Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
  • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/20—Antivirals for DNA viruses
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

• the invention relates to dihydropyrimidine compounds and pharmaceutical compositions thereof, and further relates to uses of the conpounds or the pharmaceutical compositions in the manufacture of a medicament, especially for use in preventing, managing, treating or lessening a viral disease or an HBV disease.
• the hepatitis B virus belongs to the family of hepadnaviridae. It can cause acutely and/or persistently or progressively chronic diseases. Many other clinical manifestations in the pathological morphology are also caused by HBV—in particular chronic hepatitis, cirrhosis and hepatocellular carcinoma. Additionally, coinfection with hepatitis D virus may have adverse effects on the progress of the disease.
• the conventional medicaments approved to be used for treating chronic hepatitis are interferon and lamivudine.
• the interferon has just moderate activity but has an adverse side reaction.
• lamivudine has good activity, its resistance develops rapidly during the treatment and relapse effects often appear after the treatment has stopped.
• the IC 50 value of lamivudine (3-TC) is 300 nM (Science, 2003, 299, 893-896) .
• HAP heteroaryl-substituted dihydropyrimidine
• WO 2014029193 and CN 103626752 disclose dihydropyrimidine compounds and their application in pharmaceuticals, especially their uses in medicament for treating and preventing hepatitis B.
• CN 103626752 describes dihydropyrimidine racemic compounds substituted by carboxylic acid, which can inhibit the growth of the HBV in cell culture, wherein, the EC 50 of the compound of formula (II) is 360 nm.
• the invention disclosed herein provides a series of dihydropyrimidine compounds substituted by carboxylic acid, and all of the compounds of the invention are isomer forms which were split to gain by a large number of repeating experiments.
• the compound of formular (II) is split to give the four isomer compounds of formular (III) , M1, M2, M3 and M4.
• the EC 50 of M1, M2, M3 and M4 is 48 nm, 110 nm, >16.4 ⁇ M and >16.4 ⁇ M respectively.
• the EC 50 of M1, M2 are lower than the one of the compound of formular (II) , the EC 50 of M1 is lower than the one of M3 and M2, the EC 50 of M2 is lower than M4, besides, the big differences of pharmacokinetic parameters and liver microsome stability between isomers are impossible to be predicted when reading CN 103626752.
• the inventors had researched the synthesis, antiviral activity, drug metabolism parameters and liver microsome stability of dihydropyrimidine compound isomers substituted by carboxylic acid and found the compound of the invention has an unexpected antiviral activity against HBV and a good character of drug metabolism.
• the compound of the invention can be effectively used as antiviral drugs, especially the drugs used for treating and/or preventing hepatitis B.
• the invention relates to novel dihydropyrimidine compounds and pharmaceutical compositions, and their uses in the manufacture of a medicament for preventing, managing, treating or lessening a viral disease, especially hepatitis B (HBV) infection or a disease caused by hepatitis B infection.
• HBV hepatitis B
• the inventors had researched the synthesis, antiviral activity, drug metabolism parameters and liver microsome stability of dihydropyrimidine compound isomers substituted by arboxylic acid. All of the compounds of the invention are isomer forms, the antiviral activity, drug metabolism parameters and liver microsome stability are very different among different isomers. An isomer compound having unexpectedly superior anti-HBV activity and drug metabolism was obtained.
• provided herein are compounds having Formula (I) or (Ia) , or an enantiomer, a diastereoisomer, a tautomer, a hydrate, a solvate, a prodrug, a stereoisomer, an N-oxide, or a pharmaceutically acceptable salt thereof,
• each R 1 is independently H, F, Cl, Br, I, nitro, trifluoromethyl or cyano;
• each R 2 is independently methyl or ethyl
• each R 3 is independently thiazolyl, oxazolyl or imidazolyl; optionally each of thiazolyl, oxazolyl and imidazolyl is independently substituted with methyl or cyclopropyl;
• each Z is independently O or S
• each R 4a is independently H, methyl or isopropyl
• n is independently 1, 2 or 3;
• each m is independently 0, 1 or 2;
• t 1, 2, 3 or 4.
• R 3 is
• provided herein is a pharmaceutical composition comprising the compound disclosed herein.
• the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.
• the pharmaceutical composition further comprises one or more anti-HBV agents.
• the anti-HBV agent is an HBV polymerase inhibitor, immunomodulator or interferon.
• the anti-HBV agent comprises at least one selected from the group consisting of lamivudine, telbivudine, tenofovir, entecavir, adefovir, alfaferone, alloferon, celmoleukin, clevudine, emtricitabine, famciclovir, interferon, hepatect CP, intefen, interferon ⁇ -1b, interferon ⁇ , interferon ⁇ -2a, interferon ⁇ -1a, interferon ⁇ -2, interleukin-2, mivotilate, nitazoxanide, peginterferon alfa-2a, ribavirin, roferon-A, sizofiran, euforavac, ampligen, phosphazid, heplisav, interferon ⁇ -2b, levamisole, and propagermanium.
• provided herein is use of the compound or the pharmaceutical composition in the manufacture of a medicament for preventing, managing, treating or lessening a viral disease.
• the viral disease is hepatitis B infection or a disease caused by hepatitis B infection.
• the disease caused by hepatitis B infection is cirrhosis or hepatocellular carcinoma.
• provided herein is the compound or the pharmaceutical composition for use in preventing, managing, treating or lessening a viral disease.
• the viral disease or HBV disease is hepatitis B infection or a disease caused by hepatitis B infection.
• the disease caused by hepatitis B infection is cirrhosis or hepatocellular carcinoma.
• provided herein is a method for preventing, managing, treating or lessening a viral disease in a patient comprising administering to the paitent a therapeutically effective amount of the compound or the pharmaceutical composition.
• the viral disease or HBV disease is hepatitis B infection or a disease caused by hepatitis B infection.
• the disease caused by hepatitis B infection is cirrhosis or hepatocellular carcinoma.
• kits for preventing, managing, treating or lessening a viral disease or an HBV disease which comprises administering a pharmaceutically effective amount of the compound or the pharmaceutical composition disclosed herein to a patient.
• provided herein is use of the pharmaceutical composition or the compound disclosed herein in the manufacture of a medicament for preventing, managing or treating a viral disease or an HBV disease and lessening the severity of a viral disease or an HBV disease in a organism.
• the organism is a mammal; in other embodiments, the organism is a human.
• the method further comprises contacting a kinase with an anti-HBV agent.
• a method of inhibiting HBV infection comprising contacting the cell with an effective HBV inhibiting amount of a compound disclosed herein or a pharmaceutical composition thereof. In other embodiments, the method further comprises contacting the cell with an anti-HBV agent.
• a method of treating HBV disease comprises administering to a patient in need of such treatment an effective therapeutic amount of a compound disclosed herein or a pharmaceutical composition thereof. In other embodiments, the method further comprises administering an anti-HBV agent.
• a method of inhibiting HBV infection comprises administering to a patient in need of an effective therapeutic amount of a compound disclosed herein or a pharmaceutical composition thereof. In other embodiments, the method further comprises administering an anti-HBV agent.
• provided herein include methods of preparing, separating, purifying compounds of Formula (I) or (Ia) and the specific compounds of the invention.
• grammatical articles "a” , “an” and “the” are intended to include “at least one” or “one or more” unless otherwise indicated herein or clearly contradicted by the context.
• the articles are used herein to refer to one or more than one (i.e. at least one) of the grammatical objects of the article.
• a component means one or more components, and thus, possibly, more than one component is contemplated and may be employed or used in an implementation of the described embodiments.
• patient refers to a human (including adults and children) or other animal. In one embodiment, “patient” refers to a human.
• Stereoisomers refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space. Stereoisomers include enantiomer, diastereomers, conformer (rotamer) , geometric (cis/trans) isomer, atropisomer, etc.
• Chiral refers to molecules which have the property of non-superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.
• Enantiomers refer to two stereoisomers of a compound which are non-superimposable mirror images of one another.
• Diastereomer refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boling points, spectral properties or biological activities. Mixture of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography such as HPLC.
• compounds may optionally be substituted with one or more substituents, such as those illustrated above, or compounds as exemplified by particular classes, subclasses, and species disclosed herein.
