An organic compound and use thereof

Abstract

The present application relates to a kind of compound of formula (I) shown structure, stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug, and its application in preparation treatment phosphatidylinositol 3-kinase (PI3K alpha) mediated disease drug.

Description

TECHNICAL FIELD

[0001] The present application relates to a compound, stereoisomer, tautomer, nitroso, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, for the manufacture of a medicament for preventing, managing, treating or lessening a phosphatidylinositol 3-kinase (PI3K) mediated disease in a patient. BACKGROUND

[0002] Phosphatidylinositol 3-kinases (PI3Ks) comprise a family of lipid kinases that catalyze the transfer of a phosphate group to the D-3' position of inositol lipids to produce 3- phosphorylated phosphatidylinositol (PIP), 3,4-diphosphorylated phosphatidylinositol (PIP2), and 3,4,5-triphosphorylated phosphatidylinositol (PIP3). The products of these PI3K-catalyzed reactions act as second messengers and play important roles in key cellular processes, including cell growth, differentiation, motility, proliferation, and survival.

[0003] In general, PIP2 and PIP3 recruit Akt, the product of the viral oncogene v-Akt human homolog, to the plasma membrane, where it serves as a node in intracellular signaling pathways that are important for growth and survival (Fantl et al., Cell 69:413-423 (1992); Bader et al., Nature Rev. Cancer 5:921 (2005); Vivanco and Sawyer, Nature Rev. Cancer 2:489 (2002)). Aberrant regulation of PI3K, often through activation of Akt, is one of the most prevalent events in human cancer and has been shown to occur at multiple levels. The tumor suppressor PTEN is functionally deleted in a variety of tumors, which gene dephosphorylates phosphatidylinositol at the 3' position of the inositol ring, thereby antagonizing PI3K activity. In other tumors, the pi 10a isoform, PIK3CA, and Akt are genetically amplified, and increased protein expression of their gene products has been shown in several human cancers. In addition, somatic missense mutations in PIK3CA that activate downstream signaling pathways are described at significant frequencies in a variety of human cancers (Kang et al., Proc. Natl. Acad. Sci. USA 102:802 (2005); Samuels et al., Science 304:554 (2004); Samuels et al., Cancer Cell 7:561-573 (2005)). Thus, PI3K alpha inhibitors are known to have particular value in the treatment of cancer and other diseases.

[0004] Alpelisib (BYL-719) is a phosphatidylinositol 3-kinase inhibitor developed by Novartis. Preclinical data showed that the drug has 50 times more inhibitory activity on PI3kα than other PI3K subtypes. The drug was approved for marketing in the United States in May 2019. It is used in combination with fulvestrant to treat hormone receptor-positive (HR) / human epidermal growth factor receptor 2-negative (HER2-) PIK3CA mutant advanced metastatic breast cancer in men and postmenopausal women. Alpelisib is the first PI3K inhibitor for the treatment of this type of breast cancer.

[0005] The chemical name of Alpelisib is (2S)-N1-[4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridyl]-2-thiazolyl]-1,2-pyrrolidinedicarboxamide, and its structural formula is:

[0006]

[0007] The inventors of the present application made structural modifications on the basis of Alpelisib and obtained a compound with obvious advantages in PI3kα inhibitory activity, selectivity, pharmacology and pharmacokinetics. SUMMARY

[0008] In one aspect, the present application provides a compound having the structure shown in formula (I), or a stereoisomer, enantiomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the structure shown in formula (I),

[0009]

[0010] wherein R 1 is an optionally substituted aryl or heteroaryl; the substituent is selected from halogen, alkyl, alkoxy, haloalkyl, cyano, amino or cycloalkyl;

[0011] R 2 is H, alkyl, haloalkyl, alkenyl or alkynyl.

[0012] In some embodiments, R 1 in the compound is an optionally substituted C 6-10 aryl or C 2-9 heteroaryl;

[0013] the substituent is selected from F, Cl, Br, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, cyano, amino or C 3-8 cycloalkyl.

[0014] In some embodiments, the compound has the structure 1 is optionally substituted phenyl, thiazolyl, thienyl, furanyl, pyrrolyl, pyridyl, or pyrimidinyl;

[0015] the substituents are selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, methoxy, ethoxy, CF3, CHF2, CH2F, cyano, amino, cyclopropyl, cyclobutyl, or cyclopentyl.

[0016] In some embodiments, the compound has the structure 2 is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, or C 2-6 alkynyl.

[0017] In some embodiments, the compound has the structure 2 is H, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, CF3, CHF2, CH2F, vinyl, propenyl, ethynyl, or propynyl.

[0018] In some embodiments, the compound has the structure

[0019]

[0020] A second aspect of the present application provides a composition comprising the compound described above, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or a combination thereof.

[0021] A third aspect of the present application provides a use of the compound or the composition described above in the manufacture of a medicament for preventing, managing, treating, or alleviating a phosphatidylinositol 3-kinase (PI3K) mediated disease in a patient, preferably the phosphatidylinositol 3-kinase (PI3K) mediated disease is a PI3Kα mediated disease.

[0022] In some embodiments, the phosphatidylinositol 3-kinase (PI3K) mediated disease is a PI3Kα mediated disease is a proliferative disease; a benign or malignant tumor; a cancer selected from sarcoma, lung cancer, bronchus cancer, prostate cancer, breast cancer, pancreatic cancer, gastrointestinal cancer, colon cancer, rectal cancer, thyroid cancer, liver cancer, adrenal gland cancer, stomach cancer, glioma, endometrial cancer, melanoma, kidney cancer, bladder cancer, cervix uteri cancer, vagina cancer, ovarian cancer, multiple myeloma, esophageal cancer, leukemia, lymphocytic leukemia, oral cavity cancer, brain cancer, larynx cancer, small intestine cancer, non-Hodgkin lymphoma, lymphoma, breast cancer, or squamous cell carcinoma.

[0023] The foregoing summary only illustrates certain aspects of the application, and is not intended to be limiting. These and other aspects will be described in more detail below in the detailed description of the application.

[0024] Detailed description of the application

[0025] Definitions and general terminology

[0026] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Unless otherwise indicated, the terms used in the following discussion have their ordinary meanings commonly used by those skilled in the art.

[0027] Certain embodiments of the application will now be described in detail by way of examples and with reference to the drawings in which:

[0028] It is further recognized that certain of the present features are described in terms of separate embodiments, but that the features also can be provided in combination in a single embodiment. Conversely, various features of the present application, which are, for brevity, described in separate embodiments, can also be provided separately or in any suitable subcombination.

[0029] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. All patents and publications identified are incorporated herein by reference in their entirety.

[0030] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. All patents and publications identified are incorporated herein by reference in their entirety.

[0031] The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to "one or more") of the grammatical object of the article. By way of example, "an element" means one or more elements, and thus, possibly, more than one element is contemplated and can be employed.

[0032] The term "subject" as used herein refers to an animal. Typically the animal is a mammal. A subject, for example, also refers to a primate (e.g., human, male or female), a cow, a sheep, a goat, a horse, a dog, a cat, a rabbit, a rat, a mouse, a fish, a bird, and the like. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

[0033] The term "patient" as used herein refers to a human (including adults and children) or other animal. In some embodiments, "patient" refers to a human.

[0034] The term "comprising" is a open term, which means that it includes the recited elements, but not excluding additional elements.

[0035] "stereoisomers" refers to compounds which have the same chemical constitution, but differ in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis / trans), atropisomers, and the like.

[0036] "diastereomers" refers to stereoisomers which have two or more chiral centers and which are not mirror images of one another. Diastereomers have different physical properties, e.g., melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers can be separated by high resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.

[0037] The stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.

[0038] Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its one or more chiral centers. The prefixes d and 1 or (+) and (-) are employed to designate the sign of the rotation of plane-polarized light by the compound, i.e., (-) or 1 meaning that the compound is levorotatory. A compound, which is prefixed (+) or d is dextrorotatory. A specific stereoisomer is an enantiomer, and a mixture of such isomers is called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which can occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. Any asymmetric atom (e.g., carbon) of a compound of the present disclosure can exist in the R- or S- configuration, e.g., the (R)-, (S)-, or (R,S)-configurational form, in racemic or enantiomeric enriched form. In certain embodiments, each asymmetric atom is in the (R)- or (S)- configuration with at least a 50% enantiomeric excess, at least a 60% enantiomeric excess, at least a 70% enantiomeric excess, at least a 80% enantiomeric excess, at least a 90% enantiomeric excess, at least a 95% enantiomeric excess, or at least a 99% enantiomeric excess.

[0039] Depending on the choice of starting materials and methods, the compounds of the present disclosure can be synthesized in one or more possible isomers, such as racemates and mixtures of diastereomers, depending on the number of asymmetric carbon atoms. The optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents can be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl, the substituents on the cycloalkyl can be in the cis- or trans-configuration.

[0040] Any mixture of stereoisomers can be separated into their individual components by conventional techniques, such as HPLC or fractional crystallization.

[0041] Unless otherwise stated, the structural formulae described herein include all tautomeric forms (e.g., enol and keto, and imidazolinone and imidazolidinone forms). Unless otherwise stated, the structural formulae described herein include all isomeric (e.g., optical, geometric (or conformational), and enantiomeric) forms of the substances described herein. Accordingly, single stereochemical isomers and mixtures thereof, such as racemates, enantiomeric mixtures, and diastereomeric mixtures, are within the scope of the present disclosure.

