WO2014029193A1 - Dihydropyrimidine compounds and their application in pharmaceuticals - Google Patents

Dihydropyrimidine compounds and their application in pharmaceuticals Download PDF

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Publication number
WO2014029193A1
WO2014029193A1 PCT/CN2013/001001 CN2013001001W WO2014029193A1 WO 2014029193 A1 WO2014029193 A1 WO 2014029193A1 CN 2013001001 W CN2013001001 W CN 2013001001W WO 2014029193 A1 WO2014029193 A1 WO 2014029193A1
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Prior art keywords
independently
methyl
ethyl
mmol
compound
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PCT/CN2013/001001
Other languages
French (fr)
Inventor
Yingjun Zhang
Qingyun REN
Xinchang LIU
Goldmann Siegfried
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Sunshine Lake Pharma Co., Ltd.
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Priority to SG11201408791TA priority Critical patent/SG11201408791TA/en
Priority to US14/416,061 priority patent/US9340538B2/en
Priority to EP13830553.7A priority patent/EP2888241B1/en
Priority to CA2876690A priority patent/CA2876690C/en
Priority to KR1020147036508A priority patent/KR102148678B1/en
Priority to ES13830553.7T priority patent/ES2640049T3/en
Priority to RU2015110082A priority patent/RU2655914C9/en
Priority to BR112015002858A priority patent/BR112015002858A2/en
Application filed by Sunshine Lake Pharma Co., Ltd. filed Critical Sunshine Lake Pharma Co., Ltd.
Priority to PL13830553T priority patent/PL2888241T3/en
Priority to AU2013305390A priority patent/AU2013305390C1/en
Priority to JP2015527761A priority patent/JP6263533B2/en
Priority to MX2015002511A priority patent/MX2015002511A/en
Priority to DK13830553.7T priority patent/DK2888241T3/en
Priority to MYPI2015700218A priority patent/MY182403A/en
Publication of WO2014029193A1 publication Critical patent/WO2014029193A1/en
Priority to ZA2015/00451A priority patent/ZA201500451B/en
Priority to HK15106680.5A priority patent/HK1206027A1/en

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    • 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
    • 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
    • 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
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • 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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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

Definitions

  • the invention relates to dihydropyrimidine compounds and their application in pharmaceuticals, especially for use in treating and preventing Hepatitis B.
  • the invention also relates to drugs comprising the dihydropyrimidine compounds, other antiviral agent, and the pharmaceutical compositions thereof, particularly for treating and preventing HBV infection.
  • 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 ICso value of lamivudine (3-TC) is 300 nM ⁇ Science, 2003, 299, 893-896).
  • HAP heteroaryl-substituted dihydropyrimidine
  • the invention relates to novel dihydropyrimidine compounds and methods of treating and preventing HBV infection.
  • these compounds and the pharmaceutically acceptable compositions thereof disclosed herein can inhibit HBV infection effectively.
  • each A is a bond, -0-, -S-, or -NR. 5 -; each R is -X-Z;
  • Z has Formula (II) or (Ila):
  • Z has Formula (III) or (Ilia):
  • R 9 is -(CR 7 R 7a ) t -OH
  • R 3 is C 6- io aryl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrimidinyl, pyridazinyl, thiazolyl, diazolyl, triazolyl, tetrazolyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyranyl or triazinyl; each n is independently 1 or 2; each t is independently 1 , 2, 3 or 4; and each m is independently 0, 1 , 2, 3 or 4.
  • R 3 is phenyl, ruryl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrimidinyl, pyridazinyl, thiazolyl, diazolyl, triazolyl, tetrazolyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyranyl or triazinyl.
  • R 3 has one of the following formulae:
  • R 3 has one of the following formulae:
  • R 1 is C6-10 aryl, and the aryl is independently substituted with one or more substituents which are the same or different, wherein the substituent is H, F, CI, Br, cyano, methyl, ethyl, methoxy, ethoxy, methylamino, ethylamino, nitro, 4-(trifluoromethy])phenyl, 3,5-6z ' s(trifluoromethyl)phenyl or trifluoromethyl;
  • R 2 is H, or C alkyl
  • R 5 is H, or C].4 alkyl.
  • R 1 is phenyl or a phenyl substituted with one or more substituents which are the same or different, wherein the substituent is H, F, CI, Br, nitro, 4-(trifluoromethyl)phenyl, 3,5-0is(trifluorornethyl)phenyl or trifluoromethyl.
  • Formula (IV) or (IVa) is
  • R 3 is C 6-10 aryl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrimidinyl, pyridazinyl, thiazolyl, diazolyl, triazolyl, tetrazolyl, thieny], pyrazoly], isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl
  • Z has Formula (II)
  • Z is:
  • ⁇ [0021 ] In one aspect, provided herein are compounds and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.
  • composition further comprising an anti-HBV agent.
  • the pharmaceutical composition disclosed herein, wherein the anti-HBV agent is a HBV polymerase inhibitor, immunomodulator or interferon.
  • the pharmaceutical composition disclosed herein wherein the anti-HBV agent is lamivudine, telbivudine, tenofovir, entecavir, adefovir dipivoxil, alfaferone, alloferon, celmoleukin, clevudine, emtricitabine, famciclovir, feron, hepatect CP, intefen, interferon a-lb, interferon a, interferon a-2a, interferon ⁇ -l a, interferon a-2, interleukin-2, mivotilate, nitazoxanide, peginterferon alfa-2a, ribavirin, roferon-A, sizofiran, euforavac, rintatolimod, phosphazid, heplisav, interferon a-2b, levamisole
  • 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 a HBV disease in a patient.
  • the use is disclosed herein, wherein the viral disease or HBV disease is hepatitis B infection or a disease caused by hepatitis B infection.
  • the use is disclosed herein, wherein the disease caused by hepatitis B infection is cirrhosis or hepatocellular carcinoma.
  • 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 a HBV disease in a patient, comprising administering to the patient a therapeutically effective amount of the compound or the composition disclosed herein.
  • methods for preventing, managing, treating or lessening a viral disease or a HBV disease in a patient which comprises administering a pharmaceutically effective amount of the compound disclosed herein to the patient.
  • kits for preventing, managing, treating or lessening a viral disease or a HBV disease in a patient which comprises administering a pharmaceutically effective amount of the pharmaceutical composition disclosed herein to the patient.
  • a medicament for preventing, managing or treating a viral disease or a HBV disease and lessening the severity of a viral disease or a HBV disease in a patient.
  • composition comprising the compound disclosed herein in the manufacture of a medicament for preventing, managing or treating a viral disease or a HBV disease and lessening the severity of a viral disease or a HBV disease in a patient.
  • the organism is a mammal; in other embodiments, the organism is a human.
  • the method further comprises contacting the kinase with a HBV therapeutic agent.
  • a method of inhibiting HBV infection comprising contacting the cell with an effective HBV inhibiting amount of a compound disclosed herein or a composition thereof. In other embodiments, the method further comprises contacting the cell with a HBV therapeutic agent.
  • a method of treating HBV disease in a patient comprises administering to the patient in need of such treatment an effective therapeutic amount of a compound disclosed herein or a composition thereof. In other embodiments, the method further comprises administering a HBV therapeutic agent.
  • a method of inhibiting HBV infection in a patient comprises administering to the patient in need of an effective therapeutic amount of a compound disclosed herein or a composition thereof. In other embodiments, the method further comprises administering a HBV therapeutic agent.
  • provided herein include methods of preparing, methods of separating, and methods of purifying compounds of Formula (I) or (la).
  • compounds may optionally be substituted with one or more substituents, such as those illustrated above, or as exemplified by particular classes, subclasses, and species disclosed herein.
  • 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.
  • 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.
  • alkyl groups contain 1 -10 carbon atoms.
  • alkyl groups contain 1 -8 carbon atoms.
  • alkyl groups contain 1 -6 carbon atoms, and in yet other embodiments, alkyl groups contain ] -4 carbon atoms.
  • alkyl groups contain 1 -3 carbon atoms.
  • alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), 1 -propyl (w-Pr, w-propyl, -CH 2 CH 2 CH 3 ), 2-propyl (i-Pr, / ' -propyl, -CH(CH 3 ) 2 ), 1 -butyl (w-Bu, w-butyl, -CH 2 CH 2 CH 2 CH 3 ), 2-methyl-l -propyl or isobutyl ( -Bu, /-butyl, -CH 2 CH(CH 3 ) 2 ), 1 -methylpropyl or sec-butyl (s-Bu, 5-butyl, -CH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propyl or tert-bxityl (t-B , /-butyl, -C(CH 3 ) 3 ), 1 -p
  • alkyl and the prefix “alk-” are inclusive of both straight chain and branched saturated carbon chain.
  • alkylene represents a saturated divalent hydrocarbon group derived from a straight or branched chain saturated hydrocarbon by the removal of two hydrogen atoms, and is exemplified by methylene, ethylene, isopropylene, and the like.
  • haloaliphatic or haloalkyl refers to an aliphatic radical or alkyl radical substituted with one or more halogen atoms (i.e., F, CI, Br or I,), which may be either the same or different.
  • halogen atoms i.e., F, CI, Br or I,
  • Some non-limiting examples of such radicals include trifluoromethyl and trifluoroethyl.
  • hydroxyaliphatic refers to an aliphatic radical or alkyl radical substituted with one or more hydroxy groups, wherein each t, m, aliphatic and alkyl is as defined above.
  • Some non-limiting examples include hydroxyethyl, 2-hydroxypropyl, hydroxymethyl, and the like.
  • alkenyl refers to a linear or branched-chain monovalent hydrocarbon radical of two to twelve carbon atoms with at least one site of unsaturation, i.e., a 2
  • alkenyl radical may be optionally substituted independently with one or more substituents described herein, and includes radicals having "cii” and “trans” orientations, or alternatively, "E” and “Z” orientations.
  • alkynyl refers to a linear or branched-chain monovalent hydrocarbon radical of two to twelve carbon atoms with at least one site of unsaturation, i.e., a carbon-carbon, sp triple bond, wherein the alkynyl radical may be optionally substituted independently with one or more substituents described herein. Specific examples include, but are not limited to, ethynyl (-C ⁇ CH), propynyl (propargyl, -CH 2 C ⁇ CH), and the like.
  • cycloaliphatic refers to a monovalent or multivalent non-aromatic, saturated or partially unsaturated ring having 3 to 12 carbon atoms as a monocyclic ring or 7 to 12 carbon atoms as a bicyclic ring.
  • Bicyclic carbocycles having 7 to 12 atoms can be arranged, for example, as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, and bicyclic carbocycles having 9 or 10 ring atoms can be arranged as a bicyclo [5,6] or [6,6] system.
  • cycloaliphatic groups include cycloalkyl, cycloalkenyl, and cycloalkynyl. Further examples of cycloaliphatic groups include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-l-enyl, l-cyclopent-2-enyl, l-cyclopent-3-enyl, cyclohexyl, 1 -cyclohex-l-enyl, l-cyclohex-2-enyl, l-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like.
  • heterocycle refers to a monocyclic, bicyclic or tricyclic ring system in which one or more ring members are an independently selected heteroatom and that is completely saturated or that contains one or more units of unsaturation, but not aromatic having a single point of attachment to the rest of the molecule.
  • ring members are an independently selected heteroatom and that is completely saturated or that contains one or more units of unsaturation, but not aromatic having a single point of attachment to the rest of the molecule.
  • One or more ring atoms are optionally substituted independently with one or more substituents described below.
  • the "heterocycle”, “heterocyclyl”, “heterocycloaliphatic” or “heterocyclic” group is a monocycle having 3 to 7 ring members (e.g., 1 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P or S, wherein the S or P is optionally substituted with one or more oxo to provide the group SO or S0 2 , PO or P0 2 , with the proviso that when the ring is a 3-membered ring, there is only one heteroatom) or a bicycle having 7 to 10 ring members (e.g. , 4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P or S, wherein the S or P is optionally substituted with one or more oxo to provide the group SO or S0 2 , PO or P0 2 ).
  • 3 to 7 ring members e.g., 1 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P
  • the heterocyclyl may be a carbon radical or heteroatom radical.
  • Heterocyclyl also includes radicals where heterocycle radicals are fused with a saturated, partially unsaturated ring, or heterocyclic ring.
  • Some non-limiting examples of heterocyclic rings include pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, epoxypropyl, azepanyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl,
  • each R 7 , R 7a , R 8 , R 8a , m, q and t is as disclosed herein.
