 1 h. LCMS showed that 7-bromo-2-hydroxy-9-iodo-pyrido[1,2-a]pyrimidin-4-one was completely consumed. The resulting mixture was used in the next step without further purification. MS (ESI): mass calculated for CHBrISON 443.83 m / z, found 444.8 [M+H] + .

[0211] Preparation of 7-bromo-9-iodo-2-morpholino-4H-pyrido[1,2-a]pyrimidin-4-one (Step 3 of Scheme 12) [ka] A mixture of (7-bromo-9-iodo-4-oxo-pyrido[1,2-a]pyrimidin-2-yl)methanesulfonate (12 g, 26.96 mmol, 1 equiv.) and morpholine (7.05 g, 80.89 mmol, 7.12 mL, 3 equiv.) in DCM (80 mL) was stirred at 50 °C for 12 h. LCMS showed that (7-bromo-9-iodo-4-oxo-pyrido[1,2-a]pyrimidin-2-yl)methanesulfonate was completely consumed. The reaction mixture was quenched at 0 °C by the addition of HO (50 mL) and then extracted with DCM (100 mL × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The crude product was triturated with DCM (50 mL) at 25 °C for 30 min. The compound 7-bromo-9-iodo-2-morpholino-pyrido[1,2-a]pyrimidin-4-one (10.2 g, 23.39 mmol, 86.75% yield) was obtained as a yellow solid. 1 H NMR (DMSO-d6,400MHz) δ 8.80(d,J=2.0Hz,1H), 8.56(d,J=2.0Hz,1H), 5.62(s,1H), 3.72~3.68(m,8H).

[0212] Preparation of 9-acetyl-7-bromo-2-morpholino-4H-pyrido[1,2-a]pyrimidin-4-one (Step 4 of Scheme 12) [ka] A mixture of 7-bromo-9-iodo-2-morpholino-pyrido[1,2-a]pyrimidin-4-one (5.5 g, 12.61 mmol, 1 equiv.), tributyl(1-ethoxyvinyl)stannane (6.65 g, 18.42 mmol, 6.22 mL, 1.46 equiv.), and Pd(PPh)Cl (442.67 mg, 630.67 μmol, 0.05 equiv.) in dioxane (40 mL) was stirred at 70° C. under N for 11 hours. The resulting mixture was cooled to 25° C., and HCl (2 M, 7.57 mL, 1.2 equiv.) was added. The mixture was stirred at 25° C. for 1 hour. LCMS indicated that 7-bromo-9-iodo-2-morpholino-pyrido[1,2-a]pyrimidin-4-one was completely consumed. The mixture was concentrated under reduced pressure. The aqueous layer was adjusted to pH = 7 with saturated NaHCO3 and extracted with DCM (80 mL × 3). The combined organic layers were washed with brine (80 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was triturated with petroleum ether and EtOAc (v:v = 20:1, 30 mL) at 25 °C for 30 minutes. The compound 9-acetyl-7-bromo-2-morpholino-pyrido[1,2-a]pyrimidin-4-one (3.1 g, 8.80 mmol, 69.78% yield) was obtained as a yellow solid. 1 H NMR (DMSO-d6,400MHz) δ 8.92(d,J=2.4Hz,1H), 8.02(d,J=2.4Hz,1H), 5.69(s,1H), 3.68~3.66(m,4H), 3.60~3.58(m,4H), 2.65(s,3H).

[0213] Preparation of 7-bromo-9-(1-hydroxyethyl)-2-morpholino-4H-pyrido[1,2-a]pyrimidin-4-one (Step 5 of Scheme 12) [ka] To a mixture of 9-acetyl-7-bromo-2-morpholino-pyrido[1,2-a]pyrimidin-4-one (1 g, 2.84 mmol, 1 equiv.) and CeCl3·7H2O (1.06 g, 2.84 mmol, 269.88 μL, 1 equiv.) in MeOH (25 mL) and DCM (6 mL) was added NaBH4 (64.45 mg, 1.70 mmol, 0.6 equiv.) at −70 °C under N2. The resulting mixture was stirred at −70 °C for 0.3 h. TLC (EtOAc, R f =0.25), indicating complete consumption of 9-acetyl-7-bromo-2-morpholino-pyrido[1,2-a]pyrimidin-4-one. The mixture was slowly quenched with ice water (30 mL) at 0 °C, and the organic solvent was removed under reduced pressure. The aqueous layer was extracted with EtOAc (40 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The compound 7-bromo-9-(1-hydroxyethyl)-2-morpholino-pyrido[1,2-a]pyrimidin-4-one (0.67 g, 1.89 mmol, 66.62% yield) was obtained as a yellow solid. 1 H NMR(DMSO-d6,400MHz) δ 8.76(d,J=2.0Hz,1H), 7.85(d,J=2.0Hz,1H), 5.66(s,1H), 5.51(d,J=4.4Hz,1H) , 5.52~5.15(m,1H), 3.69~3.67(m,4H), 3.62~3.59(m,4H), 1.39(d,J=6.4Hz,3H).

[0214] Preparation of 7-bromo-9-(1-bromoethyl)-2-morpholino-4H-pyrido[1,2-a]pyrimidin-4-one (Step 6 of Scheme 12) [ka] To a solution of 7-bromo-9-(1-hydroxyethyl)-2-morpholino-pyrido[1,2-a]pyrimidin-4-one (0.67 g, 1.89 mmol, 1 equiv.) in DCE (10 mL) was added PBr (563.23 mg, 2.08 mmol, 1.1 equiv.) dropwise under N at 0 °C. The resulting mixture was stirred at 50 °C for 5 h. LCMS showed that 7-bromo-9-(1-hydroxyethyl)-2-morpholino-pyrido[1,2-a]pyrimidin-4-one was completely consumed. The mixture was cooled to 0 °C and adjusted to pH = 6 with saturated NaHCO. The organic phase was separated, and the aqueous phase was extracted with DCM (10 mL × 2). The combined organic phase was washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The compound 7-bromo-9-(1-bromoethyl)-2-morpholino-pyrido[1,2-a]pyrimidin-4-one (0.63 g, 1.51 mmol, 79.85% yield) was obtained as a yellow solid. 1 H NMR (DMSO-d6,400MHz) δ 8.82(s,1H), 8.20(s,1H), 5.94~5.90(m,1H), 5.68(s,1H), 3.72~3.66(m,8H), 2.06(d,J=6.8Hz,3H).

[0215] Preparation of 7-bromo-9-(1-((3,5-difluorophenyl)amino)ethyl)-2-morpholino-4H-pyrido[1,2-a]pyrimidin-4-one (Step 7 of Scheme 12) [ka] A mixture of 7-bromo-9-(1-bromoethyl)-2-morpholino-pyrido[1,2-a]pyrimidin-4-one (0.63 g, 1.51 mmol, 1 equiv.) and 3,5-difluoroaniline (779.81 mg, 6.04 mmol, 4 equiv.) in DMA (10 mL) was stirred at 50° C. for 12 hours. LCMS showed that 7-bromo-9-(1-bromoethyl)-2-morpholino-pyrido[1,2-a]pyrimidin-4-one was completely consumed. The mixture was cooled to 0° C. and quenched with water (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with brine (30 mL×2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography (Biotage; 12 g SepaFlash® silica flash column, eluting with a 0-100% ethyl acetate / petroleum ether gradient at 60 mL / min). The solvent was concentrated to give the compound 7-bromo-9-[1-(3,5-difluoroanilino)ethyl]-2-morpholino-pyrido[1,2-a]pyrimidin-4-one (0.48 g, 1.03 mmol, 68.32% yield) as a yellow oil. 1 H NMR(DMSO-d6,400MHz) δ 8.76(d,J=2.0Hz,1H), 7.73(d,J=2.0Hz,1H), 6.91(d,J=7.2Hz,1H), 6.24(t,J=9.6Hz,1H), 6. 09(d,J=9.6Hz,2H), 5.70(s,1H), 5.09~5.06(m,1H), 3.69~3.64(m,8H), 1.47(d,J=6.8Hz,3H).

[0216] Preparation of 9-(1-((3,5-difluorophenyl)amino)ethyl)-7-((4,4-dimethyl-4,5-dihydrooxazol-2-yl)amino)-2-morpholino-4H-pyrido[1,2-a]pyrimidin-4-one (Step 8 of Scheme 12) [ka] To a mixture of 7-bromo-9-[1-(3,5-difluoroanilino)ethyl]-2-morpholino-pyrido[1,2-a]pyrimidin-4-one (0.1 g, 214.92 μmol, 1 equiv.) and 4,4-dimethyl-5H-oxazol-2-amine (167.69 mg, 859.68 μmol, 4 equiv., HBr) in dioxane (2 mL), CuI (81.86 mg, 429.84 μmol, 2 equiv.), N,N'-dimethylethane-1,2-diamine (9.47 mg, 107.46 μmol, 11.57 μL, 0.5 equiv.), and CsCO (210.07 mg, 644.76 μmol, 3 equiv.) were added under N at 25 °C. The resulting mixture was stirred at 100 °C for 12 h. LCMS and HPLC indicated the reaction was complete. The mixture was filtered, and the filtrate was concentrated under reduced pressure at 45 °C. The resulting residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100 × 30 mm × 10 μm; mobile phase: [water (10 mM NH4HCO3)-MeCN]; B%: 30% to 60%, 8 min). The solvent was removed by lyophilization. The compound 9-[1-(3,5-difluoroanilino)ethyl]-7-[(4,4-dimethyl-5H-oxazol-2-yl)amino]-2-morpholino-pyrido[1,2-a]pyrimidin-4-one (3.1 mg, 6.22 μmol, yield 2.89%, purity 100%) was obtained as a white solid. 1 H NMR(DMSO-d6,400MHz) δ 9.33(s,1H), 8.39(s,1H), 7.70(s,1H), 7.45(s,1H), 6.96(s,1H), 6.20(t,J=9.6Hz,1H), 6.05(d,J=9.6Hz,2H), 5.6 3(s,1H), 5.07(s,1H), 4.13~4.10(m,2H), 3.70~3.67(m,4H), 3.62~3.57(m,4H), 1.47(d,J=6.8Hz,3H), 1.23(s,6H). HPLC: 100% (220nm), 96.01% (254nm). MS(ESI): Mass calculation value. C 25 H 28 For F2O3N6, 498.22 m / z, actual value 499.3 [M+H] + . [ka]

[0217] General procedure for preparing compounds of Scheme 13 Preparation of methyl 6-amino-5-bromonicotinate (Step 1 of Scheme 13) [ka] To a mixture of methyl 6-aminopyridine-3-carboxylate (50 g, 328.62 mmol, 1 equiv.) in THF (800 mL) was added NBS (64.34 g, 361.48 mmol, 1.1 equiv.) in portions at 0° C. The resulting mixture was then stirred at 20° C. for 10 h. TLC (petroleum ether:ethyl acetate=2:1, R f =0.45), indicating that the reaction was complete. The mixture was quenched with ice water (200 mL), and the organic solvent was removed under reduced pressure. Water (500 mL) was added to the residue. Some brown solid formed. The filtrate was extracted with EtOAc (200 mL × 6). The combined organic layers were washed with saturated NaHCO3 (200 mL × 4) and brine (100 mL × 1), dried over Na2SO4, filtered, and concentrated under reduced pressure. The solid (47 g) was collected without further purification. The resulting residue was triturated with EtOAc (200 mL) and dried under reduced pressure (11 g). Compound methyl 6-amino-5-bromo-pyridine-3-carboxylate (58 g, 251.03 mmol, 76.39% yield) was obtained as a brown solid. 1 H NMR (DMSO-d6,400MHz) δ 8.49(s,1H), 8.08(s,1H), 7.15~7.14(m,2H), 3.78(s,3H).

[0218] Preparation of methyl 9-bromo-2-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylate (Step 2 of Scheme 13) [ka] To a mixture of methyl 6-amino-5-bromo-pyridine-3-carboxylate (21 g, 90.89 mmol, 1 equiv.) in toluene (300 mL) at 50 °C, bis(2,4,6-trichlorophenyl)propanedioate (50 g, 108.01 mmol, 1.19 equiv.) was added portionwise at 50 °C under N2. The resulting mixture was then stirred at 100 °C for 5 h. TLC (petroleum ether:ethyl acetate=2:1, R f =0.10) and LCMS showed that the reaction was complete. The brown precipitate was collected by filtration. The precipitate was washed with a small amount of ice-cold petroleum ether (200 mL) until the filtrate was colorless. The compound methyl 9-bromo-2-hydroxy-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxylate (26.5 g, 88.61 mmol, 97.49% yield) was obtained as a brown solid. 1 H NMR (DMSO-d6,400MHz) δ 9.31(s,1H), 8.45(s,1H), 5.59(s,1H), 3.92(s,3H).

[0219] Preparation of methyl 9-bromo-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylate (Step 3 of Scheme 13) [ka] To a mixture of methyl 9-bromo-2-hydroxy-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxylate (26.5 g, 88.61 mmol, 1 equiv.) and EtN (17.93 g, 177.21 mmol, 24.67 mL, 2 equiv.) in DCM (300 mL), MsCl (14.21 g, 124.05 mmol, 9.60 mL, 1.4 equiv.) was added dropwise at 0°C under N2. The resulting mixture was then stirred at 20°C for 1 h. Morpholine (23.16 g, 265.82 mmol, 23.39 mL, 3 equiv.) was then added, and the resulting mixture was stirred at 20°C for 5 h. TLC (petroleum ether:ethyl acetate = 1:1, R f=0.2) and LCMS showed that the reaction was complete. The mixture was poured into ice water (200 mL) at 0 °C, and some solid formed. This solid (9 g, off-white solid) was collected after filtration. The organic solvent was separated. The aqueous layer was extracted with DCM (150 mL × 4). The combined organic layers were washed with brine (100 mL × 1), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was triturated with DCM (50 mL) and EtOAc (100 mL), and the resulting solid (15 g, off-white solid) was then dried under reduced pressure. The compound methyl 9-bromo-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxylate (24 g, 65.19 mmol, 73.57% yield) was obtained as an off-white solid. 1 H NMR (DMSO-d6,400MHz) δ 9.24(d,J=2.0Hz,1H), 8.37(d,J=2.0Hz,1H), 5.69(s,1H), 3.90(s,3H), 3.69(s,8H).

[0220] Preparation of methyl 9-acetyl-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylate (Step 4 of Scheme 13) [ka] A mixture of methyl 9-bromo-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxylate (9 g, 24.44 mmol, 1 equiv.), tributyl(1-ethoxyvinyl)stannane (12.87 g, 35.64 mmol, 12.03 mL, 1.46 equiv.), and Pd(PPh3)2Cl2 (857.88 mg, 1.22 mmol, 0.05 equiv.) in dioxane (100 mL) was stirred at 100 °C under N2 for 5 h. TLC (petroleum ether: EtOAc = 0:1, R f=0.2) and LCMS showed that the reaction was complete. The mixture was cooled to room temperature, and 14.67 mL of 2N HCl was added, and the resulting mixture was stirred at room temperature for 1 hour. The organic solvent was removed under reduced pressure. The aqueous layer was adjusted to pH=7 with saturated NaHCO3 and extracted with DCM (100 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was triturated with petroleum ether and EtOAc (v:v=10:1, 440 mL x 1). The resulting solid was collected after filtration. Compound methyl 9-acetyl-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxylate (7 g, 21.13 mmol, 86.43% yield) was obtained as a yellow solid. 1 H NMR (DMSO-d6,400MHz) δ 9.36(d,J=2.4Hz,1H), 8.18(d,J=2.0Hz,1H), 5.72(s,1H), 3.91(s,3H), 3.68~3.65(m,8H), 2.68(s,3H).

[0221] Preparation of methyl 9-(1-hydroxyethyl)-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylate (Step 5 of Scheme 13) [ka] To a mixture of methyl 9-acetyl-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxylate (7 g, 21.13 mmol, 1 equiv.) and CeCl 7HO (7.87 g, 21.13 mmol, 28.69 μL, 1 equiv.) in DCM (15 mL) and MeOH (60 mL), NaBH (479.55 mg, 12.68 mmol, 0.6 equiv.) was added portionwise at −70 °C, and the resulting mixture was stirred at −70 °C for 0.3 h. TLC (petroleum ether: EtOAc = 0:1, R f=0.2) and LCMS showed that the reaction was complete. The mixture was slowly quenched with ice water (100 mL) at -70 °C and filtered through Celite. The filtrate was extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (50 mL × 1), dried over Na2SO4, filtered, and concentrated under reduced pressure. The compound methyl 9-(1-hydroxyethyl)-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxylate (5.6 g, 16.80 mmol, 79.52% yield) was obtained as a yellow solid. 1 H NMR(DMSO-d6,400MHz) δ 9.24(d,J=2.0Hz,1H), 8.17(d,J=2.0Hz,1H), 5.67(s,1H), 5.52(d,J=4.4Hz,1 H), 5.19~5.15(m,1H), 3.90(s,3H), 3.68~3.60(m,8H), 1.18(t,J=7.6Hz,3H).

[0222] Preparation of methyl 9-(1-bromoethyl)-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylate (Step 6 of Scheme 13) [ka] To a solution of methyl 9-(1-hydroxyethyl)-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxylate (3 g, 9.00 mmol, 1 equiv.) in DCE (50 mL) was added PBr (3.17 g, 11.70 mmol, 1.11 mL, 1.3 equiv.) dropwise at 0 °C, and the resulting mixture was stirred at 50 °C for 5 h. TLC (petroleum ether: EtOAc = 1:1, R f=0.35) and LCMS showed the reaction was complete. The mixture was quenched with ice water (50 mL) at 0 °C and adjusted to pH = 6-7 with saturated Na2CO3. The aqueous layer was extracted with DCM (50 mL × 3). The combined organic layers were washed with brine (20 mL × 1), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was triturated with EtOAc (30 mL). Compound methyl 9-(1-bromoethyl)-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxylate (1.9 g, 4.80 mmol, 53.28% yield) was obtained as a white solid. 1 H NMR(DMSO-d6,400MHz) δ 9.27(d,J=2.0Hz,1H), 8.23(d,J=2.0Hz,1H), 5.97~5.86(m,1H), 5.70(s,1H), 3.91(s,3H), 3.69(s,8H), 2.08(d,J=6.8Hz,3H).

[0223] Preparation of methyl 9-(1-((3,5-difluorophenyl)amino)ethyl)-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylate (Step 7 of Scheme 13) [ka] A solution of methyl 9-(1-bromoethyl)-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxylate (1.9 g, 4.80 mmol, 1 equiv.) and 3,5-difluoroaniline (1.86 g, 14.39 mmol, 3 equiv.) in DMA (20 mL) was stirred at 55 °C for 10 h. TLC (petroleum ether:ethyl acetate = 1:1, R f=0.26) and LCMS showed that the reaction was complete. The resulting mixture was quenched with ice water (50 mL), and some white solid formed. After filtration, this solid (1 g) was collected and concentrated under reduced pressure. The filtrate was extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (10 mL × 4), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was triturated with MeOH (30 mL) to give 1 g of a solid, which was used in the next step without further purification. The compound methyl 9-[1-(3,5-difluoroanilino)ethyl]-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxylate (2 g, 4.50 mmol, 93.85% yield) was obtained as a white solid. 1 H NMR(DMSO-d6,400MHz) δ 9.24(d,J=2.0Hz,1H), 8.00(d,J=2.0Hz,1H), 7.08(d,J=6.8Hz,1H), 6.23(t,J=7.2Hz,1H), 6.08(dd,J =2.0Hz,10.4Hz,2H), 5.73(s,1H), 5.08~5.05(m,1H), 3.86(s,3H), 3.70(s,8H), 1.48(d,J=6.4Hz,3H).