• the term “optionally substituted” can exchanged with the one “substituted or unsubstituted” .
• substituted refers to the replacement of one or more hydrogen radicals in a given structure with the radical of a specified substituent.
• an optionally substituted group may have a substituent at each substitutable position of the group. When more than one position in a given structure can be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at each position.
• R 5 , R 5a and t are as defined herein.
• C 1-6 alkyl group refers to, respectively, discloses a methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, C 6 alkyl.
• linking substituents are described. Where the structure clearly requires a linking group, the Markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable lists “alkyl” or “aryl” then it is understood that the “alkyl” or “aryl” represents a linking alkylene group or arylene group, respectively.
• alkyl refers to a saturated linear or branched chain monovalent hydrocarbon radical of 1-20 carbon atoms, wherein the alkyl radical may be optionally substituted independently with one or more substituents described herein. Unless otherwise specified, alkyl groups contain 1-20 carbon atoms. In some embodiments, alkyl groups contain 1-10 carbon atoms. In other embodiments, alkyl groups contain 1-8 carbon atoms. In still other embodiments, alkyl groups contain 1-6 carbon atoms, and in yet other embodiments, alkyl groups contain 1-4 carbon atoms. In other embodiments, alkyl groups contain 1-3 carbon atoms.
• alkyl group examples include, but are not limited to, methyl (Me, -CH 3 ) , ethyl (Et, -CH 2 CH 3 ) , 1-propyl (n-Pr, -CH 2 CH 2 CH 3 ) , 2-propyl (i-Pr, -CH (CH 3 ) 2 ) , 1-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ) , 2-methyl-1-propyl or isobutyl (i-Bu, -CH 2 CH (CH 3 ) 2 ) , 1-methylpropyl or sec-butyl (s-Bu, -CH (CH 3 ) CH 2 CH 3 ) , tert-butyl (t-Bu, -C (CH 3 ) 3 ) , 1-pentyl (-CH 2 CH 2 CH 2 CH 3 ) , and the like.
• haloalkyl or “haloalkoxy” refers to an alkyl or alkoxy radical substituted with one or more halogen atoms (i.e., F, Cl, Br or I) , which may be either the same or different. Wherein the alkyl and alkoxy groups are as defined herein. Some non-limiting examples of such radicals include but are not limited to trifluoromethyl, trifluoroethyl, trifluoromethoxy, and the like.
• alkenyl refers to a linear or branched-chain monovalent hydrocarbon radical of 2-12 carbon atoms with at least one site of unsaturation, i.e., a carbon-carbon, sp 2 double bond, wherein the alkenyl radical may be optionally substituted independently with one or more substituents described herein, and includes radicals having “cis” and “trans” orientations, or alternatively, “E” and “Z” orientations.
• alkenyl groups contain 2-8 carbon atoms.
• alkenyl groups contain 2-6 carbon atoms.
• cycloalkyl refers to a monovalent or multivalent, non-aromatic, saturated or partially unsaturated ring having 3 to 12 carbon atoms as a monocyclic, bicyclic, or tricyclic ring system, wherein the cycloalkyl radical may be optionally substituted with one or more substituents described herein.
• a cycloalkyl contains 3 to 12 carbon atoms.
• a cycloalkyl contains 3 to 8 carbon atoms, and in still other embodiments, a cycloalkyl contains 3 to 6 carbon atoms. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, and the like.
• heterocyclyl refers to a saturated or partially unsaturated, non-aromatic, monocyclic, bicyclic or tricyclic ring containing 3-12 ring atoms of which at least one ring atom is selected from nitrogen, sulfur and oxygen.
• the heterocyclyl radical may be optionally substituted with one or more substituents described herein.
• Ring sulfur atoms may be optionally oxidized to form S-oxides.
• Ring nitrogen atoms maybe optionally oxidized to form N-oxides.
• heterocyclyl may be C 2-10 heterocyclyl, which contains 2-10 carbon atoms and at least one heteroatom selected from nitrogen, sulfur and oxygen; In other embodiments, heterocyclyl may be C 2-9 heterocyclyl, which contains 2-9 carbon atoms and at least one heteroatom selected from nitrogen, sulfur and oxygen; In still other embodiments, heterocyclyl may be C 2-7 heterocyclyl, which contains 2-7 carbon atoms and at least one heteroatom selected from nitrogen, sulfur and oxygen; In yet other embodiment, heterocyclyl may be C 2-5 heterocyclyl, which contains 2-5 carbon atoms and at least one heteroatom selected from nitrogen, sulfur and oxygen.
• heterocyclyl examples include pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyrimidinyl, tetrahydropyranyl, piperidyl, morpholinyl, thiomorpholinyl, piperazinyl, homopiperazinyl, and the like.
• halogen refers to F, Cl, Br or I.
• alkoxy refers to an alkyl group, as previously defined, attached to the rest of the molecule through an oxygen atom.
• Some non-limiting examples include methoxy (MeO, -OCH 3 ) , ethyoxy (EtO, -OCH 2 CH 3 ) , 1-propoxy (n-PrO, n-propoxy, -OCH 2 CH 2 CH 3 ) , 2-propoxy (i-PrO, i-propoxy, -OCH (CH 3 ) 2 ) , 1-butoxy (n-BuO, n-butoxy, -OCH 2 CH 2 CH 2 CH 3 ) , and the like.
• aryl refers to a monocyclic, bicyclic or tricyclic carbocyclic ring system having a total of six to fourteen ring members, or six to twelve ring members, or six to ten ring members. Wherein at least one ring in the system is aromatic, wherein each ring in the system contains 3 to 7 ring members and that has one or more points of attachment to the rest of the molecule.
• the aryl is optionally substituted with one or more substituents described herein.
• heteroaryl refers to a monocyclic, bicyclic, or tricyclic ring system having a total of 5 to 14 ring members, or 5 to 12 ring members, or 5 to 10 ring members or 5 to 6 ring members, wherein at least one ring in the system is aromatic, and at least one ring in the system contains one or more heteroatoms selected from nitrogen, sulfur and oxygen, wherein each ring in the system contains 5 to 7 ring members and that hasone or more points of attachment to the rest of the molecule.
• heteroaryl may be used interchangeably with the term “heteroaryl ring” or “heteroaromatic compound” .
• heteroaryl may be C 1-9 heteroaryl, which contains 1-9 carbon atoms and at least one heteroatom selected from nitrogen, sulfur and oxygen; In other embodiments, heteroaryl may be C 1-7 heteroaryl, which contains 1-7 carbon atoms and at least one heteroatom selected from nitrogen, sulfur and oxygen; In other embodiments, heteroaryl may be C 1-6 heteroaryl, which contains 1-6 carbon atoms and at least one heteroatom selected from nitrogen, sulfur and oxygen; In still other embodiment, heteroaryl may be C 1-5 heteroaryl, which contains 1-5 carbon atoms and at least one heteroatom selected from nitrogen, sulfur and oxygen; In yet other embodiment, heteroaryl may be C 1-4 heteroaryl, which contains 1-4 carbon atoms and at least one heteroatom selected from nitrogen, sulfur and oxygen; In other embodiment, heteroaryl may be C 1-3 heteroaryl, which contains 1-3 carbon atoms and at least one heteroatom selected from nitrogen, sulfur and oxygen.
• heteroaryl rings include the following monocycles: furanyl (e.g., 2-furanyl, 3-furanyl) , imidazolyl (e.g., N-imidazolyl, 1-methyl-1H-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl) , 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl) ; and some following bicycles examples include, but are not limited to, benzothiazolyl, benzimidazolyl, and the like.
• a bond drawn from a substituent to the center of one ring within a ring system represents substitution of the substituent at any substitutable position on the rings. For example, as shown in Figure b, c, d, e, f, g and h .
• a double bond attached to the rest of the molecule by a wave bond refers to (Z) double bond isomers or (E) double bond isomers, or a mixture of (Z) double bond isomers and (E) double bond isomers.
• structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational) ) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, or geometric (or conformational) mixtures of the present compounds are within the scope disclosed herein.
