WO2017090002A2 - Inhibitors of pi3 kinases - Google Patents

Abstract

The present invention is directed to the compounds of Formula (I) or isomers, stereoisomers, tautomers, pharmaceutically acceptable salts, isotopes, solvates, metabolites, polymorphs or prodrugs thereof, wherein R1, R2, R3, R4, /A, B, L1, L2, Z, n and X are herein defined as inhibitors of PI3K. These compounds are used for the preventive and/or therapeutic treatment of diseases or disorders associated with abnormal activities of PI3K's such as Inflammation, Cancer, Restenosis, Atherosclerosis, Psoriasis, Thrombosis, immmuno-oncology, renal carcinoma, hepatitis C, haematological malignancies, and multiple myeloma.

Description

INHIBITORS OF PI3 KINASES

FIELD OF THE INVENTION

The present invention relates to novel compounds that act as inhibitors of the Phosphoinositide 3-kinase (PI3K)family. Particularly, the present invention relates to the compounds possessing inhibitory activity against ΡΙ3Κβ.

BACKGROUND OF THE INVENTION

The PI3K(s) are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer.PI3Ks are a family of related intracellular signal transducer enzymes capable of phosphorylating the hydroxyl group present at the 3 position of the inositol ring of phosphatidylinositol (PTDINS). Phosphoinositide 3-kinase (PI3K) takes center stage in many discussions regarding cancer and diabetes, but, in reality, it is much more complex than simply being a pivotal player in these and other diseases. Abnormal PI3K signaling may lead to abnormal cell growth, increased/uncontrolled cell proliferation, increased cell survival orenhanced cancer cell motility.

The phosphoinositol-3-kinase (PI3K) family is divided into four different classes: Class I, Class II, Class III, and Class IVbased on primary structure, regulation, and in vitro lipid substrate specificity.

In response to extracellular stimuli, e.g., insulin, growth factors, chemokines, the catalytic subunit of the class I lipid kinase PI3K (p1 10) recruits receptor tyrosine kinases (RTKs) or G protein-coupled receptors (GPCRs) and phosphorylates PIP2 to PIP3 that subsequently promotes growth and translation and inhibits apoptosis. PTEN is a phosphatase that antagonizes the action of PI3K by dephosphorylating PIP3 to generate PIP2. The PTEN somatic mutations occur in a large percentage of human cancers, with the highest numbers found in prostate, endometrium, central nervous system, breast and skin cancers. The PTEN loss of function accounts for 40% of cancers and is the closest rival to p53 alterations (Annu. Rev. Pathol. Mech. Dis. 2009, 4, 127-50). In the central nervous system, loss of PTEN is found in 70% of glioblastoma and marks the transition to the most aggressive grade of astrocytic tumors. In non-small cell lung carcinoma, PTEN expression is reduced or lost in 55%-74% of patients, due to down regulation via ubiquitin- mediated degradation. In breast cancer, PTEN protein is reduced in as much as 50% of cases. PTEN deletions in prostate cancer are associated with tumor aggression and poor outcome with up to 70 percent of men with prostate cancer having lost one copy of the PTEN gene at the time of diagnosis (J Oncol. 2012; 141236). On the contrary, of all the class I isoforms, mutations in only PI3Ka have been implicated in cancer development and progression, till very recently (Curr Top Microbiollmmunol. 2010, 347:21 -41 ) when it was suggested that PIK3CpD1067V mutation might function as a novel tumor-promoting genetic alteration, in certain cancers (Oncogene. 2016, 35, 1 198-205).

Classically, ΡΙ3Κβ, a class IA PI3K, has been previously explored as a target for thrombosis (Blood, 2010, 1 15, 2008-13) and also shown to play a critical role in neutrophil activation (Sci Signal. 201 1 , 4(168):ra23). Recent studies have shown that siRNA mediated down regulation of ΡΙ3Κβ and not PI3Ka induced tumor death in PTEN deficient cell lines, e.g PC3 (prostate), BT549 (Triple negative breast cancer) and U87MG (glioblastoma) (PNAS, 2008, 105, 13057-13062). The dependency of such tumors to ΡΙ3Κβ isoform has been attributed to a constitutive activity of the isoform in the absence of growth factor stimulation that generates a basal level of PIP3 (Mol Cell, 201 1 , 41 , 499- 501 ). Selective ΡΙ3Κβ inhibitor was shown to specifically suppress both the PI3K pathway activation and oncogenic transformation induced by PTEN deficiency in triple negative breast cancer (HCC70) or prostate cancer (PC3) but had no effect on PTEN positive breast cancer cell line HCC1954 (Cancer Discovery, 2012, 5, 393-4; Cancer Discovery, 2012, 2, 425-33). However, in instances where PTEN loss-of-function mutations coexisted with PIK3CA-activating mutations, as is the case in the ovarian cancer cell line A2780, down- regulation of p1 10a activity, but not of ρ1 10β activity, resulted in PI3K pathway inactivation and cell growth inhibition. Also, when PTEN deficient tumors are in any way reliant on other pathways for growth and proliferation, then inhibition of ρ1 10β by selective inhibitor did not result into tumor growth inhibition (Biochem. J., 2008, 415, 97-1 10). Thus, targeting ΡΙ3Κβ, in PTEN null tumors when no other upregulation is present is necessary and sufficient for growth inhibition and could be explored for the treatment of castration resistant prostate cancer and triple negative breast cancer (Nature, 2008, 454, 776-779).

Cancer cells have shown to evolve under very high selective pressure thus bypassing most, if not all, signaling pathway inhibition, over time. Under such circumstances, the presence of a selective ΡΙ3Κβ inhibitor will strengthen the repertoire of anti-signaling pathway inhibitors that already have approved mTOR inhibitors, PI3K delta inhibitor and a late stage PI3K alpha inhibitor in clinic. The selective ΡΙ3Κβ inhibitor can be used in monotherapy or added in combination with standard chemotherapeutic agents, or approved targeted drugs and treat a spectrum of solid tumors like prostate cancer, breast cancer, endometriosis, glioblastoma, prostate intraepithelial Neoplasia (PIN), rare diseases like Cowden syndrome, and others (Nat Rev Cancer, 2015, 15, 7-24).

The selective ΡΙ3Κβ inhibitor can also be used to treat resistant tumors, e.g. melanoma exhibiting PTEN deficiency and BRAFV600E mutation, where PTEN loss leads to resistance to BRAF inhibitors (J. Med. Chem. 2014, 57, 903-920). Blockade of androgen receptor (AR) pathway have shown to lead to upregulation of pAKT in prostate cancer and vice versa, and synergistic targeting of PI3K pathway and AR axis will delaycastration resistant prostate cancer (CRPC)(Molecular Cancer Ther, 2013, 12, 2342- 2355).

There have been ample evidence in prostate cancer where PTEN loss has eventually lead to CRPC and such progression was not inhibited by androgen deprivation treatment, suggesting a gap in the current treatment regimen that can be addressed by a selective ΡΙ3Κβ inhibitor (British Journal of Cancer, 2013, 108, 2582-2589; International Journal of Urology, 2014, 21 , 1209-1214) and combination with hormonal therapy have actually improved efficacy of PI3K targeted agents in PTEN-negative prostate cancer models (Eur Urol. 2015, 67, 1 177-85).

Also, high-grade PIN is considered a pre-cancer of the prostate as it may turn into prostate cancer over time and is characterized by aTMPRSS2-ERG molecular rearrangement as an early event which may precede prostate carcinogenesis (Neoplasia, 2006, 8, 826-832). Concurrently, it has been shown that there is a co-operation between early PTEN loss that activates AKT and aberrant expression of ERG transcription factor in response to the activated androgen receptor (Nature Medicine, 2013, 19, 1023-1031 ) that can be exploited by a selective ΡΙ3Κβ inhibitor to prevent conversion of PIN to adenocarcinoma. PI3Ka inhibition by isoform specific inhibitorwas shown to temporarily reduce Akt phosphorylation and PIP3 levels before a rebound effect via ΡΙ3Κβ isoform activation took place (CancerCell, 2015, 27, 97-108). Conversely, use of a PI3Kp-specific inhibitor suppressedAkt activation in breast and prostate cancer cells with inactivating mutations of PTEN (mPTEN) which was restored when PI3Ka was positively regulated by insulin-like growth factor receptor (CancerCell, 2015, 27, 109-122). This suggests that concomitant inhibition of PI3Ka and ΡΙ3Κβ isoforms could be an approach to efficiently suppress the growth of cancers exhibiting oncogenic PI3K activation or PTEN loss.

The PTEN hamartoma tumor syndrome (PHTS) is a spectrum of disorders, including Cowden syndrome, caused by autosomal dominant mutations of the PTEN gene characterized by small, noncancerous growths mainly on the skin and mucous membranes (Genetics in Medicine (2009) 1 1 , 687-694). People with Cowden syndrome have an increased risk of developing several types of cancer; including cancers of the breast, thyroid, and uterus and combined inhibition of both PI3Ka and ΡΙ3Κβ have shown to prevent the development of PHTS and also reverse skin hamartomas that have reached advanced stages in mice (Genes Dev, 2013, 27, 1568-80).

Hence, pharmacological inhibition of Phosphoinositide 3-kinases signaling offers promising approaches for the treatment of a variety of diseases caused by abnormal PI3 kinases.

SUMMARY OF THE INVENTION The present invention provides the compounds of Formula (I), which are inhibitors of the Phosphoinositide 3-kinases (PI3K's):

wherein R-i , R₂, R₃, R₄, A, B, L-i , L₂, Z, n and X are as defined herein.

The present invention further provides for the pharmaceutical compositions which include an effective amount of a compound of formula (I), or stereoisomers, tautomers or pharmaceutically acceptable salts, solvates, metabolites, isotopes or prodrugs thereof, ora pharmaceutically acceptable carrier.

The present invention further provides to the use of pharmaceutical compositions for the treatment or prevention of the diseases or disorders selected from the group consisting of Inflammation, Cancer, Restenosis, Atherosclerosis, Psoriasis, Thrombosis, immuno-oncology, renal carcinoma, hepatitis C, hematological malignancies, multiple myeloma or a disease or a disorder associated with abnormal activities of PI3K signaling.

The present invention further provides a method for treating a disease or a disorder modulated by PI3K's. The method further comprises administering to a patient, in need thereof, a therapeutically effective amount of a compounds of theinvention or their isomers, stereoisomers, tautomers, pharmaceutically acceptable salts, isotopes, metabolites, polymorphs, solvates or prodrugs.

The present invention further provides intermediates required for synthesis of the compounds of Formula (I).

The present invention further provides for a method of synthesis, separation, and purification of the compounds of the invention.

The present invention further provides novel compounds that are useful in the treatment of disorders like Inflammation, Cancer, Restenosis, Atherosclerosis, Psoriasis, Thrombosis, immmuno-oncology, renal carcinoma, hepatitis C, hematological malignancies, and multiple myeloma.

The present invention further provides the use of compounds of the formula (I) in the treatment of cancers such as lung Adenocarcinomas, Breast Cancer, Thyroid Carcinoma, Pancreatic Cancer, Ovarian Carcinoma, Malignant Mesothelioma, Prostate, Neuroblastic Tumors, Colorectal Carcinoma, Spitzoid Melanoma, Salivary Adenoid Cystic Carcinoma Glioblastoma Multiforme, Oral Squamous Cell Carcinoma, Acute Myeloid Leukemia.

Additional features and advantages of the invention will be apparent from the detailed description which follows, taken in conjunction by way of examples, features of the invention

DETAILED DESCRIPTION OF THE INVENTION

From the foregoing detailed description of certain embodiments and examples, it will be apparent that various modifications, additions and other alternative embodiments, examples are possible without departing from the true scope and spirit of the invention. The embodiments and examples discussed were chosen and described to provide the best illustration of the principles of the invention and its practical application to thereby enable one of ordinary skill in the art to use the invention in various embodiments and with various modifications as are suited to the particular use contemplated. All such modifications and variations are within the scope of the invention.

Definitions:

As used herein, the term "isomers" refers to different compounds that have the same molecular formula.

As used herein, the term "stereoisomers" is a general term used for all isomers of an individual molecule that differ only in the orientation of their atoms in space. It is to be understood that all stereo-isomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers and atropsiomers, as well as mixtures thereof such as forms, are included in the scope of the present application.

As used herein, the term "tautomer" refers to the coexistence of two (or more) compounds that differ from each other only in the position of one (or more) mobile atoms and in electron distribution, for example, keto-enol tautomers.

As used herein the term "isotope" refers to one of two or more atoms with the same atomic number but with different numbers of neutrons.

As used herein the term "solvates" refers to disclosed compounds having one or more molecules associated with the compounds wherein molecules do not cause the compounds to be in solution but instead the resulting solvates can have different properties from the compound when the compound is not associated with the one or more molecules.

As used herein, the term "pharmaceutically acceptable" refers to the carrier, diluent, salts, solvates or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

As used herein, the term "metabolite" as used herein refers to the formula of any derivative produced in a subject after administration of a parent compound. The derivatives may be produced from the parent compound by various biochemical transformations in the subject such as, for example, oxidation, reduction, hydrolysis, or conjugation and include, for example, oxides and demethylated derivatives.

As used herein, the term "polymorph" refers to a specific form or crystal structure of a compound.

As used herein, the term "prodrug" refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example by hydrolysis in blood as well as the zwitterionic forms of the compounds of the invention. As used herein, the term 'a therapeutically effective amount' refers to the amount of the compound of the present invention that, when administered to a subject, is effective in (i) at least partially alleviating, inhibiting, preventing and/or ameliorating a condition, or a disorder or a disease mediated by PI3 Kinases associated with abnormal activity of PI3 Kinases signaling.

As used herein, the term "alkyi," by itself or as part of another substituent, refers to linear or branched alkyi group with 1 to 10 carbon atoms.

As used herein, the term "alkenyl," by itself or as part of another substituent, means a straight or branched chain hydrocarbon radical having a single carbon-carbon double bond.

As used herein, the term "Alkynyl" refers to hydrocarbon chain which is straight or branched and contains at least one degree of unsaturation, i.e., at least one carbon- carbon triple bond.

As used herein, the term "Haloalkyl" means at least one halogen atom is substituted on an alkyi group. Both halogen and alkyi have the meaning as defined above.

As used herein, the term "Halogen or Halo" represents fluorine, chlorine, bromine, or iodine.

As used herein, the term "Optionally substituted" means that the substitution is optional and therefore it is possible for the designated atom or group to be unsubstituted. When more than one substituent is present on an atom or group, the chosen substituents are independent of each other (i.e. same or different).

As used herein, the terms "amide" refers to the bivalent functional group -N-CO-, or

As used herein, the term "Haloalkoxy" means at least one halogen atom is substituted on an alkoxy group, wherein alkoxy and halogen groups are as defined above. As used herein, the term "Alkoxy" group refers to an— O(alkyl) group, wherein alkyl group is as defined above.

The term "phenyl" means -C6H5. A phenyl group can be unsubstituted or substituted with one or more suitable substituents.

As used herein, the term "cycloalkyl" denotes a saturated carbocyclic ring containing 3 to 6 carbon atoms.

As used herein, the term "Aryl" refers to monocyclic or polycyclic aromatic ring system. Exemplary aryl groups include, but are not limited to, phenyl, naphthyl, and the like.

As used herein, the term "heteroaryl", as used herein except where noted, represents a stable 5- to 7-membered monocyclic- or stable 9- to 10-membered fused bicyclic heterocyclic ring system which contains an aromatic ring, any ring of which may be saturated, partially saturated, or unsaturated and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O and S.

As used herein, the term "acetyl" group refers to a— C(=0)CH3 group. As used herein, the terms "alkylaryl" (or "alkaryl") or "alkylheteroaryl" as used herein will refer to groups having an alkyl moiety attached to an aryl or heteroaryl ring.

As used herein, the term "Hydroxy' or 'Hydroxyl" represents— OH. As used herein, the term "Hydroxyalkyl" means at least one hydrogen atom of an alkyl group is replaced by a hydroxyl group. Alkyl group is as defined above.

As used herein, the term "alkoxycarbonyl" and as used herein denotes a group of formula— C(=0)OR wherein R is alkyl; alkyl as defined herein. As used herein, the terms "heterocyclyl", "heterocycle" or "heterocyclic", represents a stable 5- to 7-membered monocyclic or stable 8- to 1 1 -membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, or S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.

As used herein, the term "heteroatom" refers to a sulfur, nitrogen, or oxygen atom.

As used herein, the term "aminocarbonyl" refers to a monovalent group of formula -(CO)N(R2)2 where each R2 is independently hydrogen or alkyl.

As used herein, the term "cyano" refers to a substituent having a carbon atom joined to a nitrogen atom by a triple bond.

As used herein, the term "alkylamide" as used herein means an amide mono- substituted with an alkyl, such as

H

As used herein, the term "alkylamine" refers to the -alkyl-NH2 group. The present invention relates to novel compounds that act as inhibitors of the

PI3K's. Particularly, the present invention discloses compounds possessing inhibitory activity against ΡΙ3Κβ. The compounds of the present invention are useful as an active ingredient of a medicament for preventive and/or therapeutic treatment of the aforementioned diseases.

According to an embodiment of the present invention, the compounds are represented by general Formula (I):

or isomers, stereoisomers, tautomers, or pharmaceutically acceptable salts, isotopes, solvates, metabolites, polymorphs or prodrugs thereof, wherein:

A is selected from CO, CH₂;

B is selected from O, S, C, N; Z is selected from CR-i, N;

X is selected from bond, O, NR₃, CR₃R₃, and S0₂NR₃;

L-i, l_₂ is independently selected from CO, NR₅, and CR₅R₅; n is an integer between 0 and 2, inclusive;

Ri and R₂are independently selected from H, alkyi, substituted alkyi, alkenyl, alkynyl, haloalkyl, halogen, amine, amino carbonyl, nitrile, haloalkoxy, hydroxyalkyl, alkoxycarbonyl, optionally substituted aminocarbonyl, cyano, optionally substituted phenyl, cycloalkyl, carboxylic acid, CH₂COOH, NHCONR₅, CH₂CONH₂(optionally substituted with alkyi, aryl, halogenated aryl, heteroaryl),-OCH₂CONH₂, -NHCOR₅, - NHCH₂CF₃, -NHCH₂Ph, Tetrazole, any heterocycle, any fused heterocycle, OR_5, COR_5, R₃S0₂NH, S0₂NHR₅,B(OH)₂; R₃is selected from H, alkyi, aryl, alkyi aryl, optionally substituted aryl, alkyi, halogen, haloalkyl, branched alkyi, acetyl, benzoyl, cycloalkyl;

R₄is selected from aryl, optionally substituted aryl, alkylaryl, arylalkyl, cycloalkyl, heteroaryl, optionally substituted heteroaryl , optionally substituted alkylaryl, 3-6 membered heterocyclic ring with one or more heteroatom selected from O, N and S and optionally substituted with one or more substituent's independently selected from H, alkyi, alkenyl, alkynyl, haloalkyl, halogen, hydroxy, alkoxy, haloalkoxy, carboxylic acid, carboxamide; and

R₅is selected from H, alkyi, halogen, haloalkyl, hydroxy, hydroxyalkyl, alkoxycarbonyl, aminocarbonyl, amino, alkylaryl, substituted alkyi, substituted alkyi aryl, aryl, substituted aryl, alkyi carboxylic acid, alkylamide, alkylamine, alkyi nitrile, cycloalkyl, optionally substituted cycloalkyl.