[0224] Preparation of 9-(1-((3,5-difluorophenyl)amino)ethyl)-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylic acid (Step 8 of Scheme 13) [ka] A solution of methyl 9-[1-(3,5-difluoroanilino)ethyl]-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxylate (2 g, 4.50 mmol, 1 equiv.) and LiOH HO (566.48 mg, 13.50 mmol, 3 equiv.) in HO (10 mL) and THF (10 mL) was stirred at 20 °C for 1 h. TLC (petroleum ether: EtOAc = 1:1, R f=0.05) and LCMS showed that the reaction was complete. The organic solvent was removed under reduced pressure. 5 mL of water was added, and the aqueous layer was adjusted to pH=4 with 1N HCl at 0°C, resulting in the formation of some solid. After filtration, the solid was collected and concentrated under reduced pressure. The compound 9-[1-(3,5-difluoroanilino)ethyl]-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxylic acid (1.8 g, 4.18 mmol, 92.93% yield) was obtained as a white solid. 1 H NMR(DMSO-d6,400MHz) δ 13.53~13.50(m,1H), 9.21(d,J=2.0Hz,1H), 8.00(d,J=2.0Hz,1H), 7.06(d,J=6.8Hz,1H), 6.22(t,J=7.2Hz ,1H), 6.09(dd,J=2.0Hz,10.4Hz,2H), 5.71(s,1H), 5.07~5.02(m,1H), 3.69(s,8H), 1.47(d,J=6.8Hz,3H).

[0225] Preparation of Compounds of Scheme 13 (Step 9 of Scheme 13) [ka] To a solution of 9-[1-(3,5-difluoroanilino)ethyl]-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxylic acid (697.02 μmol, 1 equiv.), amine (1.05 mmol, 1.5 equiv.), and DIEA (3.49 mmol-4.18 mmol, 5 equiv.-6 equiv.) in THF (7 mL / mmol-9 mL / mmol) was added T3P (906.13 μmol, 50% purity, 1.3 equiv.) dropwise at 0°C. The resulting mixture was then stirred at 20°C for 5 h. HPLC and LCMS indicated that the reaction was nearly complete. The mixture was quenched with ice water and then extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: Phenomenex Gemini-NX 80 × 40 mm × 3 μm or Phenomenex Gemini-NX C18 75 × 30 mm × 3 μm; mobile phase: [water (10 mM NH4HCO3)-MeCN]; B%: 20% to 50%, 8 min or [water (10 mM NH4HCO3)-MeCN]; B%: 30% to 50%, 8 min). The eluent was removed by lyophilization. The aqueous solution was lyophilized to give the desired product.

[0226] compound 48 Preparation of 9-(1-((3,5-difluorophenyl)amino)ethyl)-7-(3-(dimethylamino)pyrrolidine-1-carbonyl)-2-morpholino-4H-pyrido[1,2-a]pyrimidin-4-one (Step 9 of Scheme 13) [ka] To a solution of 9-[1-(3,5-difluoroanilino)ethyl]-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxylic acid (0.3 g, 697.02 μmol, 1 equiv.), N,N-dimethylpyrrolidin-3-amine (119.39 mg, 1.05 mmol, 1.5 equiv.), and DIEA (450.41 mg, 3.49 mmol, 607.03 μL, 5 equiv.) in THF (5 mL) was added T3P (576.62 mg, 906.13 μmol, 538.90 μL, 50% purity, 1.3 equiv.) dropwise at 0° C. The resulting mixture was then stirred at 20° C. for 5 h. HPLC and LCMS indicated the reaction was nearly complete. The mixture was quenched with ice water (10 mL) and then extracted with EtOAc (10 mL × 2). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: Phenomenex Gemini-NX 80 × 40 mm × 3 μm; mobile phase: [water (10 mM NH4HCO3)-MeCN]; B%: 20% to 50%, 8 min). The eluent was removed by lyophilization. The compound 9-[1-(3,5-difluoroanilino)ethyl]-7-[3-(dimethylamino)pyrrolidine-1-carbonyl]-2-morpholino-pyrido[1,2-a]pyrimidin-4-one (205.8 mg, 389.77 μmol, 55.92% yield, 99.73% purity) was obtained as a white solid. 1 H NMR(DMSO-d6,400MHz) δ 8.88(s,1H), 7.82(s,1H), 7.03~6.96(m,1H), 6.22~6.20(m,1H), 6.08(d,J=9.6Hz,2H), 5.71(s,1H), 5.10~5.07(m,1H), 3.69(s,8H), 3. 62~3.53(m,1H), 3.44~3.40(m,2H), 3.24~3.21(m,1H), 2.55~2.52(m,1H), 2.16~1.97(m,7H), 1.69~1.68(m,1H), 1.48(d,J=6.4Hz,3H). HPLC: 99.73% (220nm), 100% (254nm). MS(ESI): Mass calculation value. C 27 H 32For F2N6O3, 526.25 m / z, actual value 527.2 [M+H] + . Chiral separation of compound 48 was performed using a Thar 80 preparative SFC; columns: (s,s) Whelk O-1, 250 x 30 mm, 10 μm internal diameter and Daicel Chiralpak IC, 250 x 30 mm, 10 μm internal diameter. Chiral analytical equipment: Waters Acquity Arc; columns: S,S_Whelk_O1, 3.5 μm, 0.46 cm internal diameter x 10 cm length. Four isomers were obtained. Compound 48-P1 (Rt = 6.501 min, ee (%) by chiral HPLC = 95.8%); compound 48-P2 (Rt = 7.525 min, ee (%) by chiral HPLC = 95.8 = 100%); compound 48-P3 (Rt = 8.298 min, ee (%) by chiral HPLC = 98.8%); and compound 48-P4 (Rt = 14.409 min, ee (%) by chiral HPLC = 99.46%).

[0227] compound 49 9-(1-((3,5-difluorophenyl)amino)ethyl)-7-(3-(dimethylamino)azetidine-1-carbonyl)-2-morpholino-4H-pyrido[1,2-a]pyrimidin-4-one was prepared according to the procedure described in Scheme 13, step 9. [ka] The desired compound (26 mg, 50.26 μmol, 21.63% yield, 99.08% purity) was obtained as a white solid. 1H NMR(DMSO-d6,400MHz) δ 8.95(d,J=2.4Hz,1H), 7.84(s,1H), 7.04(d,d,J=7.2Hz,1H), 6.25~6.20(m,1H), 6.11~6.08(m,2H), 5.72(s,1H) , 5.08(t,J=6.8Hz,1H), 4.22~3.80(m,4H), 3.66(s,8H), 3.06~3.03(m,1H), 2.05(s,6H), 1.49(d,J=6.8Hz,3H). HPLC: 99.08% (220nm), 100% (254nm). MS(ESI): Mass calculation value. C 26 H 30 For F2N6O3, 512.23 m / z, actual value 513.2 [M+H] + . [ka] [ka]

[0228] compound 50 Preparation of 9-((R)-1-((3,5-difluorophenyl)amino)ethyl)-7-((R)-3-(dimethylamino)pyrrolidine-1-carbonyl)-2-morpholino-4H-pyrido[1,2-a]pyrimidin-4-one (Steps 1-6 of Scheme 14) Preparation of (R,E)-9-(1-((tert-butylsulfinyl)imino)ethyl)-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylate (Step 1 of Scheme 14) [ka] A mixture of methyl 9-acetyl-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxylate (4.1 g, 12.37 mmol, 1 equiv.), (R)-2-methylpropane-2-sulfinamide (2.70 g, 22.27 mmol, 1.8 equiv.), and Ti(i-PrO) (14.07 g, 49.50 mmol, 14.61 mL, 4 equiv.) in THF (80 mL) was stirred at 70 °C under N for 20 h. LCMS and TLC (petroleum ether: EtOAc = 2:1, R f =0.3), indicating that the reaction was complete and that most of the (R,E)-9-(1-((tert-butylsulfinyl)imino)ethyl)-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylate was formed. The resulting mixture was quenched with ice water (100 mL) at 0 °C, and EtOAc (300 mL) was added. After filtration through Celite, the filter cake was washed with EtOAc (50 mL × 3). The organic layer was separated. The aqueous phase was extracted with EtOAc (100 mL × 1). The combined organic layers were washed with brine (50 mL × 1), dried over Na2SO4, filtered, and concentrated under reduced pressure. Isopropyl 9-[(Z)-N-[(S)-tert-butylsulfinyl]-C-methyl-carbonimidoyl]-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxylate (5.5 g, 11.89 mmol, 96.09% yield) was obtained as a brown solid. 1 H NMR(DMSO-d6,400MHz) δ 9.30~9.22(m,1H), 8.03~7.96(m,1H), 5.71~5.69(m,1H), 5.20~5.17(m, 1H), 3.65(s,8H), 2.53(s,3H), 1.35(d,J=6.0Hz,6H), 1.21~1.15(m,9H).

[0229] Preparation of isopropyl 9-((R)-1-((R)-1,1-dimethylethylsulfinamido)ethyl)-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylate (Step 2 of Scheme 14) [ka] To a solution of isopropyl 9-[(E)-N-[(S)-tert-butylsulfinyl]-C-methyl-carbonimidoyl]-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxylate (5.5 g, 11.89 mmol, 1 equiv.) and AcOH (5.71 g, 95.12 mmol, 5.44 mL, 8 equiv.) in MeOH (50 mL) and DCM (50 mL) was added NaBHCN (2.24 g, 35.67 mmol, 3 equiv.) portionwise at −15° C., and the resulting mixture was stirred at −15° C. for 5 h. TLC (petroleum ether: EtOAc = 0:1, R f =0.10) and LCMS indicated the reaction was complete. The mixture was quenched with ice water (30 mL) at 0 °C, and then saturated Na2CO3 solution was added until pH = 7. The aqueous solution was extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (Biotage®; 40 g SepaFlash® silica flash column, eluent: 0–100% ethyl acetate / petroleum ether gradient @ 30 mL / min). The eluent was removed under reduced pressure. Compound 9-[(1S)-1-[[(R)-tert-butylsulfinyl]amino]ethyl]-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxylate isopropyl (2.8 g, 6.03 mmol, 50.69% yield) was obtained as a pale yellow solid. 1 H NMR(DMSO-d6,400MHz) δ 9.24(s,1H), 8.24(s,1H), 5.95(d,J=8.4Hz,1H), 5.70(s,1H), 5.21~5.17(m,1H), 5.03 ~4.99(m,1H), 3.65(s,8H), 1.45(d,J=6.8Hz,3H), 1.35(d,J=4.4Hz,6H), 1.14(s,9H).

[0230] Preparation of (R)-9-(1-aminoethyl)-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylate (Step 3 of Scheme 14) [ka] To a solution of isopropyl 9-[(1R)-1-[[(R)-tert-butylsulfinyl]amino]ethyl]-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxylate (13.9 g, 29.92 mmol, 1 equiv.) in 100 mL of EtOAc was added HCl / EtOAc (4 M, 74.80 mL, 10 equiv.), and the resulting mixture was stirred at 20° C. for 1 h. TLC (EtOAc:MeOH=20:1, R f =0.1) and LCMS showed the reaction was complete. The mixture was concentrated under reduced pressure. The residue was triturated with EtOAc (100 mL). The solid was collected after filtration. Compound isopropyl 9-[(1R)-1-aminoethyl]-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxylate (11.5 g, 26.54 mmol, 88.70% yield, 2HCl, ee 100%) was obtained as a pale yellow solid. 1 H NMR(DMSO-d6,400MHz) δ 9.28(s,1H), 8.57(s,2H), 8.27(s,1H), 5.74(s,1H), 5.24~5.17(m,1H), 4.97 (t,J=6.0Hz,1H), 3.69(s,8H), 1.58(d,J=6.8Hz,3H), 1.37(t,J=6.0Hz,6H). Chiral analytical instrument: Waters Acquity UPC2; Column: Chiralcel OD-3 3 μm, 0.46 cm i.d. x 5 cm length. Mobile phase: A is SFC CO2, B is MeOH (0.05% IP Am); Gradient: 5% to 50% B in A over 3 min; Flow rate: 3.4 mL / min; Column temperature: 35 °C; Wavelength: 220 nm; System backpressure: 1800 psi. Rt = 1.158 min; Enantiomeric excess (%) by chiral HPLC = 100%.

[0231] Preparation of (R)-9-(1-((3,5-difluorophenyl)amino)ethyl)-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylate (Step 4 of Scheme 14) [ka] A mixture of isopropyl 9-[(1R)-1-aminoethyl]-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxylate (11 g, 25.38 mmol, 1 equiv, 2 HCl), 1,3-difluoro-5-iodo-benzene (12.18 g, 50.77 mmol, 6.09 mL, 2 equiv), Pd(dba) (2.32 g, 2.54 mmol, 0.1 equiv), XPhos (1.82 g, 3.81 mmol, 0.15 equiv), and CsCO (28.95 g, 88.85 mmol, 3.5 equiv) in dioxane (110 mL) was stirred at 100 °C under N for 20 h. Next, 1,3-difluoro-5-iodo-benzene (6.09 g, 25.38 mmol, 3.05 mL, 1 equiv.), Pd(dba) (1.16 g, 1.27 mmol, 0.05 equiv.), XPhos (907.60 mg, 1.90 mmol, 0.075 equiv.), and CsCO (8.27 g, 25.38 mmol, 1 equiv.) were added, and the resulting mixture was stirred at 100 °C under N for an additional 20 h. A TLC check indicated that no starting material had been consumed, after which another batch of 1,3-difluoro-5-iodo-benzene (6.09 g, 25.38 mmol, 3.05 mL, 1 equiv.) was added, and TLC (petroleum ether: EtOAc = 1:1, R fThe resulting mixture was stirred at 100°C under N2 for 20 hours until the reaction was nearly complete as determined by HPLC (pH = 0.2) and LCMS. After filtration through Celite, the filtrate was concentrated under reduced pressure. The residue was dissolved in EtOAc (300 mL) and washed with water (100 mL x 2). The combined organic layers were washed with brine (100 mL x 1), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (Biotage®; 120 g SepaFlash® silica flash column, eluent: 0-69% ethyl acetate / petroleum ether gradient @ 100 mL / min). The eluent was removed under reduced pressure. The compound 9-[(1R)-1-(3,5-difluoroanilino)ethyl]-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxylate (5.7 g, 12.06 mmol, 47.52% yield) was obtained as a yellow solid, and 9-[(1R)-1-aminoethyl]-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxylate (1.2 g) was recovered as a brown solid. 1 H NMR(DMSO-d6,400MHz) δ 9.21(s,1H), 7.99(s,1H), 7.07(d,J=7.2Hz,1H), 6.24~6.19(m,1H), 6.10~6.07(m,2H), 5.73(s,1H) ), 5.15~5.10(m,1H), 5.08~5.04(m,1H), 3.69(s,8H), 1.47(d,J=6.8Hz,3H), 1.32(d,J=7.2Hz,6H).

[0232] Preparation of (R)-9-(1-((3,5-difluorophenyl)amino)ethyl)-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylic acid (Step 5 of Scheme 14) [ka] A solution of isopropyl 9-[(1S)-1-(3,5-difluoroanilino)ethyl]-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxylate (5.7 g, 12.06 mmol, 1 equiv.) and aqueous NaOH (4 M, 60.32 mL, 20 equiv.) in THF (12 mL) was stirred at 20° C. for 6 h. Then, THF (10 mL) and aqueous NaOH (4 M, 15.08 mL, 5 equiv.) were added, and the resulting mixture was stirred at 20° C. for an additional 4 h. TLC (petroleum ether: EtOAc = 0:1, R f =0.05), indicating the reaction was complete. The organic solvent was removed under reduced pressure. The aqueous layer was extracted with MTBE (30 mL × 2) to remove impurities. The aqueous layer was adjusted to pH = 4 with concentrated HCl at 0 °C, resulting in the precipitation of a yellow solid. After filtration, the solid was collected and concentrated under reduced pressure. The filtrate was extracted with DCM and i-PrOH (v:v = 3:1, 30 mL × 3). The combined organic layers were washed with brine (20 mL × 1), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was triturated with EtOAc (5 mL). Compound 9-[(1S)-1-(3,5-difluoroanilino)ethyl]-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxylic acid (4.3 g, 9.99 mmol, 82.81% yield, 96.84% ee) was obtained as a pale yellow solid. 1 H NMR(DMSO-d6,400MHz) δ 13.53~13.50(m,1H), 9.20(s,1H), 8.04(s,1H), 7.07(d,J=7.2Hz,1H), 6.21(t,J=7.6Hz,1 H), 6.09~6.06(m,2H), 5.70(s,1H), 5.08~5.04(m,1H), 3.69(s,8H), 1.47(d,J=6.4Hz,3H).

[0233] Chiral analytical instrument: Waters Acquity UPC2; Column: Chiralpak IC-3 3 μm, 0.46 cm i.d. × 5 cm length; Mobile phase: A is SFC CO2, B is EtOH (0.05% IP Am); Gradient: 5% to 50% B in A over 3 min; Flow rate: 3.4 mL / min; Column temperature: 35 °C; Wavelength: 220 nm; System backpressure: 1800 psi. Rt = 1.767 min. Enantiomeric excess (%) by chiral HPLC = 96.84%.

[0234] Preparation of 9-((R)-1-((3,5-difluorophenyl)amino)ethyl)-7-((R)-3-(dimethylamino)pyrrolidine-1-carbonyl)-2-morpholino-4H-pyrido[1,2-a]pyrimidin-4-one (Step 6 of Scheme 14) [ka] To a solution of 9-[(1R)-1-(3,5-difluoroanilino)ethyl]-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxylic acid (3 g, 6.97 mmol, 1 equiv.), (3R)-N,N-dimethylpyrrolidin-3-amine (1.96 g, 10.46 mmol, 2.17 mL, 1.5 equiv., 2HCl), and DIEA (4.50 g, 34.85 mmol, 6.07 mL, 5 equiv.) in THF (25 mL) was added T3P (6.65 g, 10.46 mmol, 6.22 mL, 50% purity, 1.5 equiv.) dropwise at 0° C. The resulting mixture was then stirred at 20° C. for 10 h. HPLC and LCMS indicated the reaction was complete. The mixture was quenched with ice water (30 mL), and the organic solvent was removed under reduced pressure. The aqueous layer was extracted with DCM and i-PrOH (v:v = 3:1, 20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: Xtimate C18 10 μm 250 mm × 80 mm; mobile phase: [water (10 mM NH4HCO3)-MeCN]; B%: 30% to 55%, 24 min). The eluent was removed by lyophilization. The compound 9-[(1R)-1-(3,5-difluoroanilino)ethyl]-7-[(3R)-3-(dimethylamino)pyrrolidine-1-carbonyl]-2-morpholino-pyrido[1,2-a]pyrimidin-4-one (2.29 g, 4.34 mmol, 62.25% yield, 99.75% purity, 96.34% ee) was obtained as a pale yellow solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.88(s,1H), 7.83(s,1H), 7.02~6.98(m,1H), 6.25~6.21(m,1H), 6.11~6 .08(m,2H), 5.71(s,1H), 5.12~5.08(m,1H), 3.73(s,8H), 3.66~3.51(m, 1H), 3.47~3.42(m,2H), 3.26~3.22(m,1H), 2.68~2.62(m,1H), 2.17 and 2 .06(m,6H), 2.01~1.96(m,1H), 1.74~1.71(m,1H), 1.49(d,J=6.8Hz,3H). HPLC: 99.75% (220nm), 100% (254nm). MS(ESI): Mass calculation value. C 27 H 32 For F2N6O3, 526.25 m / z, actual value 527.3 [M+H] + .