• prodrug refers to a compound that is transformed in vivo into a compound of Formula (I) or (Ia) . Such a transformation can be affected, for example, by hydrolysis in blood or enzymatic transformation of the prodrug form to the parent form in blood or tissue.
• Prodrugs of the compounds disclosed herein may be, for example, esters. Esters that may be utilized as prodrugs in the present invention are phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound disclosed herein that contains an OH group may be acylated at this position in its prodrug form.
• prodrug forms include phosphates, such as, for example those phosphates resulting from the phosphonation of an OH group on the parent compound.
• phosphates such as, for example those phosphates resulting from the phosphonation of an OH group on the parent compound.
• a thorough discussion of prodrugs is provided in Higuchi et al., Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series; Roche et al., ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; Rautio et al., Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and Hecker et al., Prodrugs of Phosphates and Phosphonates, J Med. Chem., 2008, 51, 2328-2345, all of which are incorporated herein by reference.
• a “metabolite” is a product produced through metabolism in the body of a specified compound or salt thereof. Metabolites of a compound may be identified using routine techniques known in the art and their activities determined using tests such as those described herein. Such products may result for example from the oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzyme cleavage, and the like, of the administered compound. Accordingly, the invention includes metabolites of compounds disclosed herein, including compounds produced by a process comprising contacting a compound disclosed herein with a mammal for a period of time sufficient to yield a metabolic product thereof.
• any asymmetric atom (e.g., carbon or the like) of the compound (s) disclosed herein can be present in racemic or enantiomerically enriched, for example the (R) -, (S) -or (R, S) -configuration.
• each asymmetric atom has at least 50 %enantiomeric excess, at least 60 %enantiomeric excess, at least 70 %enantiomeric excess, at least 80 %enantiomeric excess, at least 90 %enantiomeric excess, at least 95 %enantiomeric excess, or at least 99 %enantiomeric excess in the (R) -or (S) -configuration.
• a compound prefixed with (+) or d is dextrorotatory.
• these stereoisomers are identical except that they are mirror images of one another.
• a specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture.
• a 50: 50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.
• the term “racemic mixture” or “racemate” refers to an equimolar mixture of two enantiomeric species, devoid of optical activity.
• tautomer or "tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier. Where tautomerization is possible (e.g. in solution) , a chemical equilibrium of tautomers can be reached.
• proton tautomers also known as prototropic tautomers
• Valence tautomers include interconversions by reorganization of some of the bonding electrons.
• keto-enol tautomerization is the interconversion of pentane-2, 4-dione and 4-hydroxypent-3-en-2-one tautomers.
• tautomerization is phenol-keto tautomerization.
• a specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4 (lH) -one tautomers. Unless otherwise stated, all tautomeric forms of the compounds disclosed herein are within the scope of the invention.
• pharmaceutically acceptable salts refers to organic or inorganic salts of a compound disclosed herein.
• Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmacol Sci, 1977, 66, 1-19, which is incorporated herein by reference.
• Some non-limiting examples of pharmaceutically acceptable salts include inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
• salts include adipate, malic acid salt, 2-hydracrylic acid salt, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphanic acid salt, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate
• Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
• This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oilsoluble or dispersable products may be obtained by such quaternization.
• Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
• Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, C 1-8 sulfonate or aryl sulfonate.
• a “solvate” refers to an association or complex of one or more solvent molecules and a compound disclosed herein.
• solvents that form solvates include water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.
• hydrate refers to the complex where the solvent molecule is water.
• protecting group refers to a substituent that is commonly employed to block or protect a particular functionality while reacting with other functional groups on the compound.
• an “amino-protecting group” is a substituent attached to an amino group that blocks or protects the amino functionality in the compound.
• suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC) , benzyloxycarbonyl (CBZ) and 9-fluorenylmethylenoxycarbonyl (Fmoc) .
• a “hydroxy-protecting group” refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality.
• suitable hydroxy-protecting groups include acetyl and silyl.
• a “carboxy-protecting group” refers to a substituent of the carboxy group that blocks or protects the carboxy functionality.
• Some non-limiting examples of common carboxy-protecting groups include -CH 2 CH 2 SO 2 Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrophenylsulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitroethyl, and the like.
• the compounds disclosed herein, including their salts can also be obtained in the form of their hydrates, or include other solvents such as ethanol, DMSO, and the like, used for their crystallization.
• the compounds of the present invention may inherently or by design form solvates with pharmaceutically acceptable solvents (including water) ; therefore, it is intended that the invention embrace both solvated and unsolvated forms.
• any formula given herein is also intended to represent isotopically unenriched forms as well as isotopically enriched forms of the compounds.
• Isotopically enriched 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.
• isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as 2 H (deuterium, D) , 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl, 125 I.
• the compounds of the invention include isotopically enriched compounds as defined herein, for example those into which radioactive isotopes, such as 3 H, 14 C and 18 F, or those into which non-radioactive isotopes, such as 2 H and 13 C are present.
• 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) including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
• PET positron emission tomography
• SPECT single-photon emission computed tomography
• an 18 F-enriched compound may be particularly desirable for PET or SPECT studies.
• Isotopically-enriched compounds of Formula (I) or (Ia) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.
• isotopic enrichment factor means the ratio between the isotopic abundance and the natural abundance of a specified isotope.
• a substituent in a compound of this invention is denoted deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5%deuterium incorporation at each designated 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) .
• Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 O, d 6 -acetone, DMSO-d 6
• the invention relates to novel dihydropyrimidine compounds and pharmaceutical compositions, and their uses in the manufacture of a medicament for preventing, managing, treating or lessening a viral disease, especially hepatitis B (HBV) infection or a disease caused by hepatitis B infection.
• a viral disease especially hepatitis B (HBV) infection or a disease caused by hepatitis B infection.
• HBV hepatitis B
• provided herein are compounds having Formula (I) or (Ia) or an enantiomer, a diastereoisomer, a tautomer, a hydrate, a solvate, a prodrug, a stereoisomer, an N-oxide , or a pharmaceutically acceptable salt thereof,
• each R 1 is independently H, F, Cl, Br, I, nitro, trifluoromethyl or cyano;
• each R 2 is independently methyl or ethyl
• each R 3 is independently thiazolyl, oxazolyl or imidazolyl; wherein optionally each of thiazolyl, oxazolyl and imidazolyl is independently unsubstituted or substituted with methyl or cyclopropyl;
• each Z is independently O or S
• each R 4a is independently H, methyl or isopropyl
• n is independently 1, 2 or 3;
• each m is independently 0, 1 or 2;
• t is independently 1, 2, 3 or 4;
• provided herein is one of the compounds as follows, or an enantiomer, a diastereoisomer, a tautomer, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, and not limited to:
• provided herein is a pharmaceutical composition comprising the compound disclosed herein.
• the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.
• the pharmaceutical composition further comprises an anti-HBV agent.
• the anti-HBV agent is an HBV polymerase inhibitor, immunomodulator or interferon.
• the anti-HBV agent comprises at least one selected from the group consisting of lamivudine, telbivudine, tenofovir, entecavir, adefovir dipivoxil, alfaferone, alloferon, celmoleukin, clevudine, emtricitabine, famciclovir, feron, fepatect CP, intefen, interferon ⁇ -1b, interferon ⁇ , interferon ⁇ -2, interferon ⁇ -2a, interferon ⁇ -2b, interferon ⁇ -1a, interleukin-2, mivotilate, nitazoxanide, peginterferon alfa-2a, ribavirin, roferon-A, sizofiran, euforavac, rintatolimod, phosphazid, heplisav, levamisole, and propagerman
• provided herein is use of the compound or the pharmaceutical composition in the manufacture of a medicament for preventing, managing, treating or lessening a viral disease or an HBV disease.
• the viral disease or HBV disease is hepatitis B infection or a disease caused by hepatitis B infection.
• the disease caused by hepatitis B infection is cirrhosis or hepatocellular carcinoma.
• provised herein is the compound or the pharmaceutical composition for use in preventing, managing, treating or lessening a viral disease or an HBV disease.
• the viral disease or HBV disease is hepatitis B infection or a disease caused by hepatitis B infection.
• the disease caused by hepatitis B infection is cirrhosis or hepatocellular carcinoma.