  • heterocyclylalkyl refers to heterocyclic-substituted alkyl radical.
  • heterocyclylalkoxy refers to heterocyclic-substituted alkoxy radical wherein oxygen atom serves as the attaching point to the rest of the molecule.
  • heterocyclylalkylamino refers to heterocyclic-substituted alkylamino radical wherein nitrogen atom serves as the attaching point to the rest of the molecule. Wherein the heterocyclyl, alkyl, alkoxy and alkylamino group are as defined herein.
  • Some non-limiting examples include pyrrol-2-ylmethyl, morpholin-4-ylmethyl, pyrrol-2-ylmethoxy, piperidin-2-ylethoxy, piperazin-2-ylethylamino, morpholin-4-ylpropoxy, morpholin-4-ylethylamino, and the like.
  • heteroatom refers to one or more of oxygen, sulfur, nitrogen, phosphorus or silicon, including any oxidized form of nitrogen, sulfur or phosphorus; the quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocyclic ring, for example, N (as in 3,4-dihydro-2H-pyrrolyl), ⁇ (as in pyrrolidinyl) or NR (as in N-substituted pyrrolidinyl).
  • halogen refers to F, CI, Br or I.
  • alkoxy refers to an alky] group, as previously defined, attached to the principal carbon chain through an oxygen atom (“alkoxy").
  • haloalkyl refers to alkyl, alkenyl or alkoxy, as the case may be, substituted with one or more halogen atoms.
  • haloalkyl refers to alkyl, alkenyl or alkoxy, as the case may be, substituted with one or more halogen atoms.
  • Some non-limiting examples of such radicals include trifluoromethyl, trifluoromethoxy, 2-fluoro-vinyl, and the like.
  • aryl used alone or as part of a larger moiety as in “aralkyl”, “aralkoxy” or “aryloxyalkyl” refers to monocyclic, bicyclic and tricyclic carbocyclic ring systems having a total of six to fourteen 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 a single point of attachment to the rest of the molecule.
  • aryl may be used interchangeably with the term “aryl ring”.
  • Some non-limiting examples of aryl rings include phenyl, naphthyl and anthryl.
  • heteroaryl used alone or as part of a larger moiety as in “heteroarylalkyl” or “heteroarylalkoxy” refers to monocyclic, bicyclic and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, and at least one ring in the system is inclusive of one or more heteroatoms as described herein, wherein each ring in the system contains 3 to 7 ring members and that has a single point of attachment to the rest of the molecule.
  • heteroaryl may be used interchangeably with the term “heteroaryl ring” or “heteroaromatic compound”.
  • suitable heteroaryl rings include the following monocycles: 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazoly], 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g.
  • heteroarylalkyl refers to alkyl radicals substituted with one or more heteroaryl radicals, wherein the alkyl and heteroaryl groups are as defined herein.
  • Some non-limiting examples of such radicals include pyridin-2-ylethyl, thiazol-2-ylmethyl, imidazol-2-ylethyl, pyrimidin-2-ylpropyl, and the like.
  • alkylsulfonyl refers to respectively divalent radicals -S0 2 -.
  • alkylsulfonyl refers to a sulfonyl radical substituted with an alkyl radical, forming an alkylsulfonyl (-S0 2 CH 3 ).
  • sulfamyl refers to a sulfonyl radical substituted with an amine radical, forming a sulfonamide (-S0 2 NH 2 ).
  • carboxy or “carboxyl”, whether used alone or with other terms, such as “carboxyalkyl”, refers to -C0 2 H.
  • alkylthio refers to radicals containing a linear or branched-alkyl radical of one to ten carbon atoms, attached to a divalent sulfur atom. In other embodiments, alkylthio radicals are lower alkylthio radicals having one to three carbon atoms. Some non-limiting examples of “alkylthio” include methylthio (CH 3 S-), ethylthio (CH 3 CH 2 S-), and the like.
  • aralkyl refers to aryl -substituted alkyl radicals.
  • aralkyl radicals or arylalkyl radicals are "lower aralkyl” radicals having aryl radicals attached to alkyl radicals having one to six carbon atoms.
  • aralkyl radicals or arylalkyl radicals are "phenylalkylenyl” attached to alkyl portions having one to three carbon atoms.
  • Some non-limiting examples of such radicals include benzyl, diphenylmethyl and phenylethyl.
  • each R 7 , R 7a , R 8 , R 8a , m, q and t is as disclosed herein.
  • alkylamino refers to "N-alkylamino" and "N,N-dialkylamino” wherein amino groups are independently substituted with one alkyl radical or with two alkyl radicals, respectively.
  • alkylamino radicals are "lower alkylamino” radicals having one or two alkyl radicals of one to six carbon atoms, attached to a nitrogen atom.
  • alkylamino radicals are lower alkylamino radicals having one to three carbon atoms.
  • alkylamino radicals include mono or dialkylamino such as N-methylamino, N-ethylamino, N,N-dimethylamino, N ⁇ N-diethylamino, and the like.
  • aminoalkyl refers to a linear or branched-alkyl radical having one to ten carbon atoms, substituted with one or more amino radicals.
  • aminoalkyl radicals are "lower aminoalkyl” radicals having one to six carbon atoms and one or more amino radicals.
  • Some non-limiting examples of such radicals include aminomethyl, aminoethyl, aminopropyl, aminobutyl or aminohexyl.
  • alkyl radicals in alkoxycarbonyl are "lower alkyl” radicals having one to six carbon atoms. Some non-limiting examples of such radicals include methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl.
  • carboxyalkyl refers to a linear or branched-alkyl radical having one to ten carbon atoms, substituted with one or more carboxy radicals. Some non-limiting examples of such radicals include carboxymethyl, carboxypropyl, and the like.
  • haloalkyl-substituted aryl refers to aryl radicals substituted with one or more haloalkyl radicals.
  • Some non-limiting examples of such radicals include 2-trifluoromethylphenyl, 3,5-0w(trifluoromethyl)phenyl, 3-trifluoromethylphenyl, 4- trifluoromethylphenyl, 2,6-fe(trifluoromethyl)phenyl, and the like.
  • halogen-substituted aryl refers to an aryl substituted with one or more halogen atoms.
  • radicals include fluorophenyl, difluorophenyl, triiluoropheny], chlorophenyl, dichlorophenyl, trichlorophenyl, bromophenyl, tribromophenyl, dibromophenyl, fluorochlorophenyl, fluorobromophenyl, chorobromophenyl, and the like.
  • cycloalkylalkyl refers to alkyl radicals substituted with one or more cycloalkyl radicals, wherein cycloalkyl and alkyl are as defined herein. Some non-limiting examples of such radicals include cyclohexylmethyl and cyclopropyl ethyl.
  • the cycloalkyl in the radicals may be additionally substituted with halo, alkyl, alkoxy or hydroxy.
  • 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.
  • Figure a represents possible substitution in any of the positions on the A ring and B ring, as shown in Figure b; or
  • Figure c represents possible substitution in any of the positions on the ring, as shown in Figure d.
  • FIG. a Figure b Figure c pFi-g Rure d [0073] Unless otherwise stated, 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.
  • isomeric e.g., enantiomeric, diastereomeric, and geometric (or conformational)
  • prodrug refers to a compound that is transformed in vivo into a compound of Formula (I). 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]. 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.
  • optically active compounds i.e., they have the ability to rotate the plane of plane-polarized light.
  • the prefixes D and L, or R and S are used to denote the absolute configuration of the molecule about its chiral center(s).
  • the prefixes d and 1 or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory.
  • a compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, 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.
  • proton tautomers also known as prototropic tautomers
  • Valence tautomers include interconversions by reorganization of some of the bonding electrons.
  • a "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.
  • salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • 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 + (Ci-4 alkyl) 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, Ci -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 or “Pg” 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, r-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 S0 2 Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl,
  • each A is a bond, -0-, -S-, or -NR 5 -; each R is -X-Z;
  • Z has Formula (II) or (Ila):
  • Z has Formula (III) or (Ilia):
  • R 3 is phenyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pynmidinyl, pyridazinyl, thiazolyl, diazolyl, triazolyl, tetrazolyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyranyl or triazinyl.
  • R has one of the following formulae:
  • R 3 has one of the following formulae:
  • R 1 is C6-10 aryl, and the aryl is independently substituted with one or more substituents which are the same or different, wherein the substituent is H, F, CI, Br, cyano, methyl, ethyl, methoxy, ethoxy, methylamino, ethylamino, nitro, 4-(trifluoromethyl)phenyl, 3,5-frw(trifluoromethyl)phenyl or trifluoromethyl;
  • R 2 is H, or C] .4 alkyl
  • R 5 is H, or Ci-4 alkyl.
  • R 1 is phenyl or a phenyl substituted with one or more substituents which are the same or different, wherein the substituent is H, F, CI, Br, nitro, 4-(trifluoromethyl)pheny], 3,5-& s(trifluoromethyl)phenyl or trifluoromethyl.
  • Formula (IV) or (IVa) is or an enantiomer, a diastereoisomer, a tautomer, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, wherein Z has Formula (II) or (lla):
  • Z has Formula (II) or (Ha):
  • Z is:
  • compositions and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.
  • composition further comprising an anti-HBV agent.
  • the pharmaceutical composition is disclosed herein, wherein the anti-HBV agent is a HBV polymerase inhibitor, immunomodulator or interferon.
  • the pharmaceutical composition is disclosed herein, wherein the anti-HBV agent is lamivudine, telbivudine, tenofovir, entecavir, adefovir dipivoxil, alfaferone, alloferon, celmoleukin, clevudine, emtricitabine, famciclovir, feron, fepatect CP, intefen, interferon a- lb, interferon a, interferon a-2, interferon a-2a, interferon a-2b, interferon ⁇ -l a, interleukin-2, mivotilate, nitazoxanide, peginterferon alfa-2a, ribavirin,
  • [001 01 ] in another aspect, provided herein are methods for preventing, managing, treating or lessening a viral disease or a HBV disease in a patient, which comprises administering a pharmaceutically effective amount of the compound disclosed herein to the patient.
  • kits for preventing, managing, treating or lessening a viral disease or a HBV disease in a patient which comprises administering a pharmaceutically effective amount of the pharmaceutical composition disclosed herein to the patient.
  • [001 03] in another aspect, provided herein are the compounds disclosed herein or the pharmaceutical compositions disclosed herein for use in preventing, managing or treating a viral disease or a HBV disease or lessening the severity of a viral disease or a HBV disease in a patient.
  • 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.
  • 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 a HBV therapeutic agent.
  • a method of inhibiting HBV infection comprising contacting a cell or a plurality of cells with an effective HBV inhibiting amount of a compound disclosed herein or a composition thereof.
  • the method further comprises contacting the cells with a HBV therapeutic agent.
  • a method of treating HBV disease in a patient comprises administering to the patient in need of such treatment an effective therapeutic amount of a compound disclosed herein or a composition thereof. In other embodiments, the method further comprises administering to the patient a HBV therapeutic agent.
  • a method of inhibiting a HBV infection in a patient comprises administering to the patient in need of an effective therapeutic amount of a compound disclosed herein or a composition disclosed herein. In other embodiments, the method further comprises administering to the patient a HBV therapeutic agent.
  • provided herein include methods of preparing, methods of separating, and methods of purifying the compounds of Formula (I) or (la).
  • [001 1 1 ] Provided herein includes the use of 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 (la) in association with at least one pharmaceutically acceptable carrier, adjuvant or diluent.
  • the salt is a pharmaceutically acceptable salt.
  • pharmaceutically acceptable refers to that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.
  • 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 (la) and/or for separating enantiomers of compounds of Formula (I) or (la).
  • 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 / oluenesulfonic 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 ) 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 ) 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 alky], Ce-io aryl or C 6- io aryl-C ⁇ -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 alky], Ce-io aryl or C 6- io aryl-C ⁇ -alkyl, and cyclic amines, such as piperidine, morpholine and piperaz
  • Further salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, C]-8 sulfonate or aryl sulfonate.
  • the invention features pharmaceutical compositions that include a compound of Formula (I) or (la), a compound listed herein, or a compound named in Examples 1 to 157, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • the compound disclosed herein can inhibit HBV effectively, and is suitable for use in treating 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.
  • Areas of indication which may be mentioned for the compounds disclosed herein are, for example: the treatment of acute and chronic viral infections which may lead to infectious hepatitis, for example, infections with hepatitis B viruses.