[0042] The term "prodrug" as used herein refers to a compound which in vivo is converted to a compound of Formula (I). Such conversion is effected by the hydrolysis of the prodrug in blood or by enzymatic conversion in blood or tissue to the parent structure. The prodrugs of the present application can be esters, and in the present application esters which can act as prodrugs are benzoic acid esters, aliphatic (C 1-24) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the application containing a hydroxyl group can be acylated to give a prodrug form of the compound. Other prodrug forms include phosphates, such as these phosphate compounds are phosphorylated on the hydroxyl group of the parent. A complete discussion of prodrugs is found in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and S. J. Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345. Any resulting racemate of an end product or intermediate can be resolved into the individual optical isomers by methods known to those skilled in the art, such as, by separation of the enantiomeric salts thereof. The racemate can also be resolved by chiral chromatography, such as, high performance liquid chromatography (HPLC) using chiral adsorbents.In particular, enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2nd Ed. Robert E. Gawley, Jeffrey Aubé, Elsevier, Oxford, UK, 2012); Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S. H. Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972); Chiral Separation Techniques: A Practical Approach (Subramanian, G. Ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007).

[0043] The term "tautomer" or "tautomerism" refers to structural isomers that differ in energy by a low energy barrier and can interconvert. If tautomerism is possible (as in solution), a chemical equilibrium of the tautomers can be reached. For example, protontautomer (also known as prototropic tautomer) includes interconversion by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomer includes interconversion by reorganization of some bonding electrons. A specific example of keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-keto tautomerism. A specific example of phenol-keto tautomerism is the interconversion of pyridin-4-ol and pyridin-4(lH)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the present application are within the scope of the present application.

[0044] The salts referred to herein are pharmaceutically acceptable salts, wherein "pharmaceutically acceptable salts" are well known in the art, as described in Berge et al., J. Pharmacol Sci, 1997, 66, 1-19. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral acid salts such as hydrochlorides, hydrobromides, phosphates, metaphosphates, sulfates, sulfites, nitrates, perchlorates, and organic acid salts such as carboxylate salts, sulfonate salts, sulfinate salts, sulfatc salts, and the like, specifically, but not limited to, methanesulfonate, ethanesulfonate, formate, acetate, succinate, benzoate, succinate, pamoate, salicylate, galactarate, glucoheptanoate, mandelate, 1,2-ethanedisulfonate, 2-naphthalenesulfonate, carbonate, trifluoroacetate, hydroxyacetate, isethionate, oxalate, maleate, tartrate, citrate, succinate, malonate, besylate, p-toluenesulfonate, malate, fumarate, lactate, lactobionate, or oxalate, or by other methods known to those of skill in the art such as ion exchange methods. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, besylate, brosylate, borate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, laurate, lauryl sulfate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, undecanoate, valerate, and the like. Additionally, pharmaceutically acceptable salts can include salts of acidic groups that are formed by appropriate bases, such as alkali, alkaline earth, ammonium and N+(C 1-4 alkyl)4 salts. The present application also contemplates the quaternary ammonium salts of any group containing N. Water or oil-soluble or dispersible products can be obtained by quaternization. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include, where appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed by the addition of inorganic or organic acids to a basic group, such as halogen, carboxy, sulfate, phosphate, nitrate, C 1-8 sulfate, and aromatic sulfonate.

[0045] Pharmaceutically acceptable salts can be formed with inorganic acids and organic acids, for example acetate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camsylate, chloride / hydrochloride, chlorobenzoate, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulfate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalacturonate, propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate, and trifluoroacetate. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0046] Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, sulfosalicylic acid, and the like.

[0047] "Solvate" of the present application refers to an association or complex of one or more solvent molecules with a compound of the present application. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol. The term "hydrate" refers to the complex where the solvent molecule is water.

[0048] The term "protecting group" or "PG" refers to a substituent that is commonly employed to block or protect the functionality of a particular group while undergoing a reaction elsewhere in the molecule. For example, "amino-protecting group" refers to a substituent attached to an amino group that blocks or protects the functionality of the amino group while other transformations are carried out elsewhere on the molecule. Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethyloxycarbonyl (Fmoc). Similarly, "hydroxy-protecting group" refers to a substituent of a hydroxy group that blocks or protects the functionality of the hydroxy group while other transformations are carried out elsewhere on the molecule. Suitable protecting groups for hydroxyl include acetyl and silyl. "Carboxy-protecting group" refers to a substituent of a carboxylic acid group that blocks or protects the functionality of the carboxylic acid group while other transformations are carried out elsewhere on the molecule. Typical carboxy-protecting groups include -CH2CH2SO2Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenylphosphino)ethyl, nitroethyl, and the like. For a general description of protecting groups, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and P. J. Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.

[0049] "Pharmaceutical composition" means a mixture of one or more of the compounds described herein, or a physiologically / pharmaceutically acceptable salt or prodrug thereof, with other chemical components, such as physiologically / pharmaceutically acceptable carriers or excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compound to an organism.

[0050] The term "treat," "treating" or "treatment" of any disease or disorder, as used herein in some embodiments means to ameliorate the disease or disorder (i.e., to slow or arrest or reduce the development of the disease or at least one of the clinical symptoms thereof). In other embodiments "treat" or "treatment" means to alleviate or ameliorate at least one physical parameter including those not discernible by the patient. In other embodiments, "treat" or "treatment" means to mediate or modulate a disease or disorder either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In other embodiments, "treat" or "treatment" means to prevent or delay the onset or development of a disease or disorder.

[0051] Any formula given herein is also intended to represent unlabelled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Exemplary isotopes that can be found in compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl, and 125 I.

[0052] In another aspect, the compounds according to the application include isotopically enriched compounds as defined by the application, for example, those in which a radioisotope is present, such as 3 H, 14 C, and 18 F, or in which a non-radioactive isotope is present, such as 2 H, and 13 C. Such isotopically enriched compounds are useful in metabolic studies (with 14 C), reaction kinetic studies (with, for example 2 H, or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), or for patient therapy, for example. 18 F-enriched compounds are particularly desirable for PET or SPECT studies. Isotopically-enriched compounds of Formula (I), Formula (II) can be prepared by conventional techniques known to those skilled in the art or by the procedures described in the Examples and Preparations herein using appropriate isotopically-enriched reagents in place of the non-enriched reagents previously employed.

[0053] Also, the heavier isotope, particularly deuterium (i.e., 2Substitution with heavier isotopes such as deuterium can afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements or an improvement in therapeutic index. It is believed that deuterium in the present application is regarded as a substituent of a compound of formula (I). The concentration of such heavier isotopes, particularly deuterium, can be defined in terms of an isotopic enrichment factor. The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance of the specified isotope and the natural abundance. If a substituent of a compound of the present application is designated as deuterium, the compound has an isotopic enrichment factor at each indicated deuterium atom of at least 3500 (52.5% deuterium incorporation at each indicated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation) for each specified deuterium atom. Pharmaceutically acceptable solvates of the present application include those in which the solvent can be isotopically substituted, e.g., D2O, acetone-d6, DMSO-d6.

[0054] As described herein, the compounds of the present application can be optionally substituted with one or more substituents, as in the general formula above, or as in the specific examples, subgeneric classes, and generic classes of compounds embraced by the present application. It will be appreciated that the term "optionally substituted" is used interchangeably with the term "substituted or unsubstituted." In general, the term "optionally" whether applied to "substituted" or "unsubstituted" indicates that one or more hydrogen atoms of the given structure are replaced by a particular substituent. Unless otherwise indicated, an optional substituent group can have a substituent at each substitutable position of the group. Where more than one position in the given structure can be substituted with one or more substituents selected from a specified group, the substituents can be the same or different at each position. The substituents described herein can be, but are not limited to, deuterium, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyl, alkenyl, alkynyl, heterocyclyl, thiol, nitro, aryloxy, heteroaryloxy, oxo (=0), carboxyl, hydroxyl-substituted alkoxy, hydroxyl-substituted alkyl-C(=0), alkyl-C(=0), alkyl-S(=0), alkyl-S(=0)2-, hydroxyl-substituted alkyl-S(=0), hydroxyl-substituted alkyl-S(=0)2, carboxylalkoxy, and the like.

[0055] As used herein, the term "alkyl" means a saturated straight chain or branched chain monovalent hydrocarbon radical of one to twenty carbon atoms, or one to ten carbon atoms, or one to eight carbon atoms, or one to six carbon atoms, or one to four carbon atoms, or one to three carbon atoms, wherein the alkyl group can be independently and optionally substituted with one or more substituents as described herein. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), t-butyl (t-Bu, -C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-l-butyl (-CH2CH2CH(CH3)2), 2-methyl-l-butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl, n-octyl, and the like. The terms "alkyl" and its prefix "alk" as used herein encompass both straight chain and branched chain saturated carbon chains. The term "alkylene" as used herein means a saturated divalent hydrocarbon radical derived from a straight chain or branched chain saturated hydrocarbon by the removal of two hydrogen atoms, examples of which include, but are not limited to, methylene, ethylene, isopropylene, and the like.

[0056] The term "alkoxy" as used herein refers to an alkyl group, as defined herein, attached to the parent chain through an oxygen atom. Examples of such include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, and the like. The alkoxy group can be substituted or unsubstituted, wherein the substituents can be, but are not limited to, hydroxyl, amino, halogen, cyano, alkoxy, alkyl, alkenyl, alkynyl, thiol, nitro, and the like.

[0057] The term "alkenyl" refers to a straight or branched chain monovalent hydrocarbon radical of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, wherein at least one position is unsaturated, i.e., one C-C is an sp2 double bond, wherein the alkenyl group can be independently and optionally substituted with one or more substituents described herein, including the positioning of the "trans", "cis", or "E", "Z" groups, wherein specific examples of alkenyl include, but are not limited to, ethenyl (-CH=CH2), allyl (-CH2CH=CH2), and the like.

[0058] The term "alkynyl" refers to a straight or branched chain monovalent hydrocarbon radical of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, wherein at least one position is unsaturated, i.e., one C-C is an sp triple bond, wherein the alkynyl group can be independently and optionally substituted with one or more substituents described herein, wherein specific examples of alkynyl include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH2C≡CH), and the like.