[0235] Chiral analytical equipment: Waters Acquity Arc; Column: S, S_Whelk_O1, 3.5 μm, 0.46 cm i.d. × 10 cm length. Compound 50 (Rt = 8.212 min; ee (%) by chiral HPLC = 96.34%) was obtained and identified as compound 48-P3 (Rt = 8.298 min; ee (%) by chiral HPLC = 98.8%). [ka]

[0236] compound 51 Preparation of 9-((R)-1-((3,5-difluorophenyl)amino)ethyl)-7-((S)-3-(dimethylamino)pyrrolidine-1-carbonyl)-2-morpholino-4H-pyrido[1,2-a]pyrimidin-4-one (Steps 1-6 of Scheme 15) Preparation of (R,E)-ethyl 9-(1-((tert-butylsulfinyl)imino)ethyl)-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylate (Step 1 of Scheme 15) [ka] A mixture of methyl 9-acetyl-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxylate (16 g, 48.40 mmol, 1 equiv.), (R)-2-methylpropane-2-sulfinamide (10.56 g, 87.13 mmol, 1.8 equiv.), and tetraethoxytitanium (44.16 g, 193.61 mmol, 40.15 mL, 4 equiv.) in THF (160 mL) was stirred at 75 °C under a N atmosphere for 20 h. LCMS indicated the reaction was complete. The resulting mixture was cooled to 25 °C and then diluted with water (400 mL) and ethyl acetate (250 mL). The mixture was filtered through Celite, and the filter cake was washed with ethyl acetate (40 mL). The organic phase was separated. The aqueous phase was extracted with ethyl acetate (200 mL × 4). The combined organic phase was washed with brine (300 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude product was triturated with MTBE (130 mL) at 20 °C for 1 hour. After filtration, 13.13 g of the compound ethyl 9-[(E)-N-[(R)-tert-butylsulfinyl]-C-methyl-carbonimidoyl]-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxylate (13.13 g, 29.27 mmol, 60.48% yield) was obtained as a yellow solid. 1 H NMR(DMSO-d6,400MHz) δ 9.31~9.22(m,1H), 8.05~8.00(m,1H), 5.71~5.69(m,1H), 4.40(q,J=6.8 Hz,2H), 3.65(s,8H), 2.58(s,3H), 1.36~1.33(m,3H), 1.12~1.08(m,9H).

[0237] Preparation of ethyl 9-((R)-1-((R)-1,1-dimethylethylsulfinamido)ethyl)-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylate (Step 2 of Scheme 15) [ka] To a solution of ethyl 9-[(E)-N-[(R)-tert-butylsulfinyl]-C-methyl-carbonimidoyl]-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxylate (13.13 g, 29.27 mmol, 1 equiv.) and AcOH (14.06 g, 234.18 mol, 13.39 mL, 8 equiv.) in DCM (80 mL) and MeOH (80 mL) was added NaBHCN (5.52 g, 87.82 mmol, 3 equiv.) in portions at −15° C. The resulting mixture was stirred at −15° C. for 5 hours. LCMS indicated the reaction was complete. The mixture was quenched with ice water (1.5 mL) and the pH was adjusted to 7 with saturated NaCO at 0° C. The organic phase was separated. The aqueous phase was extracted with EtOAc (150 mL × 3). The combined organic phases were washed with brine (300 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography (Biotage; 220 g SepaFlash® silica flash column, eluting with a 0–100% ethyl acetate / petroleum ether gradient; eluting with a 0–13% MeOH / ethyl acetate gradient @ 200 mL / min). The eluent was removed under reduced pressure. The compound 9-[(1R)-1-[[(R)-tert-butylsulfinyl]amino]ethyl]-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxylate (6.83 g, 15.16 mmol, 51.79% yield) was obtained as a yellow solid. 1 H NMR(DMSO-d6,400MHz) δ 9.25(s,1H), 8.25(s,1H), 5.96(d,J=8.4Hz,1H), 5.69(s,1H), 5.04~4.97(m,1H), 4.38~4.3 4(q,J=3.2Hz,2H), 3.69(s,8H), 1.46(d,J=6.8Hz,3H), 1.35(t,J=7.2Hz,3H), 1.12(s,9H).

[0238] Preparation of ethyl (R)-9-(1-aminoethyl)-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylate (Step 3 of Scheme 15) [ka] To a solution of ethyl 9-[(1R)-1-[[(R)-tert-butylsulfinyl]amino]ethyl]-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxylate (6.8 g, 15.09 mmol, 1 equiv.) in 70 mL of EtOAc was added HCl / EtOAc (4 M, 37.73 mL, 10 equiv.). The resulting mixture was stirred at 20 °C for 2 hours. LCMS indicated the reaction was complete. The mixture was concentrated under reduced pressure. The residue was triturated with EtOAc (20 mL). The solid was collected after filtration. Compound ethyl 9-[(1R)-1-aminoethyl]-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxylate (6.63 g, crude, 2HCl, ee 100%) was obtained as a yellow solid. 1 H NMR(DMSO-d6,400MHz) δ 9.30(s,1H), 8.64(s,2H), 8.29(s,1H), 5.74(s,1H), 4.98~4.95(m,1H), 4.42 (q,J=8.0Hz,2H), 3.69(s,8H), 1.58(d,J=6.4Hz,3H), 1.38(t,J=7.2Hz,3H).

[0239] Chiral analytical instrument: Waters Acquity UPC2; Column: Chiralcel OD-3 3 μm, 0.46 cm i.d. × 5 cm length; Mobile phase: A is SFC CO2, B is MeOH (0.05% IP Am); Gradient: 5% to 50% B in A over 3 min; Flow rate: 3.4 mL / min; Column temperature: 35 °C; Wavelength: 220 nm; System backpressure: 1800 psi. Rt = 1.217 min; Enantiomeric excess (%) by chiral HPLC = 100% ee.

[0240] Preparation of ethyl (R)-9-(1-((3,5-difluorophenyl)amino)ethyl)-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylate (Step 4 of Scheme 15) [ka] Ethyl 9-[(1R)-1-aminoethyl]-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxylate (6.62 g, 15.79 mmol, 1 equiv., 2HCl), 1,3-difluoro-5-iodo-benzene (5.68 g, 23.68 mmol, 2.84 mL, 1.5 equiv.), Pd(dba)(1.45 mL) in dioxane (70 mL). A mixture of CsCO (18.00 g, 55.26 mmol, 3.5 equiv.), CsCO (18.00 g, 55.26 mmol, 3.5 equiv.), and dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (1.13 g, 2.37 mmol, 0.15 equiv.) was degassed and purged with N three times, and then the mixture was stirred at 100 °C under N atmosphere for 20 h. Another batch of 1,3-difluoro-5-iodo-benzene (3.79 g, 15.79 mmol, 1.89 mL, 1 equiv.), Pd(dba) (722.87 mg, 789.41 μmol, 0.05 equiv.), CsCO (5.14 g, 15.79 mmol, 1 equiv.), and dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (564.48 mg, 1.18 mmol, 0.075 equiv.) was then added, and the resulting mixture was stirred at 100 °C under a N atmosphere for 20 h. LCMS indicated that the reaction was nearly complete. The mixture was filtered, and the filter cake was washed with EtOAc (20 mL). The filtrate was concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography (Biotage; 40 g SepaFlash® silica flash column, eluting with a 0–60% ethyl acetate / petroleum ether gradient). The eluent was removed under reduced pressure. The compound 9-[(1R)-1-(3,5-difluoroanilino)ethyl]-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxylate (3.35 g, 7.31 mmol, 46.28% yield) was obtained as a yellow solid. And 9-[(1R)-1-aminoethyl]-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxylate (1.11 g) was recovered as a brown solid. 1H NMR(DMSO-d6,400MHz) δ 9.23(s,1H), 7.99(s,1H), 7.08(d,J=7.2Hz,1H), 6.25(t,J=9.2Hz,1H), 6.09(d,J=10.0Hz,2H), 5.73(s, 1H), 5.06(t,J=6.8Hz,1H), 4.35~4.30(m,2H), 3.69(s,8H), 1.47(d,J=6.8Hz,3H), 1.30(t,J=7.2Hz,3H).

[0241] Preparation of (R)-9-(1-((3,5-difluorophenyl)amino)ethyl)-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylic acid (Step 5 of Scheme 15) [ka] To a solution of ethyl 9-[(1R)-1-(3,5-difluoroanilino)ethyl]-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxylate (3.35 g, 7.31 mmol, 1 equiv.) in THF (6 mL) was added NaOH (4 M, 7.31 mL, 4 equiv.). The resulting mixture was stirred at 20° C. for 2 hours. NaOH (4 M, 7.31 mL, 4 equiv.) was added and the resulting mixture was stirred at 20° C. for 2 hours. LCMS and TLC (petroleum ether:ethyl acetate=1:1, R f = 0), indicating the reaction was complete. HCl (4N) was added dropwise at 0 °C until pH = 3. The precipitate was collected by filtration and concentrated in vacuo. The compound 9-[(1R)-1-(3,5-difluoroanilino)ethyl]-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxylic acid (3.03 g, 7.04 mmol, 96.37% yield, 100% ee) was obtained as a yellow solid. 1 H NMR(DMSO-d6,400MHz) δ 9.22(s,1H), 8.00(s,1H), 7.09(d,J=7.2Hz,1H), 6.24(t,J=9.2Hz,1H), 6.09(d,J =9.6Hz,2H), 5.71(s,1H), 5.08~5.02(m,1H), 3.69(s,8H), 1.48(d,J=6.8Hz,3H).

[0242] Chiral analytical equipment: Waters Acquity UPC2; Column: Chiralpak IC-3 3 μm, 0.46 cm i.d. × 5 cm length; Mobile phase: A = SFC CO₂, B = EtOH (0.05% IP Am); Gradient: 5% to 50% B in A over 3 min; Flow rate: 3.4 mL / min; Column temperature: 35 °C; Wavelength: 220 nm; System backpressure: 1800 psi. Rt = 1.771 min; Enantiomeric excess (%) by chiral HPLC = 100% ee.

[0243] Preparation of 9-((R)-1-((3,5-difluorophenyl)amino)ethyl)-7-((S)-3-(dimethylamino)pyrrolidine-1-carbonyl)-2-morpholino-4H-pyrido[1,2-a]pyrimidin-4-one (Step 6 of Scheme 15) [ka] To a solution of 9-[(1R)-1-(3,5-difluoroanilino)ethyl]-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxylic acid (2.8 g, 6.51 mmol, 1 equiv.), (3S)-N,N-dimethylpyrrolidin-3-amine (1.11 g, 9.76 mmol, 1.5 equiv.), and DIEA (4.20 g, 32.53 mmol, 5.67 mL, 5 equiv.) in THF (28 mL) was added T3P (6.21 g, 9.76 mmol, 5.80 mL, 50% purity, 1.5 equiv.) dropwise at 0° C. The resulting mixture was stirred at 20° C. for 10 hours. LCMS and HPLC indicated the reaction was complete. The mixture was quenched with ice water (1.5 mL) and concentrated in vacuo. Water (40 mL) was added to the residue, and the resulting mixture was extracted with DCM and i-PrOH (v:v = 3:1, 40 mL × 3). The combined organic phase was washed with brine (70 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by preparative HPLC (column: Xtimate C18 10 μm 250 mm × 80 mm; mobile phase: [water (10 mM NH4HCO3)-MeCN]; B%: 25% to 55%, 26 min). The eluent was removed by lyophilization. The compound 9-[(1R)-1-(3,5-difluoroanilino)ethyl]-7-[(3S)-3-(dimethylamino)pyrrolidine-1-carbonyl]-2-morpholino-pyrido[1,2-a]pyrimidin-4-one (2.16 g, 4.06 mmol, 62.37% yield, 98.91% purity, 94.16% ee) was obtained as a pale yellow solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.87(s,1H), 7.82(s,1H), 6.97~6.96(m,1H), 6.22~6.20(m,1H), 6.10(d, J=10.8Hz,2H), 5.70(s,1H), 5.10~5.08(m,1H), 3.69(s,8H), 3.60~3.53( m,1H), 3.42~3.40(m,2H), 3.24~3.21(m,1H), 2.45~2.42(m,1H), 2.16(s, 3H), 2.05(s,1H), 1.97(s,3H), 1.68~1.67(m,1H), 1.48(d,J=6.4Hz,3H). HPLC: 98.91% (220nm), 99.01% (254nm). MS(ESI): Mass calculation value. C 27 H 32 For F2N6O3, 526.25 m / z, actual value 527.3 [M+H] + .

[0244] Chiral analytical equipment: Waters Acquity Arc; column: S, S_Whelk_O1, 3.5 μm, 0.46 cm i.d. × 10 cm length. Compound 51 (Rt = RT = 14.281 min, ee (%) = 94.16% by chiral HPLC) was obtained and identified as compound 48-P4 (Rt = 14.409 min, ee (%) = 99.46% by chiral HPLC). [ka]

[0245] General procedure for preparing compounds of Scheme 16 Preparation of 9-bromo-2-hydroxy-7-methyl-pyrido[1,2-a]pyrimidin-4-one (Step 1 of Scheme 16) [ka] To a solution of 3-bromo-5-methyl-pyridin-2-amine (22 g, 117.62 mmol, 1 equiv.) in DCM (300 mL) was added propanedioyl dichloride (18.24 g, 129.39 mmol, 12.58 mL, 1.1 equiv.) dropwise at 0 °C. The resulting mixture was stirred at 25 °C for 12 hours. LCMS showed that the reaction was complete. A solid formed, which was collected by filtration, washed with DCM (10 mL × 2), and dried under reduced pressure. The compound 9-bromo-2-hydroxy-7-methyl-pyrido[1,2-a]pyrimidin-4-one (46 g, 180.34 mmol, 76.66% yield) was obtained as a pale yellow solid. 1 H NMR (DMSO-d6,400MHz) δ 8.72(s,1H), 8.28(s,1H), 5.54(s,1H), 2.34(s,3H).

[0246] Preparation of 9-bromo-7-methyl-2-morpholinopyrido[1,2-a]pyrimidin-4-one (Step 2 of Scheme 16) [ka] To a solution of 9-bromo-2-hydroxy-7-methyl-pyrido[1,2-a]pyrimidin-4-one (10 g, 39.21 mmol, 1 equiv) in DCM (100 mL) was added TEA (7.93 g, 78.41 mmol, 10.91 mL, 2 equiv) and MsCl (6.29 g, 54.89 mmol, 4.25 mL, 1.4 equiv) dropwise at 0 °C. The resulting mixture was stirred at 25 °C for 1 h. Morpholine (10.25 g, 117.62 mmol, 10.35 mL, 3 equiv) was then added. The mixture was stirred at 50 °C for 12 h. LCMS showed the reaction was complete. The reaction mixture was quenched with HO (50 mL) at 0 °C and then extracted with DCM (100 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. This residue was purified by recrystallization from DCM (30 mL) and washed with EtOAc (20 mL × 2) to give the pure product, 9-bromo-7-methyl-2-morpholinopyrido[1,2-a]pyrimidin-4-one (5 g) as a yellow solid. The residue was then purified by flash silica gel chromatography (Biotage®; 40 g SepaFlash® silica flash column, eluting with a 0–60% ethyl acetate / petroleum ether gradient at 100 mL / min) to give the pure product, 9-bromo-7-methyl-2-morpholinopyrido[1,2-a]pyrimidin-4-one (2 g) as a yellow solid. After mixing the two batches of product, the compound 9-bromo-7-methyl-2-morpholinepyrido[1,2-a]pyrimidin-4-one (7 g, yield 55.1%) was obtained as a yellow solid. 1 H NMR (DMSO-d6,400MHz) δ 8.60(s,1H), 8.17(d,J=1.6Hz,1H), 5.61(s,1H), 3.68~3.64(m,8H), 2.29(s,3H). Preparation of 7-methyl-2-morpholino-9-vinylpyrido[1,2-a]pyrimidin-4-one (Step 3 of Scheme 16) [ka] A mixture of 9-bromo-7-methyl-2-morpholino-pyrido[1,2-a]pyrimidin-4-one (3 g, 9.25 mmol, 1 equiv.), potassium hydride; trifluoro(vinyl)boron (1.86 g, 13.88 mmol, 1.5 equiv.), Pd(dppf)Cl (338.57 mg, 462.72 μmol, 0.05 equiv.), and KCO (3.84 g, 27.76 mmol, 3 equiv.) in dioxane (40 mL) and HO (10 mL) was degassed and purged with N three times. The resulting mixture was then stirred at 110 °C under a N atmosphere for 2 h. LCMS indicated the reaction was complete. The reaction mixture was filtered to remove insoluble material and concentrated under reduced pressure to remove dioxane. The aqueous layer was then extracted with DCM (20 mL × 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. This residue was purified by recrystallization from DCM (10 mL) and washed with EtOAc (10 mL × 2) to give the pure product, 7-methyl-2-morpholino-9-vinyl-pyrido[1,2-a]pyrimidin-4-one (1 g), as a yellow solid. The residue was then purified by flash silica gel chromatography (Biotage®; 12 g SepaFlash® silica flash column, eluting with a 0-10% methanol:dichloromethane gradient at 60 mL / min) to give the crude product, 7-methyl-2-morpholino-9-vinylpyrido[1,2-a]pyrimidin-4-one (1.2 g), as a yellow solid. After mixing the two batches of product, a yellow solid compound 7-methyl-2-morpholine-9-vinylpyrido[1,2-a]pyrimidin-4-one (2.2 g, yield 87.9%) was obtained. 1 H NMR(DMSO-d6,400MHz) δ 8.58(s,1H), 7.97(d,J=1.6Hz,1H), 7.33(dd,J=17.6Hz,11.2Hz,1H), 6.06(d,J=17.6Hz,1H) ), 5.62(s,1H), 5.48(d,J=11.6Hz,1H), 3.69~3.67(m,4H), 3.61~3.59(m,4H), 2.33(s,3H).

[0247] Preparation of 7-methyl-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-9-carbaldehyde (Step 4 of Scheme 16) [ka] To a solution of 7-methyl-2-morpholino-9-vinyl-pyrido[1,2-a]pyrimidin-4-one (750 mg, 2.76 mmol, 1 equiv.) in dioxane (100 mL) and HO (20 mL), dipotassium; (dioxo)osmium dioxide; dihydrate (101.85 mg, 276.43 μmol, 0.1 equiv.) was added at 25°C. After the addition, the resulting mixture was stirred at 25°C for 1 h, and then NaIO (1.77 g, 8.29 mmol, 459.53 μL, 3 equiv.) was added at 0°C. The resulting mixture was stirred at 25°C for 2 h. LCMS indicated that the reaction was complete. The reaction mixture was filtered to remove insoluble materials and concentrated under reduced pressure to remove dioxane. The aqueous layer was then extracted with DCM (20 mL × 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The resulting residue was purified by flash silica gel chromatography (Biotage®; 12 g SepaFlash® silica flash column, eluting with a 0-60% dichloromethane:ethyl acetate gradient at 100 mL / min). The eluent was removed under reduced pressure. The compound 7-methyl-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-9-carbaldehyde (300 mg, 1.10 mmol, 39.71% yield) was obtained as a yellow solid. 1 H NMR (DMSO-d6,400MHz) δ 10.82(s,1H), 8.95(s,1H), 8.11(d,J=2.4Hz,1H), 5.65(s,1H), 3.83~3.80(m,4H), 3.71~3.68(m,4H), 2.41(s,3H).