According to one embodiment of the present invention, Ri forms a six membered ring with L-i . According to another embodiment, the present invention provides a pharmaceutical composition comprising compounds selected from the group of compounds represented by Formula (I) or isomers, stereoisomers, tautomers, pharmaceutically acceptable salts, isotopes, solvates, metabolites, polymorphs or prodrugs thereof, as an active ingredient or any combination thereof. The aforementioned pharmaceutical composition is used for preventive and/or therapeutic treatment of diseases caused by abnormal PI3 Kinases. Diseases involving abnormalPI3K signaling can be one or more of the following but not limited to Inflammation, Cancer, Restenosis, Atherosclerosis, Psoriasis, Thrombosis, immuno-oncology, renal carcinoma, hepatitis C, hematological malignancies and multiple myeloma. According to another embodiment of the present invention, a method is provided for the prevention and/or therapeutic treatment of a disease or a disorder selected from the group comprising of Inflammation, Cancer, Restenosis, Atherosclerosis, Psoriasis, Thrombosis, immuno-oncology, renal carcinoma, hepatitis C, hematological malignancies, multiple myeloma or a disease or a disorder associated with abnormal activities of PI3K signaling.

According to yet another embodiment of the invention, a method is provided for the prevention and/or therapeutic treatment of a disease or a disorders mentioned above by administering to a patient in need thereof, a therapeutically effective amount of a compound of the Formula I or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

According to yet another embodiment of the present invention, depending upon the particular conditions to be treated or prevented, additional therapeutic agents may be administered together with the compounds of the invention. In some cases, these additional therapeutic agents are normally administered to treat or prevent the same condition. For example, methotrexate may be combined with the compounds of this invention to treat leukemia.

According to another embodiment, additional therapeutic agent is selected from anti-inflammatory compounds, steroids, analgesics, opioids, calcitonin generelated peptide receptor antagonists, subtype-selective ion channel modulators, anticonvulsants, dual serotonin-norepinephrine reuptake inhibitors, KSP (kinesin spindle protein) inhibitors, JAKfamily kinase inhibitors, tricyclic antidepressants,cabozantinib, crizotinib, erlotinib, gefitinib, imatinib, lapatinib, nilotinib, pazopanib, pertuzumab, regorafenib, sunitinib,and trastuzumab. sorafenib, trametinib, vemurafenib arsenic trioxide, bleomycin, cabazitaxel, capecitabine, carboplatin, cisplatin, cyclophosphamide, cytarabine, dacarbazine, daunorubicin, docetaxel, doxorubicin, etoposide, fluorouracil, gemcitabine, irinotecan, lomustine, mitomycinC, oxaliplatin, paclitaxel, pemetrexed, temozolomide,vincristine,Aflibercept, bevacizumab, aldesleukin, ipilimumab, lambrolizumab, nivolumab, enzalutamide, abiraterone acetate, Fulvestrant and sipuleucel-T.

According to yet another embodiment of the present invention, a medicament is provided is used for preventive and/or therapeutic treatment of cancer. Specifically, compounds of the present invention are used for preventive and/or therapeutic treatment of cancer selected from the group comprising of lung Adenocarcinomas, Breast Cancer, Thyroid Carcinoma, Pancreatic Cancer, Ovarian Carcinoma, Malignant Mesothelioma, Prostate, Neuroblastic Tumors, Colorectal Carcinoma, Spitzoid Melanoma, Salivary Adenoid Cystic Carcinoma GlioblastomaMultiforme, Oral Squamous Cell Carcinoma, Acute Myeloid Leukemia.

One or more compounds of the Formula I can be supplied in the form of a therapeutic composition that is within scope of the present application.

It is to be understood that the above-referenced arrangements/embodiments are only illustrative of the application for the principles of the present invention. Numerous modifications and alternative arrangements can be devised without departing from the spirit and scope of the present invention. While the present invention has been fully described above with particularity and detail in connection with what is presently deemed to be the most practical and preferred embodiment(s) of the invention, it will be apparent to those of ordinary skill in the art that numerous modifications can be made without departing from the principles and concepts of the invention as set forth herein.

Biochemical assay:

All four PI3K isoforms α, β, γ and δ enzymes were sourced from Life Technologies and standardized in ADP Glo (ATP depletion or ADP detection principle) method & validated with reference compounds. Assays were performed in 384 well plates in an assay buffer containing 1 M MOPS, 1 M MgCI2 and 250mM EGTA using BIOMEK FX liquid handling platform. Enzyme concentration used in the assays ranged from 12.5nM to 25nM while the substrate (sonicated mixture of PIP2 & PS) varied from 33μΜ to 100μΜ. Assays were run at 0.5-0.6 ATP Km and DMSO concentrations were maintained at 2% for all the isoforms. Examples:

The example mentioned can be prepared according to below mentioned protocol using appropriate starting materials. Further, other available intermediates can also be used for the respective synthesis without departing from the spirit and the scope of the invention.

General Synthetic Scheme 1 :

Example 1 : Synthesis of 2-((3-fluoro-2-methylphenoxy) methyl)-5-hydroxy-2-methyl- 7-mor holinochroman-4-one

To a solution of 3-fluoro-2-methylphenol (25 g, 198.40 mmol) in acetone (500 mL) were added chloroacetone (37.70 g, 396.8 mmol), K₂C0₃ (136.89 g, 992 mmol) and catalytic amount of Kl (3.29 g, 19.84 mmol) at room temperature. The reaction mixture was stirred at 80 °C for 16 h. The mixture was allowed to room temperature, filtered and the filtrate was concentrated under reduced pressure. The crude compound was purified by flash chromatography using 2% ethyl acetate in petroleum ether as an eluent to afford intermediate B (12 g, 33%) as a thick liquid. ¹H NMR (300 MHz, CDCI₃): δ 7.08 (q, J = 8.1 Hz, 1 H), 6.71 (t, J = 8.4 Hz, 1 H), 6.46 (d, J = 8.7 Hz, 1 H), 4.53 (s, 2H), 2.31 (s, 3H), 2.21 (s, 3H). To a stirred solution of 2,4,6-Trihydroxyacetophenone (200 g, 1190 mmol) in toluene (1000 ml_) was added morpholine (510 ml_, 5.95 mol) and the reaction mixture was azeotropically refluxed for 16 h. The reaction mixture was allowed to room temperature, concentrated under reduced pressure and the resultant crude compound was purified by trituration with diethyl ether to afford intermediate A(230 g, 81 %) as a white solid

.¹H NMR (300 MHz, DMSO-cfe): δ 12.20 (s, 2H), 5.89 (s, 2H), 3.70 (t, J= 5.1 Hz, 4H), 3.23 (t, J= 5.1 Hz, 4H), 2.54 (s, 3H); ESI-MS m/z 238.11 (M+H)⁺; LCMS Purity: 97.8%

A mixture of A (55 g, 232 mmol), B (63.3 g, 348 mmol) and pyrrolidine (65.9 g, 928 mmol) in toluene (800 ml_) was stirred at 120 °C for 16 h. The reaction mixture was concentrated under reduced pressure and the resulting crude compound was purified by flash chromatography using 15% ethyl acetate in petroleum ether as an eluent to afford compound 1 (40 g, 43%) as an off-white solid.¹H NMR (300 MHz, CDCI₃): δ 11.96 (s, 1H), 7.07 (q, J= 8.0 Hz, 1H), 6.69 (t, J= 8.6 Hz, 1H), 6.57 (d, J= 8.3 Hz, 1H), 5.91 (d, J= 2.4 Hz, 1 H), 5.81 (d, J = 2.4 Hz, 1 H), 4.09 (d, J = 9.6 Hz, 1 H), 3.98 (d, J = 9.5 Hz, 1 H), 3.84 - 3.74 (t, J= 4.8 Hz, 4H), 3.31 (t, J= 4.8 Hz, 4H), 3.06 (d, J= 17.2 Hz, 1H), 2.72 (d, J= 17.2 Hz, 1H), 2.11 (s, 3H), 1.56 (s, 3H); ESI-MS m/z 402.32 (M+H)⁺; LCMS Purity: 98%.

Racemic mixture of compound 1 is separated by chiral HPLC column chromatography to get the respective isomers. The enantiomer which was more potent was selected for further analoging.

Isomer 1-1: ¹H NMR (400 MHz, CDCI₃): δ 11.95 (s, 1H), 7.07 (q, J= 7.6 Hz, 1H), 6.69 (t, J = 8.6 Hz, 1H), 6.57 (d, J= 8.3 Hz, 1H), 5.91 (d, J= 2.0 Hz, 1H), 5.86 (d, J= 2.0 Hz, 1H), 4.09 (d, J= 9.5 Hz, 1H), 3.98 (d, J= 9.5 Hz, 1H), 3.80 (t, J= 4.8 Hz, 4H), 3.32 (t, J= 5.6 Hz, 4H), 3.06 (d, J= 17.2 Hz, 1H), 2.72 (d, J= 17.1 Hz, 1H), 2.10 (s, 3H), 1.56(s, 3H). Optical Rotation [a]_D: + 58.59 (c 0.5115, CHCI₃).

Isomer 1-2: ¹H NMR (400 MHz,CDCI₃): δ 11.96 (s, 1H), 7.07 (q, J= 8.0 Hz, 1H), 6.69 (t, J = 8.7 Hz, 1H), 6.57 (d, J= 8.3 Hz, 1H), 5.91 (d, J= 2.0 Hz, 1H), 5.86 (d, J= 2.0 Hz, 1H), 4.09 (d, J= 9.5 Hz, 1H), 3.98 (d, J= 9.5 Hz, 1H), 3.80 (t, J =4.8 Hz, 4H), 3.32 (t, J= 5.6 Hz, 4H), 3.06 (d, J = 17.2 Hz, 1 H), 2.72 (d, J = 17.2 Hz, 1 H), 2.10 (s, 3H), 1.56 (s, 3H). Optical Rotation [a]_D: - 53.64 (c 0.5065, CHCI₃).

Examples 2-33 were prepared by the following procedures described in general synthetic scheme 1.

12.05 (s, 1 H), 7.19 - 7.1 1

(m, 1 H), 6.8 - 6.7 (m, 3H),

5-hydroxy-2-methyl-

5 I 5.98 - 5.94 (m, 2H), 4.08

7-morpholino-2-(m- (s, 2H), 3.7 - 3.65 (m, 384.21 tolyloxymethyl)chro

4H), 3.3 - 3.4 (m, 4H), man-4-one

3.05 - 2.95 (m, 1 H), 2.76

- 2.69 (m, 1 H), 2.26 (s, 3H), 1.43 (s, 3H)

1 1.99 (s, 1 H), 7.1 1 - 7.03

5-hydroxy-2-methyl- (m, 4H), 5.92 (s, 2H), 3.63

6 2-(4-methylbenzyl)- (t, J = 4.9 Hz, 4H), 3.35 -

7- 368.13

3.3 (m, 4H), 3.00 - 2.81 morpholinochroman

(m, 2H), 2.71 - 2.55 (m,

-4-one

2H), 2.24 (s, 3H), 1.22 (s, 3H)

12.04 (s, 1 H), 7.16 - 7.06

2-((4- (m, 2H), 7.03 - 6.92 (m, fluorophenoxy)meth

7 2H), 5.96 (s, 2H), 4.08 (s,

yl)-5-hydroxy-2- 2H), 3.64 (t, J = 4.8 Hz, 388.23 methyl-7- 4H), 3.30 (t, J = 4.8 Hz, morpholinochroman

4H), 3.07 (d, J = 17.4 Hz,

-4-one

1 H), 2.74 (d, J = 17.1 Hz, 1 H), 1.43 (s, 3H)

5-hydroxy-2-methyl- 400 MHz, DMSO-cfe: δ

7-morpholino-2-((2- 12.02 (s, 1 H), 7.62 (t, J =

8 (trifluoromethyl)phe 7.6 Hz, 2H), 7.29 (d, J = 438.17

oQ noxy)methyl)chrom 8.8 Hz, 1 H), 7.12 (t, J =

an-4-one 7.6 Hz, 1 H), 5.98-5.92 (m,

morpholinochroman 5.86 (d, J = 2.4, Hz, 1H), -4-one 4.06 (d, J = 9.4 Hz, 1H),

3.93 (d, J = 9.5 Hz, 1H), 3.84 (t, J = 4.5 Hz, 4H), 3.3 (t, J = 5.1 Hz, 4H), 3.06 (d, J= 17.2 Hz, 1H), 2.71 (d, J= 17.2 Hz, 1H), 2.17 (s, 3H), 1.55 (s, 3H)

12.05 (s, 1H), 7.40 - 7.31

5-hydroxy-2-methyl- (m, 1H), 7.32 - 7.23 (m,

2-((2-methyl-3- 2H), 5.96 (s, 2H), 4.19 (m,

24

(trifluoromethyl)phe 2H), 3.64 (t, J = 4.4 Hz,

452.39 noxy)methyl)-7- 4H), 3.3 (t, J = 4.9 Hz, morpholinochroman 4H), 3.05 (d, J= 17.6 Hz, -4-one 1H), 2.86 (d, J= 17.2 Hz,

1H), 2.17 (s, 3H), 1.49 (s, 3H)

12.05 (s, 1H), 7.16 (t, J =

8.2 Hz, 1H), 7.02 (d, J =

2-((3-chloro-2-

7.8 Hz, 1H), 6.95 (d, J = methylphenoxy)met

25 8.4 Hz, 1H), 5.96 (s, 2H), 418.02 hyl)-5-hydroxy-2- 4.13 (s, 2H), 3.65 (t, J = methyl-7-

4.9 Hz, 4H), 3.29 (t, J = morpholinochroman

4.9 Hz, 4H), 3.03 (d, J =

-4-one

17.3 Hz, 1H), 2.83 (d, J =

17.3 Hz, 1H), 2.12 (s, 3H), 1.47 (s, 3H)

26 5-hydroxy-2-methyl- 300 MHz, CDCI₃: δ 11.92

2- (s, 1H), 7.29 - 7.16 (m, 383.42

((methyl(phenyl)ami 2H), 6.81 - 6.67 (m, 3H),

u hyl)-5-hydroxy-2- (m, 2H), 6.88 - 6.79 (m, methyl-7- 1H), 5.95 (s, 2H), 4.15 (s,

morpholinochroman 2H), 3.65 (t, J = 4.8 Hz, -4-one 4H), 3.31 (m, 4H), 3.02 (d,

J= 17.3 Hz, 1H), 2.74 (d, J= 17.3 Hz, 1H), 2.21 (d, J = 2.2 Hz, 3H), 1.45 (s, 3H)

2 -((5 -hydroxy -2- ^ηΗ NMR (400 MHz, methyl-7- DMSO-tf₆): δ 12.60 (s, morpholino-4- 1H), 12.06 (s, 1H), 7.67 oxochroman-2- (dd, J = 7.6, 1.6 Hz, 1H), yl)methoxy)benzoic 7.51 -7.46 (m, 1H), 7.14 acid (d, J = 8.4 Hz, 1H), 7.02

(t, J = 7.2 Hz, 1H), 5.96

30 414.24

(s, 2H), 4.21 (d, J = 9.6

Hz, 1H), 4.1 (d, J = 10.4

Hz, 1H), 3.65 (t, J = 5.2

Hz, 4H), 3.32 - 3.29 (m, 4H), 3.25 (d, J= 17.2 Hz, 1H), 2.68 (d, J= 17.6 Hz, 1H), 1.45 (s, 3H).

2 -((5 -hydroxy -2- ^ηΗ NMR (400 MHz, methyl-7- DMSO-tf₆): δ 12.02 (s, morpholino-4- 1H), 7.38 - 7.33 (m, 1H), oxochroman-2- 7.17 (dd, J = 7.2, 1.6 Hz, I

yl)methoxy)-N,N- 1H), 7.10 (d, J = 8.4 Hz,

31 441.28 dimethylbenzamide 1H), 7.01 (t, J = 7.2 Hz,

1H), 5.96 - 5.94 (m, 2H), 4.16 -ΛΛ (m, 2H), 3.65 (t, J = 4.8 Hz, 4H), 2.97 - 2.91 (m, 4H), 2.75 -2.71 (m, 2H), 2.69 (s, 6H), 1.4

(s, 3H).

2-((3,5- ^ηΗ NMR (300 MHz, difluorophenoxy)me DMSO-tf₆): δ 12.03 (s, thyl)-5-hydroxy-2- 1 H), 6.83 - 6.75 (m, 3H), methyl-7- 5.95 (s, 2H), 4.16 (s, 2H),

32 morpholinochroman 3.64 (t, J = 4.5 Hz, 4H),

-4 -one 3.32 - 3.24 (m, 4H), 3.03

(d, J = 17.7 HZ, 1 H), 2.71

(d, J = 17.4 Hz, 1 H), 1.42

(s, 3H)

2-((2,5- ^ηΗ NMR(300 MHz, difluorophenoxy)me DMSO-de): δ 12.01 (s, thyl)-5-hydroxy-2- 1 H), 7.29 - 7.14 (m, 2H),

33 methyl-7- 6.81 - 6.75 (m, 1 H), 5.95 - morpholinochroman 5.93 (d, J = 3.9 Hz, 2H), 406.21 -4-one 4.26 - 4.18 (m, 2H), 3.64

(t, J = 4.5 Hz, 4H), 3.26 - 3.24 (m, 4H), 2.99 (d, J =

17.4 Hz, 2H), 1.44 (s, 3H)

General Synthetic Scheme 2:

Example 34: 2-((3-Fluoro-2-methylphenoxy) methyl)-2-methyl-7-morpholino-4- oxochroman-5-carboxylic acid

Triflic anhydride (0.188ml_, 1.12mmol) was added to a solution of 2-((3-fluoro-2- methylphenoxy) methyl)-5-hydroxy-2-methyl-7-morpholinochroman-4-one(300 mg, 0.75mmol), pyridine (0.12 mL, 1.49 mmol) in dichloromethane (10 mL) at room temperature and stirred for 4 h. The mixture was diluted with DCM and washed with water. The separated organic layer was dried over anhydrous Na₂S0_4, filtered and the filtrate was concentrated under reduced pressure. The crude compound was purified by flash chromatography using 20% ethyl acetate in petroleum ether as an eluent to afford2-((3- fluoro-2-methylphenoxy)methyl)-2-methyl-7-morpholino-4-oxochroman-5-yl

trifluoromethanesulfonate (219 mg, 55%) as a pale yellow solid.¹H NMR (400 MHz,CDCI₃): δ 7.09 (q, J = 8.0 Hz, 1 H), 6.71 (t, J = 8.8 Hz, 1 H), 6.58 (d, J = 8.0 Hz, 1 H), 6.28 (s, 2H), 4.13-4.00 (m, 2H), 3.83 (t, J = 4.8 Hz, 4H), 3.30 (t, J = 5.6 Hz, 4H), 3.08 (d, J = 16.8 Hz, 1 H), 2.74 (d, J = 16 Hz, 1 H), 2.1 1 (s, 3H), 1.56 (s, 3H); ESI-MS m/z 533.9 (M+H)⁺; LCMS Purity: 82%.