[0059] The term "cycloalkyl" refers to a monovalent or polyvalent, non-aromatic, saturated or partially unsaturated ring containing no heteroatoms, including a monocyclic ring of 3-12 carbon atoms or a bicyclic ring of 7-12 carbon atoms. Bicyclic carbocycles having 7-12 atoms may be bicyclic [4,5], [5,5], [5,6], or [6,6] systems, while bicyclic carbocycles having 9 or 10 atoms may be bicyclic [5,6] or [6,6] systems. Suitable cyclic aliphatic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl groups. Examples of cyclic aliphatic groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like. And the "cyclic aliphatic group" or "carbocycle", "carbocyclic group", "cycloalkyl" may be substituted or unsubstituted, wherein the substituents may be, but are not limited to, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclic group, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=O), alkyl-C(=O), alkyl-S(=O), alkyl-S(=O)2-, hydroxy-substituted alkyl-S(=O), hydroxy-substituted alkyl-S(=O)2, carboxyalkoxy and the like.

[0060] The terms "heterocycle," "heterocyclyl," "heteroalicyclic," or "heterocyclic" are used interchangeably herein and refer to a monocyclic, bicyclic, or tricyclic ring system in which one or more carbon atoms in the ring(s) are independently and optionally replaced by heteroatoms, wherein the heteroatoms have the meanings herein, the ring(s) may be fully saturated or contain one or more degrees of unsaturation, but are never aromatic, and have only one point of attachment to another molecule. One or more hydrogen atoms in the ring(s) are independently and optionally replaced by one or more substituents as described herein. In some embodiments, the "heterocycle", "heterocyclyl", "heteroalicyclic" or "heterocyclic" group is a 3-7 membered monocyclic ring (1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, wherein S or P is optionally replaced by one or more oxygen atoms to give groups such as SO, SO2, PO, PO2, and when the ring is a three-membered ring, there is only one heteroatom therein), or a 7-10 membered bicyclic ring (4-9 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, wherein S or P is optionally replaced by one or more oxygen atoms to give groups such as SO, SO2, PO, PO2).

[0061] Heterocyclyl groups can be carbon-based or heteroatom-based. "Heterocyclyl" also includes groups in which a heterocyclyl group is fused to a saturated or partially unsaturated ring or heterocycle. Examples of heterocycles include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxazolidinyl, thiazolidinyl, oxazolidinyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, piperidinyl, homopiperidinyl, epoxypropyl, azepanyl, oxepanyl, thiepanyl, 4-methoxy-piperidin-1-yl, 1,2,3,6-tetrahydropyridin-1-yl, oxazepin-2-oxo-5-azabicyclo[2.2.1]heptanyl, 2-oxo-5-azabicyclo[2.2.2]octanyl, quinolizinyl, and N-pyridinyl urea. Examples of heterocyclic groups also include 1,1-dioxothiomorpholinyl, and groups in which two carbon atoms of the ring are replaced by oxygen atoms, such as pyrimidinedionyl. Also, the heterocyclyl groups can be substituted or unsubstituted, where the substituents can be, but are not limited to, oxo (=0), hydroxy, amino, halogen, cyano, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, thiol, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=0), alkyl-C(=0), alkyl-S(=0), alkyl-S(=0)2-, hydroxy-substituted alkyl-S(=0), hydroxy-substituted alkyl-S(=0)2, carboxyalkoxy, and the like. Examples of heterocyclic groups also include 1,1-dioxothiomorpholinyl, and groups in which two carbon atoms of the ring are replaced by oxygen atoms, such as pyrimidinedionyl. Also, the heterocyclyl groups can be substituted or unsubstituted, where the substituents can be, but are not limited to, oxo (=0), hydroxy, amino, halogen, cyano, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, thiol, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=0), alkyl-C(=0), alkyl-S(=0), alkyl-S(=0)2-, hydroxy-substituted alkyl-S(=0), hydroxy-substituted alkyl-S(=0)2, carboxyalkoxy, and the like.

[0062] ​​The term "aryl" can be used alone or as part of "aralkyl," "aralkyloxy," or "aryloxyalkyl" and refers to monocyclic, bicyclic, and tricyclic carbocyclic ring systems containing a total of 6 to 14 ring members, wherein at least one ring system is aromatic, wherein each ring system contains 3 to 7 ring members, and only one attachment point to the rest of the molecule. The term "aryl" can be used interchangeably with the term "aromatic ring," e.g., aromatic rings can include phenyl, naphthyl, and anthryl. Also, the aryl group can be substituted or unsubstituted, wherein the substituents can be, but are not limited to, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, thiol, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=O)-, alkyl-C(=O)-, alkyl-S(=O)-, alkyl-S(=O)2-, hydroxy-substituted alkyl-S(=O)-, hydroxy-substituted alkyl-S(=O)2-, carboxyalkoxy, and the like.

[0063] The term "heteroaryl" refers to monocyclic, bicyclic, and tricyclic ring systems containing a total of 5 to 14 ring members, wherein at least one ring system is aromatic, and at least one ring system contains one or more heteroatoms, wherein the heteroatoms have the meaning described herein, wherein each ring system contains 3 to 7 ring members, and only one attachment point to the rest of the molecule. The term "heteroaryl" can be used interchangeably with the term "heteroaromatic ring" or "heteroaromatic compound." Also, the heteroaryl group can be substituted or unsubstituted, wherein the substituents can be, but are not limited to, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, thiol, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=O)-, alkyl-C(=O)-, alkyl-S(=O)-, alkyl-S(=O)2-, hydroxy-substituted alkyl-S(=O)-, hydroxy-substituted alkyl-S(=O)2-, carboxyalkoxy, and the like.

[0064] In other embodiments, heteroaryl groups include, but are not limited to, the following monocycles: 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 4-methylisoxazol-5-yl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, pyrimidin-5-yl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thiophenyl, 3-thiophenyl, pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazol-2-yl, pyrazinyl, pyrazin-2-yl, 1,3,5-triazinyl; and the following bicycles, but are not limited to these bicycles: benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl (e.g., 2-indolyl), purinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), and isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl), benzo[d]thiazol-2-yl, imidazo[l,5-a]pyridin-6-yl.

[0065] The term "heteroatom" means one or more O, S, N, P, and Si atoms, including forms of N, S, and P in any oxidation state; forms of primary, secondary, tertiary amines and quaternary ammonium salts; or forms in which the hydrogen on a nitrogen atom in a heterocycle is replaced by substitution, e.g., N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR (as in N-substituted pyrrolidinyl).

[0066] The term "halogen" means F, Cl, Br, or I.

[0067] The term "halo" as used herein means one or more of the halogens F, Cl, Br, or I.

[0068] The term "hydroxy-substituted" as used herein means one or more hydroxy groups substituted on the group to which they are attached.

[0069] The term "substituted" as used herein between two groups means that the group preceding the substituent is substituted with the substituent, e.g., "aryl substituted alkyl" means that the alkyl group is substituted with an aryl group, "alkoxycarbonyl substituted alkyl" means that the alkyl group is substituted with an alkoxycarbonyl group. When multiple groups are used in combination, the substituent relationship is from left to right, e.g., "arylalkyl" means that the aryl group is substituted on the alkyl group, "alkoxyalkoxy" means that the alkoxy group is substituted on the alkyl group.

[0070] The term "unsaturated" as used herein means that the moiety contains one or more degrees of unsaturation.

[0071] Description of the compounds of the present application

[0072] In one aspect, the present application provides a compound having the structure of Formula (I), or a stereoisomer, enantiomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the structure of Formula (I),

[0073]

[0074] wherein R 1 is optionally substituted aryl or heteroaryl; the substituents are selected from halo, alkyl, alkoxy, haloalkyl, cyano, amino or cycloalkyl;

[0075] R 2 is H, alkyl, haloalkyl, alkenyl or alkynyl.

[0076] In some embodiments, R 1 is optionally substituted C 6-10 aryl or C 2-9 heteroaryl;

[0077] the substituents are selected from F, Cl, Br, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, cyano, amino or C 3-8 cycloalkyl.

[0078] In other embodiments, R 1 is optionally substituted phenyl, thiazolyl, thienyl, furanyl, pyrrolyl, pyridyl or pyrimidinyl;

[0079] the substituents are selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, methoxy, ethoxy, CF3, CHF2, CH2F, cyano, amino, cyclopropyl, cyclobutyl or cyclopentyl.

[0080] In some embodiments, R 2 is H, C1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl.

[0081] In other embodiments, the compound wherein R 2 is H, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, CF3, CHF2, CH2F, vinyl, propenyl, ethynyl or propynyl.

[0082] In some embodiments, the compound has the structure

[0083]

[0084] Compositions, formulations and administration of the compounds of the present invention

[0085] The pharmaceutical composition comprises any one of the compounds of the present invention and may further comprise a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.

[0086] Examples of pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl cellulose. sodium cellulose, ethylcellulose and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycol compounds such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol, phosphate buffered solution, and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, colorants, release agents, coatings, sweeteners, flavorings and fragrances, preservatives and antioxidants.

[0087] When used for therapy, therapeutically effective amounts of the compounds of the present application can be administered as the neat chemical, but will generally be presented as the active ingredient of a pharmaceutical composition. Accordingly, the present application also provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of the present application and one or more pharmaceutically acceptable carriers, diluents or excipients. As used herein, the term "therapeutically effective amount" means the total amount of each active component that is sufficient to yield a meaningful patient benefit, e.g., reduction in viral load. When applied to an individual active ingredient, the term refers only to that ingredient, and when applied to a combination, the term refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered individually or together. The carrier(s), diluent(s) or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject. In accordance with another aspect of the present application, there is also provided a method for preparing a pharmaceutical formulation, comprising admixing a compound of the present application and one or more pharmaceutically acceptable carriers, diluents or excipients. As used herein, the term "pharmaceutically acceptable" means, within the scope of sound medical judgment, that the compounds, materials, compositions, and / or dosage forms of the present application are suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, or other complication of commensurate risk and benefit as reasonably judged by those in the field.