  • the compounds disclosed herein are particularly suitable for the treatment of chronic hepatitis B infections and the treatment of chronic hepatitis B infections and the treatment of acute and chronic hepatitis B viral infections.
  • the present invention includes pharmceutical preparations which, besides nontoxic, inert pharmaceutically suitable carriers, comprise one or more compounds (I) or (la) disclosed herein or a combination thereof or which consist of one or more active ingredients (I) or (la) disclosed herein or a combination thereof.
  • compositions mentioned above may also comprise other active pharmaceutical ingredients apart from the compounds (I) or (la).
  • 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 vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, 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, adjuvant, or vehicle which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, 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 com starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin
  • composition comprising the compound disclosed herein may be administered in any of the following routes: orally, inhaled by spray, rectally, nasally, vaginally, topically, 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 disclosed herein or the pharmaceutical composition comprising the compound 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, si
  • 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 jp-hydroxybenzoate, sorbic acid. If desired, a flavoring agent or a colorant may be added.
  • Suppository may comprise a conventional suppository subtrate, 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-limitimg 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.
  • the anti-HBV agent is a 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 a- lb, interferon a, interferon a-2a, interferon ⁇ -l a, interferon a-2, interleukin-2, mivotilate, nitazoxanide, peginterferon alfa-2a, ribavirin, roferon-A, sizofiran, euforavac, veldona, rintatolimod, phosphazid, heplisav, interferon a-2b, levamisole or propagermanium.
  • 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 or 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.
  • the amount of both the compound and the additional therapeutic agent (in those compositions which comprise an additional therapeutic agent as described above) that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Normally, 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. In other embodiment, 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. In those compositions which comprise an additional therapeutic 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 vural 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.
  • Examples of 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.
  • MS data were determined on an Agilent 6320 Series LC-MS spectrometer equipped with G 1312A binary pumps and a G 1316A TCC (Temperature Control of Column, maintained at 30 ° C).
  • G 1329A autosampler and a G 1315B 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 G 1 3 1 1 A quaternary pumps and a G 1 31 6A TCC (Temperature Control of Column, maintained at 30 ° C). A G 1329A autosampler and a G 1 31 5D DAD detector were used in the analysis, and an ESI source was used on the LC-MS spectrometer.
  • Both Spectrographs were equipped with an Agilent Zorbax SB-C18 (2.1 x 30 mm, 5 micron). Injection volume was decided by the sample concentration. The flow rate is 0.6 mL/min.
  • the mobile phase was (0.1 % formic acid in CH 3 CN as mobile phase A) in (0.1 % formic acid in H 2 0 as mobile phase B) with UV detection at 210/254 nm.
  • the conditions of gradient elution is described in Table 1 :
  • Intermediate 3A can be prepared by the process disclosed herein.
  • Compound 1 A reacts with compound 2A in an acidic condition to give intermediate 3A.
  • Intermediate 5A can be prepared by the process disclosed herein.
  • Compound 4A is hydrolyzed in an alkaline condition to give intermediate 5A.
  • Intermediate 8A wherein R 8 is alkylamino, alkoxy or amino, can be prepared by the process disclosed herein.
  • Compound 6A is transformed to an acyl chloride intermediate through acylation.
  • the acyl chloride intermediate reacts with compound 7A to give intermediate 8A.
  • Intermediate 12A can be prepared by the process disclosed herein.
  • Compound 9 A reacts with benzyl bromide to afford compound 10A, which can be transformed to compound 11A under the action of borane tetrahydrofuran.
  • Compound 11 A is then reduced through catalytic hydrogenation to give intermediate 12A.
  • Intermediate 18A can be prepared by the process disclosed herein.
  • Compound 13A reacts with benzaldehyde and sodium borohydride to give compound 14A.
  • Compound 14A then reacts with chloroacetyl chloride in an alkaline condition to afford compound 15A followed by reacting with benzyl bromide to afford compound 16A, which can be transformed to compound 17A under the action of borane tetrahydrofuran.
  • Compound 17A is then reduced through catalytic hydrogenation to give intermediate 18A.
  • Intermediate 22 A can be prepared by the process disclosed herein.
  • Compound 19A reacts with 2-aminoethanol to afford compound 21 A followed by reacting with hydrochloric acid in ethyl acetate under the action of acetic acid to give intermediate 22A.
  • Intermediate 25A wherein each R 13 and n is as defined above, can be prepared by the process disclosed herein.
  • Compound 23A reacts with compound 24A under the action of tetrakis(triphenylphosphine)palladium in an alkaline condition to give intermediate 25A.
  • Intermediate 28A can be prepared by the process disclosed herein, wherein R 3 is as defined herein.
  • Compound 26A can be transformed to compound 27A through the action of copper (I) cyanide.
  • Compound 27A then reacts with hydroxylamine hydrochloride in the presence of Pd/C to give intermediate 28A.
  • Intermediate 34A can be prepared by the process disclosed herein.
  • Compound 31A can be prepared by the reduction and bromination of compound 29A.
  • Compound 31A then reacts with compound 32A to afford compound 33A followed by reduction to give intermediate 34A.
  • Intermediate 36A can be prepared by the process disclosed herein.
  • Compound 33A is reduced twice by any reduction reaction that can reduce esters into alcohols or amides into amines to give intermidate 36A.
  • Intermediate 44A can be prepared by the process disclosed herein.
  • Compound 37A reacts with compound 38A to afford compound 39A.
  • a mixture of compound 39A and compound 40A in methanol is refluxed to afford compound 41A, followed by methylation, reduction through catalytic hydrogenation and hydrolyzation in an alkaline condition to give intermediate 44A.
  • Intermediate 47A can be prepared by the process disclosed herein.
  • Compound 45A is reacted with sodium azide and ammonium chloride to afford compound 46A followed by reduction through deprotection to give intermediate 47A.
  • Intermediate 53A can be prepared by the process disclosed herein.
  • Compound 49A can be prepared through oxidation of compound 48A.
  • Compound 49A then reacts with compound 50A to afford compound 51 A followed by basic hydrolysis, reduction and salt forming reaction to give intermediate 53A.
  • Intermediate 60A can be prepared by the process disclosed herein.
  • Compound 49A reacts with compound 50A to afford compound 54A, followed by reduction of the alkenyl and ester groups to give intermediate 60 A.
  • Intennediate 61 A can be prepared by the process disclosed herein. Compound 55A is ammonolyzed to give intermediate 61A. [00181 ] Sythesis of intermediate 69A
  • Intermidiate 69A can be prepared by the process disclosed herein.
  • Compound 62 A reacts with compound 63 A to afford compound 64A.
  • Compound 64A reacts with compound 65A to afford compound 66A.
  • Compound 66A reacts with (bromomethyl)benzene to afford compound 67A, which is reduced twice to give intermediate 69A.
  • pyrimidine 6, wherein each R , R , R , A and Z is as defined herein, can be prepared by the process illustrated in Scheme 2.
  • Amidines 7 or hydrochloride thereof, aldehydes 2 and compound 3 can be cyclized in suitable inert solvent(s) (such as alcohol reagents) to give compound 8.
  • Compound 8 can be reacted with chlorinating agent to give compound 9.
  • Compound 9 reacts with R J H in suitable inert solvent(s) to yield compound 4.
  • Compound 4 reacts with brominating agent in inert solvent(s) to give compound 5.
  • compound 5 reacts with ZH in appropriate inert solvent(s) under an alkaline condition to yield pyrimidine 6.
  • Compound 5 reacts with ⁇ to afford compound 13 followed by esterification or amidation, and hydrolyzation to give pyrimidine 14.
  • Amidines 15 or hydrochloride thereof, aldehydes 2 and compound 3 are cyclized in suitable inert solvent(s) (such as alcohol reagents) to afford compound 16.
  • Compound 17 can be prepared through amidation of compound 16.
  • Compound 17 then reacts with brominating agent in inert solvent(s) to give compound 18 followed by reacting with ZH under an alkaline condition in appropriate inert solvent(s) to yield pyrimidine 19.
  • Step A Ethyl 6-methyl-2-(thiazol-2-yl)-4-(2-(trifluoromethyl)pheny])-l,4- dihydropyrimidine-5-carboxylate
  • Step B Ethyl 6-(bromomethyl)-2-(thiazol-2-yl)-4-(2-(trinuoromethyl) phenyl)-l,4-dihydropyrimidine-5-carboxylate
  • Step C 4-((5-(ethoxycarbonyl)-2-(thiazol-2-yl)-6-(2-(trinuoromethyl) phenyl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid
  • Step A Ethyl 6-methyl-4-(2-nitrophenyl)-2-(thiazol-2-yl)-l,4-dihydro pyrimidine-5-carboxylate
  • Step B Ethyl 6-(bromomethyl)-4-(2-nitrophenyl)-2-(thiazoI-2-yl)-l,4- dihydropyrimidine-5-carboxylate
  • Step C 4-((5-(ethoxycarbonyl)-6-(2-nitrophenyl)-2-(thiazol-2-yl)-3,6- dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid
  • Step A 3-(4-( rt-butoxycarbonyl)morpholin-3-yl)propanoic acid
  • Step B 3-(morphoIin-3-yl)propanoic acid hydrochloride
  • Step C 3-(4-((6-(2-bromo-4-fluoropheny])-5-(ethoxycarbony])-2-(thiazol-2- yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholin-3-y])propanoic acid
  • Step A (5)-6,6-dimethyImorpholine-3-carboxylic acid hydrochloride
  • Step B (3S)-4-((6-(2,4-dichlorophenyI)-5-(ethoxycarbonyl)-2-(thiazoI-2-yl) -3,6-dihydropyrimidin-4-yl)methyl)-6,6-dimethylmorpholine-3-carboxyIic acid
  • Step B Ethyl 4-(2-bromo-4-fluorophenyl)-6-((3-carbamoylmorpholino) methyl)-2-(thiazol-2-yl)-l,4-dihydropyrimidine-5-carboxylate
  • Step A (2/?,3S)-benzyl 4-benzyl-2-methyI-5-oxomorpholine-3-carboxylate
  • Step B (2R,35 -benzyl 4-benzyl-2-methylmorphoIine-3-carboxyIate
  • Step D (2/?,35)-4-f(6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2- (thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)-2-methylmorpholine-3-carboxylic acid
  • Example 37 (2 f,35')-4-((6-(2-bromo-4-fluorophenyl)-5-(methoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydr opyrimidin-4-yl)methyl)-2-methylmorpholine-3-carboxylic acid
  • Step A (£)-2-(benzylamino)-3-hydroxy-3-methylbutanoic acid
  • (S)-2-amino-3-hydroxy-3-methylbutanoic acid 18.6 g, 140 mmol
  • aqueous NaOH solution 2 mol/L, 70 mL
  • benzaldehyde 14.56 g, 137 mmol
  • sodium borohydride (3 g, 80 mmol) portion wise with the temperature maintained below 10 ° C.
  • the mixture was warmed to 25 ° C and stirred for another 12 hours.
  • the aqueous layer was washed with DCM (30 mL x 3) and the organic layer was discarded.
  • the aqueous layer was cooled to 5 ° C, and adjusted to pH 1 -2 with con.HCl.
  • the mixture was stirred at 5 ° C for 4 hours, and filtered to give the title compound as a white solid (18.8 g, 60%).
  • the compound was characterized by the following spectroscopic data:
  • Step B (5)-4-benzyI-2,2-dimethyl-5-oxomorphoIine-3-carboxylic acid
  • the mixture was cooled to 3 ° C-5 ° C, and the mixture was stirred at the temprarure for 4 hours. Then the reaction mixture was warmed to room temperature, and washed with Petroleum ether (50 mL x 2). The aqueous layer was cooled to 3 ° C below and adjusted to pH 2 with con.HCl. The mixture was stirred at 6 ° C below for 12 hours, then filtered. The filter cake was washed with water to give the title compound as a white solid (18.6 g, 69%).