[0248] Preparation of Compounds of Scheme 16 (Step 5 of Scheme 16) [ka] A solution of 7-methyl-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-9-carbaldehyde (365.92 μmol, 1 equiv.), AcOH (10.98 mmol, 30 equiv.), and indoline (474.50 μmol to 731.84 μmol, 1.1 equiv. to 2.0 equiv.) in MeOH (5 mL / mmol) was stirred at 20 °C for 1 h. Then, NaCNBH (365.92 μmol to 731.84 μmol, 1 equiv. to 2 equiv.) was added portionwise at 0 °C, and the resulting mixture was stirred at 20 °C for 1 h to 2 h. TLC (petroleum ether: EtOAc = 0:1, R f =0.15) and LCMS showed that the reaction was complete. The mixture was quenched with ice water at 0 °C, and the organic solvent was removed under reduced pressure. The aqueous layer was adjusted to pH = 8 with saturated NaHCO3 and then extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (Biotage®; 12 g SepaFlash® silica flash column, eluting with a 0–60% ethyl acetate / petroleum ether gradient at 80 mL / min) or preparative HPLC (column: Welch Xtimate C18 100 × 25 mm × 3 μm or Waters Xbridge Prep OBD C18 150 × 40 mm × 10 μm or Phenomenex luna C18 80 × 40 mm × 3 μm; mobile phase: [water (0.05% HCl)-MeCN]; B%: 15%–35% for 8 min or [water (0.04% HCl)-MeCN]; B%: 45%–55% for 7 min or [water (0.04% HCl)-MeCN]; B%: 18%–55% for 7 min or [water (10 mM The desired product was obtained by eluting the product with HCl (NH4HCO3)-MeCN, B%: 25% to 55%, 8 min). The eluent was removed under reduced pressure or the aqueous solution was lyophilized to give the desired product.

[0249] compound 52 Preparation of 9-[(4-fluoroindolin-1-yl)methyl]-7-methyl-2-morpholino-pyrido[1,2-a]pyrimidin-4-one (Step 5 of Scheme 16) [ka] A solution of 7-methyl-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-9-carbaldehyde (0.1 g, 365.92 μmol, 1 equiv.), AcOH (659.22 mg, 10.98 mmol, 627.83 μL, 30 equiv.), and 4-fluoroindoline (70.26 mg, 512.29 μmol, 1.4 equiv.) in MeOH (3 mL) was stirred at 20 °C for 1 h. NaCNBH (83.45 mg, 731.84 μmol, 54.19 μL, 2 equiv.) was then added portionwise at 0 °C, and the resulting mixture was stirred at 20 °C for 1 h. TLC (petroleum ether: EtOAc = 0:1, R f =0.15), indicating the reaction was complete. The mixture was quenched with ice water (10 mL) at 0 °C, and the organic solvent was removed under reduced pressure. The aqueous layer was adjusted to pH = 8 with saturated NaHCO3 and then extracted with DCM (10 mL × 4). The combined organic layers were washed with brine (10 mL × 1), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (Biotage®; 12 g SepaFlash® silica flash column, eluent: 0-60% ethyl acetate / petroleum ether gradient @ 80 mL / min). The eluent was removed under reduced pressure. The resulting residue was diluted with HO (20 mL), and the solvent was removed by lyophilization. The compound 9-[(4-fluoroindolin-1-yl)methyl]-7-methyl-2-morpholino-pyrido[1,2-a]pyrimidin-4-one (66.4 mg, 167.01 μmol, 45.64% yield, 99.21% purity) was obtained as a white solid. 1H NMR(DMSO-d6,400MHz) δ 8.56(s,1H), 7.61(s,1H), 7.00(dd,J=14.0Hz,8.8Hz,1H), 6.39(t,J=8.8Hz,1H), 6.32(d,J=8.0Hz,1H), 5.63(s,1 H), 4.50(s,2H), 3.66~3.64(m,4H), 3.61~3.59(m,4H), 3.53(t,J=8.4Hz,2H), 3.02(t,J=8.4Hz,2H), 2.29(s,3H). LCMS: 99.21% (220nm), 100.00% (254nm). MS(ESI): Mass calculation value. C 22 H 23 For FN4O2, 394.18 m / z, actual value 395.1 [M+H] + .

[0250] compound 53 9-((4-Fluoro-2-methylindolin-1-yl)methyl)-7-methyl-2-morpholino-4H-pyrido[1,2-a]pyrimidin-4-one was prepared according to the procedure described in Scheme 16, step 5. [ka] The desired compound (51 mg, 118.63 μmol, 46.31% yield, 95.01% purity) was obtained as a white solid. 1 H NMR(DMSO-d6,400MHz) δ 8.55(s,1H), 7.53(s,1H), 6.94(dd,J=14.0Hz,8.8Hz,1H), 6.37(t,J=8.8Hz,1H), 6.03(d,J=8.0Hz,1H), 5.64(s,1H), 4.46(dd,J=18.4Hz,10. 8Hz,2H), 3.95~3.89(m,1H), 3.68~3.66(m,4H), 3.61~3.59(m,4H), 3.2 9~3.25(m,1H), 2.69~2.62(m,1H), 2.27(s,3H), 1.27(d,J=6.0Hz,3H). LCMS: 95.01% (220nm), 96.20% (254nm). MS(ESI): Mass calculation value. C 23 H 25 For FN4O2, 408.20 m / z, actual value 409.2 [M+H]+ .

[0251] compound 54 9-((4,6-Difluoroindolin-1-yl)methyl)-7-methyl-2-morpholino-4H-pyrido[1,2-a]pyrimidin-4-one was prepared following the procedure described in Scheme 16, step 5. [ka] The desired compound (12.5 mg, 29.49 μmol, 20.15% yield, 97.30% purity) was obtained as a white solid. 1 H NMR(DMSO-d6,400MHz) δ 8.56(s,1H), 7.60(s,1H), 6.30~6.24(m,2H), 5.62(s,1H), 4.53(s,2H), 3.65(t,J=4.8 Hz,4H), 3.60(t,J=7.2Hz,4H), 3.57~3.55(m,2H), 2.98(t,J=8.0Hz,2H), 2.30(s,3H). MS: 97.30% (220nm), 99.80% (254nm). MS(ESI): Mass calculation value. C 22 H 22 For F2N4O2, 412.17 m / z, actual value 413.2 [M+H] + .

[0252] compound 55 9-((4,6-Difluoro-2-methylindolin-1-yl)methyl)-7-methyl-2-morpholino-4H-pyrido[1,2-a]pyrimidin-4-one was prepared following the procedure described in Scheme 16, step 5. [ka] The desired compound (3.9 mg, 8.75 μmol, 5.98% yield, 95.66% purity) was obtained as a white solid. 1H NMR(MeOD,400MHz) δ 8.62(s,1H), 7.59(s,1H), 6.11(t,J=8.0Hz,1H), 5.82(d,J=8.0Hz,1H), 5.74(s,1H), 4.54(d,J=4.4Hz,2H), 4.06~3.93( m,1H), 3.80~3.76(m,4H), 3.73~3.69(m,4H), 3.28~3.25(m,1H), 2.70~2.64(m,1H), 2.34(s,3H), 1.33(d,J=6.4Hz,3H). LCMS: 95.66% (220nm), 98.49% (254nm). MS(ESI): Mass calculation value. C 23 H 24 For F2N4O2, 426.19 m / z, actual value 427.2 [M+H] + .

[0253] compound 56 9-((5-Fluoroindolin-1-yl)methyl)-7-methyl-2-morpholino-4H-pyrido[1,2-a]pyrimidin-4-one was prepared following the procedure described in Scheme 16, step 5. [ka] The desired compound (5.2 mg, 12.46 μmol, 8.52% yield, 94.55% purity) was obtained as a white solid. 1 H NMR(DMSO-d6,400MHz) δ 8.56(s,1H), 7.65(s,1H), 6.96(d,J=8.0Hz,1H), 6.80~6.70(m,1H), 6.45~6.42(m,1H), 5.63(s,1H), 4.42( s,2H), 3.66(t,J=5.6Hz,4H), 3.61(t,J=4.4Hz,4H), 3.45~3.43(m,2H), 2.97(t,J=8.3Hz,2H), 2.30(s,3H). MS: 94.55% (220nm), 97.88% (254nm). MS(ESI): Mass calculation value. C 22 H 23 For FN4O2, 394.18 m / z, actual value 395.2 [M+H] + .

[0254] compound 57 7-Methyl-9-((2-methylindolin-1-yl)methyl)-2-morpholino-4H-pyrido[1,2-a]pyrimidin-4-one was prepared following the procedure described in Scheme 16, step 5. [ka] The desired compound (11.2 mg, 27.37 μmol, 18.70% yield, 95.42% purity) was obtained as a white solid. 1 H NMR (DMSO-d6, 400 MHz) δ 8.55(s,1H), 7.55(s,1H), 7.05(d,J=6.4Hz,1H), 6.92(t,J=8.0Hz,1H), 6.60(t,J=7.2Hz,1H), 6.16(d,J=7.6Hz,1H), 5.64(s,1H), 4.48~4.34 (m,2H), 3.81~3.80(m,1H), 3.67(t,J=4.8Hz,4H), 3.62(t,J=4.8Hz,4H), 3.18~3.10(m,1H), 2.63(s,1H), 2.27(s,3H), 1.27(d,J=6.0Hz,3H). MS: 95.42% (220nm), 98.90% (254nm). MS(ESI): Mass calculation value. C 23 H 26 For N4O2, 390.21 m / z, actual value 391.2 [M+H] + . [ka]

[0255] General procedure for preparing compounds of Scheme 17 Preparation of 9-acetyl-7-methyl-2-morpholino-4H-pyrido[1,2-a]pyrimidin-4-one (Step 1 of Scheme 17) [ka] A mixture of 9-bromo-7-methyl-2-morpholino-pyrido[1,2-a]pyrimidin-4-one (4.2 g, 12.96 mmol, 1 equiv.), tributyl(1-ethoxyvinyl)stannane (6.820 g, 18.88 mmol, 6.37 mL, 1.46 equiv.), and Pd(PPh)Cl (454.69 mg, 647.80 μmol, 0.05 equiv.) in dioxane (50 mL) was stirred under N at 100° C. for 10 h. LCMS showed that 9-bromo-7-methyl-2-morpholino-pyrido[1,2-a]pyrimidin-4-one (4.2 g, 12.96 mmol, 1 equiv.) was completely consumed. The resulting mixture was cooled to 25°C, and HCl (2M, 7.77 mL, 1.2 equiv.) was added, and the mixture was stirred at 25°C for 1 hour. LCMS showed the reaction was complete. The organic solvent was removed under reduced pressure. The aqueous layer was adjusted to pH = 7 with saturated NaHCO3 and extracted with DCM (60 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was triturated with petroleum ether and EtOAc (v:v = 10:1, 20 mL x 2). The solid was collected after filtration. Compound 9-acetyl-7-methyl-2-morpholino-pyrido[1,2-a]pyrimidin-4-one (2.8 g, 9.75 mmol, 75.22% yield) was obtained as a yellow solid. 1 H NMR(DMSO-d6,400MHz) δ 8.74(d,J=2.0Hz,1H), 7.87(d,J=2.0Hz,1H), 5.65(s,1H), 3.69~3.65(m,4H), 3.60~3.55(m,4H), 2.67(s,3H), 2.33(s,3H).

[0256] Preparation of 9-(1-hydroxyethyl)-7-methyl-2-morpholino-4H-pyrido[1,2-a]pyrimidin-4-one (Step 2 of Scheme 17) [ka] To a mixture of 9-acetyl-7-methyl-2-morpholino-pyrido[1,2-a]pyrimidin-4-one (2.6 g, 9.05 mmol, 1 equiv.) and CeCl3·7H2O (3.37 g, 9.05 mmol, 860.11 μL, 1 equiv.) in MeOH (15 mL) and DCM (4 mL) was added NaBH4 (205.42 mg, 5.43 mmol, 0.6 equiv.) in portions at −70 °C under N2. The resulting mixture was stirred at −70 °C for 0.3 h. LCMS indicated the reaction was complete. The mixture was slowly quenched with ice water (30 mL) at 0 °C, and the organic solvent was removed under reduced pressure. The aqueous layer was extracted with EtOAc (40 mL × 3). The combined organic layers were washed with brine (30 mL × 1), dried over Na2SO4, filtered, and concentrated under reduced pressure. The compound 9-(1-hydroxyethyl)-7-methyl-2-morpholino-pyrido[1,2-a]pyrimidin-4-one (1.4 g, 4.84 mmol, 53.47% yield) was obtained as a yellow solid. 1 H NMR(DMSO-d6,400MHz) δ 8.53(s,1H), 7.76(s,1H), 5.60(s,1H), 5.36(d,J=4.4Hz,1H), 5.26~5.18(m,1 H), 3.70~3.65(m,4H), 3.61~3.54(m,4H), 2.32(s,3H), 1.38(d,J=6.4Hz,3H).

[0257] Preparation of 9-(1-bromoethyl)-7-methyl-2-morpholino-4H-pyrido[1,2-a]pyrimidin-4-one (Step 3 of Scheme 17) [ka] To a mixture of 9-(1-hydroxyethyl)-7-methyl-2-morpholino-pyrido[1,2-a]pyrimidin-4-one (0.6 g, 2.07 mmol, 1 equiv.) in DCE (10 mL) was added PBr (617.47 mg, 2.28 mmol, 1.1 equiv.) under N at 0 °C. The resulting mixture was stirred at 50 °C for 3 h. LCMS showed that the reaction was complete. The mixture was cooled to 0 °C and adjusted to pH = 7 with saturated NaHCO. The aqueous phase was extracted with DCM (30 mL × 2). The combined organic phase was washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The compound 9-(1-bromoethyl)-7-methyl-2-morpholino-pyrido[1,2-a]pyrimidin-4-one (0.52 g, 1.48 mmol, 71.19% yield) was obtained as a yellow solid. 1 H NMR(DMSO-d6,400MHz) δ 8.61(d,J=1.6Hz,1H), 8.02(d,J=1.6Hz,1H), 6.05~6.01(m,1H), 5.64(s,1H) ), 3.73~3.68(m,4H), 3.66~3.63(m,4H), 2.34(s,3H), 2.07(d,J=7.2Hz,3H).

[0258] Preparation of Compounds of Scheme 17 (Step 4 of Scheme 17) [ka] A mixture of 9-(1-bromoethyl)-7-methyl-2-morpholino-pyrido[1,2-a]pyrimidin-4-one (1.70 mmol, 1 equiv.) and 4,6-difluoro-2-methyl-indoline (3.41 mmol, 2 equiv.) or 4,6-difluoroindoline (1.70 mmol, 1 equiv.) in DMA (5 mL / mmol) without base or with DIEA (8.5 mmol, 5 equiv.) was stirred at 50 °C for 10–12 h. LCMS and HPLC indicated the reaction was complete. The resulting mixture was quenched with water, and the mixture was extracted with ethyl acetate. The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by preparative HPLC (column: Phenomenex Luna C18 250 × 50 mm × 10 μm or Phenomenex Gemini-NX 80 × 40 mm × 3 μm; mobile phase: [water (0.04% HCl)-MeCN]; B%: 55% to 85%, 10 min or [water (10 mM NH4HCO3)-MeCN]; B%: 30% to 60%, 8 min). The solvent was removed by lyophilization to give the desired product.

[0259] compound 58 Preparation of 9-(1-(4,6-difluoro-2-methylindolin-1-yl)ethyl)-7-methyl-2-morpholino-4H-pyrido[1,2-a]pyrimidin-4-one (Step 4 of Scheme 17) [ka] A mixture of 9-(1-bromoethyl)-7-methyl-2-morpholino-pyrido[1,2-a]pyrimidin-4-one (0.6 g, 1.70 mmol, 1 equiv.) and 4,6-difluoro-2-methyl-indoline (576.35 mg, 3.41 mmol, 2 equiv.) in DMA (10 mL) was stirred at 50° C. for 12 hours. LCMS and HPLC showed the reaction was complete. The resulting mixture was quenched with water (50 mL), and the mixture was extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with brine (40 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The resulting residue was purified by preparative HPLC (column: Phenomenex Luna C18 250 × 50 mm × 10 μm; mobile phase: [water (0.04% HCl)-MeCN]; B%: 55% to 85%, 10 min). The solvent was removed by lyophilization. The compound 9-[1-(4,6-difluoro-2-methyl-indolin-1-yl)ethyl]-7-methyl-2-morpholino-pyrido[1,2-a]pyrimidin-4-one (0.1716 g, 359.79 μmol, yield 21.12%, HCl) was obtained as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ8.61(d,J=11.6Hz,1H), 7.85(d,J=26.0Hz,1H), 6.24~5.94(m,2H), 5.6 4(d,J=5.6Hz,1H), 5.37~5.02(m,1H), 4.37~4.13(m,1H), 3.63~3.58(m,4 H), 3.51~3.36(m,4H), 3.28~3.19(m,1H), 2.43~2.39(m,1H), 2.33(d,J=13.0Hz,3H), 1.60(dd,J=4.0Hz,7.2Hz,3H), 1.11(dd,J=2.8,6.2Hz,3H). A solution of 9-[1-(4,6-difluoro-2-methyl-indolin-1-yl)ethyl]-7-methyl-2-morpholino-pyrido[1,2-a]pyrimidin-4-one (0.17 g, 356.43 μmol, 1 equiv., HCl) in EtOAc (5 mL) was adjusted to pH = 7 with saturated NaHCO. The organic layer was separated, and the aqueous phase was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with brine (5 mL × 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude product was triturated with MTBE and CHCN (v:v = 20:1, 30 mL). The compound 9-[1-(4,6-difluoro-2-methyl-indolin-1-yl)ethyl]-7-methyl-2-morpholino-pyrido[1,2-a]pyrimidin-4-one (140.2 mg, 312.56 μmol, 87.69% yield, 98.2% purity) was obtained as an off-white solid. 1 H NMR (DMSO-d6, 400 MHz) δ 8.61(d,J=12.0Hz,1H), 7.84(d,J=24.0Hz,1H), 6.27~5.92(m,2H), 5.67 ~5.52(m,1H), 5.37~5.05(m,1H), 4.33~4.17(m,1H), 3.63~3.59(m,4H), 3.51~3.37(m,4H), 3.25~3.17(m,1H), 2.46~2.38(m,1H), 2.33(d,J=13.0Hz,3H), 1.60(dd,J=4.0Hz,7.2Hz,3H), 1.11(dd,J=3.2Hz,6.2Hz,3H). HPLC: 98.20% (220nm), 99.52% (254nm). MS(ESI): Mass calculation value. C 24 H 26For F2O2N4, 440.20 m / z, actual value 441.2 [M+H] + .