• provided herein is to a method for preventing, managing, treating or lessening a viral disease or an HBV disease comprising administering to a paitent a therapeutically effective amount of the compound or the pharmaceutical composition.
• the viral disease or HBV disease is hepatitis B infection or a disease caused by hepatitis B infection.
• the disease caused by hepatitis B infection is cirrhosis or hepatocellular carcinoma.
• kits for preventing, managing, treating or lessening a viral disease or an HBV disease which comprises administering a pharmaceutically effective amount of the compound disclosed herein or the pharmaceutical composition disclosed herein to a patient.
• kits for preventing, managing, treating or lessening a viral disease or an HBV disease in a patient which comprises administering a pharmaceutically effective amount of the compound disclosed herein to a patient.
• kits for preventing, managing, treating or lessening a viral disease or an HBV disease in a patient which comprises administering a pharmaceutically effective amount of the pharmaceutical compositions disclosed herein to a patient.
• provided herein is use of the compound disclosed herein in the manufacture of a medicament for preventing, managing, or treating a viral disease or an HBV disease, and lessening the severity of a viral disease or an HBV disease.
• provided herein is use of the pharmaceutical composition disclosed herein in the manufacture of a medicament for preventing, managing, or treating a viral disease or an HBV disease, and lessening the severity of a viral disease or an HBV disease in a organism.
• the organism or patient is a mammal; in other embodiments, the organism or patient is a human. In still other embodiments, the method further comprises contacting the kinase or organism with an anti-HBV agent.
• a method of inhibiting HBV infection comprising contacting a cell or a plurality of cells with an effective HBV inhibiting amount of a pharmaceutically compound disclosed herein or a composition thereof.
• the method further comprises contacting the cells with an anti-HBV agent.
• a method of treating HBV disease comprises administering to a patient in need of such treatment an effective therapeutic amount of a pharmaceutically compound disclosed herein or a composition thereof. In other embodiments, the method further comprises administering to the patient an anti-HBV agent.
• a method of inhibiting an HBV infection comprises administering to a patient in need of an effective therapeutic amount of a pharmaceutically compound disclosed herein or a composition disclosed herein. In other embodiments, the method further comprises administering to the patient an anti-HBV agent.
• provided herein include methods of preparing, methods of separating, and methods of purifying the compounds of Formula (I) or (Ia) and a specific compound.
• a compound disclosed herein or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting HBV infection effectively, including those described herein.
• the compounds disclosed herein are useful in the manufacture of a medicament for inhibiting HBV infection.
• the compounds disclosed herein are also useful in the manufacture of a medicament to attenuate, prevent, manage or treat disorders through inhibition of HBV.
• a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) or (Ia) and a specific compound in association with at least one pharmaceutically acceptable carrier, adjuvant or diluent.
• Also provided herein is a method of inhibiting HBV disorders in a subject having or susceptible to such disorder, the method comprising treating the subject with a therapeutically effective amount of a compound of Formula (I) or (Ia) and a specific compound .
• pharmaceutically acceptable refers to a substance that is acceptable for use in pharmaceutical applications from a toxicological perspective and does not adversely interact with the active ingredient.
• the compounds disclosed herein also include salts of such compounds which are not necessarily pharmaceutically acceptable salts, and which may be useful as intermediates for preparing and/or purifying compounds of Formula (I) or (Ia) and/or for separating enantiomers of compounds of Formula (I) or (Ia) or and specific compounds .
• the desired salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
• an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
• an organic acid such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, malic acid, 2-hydroxy acrylic acid, lactic acid, citric acid, oxalic acid, glycolic acid, salicylic acid; a pyranosidyl acid, such as glucuronic acid or galacturonic acid; an alpha hydroxy acid, such as citric acid or tartaric acid; an amino acid, such as aspartic acid or glutamic acid; an aromatic acid, such as benzoic acid or cinnamic acid; a sulfonic acid, such as p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid or trifluoromethanesulfonic acid, and the like.
• an organic acid such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic
• the desired salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary) , an alkali metal hydroxide, ammonium, a salt of N + (R 14 ) 4 or an alkaline earth metal hydroxide, and the like.
• an inorganic or organic base such as an amine (primary, secondary or tertiary) , an alkali metal hydroxide, ammonium, a salt of N + (R 14 ) 4 or an alkaline earth metal hydroxide, and the like.
• suitable salts include organic salts derived from amino acids, such as glycine and arginine, ammonia (primary, secondary, and tertiary amines) , salts of N + (R 14 ) 4 , such as R 14 is H, C 1-4 alkyl, C 6-10 aryl or C 6-10 aryl-C 1-4 -alkyl, and cyclic amines, such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, lithium, and the like.
• amino acids such as glycine and arginine, ammonia (primary, secondary, and tertiary amines)
• salts of N + (R 14 ) 4 such as R 14 is H, C 1-4 alkyl, C 6-10 aryl or C 6-10 aryl-C 1-4 -alkyl
• cyclic amines such as piperidine, morph
• Further salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, C 1-8 sulfonate or aryl sulfonate.
• the invention features pharmaceutical compositions that include a compound of Formula (I) or (Ia) , a compound listed herein, or a compound named in Examples 1 to 32, and a pharmaceutically acceptable carrier, adjuvant, or excipient.
• the amount of the compound disclosed herein can inhibit HBV effectively, and is suitable for use in treating or lessening the disease induced by viruses, especially acute and chronic persistent HBV infections. Chronic viral diseases induced by HBV can worsen the morbidity and the chronic HBV infection can cause liver cirrhosis and/or henatocellular carcinoma in many cases.
• the compounds disclosed herein are suitable for the treatment of acute and chronic viral infections, particularly suitable for inhibiting HBV effectively.
• the compounds disclosed herein are suitable for use in treating or lessening the diseases induced by viruses in a patient, especially acute and chronic persistent HBV infections.
• Chronic viral diseases induced by HBV can worsen the morbidity and the chronic HBV infection can cause liver cirrhosis and/or henatocellular carcinoma in many cases.
• the present invention includes pharmceutical preparations which, besides nontoxic, inert pharmaceutically suitable carriers, comprise one or more compounds disclosed herein or a combination thereof or which consist of one or more active ingredients disclosed herein or a combination thereof.
• compositions mentioned above may also comprise other active pharmaceutical ingredients apart from the compounds disclosed herein.
• certain of the compounds disclosed herein can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable derivative thereof.
• pharmaceutically acceptable derivative include pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any other adducts or derivatives which upon administration to a patient in need is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.
• compositions disclosed herein additionally comprise a pharmaceutically acceptable carrier, adjuvant, or excipient, which, as used herein, includes any and all solvents, diluents, or other liquid excipient, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
• a pharmaceutically acceptable carrier includes any and all solvents, diluents, or other liquid excipient, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
• Some non-limiting examples of materials which can serve as pharmaceutically acceptable carriers include ion exchangers, aluminium, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or 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 silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc
• composition comprising the compound disclosed herein may be administered in any of the following routes: orally, inhaled by spray, locally, rectally, nasally, vaginally, parenterally such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal, or intracranial injection or infusion, or administered with the aid of an explanted reservoir, wherein the administration routes by orally, intramuscular, intraperitoneal or intravenous injection are preferred.
• the compound or the acceptable pharmaceutical composition comprising the compound disclosed herein may be administered in a unit dosage form.
• the dosage form may be in a liquid form, or a solid form.
• the liquid form includes true solution, colloids, particulates, emulsions, suspensions.
• Other dosage forms include tablets, capsules, dropping pills, aerosols, pills, powder, solutions, suspensions, emulsions, granules, suppositories, lyophilized powder for injection, clathrates, implants, patches, liniments, and the like.
• Oral tablets and capsules may comprise excipients, e.g., binders such as syrup, Arabic gum, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers such as lactose, sucrose, corn starch, calcium phosphate, sorbitol, aminoacetic acid; lubricants such as magnesium stearate, saponite, polyethylene glycol, silica, disintegrating agents such as potato starch, or acceptable moisturizing agents such as sodium lauryl sulfate. Tablets may be coated by using known methods in pharmaceutics.