  • the compound was characterized by the following spectroscopic data:
  • Step C (5)-benzyI 4-benzyl-2,2-dimethyl-5-oxomorpholine-3-carboxylate
  • Step D (5)-benzyl 4-benzyl-2,2-dimethylmorpholine-3-carboxylate
  • Step E (S)-2,2-dimethylmorpholine-3-carboxylic acid
  • Step F (35)-4-((6-(2-bromo-4-fluorophenyI)-5-(ethoxycarbonyl)-2-(thiazol- 2-yI)-3,6-dihydropyrimidin-4-yl)raethyl)-2,2-dimethylmorpholine-3-carboxylic acid
  • Step A Ethyl 4-(2-chloro-4-fluorophenyl)-l,6-dimethyl-2-(thiazol-2-yl)-l,4- dihydropyrimidine-5-carboxylate
  • Step B Ethyl 6-(bromomethyl)-4-(2-chIoro-4-fluorophenyl)-l-methyl-2- (thiazol-2-yl)-l,4-dihydropyrimidine-5-carboxylate
  • Step C 4-((6-(2-chloro-4-nuoropheny])-5-(ethoxycarbonyl)-3-methyl-2- (thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid
  • the reaction mixture was filtered and the filtrate was concentrated in vacuo.
  • the residue was dissolved in a solution of HCl in EtOAc (6 mol/L, 40 mL), and the mixture was stirred at 25 ° C for 12 hours.
  • the reaction mixture was diluted with EtOAc (200 mL) and water (100 mL), and the mixture was adjusted to pH 8-9 with aqueous ammonia.
  • the organic layer was dried over Na 2 S0 4 , and the mixture was filtered and concentrated in vacuo.
  • the compound was characterized by the following spectroscopic data:
  • Example 50 Ethyl 6-(((5)-3-((((S)-2-amino-3-methylbutanoyl)oxy)methyl)morpholino)methyl)-4-(2, 4-dichlorophenyl)-2-(thiazoI-2-yl)-l,4-dihydropyrimidine-5-carboxylate
  • Step A (S)-tert-buty ⁇ 3-((2-hydroxyethyl)carbamoyl)morphoIine-4- carboxylate
  • Step B (5)-2-(morpholine-3-carboxamido)ethyl acetate hydrochloride
  • (S)-tert-buty ⁇ 3-((2-hydroxyethyl)carbamoyl)mo holine-4-carboxylate (0.33 g, 1.2 mmol) in glacial acetic acid (0.5 mL)
  • a solution of HCl in EtOAc (6 mol/L, 15 mL
  • the mixture was concentrated in vacuo to give the title compound as glutinous semisolid (0.21 g, 70%).
  • the compound was characterized by the following spectroscopic data:
  • Step C Ethyl 6-(((5)-3-((2-acetoxyethyl)earbamoyl)morpholino)methyl)-4- (2-bromo-4-fluorophenyl)-2-(thiazol-2-yl)-l,4-dihydropyrimidine-5-carboxylate
  • Step A 5-nuoro-4'-(trifluoromethyl)-[l,l'-biphenyl]-2-carbaldehyde
  • Step B Ethyl 4-(5-fluoro-4'-(trifluoromethyl)-[l,l , -biphenyl]-2-yl)-6- methyl-2-(thiazol-2-yl)-l,4-dihydropyrimidine-5-carboxylate
  • Step C Ethyl 6-(bromomethyl)-4-(5-nuoro-4'-(trinuoromethy])-[l,r-bi phenyl]-2-yl)-2-(thiazol-2-yI)-l,4-dihydropyrimidine-5-carboxylate
  • Step D (3S)-4-((5-(ethoxycarbonyl)-6-(5-fluoro-4*-(trinuoromethyl)-[l,l '-bi phenyl]-2-yl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morphoIine-3-carboxyli c acid
  • Step A 5 1uoro-3 ⁇ 5'-WA(trifluoromethyl)-
  • Step B Ethyl 4-(5-fluoro-3',5 , -* «(trifluoromethyl)-Il,r-biphenyl]-2-yl)-6- methyl-2-(thiazol-2-yl)-l,4-dihydropyrimidine-5-carboxylate
  • Step C Ethyl e-ib omomethylH-iS-nuoro-S S'-Awttrinuoromethy -ll,! '- bi phenyl]-2-yl)-2-(thiazol-2-y])-l,4-dihydropyrimidine-5-carboxylate
  • Step D (3S)-4-((5-(ethoxycarbony])-6-(5-fluoro-3',5'-A «(trifluoromethyl)- [1 '-biphenyl]-2-yl)-2-(thiazoI-2-yI) ,6-dihydropyrimidin-4-yl)rnethyl)morpholine-3-ca rboxylic acid
  • Step A Ethyl 4-(2-bromo-4-fluorophenyl)-6-((3-((2-ethoxy-2-oxoethyI) carbamoyl)morpholino)methyl)-2-(thiazol-2-yl)-l,4-dihydropyrimidine-5-carboxylate
  • Step B 2-(4-((6-(2-bromo-4-fluorophenyI)-5-(ethoxycarbonyl)-2-(thiazol-2 -yl)-3,6-dihydropyrimidin-4-yl)methyI)morphoIine-3-carboxamido)acetic acid
  • Step A Ethyl 2-(2-cyanothiazol-4-yl)acetate
  • Step B Methyl 2-(2-carbamiraidoylthiazol-4-yl)acetate hydrochloride
  • Step C Ethyl 4-(2-bromo-4-fluorophenyl)-2-(4-(2-methoxy-2-oxoethyl) thiazol-2-yl)-6-methy]-l,4-dihydropyrimidine-5-carboxylate
  • Step D Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(4-(2- methoxy-2-oxoethyl) thiazol-2-yl)-l,4-dihydropyrimidine-5-carboxylate
  • Step E (35 -4-((6-(2-bromo-4-fluorophenyI)-5-(ethoxycarbonyl)-2-(4-(2- methoxy-2-oxoethyl)thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carb oxylic acid
  • Step A 2-(2-(4-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-6-methyl-l,4- dihydropyrimidin-2-y])thiazoI-4-yl)acetic acid
  • Step B Ethyl 4-(2-bromo-4-fluorophenyI)-6-methyl-2-(4-(2-(methylamino)- 2-oxoethyl)thiazoI-2-yl)-l,4-dihydropyrimidine-5-carboxylate
  • Step C Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyI)-2-(4-(2-(methyl amino)-2-oxoethyl)thiazoI-2-yl)-l,4-dihydropyrimidine-5-carboxylate
  • Step D (3S)-4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyI)-2-(4-(2- (methylamino)-2-oxoethyl)thiazoI-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3 -carboxylic acid
  • Step A Ethyl 4-(2-bromo-4-nuorophenyl)-2-(4-(2-(isopropylamino)-2- oxoethyl)thiazol-2 -yl)-6-methyI-l,4-dihydropyrimidine-5-carboxylate
  • Step B Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(4-(2- (isopropylamino)-2-oxoethyl)thiazoI-2-yl)-l,4-dihydropyrimidine-5-carboxylate
  • Step C 4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyI)-2-(4-(2-(iso propyIamino)-2-oxoethyl)thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3- carboxylic acid
  • Step A Ethyl 4-(2-bromo-4-fluorophenyl)-6-((2-((2-ethoxy-2-oxoethyl) carbamoyl)morpholino)methyl)-2-(thiazol-2-yl)-l,4-dihydropyrimidine-5-carboxylate
  • Step B 2-(4-((6-(2-bromo-4-fluorophenyI)-5-(ethoxycarbonyl)-2-(thiazol-2- yl)-3,6- dihydropyrimidin-4-yl)methyl)morpholine-2-carboxamido)acetic acid
  • Step B Diethyl 2-(morpholin-3-ylmethyl)malonate
  • Step C Diethyl 2-((4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2- (thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morphoIin-3-yl)methyl)maIonate
  • Step D 2-((4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyI)-2-(thiazoI-2- yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholin-3-yl)methyl)-3-ethoxy-3-oxopropanoic acid
  • Step B 2-(morpholin-3-ylmethyl)propane-l,3-diol
  • Step C Ethyl 4-(2-bromo-4-fluorophenyl)-6-((3-(3-hydroxy-2-(hydroxy methyl)propyI)morpholino)methyl)-2-(thiazoI-2-y])-l,4-dihydropyrimidine-5-carboxylat e
  • Step B 5-methyl-l,3,4-thiadiazole-2-carboximidamide hydrochloride
  • Step C Ethyl 4-(2-bromo-4-fluorophenyl)-6-methyl-2-(5-methyl-l,3,4-thia diazol-2-yl)-l,4 -dihydropyrimidine-5-carboxylate 5-methyl-l ,3,4-thiadiazole-2-carboximidamide hydrochloride (1.8 g, 10 mmol) was reacted with 2-bromo-4-fluorobenzaldehyde (2.03 g, 10 mmol) and ethyl 3-oxobutanoate (1.56 g, 12 mmol) according to the procedure as described in Example 1 , Step A to give the title compound as a yellow solid ( 1.0 g, 25%). The compound was characterized by the following spectroscopic data:
  • Step D Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(5-methyl- l,3,4-thiadiazol-2-yl)-l,4-dihydropyrimidine-5-carboxylate
  • Step E 4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyI)-2-(5-methyI-l,3, 4-thiadiazol-2-yI)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid
  • Step A l,3,4-thiadiazoIe-2-carbonitrile l ,3,4-thiadiazol-2-amine (4.05 g, 40 mmol) was reacted with CuCN (7.2 g, 80 mmol) according to the procedure as described in Example 61 , Step A to give the title compound as red liquid (1 .78 g, 40%).
  • the compound was characterized by the following spectroscopic data:
  • Step B l,3,4-thiadiazole-2-carboximidamide hydrochloride l ,3,4-thiadiazole-2-carbonitrile (1 .1 1 g, 10 mmol) was reacted with sodium methoxide (0.81 g, 15 mmol) and ammonium chloride (0.96 g, 18 mmol) according to the procedure as described in Example 61 , Step B to give the title compound as an offwhite solid ( 1.15 g, 70%).
  • Step C Ethyl 4-(2,4-dichlorophenyI)-6-methyl-2-(l,3,4-thiadiazoI-2-yl)-l,4- dihydro pyrimidine-5-carboxylate
  • Step D Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(l,3,4-thiadiazol- 2-yl)-l,4-dihydropyrimidine-5-carboxylate
  • Step E 4-((6-(2,4-dichlorophenyl)-5-(ethoxycarbonyl)-2-(l,3,4-thiadiazol-2- yl)-3,6-dihydro pyrimidin-4-yl)methyl)morpholine-3-carboxylic acid
  • Step A Ethyl 4-(2-bromo-4-fluorophenyl)-6-methyl-2-(l,3,4-thiadiazol- 2-yl)-l,4-dihydropyrimidine-5-carboxylate l ,3,4-thiadiazole-2-carboximidamide hydrochloride (1.43 g, 8.69 mmol) was reacted with 2-bromo-4-fluorobenzaldehyde (1.76 g, 8.69 mmol) and ethyl 3-oxobutanoate (1.36 g, 10.5 mmol) according to the procedure as described in Example 1 , Step A to give the title compound as a yellow solid (1.74 g, 47%).
  • the compound was characterized by the following spectroscopic data:
  • Step B Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(l,3,4-thia diazol-2-yl)-l,4-dihydropyrimidine-5-carboxylate
  • Step C 4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(l,3,4-thia diazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid
  • Step A Ethyl 4-(2-chloro-4-fluoropheny])-6-metbyl-2-(l,3,4-thiadiazol- 2-yl)-l,4-dihydropyrimidine-5-carboxylate l ,3,4-thiadiazole-2-carboximidamide hydrochloride ( 1.43 g, 8.69 mmol) was reacted with 2-chloro-4-fluorobenzaldehyde ( 1.38 g, 8.69 mmol) and ethyl 3-oxobutanoate ( 1 .36 g, 10.5 mmol) according to the procedure as described in Example 1 , Step A to give the title compound as a yellow solid ( 1.82 g, 55%).
  • the compound was characterized by the following spectroscopic data:
  • Step B Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(l,3,4-thia diazol-2-yl)-l,4-dihydropyrimidine-5-carboxylate
  • Step C 4-i(6-i2-chloro-4-nuorophenyl)-5-(ethoxycarbonyI)-2-(l ,3,4-thia diazol-2-yI)-3,6-dihydropyrimidin-4-yl)methyi)morpholine-3-carboxylic acid

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Abstract

Provided herein are dihydropyrimidine compounds and their pharmaceutical　applications, especially for use in treating and preventing HBV diseases. Specifically,provided herein are compounds having Formula (I) or (Ia), or an enantiomer, a diastereoisomer, a tautomer, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, wherein the variables of the formulas are as defined in the specification. Also provided herein is the use of the compounds having Formula (I) or (Ia), or an enantiomer, a diastereoisomer, a tautomer, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof for treating and preventing HBV diseases.