[0260] compound 59 9-(1-(4,6-Difluoroindolin-1-yl)ethyl)-7-methyl-2-morpholino-4H-pyrido[1,2-a]pyrimidin-4-one was prepared according to the procedure described in Scheme 17, Step 4. [ka] The desired compound (43.3 mg, 97.00 μmol, 22.78% yield, 95.53% purity) was obtained as a pale yellow solid. 1 H NMR(DMSO-d6,400MHz) δ 8.59(s,1H), 8.76(s,1H), 6.19(t,J=9.6Hz,1H), 6.08(dd,J=2.0Hz,J=10.8Hz,1H), 5.62(s,1H), 5.42(q,J =7.2Hz,1H), 3.66~3.56(m,9H), 3.43~3.34(m,1H), 2.91~2.88(m,2H), 2.32(s,3H), 1.50(d,J=7.2Hz,3H). HPLC: 95.53% (220nm), 98.98% (254nm). MS(ESI): Mass calculation value. C 23 H 24 For F2N4O2, 426.19 m / z, actual value 427.2 [M+H] + . [ka]

[0261] compound 60 Preparation of 4-(8-(1-((3,5-difluorophenyl)amino)ethyl)-2-morpholino-4-oxo-4H-chromen-6-yl)-1H-pyrazol-3(2H)-one (Steps 1-3 of Scheme 18) Preparation of 2-(8-(1-((3,5-difluorophenyl)amino)ethyl)-2-morpholino-4-oxo-4H-chromen-6-yl)acetamide (Step 1 of Scheme 18) [ka] To a mixture of 2-[8-[1-(3,5-difluoroanilino)ethyl]-2-morpholino-4-oxo-chromen-6-yl]acetic acid (0.25 g, 562.52 μmol, 1 equiv.) and NH4Cl (90.27 mg, 1.69 mmol, 3 equiv.) in DMF (5 mL), DIEA (218.11 mg, 1.69 mmol, 293.94 μL, 3 equiv.) and HATU (320.83 mg, 843.78 μmol, 1.5 equiv.) were added under N2 at 0 °C. The reaction mixture was stirred at 25 °C for 2 h. LCMS showed that 2-[8-[1-(3,5-difluoroanilino)ethyl]-2-morpholino-4-oxo-chromen-6-yl]acetic acid was completely consumed. The reaction mixture was quenched with ice water (20 mL), and the aqueous phase was extracted with ethyl acetate (15 mL × 3). The combined organic phase was washed with brine (15 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography (Biotage®; 4 g SepaFlash® silica flash column, eluting with a 0-100% ethyl acetate / petroleum ether gradient at 45 mL / min, followed by 0-20% MeOH / ethyl acetate at 45 mL / min). The compound 2-[8-[1-(3,5-difluoroanilino)ethyl]-2-morpholino-4-oxo-chromen-6-yl]acetamide (0.173 g, 390.13 μmol, 69.35% yield) was obtained as a yellow solid. 1 H NMR(DMSO-d6,400MHz) δ 7.73(s,1H), 7.51(s,1H), 7.46(s,1H), 6.93(d,J=6.4Hz,1H), 6.88(s,1H), 6.20(t,J=9.6Hz,1H), 6.13(d,J=9.6Hz, 2H), 5.53(s,1H), 4.98~4.91(m,1H), 3.76~3.70(m,4H), 3.55~3.50(m,4H), 3.43~3.79(m,2H), 1.48(d,J=6.8Hz,3H).

[0262] Preparation of 6-((4H-1,2,4-triazol-3-yl)methyl)-8-(1-((3,5-difluorophenyl)amino)ethyl)-2-morpholino-4H-chromen-4-one (Step 2 of Scheme 18) [ka] A mixture of 2-[8-[1-(3,5-difluoroanilino)ethyl]-2-morpholino-4-oxo-chromen-6-yl]acetamide (60 mg, 135.31 μmol, 1 equiv.) and DMF-DMA (96.74 mg, 811.83 μmol, 107.85 μL, 6 equiv.) in DMF (1 mL) was stirred at 25 °C for 36 h. The resulting mixture was concentrated under reduced pressure at 45 °C. To the resulting residue, AcOH (8.13 mg, 135.31 μmol, 7.74 μL, 1 equiv.) and NH NH HO (13.82 mg, 270.61 μmol, 13.42 μL, 98% purity, 2 equiv.) were added at 25 °C. The resulting mixture was stirred at 90 °C for 2 h. LCMS showed that 2-[8-[1-(3,5-difluoroanilino)ethyl]-2-morpholino-4-oxo-chromen-6-yl]acetamide was completely consumed. The mixture was concentrated under reduced pressure at 45 °C. The resulting residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100 × 25 mm × 5 μm; mobile phase: [water (10 mM NH4HCO3)-MeCN]; B%: 20% to 50%, 9 min). The solvent was removed by lyophilization. The compound 8-[1-(3,5-difluoroanilino)ethyl]-2-morpholino-6-(4H-1,2,4-triazol-3-ylmethyl)chromen-4-one (18.8 mg, 38.35 μmol, yield 28.35%, purity 95.37%) was obtained as a yellow solid. 1H NMR(DMSO-d6,400MHz) δ 13.75(s,1H), 8.40 and 7.81(s,1H), 7.66(s,1H), 7.49(s,1H), 6.92(d,J=6.4Hz,1H), 6.20(t,J=9.6Hz,1H), 6.11(d,J=9.6Hz ,1H), 5.53(s,1H), 4.97~4.91(m,1H), 4.04~4.01(m,2H), 3.71(t,J=4.8Hz,4H), 3.52(t,J=4.8Hz,4H), 1.48(d,J=5.6Hz,3H). HPLC: 95.37% (220nm), 100% (254nm). MS(ESI): Mass calculation value. C 24 H 23 For F2O3N5, 467.18 m / z, actual value 468.2 [M+H] + .

[0263] compound 61 Preparation of 4-(8-(1-((3,5-difluorophenyl)amino)ethyl)-2-morpholino-4-oxo-4H-chromen-6-yl)-1H-pyrazol-3(2H)-one (Step 3 of Scheme 18) [ka] A solution of 2-[8-[1-(3,5-difluoroanilino)ethyl]-2-morpholino-4-oxo-chromen-6-yl]acetamide (50 mg, 112.75 μmol, 1 equiv) in DMF-DMA (897.00 mg, 7.53 mmol, 1 mL, 66.76 equiv) was stirred at 90 °C for 12 h. The resulting mixture was concentrated under reduced pressure. Then, AcOH (437.50 mg, 7.29 mmol, 416.67 μL, 64.61 equiv) and NH NH HO (83.31 mg, 1.66 mmol, 80.89 μL, 14.76 equiv) were added at 25 °C. The reaction mixture was stirred at 90 °C for 2 h. LCMS and HPLC showed that 2-[8-[1-(3,5-difluoroanilino)ethyl]-2-morpholino-4-oxochromen-6-yl]acetamide was completely consumed. The mixture was concentrated under reduced pressure at 45 °C. The resulting residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100 × 30 mm × 10 μm; mobile phase: [water (10 mM NH4HCO3)-MeCN]; B%: 20% to 45%, 10 min). The solvent was removed by lyophilization. The compound 4-[8-[1-(3,5-difluoroanilino)ethyl]-2-morpholino-4-oxochromen-6-yl]-1,2-dihydropyrazol-3-one (12.3 mg, 24.12 μmol, yield 21.39%, purity 91.87%) was obtained as a yellow solid. 1 H NMR(DMSO-d6,400MHz) δ 8.11(s,1H), 7.91(s,1H), 7.86(s,1H), 6.90(d,J=6.4Hz,1H), 6.21~6.14(m,3H), 5.53( s,1H), 4.98~4.93(m,1H), 3.73~3.68(m,4H), 3.54~3.50(m,4H), 1.52(d,J=6.0Hz,3H). HPLC: 91.87% (220nm), 93.09% (254nm). MS(ESI): Mass calculation value. C 24 H 22 For F2O4N4, 468.16 m / z, actual value 469.3 [M+H] + .

[0264] compound 62 Preparation of 8-((7-chloro-4-fluoroindolin-1-yl)methyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (Step 6 of Scheme 9) [ka] Compound 62 (18 mg, 37.51 μmol, 15.49% yield, 97.51% purity) was obtained as an off-white solid. 1 H NMR(400MHz,DMSO-d6) δ 7.84(s,1H), 7.62(s,1H), 7.07~7.02(m,1H), 6.52(t,J=8.4Hz,1H), 5.59(s,1H), 5.02(s,2H), 3.72~3 .70(m,4H), 3.62(t,J=8.8Hz,2H), 3.59~3.54(m,4H), 3.08(t,J=8.4Hz,2H), 2.97(s,3H), 2.86(s,3H). LCMS: 97.51% (220nm), 99.52% (254nm). MS(ESI): Mass calculation value. C 25 H 25 For ClFN3O4, 485.15 m / z, observed value 486.1 [M+H] + .

[0265] compound 63 Preparation of 8-((4,6-difluoro-2-methylindolin-1-yl)methyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (Step 6 of Scheme 9) [ka] Compound 63 (153.4 mg, 316.06 μmol, 20.88% yield, 99.62% purity) was obtained as a white solid. 1H NMR(DMSO-d6,400MHz) δ 7.82(s,1H), 7.47(s,1H), 6.28(d,J=9.2Hz,1H), 6.10(d,J=9.6Hz,1H), 5.60(s,1H), 4.69~4.58(m,2H), 3.99~3.91(m,1H), 3.71 (t,J=4.8Hz,4H), 3.53(t,J=4.8Hz,4H), 3.27~3.19(m,1H), 2.95(s,3H), 2.85(s,3H), 2.68~2.63(m,1H), 1.23(d,J=6.0Hz,3H). HPLC: 99.62% (220nm), 100% (254nm). MS(ESI): Mass calculation value. C 26 H 27 For F2N3O4, 483.20 m / z, actual value 484.2 [M+H] + .

[0266] Compound 64 and Compound 65 Preparation of (S)-8-((4,6-difluoro-2-methylindolin-1-yl)methyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide and (R)-8-((4,6-difluoro-2-methylindolin-1-yl)methyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (Step 6 of Scheme 9) [ka] Chiral separation of compound 63 was carried out. Chiral preparation apparatus: CAS-TJ-ANA-SFC-L (Waters UPCC with PDA); column: Chiralpak AD-3, 50 x 4.6 mm i.d., 3 μm. Two isomers were obtained, and their structures were randomly assigned. Compound 64 (Rt = 1.318 min, ee (%) = 100% by chiral HPLC); 1H NMR(DMSO-d6,400MHz) δ 7.81(s,1H), 7.48(s,1H), 6.28(t,J=8.8Hz,1H), 6.09(d,J=10.2Hz,1H), 5.60(s,1H), 4.70~4.51(m,2H), 3.97~3.94(m ,1H), 3.70(t,J=4.8Hz,4H), 3.54(t,J=4.8Hz,4H), 3.27~3.24(m,1H), 2.95(s,3H), 2.85(s,3H), 1.23(d,J=6.0Hz,3H). HPLC: 100% (220nm), 100% (254nm). MS(ESI): Mass calculation value. C 26 H 27 For F2N3O4, 484.2 m / z, actual value 483.2 [M+H] + Compound 65 (Rt = 1.578 min, enantiomeric excess (%) by chiral HPLC = 100%). 1 H NMR(DMSO-d6,400MHz) δ 7.82(s,1H), 7.48(s,1H), 6.28(t,J=9.2Hz,1H), 6.09(d,J=10.4Hz,1H), 5.60(s,1H), 4.72~4.53(m,2H), 4.02~3.88(m,1H), 3.7 1(t,J=4.8Hz,4H), 3.53(t,J=4.8Hz,4H), 3.22~3.26(m,1H), 2.95(s,3H), 2.85(s,3H), 2.69~2.64(m,1H), 1.23(d,J=6.0Hz,3H). HPLC: 100% (220nm), 100% (254nm). MS(ESI): Mass calculation value. C 26 H 27 For F2N3O4, 484.2 m / z, actual value 483.2 [M+H] + .

[0267] compound 66 Preparation of 8-((4,6-difluoro-2,2-dimethylindolin-1-yl)methyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (Step 6 of Scheme 9) [ka] Compound 66 (15.5 mg, 30.85 μmol, 11.32% yield, 99.02% purity) was obtained as an off-white solid. 1 H NMR(400MHz,DMSO-d6) δ 7.80(s,1H), 7.41(s,1H), 6.25(t,J=8.8Hz,1H), 5.82(d,J=10.4Hz,1H), 5.61(s,1H), 4.56(s, 2H), 3.73(t,J=4.4Hz,4H), 3.56(t,J=4.4Hz,4H), 2.95~2.94(m,6H), 2.82(s,2H), 1.28(s,6H). LCMS: 99.02% (220nm), 100.00% (254nm). MS(ESI): Mass calculation value. C 27 H 29 For F2N3O4, 497.21 m / z, actual value 498.2 [M+H] + .

[0268] compound 67 Preparation of 8-(indolin-1-ylmethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (Step 6 of Scheme 9) [ka] Compound 67 (15.5 mg, 30.85 μmol, 11.32% yield, 99.02% purity) was obtained as an off-white solid. 1 H NMR(400MHz,DMSO-d6) δ 7.84(s,1H), 7.64(s,1H), 7.07(d,J=7.2Hz,1H), 6.99(t,J=7.6Hz,1H), 6.65~6.56(m,2H), 5.59(s,1 H), 4.54(s,2H), 3.67(t,J=4.4Hz,4H), 3.52(t,J=4.8Hz,4H), 3.31~3.28(m,2H), 2.98~2.86(m,8H). LCMS: 99.13% (220nm), 100.00% (254nm). MS(ESI): Mass calculation value. C 25 H 27 For N3O4, 433.20 m / z, actual value 434.2 [M+H] + .

[0269] compound 68 Preparation of 8-((4-fluoroindolin-1-yl)methyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (Step 6 of Scheme 9) [ka] Compound 68 (50.4 mg, 111.63 μmol, 46.09% yield, 100% purity) was obtained as an off-white solid. 1 H NMR(DMSO-d6,400MHz) δ 7.84(s,1H), 7.62(s,1H), 7.05~7.00(m,1H), 6.47~6.39(m,2H), 5.60(s,1H), 4.59(s,2H), 3.67(t,J=4. 4Hz,4H), 3.52(t,J=4.4Hz,4H), 3.43(t,J=8.4Hz,2H), 3.01(t,J=8.4Hz,2H), 2.97(s,3H), 2.88(s,3H). MS: 100.00% (220nm), 100.00% (254nm). MS(ESI): Mass calculation value. C 25 H 26 For FN3O4, 451.19 m / z 452.2 [M+H] + .

[0270] compound 69 Preparation of 8-((5-chloroindolin-1-yl)methyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (Step 6 of Scheme 9) [ka] Compound 69 (51.1 mg, 108.54 μmol, 44.82% yield, 99.39% purity) was obtained as an off-white solid. 1H NMR(DMSO-d6,400MHz) δ 7.84(s,1H), 7.62(s,1H), 7.12~7.08(m,1H), 7.05~7.00(m,1H), 6.64~6.61(m,1H), 5.60(s,1H), 4.55( s,2H), 3.68(t,J=4.4Hz,4H), 3.52(t,J=4.4Hz,4H), 3.38~3.37(m,2H), 2.97(s,6H), 2.91~2.76(m,2H). MS: 99.39% (220nm), 100.00% (254nm). MS(ESI): Mass calculation value. C 25 H 26 For ClN3O4, 467.16 m / z, observed value 468.2 [M+H] + .

[0271] compound 70 Preparation of 8-((6-fluoroindolin-1-yl)methyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (Step 6 of Scheme 9) [ka] Compound 70 (29.8 mg, 65.26 μmol, 26.95% yield, 98.87% purity) was obtained as an off-white solid. 1 H NMR(400MHz,DMSO-d6) δ 7.84(s,1H), 7.61(s,1H), 7.01(t,J=8.0Hz,1H), 6.51~6.48(m,1H), 6.35~6.31(m,1H), 5.59(s,1H), 4.58(s,2H), 3.68(t,J=4.8Hz,4H), 3.52(t,J=5.2Hz,4H), 3.39(t,J=8.4Hz,2H), 2.97~2.50(m,8H). LCMS: 98.87% (220nm), 100.00% (254nm). MS(ESI): Mass calculation value. C 25 H 26 For FN3O4, 451.19 m / z, actual value 452.2 [M+H] + .

[0272] compound 71 Preparation of 8-((4-chloroindolin-1-yl)methyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (Step 6 of Scheme 9) [ka] Compound 71 (22.1 mg, 45.74 μmol, 21.59% yield, 96.86% purity) was obtained as an off-white solid. 1 H NMR(400MHz,DMSO-d6) δ 7.84(s,1H), 7.61(s,1H), 7.01(t,J=8.0Hz,1H), 6.62(d,J=8.0Hz,1H), 6.56(d,J=8.0Hz,1H), 5.60(s,1 H), 4.59(s,2H), 3.68(t,J=4.4Hz,4H), 3.52(t,J=4.4Hz,4H), 3.43(t,J=8.8Hz,2H), 3.02~2.87(m,8H). LCMS: 96.86% (220nm), 98.21% (254nm). MS(ESI): Mass calculation value. C 25 H 26 For CIN3O4, 467.16 m / z, actual value 468.2 [M+H] + .

[0273] compound 72 Preparation of 8-((7-methoxyindolin-1-yl)methyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (Step 6 of Scheme 9) [ka] Compound 72 (30.9 mg, 65.12 μmol, 26.89% yield, 97.68% purity) was obtained as an off-white solid. 1H NMR(400MHz,DMSO-d6) δ 7.83(s,1H), 7.67(s,1H), 6.82~6.62(m,3H), 5.58(s,1H), 4.82(s,2H), 3.71(s,3H), 3.68(t ,J=4.4Hz,4H), 3.54(t,J=4.0Hz,4H), 3.20(t,J=9.2Hz,2H), 2.97(s,3H), 2.92~2.84(m,5H). LCMS: 97.68% (220nm), 100.00% (254nm). MS(ESI): Mass calculation value. C 26 H 29 For N3O5, 463.21 m / z, actual value 464.2 [M+H] + .

[0274] compound 73 Preparation of 8-((2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)methyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (Step 6 of Scheme 9) [ka] Compound 73 (12 mg, 27.13 μmol, 8.96% yield, 98.23% purity) was obtained as a yellow solid. 1 H NMR(DMSO-d6,400MHz) δ 7.84(s,1H), 7.79(d,J=5.2Hz,1H),7.66(s,1H),7.30(d,J=7.2Hz,1H),6.50(t,J=5.2Hz,1H),5.57(s,1 H), 4.75(s,2H), 3.66(t,J=4.8Hz,4H), 3.55(t,J=4.8Hz,4H), 3.41(t,J=8.2Hz,2H), 2.97~2.90(m,8H). HPLC: 98.23% (220nm), 99.69% (254nm). MS(ESI): Mass calculation value. C 24 H 26 For O4N4, 434.20 m / z, actual value 435.2 [M+H] + .