[0088] It will be appreciated that, in addition to ingredients particularly mentioned herein, the formulations can include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration can include flavouring agents.

[0089] Use of the compounds and compositions of the present application

[0090] The use of a compound or pharmaceutical composition of the present application for the manufacture of a medicament for the prophylaxis, management, treatment or alleviation of a phosphatidylinositol 3-kinase (PI3K) mediated disease in a patient, preferably a PI3K alpha mediated disease.

[0091] A phosphatidylinositol 3-kinase (PI3K) mediated disease includes a proliferative disease; a benign or malignant tumour; a cancer selected from sarcoma, lung cancer, bronchus cancer, prostate cancer, breast cancer, pancreatic cancer, gastrointestinal cancer, colon cancer, rectal cancer, thyroid cancer, liver cancer, adrenal gland cancer, stomach cancer, glioma, endometrial cancer, melanoma, kidney cancer, bladder cancer, cervix uteri cancer, vagina cancer, ovary cancer, multiple myeloma, oesophagus cancer, leukaemia, lymphocytic leukaemia, oral cavity cancer, brain cancer, larynx cancer, small intestine cancer, non-Hodgkin lymphoma, lymphoid cancer, mammary cancer or squamous cell cancer.

[0092] An "effective amount" or "effective dose" of a compound or pharmaceutically acceptable composition of the present application means an amount effective at treating or lessening the severity of one or more of the disorders contemplated by the present application. Compounds and compositions thereof according to the present application can be used in any amount and by any route of administration effective to treat or lessen the severity of the disease. The exact amount required will vary depending on the subject's condition, age, general condition, severity of infection, special factors, mode of administration, and the like. Compounds or compositions of the present application can be administered in combination with one or more other therapeutic agents, as discussed herein. DETAILED DESCRIPTION

[0093] In order to better enable those skilled in the art to practice the technology disclosed herein, further embodiments are described below.

[0094] General Synthetic Procedures

[0095] In general, compounds of the present application can be prepared by the methods described herein. The following reaction schemes and examples are presented to further illustrate the present application.

[0096] Those skilled in the art will appreciate that the chemical reactions described herein can be performed in various manners and that the present application is intended to embrace the total number of possible chemical compounds which can be obtained using the described reactions, as well as the impure products of the described reactions. Also, other methods for preparing compounds of the present application can be employed and the present application is intended to embrace all such possible preparative methods. For example, the synthesis of those compounds of the present application which are not exemplified herein can be successfully performed by a skilled artisan by applying the methods described herein to the synthesis of the exemplified compounds, or by applying other methods in accordance with the synthetic principles described herein. Also, the reaction conditions and precursors used in the synthesis of the compounds of the present application can be varied by a skilled artisan without departing from the spirit of the present application.

[0097] The examples described below, unless otherwise stated, all temperatures are set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Inc., Arco Chemical Company and Alfa Chemical Company, and were used without further purification, unless otherwise indicated. General reagents were purchased from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyu Chemicals Co. Ltd., Qingdao Tenglong Chemical Reagent Co. Ltd., and Qingdao Haian Chemical Factory.

[0098] Anhydrous tetrahydrofuran, dioxane, toluene, diethyl ether were dried over sodium metal under reflux. Anhydrous dichloromethane and chloroform were dried over calcium hydride under reflux. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide and N,N-dimethylformamide were used as received.

[0099] The following reactions were generally performed under an atmosphere of nitrogen or argon at positive pressure or under anhydrous conditions in a dry box (unless otherwise stated), reaction vessels were fitted with a suitable septum and substrates were introduced via syringe. Glassware was oven- or flame-dried.

[0100] Chromatography columns were packed with silica gel. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Factory. NMR spectra were recorded in CDC13, d6-DMSO, CD3OD or d6-acetone as solvent (reported in ppm) with TMS (0 ppm) or chloroform (7.25 ppm) as reference standard. When multiplets were observed, the following abbreviations were used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets). Coupling constants are reported in Hertz (Hz).

[0101] Low resolution mass spectrometry (MS) data were determined by a spectrometer of Agilent 6320 series LC-MS equipped with G1312A binary pump and a G1316A TCC (column temperature was kept at 30 °C), G1329A autosampler and G1315B DAD detector were applied for analysis, ESI source was applied for LC-MS spectrometer.

[0102] Low resolution mass spectrometry (MS) data were determined by a spectrometer of Agilent 6120 series LC-MS equipped with G1311A quaternary pump and a G1316A TCC (column temperature was kept at 30 °C), G1329A autosampler and G1315D DAD detector were applied for analysis, ESI source was applied for LC-MS spectrometer.

[0103] Both of the above spectrometers are equipped with Agilent Zorbax SB-C18 column, 2.1*30mm, 5um. The injection volume is determined by the sample concentration; the flow rate is 0.6mL / min; the peak of HPLC is recorded by reading the UV-Vis wavelength at 210nm and 254nm. The mobile phase is 0.1% formic acid acetonitrile solution (phase A) and 0.1% formic acid ultrapure water solution (phase B). The gradient elution conditions are shown in Table 1:

[0104] Table 1

[0105] Time (min) [A (CH3CN, 0.1% HCOOH)] [B (H20, 0.1% HCOOH)] 0-3 5-100 95-0 3-6 100 0 6-6.1 100-5 0-95 6.1-8 5 95

[0106] The process conditions for HPLC preparation are as follows:

[0107] (1). Take an appropriate amount of diastereoisomer mixture containing compound (II) and dissolve it with the mobile phase;

[0108] (2). Set the flow rate of the mobile phase, detection wavelength and column temperature;

[0109] (3). Take an appropriate amount of sample solution in step (1) and inject it into the high performance liquid chromatograph, record the chromatogram, complete the separation and analysis of isomers;

[0110] Chromatographic column: normal phase chromatographic column with silica gel containing polysaccharide derivatives as stationary phase; more specifically, the chromatographic column used is Daicel AD-H (10*250nm, 5um) or Daicel AD (20*250nm, 5um).

[0111] Mobile phase: a mixture of two or more of methanol, ethanol, isopropanol, acetonitrile, n-hexane, n-pentane, isohexane, n-heptane, diethylamine, triethylamine, trifluoroacetic acid, glacial acetic acid; more specifically, the volume ratio of n-hexane, n-pentane, isohexane, n-heptane in the mixture of the mobile phase is 10-20%, the volume ratio of methanol, ethanol, isopropanol, acetonitrile is 20-95%, the volume ratio of diethylamine, triethylamine, trifluoroacetic acid, glacial acetic acid is 0-2%, the total of each component in the mobile phase is 100%; more specifically, the volume ratio of n-hexane in the mixture of the mobile phase is 15-20%, the volume ratio of isopropanol is 80-90%, the volume ratio of diethylamine, triethylamine is 0.5-1%, the total of each component in the mobile phase is 100%.

[0112] Detection wavelength: 250nm-320nm;

[0113] Flow rate: 0.5-10mL / min; more specifically, 2-5mL / min;

[0114] Column temperature: 10-35℃.

[0115] The use of the following abbreviations is used throughout this application:

[0116] LiHMDS: lithium bis(trimethylsilyl)amide

[0117] THF: tetrahydrofuran

[0118] Toluene: toluene

[0119] TFA: trifluoroacetic acid

[0120] POBr3: phosphorous oxybromide

[0121] Pd(OAc)2: palladium acetate

[0122] t-Bu3PHBF4: tri-tert-butylphosphonium tetrafluoroborate

[0123] Cs2CO3: cesium carbonate

[0124] DMF: N,N-dimethylformamide

[0125] HCl: hydrochloric acid

[0126] EtOH: ethanol

[0127] DCM: dichloromethane

[0128] Et3N: triethylamine

[0129] CDI: N,N-carbonyldiimidazole

[0130] AcOH: acetic acid

[0131] Boc2O, BOC anhydride: di-tert-butyl dicarbonate

[0132] Boc: tert-butyloxycarbonyl

[0133] CH3CN: acetonitrile

[0134] DCC: dicyclohexylcarbodiimide

[0135] DMAP: N,N-dimethyl-4-pyridinamine

[0136] EA: ethyl acetate

[0137] H2O: water

[0138] NaOH: sodium hydroxide

[0139] NaI: sodium iodide

[0140] K2CO3: potassium carbonate

[0141] rt, r.t.: room temperature

[0142] The synthesis of the compounds is outlined in general formula one below:

[0143]

[0144] Compounds of formula (9) or (10) can be prepared by the following procedure: 5-acetyl-2-amino-4-methylthiazole of formula (1) is reacted with acetyl chloride to give a compound of formula (2). The compound of formula (2) is reacted with liquid bromine in 1,4-dioxane to give a compound of formula (3). The compound of formula (3) is cyclized with 2,2-dimethylthiopropionamide in ethanol to give a compound of formula (4). The compound of formula (4) is deacetylated with hydrochloric acid in ethanol to give a compound of formula (5). The compound of formula (5) is reacted with CDI to give a compound of formula (6). The compound of formula (6) is reacted with a compound of formula (7) or (8) to give a compound of formula (9) or (10).