A degassed solution of2-((3-fluoro-2-methylphenoxy)methyl)-2-methyl-7-morpholino-4- oxochroman-5-yl trifluoromethanesulfonate(210 mg, 0.39mmol) in methanol (20 mL) were added PdCI₂dppf.DCM (64 mg, 0.078mmol) and TEA (0.165 mL, 1.18mmol) in a steal bomb at room temperature. The reaction mixture was carbonized under 150 psi of CO pressure at 100 °C for 16 h. The reaction mixture was allowed to room temperature, filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The resultant compound was purified by flash chromatography using 40% ethyl acetate in petroleum ether as an eluent to affordMethyl 2-((3-fluoro-2-methylphenoxy)methyl)-2- methyl-7-morpholino-4-oxochroman-5-carboxylate(130 mg, 74 %) as an off-white solid. ESI-MS m/z 444.03 (M+H)

2 M Aqueous NaOH (0.5 mL, 1.0mmol)wasadded to a solution ofMethyl 2-((3-fluoro-2- methylphenoxy)methyl)-2-methyl-7-morpholino-4-oxochroman-5-carboxylate (130 mg, 0.3 mmol)in ethanol (5 mL) at room temperature and stirred at 50 °C for 5 h. The reaction mixture was acidified using 2 N HCI and the precipitate was filtered and dried to afford2- ((3-fluoro-2-methylphenoxy) methyl)-2-methyl-7-morpholino-4-oxochroman-5-carboxylic acid (34, 102 mg, 82 %) as a White solid.¹ H NMR (400 MHz, DMSO-cfe): δ 12.79 (s, 1 H), 7.16 (q, J = 7.2 Hz, 1 H), 6.82 - 6.74 (m, 2H), 6.51 (s, 1 H), 6.37 (d, J = 2.0 Hz, 1 H), 4.13 (q, J = 10.4 Hz, 2H), 3.68 (t, J = 4.4 Hz, 4H), 3.38 - 3.21 (m, 4H), 3.00 (d, J = 16.8 Hz, 1 H), 2.76 (d, J = 16.9 Hz, 1 H), 1.98 (s, 3H), 1.47 (s, 3H); ESI-MS m/z: 430.44 (M+H)⁺; LCMS 5 Purity: 90%

Example 35: 2-((3-Fluoro-2-methylphenoxy)methyl)-2-methyl-7-morpholino-4- oxochroman-5-carboxamide

A mixture of 34(63 mg, 0.14mmol), ammonium chloride (39 mg, 0.73 mmol), HATU(84 mg, 0.22mmol) and DIPEA (0.1 ml_, 0.58mmol) in THF (5 ml_) was stirred at room temperature 0 for 2 h. The reaction mixture was concentrated under reduced pressure and the resulting crude compound was dissolved in ethyl acetate and washed with water. Separated organic layer was dried over anhydrous Na₂S0_4, filtered and the filtrate was concentrated under reduced pressure. The crude compound was purified by flash chromatography using 15% ethyl acetate in petroleum ether as an eluent to afford2-((3-fluoro-2- 5 methylphenoxy)methyl)-2-methyl-7-morpholino-4-oxochroman-5-carboxamide (35, 95%, 60 mg) as an off-white solid.¹H NMR (400 MHz, CDCI₃): δ 7.07 (q, J = 8.0 Hz, 1 H), 6.71 (t, J = 8.8 Hz, 1 H), 6.59-6.56 (m, 2H), 6.30 (d, J = 2.5 Hz, 1 H), 5.80 (brs, 2H), 4.09 (d, J = 9.6 Hz, 1 H), 4.01 (d, J = 9.6 Hz, 1 H), 3.81 (t, J = 4.9 Hz, 4H), 3.32 (t, J = 5.0 Hz, 4H), 3.09 (d, J = 16.7 Hz, 1 H),2.75 (d, J = 16.8 Hz, 1 H), 2.1 1 (s, 3H), 1.56 (s, 3H); ESI-MS m/z. 429.24 0 (M+H)⁺; LCMS Purity: 96.7%.

Examples 34b, 36-40 were prepared by the following procedures described in general synthetic scheme 2

1H), 2.66 (d, J= 16.3 Hz, 1H),

2.13 (s, 3H), 1.47 (s, 3H)

300 MHz, DMSO-cfe: δ 7.12 (d, J = 7.4 Hz, 2H), 6.96 - 6.78

2-methyl-7- (m, 2H), 6.47 (s, 1H), 6.35 (s, morpholino-4- 1H), 4.09 (d, J = 3.1 Hz, 2H), oxo-2-(o- 3.67 (t, J = 4.8 Hz, 4H), 3.30 411.94 tolyloxymethyl)

(d, J= 7.0 Hz, 4H), 2.98 (d, J chroman-5- = 16.3 Hz, 1H), 2.73 (d, J = carboxylic acid

16.3 Hz, 1H), 2.08 (s, 3H), 1.47 (s, 3H)

300 MHz, DMSO-cfe: δ 7.67 - 7.59 (m, 2H), 7.41 (s, 1H),

2-methyl-7- 7.28 (d, J= 8.7 Hz, 1H), 7.21 - morpholino-4- 7.14 (m, 2H), 6.43 (d, J = 2.4 oxo-2-((2- Hz, 1H), 6.32 (d, J = 2.7 Hz,

(trifluoromethyl) 465.3

1H), 4.25 (q, J= 10.2 Hz, 2H), phenoxy)methy

3.67 (t, J= 4.8 Hz, 4H), 3.35 - l)chroman-5- 3.21 (m, 4H), 2.96 (d, J= 16.5 carboxamide

Hz, 1H), 2.61 (d, J= 16.5 Hz, 1H), 1.45 (s, 3H)

2-((3-fluoro-2- ^ηΗ NMR (300 MHz, DMSO- methylphenoxy d₆y δ 12.52 (bs, 1H), 11.14

)methyl)-N- (bs, 1H), 7.15 (q, J = 8.1 Hz, hydroxy-2- 1H), 6.81 -6.74 (m, 2H), 6.47 m ethyl -7- (d, J = 1.8 Hz, 1H), 6.38 (s, 445.37 morpholino-4- 1H), 4.06 (s, 2H), 3.68 (t, J =

oxochromane- 4.8 Hz, 4H), 3.13 (d, J = 4.5

5-carboxamide Hz, 4H), 2.95 (s, 2H), 2.07 (d,

J= 1.5 Hz, 3H), 1.39 (s, 3H) 8-((3-fluoro-2- ^ηΗ NMR (300 MHz, DMSO- methylphenoxy d₆y δ 12.18 (s, 1H), 7.15 -

)methyl)-8- 7.08 (m, 2H), 6.94 (d, J = 2.1 m ethyl -5- Hz, 1H), 6.82 - 6.73 (m, 2H),

B morpholino-8,9- 4.16 (s, 2H), 3.72 (t, J = 4.2 426.33 dihydropyrano[ Hz, 4H), 3.33 - 3.28 (m, 4H),

4,3,2- 3.19 (d, J= 16.5 Hz, 1H), 2.96 de]phthalazin- (d, J= 16.5 Hz, 1H), 1.95 (d, J

3(2H)-one = 1.2 Hz, 3H), 1.46 (s, 3H)

8-((3-fluoro-2- ^ηΗ NMR (300 MHz, DMSO- methyl d₆y δ 7.19 - 7.11 (m, 2H), phenoxy)methy 6.98 (d, J= 2.1 Hz, 1H), 6.83 l)-8-methyl-5- - 6.74 (m, 2H), 4.21 (s, 2H),c morpholino-8,9- 3.70 (t, J = 4.8 Hz, 4H), 3.37 427.35 dihydro-3H- (t, J= 5.1 Hz, 4H), 3.28-3.24 chromeno [4,5- (m, 1H), 3.08 (d, J= 16.5 Hz, cd] [1,2] 1H), 1.91 (d, J = 1.5 Hz, 3H), oxazin-3-one 1.50 (s, 3H)

General Synthetic Scheme 3:

Example 41a: Ethyl 2-(2-((3-fluoro-2-methylphenoxy)methyl)-2-methyl-7-morpholino- 4-oxochroman-5-yloxy)acetate

To a solution of 2-((3-fluoro-2-methylphenoxy)methyl)-5-hydroxy-2-methyl-7- morpholinochroman-4-one (0.2 g, 0.52 mmol) in THF (25 mL) were added ethyl bromoacetate (0.087 mL, 0.78 mmol) and Cs₂C0₃ (339 mg, 1.04 mmol) at room temperature and stirred at 80 °C for 3 h. The reaction mixture was allowed to room temperature, filtered and the filtrate was concentrated under reduced pressure. The crude compound was purified by flash chromatography using 40% ethyl acetate in petroleum ether as an eluent to afford intermediate 41a (0.12 g, 50%) as a white solid. ¹H NMR (400 MHz, CDCI₃): δ 7.06 (q, J = 6.8 Hz, 1 H), 6.67 (t, J = 8.4 Hz, 1 H), 6.56 (d, J = 8.4 Hz, 1 H), 6.02 (d, J = 2 Hz, 1 H), 5.91 (d, J = 2 Hz, 1 H), 4.68 (d, J = 1.2 Hz, 1 H), 4.28 (d, J = 7.6 Hz, 1 H), 4.05 (d, J = 9.6 Hz, 1 H), 3.99 (d, J = 10 Hz, 1 H), 3.8 (t, J = 4.8 Hz, 4H), 3.26 (t, J = 4.4 Hz, 4H), 3.03 (d, J = 16.4 Hz, 1 H), 2.7 (d, J = 16 Hz, 1 H), 2.12 (d, J = 2 Hz, 3H), 1.54 (s, 3H), 1.3 (t, J = 7.2 Hz, 3H); ESI-MS m/z. 487.9 (M+H)⁺; LCMS Purity: 97%. Example 41 : 2-(2-((3-fluoro-2-methylphenoxy)methyl)-2-methyl-7-morpholino-4- oxochroman-5-yloxy)acetic acid

2 M Aqueous NaOH (0.7 mL, 1.27 mmol) was added to a solution of compound-41a (0.12 g, 0.25 mmol) in ethanol (4 mL) at room temperature and stirred for 5 h. The reaction mixture was acidified using 2 N HCI and the resulting precipitate was filtered and dried to afford Example41 (0.085 g, 75%) as an off-white solid. ¹H NMR (300 MHz, DMSO-tf₆): δ 12.86 (bs, 1 H), 7.16 (q, J = 8.4 Hz, 1 H), 6.82 - 6.74 (m, 2H), 6.03 (s, 2H), 4.71 (s, 2H), 4.13 -4.07 (m, 2H), 3.66 (t, J = 4.4 Hz, 4H), 3.26 (t, J = 4.4 Hz, 4H), 2.91 (d, J = 16.4 Hz, 1 H), 2.63 (d, J = 16.4 Hz, 1 H), 2.00 (d, J = 1.2 Hz, 3H), 1.44 (s, 3H); ESI-MS m/z. 459.96 (M+H)⁺; LCMS Purity: 98%. Example 42: 2-(2-((3-fluoro-2-methylphenoxy)methyl)-2-methyl-7-morpholino-4- oxochroman-5-yloxy)acetamide

A mixture of Compound-41(0.08 g, 0.181 mmol), ammonium chloride (0.048 g, 0.909 mmol), HATU (0.103 g, 0.271 mmol) and DIPEA (0.097 mL, 0.543 mmol) in THF (10 mL) was stirred at room temperature for 6 h. The reaction mixture was concentrated under reduced pressure and the resulting crude compound was partitioned between ethyl acetate and water. Separated organic layer was dried over anhydrous Na₂S0_4, filtered and the filtrate was concentrated under reduced pressure. The crude was purified by flash chromatography using 80% ethyl acetate in petroleum ether as an eluent to afford 42(0.045 g, 56%) as a white solid. ¹H NMR (300 MHz, DMSO-ck): δ 8.08 (s, 1 H), 7.65 (s, 1 H), 7.15 (q, J = 8.1 Hz, 1 H), 6.81 - 6.73 (m,2H), 6.1 1 (d, J = 1.8 Hz, 1 H),6.02 (d, J = 1.8 Hz, 1 H), 4.5 - 4.38 (m, 2H), 4.1 1 (s, 2H), 3.67 (t, J = 4.2 Hz, 4H), 3.32 - 3.28 (m, 4H), 2.95 - 2.89 (m, 1 H), 2.72 - 2.66 (m, 1 H), 1.97 (s, 3H), 1.45 (s, 3H); ESI-MS m/z. 458.9 (M+H)⁺; LCMS Purity: 97%.

Scheme 4: General Synthetic Scheme

Example 43: 2-((3-Fluoro-2-methylphenoxy)methyl)-2-methyl-7-morpholino-4- oxochroman-5-carbonitrile

A mixture of 2-((3-fluoro-2-methylphenoxy)methyl)-2-methyl-7-morpholino-4-oxochroman- 5-yl trifluoromethanesulfonate (0.7 g, 1.31 mmol), zinc cyanide (0.461 g, 3.93 mmol) and Pd(PPh₃)₄ (0.303 g, 0.26 mmol) in DMF (10 ml_) was stirred at 80 °C for 4 h. The reaction mixture was allowed to room temperature and partitioned between ethyl acetate and water. Separated organic layer was dried over anhydrous Na₂S0₄ and filtered. The filtrate was concentrated under reduced pressure and purified by flash chromatography using 35% ethyl acetate in petroleum ether as an eluent to afford 43(0.39 g, 73%) as an off-white solid. ¹ H NMR (300 MHz, DMSO-cfe): δ 7.07 (m, 1 H), 6.87 (d, J = 2.7 Hz, 1 H), 6.68 (t, J = 8.4 Hz, 1 H), 6.56 (d, J = 8.1 Hz, 1 H), 6.43 (d, J = 2.1 Hz, 1 H), 4.04 (q, J = 9.9 Hz, 2H), 3.83 (t, J = 4.8 Hz, 4H), 3.31 (t, J = 5.4 Hz, 4H), 3.1 (d, J = 16.5 Hz, 1 H), 2.81 (d, J = 16.8 Hz, 1 H), 2.06 (s, 3H), 1.25 (s, 3H); ESI-MS m/z 41 1.03 (M+H)⁺; LCMS Purity: 96%

Isomer 43-1 : ¹H NMR (300 MHz, CDCI₃): δ 7.07 (d, J = 7.5 Hz, 1 H), 6.87 (d, J = 2.5 Hz, 1 H), 6.69 (t, J = 8.6 Hz, 1 H), 6.56 (d, J = 8.3 Hz, 1 H), 6.43 (d, J = 2.5 Hz, 1 H), 4.09 (d, J = 10.0 Hz, 2H), 3.83 (t, J = 4.5 Hz, 4H), 3.32 (t, J = 4.5 Hz, 4H), 3.09 (d, J = 16.7 Hz, 1 H), 2.79 (d, J = 16.7 Hz, 1 H), 2.07 (s, 3H), 1.27 (s, 3H).

Example 44: 2-((3-Fluoro-2-methylphenoxy) methyl)-2-methyl-7-morpholino-5-(1 H- tetrazol-5-yl) chroman-4-one

A solution of 2-((3-fluoro-2-methylphenoxy) methyl)-2-methyl-7-morpholino-4-oxochroman- 5-carbonitrile(0.1 g, 0.24 mmol), TMS azide (56 mg, 0.48 mmol) and di-n-butyl tin oxide (12 mg, 0.05 mmol) in DME (10 mL) was irradiated under microwave condition at 1 10 °C for 1 h. The reaction mixture was allowed to room temperature, diluted with ethyl acetate and filtered through a pad of celite. The filtrate was concentrated under reduced pressure and purified by flash chromatography using 80% ethyl acetate in petroleum ether as an eluent to afford 44 (36%, 41 mg) as an off-white solid. ¹H NMR (300 MHz, DMSO-cfe): δ 16.09 (s, 1 H), 7.17 (q, J = 8.0 Hz, 1 H), 6.87 - 6.72 (m, 2H), 6.63 (d, J = 2.1 Hz, 1 H), 6.53 (d, J = 2.1 Hz, 1 H), 4.17 (s, 2H), 3.67 (t, J = 4.2 Hz, 4H), 3.38 - 3.22 (m, 4H), 2.97 (d, J = 16.5 Hz, 1 H), 2.70 (d, J = 16.5 Hz, 1 H), 2.00 (s, 3H), 1.51 (s, 3H); ESI-MS m/z 454.34 (M+H)⁺; LCMS Purity: 96%.

Example 45: 5-(Aminomethyl)-2-((3-fluoro-2-methylphenoxy) methyl)-2-methyl-7- morpholinochroman-4-one

A solution of2-((3-fluoro-2-methylphenoxy)methyl)-2-methyl-7-morpholino-4-oxochroman-5- yl trifluoromethanesulfonate(100 mg, 0.24 mmol) in ethanol (5 mL) and 7 M methanolic ammonia (1 mL) was added to a suspension of 10% Pd/C (20 mg) in ethanol (10 mL) under nitrogen atmosphere. The reaction mixture was hydrogenated under 50 psi hydrogen pressure at room temperature for 16 h. The mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The crude compound was purified by flash chromatography using 2% methanol in dichloromethane as an eluent to afford 45 (15 mg, 15 %) as brown solid. ¹H NMR (400 MHz, CDCI₃): δ 7.06 (q, J = 8.4 Hz, 1H), 6.68 (t, J= 8.8 Hz, 1H), 6.57 (d, J= 8.0 Hz, 1H), 6.48 (d, J= 2.4 Hz, 1H), 6.22 (d, J = 2.4 Hz, 1H), 4.12 - 3.96 (m, 4H), 3.81 (t, J= 4.8 Hz, 4H), 3.32 (t, J= 5.6 Hz, 4H), 3.05 (d, J = 16.0 Hz, 1H), 2.71 (d, J= 16.4 Hz, 1H), 2.1 (s, 3H), 1.25 (s, 3H); ESI-MS m/z 415.38 (M+H)⁺; LCMS Purity: 88%.

Example 46: 2-Methyl-7-morpholino-2-(o-tolyloxymethyl)chroman-4-one

A solution of2-methyl-7-morpholino-4-oxo-2-(o-tolyloxymethyl)chroman-5-yl trifluoromethanesulfonate(80 mg, 0.15 mmol)in ethanol (5 mL) was added to a suspension of 10% Pd on C (40 mg) in ethanol (10 mL) under nitrogen atmosphere. The reaction mixture was hydrogenated under 50 psi hydrogen pressure at room temperature for 4 h. The mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The resultant compound was purified by flash chromatography using 30% ethyl acetate in petroleum ether as an eluent to afford46(20 mg, 52%) as a pale yellow solid.¹H NMR (400 MHz, CDCI₃): δ 7.78 (d, J = 8.9 Hz, 1H), 7.28 - 7.18 (m, 2H), 6.87 (td, J= 7.4, 1.1 Hz, 1H), 6.79-6.74 (m, 1H), 6.52 (dd, J= 9.0, 2.5 Hz, 1H), 6.28 (d, J =2.4 Hz, 1H), 4.10 (d, J= 9.5 Hz, 1H), 4.00 (d, J= 9.4 Hz, 1H), 3.88-3.78 (m, 4H), 3.32- 3.32 (m, 4H), 3.06 (d, J= 16.8 Hz, 1H), 2.73 (d, J= 16.8 Hz, 1H), 2.19 (s, 3H), 1.56 (s, 3H); ESI-MS m/z 368.5 (M+H)⁺; LCMS Purity: 97%.

Scheme 5: General Synthetic Scheme

Example 47: 5-(Benzylamino)-2-((3-fluoro-2-methylphenoxy) methyl)-2-methyl-7- morpholinochroman-4-one

A degassed suspension of 2-((3-fluoro-2-methylphenoxy)methyl)-2-methyl-7-morpholino-4- oxochroman-5-yl thfluoromethanesulfonate(1.5 g, 2.81 mmol), Pd₂(dba)₃ (0.367 g, 0.40 mmol), Xantphos (231 mg, 0.40 mmol) and DBU (0.6 ml_, 4.02 mmol) in toluene (15 ml_) was added benzyl amine (442 mg, 4.13 mmol) at room temperature. The mixture was refluxed for 4 h and allowed to cool to room temperature. The reaction mixture was diluted with ethyl acetate, filtered through a pad of celite and the filtrate was washed with water. The organic layer was concentrated under reduced pressure, the resultant crude compound was purified by flash chromatography using 20% ethyl acetate in petroleum ether as an eluent to afford 47 (0.4 g, 40%) as an off-white solid. ¹H NMR (300 MHz, CDCI₃): δ 9.46 (t, J = 6.2 Hz,1 H), 7.35 - 7.25 (m, 5H), 7.07 (q, J = 6.9 Hz, 1 H), 6.67 (t, J = 7.2 Hz, 1 H), 6.58 (d, J = 8.1 Hz, 1 H), 5.69 (d, J = 2.1 Hz, 1 H), 5.48 (d, J = 2.1 Hz, 1 H), 4.42 (d, J = 5.4 Hz, 2H), 4.08 (d, J = 9.6 Hz, 1 H), 3.98 (d, J = 9.6 Hz, 1 H), 3.74 (t, J = 5.1 Hz, 4H), 3.18 (t, J = 4.8 Hz, 4H), 3.03 (d, J = 16.8 Hz, 1 H), 2.70 (d, J = 16.8 Hz, 1 H), 2.12 (s, 3H).1.53 (s, 3H); ESI-MS m/z: 491.33 (M+H)⁺; LCMS Purity: 86%.