[0275] compound 74 Preparation of 8-((2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl)methyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (Step 6 of Scheme 9) [ka] Compound 74 (27.1 mg, 62.26 μmol, 25.71% yield, 99.82% purity) was obtained as a white solid. 1 H NMR(DMSO-d6,400MHz) δ 7.93(s,1H), 7.88(d,J=4.4Hz,1H), 7.85(s,1H), 7.65(s,1H), 7.12(d,J=4.4Hz,1H), 5.60(s,1H), 4.62(s,2H) , 3.67(t,J=4.4Hz,4H), 3.53(t,J=4.4Hz,4H), 3.39~3.35(m,2H), 3.02~2.99(m,2H), 2.97(s,3H), 2.88(s,3H). MS: 99.82% (220nm), 100.00% (254nm). MS(ESI): Mass calculation value. C 24 H 26 For N4O4, 434.20 m / z, actual value 435.2 [M+H] + .

[0276] compound 75 Preparation of 8-((6-fluoro-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)methyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (Step 6 of Scheme 9) [ka] Compound 75 (42.9 mg, 94.81 μmol, 39.15% yield, 100% purity) was obtained as a white solid. 1H NMR(DMSO-d6,400MHz) δ 7.85(s,1H), 7.61(s,1H), 7.57(s,1H), 6.88(d,J=10.4Hz,1H), 5.60(s,1H), 4.64(s,2H), 3.68(t,J =4.4Hz,4H), 3.53(t,J=4.8Hz,4H), 3.52~3.50(m,2H), 3.03~3.00(m,2H), 2.98(s,3H), 2.89(s,3H). MS: 100.00% (220nm), 100.00% (254nm). MS(ESI): Mass calculation value. C 24 H 25 For FN4O4, 452.19 m / z, actual value 452.3 [M+H] + .

[0277] compound 76 Preparation of 8-((2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)methyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (Step 6 of Scheme 9) [ka] Compound 76 (25.9 mg, 59.61 μmol, 24.61% yield, 100.00% purity) was obtained as an off-white solid. 1 H NMR(400MHz,DMSO-d6) δ 7.86(s,1H), 7.70(d,J=4.4Hz,1H), 7.64(s,1H), 6.94(t,J=7.6Hz,1H)), 6.88(d,J=8.0Hz,1H), 5.60(s,1H), 4.59(s ,2H), 3.68~3.64(m,4H), 3.53~3.50(m,4H), 3.42(t,J=8.4Hz,2H), 3.03(t,J=8.4Hz,2H), 2.98(s,3H), 2.90(s,3H). LCMS: 100.00%(220nm), 100.00%(254nm). MS(ESI): Mass calculation value. C 24 H 26 For N4O4, 434.20 m / z, actual value 435.2 [M+H] + . [ka]

[0278] compound 77 Preparation of (Z)-8-((4,6-difluoroindolin-1-yl)methyl)-4-(hydroxyimino)-N,N-dimethyl-2-morpholino-4H-chromene-6-carboxamide (Scheme 19) [ka] A mixture of 8-[(4,6-difluoroindolin-1-yl)methyl]-N,N-dimethyl-2-morpholino-4-oxo-chromene-6-carboxamide (0.1 g, 213.00 μmol, 1 equiv.) and NHOH·HCl (29.60 mg, 426.00 μmol, 2 equiv.) in i-PrOH (3 mL) was heated at 130 °C for 30 min in a microwave oven. LCMS showed that 8-[(4,6-difluoroindolin-1-yl)methyl]-N,N-dimethyl-2-morpholino-4-oxo-chromene-6-carboxamide was completely consumed. The resulting mixture was concentrated under reduced pressure at 45 °C. The resulting residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100 × 30 mm × 10 μm; mobile phase: [water (10 mM NH4HCO3)-MeCN]; B%: 30% to 60%, 10 min). The solvent was removed by lyophilization. The compound (4Z)-8-[(4,6-difluoroindolin-1-yl)methyl]-4-hydroxyimino-N,N-dimethyl-2-morpholino-chromene-6-carboxamide (15.9 mg, 32.82 μmol, 15.41% yield) was obtained as a pale yellow solid. 1 H NMR(DMSO-d6,400MHz) δ 7.63(s,1H), 7.26(s,1H), 6.81(s,1H), 6.31~6.11(m,2H), 4.35(s,2H), 3.71(t ,J=4.4Hz,4H), 3.49(t,J=8.8Hz,2H), 3.21(t,J=4.8Hz,4H), 2.98~2.88(m,8H). HPLC: 100% (220nm), 100% (254nm). MS(ESI): Mass calculation value. C 25 H 26For O4N4F2, 484.19 m / z, actual value 485.3 [M+H] + .

[0279] compound 78 Preparation of 8-((4,6-difluoroindolin-1-yl)methyl)-N,N-diethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (Step 4 of Scheme 11) [ka] Compound 78 (43.5 mg, 85.62 μmol, 37.88% yield, 97.93% purity) was obtained as a white solid. 1 H NMR(DMSO-d6,400MHz) δ 7.78(s,1H), 7.52(s,1H), 6.41(d,J=8.4Hz,1H), 6.33~6.28(m,1H), 5.59(s,1H), 4.64(s,2H), 3.70(t,J=4.8Hz ,4H), 3.54~3.52(m,4H), 3.49~3.47(m,2H), 3.29~3.27(m,4H), 2.99(t,J=8.0Hz,2H), 1.12(s,3H), 1.00(s,3H). MS: 97.93% (220nm), 99.19% (254nm). MS(ESI): Mass calculation value. C 27 H 29 For F2N3O4, 497.21 m / z, actual value 498.3 [M+H] + .

[0280] compound 79 Preparation of 8-((4,6-difluoroindolin-1-yl)methyl)-N-ethyl-N-methyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (Step 4 of Scheme 11) [ka] Compound 79 (18 mg, 36.39 μmol, 16.10% yield, 97.74% purity) was obtained as a white solid. 1H NMR(400MHz,DMSO-d6) δ 7.81(s,1H), 7.53(s,1H), 6.41~6.30(m,2H), 5.59(s,1H), 4.64(s,2H), 3.68(s, 4H), 3.53~3.49(m,6H), 3.19~3.12(m,2H), 3.01~2.79(m,5H), 1.12~0.94(m,3H). LCMS: 97.74% (220nm), 100.00% (254nm). MS(ESI): Mass calculation value. C 26 H 27 For F2N3O4, 483.20 m / z, actual value 484.2 [M+H] + .

[0281] compound 80 Preparation of 8-((4,6-difluoroindolin-1-yl)methyl)-N-ethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (Step 4 of Scheme 11) [ka] Compound 80 (15.7 mg, 32.00 μmol, 28.31% yield, 95.68% purity) was obtained as a white solid. 1 H NMR(400MHz,DMSO-d6) δ 8.75~8.73(m,1H), 8.40(s,1H), 8.04(s,1H), 6.44(d,J=8.4Hz,1H), 6.32(t,J=7.6Hz,1H), 5.59(s,1H), 4.62(s,2H), 3.6 9~3.66(m,4H), 3.54~3.50(m,4H), 3.46(t,J=8.0Hz,2H), 3.24~3.20(m,2), 2.96(t,J=8.0Hz,2H), 1.12(t,J=7.2Hz,3H). LCMS: 95.68% (220nm), 99.33% (254nm). MS(ESI): Mass calculation value. C 25 H 25 For F2N3O4, 469.18 m / z, actual value 470.2 [M+H] + .

[0282] compound 81 Preparation of 8-((4,6-difluoroindolin-1-yl)methyl)-N-isopropyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (Step 4 of Scheme 11) [ka] Compound 81 (9.5 mg, 19.50 μmol, 17.25% yield, 99.24% purity) was obtained as a white solid. 1 H NMR(400MHz,DMSO-d6) δ 8.55(d,J=7.6Hz,1H), 8.41(s,1H), 8.04(s,1H), 6.43(d,J=8.8Hz,1H), 6.33(t,J=8.0Hz,1H), 5.59(s,1H), 4.62(s,2H), 4. 12~4.05(m,1H), 3.73~3.63(m,4H), 3.55~3.50(m,4H), 3.46(t,J=8.4Hz,2H), 2.95(t,J=8.4Hz,2H), 1.16(d,J=6.8Hz,6H). LCMS: 99.24% (220nm), 99.84% (254nm). MS(ESI): Mass calculation value. C 26 H 27 For F2N3O4, 483.20 m / z, actual value 484.2 [M+H] + .

[0283] compound 82 Preparation of 8-((4,6-difluoroindolin-1-yl)methyl)-N-(1-methylpiperidin-4-yl)-2-morpholino-4-oxo-4H-chromene-6-carboxamide (Step 4 of Scheme 11) [ka] Compound 82 (14.1 mg, 25.58 μmol, 22.63% yield, 97.71% purity) was obtained as a white solid. 1H NMR(DMSO-d6,400MHz) δ 8.56(d,J=8.0Hz,1H), 8.41(s,1H), 8.03(s,1H), 6.47~6.44(m,1H), 6.34~6.2 9(m,1H), 5.60(s,1H), 4.63(s,2H), 3.78~3.71(m,1H), 3.69~3.67(m,4H), 3.5 3~3.51(m,4H), 3.44(t,J=8.8Hz,2H), 2.95(t,J=8.4Hz,2H), 2.78(d,J=10.4H z,2H), 2.16(s,3H), 1.97~1.91(m,2H), 1.75~1.72(m,2H), 1.64~1.56(m,2H). MS: 97.71% (220nm), 98.11% (254nm). MS(ESI): Mass calculation value. C 29 H 32 For F2N4O4, 538.24 m / z, actual value 539.3 [M+H] + .

[0284] compound 83 Preparation of 8-((4,6-difluoroindolin-1-yl)methyl)-2-morpholino-4-oxo-N-(tetrahydro-2H-pyran-4-yl)-4H-chromene-6-carboxamide (Step 4 of Scheme 11) [ka] Compound 83 (18.8 mg, 35.45 μmol, 31.37% yield, 99.11% purity) was obtained as a white solid. 1H NMR(DMSO-d6,400MHz) δ 8.64(d,J=7.6Hz,1H), 8.43(s,1H), 8.05(s,1H), 6.47~6.44(m,1H), 6.34~6.30 (m,1H), 5.60(s,1H), 4.63(s,2H), 4.01~3.99(m,1H), 3.89(d,J=4.8Hz,2H), 3. 69~3.67(m,4H), 3.53~3.51(m,4H), 3.45(t,J=8.8Hz,2H), 3.40(s,1H), 3.37(d ,J=1.6Hz,1H), 2.95(t,J=9.2Hz,2H), 1.75(d,J=9.6Hz,2H), 1.66~1.59(m,2H). MS: 99.11% (220nm), 100.00% (254nm). MS(ESI): Mass calculation value. C 28 H 29 For F2N3O5, 525.21 m / z, actual value 526.2 [M+H] + .

[0285] compound 84 Preparation of 8-((4,6-difluoroindolin-1-yl)methyl)-N-(2-hydroxy-2-methylpropyl)-2-morpholino-4-oxo-4H-chromene-6-carboxamide (Step 4 of Scheme 11) [ka] Compound 84 (21 mg, 40.89 μmol, 36.18% yield, 100% purity) was obtained as a white solid. 1 H NMR(DMSO-d6,400MHz) δ 8.55(t,J=6.0Hz,1H), 8.42(s,1H), 8.05(s,1H), 6.46(d,J=10.4Hz,1H), 6.31(t,J=8.0Hz,1H), 5.60(s,1H), 4.63(s,2H) , 4.56(s,1H), 3.69~3.67(m,4H), 3.54~3.51(m,4H), 3.46(t,J=8.8Hz,2H), 3.24(d,J=6.0Hz,2H), 2.96(t,J=8.4Hz,2H). HPLC: 100% (220nm), 99.72% (254nm). MS(ESI): Mass calculation value. C 27 H 29For F2O5N3, 513.21 m / z, actual value 514.2 [M+H] + .

[0286] compound 85 Preparation of 8-((4,6-difluoroindolin-1-yl)methyl)-N-isobutyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (Step 4 of Scheme 11) [ka] Compound 85 (24.1 mg, 47.57 μmol, 42.09% yield, 98.20% purity) was obtained as a white solid. 1 H NMR(DMSO-d6,400MHz) δ 8.75(t,J=5.6Hz,1H), 8.41(s,1H), 8.04(s,1H), 6.45(d,J=10.4Hz,1H), 6.31(t,J=8.0Hz,1H), 5.60(s,1H), 4.63(s,2H), 3.69~3.67(m ,4H), 3.53~3.51(m,4H), 3.46(t,J=8.8Hz,2H), 3.07(t,J=6.0Hz,2H), 2.98(t,J=8.4Hz,2H), 1.90~1.80(m,1H), 0.87(d,J=6.8Hz,6H). HPLC: 98.20% (220nm), 98.72% (254m). MS(ESI): Mass calculation value. C 27 H 29 For O4N3F2, 497.21 m / z, actual value 498.2 [M+H] + .

[0287] compound 86 Preparation of 8-((4,6-difluoroindolin-1-yl)methyl)-N-methyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (Step 4 of Scheme 11) [ka] Compound 86 (8.1 mg, 16.45 μmol, 14.55% yield, 92.48% purity) was obtained as a pale yellow solid. 1H NMR(400MHz,DMSO-d6) δ 8.68~8.67(m,1H), 8.38(s,1H), 8.05(s,1H), 6.43(d,J=10.8Hz,1H), 6.32(t,J=7.6Hz,1H), 5.59(s,1H), 4.63(s ,2H), 3.69~3.67(m,4H), 3.55~3.52(m,4H), 3.46(t,J=8.4Hz,2H), 2.95(t,J=8.4Hz,2H), 2.77(d,J=4.4Hz,3H). LCMS: 92.48% (220nm), 90.06% (254nm). MS(ESI): Mass calculation value. C 24 H 23 For F2N3O4, 455.17 m / z, actual value 456.1 [M+H] + .

[0288] compound 87 Preparation of 8-((4,6-difluoroindolin-1-yl)methyl)-6-(3,3-dimethylazetidine-1-carbonyl)-2-morpholino-4H-chromen-4-one (Step 4 of Scheme 11) [ka] Compound 87 (47.1 mg, 92.03 μmol, 50.89% yield, 99.56% purity) was obtained as a white solid. 1 H NMR(DMSO-d6,400MHz) δ 8.09(s,1H), 7.76(s,1H), 6.44(d,J=12.0Hz,1H), 6.31(t,J=8.0Hz,1H), 5.60(s,1H), 4.67(s,2H), 3.86(s,2H) , 3.72(s,2H), 3.70~3.68(m,4H), 3.54~3.53(m,4H), 3.49(d,J=8.0Hz,2H), 2.98(t,J=8.0Hz,2H), 1.22(s,6H). MS: 99.56% (220nm), 100.00% (254nm). MS(ESI): Mass calculation value. C 28 H 29 For F2N3O4, 509.21 m / z, actual value 510.3 [M+H] + .

[0289] compound 88 Preparation of 1-(8-((4,6-difluoroindolin-1-yl)methyl)-2-morpholino-4-oxo-4H-chromene-6-carbonyl)-3-methylazetidine-3-carbonitrile (Step 4 of Scheme 11) [ka] Compound 88 (21.2 mg, 40.73 μmol, 22.52% yield, 100% purity) was obtained as a white solid. 1 H NMR(400MHz,DMSO-d6) δ 8.10(s,1H), 7.80(s,1H), 6.48(d,J=8.4Hz,1H), 6.31(t,J=8.4Hz,1H), 5.62(s,1H), 4.66(s,2H), 4.62~4.60(m,1H), 4.38~4.32(m,1H) , 4.19~4.15(m,1H), 4.06~4.01(m,1H), 3.71~3.66(m,4H), 3.56~3.52(m,4H), 3.49(t,J=8.8Hz,2H), 2.98(t,J=8.4Hz,2H), 1.64(s,3H). LCMS: 100.00%(220nm), 100.00%(254nm). MS(ESI): Mass calculation value. C 28 H 26 For F2N4O4, 520.19 m / z, actual value 521.3 [M+H] + .

[0290] compound 89 Preparation of 8-((4,6-difluoroindolin-1-yl)methyl)-6-(3-hydroxyazetidine-1-carbonyl)-2-morpholino-4H-chromen-4-one (Step 4 of Scheme 11) [ka] Compound 89 (19.5 mg, 39.20 μmol, yield 21.68%, purity 100.00%) was obtained as a white solid. 1H NMR(400MHz,DMSO-d6) δ 8.06(s,1H), 7.76(s,1H), 6.44(d,J=10.4Hz,1H), 6.32(t,J=8.4Hz,1H),5. 76(d,J=6.4Hz,1H), 5.60(s,1H), 4.65(s,2H), 4.49~4.45(m,1H), 4.39~4.3 6(m,1H), 4.27~4.23(m,1H), 3.99~3.94(m,1H), 3.81~3.77(m,1H), 3.72~3. 65(m,4H), 3.53~3.52(m,4H), 3.48(t,J=8.0Hz,2H), 2.97(t,J=8.0Hz,2H). LCMS: 100.00%(220nm), 100.00%(254nm). MS(ESI): Mass calculation value. C 26 H 25 For F2N3O5, 497.18 m / z, actual value 498.2 [M+H] + . [ka]

[0291] compound 90 Preparation of (R)-8-((4,6-difluoroindolin-1-yl)methyl)-N,N-dimethyl-2-(2-methylmorpholino)-4-oxo-4H-chromene-6-carboxamide and (R)-8-((4-fluoroindolin-1-yl)methyl)-N,N-dimethyl-2-(2-methylmorpholino)-4-oxo-4H-chromene-6-carboxamide (Steps 1-7 of Scheme 20) Preparation of methyl (R)-8-bromo-2-(2-methylmorpholino)-4-oxo-4H-chromene-6-carboxylate (Step 1 of Scheme 20) [ka] A solution of methyl 8-bromo-2-ethylsulfanyl-4-oxo-chromene-6-carboxylate (8 g, 23.31 mmol, 1 equiv.), (2R)-2-methylmorpholine (4.81 g, 34.97 mmol, 1.03 mL, 1.5 equiv., HCl), and DIEA (9.04 g, 69.93 mmol, 12.18 mL, 3 equiv.) in MeCN (80 mL) was stirred at 105° C. for 15 h. DIEA (3.01 g, 23.31 mmol, 4.06 mL, 1 equiv.) was then added, and the reaction mixture was stirred at 110° C. for 15 h. TLC (petroleum ether: EtOAc = 1:1, R f =0.15) and LCMS showed that approximately 40% of methyl 8-bromo-2-[(2R)-2-methylmorpholin-4-yl]-4-oxo-chromene-6-carboxylate had formed, and approximately 18% of methyl 8-bromo-2-ethylsulfanyl-4-oxo-chromene-6-carboxylate remained. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc (100 mL) and water (100 mL). Some brown solid formed. This solid was collected after filtration. For the filtrate, the organic layer was separated, and the aqueous layer was extracted with EtOAc (50 mL × 2). The combined organic layers were washed with water (30 mL × 2) and brine (30 mL × 1), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was triturated with EtOAc (15 mL) and petroleum ether (60 mL). The solid was collected after filtration. The compound methyl 8-bromo-2-[(2R)-2-methylmorpholin-4-yl]-4-oxo-chromene-6-carboxylate (6.7 g, 17.53 mmol, 75.20% yield) was obtained as a brown solid. 1 H NMR(DMSO-d6,400MHz) δ 8.40(s,1H), 8.32(s,1H), 5.65(s,1H), 4.02~3.89(m,6H), 3.64~3.61(m,2H), 3.17~3.15(m,1H), 2.84(t,J=2.4Hz,1H), 1.10(d,J=6.4Hz,3H).