[0145] The synthesis of compounds is summarized in the following general scheme:

[0146]

[0147] Compounds of formula (16) can be prepared by the following procedure: 4-methyl-2-aminothiazole of formula (11) is reacted with acetyl chloride to give a compound of formula (12). The compound of formula (12) is coupled with 2-chloropyrimidine derivatives containing different substituents in the presence of palladium acetate to give a compound of formula (13). The compound of formula (13) is deprotected from the acetyl group in the presence of dilute hydrochloric acid in ethanol to give a compound of formula (14). The compound of formula (14) is reacted with N,N'-carbonyldiimidazole in dichloromethane to give a compound of formula (15). The compound of formula (15) is reacted with S-alanyl amide derivatives to give a compound of formula (16).

[0148] Example

[0149] Example 1 Synthesis of 2-(3-(2-(tert-butyl)-4'-methyl-[4,5'-bithiazol]-2'-yl)ureido)acetamide

[0150]

[0151] Step 1) Synthesis of N-(5-acetyl-4-methylthiazol-2-yl)acetamide

[0152] To the reaction flask was added 5-acetyl-2-amino-4-methylthiazole (10.00 g, 64.02 mmol), tetrahydrofuran (150 mL) and dichloromethane (100 mL) sequentially, acetyl chloride (7.54 g, 96.03 mmol) was added dropwise slowly under ice-bath, after the addition was completed, the system was transferred to room temperature and reacted for 22 hours. The reaction was stopped, saturated sodium bicarbonate solution (100 mL) was added to quench the reaction, THF and DCM were removed by distillation under reduced pressure, the aqueous phase was extracted with ethyl acetate (3*100 mL), the combined organic phase was rotary evaporated to dryness, and the crude product was purified by column chromatography to obtain the title compound as a white solid (5.10 g, 40%).

[0153] MS (ESI, pos.ion) m / z: 199.1 [M+H] + ;

[0154] 1 H NMR (400 MHz, DMSO-d6) d (ppm) 12.42 (s, 1H), 2.55 (s, 3H), 2.46 (s, 3H), 2.16 (s, 3H).

[0155] Step 2) Synthesis of N-(5-(2-bromoacetyl)-4-methylthiazol-2-yl)acetamide

[0156] To the reaction flask was added N-(5-acetyl-4-methylthiazol-2-yl)acetamide (3.80 g, 19.19 mmol) and 1,4-dioxane (46 mL) sequentially, the system was warmed to 50 °C, liquid bromine (3.68 g, 23.03 mmol) was dissolved in 1,4-dioxane (30 mL) and added slowly dropwise to the reaction system, after the addition was completed, the system was stirred at 50 °C for 20 hours. The reaction was stopped, 1,4-dioxane was removed by distillation under reduced pressure, saturated sodium bicarbonate solution was added to adjust the solution pH = 8, the system was stirred at room temperature for 20 minutes, suction filtration was performed, and the filter cake was dried under vacuum at 60 °C to obtain the title compound as a light yellow solid (5.15 g, 96.8%).

[0157] MS (ESI, pos.ion) m / z: 278.3 [M+H] + ;

[0158] 1 H NMR (400 MHz, DMSO-d6) d (ppm) 12.52 (s, 1H), 4.70 (s, 2H), 2.50 (s, 3H), 2.13 (s, 3H).

[0159] Step 3) Synthesis of N-(2-(tert-butyl)-4'-methyl-[4,5'-bithiazol]-2'- yl)acetamide

[0160] To the reaction flask was added N-(5-(2-bromoacetyl)-4-methylthiazol-2-yl)acetamide (5.15 g, 18.59 mmol), 2,2-dimethylthiopropionamide (3.26 g, 27.90 mmol) and ethanol (85 mL) successively, after the addition was completed, the reaction was stirred at room temperature for 16 hours. The reaction was stopped, concentrated, and purified by column chromatography to obtain the title compound as a light yellow solid (4.75 g, 86.7%).

[0161] MS (ESI, pos.ion) m / z: 296.2 [M+H] + ;

[0162] 1 H NMR (400 MHz, CDCl3) d (ppm) 9.59 (s, 1H), 2.78 (s, 3H), 2.46 (s, 3H), 1.45 (s, 9H).

[0163] Step 4) Synthesis of 2-(tert-butyl)-4'-methyl-[4,5'-bithiazol]-2'-amine

[0164] To the reaction flask was added N-(2-(tert-butyl)-4'-methyl-[4,5'-bitthiazol]-2'- yl)acetamide (4.70 g, 15.93 mmol), hydrochloric acid (6.60 mL, 79.65 mmol) and ethanol (50 mL) successively, after the addition was completed, the reaction was stirred at 80 °C for 15 hours. The reaction was stopped, the ethanol was rotary evaporated, water (30 mL) was added, the aqueous phase was adjusted to pH = 8 with saturated sodium bicarbonate solution, stirred for 30 minutes, suction filtered, and the solid was purified by column chromatography to obtain the title compound as a light yellow solid (2.50 g, 62.0%).

[0165] MS (ESI, pos.ion) m / z: 254.2 [M+H] + ;

[0166] 1 H NMR (400 MHz, CDCl3) d (ppm) 6.91 (s, 1H), 2.43 (s, 3H), 1.44 (s, 9H).

[0167] Step 5) Synthesis of N-(2-(tert-butyl)-4'-methyl-[4,5'-bithiazol]-2'-yl)-1H- imidazole-1-carboxamide Step 6) Synthesis of 2-(3-(2-(tert-butyl)-4'-methyl-[4,5'-bithiazol]-2'- yl)ureido)acetamide

[0168] To the reaction flask was added 2-(tert-butyl)-4'-methyl-[4,5'-bitthiazol]-2'-amine (0.40 g, 1.58 mmol), 1,1'-carbonyldiimidazole (0.51 g, 3.16 mmol) and dichloromethane (15 mL) successively, after the addition was completed, the reaction was stirred at room temperature for 2 hours. The reaction was stopped, suction filtered, and the filter cake was rotary evaporated to obtain the title compound as a white solid (0.45 g, 82.1%)

[0169] 1 H NMR (400 MHz, DMSO-d6) d (ppm) 7.64 (s, 1H), 7.22 (s, 1H), 7.01 (s, 1H), 6.96 (s, 1H), 2.31 (s, 3H), 1.38 (s, 9H).

[0170] Step 1) Synthesis of (S)-2-(3-(2-(tert-butyl)-4'-methyl-[4,5'-bithiazol]-2'- yl)ureido)propanamide

[0171] To the reaction flask was added N-(2-(tert-butyl)-4'-methyl-[4,5'- bithiazol]-2'-yl)-1H-imidazole-1-carboxamide (0.43 g, 1.24 mmol), 2- aminoacetamide (0.11 g, 1.47 mmol) and triethylamine (0.52 mL, 3.72 mmol) in dichloromethane (15 mL) at room temperature for 20 hours. After the reaction was completed, suction filtered, the filter cake was slurried in methanol (6 mL), suction filtered, and the filter cake was oven dried to give the title compound as a white solid (0.32 g, 73.2%).

[0172] MS (ESI, pos.ion) m / z: 354.6 [M+H] + ;

[0173] 1 H NMR (400 MHz, DMSO-d6) d (ppm) 10.52 (s, 1H), 7.48 (s, 1H), 7.44 (s, 1H), 7.11 (s, 1H), 6.78 (s, 1H), 3.75 (d, J = 5.0 Hz, 2H), 2.42 (s, 3H), 1.40 (s, 9H).

[0174] 13 C NMR (151 MHz, DMSO-d6) d (ppm) 180.3, 171.2, 157.9, 154.3, 147.0, 143.5, 118.9, 112.2, 49.1, 42.8, 37.7, 31.0, 17.3.

[0175] Example 2 Synthesis of (S)-2-(3-(2-(tert-butyl)-4'-methyl-[4,5'- bithiazol]-2'-yl)ureido)propanamide

[0176]

[0177] Step 1) Synthesis of (S)-2-(3-(2-(tert-butyl)-4'-methyl-[4,5'-bithiazol]-2'- yl)ureido)butanamide Step 1) Synthesis of (S)-2-(3-(2-(tert-butyl)-4'-methyl-[4,5'-bithiazol]-2'- yl)ureido)pentanamide

[0178] The title compound was prepared by the method described in Step 6 of Example 1, i.e. reaction of N-(2-(tert-butyl)-4'-methyl-[4,5'-bitiadiazol]-2'-yl)-lH-imidazole-l- carboxamide (0.36 g, 1.04 mmol), (2S)-2-aminopropanamide hydrochloride (0.15 g, 1.24 mmol) and triethylamine (0.43 mL, 3.12 mmol) in dichloromethane (15 mL) at room temperature for 20 h. After the reaction was completed, the solvent was evaporated and the resulting solid was purified by column chromatography (dichloromethane:methanol = 20: 1 (v:v)) to give the title compound as a white solid (0.30 g, 78.9%).

[0179] MS (ESI, pos.ion) m / z: 368.3 [M+H] + ;

[0180] 1 H NMR (400 MHz, DMSO-d6) d (ppm) 10.35 (s, 1H), 7.58 (s, 1H), 7.43 (s, 1H), 7.13 (s, 1H), 6.90 (d, J = 6.8 Hz, 1H), 4.22 - 4.19 (m, 1H), 3.17 (d, J = 4.8 Hz, 3H), 2.41 (s, 3H), 1.40 (s, 9H).

[0181] 13 C NMR (101 MHz, DMSO-d6) d 180.3, 174.5, 157.7, 153.5, 147.0, 143.5, 119.0, 112.2, 49.0 (d, J = 13.2 Hz), 37.7, 31.0, 20.1, 17.3.