Description

DIHYDROPYRIMIDINE COMPOUNDS AND THEIR APPLICATION IN
PHARMACEUTICALS
RELATED APPLICATIONS
[0001 ] This application claims the benefit of Chinese Patent Applications No.201210303033.4, filed August 24, 2012, and No.201310116949.3, filed April 03, 2013, which are hereby incorporated by reference in theri entireties.
FIELD OF THE INVENTION
[0002] The invention relates to dihydropyrimidine compounds and their application in pharmaceuticals, especially for use in treating and preventing Hepatitis B. The invention also relates to drugs comprising the dihydropyrimidine compounds, other antiviral agent, and the pharmaceutical compositions thereof, particularly for treating and preventing HBV infection.
BACKGROUND OF THE INVENTION
[0003] 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.
[0004] The conventional medicaments approved to be used for treating chronic hepatitis are interferon and lamivudine. However, the interferon has just moderate activity but has an adverse side reaction. Although lamivudine has good activity, its resistance develops rapidly during the treatment and relapse effects often appear after the treatment has stopped. The ICso value of lamivudine (3-TC) is 300 nM {Science, 2003, 299, 893-896).
[0005] Deres, et al, have reported heteroaryl-substituted dihydropyrimidine (HAP) compounds which were represented by Bay41 -4109 and Bay39-5493, and these compounds play a role in blocking HBV replication by preventing the proper formation of viral core particles (nucleocapsids). Bay41-4109 has demonstrated better drug metabolic parameters in clinical study (Science, 2003, 299, 893-896). The study of these compounds' mechanism of action indicated that through reacting with 113-143 amino acid residues of a core protein, heteroaryl-substituted dihydropyrimidine compounds have changed the angle between dimers which can form nucleocapsids, and led to forming unstably expanded nucleocapsids, which accelerate the degradation of the core protein (Biochem. Pharmacol., 2003, 66, 2273-2279).
[0006] New and effective antiviral compounds are urgently needed, especially for treating and/or preventing HBV infection.
SUMMARY OF THE INVENTION
[0007] The invention relates to novel dihydropyrimidine compounds and methods of treating and preventing HBV infection.
[0008] Specifically, these compounds and the pharmaceutically acceptable compositions thereof disclosed herein can inhibit HBV infection effectively.
[0009] In one aspect, provided herein are compounds having Formula (I) or (la) as shown below:
Figure imgf000003_0001
or an enantiomer, a diastereoisomer, a tautomer, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, wherein: each A is a bond, -0-, -S-, or -NR.5-; each R is -X-Z;
-(CR7R7V or -C(=0)-
Z has Formula (II) or (Ila):
Figure imgf000004_0001
wherein each B is a bond, -(CR7R7a)m- or -C(=0)-; each W is CR7 or N; each Y is -(CR7R7a)m-, -0-, -S-, -S(=0)q- or -NR6-; each R1 is aryl or heteroaryl; each R2 is H, alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl or alkoxycarbonyl; each R3 is aryl or heteroaryl; each R4 is H, or alkyl;
R5 is H, alkyl, -(CR7R7a)m-C(=0)0-R8, alkenyl or alkynyl; each R6 is alkyl, -(CR7R7a)m-C(=0)0-R8, alkenyl or alkynyl; each R7a and R7 is independently H, F, CI, Br, alkyl, haloalkyl, -(CH2)m-OH or -(CH2)m-C(=0)0-R8; each R8 and R8a is independently H, alkyl, haloalkyl, aminoalkyl, Boc-NH-alkyl, alkoxy, -(CH2)m-OH, -(CH2)m-C(=0)0-(CH2),n-H or -(CH2)m-OC(=0)-(CH2)m-H;
Boc is /er/-butyloxycarbonyl; each R9 is independently -(CR7R7a),-OH, -(CR7R7a)m-S(=0)q-R8, -(CR7R7a)m-OS(=0)q-R8, -(CR7R7a)m-S(=0)qO-R8, -(CR7R7a)m-C(=0)-R8,
-(CR7R7a)m-C(=0)0-R8, -(CR7R7a)m-C(=0)0-(CR7R7a)m-OC(=0)0-R8, -(CR7R7a)m-C(=0)0-(CR7R7a)m-OC(=0)-R8, -(CR7R a)m-C(=0)0-(CR7R7a)m-C(=0)0-R8, -(CR7R7a)rOC(=0)-R8, triazolyl, tetrazolyl or -(CR7R7a)m-C(=0)N(R8)2, with the proviso that when R9 is -(CR7R7a)t-OH, R3 is aryl, furyl, imidazoiyl, isoxazolyl, oxazolyl, pyrrolyl, pyrimidinyl, pyridazinyl, thiazolyl, diazolyl, triazolyl, tetrazolyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyranyl or triazinyl; each n is independently 1 , 2 or 3; each t is independently 1 , 2, 3 or 4; each m is independently 0, 1 , 2, 3 or 4; each q is independently 0, 1 or 2; and optionally each of aryl, heteroaryl, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyi, alkoxycarbonyl, aralkyl, heteroarylalkyl, aminoalkyl, alkoxy, furanyl, imidazoiyl, isoxazolyl, oxazolyl, pyrrolyl, pyrimidinyl, pyridazinyl, thiazolyl, diazolyl, triazolyl, tetrazolyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyranyl, triazinyl, heterocyclyl and heterocyclylalkyl described above, is independently substituted with one or more substituents which are the same or different, wherein the substituent is H, F, CI, Br, I, alkyl, alkoxy, cyano, hydroxy, nitro, alkylamino, amino, trifluoromethyl, trifluoromethoxy, -(CR7R7a)m-C(=0)0-R8a, haloalkyl-substituted aryl, halogen-substituted aryl, -(CR7R7a)m-C(=0)N(R8a)2 or trifluoromethylsulfonyl.
[0010] In certain embodiments, Z has Formula (III) or (Ilia):
Figure imgf000005_0001
wherein each B is a bond or -(CR7R7a)m-; each Y is -(CR7R7a)m-, -0-, -S-, -S(=0)q- or -NR6-; each R6 is CM alkyl, -(CR7R7a)m-C(=0)0-R8, C2-4 alkenyl or C2-4 alkynyl; each R7a and R7 is independently H, F, CI, Br, CM alkyl, -(CH2)m-OH, C haloalkyl or -(CH2)m-C(=0)0-R8; each R8 is independently H, C1 -6 alkyl, C] -4 haloalkyl,
Figure imgf000006_0001
Boc-NH-C, _4-alkyl, CM alkoxy, -(CH2)m-OH, -(CH2)m-C(=0)0-(CH2)m-H or -(CH2)m-OC(=0)-(CH2)m-H; each R9 is independently -(CR7R7a),-OH, -(CR7R7a)m-C(=0)-R8, -(CR7R7a)m-C(=0)0-R8, -(CR7R7a)m-C(=0)0-(CR7R7a)m-OC(=0)0-R8, -(CR7R7a)m-C(=O)O-(CR7R7a)m-0C(=O)-R8, -(CR7R7a)m-C(=0)0-(CR7R7a)m-C(=0)0-R8, -(CR7R7a),-OC(=0)-R8, triazolyl, tetrazolyl or -(CR7R7a)m-C(=0)N(R8)2. with the proviso that when R9 is -(CR7R7a)t-OH, R3 is C6-io aryl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrimidinyl, pyridazinyl, thiazolyl, diazolyl, triazolyl, tetrazolyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyranyl or triazinyl; each n is independently 1 or 2; each t is independently 1 , 2, 3 or 4; and each m is independently 0, 1 , 2, 3 or 4.
[001 1 ] In other embodiments, Z is
Figure imgf000006_0002
Figure imgf000007_0001
wherein each R6 is independently methyl, ethyl or propyl; each R7 and R7a is independently H, methyl, ethyl, -(CH2)m-OH, -(CH2)ra-C(=0)0-R8 or propyl; each R8 is independently H, methyl, ethyl, propyl, isopropyl, butyl, 1-methylpropyl, 2-methylpropyl, aminomethyl, 1 -amino-2-methylpropyl, 1 -aminoethyl, 2-aminoethyl, 1 -aminobutyl, 1 -aminopropyl, 2-aminopropyl, Boc-NH-methyl, l -Boc-NH-2-methylpropyl, 1 -Boc-NH-ethyl, 2-Boc-NH-ethyl, 1 -Boc-NH-butyl, 1 -Boc-NH-propyl, 2-Boc-NH-propyl, methoxy, ethoxy, -(CH2)m-OH, -(CH2)m-C(=0)0-(CH2)m-H, -(CH2)m-OC(=0)-(CH2)m-H or /er/-butyl; and each R9 is independently triazolyl, tetrazolyl, -(CR7R7a)t-OH, -(CR7R7a)m-C(=0)-R8, -(CR7R7a)m-C(=0)0-R8, -(CR7R7a)m-C(=0)0-(CR7R7a)m- OC(=0)0-R8,
-(CR7R7a)m-C(=0)0-(CR7R7a)m-OC(=0)-R8, -(CR7R7a),-OC(=0)-R8 or
-(CR7R7a)m-C(=0)N(R8)2, with the proviso that when R9 is -(CR7R7a),-OH, R3 is phenyl, ruryl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrimidinyl, pyridazinyl, thiazolyl, diazolyl, triazolyl, tetrazolyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyranyl or triazinyl.
[0012] In certain embodiments, R3 is C6-io aryl or 5-6 membered heteroaryl, and optionally each of the heteroaryl and aryl is independently substituted with one or more substituents which are the same or different, wherein the substituent is H, F, CI, Br, I, methyl, ethyl, propyl, isopropyl, butyl, methoxy, ethoxy, methylamino, ethylamino, cyano, hydroxy, nitro, amino, trifluoromethyl, trifluoromethoxy, -(CR7R7a)m-C(=0)0-R8a, -(CR7R7a)m-C(=0)N(R8a)2 or trifluoromethylsulfonyl; each R7a and R7 is independently H, F, CI, Br, CM alkyl, C,-4 haloalkyl, -(CH2)m-OH or -(CH2)m-C(=0)0-R8; and each R8a and R8 is independently H, C alkyl,
Figure imgf000008_0001
haloalkyl, amino-Ci-4-alkyl, Boc-NH-C -alkyl, C1-4 alkoxy, -(CH2)m-OH, -(CH2)m-C(=0)0-(CH2)m-H or -(CH2)m-OC(=0)-(CH2)m-H.
[0013] In other embodiments, R3 has one of the following formulae:
Figure imgf000008_0002
wherein each X1 is independently O, S, NR1 1 or CR12R12a; each X2, X3, X4, X5 and X6 is independently N or CR12; wherein at most three or four of the X2, X3, X4, X5 and X6 are N; each R10 is independently H, F, CI, Br, I, methyl, ethyl, propyl, isopropyl, butyl, methoxy, ethoxy, methylamino, ethylamino, cyano, hydroxy, nitro, amino, trifluoromethyl, trifluoromethoxy, -(CR7R7a)m-C(=0)0-R8a, -(CR7R7a)m-C(=0)N(R8a)2 or trifluoromethylsulfonyl; each R1 1 is independently H, methyl, ethyl, propyl, isopropyl, butyl, trifluoromethyl, -(CR7R7a)m-C(0)N(R8a)2 or -(CR7R7a)m-C(=0)0-R8a; each R12 and Rl 2a is independently H, F, CI, Br, 1, methyl, ethyl, propyl, isopropyl, butyl, methoxy, ethoxy, methylamino, ethylamino, cyano, hydroxy, nitro, amino, trifluoromethyl, trifluoromethoxy, -(CR7R7a)m-C(=0)0-R8a, -(CR7R7a)m-C(=0)N(R8a)2 or tri fluoromethylsul fonyl ; each R7a and R7 is independently H, F, CI, Br, C alkyl, -(CH2)m-OH, C haloalkyl or -(CH2)m-C(=0)0-R8; each R8a and R8 is independently H, C]-4 alkyl, C]-4 haloalkyl, amino-Ci-4-alkyl, Boc-NH-C]-4-alkyl, CM alkoxy, -(CH2)m-OH, -(CH2)m-C(=0)0-(CH2)m-H or -(CH2)m-OC(=0)-(CH2)m-H; each m is independently 0, 1 , 2, 3 or 4; and each p is independently 0, 1 , 2 or 3.