[0292] Preparation of methyl (R)-2-(2-methylmorpholino)-4-oxo-8-vinyl-4H-chromene-6-carboxylate (Step 2 of Scheme 20) [ka] A mixture of methyl 8-bromo-2-[(2R)-2-methylmorpholin-4-yl]-4-oxo-chromene-6-carboxylate (6.7 g, 17.53 mmol, 1 equiv.), Pd(dppf)Cl (1.28 g, 1.75 mmol, 0.1 equiv.), KCO (4.85 g, 35.06 mmol, 2 equiv.), and potassium trifluoro(vinyl)borohydride (3.52 g, 26.29 mmol, 1.5 equiv.) in dioxane (60 mL) and HO (10 mL) was stirred at 100 °C under N for 5 h. TLC (petroleum ether: EtOAc = 0:1, R f =0.18) and LCMS showed that the reaction was complete. After filtration through a pad of Celite, the filtrate was concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and water (50 mL). Some off-white solid formed. This solid was collected after filtration. The filtrate was extracted with DCM (50 mL × 3). The combined organic layers were washed with brine (50 mL × 4), dried over Na2SO4, filtered, and concentrated under reduced pressure. The combined crude products were triturated with EtOAc (15 mL) and petroleum ether (60 mL). The solid was collected after filtration. Compound 2-[(2R)-2-methylmorpholin-4-yl]-4-oxo-8-vinyl-chromene-6-carboxylate methyl ester (5.7 g, 17.31 mmol, 98.73% yield) was obtained as a brown solid. 1 H NMR(DMSO-d6,400MHz) δ 8.39(s,1H), 8.31(s,1H), 7.20~7.13(m,1H), 6.07(dd,J=6.0Hz,18.0Hz,1H), 5.62~5.58(m,2H), 4.0 2~3.90(m,6H), 3.62~3.56(m,2H), 3.15~3.09(m,1H), 2.79(t,J=10.8Hz,1H), 1.17(d,J=6.0Hz,3H).

[0293] Preparation of (R)-2-(2-methylmorpholino)-4-oxo-8-vinyl-4H-chromene-6-carboxylic acid (Step 3 of Scheme 20) [ka] A solution of methyl 2-[(2R)-2-methylmorpholin-4-yl]-4-oxo-8-vinyl-chromene-6-carboxylate (5.7 g, 17.31 mmol, 1 equiv.) and LiOH HO (2.18 g, 51.92 mmol, 3 equiv.) in THF (30 mL) and HO (30 mL) was stirred at 20 °C for 1 h. TLC (petroleum ether: EtOAc = 0:1, R f =0.20) and LCMS showed that the reaction was complete. Half of the organic solvent was removed under reduced pressure. The remaining aqueous phase and half of the THF phase were brought to pH=4 with 1N HCl at 0°C, and some white solid formed. This solid was collected after filtration. The compound 2-[(2R)-2-methylmorpholin-4-yl]-4-oxo-8-vinyl-chromene-6-carboxylic acid (5.1 g, 16.17 mmol, 93.45% yield) was obtained as an off-white solid. 1 H NMR(DMSO-d6,400MHz) δ 13.22(s,1H), 8.39(s,1H), 8.33(s,1H), 7.56~7.49(m,1H), 6.06(d,J=17.6Hz,1H), 5.61~5.57(m,2H) ), 3.95~3.92(m,3H), 3.63~3.57(m,2H), 3.15~3.12(m,1H), 2.82~2.79(m,1H), 1.17(d,J=6.4Hz,3H).

[0294] Preparation of (R)-N,N-dimethyl-2-(2-methylmorpholino)-4-oxo-8-vinyl-4H-chromene-6-carboxamide (Step 4 of Scheme 20) [ka] To a mixture of 2-[(2R)-2-methylmorpholin-4-yl]-4-oxo-8-vinyl-chromene-6-carboxylic acid (5.1 g, 16.17 mmol, 1 equiv.), DIEA (10.45 g, 80.87 mmol, 14.09 mL, 5 equiv.), and N-methylmethanamine (3.96 g, 48.52 mmol, 4.45 mL, 3 equiv., HCl) in THF (50 mL) was added T3P (15.44 g, 24.26 mmol, 14.43 mL, 50% purity, 1.5 equiv.) dropwise at 0° C. The resulting mixture was stirred at 20° C. for 8 h. TLC (EtOAc:MeOH=15:1, R f =0.12) and LCMS showed that the reaction was nearly complete. The reaction mixture was poured into ice water (200 mL) and adjusted to pH=6 with 1N HCl. The mixture was extracted with EtOAc (80 mL×4). The combined organic layers were washed with brine (50 mL×1), dried over Na2SO4, filtered, and concentrated under reduced pressure. The aqueous layer was further extracted with DCM and i-PrOH (v:v=3:1, 80 mL×4). The combined organic layers were washed with brine (50 mL×1), dried over Na2SO4, filtered, and concentrated under reduced pressure. Compound N,N-dimethyl-2-[(2R)-2-methylmorpholin-4-yl]-4-oxo-8-vinyl-chromene-6-carboxamide (3 g, 8.76 mmol, 54.17% yield) was obtained as a brown solid. 1 H NMR(DMSO-d6,400MHz) δ 7.93(s,1H), 7.81(s,H), 7.18(dd,J=7.6Hz,1H), 6.08(d,J=22.0Hz,1H), 5.61(s,1H), 5.56(d,J=22.0Hz,1H), 4.02 ~3.92(m,3H), 3.63~3.60(m,2H), 3.13~3.10(m,1H), 3.01 and 2.94(s,6H), 2.79~2.72(m,1H), 1.16(d,J=6.0Hz,3H).

[0295] Preparation of (R)-8-formyl-N,N-dimethyl-2-(2-methylmorpholino)-4-oxo-4H-chromene-6-carboxamide (Step 5 of Scheme 20) [ka] A mixture of N,N-dimethyl-2-[(2R)-2-methylmorpholin-4-yl]-4-oxo-8-vinyl-chromene-6-carboxamide (0.5 g, 1.46 mmol, 1 equiv.) and KOsO·2HO (53.81 mg, 146.03 μmol, 0.1 equiv.) in THF (10 mL) and HO (10 mL) was stirred at 20 °C for 30 min. The mixture was then cooled to 0 °C, and NaIO (937.05 mg, 4.38 mmol, 242.76 μL, 3 equiv.) was added portionwise at 0 °C, and the resulting mixture was stirred at 0 °C for 30 min. TLC (EtOAc:MeOH = 15:1, R f =0.15) and LCMS showed that the reaction was complete. The mixture was extracted with DCM and i-PrOH (v:v=3:1, 20 mL × 3). The combined organic layers were washed with brine (10 mL × 1), dried over Na2SO4, filtered, and concentrated under reduced pressure. Compound 8-formyl-N,N-dimethyl-2-[(2R)-2-methylmorpholin-4-yl]-4-oxo-chromene-6-carboxamide (0.5 g, 1.45 mmol, 99.43% yield) was obtained as a brown solid. 1 H NMR (DMSO-d, 400 MHz) δ 10.41 (s, 1H), 8.17 (s, 1H), 8.14 (s, 1H), 5.68 (s, 1H), 4.10–4.02 (m, 3H), 3.62–3.59 (m, 2H), 3.02–2.99 (m, 1H), 2.99 and 2.92 (s, 6H), 2.82–2.79 (m, 1H), 1.05 (d, J = 6.4 Hz, 3H).

[0296] Preparation of (R)-8-((4,6-difluoroindolin-1-yl)methyl)-N,N-dimethyl-2-(2-methylmorpholino)-4-oxo-4H-chromene-6-carboxamide (Step 6 of Scheme 20) [ka] A solution of 8-formyl-N,N-dimethyl-2-[(2R)-2-methylmorpholin-4-yl]-4-oxo-chromene-6-carboxamide (0.5 g, 1.16 mmol, 80% purity, 1 equiv.), AcOH (2.09 g, 34.85 mmol, 1.99 mL, 30 equiv.), and 4,6-difluoroindoline (270.32 mg, 1.74 mmol, 1.5 equiv.) in MeOH (3 mL) was stirred at 20° C. for 1.5 h. NaBHCN (145.99 mg, 2.32 mmol, 2 equiv.) was then added portionwise at 0° C., and the resulting mixture was stirred at 20° C. for 1 h. HPLC and LCMS indicated the reaction was complete. The mixture was quenched with ice water (10 mL) at 0° C., and the organic solvent was removed under reduced pressure. The aqueous layer was adjusted to pH 8 with saturated NaHCO3 and then extracted with EtOAc (10 mL × 4). The combined organic layers were washed with brine (10 mL × 1), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (Column: Waters Xbridge C18 150 × 50 mm × 10 μm; Mobile phase: [water (10 mM NH4HCO3)-MeCN]; B%: 30% to 50%, 10 min). The eluent was removed by lyophilization. Compound 8-[(4,6-difluoroindolin-1-yl)methyl]-N,N-dimethyl-2-[(2R)-2-methylmorpholin-4-yl]-4-oxo-chromene-6-carboxamide (140.6 mg, 289.02 μmol, 24.88% yield, 99.39% purity) was obtained as a white solid. 1 H NMR(DMSO-d6,400MHz) δ 7.85(s,1H), 7.61(s,1H), 6.50~6.46(m,1H), 6.34~6.29(m,1H), 5.61(s,1H), 4.66~4.60(m,2H), 3.94~3.87( m,3H), 3.56~3.50(m,2H), 3.43(t,J=8.8Hz,2H), 2.98~2.90(m,9H), 2.75~2.69(m,1H), 1.07(d,J=6.4Hz,3H). HPLC: 99.39% (220nm), 98.68% (254nm). MS(ESI): Mass calculation value. C 26 H 27 For F2N3O4, 483.20 m / z, actual value 484.2 [M+H]+ .

[0297] compound 91 Preparation of (R)-8-((4-fluoroindolin-1-yl)methyl)-N,N-dimethyl-2-(2-methylmorpholino)-4-oxo-4H-chromene-6-carboxamide (Step 7 of Scheme 20) [ka] A solution of 8-formyl-N,N-dimethyl-2-[(2R)-2-methylmorpholin-4-yl]-4-oxo-chromene-6-carboxamide (5.5 g, 15.97 mmol, 1 equiv.), AcOH (1.92 g, 31.94 mmol, 1.83 mL, 2 equiv.), and 4-fluoroindoline (2.19 g, 15.97 mmol, 1 equiv.) in MeOH (50 mL) was stirred at 20° C. for 1.5 h. NaBHCN (1.51 g, 23.96 mmol, 1.5 equiv.) was then added in portions at 0° C. under N. The resulting mixture was stirred at 0° C. for 1 h. LCMS and HPLC indicated that 8-formyl-N,N-dimethyl-2-[(2R)-2-methylmorpholin-4-yl]-4-oxo-chromene-6-carboxamide was completely consumed. The mixture was quenched with ice water (50 mL) at 0 °C, and the organic solvent was removed under reduced pressure. The aqueous layer was adjusted to pH = 8 with saturated NaHCO3 and then extracted with DCM and i-PrOH (v:v = 3:1, 80 mL × 3). The combined organic layers were washed with brine (30 mL × 1), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (Biotage®; 80 g SepaFlash® silica flash column, eluent: 0–14% gradient methanol / ethyl acetate @ 130 mL / min). The eluent was removed under reduced pressure. The crude product (4.49 g) was further purified by preparative HPLC (column: Xtimate C18 10 μm 250 × 80 mm; mobile phase: [water (10 mM NH4HCO3)-MeCN]; B%: 25% to 55%, 30 min). The eluent was removed by lyophilization. The solvent was removed by lyophilization. Compound 8-[(4-fluoroindolin-1-yl)methyl]-N,N-dimethyl-2-[(2R)-2-methylmorpholin-4-yl]-4-oxo-chromene-6-carboxamide (3.16 g, 6.78 mmol, 42.48% yield, 99.94% purity) was obtained as a white solid. This batch was combined with ET34641-507 and ET34641-509, dried by lyophilization, and then QC checked together for derivatization. A total of 0.65g + 1.86g + 3.16g = 5.67g was obtained. 1H NMR(400MHz,DMSO-d6) δ 7.85(s,1H), 7.63(s,1H), 7.06~7.00(m,1H), 6.50(d,J=7.6z,1H), 6.42(t,J=8.8Hz,1H), 5.61(s,1H), 4.57(s,2H), 3.97~3.86 (m,3H), 3.54~3.53(m,2H), 3.45~3.40(m,2H), 3.07~3.06(m,1H), 2.98~2.88(m,8H), 2.76~2.72(m,1H), 1.05(d,J=6.4Hz,3H). HPLC: 99.94% (220nm), 99.70% (254nm). MS(ESI): Mass calculation value. C 26 H 28 For FN3O4, 465.21 m / z, actual value 466.2 [M+H] + . [ka]

[0298] compound 92 Preparation of (S)-8-((4,6-difluoroindolin-1-yl)methyl)-2-(2-(fluoromethyl)morpholino)-N,N-dimethyl-4-oxo-4H-chromene-6-carboxamide (Steps 1-8 of Scheme 21) Preparation of (S)-8-bromo-2-(2-(hydroxymethyl)morpholino)-4-oxo-4H-chromene-6-carboxylate (Step 1 of Scheme 21) [ka] To a mixture of methyl 8-bromo-2-ethylsulfanyl-4-oxo-chromene-6-carboxylate (10 g, 29.14 mmol, 1 equiv.) and [(2S)-morpholin-2-yl]methanol (6.83 g, 44.45 mmol, 1.53 equiv., HCl) in CH3CN (100 mL) was added DIEA (15.06 g, 116.56 mmol, 20.30 mL, 4 equiv.). The resulting mixture was stirred at 100 °C under N2 for 36 h. LCMS indicated that methyl 8-bromo-2-ethylsulfanyl-4-oxo-chromene-6-carboxylate was nearly consumed. The mixture was concentrated under reduced pressure at 45 °C. The residue was dissolved in EtOAc (150 mL) and HO (200 mL). The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (80 mL × 2). The combined organic phase was washed with brine (50 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography (Biotage®; 80 g SepaFlash® silica flash column, eluent: 0-80% ethyl acetate / petroleum ether gradient @ 60 mL / min). The solvent was concentrated in vacuo. The compound 8-bromo-2-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-4-oxo-chromene-6-carboxylate (6.4 g, 16.07 mmol, 55.15% yield) was obtained as a yellow solid. 1 H NMR(DMSO-d6,400MHz) δ 8.42(s,1H), 8.35(s,1H), 5.63(s,1H), 4.89(t,J=5.6Hz,1H), 4.04~3.99(m,1H), 3.96(d,J=8.4Hz,2H ), 3.89(s,3H), 3.63~3.61(m,2H), 3.51~3.47(m,2H), 3.24(t,J=11.6Hz,1H), 2.99(t,J=11.6Hz,1H).

[0299] Preparation of (S)-methyl 2-(2-(hydroxymethyl)morpholino)-4-oxo-8-vinyl-4H-chromene-6-carboxylate (Step 2 of Scheme 21) [ka] To a mixture of methyl 8-bromo-2-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-4-oxo-chromene-6-carboxylate (6.4 g, 16.07 mmol, 1 equiv.) and potassium trifluoro(vinyl)boranide (3.23 g, 24.11 mmol, 1.5 equiv.) in dioxane (50 mL) and HO (10 mL) was added KCO (4.44 g, 32.14 mmol, 2 equiv.) and Pd(dppf)Cl (588.01 mg, 803.61 μmol, 0.05 equiv.). The resulting mixture was stirred at 100 °C under N for 12 h. LCMS showed that methyl 8-bromo-2-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-4-oxo-chromene-6-carboxylate was completely consumed. The mixture was cooled to room temperature and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure. The residue was dissolved in EtOAc (70 mL) and H2O (100 mL). The organic layer was separated, and the aqueous phase was extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with brine (35 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The compound 2-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-4-oxo-8-vinyl-chromene-6-carboxylate methyl ester (4.3 g, 12.45 mmol, 77.47% yield) was obtained as a yellow solid. 1 H NMR(DMSO-d6,400MHz) δ 8.39(s,1H), 8.33(s,1H), 7.19~7.12(dd,J=10.8Hz,17.6Hz,1H), 6.08(d,J=17.6Hz,1H), 5.61~5.59(m,2H), 4.83(t,J=6.4H) z,1H), 3.99~3.94(m,2H), 3.89(s,3H), 3.64~3.56(m,2H), 3.51~3.47(m,2H), 3.17(t,J=11.6Hz,1H), 2.95(t,J=11.6Hz,1H).

[0300] Preparation of (S)-2-(2-(hydroxymethyl)morpholino)-4-oxo-8-vinyl-4H-chromene-6-carboxylic acid (Step 3 of Scheme 21) [ka] To a solution of methyl 2-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-4-oxo-8-vinyl-chromene-6-carboxylate (4.3 g, 12.45 mmol, 1 equiv.) in THF (30 mL) was added a solution of LiOH·HO (1.57 g, 37.35 mmol, 3 equiv.) in HO (10 mL) at 0 °C. The resulting mixture was stirred at 25 °C for 30 min. LCMS showed that the reaction was complete. The mixture was cooled to 0 °C and adjusted to pH = 4 with 2 N HCl. The aqueous phase was extracted with DCM and i-PrOH (v:v = 3:1, 45 mL × 5). The combined organic phase was washed with brine (35 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The compound 2-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-4-oxo-8-vinyl-chromene-6-carboxylic acid (2.5 g, 7.55 mmol, 60.60% yield) was obtained as a yellow solid. 1 H NMR(DMSO-d6,400MHz) δ 13.25(s,1H), 8.40(s,1H), 8.33(s,1H), 7.15(dd,J=11.2Hz,17.6Hz,1H), 6.07(d,J=17.6Hz,1H), 5.59~5.56(m ,2H), 3.99~3.92(m,3H), 3.63~3.61(m,2H), 3.55~3.50(m,2H), 3.17(t,J=11.6Hz,1H), 2.94(t,J=11.6Hz,1H).

[0301] Preparation of (S)-2-(2-(hydroxymethyl)morpholino)-N,N-dimethyl-4-oxo-8-vinyl-4H-chromene-6-carboxamide (Step 4 of Scheme 21) [ka] To a mixture of 2-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-4-oxo-8-vinyl-chromene-6-carboxylic acid (2.5 g, 7.55 mmol, 1 equiv.) and N-methylmethanamine (1.85 g, 22.64 mmol, 2.07 mL, 3 equiv., HCl) in DMF (20 mL), DIEA (4.88 g, 37.73 mmol, 6.57 mL, 5 equiv.) and HATU (4.30 g, 11.32 mmol, 1.5 equiv.) were added under N at 0° C. The resulting mixture was stirred at 25° C. for 2 hours. LCMS showed the reaction was complete. The mixture was poured into ice water (10 mL) and then extracted with DCM and i-PrOH (v:v=3:1, 15 mL×4). The combined organic phase was washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give the compound 2-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-N,N-dimethyl-4-oxo-8-vinyl-chromene-6-carboxamide (5 g, crude) as a yellow oil. 1 H NMR(DMSO-d6,400MHz) δ 7.94(s,1H), 7.81(s,1H), 7.17(dd,J=11.2Hz,17.6Hz,1H), 6.10(d,J=17.2Hz,1H), 5.59~5.5 5(m,2H), 3.99~3.91(m,3H), 3.63~3.54(m,4H), 3.16~3.13(m,2H), 3.01(s,3H), 2.95(s,3H).