• excipients e.g., binders such as syrup, Arabic gum, sorbitol, tragacanth, or polyvinylpyrrolidone
• fillers such as lactose, sucrose, corn starch, calcium phosphate, sorbitol, aminoacetic acid
• lubricants such as magnesium stearate, saponite, polyethylene glycol,
• Oral solution may be made as a suspension of water and oil, a solution, an emulsion, syrup or an elixir, or made as a dried product to which water or other medium is added before use.
• This liquid preparation may comprise conventional additives, e.g., suspending agents such sorbitol, cellulose methyl ether, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, hydrogenated edible grease; emulsifying agents such as lecithin, sorbitan monooleate, Arabic gum; or non-aqueous carriers (possibly including edible oil) , such as almond oil, grease such as glycerin, ethylene glycol, or ethanol; antiseptics such as methyl or propyl p-hydroxybenzoate, sorbic acid. If desired, a flavoring agent or a colorant may be added.
• Suppository may comprise a conventional suppository substrate, such as cocoa butter or other glyceride.
• the liquid dosage form is usually made of the compound and a sterilized carrier.
• the preferred carrier is water.
• the compound can be dissolved in the carrier or made into a suspension.
• the compound is firstly dissolved in water, and then filtered and sterilized before being packaged into an enclosed bottle or ampoule.
• the compound disclosed herein may be made into a suitable form of ointment, lotion or cream, wherein the active ingredient is suspended or dissolved in one or more carrier (s) .
• the carriers used for an ointment include mineral oil, liquid vaseline, albolene, propylene glycol, polyoxyethylene, polyoxypropylene, emulsified wax, water, and the like;
• Some non-limiting examples of the carriers used for a lotion and a cream include mineral oil, sorbitan monostearic ester, tween 60, cetyl esters wax, hexadecylene aromatic alcohol, 2-octyl dodecanol, benzyl alcohol, water, and the like.
• the total dose of the active compound disclosed herein is about 0.5 to 500 mg every 24 hours, preferably 1 to 100 mg per kg body weight. If appropriate, the drug is administrated by single dose for multiple times, to thereby achieve the desired effect.
• the amount of the active compound in a single dose is preferably about 1 to 80 mg, more preferably 1 to 50 mg per kg weight body. Nevertheless, the dose may also be varied according to the type and body weight of the object to be treated, the kind and extent of severity of diseases, the type of the preparation and the administration manner of the drug, and the administration period or the time interval.
• the pharmaceutical composition further comprising an anti-HBV agent.
• anti-HBV agent is an HBV polymerase inhibitor, immunomodulator or interferon.
• the anti-HBV agent is lamivudine, telbivudine, tenofovir, entecavir, adefovir dipivoxil, alfaferone, alloferon, celmoleukin, clevudine, emtricitabine, famciclovir, feron, hepatect CP, intefen, interferon ⁇ -1b, interferon ⁇ , interferon ⁇ -2a, interferon ⁇ -1a, interferon ⁇ -2, interleukin-2, mivotilate, nitazoxanide, peginterferon alfa-2a, ribavirin, roferon-A, sizofiran, euforavac, veldona, rintatolimod, phosphazid, heplisav, interferon ⁇ -2b, levamisole or propagermanium and so on.
• a compound and the pharmaceutical composition in the manufacture of a medicament for preventing, managing, treating or lessening the HBV disease in a patient, comprising administering a pharmaceutically effective amount to a patient.
• the HBV disease is a hepatic disease caused by hepatitis B virus infection or hepatitis B infection, including acute hepatitis, chronic hepatitis, cirrhosis and hepatocellular carcinoma.
• the symptoms of acute hepatitis B virus infection may be asymptomatic or may be the same as acute hepatitis.
• a patient with chronic virus infection may develop active disease, which can progress to cirrhosis and liver cancer.
• those additional agents may be administered separately from the compound-containing composition, as part of a multiple dosage regimen.
• those agents may be part of a single dosage form, mixed together with the compound disclosed herein in a single composition. If administered as part of a multiple dosage regimen, the two active agents may be submitted simultaneously, sequentially or within a period of time from one another which would result in the desired activity of the agents.
• both the compound and the additional therapeutic agent in those compositions which comprise an additional therapeutic agent as described above
• the amount of additional therapeutic agent present in the compositions disclosed herein will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent.
• the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.
• that additional therapeutic agent and the compound disclosed herein may act synergistically.
• the compound disclosed herein exhibits a relatively strong antiviral effect.
• This kind of compound has unexpected antiviral activity to HBV, and thus is adapted to be used for treating various virus-caused diseases, in particular acute and chronic viral diseases caused by HBV may lead to various syndromes having different extents of severity.
• chronic HBV infection may lead to hepatic cirrhosis and /or liver cell carcinoma.
• indications capable of being treated by the compound disclosed herein include: acute and chronic viral infections capable of leading to infectious hepatitis, such as HBV infection, and particularly preferred chronic HBV infection and acute HBV infection.
• the invention further relates to the use of the compounds and compositions defined above for producing a medicament for the treatment and prophylaxis of the diseases described above, preferably of viral diseases, in particular of hepatitis B.
• the compounds disclosed herein may be prepared by methods described herein, wherein the substituents are as defined for Formulas (I) or (Ia) , above, except where further noted.
• the following non-limiting schemes and examples are presented to further exemplify the invention.
• temperatures are set forth in degrees Celsius (°C) .
• Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, and were used without further purification unless otherwise indicated.
• Common solvents were purchased from commercial suppliers such as Shantou XiLong Chemical Factory, Guangdong Guanghua Reagent Chemical Factory Co. Ltd., Guangzhou Reagent Chemical Factory, Tianjin YuYu Fine Chemical Ltd., Qingdao Tenglong Reagent Chemical Ltd., and Qingdao Ocean Chemical Factory.
• Anhydrous THF, dioxane, toluene, and ether were obtained by refluxing the solvent with sodium.
• Anhydrous CH 2 Cl 2 and CHCl 3 were obtained by refluxing the solvent with CaH 2 .
• EtOAc, PE, hexane, DMAC and DMF were treated with anhydrous Na 2 SO 4 prior use.
• reaction flasks were typically fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware was oven dried and/or heat dried.
• MS data were determined on an Agilent 6320 Series LC-MS spectrometer equipped with G1312A binary pumps and a G1316A TCC (Temperature Control of Column, maintained at 30 °C) .
• G1329A autosampler and a G1315B DAD detector were used in the analysis, and an ESI source was used on the LC-MS spectrometer.
• MS data were determined on an Agilent 6120 Series LC-MS spectrometer equipped with G1311A quaternary pumps and a G1316A TCC (Temperature Control of Column, maintained at 30 °C) .
• G1329A autosampler and a G1315D DAD detector were used in the analysis, and an ESI source was used on the LC-MS spectrometer.
• Pyrimidine compound 7A can be prepared by a general synthetic procedure illustrated in Scheme 1, wherein each R 1 , R 2 , R 3 , R 4 , R 4a , Z, m and n is as defined herein.
• compound 1A, compound 2A and compound 3A can react to obtain compound 4A in the presence of a base.
• Purification of compound 4A by preparative chromatography can give compound 5A, and then compound 5A can react with brominating agent to give compound 6A.
• the compound 6A can react with compound 6A-1 or its salt to give target compound 7A.
• the target compound 13A can be prepared by the process illustrated in Scheme 2, wherein Z is as defined herein.
• R is hydrogen or methyl.
• Pg is an amino protecting group, such as Boc, Fmoc, Cbz, and the like.
• Compound 8A can be converted to compound 9A in the presence of an oxidant (eg. Dess-Martin periodinane) .
• Wittig reaction of compound 9A with Wittig reagent can give compound 10A.
• Compound 10A can be converted to compound 11A by hydrolysis, and then compound 11A can be reduced to afford compound 12A in the presence of a reductant. Subsequently, the protecting group Pg of compound 12A can be removed to afford compound 13A.
• the target compound 13A can be prepared by the process illustrated in Scheme 3, wherein Z is as defined herein.
• R is hydrogen or methyl.
• Pg is an amino protecting group, such as Boc, Fmoc, Cbz, and the like.