[0014] In other embodiments, R3 has one of the following formulae:
Figure imgf000009_0001
wherein each R10 is independently H, F, CI, methyl, ethyl, cyano, hydroxy nitro, amino, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, -(CR7R7a)m-C(=0)0-R8a, -(CR7R7a)m-C(=0)N(R8a)2 or trifluoromethylsulfonyl; each R1 1 is independently H, methyl, ethyl, propyl, isopropyl, butyl, trifluoromethyl or
(CR7R7a)m-C(=0)0-R5a; each R7a and R7 is independently H, methyl, ethyl, -(CH2)M-OH, -(CH2)M-C(=0)0-R8 or propyl; each R8 and R8a is independently H, methyl, ethyl, propyl, isopropyl, butyl, 2-methylpropyl, 1 -methylpropyl, aminomethyl, l -amino-2-methylpropyl, 1 -aminoethyl, 2-aminoethyl, 1-aminobutyl, 1-aminopropyl, 2-aminopropyl, Boc-NH-methyl, l -Boc-NH-2-methylpropyl, 1 -Boc-NH-ethyl, 2-Boc-NH-ethyl, 1 -Boc-NH-butyl, ] -Boc-NH-propyl, 2-Boc-NH-propyl, methoxy, ethoxy, -(CH2)M-OH,
Figure imgf000010_0001
or tert-bulyl; and each p is independently 0, 1 , 2 or 3.
[0015] In certain embodiments, R1 is C6-10 aryl, and the aryl is independently substituted with one or more substituents which are the same or different, wherein the substituent is H, F, CI, Br, cyano, methyl, ethyl, methoxy, ethoxy, methylamino, ethylamino, nitro, 4-(trifluoromethy])phenyl, 3,5-6z's(trifluoromethyl)phenyl or trifluoromethyl;
R2 is H, or C alkyl; and
R5 is H, or C].4 alkyl.
[0016] In other embodiments, R1 is phenyl or a phenyl substituted with one or more substituents which are the same or different, wherein the substituent is H, F, CI, Br, nitro, 4-(trifluoromethyl)phenyl, 3,5-0is(trifluorornethyl)phenyl or trifluoromethyl.
[0017] In certain embodiments, Formula (IV) or (IVa) is
Figure imgf000010_0002
or an enantiomer, a diastereoisomer, a tautomer, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, wherein Z has Formula (II) or (Ila):
Figure imgf000011_0001
wherein each B is a bond or -(CR R a)m-; each W is CR7 or N; each Y is -(CR7R7a)m-, -0-, -S-, -S(=0)q- or -NR6-;
2
each R is H, or C alkyl; each R is C6-io aryl or 5-6 membered heteroaryl, and optionally each of the heteroaryl and aryl is independently substituted with one or more substituents which are the same or different, wherein the substituent is H, F, CI, methyl, ethyl, propyl, cyano, trifluoromethyl, methoxy, -(CR7R7a)m-C(=0)N(R8a)2 or -(CR7R7a)m-C(=0)0-R8a; each R6 is C alkyl; each R7a and R7 is independently H, -(CH2)m-OH, -(CH2)m-C(=0)0-R8 or CM alkyl; each R8 and R8a is independently H,
Figure imgf000011_0002
Boc-NH-Ci-4-alkyl, Ci_4 alkoxy, -(CH2)m-OH, -(CH2)m-C(=0)0-(CH2)m-H, -(CH2)m-OC(=0)-(CH2)m-H or C1-6 alkyl; each R9 is independently triazolyl, tetrazolyl, -(CR7R7a)t-OH,
-(CR7R7a)m-C(=0)0-(CR7R7a)m-OC(=0)0-R8, -(CR7R7a)m-C(=0)-R8,
-(CR7R7a)m-C(=0)0-R8, -(CR7R7a)m-C(=0)0-(CR7R7a)m-OC(=0)-R8, -(CR7R7a),-OC(=0)-R8 or -(CR7R7a)m-C(=0)N(Rx)2, with the proviso that when R9 is -(CR7R7a),-OH, R3 is C6-10 aryl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrimidinyl, pyridazinyl, thiazolyl, diazolyl, triazolyl, tetrazolyl, thieny], pyrazoly], isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyranyl or triazinyl; each R13 is independently - H. F, CI, Br, cyano, nitro, 4-(trifluoromethyl)phenyl, 3,5-Z?w(trifluoromethyl)phenyl or trifluoromethyl; each n is independently 1 or 2; each t is independently 1, 2, 3 or 4; each m is independently 0, 1 , 2, 3 or 4; and each q is independently 0, 1 or 2. [0018] In certain embodiments, Z has Formula (II)
Figure imgf000012_0001
wherein each B is a bond or -(CR7R7a)m-; each W is CR7 or N; each Y is -(CR7R7a)m-, -0-, -S-, -S(=0)q- or -NR6-; each R6 is methyl, ethyl or propyl; each R7a and R7 is independently H, methyl, -(CH2)m-OH, -(CH2)m-C(=0)0-R8, ethyl or propyl; each R8 is independently H, methyl, ethyl, propyl, isopropyl, butyl, 1 -methylpropyl, 2-methylpropyl, ter/-butyl, aminomethyl, 1 -amino-2-methylpropyl, 1 -aminoethyl, 2-aminoethyl, 1 -aminobutyl, 1 -aminopropyl, 2-aminopropyl, Boc-NH-m ethyl, l -Boc-NH-2-methylpropyl, 1-Boc-NH-ethyl, 2-Boc-NH-ethyl, 1 -Boc-NH-butyl, 1 -Boc-NH-propyl, 2-Boc-NH-propyl, methoxy, ethoxy, -(CH2)m-OH,
-(CH2)m-C(=0)0-(CH2)m-H or -(CH2)m-OC(=0)-(CH2)m-H; each R a is independently H, methyl, ethyl, isopropyl or propyl; each R9 is independently -(CR7R7a),-OH, -(CR7R7a)m-C(=0)0-R8, -(CR7R7a)m-C(=0)0-(CR7R7a)m-OC(=0)0-R8, -(CR7R7a)m-C(=0)0-(CR7R7a)m-OC(=0)-R8, -(CR7R7a)t-OC(=0)-R8, triazolyl, tetrazolyl or -(CR7R7a)m-C(=0)N(R8)2, with the proviso that when R9 is -(CR7R7a),-OH, R3 is phenyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrimidinyl, pyridazinyl, thiazolyl, diazolyl, triazolyl, tetrazolyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyranyl or triazinyl; each m is independently 0, 1 , 2, 3 or 4; and each t is independently 1 , 2, 3 or 4.
[0019] In other embodiments, Z is:
Figure imgf000013_0001
Figure imgf000014_0001

Figure imgf000015_0001
 [0021 ] In one aspect, provided herein are compounds and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.
[0022] In certain embodiments, provided herein is the pharmaceutical composition further comprising an anti-HBV agent.
[0023] In certain embodiments, the pharmaceutical composition disclosed herein, wherein the anti-HBV agent is a HBV polymerase inhibitor, immunomodulator or interferon.
[0024] In certain embodiments, the pharmaceutical composition disclosed herein, wherein the anti-HBV agent is lamivudine, telbivudine, tenofovir, entecavir, adefovir dipivoxil, alfaferone, alloferon, celmoleukin, clevudine, emtricitabine, famciclovir, feron, hepatect CP, intefen, interferon a-lb, interferon a, interferon a-2a, interferon β-l a, interferon a-2, interleukin-2, mivotilate, nitazoxanide, peginterferon alfa-2a, ribavirin, roferon-A, sizofiran, euforavac, rintatolimod, phosphazid, heplisav, interferon a-2b, levamisole, or propagermanium.
[0025] In another aspect, 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 a HBV disease in a patient.
[0026] In certain embodiments, the use is disclosed herein, wherein the viral disease or HBV disease is hepatitis B infection or a disease caused by hepatitis B infection.
[0027] In other embodiments, the use is disclosed herein, wherein the disease caused by hepatitis B infection is cirrhosis or hepatocellular carcinoma.
[0028] In another aspect, 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 a HBV disease in a patient, comprising administering to the patient a therapeutically effective amount of the compound or the composition disclosed herein. [0029] In another aspect, provided herein are methods for preventing, managing, treating or lessening a viral disease or a HBV disease in a patient, which comprises administering a pharmaceutically effective amount of the compound disclosed herein to the patient.
[0030] In another aspect, provided herein are methods for preventing, managing, treating or lessening a viral disease or a HBV disease in a patient, which comprises administering a pharmaceutically effective amount of the pharmaceutical composition disclosed herein to the patient.
[0031 ] In another aspect, provided herein is use of the compound disclosed herein in the manufacture of a medicament for preventing, managing or treating a viral disease or a HBV disease and lessening the severity of a viral disease or a HBV disease in a patient.
[0032] In another aspect, provided herein is use of the pharmaceutical composition comprising the compound disclosed herein in the manufacture of a medicament for preventing, managing or treating a viral disease or a HBV disease and lessening the severity of a viral disease or a HBV disease in a patient.
[0033] In some embodiments, the organism is a mammal; in other embodiments, the organism is a human. In still other embodiments, the method further comprises contacting the kinase with a HBV therapeutic agent.
[0034] In another aspect, provided herein is a method of inhibiting HBV infection, comprising contacting the cell with an effective HBV inhibiting amount of a compound disclosed herein or a composition thereof. In other embodiments, the method further comprises contacting the cell with a HBV therapeutic agent.
[0035] In another aspect, provided herein is a method of treating HBV disease in a patient, the method comprises administering to the patient in need of such treatment an effective therapeutic amount of a compound disclosed herein or a composition thereof. In other embodiments, the method further comprises administering a HBV therapeutic agent. [0036] In another aspect, provided herein is a method of inhibiting HBV infection in a patient, the method comprises administering to the patient in need of an effective therapeutic amount of a compound disclosed herein or a composition thereof. In other embodiments, the method further comprises administering a HBV therapeutic agent.
[0037] In another aspect, provided herein include methods of preparing, methods of separating, and methods of purifying compounds of Formula (I) or (la).
[0038] The foregoing merely summarizes certain aspects disclosed herein and is not intended to be limiting in nature. These aspects and other aspects and embodiments are described more fully below.
DETAILED DESCRIPTION OF THE INVENTION
DEFINITIONS AND GENERAL TERMINOLOGY
[0039] Reference will now be made in detail to certain embodiments disclosed herein, examples of which are illustrated in the accompanying structures and formulas. The invention is intended to cover all alternatives, modifications, and equivalents that may be included within the scope disclosed herein as defined by the claims. One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice disclosed herein. Described herein is in no way limited to the methods and materials. In the event that one or more of the incorporated literature, patents, and similar materials differ from or contradict this application, including but not limited to defined terms, term usage, described techniques, or the like, this application controls.
[0040] As used herein, the following definitions shall be applied unless otherwise indicated. For purposes disclosed herein, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, and the Handbook of Chemistry and Physics, 75 thEd. 1994. Additionally, general principles of organic chemistry are described in Sorrell et al., "Organic Chemistry", University Science Books, Sausalito: 1999, and Smith et al., "March s' Advanced Organic Chemistry", John Wiley & Sons, New York: 2007, all of which are incorporated herein by reference in their entireties.
[0041 ] As described herein, compounds may optionally be substituted with one or more substituents, such as those illustrated above, or as exemplified by particular classes, subclasses, and species disclosed herein. In general, the term "substituted" refers to the replacement of one or more hydrogen radicals in a given structure with the radical of a specified substituent. Unless otherwise indicated, 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. Wherein the substituents include, but are not limited to, hydroxy, amino, halo, cyano, trifluoromethoxy, aralkyi, heteroarylalkyl, haloalkyl, heterocyclylalkyl, alkylamino, trifluoromethylsulfonyl, aryl, heteroaryl, alkoxy, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy-substituted alkyl, cycloalkyl, cycloalkylalkyl, alkoxycarbonyl, haloalkyl-substituted aryl, halogen-substituted aryl, -(CR7R7a)m-C(=0)N(R8a)2, -(CR7R7a)m-C(=0)0-R8, -(CR7R7a)m-C(=0)R8, -(CR7R7a)m-C(=0)-(CR7R7a)m-OH, -(CR7R7a)t-OC(=0)-R8, -(CR7R7a)m-C(=0)-(CR7R7a)m-0-(CR7R7a)m-0-R ( -(CR7R7a)m-C(=0)-(CR7R7a)m-N(R7R7a), -(CR7R7a)m-S(=0)q-R8, -(CR7R7a)m-OS(=0)q-R8, -(CR7R7a)m-S(=0)qO-R8,
-(CR7R7a)m-C(=0)0-R8a, -(CH2)m-OH, -(CH2)m-C(=0)0-(CH2)m-H,
-(CH2)m-OC(=0)-(CH2)m-H, -(CR7R7a)m-C(=0)0-(CR7R7a)m-OC(=0)0-R8, -(CR7R7a)m- C(=0)0-(CR7R7a)m-OC(=0)-R8, -(CR7R7a),-OH, -(CR7R7a)m-C(=0)0-(CR7R7a)m-C(=0)0-R8 or -(CR7R7a)m-C(=0)N(R8)2, and the like. Each R7, R7a, R8, R8a, m, q and t is as disclosed herein.