[0182] Example 3 Synthesis of (S)-2-(3-(2-(tert-butyl)-4'-methyl-[4,5'-bitiadiazol]-2'- yl)ureido)butanamide

[0183]

[0184] Step 1) Synthesis of N-(5-(4,6-dimethoxypyrimidin-2-yl)-4-methylthiazol-2- yl)acetamide Step 2) Synthesis of N-(5-(4,6-dimethoxypyrimidin-2-yl)-4-methylthiazol-2- yl)-1H-imidazole-1-carboxamide

[0185] The title compound was prepared by the method described in Reference Example 1, step 6, i.e. reaction of N-(2-(tert-butyl)-4'-methyl-[4,5'-bithiazol]-2'-yl)-1H-imidazole-1-carboxamide (0.36 g, 1.04 mmol), (2S)-2-aminobutanamide (0.13 g, 1.25 mmol) and triethylamine (0.43 mL, 3.12 mmol) in dichloromethane (15 mL) at room temperature for 20 hours. After the reaction was completed, the solvent was evaporated and the resulting solid was purified by column chromatography (dichloromethane:methanol = 15:1 (v:v)) to give the title compound as a white solid (0.24 g, 60.8%).

[0186] MS (ESI, pos.ion) m / z: 382.2 [M+H] + ;

[0187] 1 H NMR (400 MHz, DMSO-d6) d (ppm) 10.33 (s, 1H), 7.60 (s, 1H), 7.44 (s, 1H), 7.15 (s, 1H), 6.88 (d, J = 7.6 Hz, 1H), 4.14 (ddd, J = 15.7, 11.7, 5.9 Hz, 1H), 2.44 (d, J = 10.9 Hz, 3H), 1.84 - 1.67 (m, 1H), 1.63 - 1.54 (m, 1H), 1.40 (s, 9H), 0.85 (t, J = 7.4 Hz, 3H).

[0188] 13 C NMR (101 MHz, DMSO-d6) d (ppm) 180.3, 173.6, 157.7, 153.7, 147.0, 143.6, 119.0, 112.2, 54.1, 37.7, 31.0, 26.6, 17.3, 9.9.

[0189] Example 4. Synthesis of (S)-2-(3-(2-(tert-butyl)-4'-methyl-[4,5'-bithiazol]-2'- yl)ureido)pentanamide

[0190]

[0191] Step 3) Synthesis of 5-(4,6-dimethoxypyrimidin-2-yl)-4-methylthiazol-2- amine Step 4) Synthesis of N-(5-(4,6-dimethoxypyrimidin-2-yl)-4-methylthiazol-2- yl)-1H-imidazole-1-carboxamide

[0192] The title compound was prepared by the method described in Reference Example 1, step 6, i.e. reaction of N-(2-(tert-butyl)-4'-methyl-[4,5'-bithiazol]-2'-yl)-1H-imidazole-1-carboxamide (0.38 g, 1.09 mmol), (2S)-2-aminopentanamide (0.15 g, 1.31 mmol) and triethylamine (0.45 mL, 3.27 mmol) in dichloromethane (15 mL) at room temperature for 20 hours. After the reaction, the solvent was evaporated and the resulting solid was purified by column chromatography (dichloromethane:methanol = 20:1 (v:v)) to give the title compound as a white solid (0.37 g, 85.6%).

[0193] MS (ESI, pos.ion) m / z: 396.1 [M+H] + ;

[0194] 1 H NMR (400 MHz, DMSO-d6) d (ppm) 10.30 (s, 1H), 7.60 (s, 1H), 7.43 (s, 1H), 7.13 (s, 1H), 6.85 (d, J = 7.8 Hz, 1H), 4.23 - 4.08 (m, 2H), 3.17 (d, J = 5.2 Hz, 1H), 2.41 (s, 3H), 1.66 (td, J = 13.4, 7.9 Hz, 1H), 1.60 - 1.48 (m, 1H), 1.39 (s, 9H), 0.89 (t, J = 7.3 Hz, 3H).

[0195] 13 C NMR (151 MHz, DMSO-d6) d (ppm) 180.2, 173.9, 157.7, 153.7, 147.0, 143.6, 119.0, 112.2, 52.9, 37.7, 35.7, 31.0, 18.6, 17.3, 14.2.

[0196] Example 5 Synthesis of 2-(3-(5-(4,6-dimethylpyrimidin-2-yl)-4-methylthiazol-2-yl)ureido)acetamide

[0197]

[0198] Step 5) Synthesis of 2-(3-(5-(4,6-dimethoxypyrimidin-2-yl)-4-methylthiazol- 2-yl)ureido)acetamide

[0199] Into a 250 mL reaction flask, was added 4-methyl-2-aminothiazole (10.00 g, 87.72 mmol), dichloromethane (100 mL) and triethylamine (24.40 mL, 175.44 mmol) sequentially, the reaction was cooled to 0 °C, acetyl chloride (7.48 mL, 105.26 mmol) was added dropwise slowly, after the addition was completed, the temperature was raised to room temperature and the reaction was allowed to proceed for 16 hours. The reaction was stopped, water (100 mL) was added to quench the reaction, the organic phase was collected, concentrated and triturated, and column chromatography purification (petroleum ether: ethyl acetate (v:v) = 3:1) gave the title compound as a white solid (10.37 g, 75.8%).

[0200] MS (ESI, pos.ion) m / z: 157.1 [M+H] + ;

[0201] 1 H NMR (400 MHz, CDCl3) d (ppm): 11.31 (s, 1H), 6.56 (d, J = 0.8 Hz, 1H), 2.38 (d, J = 0.5 Hz, 3H), 2.24 (s, 3H).

[0202] Step 1) Synthesis of (S)-2-(3-(5-(4,6-dimethoxypyrimidin-2-yl)-4-methylthiazol- 2-yl)ureido)propanamide

[0203] Into a 100 mL reaction flask, was added N-(4-methylthiazol-2-yl)acetamide (2.00 g, 12.82 mmol), 2-chloro-4,6-dimethylpyrimidine (2.00 g, 14.10 mmol), cesium carbonate (8.35 g, 25.64 mmol), palladium acetate (0.29 g, 1.28 mmol), boron trifluoride tri-tert-butylphosphine (0.74 g, 2.56 mmol) and N,N-dimethylformamide (30 mL) sequentially, the system was protected by nitrogen, the temperature was raised to 90 °C and the reaction was allowed to proceed overnight. The reaction was stopped, cooled to room temperature, suction filtered, water (30 mL) and ethyl acetate (30 mL) were added to the filtrate, allowed to stand and separate, the ethyl acetate layer was collected, concentrated and triturated, and column chromatography purification (petroleum ether: ethyl acetate (v:v) = 3:1) gave the title compound as a yellow solid (1.80 g, 53.6%).

[0204] MS (ESI, pos.ion) m / z: 263.2 [M+H] + ;

[0205] 1 H NMR (400 MHz, CDCl3) d (ppm): 11.37 (s, 1H), 6.61 (s, 1H), 2.61 (s, 3H), 2.28 (s, 6H), 2.06 (s, 3H).

[0206] Step 1) Synthesis of (S)-2-(3-(5-(4,6-dimethoxypyrimidin-2-yl)-4-methylthiazol- 2-yl)ureido)butanamide

[0207] Into a 100 mL reaction flask, was added N-(5-(4,6-dimethylpyrimidin-2-yl)-4- methylthiazol-2-yl)acetamide (1.70 g, 6.49 mmol), ethanol (20 mL) and concentrated hydrochloric acid (6.50 mL, 77.88 mmol) sequentially. After the addition was completed, the temperature was raised to 80 °C and the reaction was allowed to proceed for 4 hours. The reaction was stopped, water (30 mL) was added, the aqueous phase was adjusted to pH = 8 with saturated sodium bicarbonate solution, ethyl acetate (150 mL) was added, the layers were separated, and the ethyl acetate layer was collected and concentrated. Purification was performed by column chromatography (petroleum ether: ethyl acetate (v:v) = 2:1) to give the title compound as a white solid (0.96 g, 67.1%).

[0208] MS (ESI, pos.ion) m / z: 221.1 [M+H] + ;

[0209] 1 H NMR (400 MHz, DMSO-d6) d (ppm): 7.28 (s, 2H), 6.86 (s, 1H), 2.58 (s, 3H), 2.35 (s, 6H).

[0210] Step 1) Synthesis of (S)-2-(3-(5-(4,6-dimethoxypyrimidin-2-yl)-4-methylthiazol- 2-yl)ureido)pentanamide Step 1) Synthesis of N-(5-(4,6-dimethoxypyrimidin-2-yl)-4-methylthiazol-2- yl)acetamide

[0211] Into a 25 mL reaction flask, was added 5-(4,6-dimethylpyrimidin-2-yl)-4-methylthiazol- 2-amine (0.20 g, 0.91 mmol), N,N-carbonyldiimidazole (0.29 g, 1.82 mmol) and dichloromethane (7 mL) sequentially. After the addition was completed, the reaction was allowed to proceed at room temperature for 4 hours. The reaction was stopped, filtered, the filter cake was washed with dichloromethane (2 mL), the solid was collected, and the residual solvent was rotary evaporated to give the title compound as a white solid (0.25 g, 87.7%).

[0212] Step 2) Synthesis of N-(5-(4,6-dimethoxypyrimidin-2-yl)-4-methylthiazol-2- yl)-1H-imidazole-1-carboxamide

[0213] Into a reaction flask, was added N-(5-(4,6-dimethylpyrimidin-2-yl)-4-methylthiazol-2-yl)- 1H-imidazol-1-yl-formamide (0.25 g, 0.80 mmol), 2-aminoacetamide (0.07 g, 0.96 mmol), N,N-dimethylformamide (5 mL) and triethylamine (0.33 mL, 2.40 mmol) sequentially. After the addition was completed, the reaction was allowed to proceed at room temperature for 5 hours. The reaction was stopped, water (50 mL) was added, filtered, the filter cake was slurried in ethyl acetate (6 mL) at room temperature for 30 minutes, filtered, and dried to give the title compound as a white solid (0.22 g, 86.3%).