Example 48: 5-Amino-2-((3-fluoro-2-methylphenoxy) methyl)-2-methyl-7- morpholinochroman-4-one

A solution of5-(benzylamino)-2-((3-fluoro-2-methylphenoxy) methyl)-2-methyl-7- morpholinochroman-4-one(400 mg, 0.81 mmol) in methanol (5 ml_) was added to a suspension of 10% Pd(OH)₂-C (150 mg) in methanol (10 ml_) under nitrogen atmosphere. The reaction mixture was hydrogenated under 75 psi hydrogen pressure at room temperature for 4 h. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The crude compound was purified by flash chromatography using 30% ethyl acetate in petroleum ether as an eluent to afford48 (250 mg, 75%) as an off-white solid.¹ H NMR (300 MHz, CDCI₃) δ 7.06 (q, J = 8.1 Hz, 1 H), 6.67 (t, J = 8.7 Hz, 1 H), 6.57 (d, J = 8.3 Hz, 1 H), 6.33 (br s, 2H), 5.74 (d, J = 2.1 Hz, 1 H), 5.57 (d, J = 2.1 Hz, 1 H), 4.07 (d, J = 9.3 Hz, 1 H), 3.97 (d, J = 9.3 Hz, 1 H), 3.78 (t, J = 5.1 Hz, 4H), 3.24 (t, J = 4.8 Hz, 4H), 3.00 (d, J = 16.5 Hz, 1 H), 2.68 (d, J = 17.1 Hz, 1 H), 2.12 (s, 3H).1.53 (s,3H); ESI-MS m/z. 401.03 (M+H)⁺; LCMS Purity: 95% Example 49: 2-((3-Fluoro-2-methylphenoxy)methyl)-2-methyl-7-morpholino-5-(2,2,2- trifluoroethylamino)chroman-4-one

A degassed suspension of 2-((3-fluoro-2-methylphenoxy)methyl)-2-methyl-7-morpholino-4- oxochroman-5-yl trifluoromethanesulfonate(200 mg, 0.37 mmol), Pd₂dba₃ (69 mg, 0.075 mmol), Xantphos (44 mg, 0.075 mmol) and DBU (0.1 ml_, 0.75 mmol) in dioxane (5 ml_) was added 2,2,2-thfluoroethanamine (0.06 ml, 0.75 mmol) in a sealed tube and heated to 100 °Cfor 4 h and diluted with ethyl acetate, filtered through a pad of celite and the filtrate was washed with water. The organic layer was concentrated under reduced pressure and the resultant crude compound was purified by flash chromatography using 30% ethyl acetate in petroleum ether as an eluent to afford 49 (15 mg, 8%) as an off-white solid. ¹H NMR (400 MHz, CDCI₃): δ 9.40 (t, J = 6.8 Hz, 1 H), 7.06 (q, J = 8.4 Hz, 1 H), 6.67 (t, J = 8.4 Hz, 1 H), 6.57 (d, J = 8.4 Hz, 1 H), 5.78 (d, J = 2.0 Hz, 1 H), 5.62 (d, J = 2.0 Hz, 1 H), 4.07 (d, J = 9.2 Hz, 1 H), 3.97 (d, J = 9.2 Hz, 1 H), 3.88 - 3.75 (m, 6H), 3.29 (t, J = 5.2 Hz, 4H), 3.00 (d, J = 16.4 Hz, 1 H), 2.69 (d, J = 16.4 Hz, 1 H), 2.10 (s, 3H), 1.53 (s,3H); ESI-MS m/z 483.36 (M+H)⁺; LCMS Purity: 97.8%.

Example 50: N-(2-((3-fluoro-2-methylphenoxy)methyl)-2-methyl-7-morpholino-4- oxochroman-5-yl)acetamide

Acetyl chloride(0.01 ml_, 0.225 mmol) was added to a solution 5-amino-2-((3-fluoro-2- methylphenoxy) methyl)-2-methyl-7-morpholinochroman-4-one (0.06 g, 0.15 mmol) and TEA (0.03 ml_, 0.225 mmol) in DCM (5 ml_) at 0 °C.The mixture was stirred at room temperature for 2 h and diluted with DCM and water. Separated organic layer was dried over anhydrous Na₂S0₄, filtered and the filtrate was concentrated under reduced pressure. The crude compound was purified by trituration with pentane to afford 50(31 mg, 47%) as an off-white solid. ¹H NMR (300 MHz, DMSO-cfe) δ 12.01 (s, 1 H), 7.82 (d, J = 2.4 Hz, 1 H), 7.16 (q, J = 8.1 Hz, 1 H), 6.87 - 6.69 (m, 2H), 6.12 (d, J = 2.1 Hz, 1 H), 4.13 (s, 2H), 3.68 (t, J = 5.1 Hz, 4H), 3.35 - 3.21 (m, 4H), 3.03 (d, J = 17.1 Hz, 1 H), 2.82 (d, J = 16.8 Hz, 1 H), 2.12 (s, 3H), 1.97 (s, 3H), 1.47 (s, 3H); ESI-MS m/z 443.35 (M+H)⁺; LCMS Purity: 90%. Example 51 : N-(2-((3-fluoro-2-methylphenoxy)methyl)-2-methyl-7-morpholino-4- oxochroman-5-yl)methanesulfonamide

Methane sulfonylchloride(0.02 ml_, 0.25 mmol) was added to a solution 5-amino-2-((3- fluoro-2-methylphenoxy) methyl)-2-methyl-7-morpholinochroman-4-one (40 mg, 0.1 mmol) and TEA (0.03 ml_, 0.225 mmol) in DCM (5 ml_) at 0 °C. The mixture was stirred at room temperature for 2 h and diluted with DCIVlandwater.Separated organic layer was dried over anhydrous Na₂S0₄, filtered andthe filtrate was concentrated under reduced pressure. The crude compound was purified by flash chromatography using 30% ethyl acetate in petroleum ether as an eluent to afford 51 (18 mg, 38%) as a pale yellow solid. H NMR (400 5 MHz, CDCIs): δ 1 1.63 (s, 1 H), 7.07 (q, = 8.0 Hz, 1 H), 6.75 (d, J = 2.4 Hz, 1 H), 6.71 (t, J = 8.4 Hz, 1 H), 6.57 (d, J = 8.3 Hz, 1 H), 6.01 (d, = 2.4 Hz, 1 H), 4.09 (d, J = 9.6 Hz, 1 H), 3.98 (d, J = 9.6 Hz, 1 H), 3.81 (t, J = 5.0 Hz, 4H), 3.34 (t, J = 5.0 Hz, 4H), 3.08-2.99 (m, 4H), 2.73 (d, J = 17.0 Hz, 1 H), 2.09 (s, 3H), 1.54(s,3H); ESI-MS m/z: 491.33 (M+H)⁺; LCMS Purity: 94%.

10 Example 52: 1-(2-((3-Fluoro-2-methylphenoxy)methyl)-2-methyl-7-morpholino-4- oxochroman-5-yl)urea

Phenyl chlroformate(0.04 mL, 0.27 mmol) was added to a solution 5-amino-2-((3-fluoro-2- methylphenoxy) methyl)-2-methyl-7-morpholinochroman-4-one (100 mg, 0.25 mmol) and TEA (0.04 mL, 0.27 mmol) in DCM (10 mL) at 0 "Candthereactionmixture was stirred at

15 room temperature for 4 h. The reaction mixture was concentrated under reduced pressure and the resultant crude compound was added methanolic ammonia (10 mL) in a sealed tube and heated at 80 °C for 4 h. The reaction mixture was allowed to room temperature, concentrated under reduced pressure and the resultant crude compound was purified by flash chromatography using 25% ethyl acetate in petroleum ether as an eluent to afford

20 52(12 mg, 15%) as an off-white solid.¹ H NMR (300 MHz, CDCI₃): δ 11.55 (s, 1 H), 7.75 (d, J = 2.4 Hz, 1 H), 7.1 1 (q, =10.8 Hz, 1 H), 6.71 (t, J =8.7 Hz, 1 H), 6.58 (d, J =8.4 Hz, 1 H), 5.94 (d, J = 2.4 Hz, 1 H), 4.61 (s, 2H), 4.09 (d, J = 9.5 Hz, 1 H), 3.97 (d, J = 9.6 Hz, 1 H), 3.79 (t, J = 4.9 Hz, 4H), 3.36 (t, J = 4.9 Hz, 4H), 3.05 (d, J = 16.8 Hz, 1 H), 2.70 (d, J = 16.8 Hz, 1 H), 2.1 1 (s, 3H), 1.55 (s, 3H); ESI-MS m/z: 444.51 (M+H)⁺; LCMS Purity: 97%

25 Examples 53 was prepared by the following procedures described in general synthetic scheme 4

Example 54:(2-Methyl-7-morpholino-4-oxo-2-((o-tolyloxy)methyl)chroman-5- yl)boronic acid

A degassed suspension of 2-methyl-7-morpholino-4-oxo-2-((o-tolyloxy)methyl)chroman-5- yl trifluoromethanesulfonate(0.1 g, 0.19 mmol) in dioxane (10 ml_) were added PdCI₂dppf.DCM (32 mg, 0.03 mmol) and KOAc (38 mg, 0.38 mmol) in a sealed tube at room temperature. The reaction mixture was heated at 100 °C for 16 h. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The crude compound was purified by flash chromatography using 20% ethyl acetate in petroleum ether as an eluent to afford 2-methyl-7-morpholino-5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2-((o-tolyloxy)methyl)chroman-4-one(0.8 g, 84%) 54a as a white solid. ¹ H NMR (400 MHz, CDCI₃): δ 7.12 (m, 1 H), 6.89 (t, J = 1.5 Hz, 1 H), 6.77 (d, J = 8.4 Hz, 1 H), 6.51 (d, J = 2.1 Hz, 1 H), 6.24 (d, J = 2.1 Hz, 1 H), 4.10 (d, J = 9.3 Hz, 1 H), 3.99 (d, J = 9.3 Hz, 1 H), 3.82 (t, J = 4.8 Hz, 4H), 3.31 (t, J = 4.5 Hz, 4H), 3.13 (d, J = 16.8 Hz, 1 H), 2.74 (d, J = 16.8 Hz, 1 H), 2.19 (s, 3H), 1.44 (s,12H), 1 .26 (s, 3H).

Conc.HCI (10 ml_) was added to 54a (0.8 g, 0.15 mmol) in a sealed tube and heated at 100 °C for 24 h. The reaction mixture was allowed to room temperature and diluted with water extracted using ethyl acetate. Separated organic layer was dried over anhydrous Na₂S0₄, filtered and the filtrate was concentrated under reduced pressure. The crude compound was purified by mass triggered preparative HPLC method to afford 54(6 mg, 8%) as a white solid. ¹H NMR (400 MHz, CDCI₃): δ 7.65 (s, 2H), 7.40 (d, J = 2.8 Hz, 1 H), 7.12 (d, J = 7.0 Hz, 2H), 6.89 (t, J = 7.6 Hz,, 1 H), 6.77 (d, J = 8.5 Hz, 1 H), 6.35 (d, J = 2.8 Hz, 1 H), 4.1 1 (d, J = 9.5 Hz, 1 H), 3.99 (d, J = 9.5 Hz, 1 H), 3.83 (t, J = 4.8 Hz,, 4H), 3.40 (t, J = 5.2 Hz,, 4H), 3.16 (d, J = 16.8 Hz, 1 H), 2.83 (d, J = 16.8 Hz, 1 H), 2.17 (s, 3H), 1.55 (s, 3 H), ESI- MS m/z. 412.08 (M+H)⁺; LCMS Purity: 95%.

Example 55: Ethyl 2-(2-((3-fluoro-2-methylphenoxy)methyl)-2-methyl-7-morpholino- 4-oxochroman-5-yl)acetate A degassed suspension of 55a prepared similar to 54a, PdCI₂dppf.DCM (0.079 g, 0.097 mmol), ethyl bromoacetate (0.326 g, 1.95 mmol) and K₂C0₃ (0.539 g, 3.91 mmol) in dioxane (20 ml_) at room temperature. The mixture was refluxed for 5h and allowed to cool to room temperature. The reaction mixture was diluted with ethyl acetate, filtered through a pad of celite and the filtrate was washed with water. The organic layer was concentrated under reduced pressure, the resultant crude compound was purified by flash chromatography using 50% ethyl acetate in petroleum ether as eluent to afford 55 (0.3 g, 65%) as an off-white solid. LCMS Purity: 46%. Example56:2-(2-((3-fluoro-2-methylphenoxy)methyl)-2-methyl-7-morpholino-4- oxochroman-5-yl)acetic acid

2 M NaOH (1.9 mL, 3.81 mmol) was added to a solution of 55(0.3 g, 0.636 mmol) in ethanol (10 mL) at room temperature and stirred for 5 h. The reaction mixture was acidified using 2 N HCI and the resultant precipitate was filtered and dried under vacuo to afford 56(0.2 g, 69%) as an off-white solid. ¹H NMR (300 MHz, DMSO-ck): 51 1.85 (bs, 1 H), 7.15 (q, J = 8.1 Hz, 1 H), 6.81 - 6.74 (m, 2H), 6.48 (s, 1 H), 6.28 (d, J = 2.4 Hz, 1 H), 4.15 - 4.07 (m, 2H), 3.83 (d, J = 12.0 Hz, 2H), 3.68 (t, J = 4.2 Hz, 4H), 3.31 - 3.26 (m, 4H), 2.92 (d, J = 16.5 Hz, 1 H), 2.62 (d, J = 16.5 Hz, 1 H), 2.01 (d, J = 1.5 Hz, 3H), 1.43 (s, 3H) ); ESI-MS m/z: 444.41 (M+H)⁺; LCMS Purity: 93%.

Scheme 7: General Synthetic Scheme for ortho-substituted halogens

Example 58: Synthesis of 6-chloro-5-hydroxy-2-methyl-7-morpholino-2-(o- tolyloxymethyl) chroman-4-one

To a solution of 5-hydroxy-2-methyl-7-morpholino-2-(o-tolyloxymethyl)chroman-4-one (200 mg, 0.522 mmol) in carbon tetrachloride (10 ml_) were added N-chlorosuccinimide (83 mg, 0.626 mmol) and benzoyl peroxide (151 mg, 0.626 mmol) at room temperature and the reaction mixture was stirred at 85 °C for 16 h. The mixture was allowed to room temperature and concentrated under reduced pressure. The crude compound was purified by flash chromatography using 30% ethyl acetate in petroleum ether as an eluent to afford pale yellow solid (150 mg). The compound was purified by SFC purification to afford title compound 58 (20 mg, 10%) as a white solid. ¹H NMR (400 MHz, DMSO-cfe) δ 1 1.96 (s, 1 H), 7.15 - 7.06 (m, 2H), 6.9 (d, J = 8.0 Hz, 1 H), 6.83 (t, J = 7.2 Hz, 1 H), 6.15 (s, 1 H), 4.18-4.10 (m, 2H), 3.71 (t, J = 4.4 Hz, 4H), 3.18 - 3.02 (m, 6H), 1.94 (s, 3H), 1.51 (s, 3H); ESI-MS m/z: 417.90 (M+H)⁺; LCMS Purity: 97.45%. The regio isomer 58A was also isolated.

Example 59: 6-fluoro-5-hydroxy-2-methyl-7-morpholino-2-((o- tolyloxy)methyl)chroman-4-one

To a solution of 5-hydroxy-2-methyl-7-morpholino-2-((o-tolyloxy)methyl)chroman-4-one (4 g, 10.43 mmol) in acetonitrile (200 ml_) was added Selectfluor (4.4 g, 12.42 mmol) at room temperature and the reaction mixture was stirred at 85 °C for 12 h. The mixture was allowed to room temperature and concentrated under reduced pressure. The crude compound was purified by SFC purification to afford title compound 59 (0.55 g, 13%) as a white solid. ¹H NMR (300 MHz, DMSO-tf₆): δ 1 1.8 (s, 1 H), 7.14 - 7.09 (m, 2H), 6.91 (d, J = 7.8 Hz, 1 H), 6.83 (t, J = 7.5 Hz, 1 H), 5.98 (d, J = 6.3 Hz, 1 H), 4.1 1 (s, 2H), 3.69 (t, J = 4.2 Hz, 4H), 3.19 (t, J = 4.8 Hz, 4H), 3.04 (m, 2H), 1.99 (s, 3H), 1.49 (s, 3H). ESI-MS m/z: 402.2 (M+H)⁺;

Examples given below were prepared using the methodology shown above. Compound could be racemic or separated.

2H), 5.96 (d, J =

6.0 Hz, 1 H),

4.15 (s, 2H),

3.69 (t, J = 4.2

Hz, 4H), 3.21 - 3.17 (m, 4H),

3.1 1 - 2.91 (m,

2H), 1.93 (s,

3H), 1.48 (s, 3H)

General Synthetic Scheme 8:

Example 61 : Ethyl 2-(2-((3-fluoro-2-methylphenoxy)methyl)-5-hydroxy-2-methyl-7- morpholino-4-oxochroman-3-yl)acetate

HMPA (9.4 mL, 52.36 mmol) was added to a stirred solution of 2M LDA (9.4 mL, 99.68 mmol) in dry THF (20 mL) at -78 °C and stirred for 1.5 h at the same temperature. 2-((3- Fluoro-2-methylphenoxy)methyl)-5-hydroxy-2-methyl-7-morpholinochroman-4-one (1.5 g, 3.74 mmol) in dry THF (15 mL) was added drop wise over a period of 10 min at -78 °C and stirred for another 1.5 h at the same temperature. Ethylbromoacetate (1.5 mL, 8.10 mmol) was added to the solution and allowed to warm to -40 °C and stirred for 1 h. The reaction mixture was quenched with saturated NH₄CI and partitioned between ethyl acetate and water. Separated organic layer was dried over Na₂S0₄, filtered and the filtrate was concentrated under reduced pressure. The crude was purified by flash chromatography using 20% ethyl acetate in petroleum ether as an eluent to afford61(1.5 g, 55%)as an off- white solid. ¹H NMR (300 MHz, CDCI₃): δ 1 1.65 (s, 1 H), 7.2 - 7.02 (m, 1 H), 6.72 - 6.63 (m, 2H), 5.92 - 5.82 (m, 2H), 4.23 - 4.1 1 (m, 4H), 3.96 - 3.52 (m, 5H), 3.32 - 3.27 (m, 4H), 3.03 - 2.80 (m, 1 H), 2.36 - 2.31 (m, 1 H), 2.17 (s, 2H), 1.96 (s, 1 H), 1.63 (s, 1 H), 1.56 - 1.37 (m, 3H), 1.37 (s, 2H); ESI-MS m/z 488.27 (M+H)⁺; LCMS Purity: 92%.