[0302] Preparation of (S)-8-formyl-2-(2-(hydroxymethyl)morpholino)-N,N-dimethyl-4-oxo-4H-chromene-6-carboxamide (Step 5 of Scheme 21) [ka] To a solution of 2-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-N,N-dimethyl-4-oxo-8-vinyl-chromene-6-carboxamide (4.5 g, 12.56 mmol, 1 equiv) in THF (30 mL) and HO (10 mL) was added KOsO·2HO (462.64 mg, 1.26 mmol, 0.1 equiv) at 25 °C, and the resulting mixture was stirred at 25 °C for 30 min. The mixture was then cooled to 0 °C, and NaIO (8.06 g, 37.67 mmol, 2.09 mL, 3 equiv) was added in portions. The reaction mixture was stirred at 0 °C for 30 min. LCMS indicated the reaction was complete. The mixture was quenched with ice water (80 mL) and then extracted with DCM and i-PrOH (v:v=3:1, 50 mL×5). The combined organic phase was washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. Compound 8-formyl-2-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-N,N-dimethyl-4-oxo-chromene-6-carboxamide (2.7 g, crude) was obtained as a yellow oil. 1 H NMR(DMSO-d6,400MHz) δ 10.40(s,1H), 8.17(s,1H), 7.88(s,1H), 5.64(s,1H), 3.81~3.74(m,2H) , 3.51~3.47(m,3H), 3.17(s,6H), 2.94~2.90(m,2H), 2.87~2.83(m,2H).

[0303] Preparation of (S)-8-((4,6-difluoroindolin-1-yl)methyl)-2-(2-(hydroxymethyl)morpholino)-N,N-dimethyl-4-oxo-4H-chromene-6-carboxamide (Step 6 of Scheme 21) [ka] To a mixture of 8-formyl-2-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-N,N-dimethyl-4-oxo-chromene-6-carboxamide (0.2 g, 277.50 μmol, 50% purity, 1 equiv.) and 4,6-difluoroindoline (64.58 mg, 416.25 μmol, 1.5 equiv.) in MeOH (5 mL) was added AcOH (499.93 mg, 8.32 mmol, 476.13 μL, 30 equiv.). The resulting mixture was stirred at 25° C. under N for 1 h. The mixture was cooled to 0° C., and NaBHCN (34.88 mg, 555.00 μmol, 2 equiv.) was added in portions. The resulting mixture was stirred at 25° C. for 1 h. LCMS indicated the reaction was complete. The mixture was quenched with ice water (0.5 mL) and then concentrated in vacuo. The resulting residue was purified by preparative HPLC (Column: Waters Xbridge BEH C18 100 × 25 mm × 5 μm; Mobile phase: [water (10 mM NH4HCO3)-MeCN]; B%: 20% to 55%, 10 min). The solvent was concentrated in vacuo. The compound 8-[(4,6-difluoroindolin-1-yl)methyl]-2-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-N,N-dimethyl-4-oxo-chromene-6-carboxamide (5.8 mg, 11.02 μmol, yield 3.97%, purity 94.9%) was obtained as a white solid. 1 H NMR(DMSO-d6,400MHz) δ 7.84(s,1H), 7.59(s,1H), 6.43(d,J=10.0Hz,1H), 6.31(t,J=12.8Hz,1H), 5.58(s,1H), 4.82(t,J=5.6Hz,1H), 4.62(s, 2H), 4.02~3.84(m,3H), 3.63~3.42(m,5H), 3.37~3.33(m,2H), 3.15~3.11(m,1H), 2.99~2.92(m,6H), 2.90~2.87(m,2H). HPLC: 94.91% (220nm), 95.24% (254nm). MS(ESI): Mass calculation value. C 26 H 27 For O5N3F2, 499.19 m / z, actual value 500.2 [M+H] + .

[0304] Preparation of (S)-(4-(8-((4,6-difluoroindolin-1-yl)methyl)-6-(dimethylcarbamoyl)-4-oxo-4H-chromen-2-yl)morpholin-2-yl)methyl methanesulfonate (Step 7 of Scheme 21) [ka] To a mixture of 8-[(4,6-difluoroindolin-1-yl)methyl]-2-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-N,N-dimethyl-4-oxo-chromene-6-carboxamide (150 mg, 300.30 μmol, 1 equiv.) and DIEA (116.43 mg, 900.89 μmol, 156.92 μL, 3 equiv.) in DCM (10 mL) was added methylsulfonyl methanesulfonate (62.77 mg, 360.36 μmol, 1.2 equiv.) in portions at 0° C. under N. The resulting mixture was stirred at 25° C. for 3 h. LCMS showed that approximately 14% of 8-[(4,6-difluoroindolin-1-yl)methyl]-2-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-N,N-dimethyl-4-oxo-chromene-6-carboxamide remained, and approximately 43% of [(2S)-4-[8-[(4,6-difluoroindolin-1-yl)methyl]-6-(dimethylcarbamoyl)-4-oxo-chromen-2-yl]morpholin-2-yl]methyl methanesulfonate was detected. The mixture was quenched with ice water (30 mL) and then extracted with DCM and i-PrOH (v:v = 3:1, 15 mL × 3). The combined organic phase was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography (Biotage®; 4 g SepaFlash® silica flash column, eluting with a 0-100% ethyl acetate / petroleum ether gradient followed by a 0-40% methanol / ethyl acetate gradient @ 50 mL / min). The solvent was concentrated in vacuo. The compound [(2S)-4-[8-[(4,6-difluoroindolin-1-yl)methyl]-6-(dimethylcarbamoyl)-4-oxo-chromen-2-yl]morpholin-2-yl]methyl methanesulfonate (0.1 g, 173.13 μmol, 57.65% yield) was obtained as a yellow solid. MS (ESI): Mass calculated. C 27 H 29 For O7N3F2S, 577.17 m / z, actual value 578.2 [M+H] + .

[0305] compound 93 Preparation of (S)-8-((4,6-difluoroindolin-1-yl)methyl)-2-(2-(fluoromethyl)morpholino)-N,N-dimethyl-4-oxo-4H-chromene-6-carboxamide (Step 8 of Scheme 21) [ka] To a solution of methyl [(2S)-4-[8-[(4,6-difluoroindolin-1-yl)methyl]-6-(dimethylcarbamoyl)-4-oxo-chromen-2-yl]morpholin-2-yl]methanesulfonate (0.1 g, 173.13 μmol, 1 equiv.) in CH3CN (2 mL), tetramethylammonium fluoride tetrahydrate (143.01 mg, 865.66 μmol, 5 equiv.) was added at 80 °C under N2, and the resulting mixture was stirred at 80 °C for 12 h. LCMS indicated the reaction was complete. The mixture was concentrated under reduced pressure at 45 °C. The resulting residue was purified by preparative HPLC (column: Phenomenex C18 80 × 40 mm × 3 μm; mobile phase: [water (NH4HCO3)-MeCN]; B%: 35% to 65%, 8 min). The solvent was removed by lyophilization. The compound 8-[(4,6-difluoroindolin-1-yl)methyl]-2-[(2S)-2-(fluoromethyl)morpholin-4-yl]-N,N-dimethyl-4-oxo-chromene-6-carboxamide (13.5 mg, 25.71 μmol, 14.85% yield, 95.5% purity) was obtained as a white solid. 1 H NMR(DMSO-d6,400MHz) δ 7.85(s,1H), 7.61(s,1H), 6.46(d,J=8.8Hz,1H), 6.34~6.30(m,1H), 5.63(s,1H), 4.63(d,J=8.8Hz,2H), 4.54~4.34(m,2H), 4 .06~3.92(m,3H), 3.88~3.72(m,2H), 3.60(t,J=8.4Hz,1H), 3.46(t,J=8.4Hz,2H), 3.13(t,J=8.4Hz,1H), 2.98~2.90(m,8H). HPLC: 95.95% (220nm), 97.29% (254nm). MS(ESI): Mass calculation value. C 26 H 26For O4N3F3, 501.19 m / z, actual value 502.2 [M+H] + . [ka]

[0306] compound 94 Preparation of 9-(1-((3,4-difluorophenyl)amino)ethyl)-7-((R)-3-(dimethylamino)pyrrolidine-1-carbonyl)-2-morpholino-4H-pyrido[1,2-a]pyrimidin-4-one (Steps 1-3 of Scheme 13) Preparation of methyl 9-(1-((3,4-difluorophenyl)amino)ethyl)-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylate (Step 1 of Scheme 22) [ka] A solution of methyl 9-(1-bromoethyl)-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxylate (0.5 g, 1.26 mmol, 1 equiv.) and 3,4-difluoroaniline (488.75 mg, 3.79 mmol, 3 equiv.) in DMA (5 mL) was stirred at 55 °C for 10 h. TLC (petroleum ether:ethyl acetate = 1:1, R f =0.26) and LCMS showed that the reaction was complete. The resulting mixture was quenched with ice water (20 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (5 mL × 4), dried over Na2SO4, filtered, and concentrated under reduced pressure. The compound methyl 9-[1-(3,4-difluoroanilino)ethyl]-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxylate (0.9 g, crude) was obtained as a yellow solid. 1H NMR(DMSO-d6,400MHz) δ 9.23(s,1H), 8.00(s,1H), 7.05~7.00(m,1H), 6.71(d,J=6.8Hz,1H), 6.49~6.46(m,1H), 6.31~6. 29(m,1H), 5.72(s,1H), 5.00(t,J=6.8Hz,1H), 3.85(s,3H), 3.70(s,8H), 1.46(d,J=6.8Hz,3H).

[0307] Preparation of 9-(1-((3,4-difluorophenyl)amino)ethyl)-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylic acid (Step 2 of Scheme 22) [ka] A solution of methyl 9-[1-(3,4-difluoroanilino)ethyl]-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxylate (0.9 g, 1.01 mmol, 50% purity, 1 equiv.) and LiOH HO (127.46 mg, 3.04 mmol, 3 equiv.) in HO (5 mL) and THF (5 mL) was stirred at 20 °C for 1 h. TLC (petroleum ether: EtOAc = 0:1, R f =0.05) and LCMS showed that the reaction was complete. The organic solvent was removed under reduced pressure. 10 mL of water was added, and the aqueous layer was extracted with MTBE (5 mL × 3) to remove impurities. The aqueous layer was adjusted to pH = 4 with 1 N HCl at 0 °C, and some solid formed. After filtration, the solid was collected and concentrated under reduced pressure. Compound 9-[1-(3,4-difluoroanilino)ethyl]-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxylic acid (0.35 g, 813.19 μmol, 80.31% yield) was obtained as a pale yellow solid. 1H NMR(DMSO-d6,400MHz) δ 9.20(s,1H), 8.02(s,1H), 7.08~7.00(m,1H), 6.64(d,J=6.8Hz,1H), 6.41~6.36(m,1H), 6 .21~6.16(m,1H), 5.70(s,1H), 5.00(t,J=6.8Hz,1H), 3.70(s,8H), 1.46(d,J=6.8Hz,3H).

[0308] Preparation of 9-(1-((3,4-difluorophenyl)amino)ethyl)-7-((R)-3-(dimethylamino)pyrrolidine-1-carbonyl)-2-morpholino-4H-pyrido[1,2-a]pyrimidin-4-one (Step 3 of Scheme 22) [ka] To a solution of 9-[1-(3,4-difluoroanilino)ethyl]-2-morpholino-4-oxo-pyrido[1,2-a...

Claims

1. Structural formula (I): 【Chemistry 252】 A compound having the formula During the ceremony, A represents carbon and B represents oxygen, or each of A and B represents nitrogen; W represents -CHR-Q- or -Q-CHR-; where Q is a bond, O, S, CH ２ or NR′, where R and R′ are independently hydrogen, C １～４ Alkyl, or C substituted with —OH or halo １～４ alkyl; R ｗ represents Ar or a substituted or unsubstituted indoline group, where Ar is a group containing a substituted or unsubstituted 6-membered aromatic or heteroaromatic ring; R ２ is C １～３ Alkyl, CN, CH ２ O.H., C.H. ２ F or CONH ２ represents; R １ H, NH ２ , OH, CN, CF ３ , CHO, COC １～４ Alkyl, CH ２ C(=O)-NR １ａ R １ｂ , C(═O)—NR １ａ R １ｂ , C.H. ２ COOR １ｃ , N.R. １ｄ R １ｅ , C １～４ Alkyl, O-C １～４ Alkyl, Het, Ar, NR １ｈ (C=O)R １ｉ , N.R. １ｊ (C=O)NR １ｋ R １ｌ , N.R. １ｊ (SO ２ ) R １ｍ , S.O. ２ N.R. １ｎ R １ｏ , 【Chemistry 253】 P(O)MeMe, P(O)OMeOMe; where A is carbon, B is oxygen, and R ｗ When is Ar, R １ NH ２ ,CN,CHO,COC １～４ Alkyl, CH ２ C(=O)-NR １ａ R １ｂ , C.H. ２ COOR １ｃ , N.R. １ｄ R １ｅ , O-C ２～４ Alkyl, Het, NR １ｈ (C=O)R １ｉ , N.R. １ｊ (C=O)NR １ｋ R １ｌ , N.R. １ｊ (SO ２ ) R １ｍ , S.O. ２ N.R. １ｎ R １ｏ , N.R. １ｊ (C=O)C(CN)C(OH)R １ｐ , P(O)MeMe, P(O)OMeOMe; when A and B are nitrogen, R ｗ is Ar, R １ NH ２ ,CN,CHO,COC １～４ Alkyl, CH ２ C(=O)-NR １ａ R １ｂ , C.H. ２ COOR １ｃ , N.R. １ｄ R １ｅ , O-C ２～４ Alkyl, Het, NR １ｈ (C=O)R １ｉ , N.R. １ｊ (C=O)NR １ｋ R １ｌ , N.R. １ｊ (SO ２ ) R １ｍ , S.O. ２ N.R. １ｎ R １ｏ , N.R. １ｊ (C=O)C(CN)C(OH)R １ｐ , P(O)MeMe, P(O)OMeOMe, C(=O)-NR １ｑ R １ｒ where R １ｑ and R １ｒ Together, C １～３ Alkyl and NR ３ａ R ３ｂ forming a 3-8 membered nitrogen-containing heterocyclyl ring having one or more substituents selected from the group consisting of: Here, R １ａ , R １ｂ , R １ｃ , R １ｄ , R １ｅ , R １ｈ , R １ｉ , R １ｊ , R １ｋ , R １ｌ , R １ｍ , R １ｎ , R １ｏ , R １ｐ each independently represents H, C １～４ Alkyl, C ３～８ Cycloalkyl, C ３～８ Heterocycloalkyl, or hydroxyl, OMe, CN, fluoro, NR ３ａ R ３ｂ , C ３～８ Cycloalkyl, C ３～８ C substituted with one or more substituents selected from the group consisting of heterocycloalkyl １～４ alkyl; R １ａ and R １ｂ , R １ｄ and R １ｅ , R １ｎ and R １ｏ are optionally joined together to form C １～３ Alkyl and NR ３ａ R ３ｂ forming a 3-8 membered nitrogen-containing heterocyclyl ring having one or more substituents selected from the group consisting of: C １～４ Alkyl is unsubstituted or is selected from the group consisting of OH, F, NR １ｄ R １ｅ and is substituted with one or more substituents selected from the group consisting of: R ３ａ and R ３ｂ are each independently H and C １～４ selected from the group consisting of alkyl; Het is O, S, S (=O) ｐ and N; a substituted heterocyclyl is selected from halo, NR ３ａ R ３ｂ , C １～４ having 1 or 2 substituents each independently selected from the group consisting of alkyl, OH, OMe, and CN; n represents 0, 1, 2, 3 or 4; and p represents 1 or 2; or a pharma- ceutically acceptable form or isotopic derivative thereof.

2. A is carbon and B is oxygen, structural formula (Ia): 【Chemical 254】 2. The compound of claim 1 having the formula:

3. R ｗ 3. The compound of claim 2, wherein: is Ar; W is --CHR 4 --NR 5 --; and each of R 4 and R 5 is independently selected from H, methyl, or ethyl.

4. R ｗ The compound of claim 2, wherein: is a substituted or unsubstituted indoline group; W is --CHR.sup.4; and R.sup.4 is selected from H, methyl, or ethyl.

5. Each of A and B is nitrogen, structural formula (Ib): 【255】 2. The compound of claim 1 having the formula:

6. R ｗ 6. The compound of claim 5, wherein: is Ar; W is --CHR 4 --NR 5 --; and each of R 4 and R 5 is independently selected from H, methyl, or ethyl.

7. R ｗ The compound of claim 5, wherein: is a substituted or unsubstituted indoline group; W is --CHR.sup.4; and R.sup.4 is selected from H, methyl, or ethyl.

8. Ar or the indoline group is a halogen, C １～４ Alkyl, O.C. １～４ Alkyl, CN, CHF ２ , C.F. ３ and C.H. ２ The compound of claims 1 to 7, substituted with one or more substituents selected from the group consisting of OH.

9. W-R ｗ Below: 【256】 is selected from In the formula, R is independently hydrogen, C １～４ Alkyl, or C substituted with —OH or halo １～４ 9. The compound of claim 8, wherein the aryl group is selected from alkyl.

10. The compound of claim 8 , wherein n is 0.

11. The compound of claim 8, wherein n is 1.

12. R ２ is C １～３ The compound of claim 11 , which is alkyl.

13. R ２ is CH ２ OH, CN or CONH ２ 12. The compound of claim 11, wherein

14. R １ is C(=O)-NR １ａ R １ｂ and R １ａ and R １ｂ each independently represents H and C １～４ The compound according to any one of claims 1 to 7, wherein the aryl group is selected from alkyl.

15. R １ is C(=O)-NR １ｑ R １ｒ and R １ｑ and R １ｒ Together, C １～３ Alkyl and NR ３ａ R ３ｂ The compound according to any one of claims 1 to 7, which forms a 3-8 membered nitrogen-containing heterocyclyl ring optionally substituted with one or more of:

16. R ３ａ and R ３ｂ 16. The compound of claim 15, wherein each of is methyl.

17. R １ is optionally substituted with hydroxy; １～４ Alkyl, —O—C １～４ Alkyl and NR １ｃ R １ｄ The compound according to any one of claims 1 to 7,

18. A compound selected from the group consisting of: 【Table 6】

19. A pharmaceutical composition comprising a compound described in any one of claims 1 to 7 and 18, and a pharma- ceutically acceptable excipient, carrier, or diluent, which is effective for treating cancer or a related disease or disorder.

20. 20. The pharmaceutical composition of claim 19, wherein the pharmaceutical composition is suitable for oral administration.

21. 20. The pharmaceutical composition of claim 19, wherein the pharmaceutical composition is useful for treating or ameliorating breast cancer, colon cancer, endometrial cancer, kidney cancer, lung cancer, melanoma, prostate cancer, thyroid cancer or leukemia.

22. A unit dosage form comprising the pharmaceutical composition of claim 19, suitable for oral administration.

23. Use of a compound according to any one of claims 1 to 7 and 18 together with a pharma- ceutically acceptable excipient, carrier or diluent in the preparation of a medicament for treating cancer, or a related disease or disorder.

24. 24. The use according to claim 23, wherein the cancer is selected from breast cancer, colon cancer, endometrial cancer, renal cancer, lung cancer, melanoma, prostate cancer, thyroid cancer and leukemia.

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