[0214] MS (ESI, pos.ion) m / z: 321.1 [M+H] + ;

[0215] 1 H NMR (400 MHz, DMSO-d6) d (ppm) 10.57 (br s, 1H), 7.49 (s, 1H), 7.12 (s, 1H), 6.99 (s, 1H), 6.83 (s, 1H), 3.76 (d, J = 5.2 Hz, 2H), 2.68 (s, 3H), 2.40 (s, 6H).

[0216] 13 C NMR (151 MHz, DMSO-d6) d (ppm) 171.1, 166.6, 161.3, 160.2, 154.1, 150.2, 123.0, 116.6, 42.8, 24.1, 18.3.

[0217] Example 6 Synthesis of 2(S)-2-(3-(5-(4,6-dimethylpyrimidin-2-yl)-4- methylthiazol-2-yl)ureido)propanamide

[0218]

[0219] Step 3) Synthesis of 5-(4,6-dimethoxypyrimidin-2-yl)-4-methylthiazol-2- amine Step 4) Synthesis of N-(5-(4,6-dimethoxypyrimidin-2-yl)-4-methylthiazol-2- yl)-1H-imidazole-1-carboxamide

[0220] The title compound was prepared by following the procedure described in Step 5 of Example 5, i.e. N-(5-(4,6-dimethylpyrimidin-2-yl)-4-methylthiazol-2-yl)-1H-imidazol-1- ylformamide (0.30 g, 0.95 mmol), (2S)-2-aminopropanamide (0.10 g, 1.14 mmol), N,N- dimethylformamide (5 mL) and triethylamine (0.40 mL, 2.85 mmol), after the addition was complete, the reaction was stirred at room temperature for 5 h. After the reaction was completed, water (50 mL) was added, the resulting solid was suction filtered and the wet product was dried in oven to give the title compound as a white solid (0.28 g, 87.8%).

[0221] MS (ESI, pos.ion) m / z: 335.2 [M+H] + ;

[0222] 1H NMR (400 MHz, DMSO-d6) d (ppm) 10.49 (br s, 1H), 7.59 (s, 1H), 7.15 (s, 1H), 7.00-6.92 (m, 2H), 4.23 (q, J = 6.9 Hz, 1H), 2.68 (s, 3H), 2.40 (s, 6H), 1.28 (d, J = 6.9 Hz, 3H).

[0223] 13 C NMR (151 MHz, DMSO-d6) d (ppm): 174.4, 166.6, 161.3, 160.1, 153.4, 150.3, 123.1, 116.6, 48.9, 24.1, 20.1, 18.3.

[0224] Example 7 Synthesis of (S)-2-(3-(5-(4,6-dimethylpyrimidin-2-yl)-4- methylthiazol-2-yl)ureido)butanamide

[0225]

[0226] Step 5) Synthesis of 2-(3-(5-(4,6-dimethoxypyrimidin-2-yl)-4-methylthiazol- 2-yl)ureido)acetamide Example No.

[0227] The title compound was prepared according to the procedure described in Step 5 of Example 5, i.e. N-(5-(4,6-dimethylpyrimidin-2-yl)-4-methylthiazol-2-yl)-1H-imidazol-1- ylformamide (0.32 g, 1.02 mmol), (S)-2-aminobutanamide (0.12 g, 1.22 mmol), N,N- dimethylformamide (5 mL) and triethylamine (0.43 mL, 3.06 mmol) and the reaction was stirred at room temperature for 5 h after the addition was complete. After the reaction was complete, water (50 mL) was added and the resulting solid was suction filtered and slurried in ethyl acetate (6 mL) at room temperature for 30 min, suction filtered and the wet product was dried in oven to give the title compound as a white solid (0.31 g, 87.3%).

[0228] MS (ESI, pos.ion) m / z: 349.2 [M+H] + ;

[0229] 1H NMR (400 MHz, DMSO-d6) d (ppm) 10.46 (br s, 1H), 7.61 (s, 1H), 7.16 (s, 1H), 6.99 (s, 1H), 6.93 (d, J = 7.6 Hz, 1H), 4.22 - 4.17 (m, 1H), 2.68 (s, 3H), 2.40 (s, 6H), 1.76 - 1.67 (m, 1H), 1.65 - 1.56 (m, 1H), 0.85 (t, J = 7.2 Hz, 3H).

[0230] 13 C NMR (151 MHz, DMSO-d6) d (ppm) 173.5, 166.6, 161.3, 160.1, 153.6, 150.3, 123.1, 116.5, 55.4, 54.0, 26.6, 24.1, 9.8.

[0231] Example 8. Synthesis of (S)-2-(3-(5-(4,6-dimethylpyrimidin-2-yl)-4- methylthiazol-2-yl)ureido)pentanamide

[0232]

[0233] Example 1 Example 2

[0234] The title compound was prepared by following the procedure described in Example 5, Step 5, i.e. N-(5-(4,6-dimethylpyrimidin-2-yl)-4-methylthiazol-2-yl)-1H- imidazol-1-ylformamide (0.30 g, 0.96 mmol), (S)-2-aminopentanamide (0.13 g, 1.15 mmol), N,N-dimethylformamide (5 mL) and triethylamine (0.40 mL, 2.88 mmol), after the addition was complete, the reaction was stirred at room temperature for 5 h. After the reaction was completed, water (50 mL) was added, the resulting solid was suction filtered and slurried in ethyl acetate (6 mL) at room temperature for 30 min, suction filtered and the wet product was dried in oven to give the title compound as a white solid (0.30 g, 86.7%).

[0235] MS (ESI, pos.ion) m / z: 363.2 [M+H] + ;

[0236] 1H NMR (400 MHz, DMSO-d6) d (ppm) 10.43 (br s, 1H), 7.61 (s, 1H), 7.14 (s, 1H), 6.98 (s, 1H), 6.90 (d, J = 7.8 Hz, 1H), 4.25 - 4.20 (m, 1H), 2.68 (s, 3H), 2.40 (s, 6H), 1.70 - 1.61 (m, 1H), 1.58 - 1.51 (m, 1H), 1.34 - 1.23 (m, 2H), 0.90 (t, J = 7.3 Hz, 3H).

[0237] 13 C NMR (151 MHz, DMSO-d6) d (ppm) 173.8, 166.6, 161.3, 160.1, 153.6, 150.3, 123.1, 116.5, 52.8, 35.8, 24.1, 18.6, 18.3, 14.2.

[0238] Example 9 Synthesis of 2-(3-(5-(4,6-dimethoxy-pyrimidin-2-yl)-4-methyl- thiazol-2-yl)ureido)acetamide

[0239]

[0240] Example 3

[0241] The title compound was prepared according to the procedure described in Example 5, Step 2, i.e. N-(4-methylthiazol-2-yl)acetamide (3.20 g, 20.51 mmol), 2-chloro-4,6-dimethoxy-pyrimidine (3.94 g, 22.56 mmol), cesium carbonate (13.36 g, 41.02 mmol), palladium acetate (0.46 g, 2.05 mmol), tri-tert-butylphosphonium tetrafluoroborate (1.19 g, 4.10 mmol) and DMF (45 mL) were reacted at 90 °C under nitrogen atmosphere. After completion of the reaction, the reaction mixture was cooled to room temperature, added 200 mL of water and stirred for 15 min. The reaction mixture was filtered and the filter cake was purified by column chromatography (petroleum ether: ethyl acetate (v:v) = 3:1) to give the title compound as a yellow solid (2.70 g, 45.0%).

[0242] MS (ESI, pos, ion): m / z: 295.1 [M+H] + .

[0243] Example 4

[0244] The title compound was prepared according to the procedure described in Step 3 of Example 5, i.e. N-(5-(4,6-dimethoxy pyrimidin-2-yl)-4-methylthiazol-2-yl)acetamide (2.70 g, 9.18 mmol) and hydrochloric acid (9.18 mL, 110.16 mmol) in ethanol (27 mL) at 80 °C for 4 h. After the reaction was completed, 150 mL of ethyl acetate and 30 mL of water were added, and the pH of the aqueous phase was adjusted to 8 by adding saturated sodium bicarbonate solution. The organic phase was collected by liquid-liquid extraction, and the title compound was obtained as a white solid (1.00 g, 43.3%) after concentration and column chromatography (petroleum ether: ethyl acetate (V:V) = 2:1).

[0245] MS (ESI, pos, ion) m / z: 253.1 [M+H] +

[0246] 1 H NMR (400 MHz, DMSO-d6) d (ppm) 7.42 (s, 2H), 5.86 (s, 1H), 3.87 (s, 6H), 2.58 (s, 3H).

[0247] Example 5 Example 6

[0248] The title compound was prepared according to the procedure described in Step 4 of Example 5, i.e. (5-(4,6-dimethoxy pyrimidin-2-yl)-4-methylthiazol-2-amine (0.40 g, 1.59 mmol) and N,N'-carbonyldiimidazole (0.52 g, 3.18 mmol) in DCM (30 mL) at room temperature for 4.5 h. After the reaction was completed, the solid was collected by filtration, and the solvent was removed by rotary evaporation to obtain the title compound as a white solid (0.47 g, 85.5%).

[0249] Example 7

[0250] The title compound was prepared according to the procedure described in Step 5 of Example 5, i.e. N-(5-(4,6-dimethoxy pyrimidin-2-yl)-4-methylthiazol-2-yl)-1H-imidazole-1-carboxamide (0.23 g, 0.66 mmol), 2-aminoacetamide (0.06 g, 0.79 mmol), N,N-dimethylformamide (5 mL), and triethylamine (0.28 mL, 1.98 mmol) at room temperature for 5 h. After the reaction was completed, water (50 mL) was added, and the solid was collected by filtration. The wet product was slurried in ethyl acetate (6 mL) at room temperature for 30 min, and the title compound was obtained as a white solid after filtration and drying (0.19 g, 81.2%).