Example 62: 2-((3-fluoro-2-methylphenoxy)methyl)-5-hydroxy-2,3-dimethyl-7- morpholinochroman-4-one

This was prepared similarly to 49 except Methyl iodide was used instead of Ethylbromoacetate to afford 62(3.5 g, 84%) as an off-white solid. ¹H NMR (300 MHz, CDCI₃): δ 1 1.98 (s, 1 H), 7.08 (q, J = 8.1 Hz, 1 H), 6.69 (t, J = 8.7 Hz, 1 H), 6.61 (d, J = 8.1 Hz, 1 H), 5.92 (d, J = 2.4 Hz, 1 H), 5.86 (d, J = 2.1 Hz, 1 H), 4.16 - 4.06 (m, 1 H), 4.0 (d, J = 10.2 Hz, 1 H), 3.79 (t, J = 4.8 Hz, 4H), 3.30 (t, J = 5.1 Hz, 4H), 3.26 - 3.2 (m, 1 H), 2.13 (s, 2H), 2.0 (s, 1 H), 1.39 (s, 3H), 1.25 (d, J = 6.9 Hz, 3H); ESI-MS m/z 415.85 (M+H)⁺; LCMS Purity: 95%.

Example 63: 2-(2-((3-Fluoro-2-methylphenoxy)methyl)-5-hydroxy-2-methyl-7- morpholino-4-oxochroman-3-yl)acetic acid

2 M NaOH (20 ml_, 40 mmol) was added to a solution ofsolution of Methyl 3-(2-ethoxy-2- oxoethyl)-2-((3-fluoro-2-methylphenoxy)methyl)-2-methyl-7-morpholino-4-oxochroman-5- carboxylate (1.2 g, 2.46 mmol) in ethanol (20 ml_) at room temperature and stirred for 5 h. The reaction mixture was acidified using 2 N HCI and the resultant precipitate was filtered and dried under vacuumto afford63(1.0 g, 88%) as an off-white solid.¹ H NMR (400 MHz, CDCI₃): δ 1 1.56 (s, 1 H), 7. 06 (m, 1 H), 6.66 - 6.60 (m, 2H), 5.92 - 5.82 (m, 2H), 4.14 - 3.97 (m, 2H), 3.82 - 3.53 (m, 4H), 3.57 - 3.54 (m, 1 H), 3.36 - 3.28 (m, 4H), 2.95 - 2.86 (m, 1 H), 2.52 - 2.35 (m, 1 H), 2.09 (s, 3H), 1.37 (s, 3H); ESI-MS m/z 460.28 (M+H)⁺; LCMS Purity: 99%.

Example 64: 2-(2-((3-Fluoro-2-methylphenoxy)methyl)-5-hydroxy-2-methyl-7- morpholino-4-oxochroman-3-yl)acetamide A mixture of 2-(2-((3-fluoro-2-methylphenoxy)methyl)-5-hydroxy-2-methyl-7-morpholino-4- oxochroman-3-yl)acetic acid(1 g, 2.17 mmol), ammonium chloride (0.577 g, 10.89 mmol), HATU (1.24 g, 3.26 mmol) and DIPEA (0.78 mL, 4.35 mmol) in THF (20 ml_)was stirred at room temperature for 6 h. The reaction mixture was concentrated under reduced pressure and the resulting crude compound was partitioned between ethyl acetate and water. Separated organic layer was dried over anhydrous Na₂S0_4, filtered and the filtrate was concentrated under reduced pressure. The crude compound was purified by flash chromatography using 15% ethyl acetate in petroleum ether as an eluent to afford 64 (0.6 g, 60%) as a red solid.¹H NMR (300 MHz, CDCI₃): δ 11.65 (s, 1H), 7.1 - 7.02 (m, 1H), 6.72 - 6.45 (m, 2H), 6.06 (bs, 1 H), 5.94 - 5.80 (m, 2H), 5.39 (bs, 1 H), 4.23 - 4.03 (m, 2H), 3.95-3.55 (m , 5H), 3.38-3.27 (m, 4H), 2.83 - 2.67 (m, 1 H), 2.41 -2.33 (m, 1H), 2.17 (s, 2H), 1.91 (s, 1H), 1.67 (s, 1H), 1.38 (s, 2H); ESI-MS m/z: 459.22 (M+H)⁺; LCMS Purity: 97%.

Isomer 64-1: ¹H NMR (300 MHz, CDCI₃): δ 11.65 (d, J= 8.8 Hz, 1H), 7.06 (d, J= 7.5 Hz, 1H), 6.67 (t, J= 8.4 Hz, 1H), 6.49 (d, J= 8.3 Hz, 1H), 6.06 (s, 1H), 5.87 (d, J= 16.8 Hz, 2H), 5.41 (s, 1H), 4.21 (d, J= 10.4 Hz, 1H), 4.05 (d, J=4.7 Hz, 1H), 3.80-3.76 (t, J=4.5 Hz , 4H), 3.59 (d, J= 6.6 Hz, 1H), 3.31 (t, J= 4.5 Hz, 4H), 2.82 (d, J= 3.8 Hz, 1H), 2.38 (d, J= 3.8 Hz, 1H), 2.06 (s, 3H), 1.52 (s, 3H).

Isomer 64-2: ¹H NMR (300 MHz, CDCI₃): δ 11.62 (s, 1 H), 7.03 (d, J = 7.5 Hz, 1 H), 6.66 (t, J= 8.4 Hz, 1H), 6.49 (d, J= 8.3 Hz, 1H), 6.06 (s, 1H), 5.85 (d, J= 16.8 Hz, 2H), 5.39 (s, 1H), 4.18 (d, J= 10.4 Hz, 1H), 4.02 (d, J= 4.7 Hz, 1H), 3.78 - 3.76 (t, J= 4.5 Hz , 4H), 3.56 (d, J= 6.6 Hz, 1H), 3.31 (t, J= 4.5 Hz, 4H), 2.78 (d, J= 3.8 Hz, 1H), 2.36 (d, J= 3.8 Hz, 1H), 2.06 (s, 3H), 1.49 (s, 3H).

Examples 65-76 were prepared by the procedures described in scheme 8

300 MHz, DMSO-cfe: δ 12.28

3-cyclopropyl- (s, 1H), 7.16 - 7.09 (m, 2H), 5-hydroxy-2- 6.97 - 6.80 (m, 2H), 5.95 -

71 methyl-7- 5.90 (m, 2H), 4.18-4.05 (m,

morpholino-2- 2H), 3.80 - 3.62 (m, 4H), 424.37

(0- 3.22 -2.92 (m, 5H), 2.04 (s, tolyloxymethyl) 1H), 1.95 (s, 2H), 1.56 - chroman-4-one 1.35 (m, 4H), 0.92 - 0.78 (m,

2H), 0.63- 0.49 (m, 2H)

300 MHz, DMSO-cfe: δ 11.82

(s, 1H), 7.42 (bs, 1H), 7.35

2-(5-hydroxy-2- (bs, 1H), 7.20 - 7.01 (m, methyl-7- 2H), 6.95 - 6.75 (m, 2H),

72 OH 0°Y^NH2 morpholino-4- 5.97 (s, 1H), 5.91 (s, 1H),

oxo-2-(o- 4.17 - 4.05 (m, 2H), 3.68 - 441.4 tolyloxymethyl) 3.55 (m, 4H), 3.42 - 3.22 (m, chroman-3- 5H), 2.75 - 2.63 (m, 1H), yl)acetamide 2.28-2.18 (m, 1H), 2.16 (s,

2H), 1.83 (s, 1H), 1.53 (s, 1H), 1.28 (s, 2H)

400 MHz, CDCI₃: δ 11.67 (s, 1H), 7.18 - 7.12 (m, 2H),

2-(5-hydroxy-2- 6.89 (t, J= 8.0 Hz, 1H), 6.84 methyl-7- (d, J= 7.6 Hz, 1H), 5.99 (bs,

72-1 OH 0°Y^NH2 morpholino-4- 1H), 5.91 (d, J=2.4 Hz, 1H),

oxo-2-(o- 5.86 (d, J = 2.0 Hz, 1H), 441.4 tolyloxymethyl) 5.27 (bs, 1H), 4.22 (d, J = chroman-3- 10.4 Hz, 1H), 4.09 (d, J = yl)acetamide 10.0 Hz, 1H), 3.96 (dd, J =

8.4, 3.2 Hz, 1H), 3.79 (t, J =

4.8 Hz, 4H), 3.34 - 3.29 (m, 4H), 2.66 (dd, J = 14.4, 8.4

Hz, 1H), 2.43 (dd, J = 14.4, 3.2 Hz, 1H), 2.26 (s, 3H), 1.38 (s, 3H)

400 MHz, CDCI₃: δ 11.65 (s, 1H), 7.12 - 7.05 (m, 2H), 6.85 (t, J =7.2 Hz, 1H), 6.67

(d, J= 8.0 Hz, 1H), 6.02 (bs,

2-(5-hydroxy-2- 1H), 5.87 (d, J=2.4 Hz, 1H), methyl-7- 5.82 (d, J = 3.2 Hz, 1H),

72-2 OH o° ^NH2 morpholino-4- 5.32 (bs, 1H), 4.08 (d, J =

oxo-2-(o- 10.4 Hz, 1H), 4.00 (d, J = 441.4 tolyloxymethyl) 10.4 Hz, 1H), 3.78 (t, J= 5.6 chroman-3- Hz, 4H), 3.60 (dd, J= 9.2, yl)acetamide 3.2 Hz, 1H), 3.28 (t, J = 4.4

Hz, 4H), 2.87 - 2.76 (m, 1H), 2.35 (dd, J = 15.2, 2.8

Hz, 1H), 2.01 (s, 3H), 1.68

(s, 3H)

400 MHz, CDCI₃: δ 11.55 (s,

2-(5-hydroxy-2- 1H), 7.21 - 7.08 (m, 2H), methyl-7- 6.95 - 6.71 (m, 2H), 5.95 -

73 morpholino-4- 5.81 (m, 2H), 4.28 - 4.02

oxo-2-(o- (m, 2H), 3.82 - 3.61 (m, 5H), 423.05

prepared by dehydration tolyloxymethyl) 3.35 - 3.08 (m, 5H), 2.91 - of corresponding amide chroman-3- 2.62 (m, 1H), 2.25 (s, 2H),

yl)acetonitrile 2.07 (s, 1H), 1.74 (s, 1H),

1.49 (s, 2H).

methyl)-5- 1H), 6.59 (d, J= 8.4 Hz, 1H),

Following examples were prepared using the procedures described in scheme 4&8

Mass

(M+H)

Example Structure Nomenclature ¹H NMR values or

(M-H) ο °γ^ΟΗ 2-(2-((3-Fluoro- ^ηΗ NMR (400 MHz, CDCI₃): δ

77 2- 7.75 - 7.68 (m, 1 H), 7.14 - 443.93 methylphenoxy) 6.85 (m, 1 H), 6.7 (t, J = 8.8

cheme 9: General Synthetic Scheme

Example 80: 3-(Carboxymethyl)-2-((3-fluoro-2-methylphenoxy)methyl)-2-methyl-7- morpholino-4-oxochroman-5-carboxylic acid

PdCI2(dppf) (0.1 17 g, 0,161 mmol) was added to a degassed solution of methyl 2-((3- fluoro-2-methylphenoxy)methyl)-2-methyl-7-morpholino-4-oxo-5-

(((trifluoromethyl)sulfonyl)oxy)chromane-3-carboxylate (0.5 g, 0.845mmol) (which was prepared by known methods) and TEA (0.16 ml, 1.614 mmol) in methanol (20 mL). The reaction mixture was carbonized in a steal bomb under 120 psi CO gas pressure at 100 °C for 8 h. The reaction mixture was concentrated under reduced pressure and the crude compound was purified by flash chromatography using 30% ethyl acetate in petroleum ether as an eluent to affordmethyl 3-(2-ethoxy-2-oxoethyl)-2-((3-fluoro-2- methylphenoxy)methyl)-2-methyl-7-morpholino-4-oxochroman-5-carboxylate(0.3 g, 71 %) as a pale yellow solid.¹H NMR (300 MHz, CDCI₃): δ 7.1 - 7.08 (m, 1 H), 6.76 - 6.56 (m, 2H), 6.45 (d, J = 2.0 Hz, 1 H), 6.30 (d, J = 2A Hz, 1 H), 4.21 (d, J = 7.5 Hz, 1 H), 4.01 - 3.94 (m, 4H), 3.90 (s, 3H), 3.81 - 3.79 (m, 4H), 3.31 - 3.27 (m, 4H), 3.01 - 2.95 (m, 1 H), 2.28 - 2.27 (m, 1 H), 2.16 (s, 3H), 1.35 (s, 3H), 1.24 (t, J = 5.4 Hz, 3H); ESI-MS m/z. 530.29 (M+H)⁺; LCMS Purity: 79%. 3-(Carboxymethyl)-2-((3-fluoro-2-methylphenoxy)methyl)-2-methyl-7-morpholino-4- oxochroman-5-carboxylic acid80was synthesized using procedure in scheme 8. yield 77 %,off-white solid.¹H NMR (300 MHz, DMSO-cfe) δ 12.85 (s, 1 H) , 12.20 (s, 1 H), 7.2 - 7.09 (m, 1 H), 6.89 - 6.69 (m, 2H), 6.53 - 6.48 (m, 1 H), 6.39 - 6.33 (m, 1 H), 4.30 - 4.10 (m, 2H), 3.85 - 3.83 (m, 1 H), 3.65 - 3.72 (m, 4H), 3.28 - 3.40 (m, 4H), 2.7 - 2.75 (m, 1 H), 2.33 - 2.27 (m, 1 H), 2.07 (s, 3H), 1.22 (s, 3H); ESI-MS m/z 486.39 (M+H)⁺; LCMS Purity: 85%.

Example 81 : 3-(2-Amino-2-oxoethyl)-2-((3-fluoro-2-methylphenoxy)methyl)-2-methyl- 7-morpholino-4-oxochroman-5-carboxamide

A mixture of 3-(carboxymethyl)-2-((3-fluoro-2-methylphenoxy)methyl)-2-methyl-7- morpholino-4-oxochroman-5-carboxylic acid(0.21 g, 0.43 mmol), ammonium chloride (0.1 14 g, 2.15 mmol), HATU(0.328 g, 0.86 mmol) and DIPEA (0.1 1 mL, 0.86 mmol) in THF (5 mL) was stirred at room temperature for 6 h. The reaction mixture was concentrated under reduced pressure and partitioned between ethyl acetate and water. The organic layer was separated and dried over anhydrous Na₂S0_4, filtered and the filtrate was concentrated under reduced pressure. The crude compound was purified by mass triggered method to afford 81(0.1 g, 46%) as pale green solid.1 H NMR (300 MHz, DMSO- cfe): δ 7.38 (bs, 2H), 7.30 (bs, 2H), 7.22 - 7.10 (m, 1 H), 6.90 - 6.62 (m, 2H), 6.42 - 6.32 (m, 2H), 4.19 - 4.16 (m, 2H), 3.81 - 3.76 (m, 1 H), 3.67 (m, 4H), 3.3 - 3.4 (m, 4H), 2.72 (m, 1 H), 2.27 (m, 1 H), 2.09 (s, 3H), 1.24 (s, 3H); ESI-MS m/z 485.94 (M+H)⁺; LCMS Purity: 96%.

Examples 82-91were prepared by the procedures described above mainly in general synthetic scheme 2, 5, 8 and 9

1.02 (m, 3H)

400 MHz, CDCI₃: δ 7.20 - 7.04 (m, 2H), 7.00 - 6.78

2,3-dimethyl-7- (m, 2H), 6.36 - 6.20 (m, morpholino-4- ° 2H), 4.19 - 4.01 (m, 2H),

oxo-2-(o- 3.75 - 3.51 (m, 4H), 3.53 - 425.92 tolyloxymethyl)

2.65 (m 5H), 2.14 (s, 2H), chroman-5- 1.99 (s, 1 H), 1.53 (s, 1 H), carboxylic acid

1.26 (s, 2H), 1.15 - 1.01

(m, 3H)

400 MHz, CDCI₃: δ 7.15 - 6.98 (m, 1 H), 6.75 - 6.45

2-((3-fluoro-2- (m, 3H), 6.31 - 6.24 (m, methylphenoxy

1 H), 5.81 (bs, 2H), 4.18 -

)methyl)-2,3- 3.98 (m, 2H), 3.80 (t, J = dimethyl-7- 442.98

4.8 Hz, 4H), 3.38 - 3.28 morpholino-4- (m, 5H), 2.13 (s, 2H), 2.01 oxochroman-5- (s, 1 H), 1.62 (s, 1 H), 1.36 carboxamide

(s, 2H), 1.30 - 1.18 (m, 3H)

2-((3-fluoro-2- ^ηΗ NMR (400 MHz, methylphenoxy CDCI₃): δ 7.10 - 7.03 (m,

)methyl)-2,3- 1 H), 6.86 (dd, J = 8.8, 2.4 dimethyl-7- Hz, 1 H), 6.72 - 6.51 (m,

N morpholino-4- 2H), 6.41 (dd, J = 12.0, 2.4

oxochromane- Hz, 1 H), 4.15 -4.02 (m, 424.82

5-carbonitrile 2H), 3.83 (t, J = 4.8 Hz,

4H), 3.32 - 3.28 (m, 4H), 2.92 (q, J = 6.8 Hz, 1 H), 2.12 (d, J = 1.6 Hz, 2H), 1.95 (d, J = 1.6 Hz, 1 H),

)methyl)-2- (s, 1H), 6.76 - 6.70 (m,

Scheme 10: General Synthetic Scheme

n-BuLi, -78 C, 4h Example 92: Synthesis of 2-((3-fluoro-2-methylphenoxy)methyl)-5-hydroxy-3- (hydroxymethyl)-2-methyl-7-morpholinochroman-4-one

To a stirred solution of n-butyllithium(1.6 M) (4.67 mL, 7.47 mmol) in anhydrous THF (15 mL) was added dropwise 2,2,6,6-tetramethylpiperidine (1.05 g, 7.47 mmol) at -10 °C. The solution was allowed to stirred at 0 °C for 30 minutes then cooled to -78 °C. 2-((3-fluoro-2- methylphenoxy)methyl)-5-hydroxy-2-methyl-7-morpholinochroman-4-one (1.0 g, 2.49 mmol) in anhydrous THF (10 mL) was added dropwise and stirred for an additional 1 hour. 1 H-benzotriazole- methanol (0.55 g, 3.74 mmol) in anhydrous THF (20 mL) was added dropwise over a period of 30 minutes and kept 2 hours at this temperature. The reaction was quenched with Sat.NH₄CI and diluted with ethyl acetate (50 mL). The organic layer was dried over Na₂S04, filtered, and concentrated in vacuo. The crude compound was purified by Grace column chromatography (C-18 Reverse phase column), using 60% (0.1 % FA) acetonitrile in (0.1 % FA) water as an eluent to afford 92 (430 mg, 40%) as an off white solid. lsomer-92-1 : ¹H NMR (300 MHz, DMSO-tf₆):512.01 (bs, 1 H), 7.21 -7.1 1 (m, 1 H), 6.85-6.71 (m, 2H), 5.97 (d, J = 2.1 Hz, 1 H), 5.92 (d, J = 2.1 Hz, 1 H), 4.85 (t, J = 5.4 Hz, 1 H), 4.28 - 4.15 (m, 2H), 3. 87 - 3.75 (m, 2H), 3.64 (t, J = 4.5 Hz, 4H), 3.29 (t, J = 4.5 Hz, 4H), 2.91 (t, J = 5.4 Hz, 1 H), 1.95 (d, J = 1.8 Hz, 3H), 1.58 (s, 3H) lsomer-92-2: ¹H NMR (300 MHz, DMSO-tf₆):512.02 (bs, 1 H), 7.21 -7.1 1 (m, 1 H), 6.85-6.71 (m, 2H), 5.97 (d, J = 2.1 Hz, 1 H), 5.92 (d, J = 2.1 Hz, 1 H), 4.81 (t, J = 5.7 Hz, 1 H), 4.28 - 4.15 (m, 2H), 3. 87 - 3.75 (m, 2H), 3.64 (t, J = 4.5 Hz, 4H), 3.29 (t, J = 4.5 Hz, 4H), 2.91 (t, J = 5.4 Hz, 1 H), 1.95 (d, J = 1.8 Hz, 3H), 1.58 (s, 3H).

cheme 11 : General Synthetic Scheme

Example 93: Synthesis of 2-((3-fluoro-2-methylphenoxy)methyl)-5-hydroxy-2- methyl-7-morpholino-2H-benzo[e][1,3]oxazin-4(3H)-one A mixture of compound-A (1.5 g, 6.329 mmol), compound-B (1.72 g, 9.49 mmol) and piperidine (1.61 g, 18.98mmol) in toluene (50 ml_) was stirred at 120 °C for 16 h. The reaction mixture was concentrated under reduced pressure and the resulting crude compound was purified by flash chromatography using 30% ethyl acetate in petroleum ether as an eluent to afford compound 93(1.3 g, 51 %) as an off-white solid. ¹H NMR (300 MHz, DMSO-tf₆): δ 1 1.78 (bs, 1 H), 8.82 (s, 1 H), 7.12 (q, J = 8.1 Hz, 1 H), 6.81 - 6.71 (m, 2H), 5.96 (d, J = 1.8 Hz, 1 H), 5.92 (d, J = 1.8 Hz, 1 H), 4.15 - 4.02 (m, 2H), 3.65 (t, J = 4.5 Hz, 4H), 3.18 (t, J = 4.2 Hz, 4H), 1.95 (d, J = 1.5 Hz, 3H), 1.64 (s, 3H); ESI-MS m/z. 403.03 (M+H)⁺; LCMS Purity: 95%.