• Compound 10A can be reduced to afford compound 14A in the presence of a reductant, and then compound 14A can be converted to compound 12A by hydrolysis. Subsequently, the protecting group Pg of compound 12A can be removed to afford compound 13A.
• the target compound 21A can be prepared by the process illustrated in Scheme 4, wherein Z is as defined herein.
• R is hydrogen or methyl.
• Pg is an amino protecting group, such as Boc, Fmoc, Cbz, and the like.
• Compound 15A can be converted to compound 16A in the presence of a reductant.
• Compound 16A can be converted to compound 17A in the presence of an oxidant (eg. Dess-Martin periodinane) .
• Wittig reaction of compound 17A with Wittig reagent to give compound 18A.
• Compound 18A can be reduced to afford compound 19A, and then compound 19A can be converted to compound 20A by hydrolysis.
• the protecting group Pg of compound20A can be removed to afford compound 21A.
• the target compound 26A can be prepared by the process illustrated in scheme Scheme 5, wherein Z is as defined herein.
• R is hydrogen or methyl.
• R 6 is hydrogen, methyl ethyl, propyl or isopropyl.
• Pg is an amino protecting group, such as Boc, Fmoc, Cbz, and the like.
• Compound 23A can be reduced to afford compound 24A, and then compound 24A can be converted to compound 24A by hydrolysis. Subsequently, the protecting group Pg of compound 25A can be removed to afford compound 26A.
• the target compound 30A can be prepared by the process illustrated in Scheme 6, wherein Z is as defined herein.
• Pg is an amino protecting group, such as Boc, Fmoc, Cbz, and the like.
• Compound 27A can be converted to compound 28A in the presence of CuI and MeLi, and then compound 28A can be converted to compound 29A by hydrolysis. Subsequently, the protecting group Pg of compound 29A can be removed to afford compound 30A.
• the target compound 33A can be prepared by the process illustrated in Scheme 7, wherein R 1 , R 2 , R 3 , R 4 , R 4a , Z, m and n are as defined herein.
• Compound 4A can give compound 31A by preparative chromatography, and compound 31A can react with brominating agent to give compound 32A, and then compound 32A can react with compound 6A-1 or its salt to give target compound 33A.
• Step 1) (R) -ethyl 4- (2-bromo-4-fluorophenyl) -6-methyl-2- (thiazol-2-yl) -1, 4-dihydropyrimidine -5-carboxylate
• Step 2) (R) -ethyl 4- (2-bromo-4-fluorophenyl) -6- (bromomethyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate
• Step 1) (R) -benzyl 2- (3-ethoxy-2-methyl-3-oxoprop-1-en-1-yl) morpholine-4-carboxylate
• Step 2) (R) -3- (4- ( (benzyloxy) carbonyl) morpholin-2-yl) -2-methylacrylic acid
• the separated water phase was adjusted to pH 7 with aqueous NaOH (3 mol/L) , and then centrifuged. The supernatant liquid was concentrated in vacuo to give the title compound as a white solid (0.4 g, 100%) .
• the compound was characterized by the following spectroscopic data:
• Step 2) 3- ( (R) -4- ( (benzyloxy) carbonyl) morpholin-2-yl) butanoic acid
• the separated water phase was extracted with EtOAc (40 mL) , and then the separated water phase was adjusted to pH 7 with aqueous NaOH (3 mol/L) , then centrifuged. The supernatant liquid was concentrated in vacuo to give the title compound as a white solid (0.85 g, 100%) .
• the compound was characterized by the following spectroscopic data:
• the separated water phase was cooled to 10 °C and adjusted to 2 with concentrated hydrochloric acid, then the resulting water phase was stirred at 5 °C for 4 hours to precipitate out solid, the resulting mixture was filter to give the title compound as a white solid (19.5 g, 68%) .
• the compound was characterized by the following spectroscopic data:
• the mixture was stirred at 5 °C for 4 hours, the mixture was warmed to 25 °C.
• the resulting mixture was extracted with PE (50 mL ⁇ 2) .
• the separated water phase was cooled to 15 °C, and to the water phase was added concentrated hydrochloric acid until a lot of solid precipitate was formed.
• the mixture was stirred at 10 °C for 12 hours, then filtered.
• the filter cake was washed with water to give the title compound as a white solid (18.1 g, 71%) .
• the compound was characterized by the following spectroscopic data:
• Step 2) (2R, 3R) -tert-butyl 3- (3-methoxy-2-methyl-3-oxopropyl) -2-methylmorpholine-4-carboxylate
• Step 2) (R) -tert-butyl 3- (3-ethoxy-3-oxoprop-1-en-1-yl) morpholine-4-carboxylate
• Step 1) (R) -ethyl 4- (2-chloro-4-fluorophenyl) -6-methyl-2- (thiazol-2-yl) -1, 4-dihydropyrimidine -5-carboxylate
• the title compound was prepared by the procedure described in step 1 of Example 1 using ethyl 4- (2-chloro-4-fluorophenyl) -6-methyl-2- (thiazol-2-yl) -1, 4-dihydropyrimidine -5-carboxylate (5 g, 13.2 mmol, synthetic procedures disclosed in WO2010069147A ) to give the title compound as a yellow solid (2.1 g, 42%) .
• the compound was characterized by the following spectroscopic data:
• Step 2) (R) -ethyl 6- (bromomethyl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate
• the title compound was prepared by the procedure described in step 2 of Example 1 using (R) -ethyl 4- (2-chloro-4-fluorophenyl) -6-methyl-2- (thiazol-2-yl) -1, 4-dihydropyrimidine -5-carboxylate (0.91 g, 2.4 mmol) , CCl 4 (20 mL) and NBS (0.47 g, 2.64 mmol) to give the title compound as a yellow solid (0.8 g, 73%) .
• the compound was characterized by the following spectroscopic data:
• the title compound was prepared by the procedure described in step 6 of Example 2 using (R) -ethyl 6- (bromomethyl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (0.46 g, 1 mmol) , (R) -3- (morpholin-2-yl) propanoic acid hydrochloric (0.2 g, 1 mmol) , potassium carbonate (0.28 g, 2 mmol) and anhydrous ethyl alcohol (10 mL) to give the title compound as a yellow solid (0.25 g, 47%) .
• the compound was characterized by the following spectroscopic data:
• Step 1) (R) -methyl 4- (2-chloro-4-fluorophenyl) -6-methyl-2- (thiazol-2-yl) -1, 4-dihydropyrimidine -5-carboxylate
• the title compound was prepared by the procedure described in step 1 of Example 1 using methyl 4- (2-chloro-4-fluorophenyl) -6-methyl-2- (thiazol-2-yl) -1, 4-dihydropyrimidine -5-carboxylate (5 g, 13.7 mmol, synthetic procedures disclosed in WO2010069147A ) to give the title compound as a yellow solid (2.1 g, 42%) .
• the compound was characterized by the following spectroscopic data:
• Step 2) (R) -methyl 6- (bromomethyl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate
• the title compound was prepared by the procedure described in step 2 of Example 1 using (R) -methyl 4- (2-chloro-4-fluorophenyl) -6-methyl-2- (thiazol-2-yl) -1, 4-dihydropyrimidine -5-carboxylate (0.88 g, 2.4 mmol) , CCl 4 (20 mL) and NBS (0.47 g, 2.64 mmol) to give the title compound as a yellow solid (0.78 g, 73%) .
• the compound was characterized by the following spectroscopic data:
• Step 1) (R) -methyl 4- (2-bromo-4-fluorophenyl) -6-methyl-2- (thiazol-2-yl) -1, 4-dihydropyrimidine -5-carboxylate
• the title compound was prepared by the procedure described in step 1 of Example 1 using methyl 4- (2-bromo-4-fluorophenyl) -6-methyl-2- (thiazol-2-yl) -1, 4-dihydropyrimidine -5-carboxylate (5 g, 12.2 mmol, synthetic procedures disclosed in WO2010069147A ) to give the title compound as a yellow solid (2 g, 40%) .