[0042] The term "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. 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 ] -4 carbon atoms. In other embodiments, alkyl groups contain 1 -3 carbon atoms. Further examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1 -propyl (w-Pr, w-propyl, -CH2CH2CH3), 2-propyl (i-Pr, /'-propyl, -CH(CH3)2), 1 -butyl (w-Bu, w-butyl, -CH2CH2CH2CH3), 2-methyl-l -propyl or isobutyl ( -Bu, /-butyl, -CH2CH(CH3)2), 1 -methylpropyl or sec-butyl (s-Bu, 5-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl or tert-bxityl (t-B , /-butyl, -C(CH3)3), 1 -pentyl (w-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), 1-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, 1 -heptyl, 1 -octyl, and the like. The terms "alkyl" and the prefix "alk-" are inclusive of both straight chain and branched saturated carbon chain. The term "alkylene", as used herein, represents a saturated divalent hydrocarbon group derived from a straight or branched chain saturated hydrocarbon by the removal of two hydrogen atoms, and is exemplified by methylene, ethylene, isopropylene, and the like.
[0043] The term "haloaliphatic" or "haloalkyl" refers to an aliphatic radical or alkyl radical substituted with one or more halogen atoms (i.e., F, CI, Br or I,), which may be either the same or different. Some non-limiting examples of such radicals include trifluoromethyl and trifluoroethyl.
[0044] The term "hydroxyaliphatic", "-(CR7R7a),-OH", "-(CR7R7a)m-OH", "hydroxy-substituted alkyl" or "hydroxyalkyl" refers to an aliphatic radical or alkyl radical substituted with one or more hydroxy groups, wherein each t, m, aliphatic and alkyl is as defined above. Some non-limiting examples include hydroxyethyl, 2-hydroxypropyl, hydroxymethyl, and the like.
[0045] The term "alkenyl" refers to a linear or branched-chain monovalent hydrocarbon radical of two to twelve carbon atoms with at least one site of unsaturation, i.e., a 2
carbon-carbon, sp double bond, wherein the alkenyl radical may be optionally substituted independently with one or more substituents described herein, and includes radicals having "cii" and "trans" orientations, or alternatively, "E" and "Z" orientations. Some non-limiting examples include ethenyl or vinyl (-CH=CH2), allyl (-CH2CH=CH2), and the like.
[0046] The term "alkynyl" refers to a linear or branched-chain monovalent hydrocarbon radical of two to twelve carbon atoms with at least one site of unsaturation, i.e., a carbon-carbon, sp triple bond, wherein the alkynyl radical may be optionally substituted independently with one or more substituents described herein. Specific examples include, but are not limited to, ethynyl (-C≡CH), propynyl (propargyl, -CH2C≡CH), and the like.
[0047] The term "cycloaliphatic", "carbocycle", "carbocyclyl" or "cycloalkyl" refers to a monovalent or multivalent non-aromatic, saturated or partially unsaturated ring having 3 to 12 carbon atoms as a monocyclic ring or 7 to 12 carbon atoms as a bicyclic ring. Bicyclic carbocycles having 7 to 12 atoms can be arranged, for example, as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, and bicyclic carbocycles having 9 or 10 ring atoms can be arranged as a bicyclo [5,6] or [6,6] system. Some non-limiting examples of cycloaliphatic groups include cycloalkyl, cycloalkenyl, and cycloalkynyl. Further examples of cycloaliphatic groups include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-l-enyl, l-cyclopent-2-enyl, l-cyclopent-3-enyl, cyclohexyl, 1 -cyclohex-l-enyl, l-cyclohex-2-enyl, l-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like. And the term "cycloaliphatic", "carbocycle", "carbocyclyl" or "cycloalkyl" may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, hydroxy, amino, halo, cyano, trifluoromethoxy, aralkyl, heteroarylalkyl, haloalkyl, heterocyclylalkyl, alkylamino, trifluoromethylsulfonyl, aryl, heteroaryl, alkoxy, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, cycloalkyl, cycloalkylalkyl, alkoxycarbonyl, hydroxy-substituted alkyl, haloalkyl-substituted aryl, halogen-substituted aryl, -(CR7R7a)m-C(=0)N(R8a)2, -(CR7R7a)m-C(=0)0-R8, -(CR7R7a)m-C(=0)R8,
-(CR7R7a)m-C(=0)-(CR7R7VOH, -(CH2)m-OH, -(CH2)m-C(=0)0-(CH2)m-H,
Figure imgf000021_0001
-(CR7R7a)m-C(=0)-(CR7R7a)m-0-(CR7R7a)m-0-Rs, -(CR7R7a)m-C(=0)-(CR7R7a)m-N(R7R7a), -(CR7R7a)m-S(=0)q-R8, -(CR7R7a)m-OS(=0)q-R8, -(CR7R7a)m-S(=0)pO-R8,
-(CR7R7a)m-C(=0)0-R8a, -(CR7R7a)m-C(=0)0-(CR7R7a)m-OC(=0)0-R8, -(CR7R7a)m-C(=0)0-(CR7R7a)m-OC(=0)-R8, -(CR7R7a),-OH, -(CR7R7a)m-C(=0)0-(CR7R7a)m-C(=0)0-R8 or -(CR7R7a)m-C(=0)N(R8)2, and the like. Each R7, R7a, R8, m, R8a, q and t is as disclosed herein.
[0048] The term "heterocycle", "heterocyclyl", "heterocycloaliphatic" or "heterocyclic" as used interchangeably herein refers to a monocyclic, bicyclic or tricyclic ring system in which one or more ring members are an independently selected heteroatom and that is completely saturated or that contains one or more units of unsaturation, but not aromatic having a single point of attachment to the rest of the molecule. One or more ring atoms are optionally substituted independently with one or more substituents described below. In some embodiments, the "heterocycle", "heterocyclyl", "heterocycloaliphatic" or "heterocyclic" group is a monocycle having 3 to 7 ring members (e.g., 1 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P or S, wherein the S or P is optionally substituted with one or more oxo to provide the group SO or S02, PO or P02, with the proviso that when the ring is a 3-membered ring, there is only one heteroatom) or a bicycle having 7 to 10 ring members (e.g. , 4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P or S, wherein the S or P is optionally substituted with one or more oxo to provide the group SO or S02, PO or P02).
[0049] The heterocyclyl may be a carbon radical or heteroatom radical. "Heterocyclyl" also includes radicals where heterocycle radicals are fused with a saturated, partially unsaturated ring, or heterocyclic ring. Some non-limiting examples of heterocyclic rings include pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, epoxypropyl, azepanyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl, dihydroindolinyl, 2H-pyranyl, 4H-pyranyl, dioxolanyl, 1 ,3-dioxopentyl, pyrazolinyl, dithianyl, dithiolanyl, dihydrothienyl, pyrazolidinylimidazolinyl, imidazolidinyl, 1 ,2,3,4-tetrahydroisoquinolinyl, 3-azabicyclo[3, l ,0]hexyl, 3-azabicyclo[4, l ,0]heptyl, azabicyclo[2,2,2]hexyl, 3H-indolylquinolizinyl and N-pyridyl urea. Further examples of heterocyclyl groups include 1 ,1 -dioxothiomorpholinyl and heterocyclic group wherein 2 carbon atoms on the ring are substituted with oxo (=0) moieties are pyrimidindionyl. And the heterocyclyl disclosed herein, may be substituted or unsubstituted, wherein the substituents include, but are not limited to, hydroxy, amino, halo, cyano, trifluoromethoxy, aralkyl, heteroarylalkyl, haloalkyl, heterocyclylalkyl, alkylamino, trifluoromethylsulfonyl, aryl, heteroaryl, alkoxy, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy-substiruted alkyl, cycloalkyl, cycloalkylalkyl, alkoxycarbonyl, haloalkyl-substituted aryl, halogen-substituted aryl, -(CR7R7a)m-C(=0)N(R8a)2, -(CR7R7a)m-C(=0)0-R8, -(CR7R7a)m-C(=0)R8, -(CR7R7a)m-C(=0)-(CR7R7a)m-OH, -(CR7R7a)t-OC(=0)-R8, -(CR7R7a)m-C(=0)-(CR7R7a)m-0-(CR7R7a)m-0-R8, -(CR7R7a)m-C(=0)-(CR7R7a)m-N(R7R7a), -(CR7R7a)m-S(=0)q-R8, -(CR7R7a)m-OS(=0)q-R8, -(CR7R7a)m-S(=0)qO-R8,
-(CR7R7a)m-C(=0)0-R8a, -(CR7R7a)m-C(=0)0-(CR7R7a)m-OC(=0)0-R8, -(CR7R7a)m-C(=0)0 -(CR7R7a)m-OC(=0)-R8, -(CR7R7a)t-OH, -(CH2)m-OH, -(CH2)m-C(=0)0-(CH2)m-H, -(CH2)m-OC(=0)-(CH2)m-H, -(CR7R7a)m-C(=0)0-(CR7R7a)m-C(=0)0-R8 or
-(CR7R7a)m-C(=0)N(R8)2, and the like, wherein each R7, R7a, R8, R8a, m, q and t is as disclosed herein.
[0050] The term "heterocyclylalkyl" refers to heterocyclic-substituted alkyl radical. The term "heterocyclylalkoxy" refers to heterocyclic-substituted alkoxy radical wherein oxygen atom serves as the attaching point to the rest of the molecule. The term "heterocyclylalkylamino" refers to heterocyclic-substituted alkylamino radical wherein nitrogen atom serves as the attaching point to the rest of the molecule. Wherein the heterocyclyl, alkyl, alkoxy and alkylamino group are as defined herein. Some non-limiting examples include pyrrol-2-ylmethyl, morpholin-4-ylmethyl, pyrrol-2-ylmethoxy, piperidin-2-ylethoxy, piperazin-2-ylethylamino, morpholin-4-ylpropoxy, morpholin-4-ylethylamino, and the like.
[0051 ] The term "heteroatom" refers to one or more of oxygen, sulfur, nitrogen, phosphorus or silicon, including any oxidized form of nitrogen, sulfur or phosphorus; the quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocyclic ring, for example, N (as in 3,4-dihydro-2H-pyrrolyl), ΝΗ (as in pyrrolidinyl) or NR (as in N-substituted pyrrolidinyl).
[0052] The term "halogen" refers to F, CI, Br or I.
[0053] The term "unsaturated" as used herein, refers to that a moiety has one or more units of unsaturation.
[0054] The term "alkoxy" as used herein, refers to an alky] group, as previously defined, attached to the principal carbon chain through an oxygen atom ("alkoxy").
[0055] The term "haloalkyl", "haloalkenyl" or "haloalkoxy" refers to alkyl, alkenyl or alkoxy, as the case may be, substituted with one or more halogen atoms. Some non-limiting examples of such radicals include trifluoromethyl, trifluoromethoxy, 2-fluoro-vinyl, and the like.