Example 94a:Synthesis of 2-((3-fluoro-2-methylphenoxy)methyl)-5-methoxy-2,3- dimethyl-7-morpholino-2H-benzo[e][1,3]oxazin-4(3H)-one To a solution of Compound 93 (0.5 g, 1243 mmol) in THF (15 ml_) was added 60% NaH (0.15 g, 6.21 mmol) at 0 °C and followed by addition of methyl iodide (0.35 ml_, 2.48 mmol) at 0 °C .The reaction mixture was stirred at room temperature for 2 h. The mixture was cooled to 0 °C and quenched with water and extracted with ethyl acetate, the organic layer was dried over anhydrous Na₂S0_4, filtered and the filtrate was concentrated under reduced pressure. The crude compound was purified by flash chromatography using 20% ethyl acetate in petroleum ether as an eluent to afford 94a(0.2 g, 37%) as a white solid. ESI-MS m/z: 431.15 (M+H)⁺; LCMS Purity: 66%.

Example 94: Synthesis of 2-((3-fluoro-2-methylphenoxy)methyl)-5-hydroxy-2,3- dimethyl-7-morpholino-2H-benzo[e][1,3]oxazin-4(3H)-one

BCI₃ (2M in DCM, 0.87 ml_, 1.74 mmlo) was added to a solution of compound-94a (0.15 g, 0.35 mmol) in DCM at 0 °C and stirred for 2 h at room temperature. The reaction mixture was quenched with NaHC03 and diluted with DCM. The separated organic layer was dried over anhydrous Na₂S0_4, and filtered, the filtrate was concentrated under reduced pressure to afford crude compound. The compound was purified by flash chromatography using 50% ethyl acetate in petroleum ether as eluent to afford 94(50 mg, 34%). ¹H NMR (400 MHz, DMSO-tf₆): δ 1 1.82 (bs, 1 H), 7.13 (q, J = 7.6 Hz, 1 H), 6.81 - 6.74 (m, 2H), 5.97 (s, 1 H), 5.92 (s, 1 H), 4.32 (d, J = 12.0 Hz, 1 H), 4.23 (d, J = 10.4 Hz, 1 H), 3.64 (t, J = 4.8 Hz, 4H), 3.21 - 3.16 (m, 4H), 3.03 (s, 3H), 1.93 (s, 3H), 1.76 (s, 3H); ESI-MS m/z: 417.43 (M+H)⁺; LCMS Purity: 84%.

Example 95a: Synthesis of ethyl 2-(5-(2-ethoxy-2-oxoethoxy)-2-((3-fluoro-2- methylphenoxy)methyl)-2-methyl-7-morpholino-4-oxo-2H-benzo[e][1,3]oxazin-3(4H)- yl)acetate

To a solution of Compound 93 (0.3 g, 1.25 mmol) in THF (25 ml_) was added NaH (0.2 g, 6.25 mmol) at 0 °C and followed by addition of ethyl bromoacetate (0.30 g, 1.87 mmol) at 0 °C The reaction mixture was stirred at room temperature for 8 h. The mixture was cooled to 0 °C and quenched with water and extracted with ethyl acetate, the organic layer was dried over anhydrous Na₂S0_4, filtered and the filtrate was concentrated under reduced pressure. The crude compound was purified by flash chromatography using 50% ethyl acetate in petroleum ether as an eluent to afford 95a(0.2 g, 46%)as a white solid. ¹H NMR (300 MHz, DMSO-ck): δ 7.1 1 (m, 1 H), 6.82 - 6.64 (m, 2H), 6.21 (s, 1 H), 6.03 (s, 1 H), 4.32 - 4.18 (m, 4H), 4.17 - 4.04 (m, 6H), 3.67 (m, 4H), 3.30 - 3.15 (m, 4H), 2.01 (s, 3H), 1.78 (s, 3H), 1.20 (t, J = 1.2 Hz, 6H); ESI-MS m/z. 575.2 (M+H)⁺. Example 95: Synthesis of 2-(2-((3-fluoro-2-methylphenoxy)methyl)-5-hydroxy-2- methyl-7-morpholino-4-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)acetic acid

BBr3 (2M in DCM, 0.87 ml_, 1.74 mmol) was added to a solution of Compound-95a (0.2 g, 0.348 mmol) in DCM at 0 °C and stirred for 16 h at room temperature. The reaction mixture was quenched with NaHC0₃ solution and diluted with DCM. The separated organic layer was dried over anhydrous Na₂S0_4, filtered and the filtrate was concentrated under reduced pressure. The crude compound was purified by flash chromatography using 80% ethyl acetate in petroleum ether as eluent to afford 95(0.016 g, 10%) as a white solid. ¹H NMR (300 MHz, CD₃OD): δ 8.55 (bs, 1 H), 7.04 (q, J = 8.1 Hz, 1 H), 6.66 - 6.60 (m, 2H), 5.98 (d, J = 2.1 Hz, 1 H), 5.89 (d, J = 2.4 Hz, 1 H), 4.38 (d, J = 17.1 Hz, 1 H), 4.31 - 4.23 (m, 2H), 3.93 (d, J = 17.1 Hz, 1 H), 3.75 (t, J = 4.8 Hz, 4H), 3.18 (t, J = 5.1 Hz, 4H), 2.03 (d, J = 1.2 Hz, 3H), 1.87 (s, 3H); ESI-MS m/z. 461.24 (M+H)⁺; LCMS Purity: 99%.

Scheme 12: General Synthetic Scheme

Example 96a: Ethyl 2-(2-((3-fluoro-2-methylphenoxy)methyl)-5-hydroxy-2,3-dimethyl- 7-morpholino-4-oxochroman-3-yl)acetate HMPA (21.25 mL, 122.1 mmol) was added to a stirred solution of LDA (2M in THF, 21.06 mL, 42.12 mmol) in dry THF (20 mL) at -78 °C and stirred for 1.5 h at the same temperature. Compound 62 (3.5 g, 8.42 mmol) in dry THF (20 mL) was added drop wise over a period of 10 min at -78 °C and stirred for another 1.5 h at the same temperature. Ethyl bromoacetate (2.09 mL, 21.06 mmol) was added to the solution and allowed to warm to -40 °C and stirred for 1 h. The reaction mixture was quenched with saturated NH₄CI and partitioned between ethyl acetate and water. Separated organic layer was dried over Na₂S0₄, filtered and the filtrate was concentrated under reduced pressure. The crude was purified by flash chromatography using 20% ethyl acetate in petroleum ether as an eluent to afford 96a(3.1 g, 73%) as an off-white solid.¹H NMR (300 MHz, CDCI₃): δ 1 1 .78 (s, 1 H), 7.02 (q, J = 8.4 Hz, 1 H), 6.65 (t, J = 8.4 Hz, 1 H), 6.48 (d, J = 8.4 Hz, 1 H), 5.91 (s, 1 H), 5.82 (s, 1 H), 4.21 - 3.95 (m, 4H), 3.85 - 3.75 (m, 4H), 3.35 - 3.23 (m, 4H), 2.82 (d, J = 12.9 Hz, 1 H), 2.53 (d, J = 12.9 Hz, 1 H), 2.01 (s, 3H), 1.49 (s, 3H), 1.41 (s, 3H), 1.17 (t, J = 6.9 Hz, 3H); ESI-MS m/z. 501 .9 (M+H)⁺; LCMS Purity: 94%.

Example 96:2-(2-((3-fluoro-2-methylphenoxy)methyl)-5-hydroxy-2,3-dimethyl-7- morpholino-4-oxochroman-3-yl)acetic acid

2 M NaOH (21 ml_, 41.87 mmol) was added to a solution of compound 96a (2.1 g, 4.18 mmol) in ethanol (20 ml_) at room temperature and stirred for 24 h. The reaction mixture was acidified using 2 N HCI and the resultant precipitate was filtered and dried under vacuo to afford 96(1.8 g, 91 %) as an off-white solid as diastereomers. The major isomer 96-1 was easily isolated. ¹H NMR (400 MHz, DMSO-cfe): δ 12.19 (s, 1 H), 1 1.88 (s, 1 H), 7.10 (q, J = 8.1 Hz, 1 H), 6.81 - 6.7 (m, 2H), 5.93 (d, J = 2.0 Hz, 1 H), 5.91 (d, J = 2.0 Hz, 1 H), 4.22 (d, J = 1 1.2 Hz, 1 H), 4.14 (d, J = 1 1.6 Hz, 1 H), 3.63 (t, J = 5.2 Hz, 4H), 3.27 (t, J = 4.8 Hz, 4H), 2.58 - 2.44 (m, 2H), 1.86 (s, 3H), 1.48 (s, 3H), 1.31 (s, 3H); ESI-MS m/z:473.87 (M+H)⁺; LCMS Purity: 96.2%. Minor diasteromer96-2 was also isolated using chiral separation

Example 97:2-(2-((3-fluoro-2-methylphenoxy)methyl)-5-hydroxy-2,3-dimethyl-7- morpholino-4-oxochroman-3-yl)acetamide

A mixture of Compound96 (1.6 g, 3.37 mmol), ammonium chloride (0.903 g, 16.89 mmol), HATU (1.92 g, 5.06 mmol) and DIPEA (1.81 ml_, 10.13 mmol) in THF (10 ml_) was stirred at room temperature for 6 h. The reaction mixture was concentrated under reduced pressure and the resulting crude compound was partitioned between ethyl acetate and water. Separated organic layer was dried over anhydrous Na₂S0_4, filtered and the filtrate was concentrated under reduced pressure. The crude compound was purified by flash chromatography using 30% ethyl acetate in petroleum ether as an eluent to afford 97 (1.3 g, 82%) as an off-white solid. ¹H NMR (300 MHz, , DMSO-cfe): δ 1 1.88 (s, 1 H), 7.26 (bs, 1 H), 7.10 (q, J = 8.1 Hz, 1 H), 6.77 (bs, 1 H), 6.76 - 6.69 (m, 2H), 5.92 (d, J = 1.8 Hz, 1 H), 5.89 (d, J = 2.4 Hz, 1 H), 4.2 (d, J = 1 1.4 Hz, 1 H), 4.14 (d, J = 1 1.1 Hz, 1 H), 3.64 (t, J = 5.1 Hz, 4H), 3.25 (t, J = 4.5 Hz, 4H), 2.47 - 2.36 (m, 2H), 1.88 (s, 3H), 1.47 (s, 3H), 1.30 (s, 3H); ESI-MS m/z:472.82 (M+H)⁺; LCMS Purity: 98%.

Example 98: 2-(2-((3-fluoro-2-methylphenoxy)methyl)-5-hydroxy-2,3-dimethyl-7- morpholino-4-oxochroman-3-yl)acetonitrile

Triflic anhydride (0.1 mL, 0.63 mmol) was added to a solution of 2-(2-((3-fluoro-2- methylphenoxy)methyl)-5-hydroxy-2,3-dimethyl-7-morpholino-4-oxochroman-3- yl)acetamide (0.2 g, 0.42 mmol) and pyridine (0.07 mL, 0.846 mmol) in DCM (5 mL) at 0 °C and stirred for same temperature for 30 min. The reaction mixture was diluted with dichloromethane and washed with water. The separated organic layer was dried over anhydrous Na₂S0₄, filtered and the filtrate was evaporated under reduced pressure. The crude compound was purified by flash chromatography using 20-25% ethyl acetate in petroleum ether as an eluent to afford 2-(2-((3-fluoro-2-methylphenoxy)methyl)-5-hydroxy- 2,3-dimethyl-7-morpholino-4-oxochroman-3-yl)acetonitrile98 (75 mg, 39%) as an off-white solid. . ¹H NMR (400 MHz, CDCI₃): δ 1 1.62 (s, 1 H), 7.08 (q, J = 7.6 Hz, 1 H), 6.70 (t, J = 8.4 Hz, 1 H), 6.58 (d, J = 8.4 Hz, 1 H), 5.93 (d, J = 1.6 Hz, 1 H), 5.84 (d, J = 2.0 Hz, 1 H), 4.26 (d, J = 9.6 Hz, 1 H), 4.09 (d, J = 10.4 Hz, 1 H), 3.79 (t, J = 4.8 Hz, 4H), 3.25 (t, J = 4.8 Hz, 4H), 2.92 - 2.79 (m, 2H), 2.08 (s, 3H), 1.62 (s, 3H), 1.47 (s, 3H); ESI-MS m/z:454.81 (M+H)⁺; LCMS Purity: 99%.

Example 99: 3-((1 H-tetrazol-5-yl)methyl)-2-((3-fluoro-2-methylphenoxy)methyl)-5- hydroxy-2,3-dimethyl-7-morpholinochroman-4-one

To a solution of 98(1 g, 2.2 mmol) in THF (10 mL) were added TMS azide (1.48 mL, 1 1.36 mmol) and 1 M TBAF (3.4 mL, 3.4 mmol) at 0 °C and the reaction mixture was irradiated with microwave irradiation at 1 10 °C for 1 h. The mixture was cooled to room temperature and poured into ice water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na₂S0_4, filtered and the filtrate was concentrated under reduced pressure. The crude compound was purified by flash chromatography using 80% ethyl acetate in petroleum ether as an eluent to afford 99(0.6 g, 55%) as a white solid. ¹H NMR (300 MHz, DMSO-tf₆):□ 16.02 (bs, 1 H), 1 1.60 (s, 1 H), 7.10 (q, J = 8.1 Hz, 1 H), 6.78 - 6.70 (m, 2H), 5.94 (s, 2H), 4.19 (q, J = 14.8 Hz, 2H), 3.65 (t, J = 3.9 Hz, 4H), 3.32 - 3.21 (m, 4H), 2.56 - 2.43 (m, 2H), 1.82 (s, 3H), 1.61 (s, 3H), 1.25 (s, 3H); ESI-MS m/z:498.1 (M+H)⁺

Scheme 13: General Synthetic Scheme

Example 100: 2-(6-fluoro-2-((3-fluoro-2-methylphenoxy)methyl)-5-hydroxy-2,3- dimethyl-7-morpholino-4-oxochroman-3-yl)acetic acid To a solution of 2-(2-((3-fluoro-2-methylphenoxy)methyl)-5-hydroxy-2,3-dimethyl-7- morpholino-4-oxochroman-3-yl)acetic acid (4 g, 8.45 mmol) in acetonitrile (100 mL) was added Selectfluor (3.17 g, 8.96 mmol) at room temperature and the reaction mixture was stirred at 85 °C for 16 h. The mixture was allowed to room temperature and concentrated under reduced pressure. The crude compound was purified by SFC purification to afford title compound 100and regioisomer101 (1.0 g, 24%) as a white solid. ¹H NMR (400 MHz, DMSO-tf₆): 512.3 (bs, 1 H), 1 1.58 (bs, 1 H), 7.10 (q, J = 8.0 Hz, 1 H), 6.78 (d, J = 8.4 Hz, 1 H), 6.74 (t, J= 8.8 Hz, 1 H), 5.92 (d, J = 6.4 Hz, 1 H), 4.26 (d, J = 1 1.2 Hz, 1 H), 4.16 (d, J = 1 1.2 Hz, 1 H), 3.68 (t, J = 4.4 Hz, 4H), 3.17 (t, J = 4.4 Hz, 4H), 2.55 (d, J = 12.8 Hz, 2H), 1.81 (d, J = 0.8 Hz, 3H), 1.48 (s, 3H), 1.32 (s, 3H). LCMS Purity: 91.6%.Chiral purity: 99.6%

Examples 96-2, 101-104were prepared by the procedures described in general synthetic schemes12-13.

(m, 4H), 2.61 - 2.54 (m, 2H), 1.81

(d, J = 1.5 Hz, 3H), 1.54 (s, 3H), 1.34

(s, 3H).

2-(2-((3-fluoro-2- ¹H NMR (400 MHz, methylphenoxy)methyl)- DMSO-tf₆): δ 8.83

5 -hy d roxy -2 , 3 -d i m ethy I - (bs, 1 H), 7.12 (q, J

7-morpholino-4- = 8.1 Hz, 1 H), 6.79 oxochroman-3-yl)-N,N- - 6.73 (m, 2H), dimethylacetamide 5.94 (dd, J = 9.0,

OH O

2.4 Hz, 2H), 4.14 -

4.05 (m, 2H), 3.65 501.35 (t, J = 4.2 Hz, 4H), 3.18 (t, J = 4.8 Hz, 4H), 2.56 - 2.43

(m, 2H), 2.50 (s, 6H), 1.95 (d, J = 1.8

Hz, 3H), 1.64 (s, 3H), 1.23 (s, 3H).