• the compound was characterized by the following spectroscopic data:
• Step 2) (R) -methyl 4- (2-bromo-4-fluorophenyl) -6- (bromomethyl) -2- (thiazol-2-yl) -1, 4- dihydropyrimidine-5-carboxylate
• the title compound was prepared by the procedure described in step 2 of Example 1 using (R) -methyl 4- (2-bromo-4-fluorophenyl) -6-methyl-2- (thiazol-2-yl) -1, 4-dihydropyrimidine -5-carboxylate (0.98 g, 2.4 mmol) , CCl 4 (20 mL) and NBS (0.47 g, 2.64 mmol) to give the title compound as a yellow solid (0.8 g, 68%) .
• the compound was characterized by the following spectroscopic data:
• Step 1) (R) -ethyl 4- (2, 4-dichlorophenyl) -6-methyl-2- (thiazol-2-yl) -1, 4-dihydropyrimidine -5-carboxylate
• the title compound was prepared by the procedure described in step 1 of Example 1 using ethyl 4- (2, 4-dichlorophenyl) -6-methyl-2- (thiazol-2-yl) -1, 4-dihydropyrimidine -5-carboxylate (5 g, 12.6 mmol, synthetic procedures disclosed in WO2010069147A ) to give the title compound as a yellow solid (1.9 g, 38%) .
• the compound was characterized by the following spectroscopic data:
• Step 2) (R) -ethyl 6- (bromomethyl) -4- (2, 4-dichlorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate
• the title compound was prepared by the procedure described in step 2 of Example 1 using ( (R) -ethyl 4- (2, 4-dichlorophenyl) -6-methyl-2- (thiazol-2-yl) -1, 4-dihydropyrimidine -5-carboxylate (0.95 g, 2.4 mmol) , CCl 4 (20 mL) and NBS (0.47 g, 2.64 mmol) to give the title compound as a yellow solid (0.74 g, 65%) .
• the compound was characterized by the following spectroscopic data:
• Step 1) (R) -methyl 4- (2, 4-dichlorophenyl) -6-methyl-2- (thiazol-2-yl) -1, 4-dihydropyrimidine -5-carboxylate
• the title compound was prepared by the procedure described in step 1 of Example 1 using methyl 4- (2, 4-dichlorophenyl) -6-methyl-2- (thiazol-2-yl) -1, 4-dihydropyrimidine -5-carboxylate (5 g, 13.1 mmol, synthetic procedures disclosed in WO2008154820A) to give the title compound as a yellow solid (1.9 g, 38%) .
• the compound was characterized by the following spectroscopic data:
• Step 2) (R) -methyl 6- (bromomethyl) -4- (2, 4-dichlorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate
• the title compound was prepared by the procedure described in step 2 of Example 1 using (R) -methyl 4- (2, 4-dichlorophenyl) -6-methyl-2- (thiazol-2-yl) -1, 4-dihydropyrimidine -5-carboxylate (0.92 g, 2.4 mmol) , CCl 4 (20 mL) and NBS (0.47 g, 2.64 mmol) to give the title compound as a yellow solid (0.72 g, 65%) .
• the compound was characterized by the following spectroscopic data:
• Step 2) (S) -tert-butyl 3- (3-ethoxy-3-oxoprop-1-en-1-yl) morpholine-4-carboxylate
• the title compound was prepared by the procedure described in step 6 of Example 2 using (R) -ethyl 4- (2-bromo-4-fluorophenyl) -6- (bromomethyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (0.5 g, 1 mmol) , (S) -3- (morpholin-3-yl) propanoic acid hydrochloride (0.2 g, 1 mmol) , potassium carbonate (0.28 g, 2 mmol) and anhydrous ethyl alcohol (10 mL) to give the title compound as a yellow solid (0.23 g, 39%) .
• the compound was characterized by the following spectroscopic data:
• the title compound was prepared by the procedure described in step 6 of Example 2 using (R) -methyl 6- (bromomethyl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (0.44 g, 1 mmol) , (S) -3- (morpholin-3-yl) propanoic acid hydrochloride (0.2 g, 1 mmol) , potassium carbonate (0.14 g, 1 mmol) and anhydrous ethyl alcohol (10 mL) to give the title compound as a yellow solid (0.2 g, 39%) .
• the compound was characterized by the following spectroscopic data:
• the title compound was prepared by the procedure described in step 6 of Example 2 using (R) -methyl 6- (bromomethyl) -4- (2, 4-dichlorophenyl) -2- (thiazol-2-yl) -1, 4- dihydropyrimidine-5-carboxylate (0.46 g, 1 mmol) , (S) -3- (morpholin-3-yl) propanoic acid hydrochloride (0.2 g, 1 mmol) , potassium carbonate (0.14 g, 1 mmol) and anhydrous ethyl alcohol (10 mL) to give the title compound as a yellow solid (0.22 g, 41%) .
• the compound was characterized by the following spectroscopic data:
• Step 2) (S) -tert-butyl 2- (3-ethoxy-3-oxoprop-1-en-1-yl) morpholine-4-carboxylate
• the title compound was prepared by the procedure described in step 2 of Example 14 using (R) -tert-butyl 2-formylmorpholine-4-carboxylate (1.81 g, 8.4 mmol) , DCM (40mL) and ethyl 2- (triphenylphosphoranylidene) acetate (2.93 g, 8.4 mmol) to give the title compound as colorless oil (1.94 g, 81%) .
• the compound was characterized by the following spectroscopic data:
• the title compound was prepared by the procedure described in step 3 of Example 14 using (S) -tert-butyl 2- (3-ethoxy-3-oxoprop-1-en-1-yl) morpholine-4-carboxylate (1.94 g, 6.8 mmol) , Pd/C (10%, 0.2 g) and anhydrous ethanol (40 mL) to give the title compound as colorless oil (1.78 g, 91%) .
• the compound was characterized by the following spectroscopic data:
• the title compound was prepared by the procedure described in step 6 of Example 2 using (R) -ethyl 4- (2-bromo-4-fluorophenyl) -6- (bromomethyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (0.5 g, 1 mmol) , (S) -3- (morpholin-2-yl) propanoic acid hydrochloride (0.2 g, 1 mmol) , potassium carbonate (0.28 g, 2 mmol) and anhydrous ethyl alcohol (10 mL) to give the title compound as a yellow solid (0.33 g, 56%) .
• the compound was characterized by the following spectroscopic data:
• the title compound was prepared by the procedure described in step 6 of Example 2 using (R) -ethyl 6- (bromomethyl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (0.46 g, 1 mmol) , (S) -3- (morpholin-2-yl) propanoic acid hydrochloride (0.2 g, 1 mmol) , potassium carbonate (0.28 g, 2 mmol) and anhydrous ethyl alcohol (10 mL) to give the title compound as a yellow solid (0.29 g, 54%) .
• the compound was characterized by the following spectroscopic data:
• the title compound was prepared by the procedure described in step 6 of Example 2 using (R) -methyl 6- (bromomethyl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (0.89 g, 2 mmol) , (S) -3- (morpholin-2-yl) propanoic acid hydrochloride (0.4 g, 2 mmol) , potassium carbonate (0.28 g, 2 mmol) and anhydrous ethyl alcohol (20 mL) to give the title compound as a yellow solid (0.41 g, 39%) .
• the compound was characterized by the following spectroscopic data:
• the title compound was prepared by the procedure described in step 6 of Example 2 using (R) -methyl 6- (bromomethyl) -4- (2, 4-dichlorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (0.46 g, 1 mmol) , (S) -3- (morpholin-2-yl) propanoic acid hydrochloride (0.2 g, 1 mmol) , potassium carbonate (0.14 g, 1 mmol) and anhydrous ethyl alcohol (10 mL) to give the title compound as a yellow solid (0.2 g, 37%) .
• the compound was characterized by the following spectroscopic data:
• the water phase was cooled to 5°C, adjusted to pH 1-2 with concentrated hydrochloric acid, and the resulting mixture was stirred at 5°C for 4 hours to precipitate out solid, then the mixture was filtrated to give the title compound as a white solid (20.9 g, 73%) .
• the compound was characterized by the following spectroscopic data:
• Step 1) methyl 4- (2-chlorophenyl) -6-methyl-2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate
• Step 2) (R) -methyl 4- (2-chlorophenyl) -6-methyl-2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate
• the title compound was prepared by the procedure described in step 1 of Example 1 using methyl 4- (2-chlorophenyl) -6-methyl-2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (5 g, 14.38 mmol) , the crude procduct was purified by pre-HPLC to give the title compound as a yellow solid (2.33 g, 47%) .