[0251] MS (ESI, pos, ion) m / s: 353.1 [M+H] +

[0252] 1 H NMR (400 MHz, DMSO-d6) d (ppm) 10.74 (s, 1H), 7.51 (s, 1H), 7.12 (s, 1H), 6.85 (t, J = 4.8 Hz, 1H), 5.98 (s, 1H), 3.91 (s, 6H), 3.76 (d, J = 5.2 Hz, 2H), 2.68 (s, 3H).

[0253] 13 C NMR (101 MHz, DMSO-d6) d (ppm) 171.2, 171.1, 160.9, 160.6, 154.1, 151.6, 122.5, 86.2, 54.4, 49.1, 42.8, 18.6.

[0254] Example 10 Synthesis of (2S)-2-[[5-(4,6-dimethoxy-pyrimidin-2-yl)-4-methyl- thiazol-2-yl]formamid]propanamide

[0255]

[0256] The title compound was prepared by following the procedure described in Example 5, Step 5, i.e. N-(5-(4,6-dimethoxy-pyrimidin-2-yl)-4-methyl-thiazol-2-yl)-1H-imidazole-1- carboxamide (0.25 g, 0.72 mmol), (2S)-2-aminopropanamide (0.08 g, 0.86 mmol), N,N- dimethylformamide (5 mL) and triethylamine (0.30 mL, 2.16 mmol) and the reaction was stirred at room temperature for 5 h. After completion of the reaction, water (50 mL) was added and the solid obtained was filtered, slurried in ethyl acetate (6 mL) at room temperature for 30 min, filtered and dried to obtain the title compound as a white solid (0.22 g, 84.2%).

[0257] MS (ESI, pos, ion) m / s: 367.1 [M+H] +

[0258] 1 H NMR (400 MHz, DMSO-d6) d (ppm) 10.56 (s, 1H), 7.60 (s, 1H), 7.15 (s, 1H), 6.97 (d, J = 7.0 Hz, 1H), 5.98 (s, 1H), 4.25 - 4.17 (m, 1H), 3.91 (s, 6H), 2.68 (s, 3H), 1.28 (d, J = 6.9 Hz, 3H).

[0259] 13 1H NMR (400 MHz, DMSO-d6) d (ppm) 10.52 (s, 1H), 7.62 (s, 1H), 7.16 (s, 1H), 6.93 (d, J = 7.7 Hz, 1H), 5.98 (s, 1H), 4.24 - 4.17 (m, 1H), 3.92 (s, 6H), 2.68 (s, 3H), 1.76 - 1.67 (m, 1H), 1.64-1.56 (m, 1H), 0.85 (t, J = 7.4 Hz, 3H).

[0260] Example 11 Synthesis of (2S)-2-[[5-(4,6-dimethoxy-pyrimidin-2-yl)-4-methyl- thiazol-2-yl]formamid]butanamide

[0261]

[0262] The title compound was prepared by following the procedure described in Example 5, Step 5, i.e. N-(5-(4,6-dimethoxy-pyrimidin-2-yl)-4-methyl-thiazol-2-yl)-1H-imidazole-1- carboxamide (0.21 g, 0.61 mmol), (2S)-2-aminobutanamide (0.07 g, 0.73 mmol), N,N- dimethylformamide (5 mL) and triethylamine (0.25 mL, 1.83 mmol) and stirring at room temperature for 5 h. After completion of the reaction, water (50 mL) was added and the solid obtained was filtered, slurried in ethyl acetate (6 mL) at room temperature for 30 min, filtered and dried to obtain the title compound as a white solid (0.18 g, 80.3%).

[0263] MS (ESI, pos, ion) m / s: 381.2 [M+H] +

[0264] 1 1H NMR (400 MHz, DMSO-d6) d (ppm) 10.52 (s, 1H), 7.62 (s, 1H), 7.16 (s, 1H), 6.93 (d, J = 7.7 Hz, 1H), 5.98 (s, 1H), 4.24 - 4.17 (m, 1H), 3.92 (s, 6H), 2.68 (s, 3H), 1.76 - 1.67 (m, 1H), 1.64-1.56 (m, 1H), 0.85 (t, J = 7.4 Hz, 3H).

[0265] 13 1H NMR (400 MHz, DMSO-d6) d (ppm) 10.52 (s, 1H), 7.62 (s, 1H), 7.16 (s, 1H), 6.93 (d, J = 7.7 Hz, 1H), 5.98 (s, 1H), 4.24 - 4.17 (m, 1H), 3.92 (s, 6H), 2.68 (s, 3H), 1.76 - 1.67 (m, 1H), 1.64-1.56 (m, 1H), 0.85 (t, J = 7.4 Hz, 3H).

[0266] Example 12 Synthesis of (2S)-2-[[5-(4,6-dimethoxy-pyrimidin-2-yl)-4-methyl- thiazol-2-yl]formamid]pentanamide

[0267]

[0268] The title compound was prepared by the method described in Example 5, Step 5, i.e. N-(5-(4,6-dimethoxy-pyrimidin-2-yl)-4-methyl-thiazol-2-yl)-1H-imidazole-1- carboxamide (0.26 g, 0.75 mmol), (2S)-2-aminopentanamide (0.10 g, 0.90 mmol), N,N- dimethylformamide (5 mL) and triethylamine (0.31 mL, 2.25 mmol), after the addition was completed, the reaction was carried out at room temperature for 5 hours. After the reaction was completed, water (50 mL) was added, the obtained solid was extracted by filtration and was placed in ethyl acetate (6 mL) at room temperature for 30 minutes, extracted by filtration and the wet product was dried to obtain the title compound as a white solid (0.25 g, 84.5%).

[0269] MS (ESI, pos, ion) m / s: 395.2 [M+H] +

[0270] 1 H NMR (400 MHz, DMSO-d6) d (ppm) 10.49 (s, 1H), 7.62 (s, 1H), 7.14 (s, 1H), 6.91 (d, J = 7.9 Hz, 1H), 5.97 (s, 1H), 4.25 - 4.16 (m, 1H), 3.91 (s, 6H), 2.68 (s, 3H), 1.70 - 1.61 (m, 1H), 1.59 - 1.49 (m, 1H), 1.34-1.25 (m, 2H), 0.89 (t, J = 7.3 Hz, 3H).

[0271] 13 C NMR (151 MHz, DMSO-d6) d (ppm) 173.9, 171.0, 160.7, 160.6, 153.6, 151.7, 122.5, 86.2, 54.4, 53.0, 35.6, 18.6, 14.2.

[0272] Biological test

[0273] Example A: Evaluation of the inhibitory effect of the compounds of the present application on PI3K a kinase

[0274] Experimental method:

[0275] The ADP-Glo Luminescent Assay method was used to determine the inhibitory effect of the compound on PI3Kɑ kinase. During the experiment, PI3Kɑ was first dissolved in the HEPES buffer prepared in advance (3 mM MgCl2, 1 mM EGTA, 100 mM NaCl, 0.03 CHAPS, 2 mM DTT, 50 mM HEPES, pH 7.5) with a concentration of 1.5 ug / ml. 2.5 ul of PI3Kɑ solution was taken and dissolved in a 384-well plate, 10 concentration gradients of test compounds (DMSO final concentration of 1%) were added to each well, and PIKa group without adding and test compound group without adding were set. The standard reference compound was selected as Staurosporine. Then 2.5 ul of substrate solution was added to each well, and incubated at room temperature for 60 min. Then 5 ul of ADP-Glo reagent was added to each well to terminate the reaction, and equilibrated at room temperature for 120 min. Then 10 ul of kinase detection reagent was added to each well, mixed well, and incubated at room temperature for 30 min to generate a stable fluorescence signal. The fluorescence signal was read by a fluorescence microplate reader, and the value was expressed as relative fluorescence intensity (RLU). According to the experimental results, the enzyme activity inhibition rate was calculated, and the calculation formula was as follows: inh% = (Max-Signal) / (Max-Min)*100, wherein Max is the value measured without adding the drug, Min is the value measured without adding PI3Kɑ kinase, and Signal is the value measured at the current concentration of the sample.

[0276] The standard curve was obtained by a series of concentration experiments, and the IC 50 .

[0277] Table A Test results of the activity inhibition of the compound of the present application on PI3Kɑ

[0278] Example 8 IC 50 (nM) Example 9 4 ​ 8 ​ 7.1 ​ 3 ​ 6 ​ 3179 ​ 726 ​ 8167 ​ 9195

[0279] The experimental results show that the compound of the present application has good inhibitory effect on the activity of PI3Kɑ.

[0280] It is obvious to those skilled in the art that the content of the present application is not limited to the foregoing illustrative embodiments, but can be embodied in other specific forms without departing from the essential characteristics thereof. Therefore, it is intended that each of the embodiments be considered as illustrative and non-limiting, and should be construed in accordance with the appended claims, rather than the foregoing embodiments, and all changes within the meaning and range equivalent to the appended claims are included herein.

Claims

1. A compound having the structure ###0001### 2. A composition comprising the compound of claim 1 and a pharmaceutically acceptable adjuvant.

3. Use of the compound of claim 1 or the composition of claim 2 for the manufacture of a medicament for the prevention or treatment of a PI3Kα mediated disease in a patient; said disease selected from the group consisting of sarcoma, lung cancer, bronchus cancer, prostate cancer, breast cancer, pancreatic cancer, gastrointestinal cancer, thyroid cancer, liver cancer, adrenal cancer, glioma, endometrial cancer, melanoma, kidney cancer, bladder cancer, vaginal cancer, ovarian cancer, multiple myeloma, esophageal cancer, leukemia, oral cancer, brain cancer, laryngeal cancer, lymphoma, or squamous cell cancer.

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