2-(2-((3-fluoro-2- ^ηΗ NMR(300 MHz, methylphenoxy)methyl)- DMSO-de): δ 1 1.82

5-hydroxy-2,3-dimethyl- (s, 1 H), 7.71 - 7.68

7-morpholino-4- (m, 1 H), 7.10 (q, J

OH O

oxochroman-3-yl)-N- = 7.5 Hz, 1 H), 6.77 methylacetamide - 6.70 (m, 2H), 5.93 487.27

- 5.89 (m, 2H), 4.15

(q, J = 1 1.1 Hz, 2H), 3.65 - 3.62 (m, 4H), 3.27 - 3.25 (m, 4H), 2.68 (s, 2H),

Scheme 14: General Synthetic Scheme

Example 105a: 5-hydroxy-2-methyl-7-morpholino-2-((o-tolyloxy)methyl)chroman-4- one-3,3-d₂

K₂C0₃ (0.54 g, 3.91 mmol) was added to a suspension of 2-((3-fluoro-2- methylphenoxy)methyl)-5-hydroxy-2-methyl-7-morpholinochroman-4-one (0.5 g, 1.30 mmol) in DMF (10 mL) and D₂0 (2.5 mL) at room temperature. The mixture was stirred at room temperature for 16 h and diluted with ethyl acetate and ice water. Separated organic layer was dried over anhydrous Na₂S0₄, filtered and the filtrate was concentrated under reduced pressure. The crude compound was purified by flash chromatography using 50% ethyl acetate in petroleum ether as an eluent to afford 105a(0.4 g, 80%) as a white solid. ¹H NMR (400 MHz, CDCI₃): δ 1 1.98 (s, 1 H), 7.2 - 7.10 (m, 2H), 6.87 (d, J =7.6 Hz, 1 H), 6.77 (d, J = 8.4 Hz, 1 H), 5.91 (d, J =2.8 Hz, 1 H), 5.87 (d, J =2.4 Hz, 1 H), 4.1 (d, J = 9.2 Hz, 1 H), 3.97 (d, J = 9.6 Hz, 1 H),3.79 (t, J = 4.8 Hz, 4H), 3.31 (t, J = 4.8 Hz, 4H), 2.19 (s 3H),

I .55 (s, 3H); ESI-MS m/z: 3.86.26 (M+H)⁺; LCMS Purity: 98%

Example 105b: ieri-Butyl 2-(5-hydroxy-2-methyl-7-morpholino-4-oxo-2-((o- tolyloxy)methyl)chroman-3-yl-3-d)acetate

HMPA (2.6 mL, 14.53 mmol) was added to a stirred solution of 2M LDA (2.59 mL, 5.19 mmol) in dry THF (20 mL) at -78 °C and stirred for 1.5 h at the same temperature. Compound 105a(0.4 g, 1.04 mmol) in dry THF (15 mL) was added drop wise over a period of 10 min at -78 °C and stirred for another 1.5 h at the same temperature. Ethyl bromoacetate (0.573 mL, 5.19 mmol) was added to the solution at -78 °C and allowed to warm to -40 °C and stirred for 1 h. The reaction mixture was quenched with saturated NH₄CI and partitioned between ethyl acetate and water. Separated organic layer was dried over Na₂S0₄, filtered and the filtrate was concentrated under reduced pressure. The crude was purified by flash chromatography using 30% ethyl acetate in petroleum ether as an eluent to afford 105b(0.28 g, 54%) as an off-white solid. ¹H NMR (400 MHz, CDCI₃): δ

I I .72 (s, 1 H), 7.19 - 7.05 (m, 2H), 6.9 (d, J =7.2 Hz, 1 H), 6.8 (d, J = 8.8 Hz, 1 H), 5.91 (d, J =2.4 Hz, 1 H), 5.85 (d, J =2.4 Hz, 1 H), 4.21 (d, J = 10 Hz, 1 H), 4.16 (d, J = 9.6 Hz, 1 H), 3.79 (t, J = 4.4 Hz, 4H), 3.29 (t, J = 4.4 Hz, 4H), 2.66 (d, J = 15.6 Hz, 1 H), 1.81 (d, J = 16 Hz, 1H), 2.26 (s, 2H), 2.04 (s, 1H), 1.62 (s, 1H), 1.47 (s, 2H), 1.36 (s, 9H); ESI-MS m/z: 499.3 (M+H)⁺; LCMS Purity: 70%.

Example 105: 2-(5-hydroxy-2-methyl-7-morpholino-4-oxo-2-((o- tolyloxy)methyl)chroman-3-yl-3-d)acetic acid Trifluoroacetic acid (1 mL, 16.8 mmol) was added to a solution of Compound 105b(0.28 g, 0.562 mmol) in DCM (2.5 mL) at 0 °C. The mixture was stirred at room temperature for 4 h and diluted with DCM and ice water. Separated organic layer was dried over anhydrous Na₂S0₄, filtered and the filtrate was concentrated under reduced pressure. The crude compound was purified by flash chromatography using 80% ethyl acetate in petroleum ether as an eluent to afford 105(210 mg, 85%) as a white solid. ¹H NMR (400 MHz CDCI₃):611.59 (s, 1H), 7.19-7.11 (m, 2H), 6.89 (t, J= 7.2 Hz, 1H), 6.82 (d, J= 8.1 Hz, 1H), 5.92 (d, J= 2.4 Hz, 1H), 5.87 (d, J= 2.4 Hz, 1H), 4.25 (d, J= 10 Hz, 1H ), 3.99 (d, J= 10.4 Hz, 1H), 3.79 (t, J= 4.8 Hz, 4H), 3.31 (t, J= 5.7 Hz, 4H), 2.83 (d, J= 16 Hz, 1H), 2.43 (d, J = 16 Hz, 1H), 2.25 (s, 3H), 1.36 (s, 3H); ESI-MS m/z.443.37 (M+H)⁺; LCMS Purity: 98% Diastereomeric mixture of compound 105 is separated by chiral HPLC column chromatography to get the respective isomers.

Isomer 105-1: ¹H NMR(300 MHz, CDCI3): δ 11.59 (s, 1H), 7.19-7.11 (m, 2H), 6.89 (t, J = 7.2 Hz, 1H), 6.82 (t, J= 8.1 Hz, 1H), 5.92 (d, J=2.1 Hz, 1H), 5.87 (d, J=2.4 Hz, 1H), 4.25 (d, J= 10.2 Hz, 1H ), 3.99 (d, J= 10.2 Hz, 1H), 3.79 (t, J= 4.8 Hz, 4H), 3.31 (t, J= 5.7 Hz, 4H), 2.83 (d, J= 16.2 Hz, 1H), 2.44 (d, J= 16.2 Hz, 1H), 2.25 (s, 3H), 1.25 (s, 3H); ESI- MS m/z.443.3 (M+H)⁺; LCMS Purity: 93%

Isomer 105-2: ¹H NMR(400 MHz, DMSO-d₆): δ 12.05 (bs, 1H), 11.72 (s, 1H), 7.19-7.11 (m, 2H), 6.97 (d, J= 7.6 Hz, 1H), 6.86 (t, J= 7.6 Hz, 1H), 5.98 (s, 2H ), 4.22 (d, J= 11.2 Hz, 1H ), 4.16 (d, J= 11.2 Hz, 1H), 3.65 (t, J= 4.8 Hz, 4H), 3.36-3.31 (m, 4H), 2.46 (d, J= 16.8 Hz, 1H), 2.38 (d, J= 16.8 Hz, 1H), 2.16 (s, 3H), 1.25 (s, 3H); ESI-MS m/z 443.2 (M+H)⁺; LCMS Purity: 98% Scheme 15: General S nthetic Scheme

Example 106a:6-fluoro-5-hydroxy-2-methyl-7-morpholino-2-((o- tolyloxy)methyl)chroman-4-one-3,3-d₂: Itwas prepared using the similar procedure used for 105a and obtained 106a as white solid in 83% yield. ¹H NMR (300 MHz, DMSO-cfe): δ 1 1.8 (s, 1 H), 7.14 - 7.08 (m, 2H), 6.91 - 6.81 (m, 2H), 5.99 (d, J = 6.6 Hz, 1 H), 4.1 1 (s, 2H), 3.69 (t, J = 4.2 Hz, 4H), 3.19 (t, J = 4.8 Hz, 4H), 1.98 (s, 3H), 1.48 (s, 3H). ESI-MS m/z. 404.2 (M+H)⁺;

Example 106b:tert-butyl 2-(6-fluoro-5-hydroxy-2-methyl-7-morpholino-4-oxo-2-((o- tolyloxy)methyl)chroman-3-yl-3-d)acetate

It was prepared using the similar procedure used for Example 105b and obtained 106b as off-white solid in 83% yield. ¹H NMR (400 MHz, CDCI₃): δ 1 1.5 (s, 1 H), 7.17 - 7.14 (m, 2H), 6.94 - 6.78 (m, 2H), 5.88 (d, J = 5.6 Hz, 1 H), 4.23 (d, J =10.4 Hz, 1 H), 3.98 (d, J = 10.0 Hz, 1 H), 3.83 (t, J = 5.2 Hz, 4H), 3.30 - 3.21 (m, 4H), 2.67 (d, J = 16.0 Hz, 1 H), 2.35 (d, J = 16.5 Hz, 1 H), 2.26 (s, 3H), 1.41 (s, 9H), 1.35 (s, 3H).

Example 106:2-(6-fluoro-5-hydroxy-2-methyl-7-morpholino-4-oxo-2-((o- tolyloxy)methyl)chroman-3-yl-3-d)acetic acid

It was prepared using the similar procedure used for Example 105 and obtained 106 as white solid. Diastereomeric mixture of compound 106 was separated by chiral HPLC column chromatography to get the respective isomers106-1 &106-2. 106-1: ¹H NMR (300 MHz, CDCI3): δ 11.39 (s, 1H), 7.16-7.10 (m, 2H), 6.86 (t, J= 7.2 Hz, 1H ), 6.81 (d, J= 6.1 Hz, 1H), 5.89 (d, J= 6.3 Hz, 1H), 4.26 (d, J= 10.5 Hz, 1H), 3.98 (d, J = 10.2 Hz, 1H), 3.84 (t, J= 4.5 Hz, 4H), 3.33 - 3.19 (m, 4H), 2.83 (d, J=16.2 Hz, 1H), 2.41 (d, J= 16.5 Hz, 1H), 2.23 (s, 3H), 1.35 (s, 3H); ESI-MS m/z.461.13 (M+H)⁺; 106-2: ¹H NMR (300 MHz, CDCI3): δ 11.4 (s, 1H), 7.16-7.06 (m, 2H), 6.90 (d, J= 7.8 Hz, 1H ), 6.83 (t, J= 7.2 Hz, 1H), 5.98 (d, J= 6.3 Hz, 1H), 4.11 (m, 2H), 3.69 (t, J= 4.5 Hz, 4H), 3.19 (t, J= 4.2 Hz, 4H), 3.08 (d, J= 17.4 Hz, 1H), 2.97 (d, J= 18 Hz, 1H), 1.99 (s, 3H), 1.49 (s, 3H); ESI-MS m/z.461.13 (M+H)⁺;

Scheme 16: General Synthetic Scheme

Example107:3-((2H-tetrazol-5-yl)methyl)-2-((3-fluoro-2-methylphenoxy)methyl)-5- hydroxy-2-methyl-7-morpholinochroman-4-one-3-d: To a solution of 2-(2-((3-fluoro-2- methylphenoxy)methyl)-5-hydroxy-2-methyl-7-morpholino-4-oxochroman-3-yl)acetonithle (1 g, 2.27 mmol) in THF (10 mL) were added TMS azide (1.48 mL, 11.36 mmol) and 1M TBAF (3.4 mL, 3.4 mmol) at 0 °C and the reaction mixture was irradiated with microwave irradiation at 110 °C for 1 h. The mixture was cooled to room temperature and poured into ice water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na₂S0_4, filtered and the filtrate was concentrated under reduced pressure. The crude compound was purified by flash chromatography using 80% ethyl acetate in petroleum ether as an eluent to afford 107a(0.6 g, 55%) as a white solid.

¹H NMR (300 MHz, DMSO-ck): δ 15.98 (bs, 1H), 11.58 (s, 1H), 7.16 (q, J =1.5 Hz, 1H), 6.85-6.70 (m, 2H), 6.03-5.92 (m, 2H), 4.38-4.18 (m, 2H), 4.05-3.97 (m, 1H), 3.65 (t, J= 4.5 Hz, 4H), 3.35-3.21 (m, 4H), 3.28-3.23 (m, 1H), 3.15-3.05 (m, 1H), 2.03 (d, J= 1.5 Hz, 2H), 1.83 (d, J= 1.5 Hz, 1H), 1.06 (s, 1H), 1.38 (s, 2H) ); ESI-MS m/z: 484.24 (M+H)⁺; LCMS Purity: 99%

K₂C0₃ (0.54 g, 3.91 mmol) was added to compound 107a(0.5 g, 1.30 mmol) in DMF (10 ml_) and D₂0 (2.5 ml_) at room temperature. The mixture was stirred at room temperature for 16 h and diluted with ethyl acetate and ice water. Separated organic layer was dried over anhydrous Na₂S0₄, filtered and the filtrate was concentrated under reduced pressure. The crude compound was purified by flash chromatography. Diastereomeric mixture of compound 107 is separated by chiral HPLC column chromatography to get the respective isomers. 107-1:¹H NMR (300 MHz, DMSO-cfe): δ 11.62 (s, 1H), 7.15 (q, J= 7.5 Hz, 1H), 6.83-6.71 (m, 2H), 5.98-5.91 (m, 2H),4.31 (d, J= 11.1 Hz, 1H),4.18 (d, J= 11.1 Hz, 1 H),4.05-3.97 (m, 1H), 3.65 (t, J= 4.2 Hz, 4H), 3.35-3.21 (m, 4H), 3.15 (d, J= 15.3 Hz, 1H), 2.99 -2.88 (m, 1H), 1.83 (d, J= 1.5 Hz, 3H), 1.52 (s, 3H); ESI-MS m/z.485.25 (M+H)⁺; LCMS Purity: 97%

107-2:¹H NMR (300 MHz, DMSO-cfe): δ 11.72 (s, 1H), 7.11 (q, J= 7.8 Hz, 1H), 6.79-6.68 (m, 2H), 6.01 - 5.95 (m, 2H),4.05 - 3.97 (m, 2H), 3.65 (t, J = 4.8 Hz, 4H), 3.35 - 3.21 (m, 4H), 3.01 -2.88 (m, 2H), 2.01 (d, J= 1.5 Hz, 3H), 1.35 (s, 3H); ESI-MS m/z: 485.25 (M+H)⁺; LCMS Purity: 96%

The below are the list of examples, but not to be limited to these numbers, can also be synthesized by following the general synthesis described above

Example108: 2-(2-((3-fluoro-2-methylphenoxy)methyl)-5-hydroxy-2-methyl-7-morpholino- 4-oxochroman-3-yl-3-d)acetic acid Example109: 2-(6-fluoro-2-((3-fluoro-2-methylphenoxy)methyl)-5-hydroxy-2-methyl-7- morpholino-4-oxochroman-3-yl-3-d)acetic acid

Example110: 2-(3,6-difluoro-2-((3-fluoro-2-methylphenoxy)methyl)-5-hydroxy-2-methyl-7- morpholino-4-oxochroman-3-yl)acetic acid

Examplel 11 : 2-(3-fluoro-2-((3-fluoro-2-methylphenoxy)methyl)-5-hydroxy-2-methyl-7- morpholino-4-oxochroman-3-yl)acetic acid

Examplel 12: 2-(2-((3-fluoro-2-methylphenoxy)methyl)-5-hydroxy-2,3-dimethyl-7-(3- methylmorpholino)-4-oxochroman-3-yl)acetic acid

Examplel 13: 2-(2-((3-fluoro-2-methylphenoxy)methyl)-5-hydroxy-2,3-dimethyl-4-oxo-7-(3- oxomorpholino)chroman-3-yl)acetic acid

Examplel 14: 3-benzyl-2-((3-fluoro-2-methylphenoxy)methyl)-5-hydroxy-2,3-dimethyl-7- morpholinochroman-4-one

Examplel 15: 3-(2-(dimethylamino)ethyl)-2-((3-fluoro-2-methylphenoxy)methyl)-5-hydroxy- 2,3-dimethyl-7-morpholinochroman-4-one

Examplel 16: 2-(5-hydroxy-2,3-dimethyl-7-morpholino-4-oxo-2-(phenoxymethyl)-3,4- dihydro-2H-pyrano[3,2-c]pyridin-3-yl)acetic acid

PI3K beta biochemical activity of few examples is given below:

+++ : IC50 < 1000nM; ++ : IC50 = 1000nM - 10uM; + : IC50 > 10uM

Claims

CLAIMS We claim:

1. A compound of Formula (I)

or isomers, stereoisomers, tautomers, or pharmaceutically acceptable salts, isotopes, solvates, metabolites, polymorphs or prodrugs thereof, wherein:

A is selected from CO, CH₂;

B is selected from O, S, C, N;

Z is selected from CR-i, N; X is selected from bond, O, NR₃, CR₃R₃, and S0₂NR₃;

L-i, l_₂ is independently selected from CO, NR₅, and CR₅R₅; n is an integer between 0 and 2, inclusive;

Ri and R₂ are independently selected from H, alkyi, substituted alkyi, alkenyl, alkynyl, haloalkyl, halogen, amine, aminocarbonyl, nitrile, haloalkoxy, hydroxyalkyl, alkoxycarbonyl, optionally substituted aminocarbonyl, cyano, optionally substituted phenyl, cycloalkyl, carboxylic acid, CH₂COOH, NHCONR₅, CH₂CONH₂(optionally substituted with alkyi, aryl, halogenated aryl, heteroaryl),-OCH₂CONH₂, -NHCOR₅, - NHCH₂CF₃, -NHCH₂Ph, Tetrazole, any heterocycle, any fused heterocycle, OR_5, COR_5, R₃S0₂NH, S0₂NHR₅,B(OH)₂; R₃ is selected from H, alkyi, aryl, alkyi aryl, optionally substituted aryl, alkyi, halogen, haloalkyl, branched alkyi, acetyl, benzoyl, cycloalkyl;

R₄ is selected from aryl, optionally substituted aryl, alkylaryl, arylalkyl, cycloalkyl, heteroaryl, optionally substituted heteroaryl , optionally substituted alkylaryl, 3-6 membered heterocyclic ring with one or more heteroatom selected from O, N and S and optionally substituted with one or more substituent's independently selected from H, alkyi, alkenyl, alkynyl, haloalkyl, halogen, hydroxy, alkoxy, haloalkoxy, carboxylic acid, carboxamide;

R₅ is selected from H, alkyi, halogen, haloalkyl, hydroxy, hydroxyalkyl, alkoxycarbonyl, aminocarbonyl, amino, alkylaryl, substituted alkyi, substituted alkyi aryl, aryl, substituted aryl, alkyi carboxylic acid, alkylamide, alkylamine, alkyi nitrile, cycloalkyl, optionally substituted cycloalkyl; and wherein Ri forms a six membered ring with l_i

2. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt form thereof.

3. The pharmaceutical composition as claimed in claim 2, wherein said composition is used for prevention and/or therapeutic treatment of diseases or disorders associated with abnormal activities of PI3 kinases.

4. The pharmaceutical composition as claimed in claim 3, wherein said diseases or disorders associated with abnormal activities of PI3 kinases, especially possessing inhibitory activity against ΡΙ3Κβ.

5. The pharmaceutical composition as claimed in claim 3, wherein said diseases or disorders is selected from the group consisting of Inflammation, Cancer, Restenosis, Atherosclerosis, Psoriasis, Thrombosis, immmuno-oncology, renal carcinoma, hepatitis C, haematological malignancies, and multiple myeloma.

6. A method for treating a disease or disorder associated with abnormal activities of PI3K's activity wherein said disease or disorder is selected from the group consisting of Inflammation, Cancer, Restenosis, Atherosclerosis, Psoriasis, Thrombosis, immuno- oncology, renal carcinoma, hepatitis C, hematological malignancies, multiple myeloma or a disease or a disorder associated with abnormal activities of PI3K signaling in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

7. The method as claimed in Claim 6, wherein said cancer is selected from the group consisting of lung Adenocarcinomas, Breast Cancer, Thyroid Carcinoma, Pancreatic Cancer, Ovarian Carcinoma, Malignant Mesothelioma, Prostate, Neuroblastic Tumors, Colorectal Carcinoma, Spitzoid Melanoma, Salivary Adenoid Cystic Carcinoma Glioblastoma Multiforme, Oral Squamous Cell Carcinoma, Acute Myeloid Leukemia.