• the compound was characterized by the following spectroscopic data:
• Step 1) ethyl 4- (2-chlorophenyl) -6-methyl-2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate
• the resulting mixture was filtered and the filter cake was washed with ethanol (10 mL) and water (100 mL) in turn. The filter cake was then dried under vacuum to give the title compound as a yellow solid (11.06 g, 50%) .
• the compound was characterized by the following spectroscopic data:
• Step 2) (R) -ethyl 4- (2-chlorophenyl) -6-methyl-2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate
• the title compound was prepared by the procedure described in step 1 of Example 1 using ethyl 4- (2-chlorophenyl) -6-methyl-2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (5 g, 13.82 mmol) , the crude procduct was purified by pre-HPLC to give the title compound as a yellow solid (2.12 g, 42%) .
• the compound was characterized by the following spectroscopic data:
• the title compound was prepared by the procedure described in step 3 of Example 33 using (R) -ethyl 4- (2-chlorophenyl) -6-methyl-2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (0.398 g, 1.10 mmol) , CCl 4 (10 mL) and NBS (0.219 g, 1.21 mmol) to give the title compound as a yellow dope (0.34 g, 70%) .
• the title compound was prepared by the procedure described in step 4 of Example 33 using (R) -ethyl 6- (bromomethyl) -4- (2-chlorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (0.34 g, 0.77 mmol) , potassium carbonate (0.307 g, 2.20 mmol) , (R) -3- (morpholin-2-yl) propanoic acid hydrochloride (0.15 g, 0.77 mmol) and anhydrous ethyl alcohol (15 mL) to give the title compound as a yellow solid (0.155 g, 35%) .
• the compound was characterized by the following spectroscopic data:
• Step 1) (S) -ethyl 4- (2-bromo-4-fluorophenyl) -6-methyl-2- (thiazol-2-yl) -1, 4-dihydropyrimidine -5-carboxylate
• the title compound was prepared by the procedure described in step 1 of Example 1 using 4- (2-bromo-4-fluorophenyl) -6- (bromomethyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (5 g, 11.8 mmol) , the crude product was purified by pre-HPLC to give the title compound as a yellow solid (1.74 g, 35%) .
• the compound was characterized by the following spectroscopic data:
• Step 2) (S) -ethyl 4- (2-bromo-4-fluorophenyl) -6- (bromomethyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate
• the title compound was prepared by the procedure described in step 2 of Example 1 using (S) -ethyl 4- (2-bromo-4-fluorophenyl) -6-methyl-2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (1 g, 2.4 mmol) , CCl 4 (20 mL) and NBS (0.47 g, 2.64 mmol) to give the title compound as a yellow solid (0.83 g, 68%) .
• the compound was characterized by the following spectroscopic data:
• Step 1) (S) -ethyl 4- (2-chloro-4-fluorophenyl) -6-methyl-2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate
• the title compound was prepared by the procedure described in step 1 of Example 1 using 4- (2-chloro-4-fluorophenyl) -6-methyl-2- (thiazol-2-yl) -1, 4-dihydropyrimidine -5-carboxylate (5 g, 13.2 mmol) to give the title compound as a yellow solid (1.7 g, 34%) .
• the compound was characterized by the following spectroscopic data:
• Step 2) (S) -ethyl 6- (bromomethyl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate
• the title compound was prepared by the procedure described in step 6 of Example 2 using (S) -ethyl 6- (bromomethyl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (0.46 g, 1 mmol) , (R) -3- (morpholin-2-yl) propanoic acid hydrochloric (0.2 g, 1 mmol) , potassium carbonate (0.28 g, 2 mmol) and anhydrous ethyl alcohol (10 mL) to give the title compound as a yellow solid (0.26 g, 50%) .
• the compound was characterized by the following spectroscopic data:
• the title compound was prepared by the procedure described in step 6 of Example 2 using (S) -ethyl 6- (bromomethyl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (0.46 g, 1 mmol) , (S) -3- (morpholin-3-yl) propanoic acid hydrochloride (0.2 g, 1 mmol) , potassium carbonate (0.28 g, 2 mmol) and anhydrous ethyl alcohol (10 mL) to give the title compound as a yellow solid (0.27 g, 50%) .
• the compound was characterized by the following spectroscopic data:
• Step 1) (S) -methyl 4- (2-chloro-4-fluorophenyl) -6-methyl-2- (thiazol-2-yl) -1, 4-dihydropyrimidine -5-carboxylate
• the title compound was prepared by the procedure described in step 1 of Example 1 using methyl 4- (2-chloro-4-fluorophenyl) -6-methyl-2- (thiazol-2-yl) -1, 4-dihydropyrimidine -5-carboxylate (5 g, 13.7 mmol) to give the title compound as a yellow solid (1.8 g, 36%) .
• the compound was characterized by the following spectroscopic data:
• Step 2) (S) -methyl 6- (bromomethyl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate
• the title compound was prepared by the procedure described in step 6 of Example 2 using (S) -methyl 6- (bromomethyl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (0.89 g, 2 mmol) , (S) -3- (morpholin-3-yl) propanoic acid hydrochloride (0.4 g, 2 mmol) , potassium carbonate (0.28 g, 2 mmol) and anhydrous ethyl alcohol (20 mL) to give the title compound as a yellow solid (0.39 g, 37%) .
• the compound was characterized by the following spectroscopic data:
• Step 1) (S) -methyl 4- (2-bromo-4-fluorophenyl) -6-methyl-2- (thiazol-2-yl) -1, 4-dihydropyrimidine -5-carboxylate
• the title compound was prepared by the procedure described in step 1 of Example 1 using methyl 4- (2-bromo-4-fluorophenyl) -6-methyl-2- (thiazol-2-yl) -1, 4-dihydropyrimidine -5-carboxylate (5 g, 12.2 mmol) to give the title compound as a yellow solid (1.7 g, 34%) .
• the compound was characterized by the following spectroscopic data:
• Step 2) (S) -methyl 4- (2-bromo-4-fluorophenyl) -6- (bromomethyl) -2- (thiazol-2-yl) -1, 4 -dihydropyrimidine-5-carboxylate
• Step 1) (S) -ethyl 4- (2, 4-dichlorophenyl) -6-methyl-2- (thiazol-2-yl) -1, 4-dihydropyrimidine -5-carboxylate
• the title compound was prepared by the procedure described in step 1 of Example 1 using ethyl 4- (2, 4-dichlorophenyl) -6-methyl-2- (thiazol-2-yl) -1, 4-dihydropyrimidine -5-carboxylate (5 g, 12.6 mmol) to give the title compound as a yellow solid (1.5 g, 30%) .
• the compound was characterized by the following spectroscopic data:
• Step 2) (S) -ethyl 6- (bromomethyl) -4- (2, 4-dichlorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate
• Step 1) (S) -methyl 4- (2, 4-dichlorophenyl) -6-methyl-2- (thiazol-2-yl) -1, 4-dihydropyrimidine -5-carboxylate
• the title compound was prepared by the procedure described in step 1 of Example 1 using methyl 4- (2, 4-dichlorophenyl) -6-methyl-2- (thiazol-2-yl) -1, 4-dihydropyrimidine -5-carboxylate (5 g, 13.1 mmol) to give the title compound as a yellow solid (1.6 g, 32%) .
• the compound was characterized by the following spectroscopic data:
• Step 2) (S) -methyl-6- (bromomethyl) -4- (2, 4-dichlorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-ca rboxylate
• the title compound was prepared by the procedure described in step 6 of Example 2 using (S) -ethyl 4- (2-bromo-4-fluorophenyl) -6- (bromomethyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (0.5 g, 1 mmol) , (S) -3- (morpholin-2-yl) propanoic acid hydrochloride (0.2 g, 1 mmol) , potassium carbonate (0.28 g, 2 mmol) and anhydrous ethyl alcohol (10 mL) to give the title compound as a yellow solid (0.21 g, 36%) .
• the compound was characterized by the following spectroscopic data:

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