8. A compound which is:

> 2-((3-fluoro-2-methylphenoxy)methyl)-5-hydroxy-2-methyl-7-morpholinochroman-4- one

> 5-hydroxy-2-methyl-7-morpholino-2-(p-tolyloxymethyl)chroman-4-one

> 2-(benzyloxymethyl)-5-hydroxy-2-methyl-7-morpholinochroman-4-one

> 5-hydroxy-2-methyl-7-morpholino-2-(o-tolyloxymethyl)chroman-4-one

> 5-hydroxy-2-methyl-7-morpholino-2-(m-tolyloxymethyl)chroman-4-one

> 5-hydroxy-2-methyl-2-(4-methylbenzyl)-7-morpholinochroman-4-one

> 2-((4-fluorophenoxy)methyl)-5-hydroxy-2-methyl-7-morpholinochroman-4-one

> 5-hydroxy-2-methyl-7-morpholino-2-((2-(trifluoromethyl)phenoxy)methyl)chroman-4- one

> 5-hydroxy-2-methyl-7-morpholino-2-((3-(trifluoromethyl)phenoxy)methyl)chroman-4- one

> 2-(3-fluorobenzyl)-5-hydroxy-2-methyl-7-morpholinochroman-4-one

> 2-benzyl-5-hydroxy-2-methyl-7-morpholinochroman-4-one

> 5-hydroxy-2-methyl-7-morpholino-2-phenethylchroman-4-one

> 2-((4-chlorophenoxy)methyl)-5-hydroxy-2-methyl-7-morpholinochroman-4-one

> 2-((4-(dimethylamino)phenoxy)methyl)-5-hydroxy-2-methyl-7-morpholino-chroman- 4-one

> N-((5-hydroxy-2-methyl-7-morpholino-4-oxochroman-2-yl)methyl)benzamide

> N-benzyl-5-hydroxy-2-methyl-7-morpholino-4-oxochroman-2-carboxamide

> 5-hydroxy-2,2-dimethyl-7-morpholinochroman-4-one > N-((5-hydroxy-2-methyl-7-morpholino-4-oxochroman-2-yl)methyl)-N- phenylacetamide

> 2-((3-(dimethylamino)phenoxy)methyl)-5-hydroxy-2-methyl-7-morpholinochroman-4- one

> 5-hydroxy-2-(4-methoxybenzyl)-2-methyl-7-morpholinochroman-4-one

> 5-hydroxy-2-methyl-7-morpholino-2-((phenylamino)methyl)chroman-4-one

> 2-((4-chlorophenoxy)methyl)-5-hydroxy-2-methyl-7-morpholinochroman-4-one

> 2-((4-(dimethylamino)phenoxy)methyl)-5-hydroxy-2-methyl-7-morpholino-chroman- 4-one

> 1 -(5-hydroxy-2-methyl-7-morpholino-4-oxochroman-2-yl)-N- phenylmethanesulfonamide

> 2-((4-fluoro-2-methylphenoxy)methyl)-5-hydroxy-2-methyl-7-morpholinochroman-4- one

> 5-hydroxy-2-methyl-2-((2-methyl-3-(trifluoromethyl)phenoxy)methyl)-7- morpholinochroman-4-one

> 2-((3-chloro-2-methylphenoxy)methyl)-5-hydroxy-2-methyl-7-morpholinochroman-4- one

> 5-hydroxy-2-methyl-2-((methyl(phenyl)amino)methyl)-7-morpholinochroman-4-one

> N-benzyl-N-((5-hydroxy-2-methyl-7-morpholino-4-oxochroman-2- yl)methyl)acetamide

> 5-hydroxy-2-methyl-7-morpholino-2-(phenoxymethyl)chroman-4-one

> 2-((2-fluoro-3-methylphenoxy)methyl)-5-hydroxy-2-methyl-7-morpholinochroman-4- one

> 2-((5-hydroxy-2-methyl-7-morpholino-4-oxochroman-2-yl)methoxy)benzoic acid

> 2-((5-hydroxy-2-methyl-7-morpholino-4-oxochroman-2-yl)methoxy)-N,N- dimethylbenzamide

> 2-((3,5-difluorophenoxy)methyl)-5-hydroxy-2-methyl-7-morpholinochroman-4-one

> 2-((2,5-difluorophenoxy)methyl)-5-hydroxy-2-methyl-7-morpholinochroman-4-one

> 2-((3-Fluoro-2-methylphenoxy) methyl)-2-methyl-7-morpholino-4-oxochroman-5- carboxylic acid

> 2-((3-Fluoro-2-methylphenoxy)methyl)-2-methyl-7-morpholino-4-oxochroman-5- carboxamide > 2-methyl-7-morpholino-4-oxo-2-((o-tolyloxy)methyl)chroman-5-yl

trifluoromethanesulfonate

> 2-((3-fluoro-2-methylphenoxy)methyl)-N,2-dimethyl-7-morpholino-4-oxochroman-5- carboxamide

> 2-((3-fluoro-2-methylphenoxy)methyl)-N,N,2-tnmethyl-7-morpholino-4-oxochroman- 5-carboxamide

> 2-methyl-7-morpholino-4-oxo-2-(o-tolyloxymethyl)chroman-5-carboxamide

> 2-methyl-7-morpholino-4-oxo-2-(o-tolyloxymethyl)chroman-5-carboxylic acid

> 2-methyl-7-morpholino-4-oxo-2-((2-(trifluoromethyl)phenoxy)methyl)chroman-5- carboxamide

> 2-((3-fluoro-2-methylphenoxy)methyl)-N-hydroxy-2-methyl-7-morpholino-4- oxochromane-5-carboxamide

> 8-((3-fluoro-2-methylphenoxy)methyl)-8-methyl-5-morpholino-8,9- dihydropyrano[4,3,2-de]phthalazin-3(2H)-one

> 8-((3-fluoro-2-methylphenoxy)methyl)-8-methyl-5-morpholino-8,9-dihydro-3H- chromeno [4,5-cd] [1 ,2] oxazin-3-one

> 2-(2-((3-fluoro-2-methylphenoxy)methyl)-2-methyl-7-morpholino-4-oxochroman-5- yloxy)acetic acid

> Ethyl 2-(2-((3-fluoro-2-methylphenoxy)methyl)-2-methyl-7-morpholino-4- oxochroman-5-yloxy)acetate

> 2-(2-((3-fluoro-2-methylphenoxy)methyl)-2-methyl-7-morpholino-4-oxochroman-5- yloxy)acetamide

> 2-((3-Fluoro-2-methylphenoxy)methyl)-2-methyl-7-morpholino-4-oxochroman-5- carbonitrile

> 2-((3-Fluoro-2-methylphenoxy) methyl)-2-methyl-7-morpholino-5-(1 H-tetrazol-5-yl) chroman-4-one

> 5-(Aminomethyl)-2-((3-fluoro-2-methylphenoxy) methyl)-2-methyl-7- morpholinochroman-4-one

> 2-Methyl-7-morpholino-2-(o-tolyloxymethyl) chroman-4-one

> 5-(Benzylamino)-2-((3-fluoro-2-methylphenoxy) methyl)-2-methyl-7- morpholinochroman-4-one > 5-Amino-2-((3-fluoro-2-methylphenoxy) methyl)-2-methyl-7-morpholinochroman-4 one

> 2-((3-Fluoro-2-methylphenoxy)methyl)-2-methyl-7-morpholino-5-(2,2,2- trifluoroethylamino)chroman-4-one

> N-(2-((3-fluoro-2-methylphenoxy)methyl)-2-methyl-7-morpholino-4-oxochroman-5- yl)acetamide

> N-(2-((3-fluoro-2-methylphenoxy)methyl)-2-methyl-7-morpholino-4-oxochroman-5- yl)methanesulfonamide

> 1 -(2-((3-Fluoro-2-methylphenoxy)methyl)-2-methyl-7-morpholino-4-oxochroman-5- yl)urea

> 5-amino-2-methyl-7-morpholino-2-(o-tolyloxymethyl)chroman-4-one

> (2-Methyl-7-morpholino-4-oxo-2-((o-tolyloxy)methyl)chroman-5-yl)boronic acid

> Ethyl 2-(2-((3-fluoro-2-methylphenoxy)methyl)-2-methyl-7-morpholino-4 oxochroman-5-yl)acetate

> 2-(2-((3-fluoro-2-methylphenoxy)methyl)-2-methyl-7-morpholino-4-oxochroman-5- yl)acetic acid

> 2-(2-((3-fluoro-2-methylphenoxy)methyl)-2-methyl-7-morpholino-4-oxochroman-5- yl)acetamide

> 6-chloro-5-hydroxy-2-methyl-7-morpholino-2-(o-tolyloxymethyl) chroman-4-one

> 8-chloro-5-hydroxy-2-methyl-7-morpholino-2-((o-tolyloxy)methyl)chroman-4-one

> 6-fluoro-5-hydroxy-2-methyl-7-morpholino-2-((o-tolyloxy)methyl)chroman-4-one

> 6-fluoro-2-((3-fluoro-2-methylphenoxy)methyl)-5-hydroxy-2-methyl-7- morpholinochroman-4-one

> 6-fluoro-2-((3-fluoro-2-methylphenoxy)methyl)-5-hydroxy-2-methyl-7- morpholinochroman-4-one

> Ethyl 2-(2-((3-fluoro-2-methylphenoxy)methyl)-5-hydroxy-2-methyl-7-morpholino-4 oxochroman-3-yl)acetate

> 2-((3-fluoro-2-methylphenoxy)methyl)-5-hydroxy-2,3-dimethyl-7- morpholinochroman-4-one

> 2-(2-((3-Fluoro-2-methylphenoxy)methyl)-5-hydroxy-2-methyl-7-morpholino-4- oxochroman-3-yl)acetic acid > 2-(2-((3-Fluoro-2-methylphenoxy)methyl)-5-hydroxy-2-methyl-7-morpholino-4- oxochroman-3-yl)acetamide

> 5-hydroxy-2,3-dimethyl-7-morpholino-2-(o-tolyloxymethyl)chroman-4-one

> 5-hydroxy-2,3,3-tnmethyl-7-morpholino-2-(o-tolyloxymethyl)chroman-4-one

> 2-(5-hydroxy-2-methyl-7-morpholino-4-oxo-2-(o-tolyloxymethyl)chroman-3- yl)acetamide

> 2-(5-hydroxy-2-methyl-7-morpholino-4-oxo-2-(o-tolyloxymethyl)chroman-3-yl)acetic acid

> 3-ethyl-5-hydroxy-2-methyl-7-morpholino-2-(o-tolyloxymethyl)chroman-4-one

> 2-(5-methoxy-2-methyl-7-morpholino-4-oxo-2-(o-tolyloxymethyl)chroman-3-yl)acetic acid

> 3-cyclopropyl-5-hydroxy-2-methyl-7-morpholino-2-(o-tolyloxymethyl)chroman-4-one

> 2-(5-hydroxy-2-methyl-7-morpholino-4-oxo-2-(o-tolyloxymethyl)chroman-3- yl)acetamide

> 2-(5-hydroxy-2-methyl-7-morpholino-4-oxo-2-(o-tolyloxymethyl)chroman-3- yl)acetamide

> 2-(5-hydroxy-2-methyl-7-morpholino-4-oxo-2-(o-tolyloxymethyl)chroman-3- yl)acetamide

> 2-(5-hydroxy-2-methyl-7-morpholino-4-oxo-2-(o-tolyloxymethyl)chroman-3- yl)acetonitrile

> 2-(2-((3-fluoro-2-methylphenoxy)methyl)-5-hydroxy-2-methyl-7-morpholino-4- oxochroman-3-yl)acetonitrile

> 3-(2-((3-fluoro-2-methylphenoxy)methyl)-5-hydroxy-2-methyl-7-morpholino-4- oxochroman-3-yl)propanamide

> 3-(2-((3-fluoro-2-methylphenoxy)methyl)-5-hydroxy-2-methyl-7-morpholino-4- oxochroman-3-yl)propanoic acid

> 2-(2-((3-Fluoro-2-methylphenoxy)methyl)-2-methyl-7-morpholino-4-oxochroman-3- yl)acetic acid

> 2-(2-((3-Fluoro-2-methylphenoxy)methyl)-2-methyl-7-morpholino-4-oxochroman-3- yl)acetamide

> 2-(2-methyl-7-morpholino-4-oxo-2-(o-tolyloxymethyl)chroman-3-yl)acetic acid > 3-(Carboxymethyl)-2-((3-fluoro-2-methylphenoxy)methyl)-2-methyl-7-morpholino-4- oxochroman-5-carboxylic acid

> 3-(2-Amino-2-oxoethyl)-2-((3-fluoro-2-methylphenoxy)methyl)-2-methyl-7- morpholino-4-oxochroman-5-carboxamide

> 2,3-dimethyl-7-morpholino-4-oxo-2-(o-tolyloxymethyl)chroman-5-carboxamide

> 2,3-dimethyl-7-morpholino-4-oxo-2-(o-tolyloxymethyl)chroman-5-carboxylic acid

> 2-((3-fluoro-2-methylphenoxy)methyl)-2,3-dimethyl-7-morpholino-4-oxochroman-5- carboxamide

> 2-((3-fluoro-2-methylphenoxy)methyl)-2,3-dimethyl-7-morpholino-4-oxochromane-5- carbonitrile

> 5-amino-2-((3-fluoro-2-methylphenoxy)methyl)-2,3-dimethyl-7-morpholinochroman-

4- one

> 2-(5-cyano-2-((3-fluoro-2-methylphenoxy)methyl)-2-methyl-7-morpholino-4- oxochroman-3-yl)acetamide

> 1 -(2-((3-fluoro-2-methylphenoxy)methyl)-2,3-dimethyl-7-morpholino-4-oxochroman-

5- yl)urea

> 3-(cyanomethyl)-2-((3-fluoro-2-methylphenoxy)methyl)-2,3-dimethyl-7-morpholino-4- oxochromane-5-carbonitrile

> 2-(8-((3-fluoro-2-methylphenoxy)methyl)-8-methyl-5-morpholino-3-oxo-2,3,8,9- tetrahydropyrano[4,3,2-de]phthalazin-9-yl)acetic acid

> 2-((3-fluoro-2-methylphenoxy)methyl)-5-hydroxy-3-(hydroxymethyl)-2-methyl-7- morpholinochroman-4-one

> 2-((3-fluoro-2-methylphenoxy)methyl)-5-hydroxy-2-methyl-7-morpholino-2H- benzo[e][1 ,3]oxazin-4(3H)-one

> 2-((3-fluoro-2-methylphenoxy)methyl)-5-methoxy-2,3-dimethyl-7-morpholino-2H- benzo[e][1 ,3]oxazin-4(3H)-one

> 2-((3-fluoro-2-methylphenoxy)methyl)-5-hydroxy-2,3-dimethyl-7-morpholino-2H- benzo[e][1 ,3]oxazin-4(3H)-one

> ethyl 2-(5-(2-ethoxy-2-oxoethoxy)-2-((3-fluoro-2-methylphenoxy)methyl)-2-methyl-7- morpholino-4-oxo-2H-benzo[e][1 ,3]oxazin-3(4H)-yl)acetate

> 2-(2-((3-fluoro-2-methylphenoxy)methyl)-5-hydroxy-2-methyl-7-morpholino-4-oxo- 2H-benzo[e][1 ,3]oxazin-3(4H)-yl)acetic acid > 2-(2-((3-fluoro-2-methylphenoxy)methyl)-5-hydroxy-2,3-dimethyl-7-morpholino-4- oxochroman-3-yl)acetic acid

> ethyl 2-(2-((3-fluoro-2-methylphenoxy)methyl)-5-hydroxy-2,3-dimethyl-7-morpholino 4-oxochroman-3-yl)acetate

> 2-(2-((3-fluoro-2-methylphenoxy)methyl)-5-hydroxy-2,3-dimethyl-7-morpholino-4- oxochroman-3-yl)acetamide

> 2-(2-((3-fluoro-2-methylphenoxy)methyl)-5-hydroxy-2,3-dimethyl-7-morpholino-4- oxochroman-3-yl)acetonitrile

> 3-((1 H-tetrazol-5-yl)methyl)-2-((3-fluoro-2-methylphenoxy)methyl)-5-hydroxy-2,3- dimethyl-7-morpholinochroman-4-one

> 2-(6-fluoro-2-((3-fluoro-2-methylphenoxy)methyl)-5-hydroxy-2,3-dimethyl-7- morpholino-4-oxochroman-3-yl)acetic acid

> 2-(8-fluoro-2-((3-fluoro-2-methylphenoxy)methyl)-5-hydroxy-2,3-dimethyl-7- morpholino-4-oxochroman-3-yl)acetic acid

> 2-(2-((3-fluoro-2-methylphenoxy)methyl)-5-hydroxy-2,3-dimethyl-7-morpholino-4- oxochroman-3-yl)-N,N-dimethylacetamide

> 2-(2-((3-fluoro-2-methylphenoxy)methyl)-5-hydroxy-2,3-dimethyl-7-morpholino-4- oxochroman-3-yl)-N-methylacetamide

> 2-(2-((3-fluoro-2-methylphenoxy)methyl)-5-hydroxy-2,3-dimethyl-7-morpholino-4- oxochroman-3-yl)-N-(2-hydroxyethyl)-N-methylacetamide

> 5-hydroxy-2-methyl-7-morpholino-2-((o-tolyloxy)methyl)chroman-4-one-3,3-d2

> tert-Butyl 2-(5-hydroxy-2-methyl-7-morpholino-4-oxo-2-((o-tolyloxy)methyl)chroman 3-yl-3-d)acetate

> 2-(5-hydroxy-2-methyl-7-morpholino-4-oxo-2-((o-tolyloxy)methyl)chroman-3-yl-3- d)acetic acid

> 6-fluoro-5-hydroxy-2-methyl-7-morpholino-2-((o-tolyloxy)methyl)chroman-4-one-3,3- d2

> tert-butyl 2-(6-fluoro-5-hydroxy-2-methyl-7-morpholino-4-oxo-2-((o tolyloxy)methyl)chroman-3-yl-3-d)acetate

> 2-(6-fluoro-5-hydroxy-2-methyl-7-morpholino-4-oxo-2-((o-tolyloxy)methyl)chroman- 3-yl-3-d)acetic acid > 3-((2H-tetrazol-5-yl)methyl)-2-((3-fluoro-2-methylphenoxy)methyl)-5-hydroxy-2- methyl-7-morpholinochroman-4-one-3-d

> 2-(2-((3-fluoro-2-methylphenoxy)methyl)-5-hydroxy-2-methyl-7-morpholino-4- oxochroman-3-yl-3-d)acetic acid

> 2-(6-fluoro-2-((3-fluoro-2-methylphenoxy)methyl)-5-hydroxy-2-methyl-7-morpholino 4-oxochroman-3-yl-3-d)acetic acid

> 2-(3,6-difluoro-2-((3-fluoro-2-methylphenoxy)methyl)-5-hydroxy-2-methyl-7- morpholino-4-oxochroman-3-yl)acetic acid

> 2-(3-fluoro-2-((3-fluoro-2-methylphenoxy)methyl)-5-hydroxy-2-methyl-7-morpholino 4-oxochroman-3-yl)acetic acid

> 2-(2-((3-fluoro-2-methylphenoxy)methyl)-5-hydroxy-2,3-dimethyl-7-(3- methylmorpholino)-4-oxochroman-3-yl)acetic acid

> 2-(2-((3-fluoro-2-methylphenoxy)methyl)-5-hydroxy-2,3-dimethyl-4-oxo-7-(3- oxomorpholino)chroman-3-yl)acetic acid

> 3-benzyl-2-((3-fluoro-2-methylphenoxy)methyl)-5-hydroxy-2,3-dimethyl-7- morpholinochroman-4-one

> 3-(2-(dimethylamino)ethyl)-2-((3-fluoro-2-methylphenoxy)methyl)-5-hydroxy-2,3- dimethyl-7-morpholinochroman-4-one

> 2-(5-hydroxy-2,3-dimethyl-7-morpholino-4-oxo-2-(phenoxymethyl)-3,4-dihydro-2H- pyrano[3,2-c]pyridin-3-yl)acetic acid