[0056] The term "aryl" used alone or as part of a larger moiety as in "aralkyl", "aralkoxy" or "aryloxyalkyl" refers to monocyclic, bicyclic and tricyclic carbocyclic ring systems having a total of six to fourteen 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 a single point of attachment to the rest of the molecule. The term "aryl" may be used interchangeably with the term "aryl ring". Some non-limiting examples of aryl rings include phenyl, naphthyl and anthryl. The aryl may be substituted or unsubstituted, wherein the substituents include, but are not limited to, hydroxy, amino, halo, cyano, trifluoromethoxy, aralkyl, heteroarylalkyl, haloalkyl, heterocyclylalkyl, alkylamino, trifluoromethylsulfonyl, aryl, heteroaryl, alkoxy, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy-substituted alkyl, cycloalkyl, cycloalkylalkyl, alkoxycarbonyl, haloalkyl-substituted aryl, halogen-substituted aryl, -(CR7R7a)m-C(=0)N(R8a)2, -(CR7R7a)m-C(=0)0-R8, -(CR7R7a)m-C(=0)R8,
-(CR7R7a)m-C(=0)-(CR7R7a)m-OH, -(CR7R7a)m-C(=0)-(CR7R7a)m-0-(CR7R7a)m-0-R8, -(CR7R7a)m-C(=0)-(CR7R7a)m-N(R7R7a), -(CR7R7a)m-S(=0)q-R8, -(CR7R7a)m-OS(=0)q-R8, -(CR7R7a)m-S(=0)qO-R8, -(CR7R7a)m-C(=0)OR8a, -(CR7R7a)m-C(=0)0-(CR7R7a)m-OC(=0)0-R8, -(CR7R7a),-OH, -(CR7R7a)m-C(=0)0- (CR7R7a)m-OC(=0)-R8, -(CH2)m-OH, -(CH2)m-C(=0)0-(CH2)m-H,
-(CH2)m-OC(=0)-(CH2)m-H, -(CR7R7a)t-OC(=0)-R8, -(CR7R7a)m-C(=0)0-(CR7R7a)m-C(=0)0-R8 or -(CR7R7a)m-C(=0)N(R8)2, and the like, wherein each R7, R7a, R8, R8a, m, q and t is as disclosed herein.
[0057] The term "heteroaryl" used alone or as part of a larger moiety as in "heteroarylalkyl" or "heteroarylalkoxy" refers to monocyclic, bicyclic and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, and at least one ring in the system is inclusive of one or more heteroatoms as described herein, wherein each ring in the system contains 3 to 7 ring members and that has a single point of attachment to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the term "heteroaryl ring" or "heteroaromatic compound". The heteroaryl defined herein may be substituted or unsubstituted, wherein the substituents include, but are not limited to, hydroxy, amino, halo, cyano, trifluoromethoxy, aralkyl, heteroarylalkyl, haloalkyl, heterocyclylalkyl, alkylamino, trifluoromethylsulfonyl, aryl, heteroaryl, alkoxy, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy-substituted alkyl, cycloalkyl, cycloalkylalkyl, alkoxycarbonyl, haloalkyl-substituted aryl, halogen-substituted aryl, -(CR7R7a)m-C(=0)N(R8a)2, -(CR7R7a)m-C(=0)-(CR7R7a)m-OH, -(CR7R7a),-OC(=0)-R8, -(CR7R7a)m-C(=0)-(CR7R7a)m-0-(CR7R7a)m-0-R8, -(CR7R7a)m-C(=0)-(CR7R7a)m-N(R7R7a), -(CR7R7a)m-S(=0)q-R8, -(CR7R7a)m-OS(=0)q-R8, -(CR7R7a)m-S(=0)qO-R8,
-(CR7R7a)m-C(=0)-R8, -(CR7R7a)m-C(=0)0-R8, -(CR7R7a)m-C(=0)OR8a,
-(CR7R7a)m-C(=0)0-(CR7R7a)m-OC(=0)0-R8, -(CH2)m-OH, -(CH2)m-C(=0)0-(CH2)m-H, -(CH2)m-OC(=0)-(CH2)m-H, -(CR7R7a)m-C(=0)0-(CR7R7a)m-OC(=0)-R8, -(CR7R7a)t-OH, -(CR7R7a)m-C(=0)0-(CR7R7a)m-C(=0)0-R8 or -(CR7R7a)m-C(=0)N(R8)2, and the like, wherein each R7, R7a, R8, R8a, m, q and t is as disclosed herein.
[0058] In other embodiments, some non-limiting examples of suitable heteroaryl rings include the following monocycles: 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazoly], 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 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-thienyl, 3-thienyl, pyranyl, 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, pyrazinyl, 1 ,3,5-triazinyl, diazolyl, thiadiazolyl, triazinyl; and the following bicycles: benzothiazolyl, benzimidazolyl, benzofuryl, benzothiophenyl, indolyl (e.g., 2-indolyl), purinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), or isoquinolinyl (e.g., 1 -isoquinolinyl, 3-isoquinolinyl or 4-isoquinolinyl), and the like.
[0059] The term "heteroarylalkyl" refers to alkyl radicals substituted with one or more heteroaryl radicals, wherein the alkyl and heteroaryl groups are as defined herein. Some non-limiting examples of such radicals include pyridin-2-ylethyl, thiazol-2-ylmethyl, imidazol-2-ylethyl, pyrimidin-2-ylpropyl, and the like.
[0060] The term "sulfonyl", whether used alone or linked to other terms such as "alkylsulfonyl", refers to respectively divalent radicals -S02-. The term "alkylsulfonyl", refers to a sulfonyl radical substituted with an alkyl radical, forming an alkylsulfonyl (-S02CH3).
[0061] The term "sulfamyl", "aminosulfonyl" or "sulfonamidyl" refers to a sulfonyl radical substituted with an amine radical, forming a sulfonamide (-S02NH2).
[0062] The term "carboxy" or "carboxyl", whether used alone or with other terms, such as "carboxyalkyl", refers to -C02H. The term "carbonyl", whether used alone or with other terms, such as "aminocarbonyl" or "carbonyloxy", refers to -(C=0)-.
[0063] The term "alkylthio" refers to radicals containing a linear or branched-alkyl radical of one to ten carbon atoms, attached to a divalent sulfur atom. In other embodiments, alkylthio radicals are lower alkylthio radicals having one to three carbon atoms. Some non-limiting examples of "alkylthio" include methylthio (CH3S-), ethylthio (CH3CH2S-), and the like.
[0064] The term "aralkyl" or "arylalkyl" refers to aryl -substituted alkyl radicals. In some embodiments, aralkyl radicals or arylalkyl radicals are "lower aralkyl" radicals having aryl radicals attached to alkyl radicals having one to six carbon atoms. In other embodiments, aralkyl radicals or arylalkyl radicals are "phenylalkylenyl" attached to alkyl portions having one to three carbon atoms. Some non-limiting examples of such radicals include benzyl, diphenylmethyl and phenylethyl. And the aryl in said aralkyl can be additionally substituted with hydroxy, amino, halo, cyano, trifluoromethoxy, aralkyl, heteroaryl alkyl, haloalkyl, heterocyclylalkyl, alkylamino, trifluoromethylsulfonyl, aryl, heteroaryl, alkoxy, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy-substituted alkyl, cycloalkyl, cycloalkylalkyl, alkoxycarbonyl, haloalkyl-substituted aryl, halogen-substituted aryl, -(CR7R7a)m-C(=0)N(R8a)2, -(CR7R7a),-OC(=0)-R8, -(CR7R7a)m-C(=0)-(CR7R7a)m-OH, -(CR7R7a)m-C(=0)-(CR7R7a)m-0-(CR7R7a)m-0-R8, -(CH2)m-OH, -(CH2)m-C(=0)0-(CH2)m-H, -(CH2)m-OC(=0)-(CH2)m-H, -(CR7R7a)m-C(=0)-(CR7R7a)m-N(R7R7a), -(CR7R7a)m-S(=0)q-R8, -(CR7R7a)m-OS(=0)q-R8,-(CR7R7a)m-S(=0)qO-R8,-(CR7R7a)m-C(=0)-R8,
-(CR7R7a)m-C(=0)0-R8a, -(CR7R7a)m-C(=0)0-R8, -(CR7R7a)m-C(=0)0-(CR7R7a)m-OC(=0)0-R8, -(CR7R7a)t-OH, -(CR7R7a)m-C(=0)0- (CR7R7a)m-OC(=0)-R8, -(CR7R7a)m-C(=0)0-(CR7R7a)m-C(=0)0-R8 or
-(CR7R7a)m-C(=0)N(R8)2, and the like, wherein each R7, R7a, R8, R8a, m, q and t is as disclosed herein.
[0065] The term "alkylamino" refers to "N-alkylamino" and "N,N-dialkylamino" wherein amino groups are independently substituted with one alkyl radical or with two alkyl radicals, respectively. In other embidiments, alkylamino radicals are "lower alkylamino" radicals having one or two alkyl radicals of one to six carbon atoms, attached to a nitrogen atom. In still other embodiments, alkylamino radicals are lower alkylamino radicals having one to three carbon atoms. Some non-limiting examples of suitable alkylamino radicals include mono or dialkylamino such as N-methylamino, N-ethylamino, N,N-dimethylamino, N^N-diethylamino, and the like.
[0066] The term "aminoalkyl" refers to a linear or branched-alkyl radical having one to ten carbon atoms, substituted with one or more amino radicals. In some embodiments, aminoalkyl radicals are "lower aminoalkyl" radicals having one to six carbon atoms and one or more amino radicals. Some non-limiting examples of such radicals include aminomethyl, aminoethyl, aminopropyl, aminobutyl or aminohexyl.
[0067] The term "alkoxycarbonyl" refers to alkyl-0-C(=0)-, wherein the alkyl is as defined herein. In some embodiments, alkyl radicals in alkoxycarbonyl are "lower alkyl" radicals having one to six carbon atoms. Some non-limiting examples of such radicals include methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl.
[0068] The term "carboxyalkyl" refers to a linear or branched-alkyl radical having one to ten carbon atoms, substituted with one or more carboxy radicals. Some non-limiting examples of such radicals include carboxymethyl, carboxypropyl, and the like.
[0069] The term "haloalkyl-substituted aryl" refers to aryl radicals substituted with one or more haloalkyl radicals. Some non-limiting examples of such radicals include 2-trifluoromethylphenyl, 3,5-0w(trifluoromethyl)phenyl, 3-trifluoromethylphenyl, 4- trifluoromethylphenyl, 2,6-fe(trifluoromethyl)phenyl, and the like.
[0070] The term "halogen-substituted aryl" refers to an aryl substituted with one or more halogen atoms. Some non-limiting examples of such radicals include fluorophenyl, difluorophenyl, triiluoropheny], chlorophenyl, dichlorophenyl, trichlorophenyl, bromophenyl, tribromophenyl, dibromophenyl, fluorochlorophenyl, fluorobromophenyl, chorobromophenyl, and the like.
[0071 ] The term "cycloalkylalkyl" refers to alkyl radicals substituted with one or more cycloalkyl radicals, wherein cycloalkyl and alkyl are as defined herein. Some non-limiting examples of such radicals include cyclohexylmethyl and cyclopropyl ethyl. The cycloalkyl in the radicals may be additionally substituted with halo, alkyl, alkoxy or hydroxy.
[0072] As described herein, a bond drawn from a substituent to the center of one ring within a ring system (as shown below) represents substitution of the substituent at any substitutable position on the rings. For example, Figure a represents possible substitution in any of the positions on the A ring and B ring, as shown in Figure b; or Figure c represents possible substitution in any of the positions on the ring, as shown in Figure d.
Figure imgf000028_0001
Figure a Figure b Figure c pFi-g Rure d [0073] Unless otherwise stated, 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.
[0074] The term "prodrug" refers to a compound that is transformed in vivo into a compound of Formula (I). 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].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. Other prodrug forms include 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.
[0075] Unless otherwise stated, all tautomeric forms of the compounds disclosed herein are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
[0076] 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.
[0077] Stereochemical definitions and conventions used herein generally follow Parker, et al., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York and Eliel, et al., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds disclosed herein may contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds disclosed herein, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention. 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 chiral center(s). The prefixes d and 1 or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, 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.
[0078] The term "tautomer" or "tautomeric form" refers to structural isomers of different energies which are interconvertible via a low energy barrier. Some non-limiting examples of proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by reorganization of some of the bonding electrons.
[0079] A "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 salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, 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, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(Ci-4 alkyl) 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, Ci-8 sulfonate or aryl sulfonate.
[0080] A "solvate" refers to an association or complex of one or more solvent molecules and a compound disclosed herein. Some non-limiting examples of solvents that form solvates include water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. The term "hydrate" refers to the complex where the solvent molecule is water. [0081 ] The term "protecting group" or "Pg" refers to a substituent that is commonly employed to block or protect a particular functionality while reacting with other functional groups on the compound. For example, an "amino-protecting group" is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Some non-limiting examples of suitable amino-protecting groups include acetyl, trifluoroacetyl, r-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) and 9-fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a "hydroxy-protecting group" refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Some non-limiting examples of 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 -CH2CH2S02Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl,
2-(p-toluenesulfonyl)ethyl, 2-(/>-nitrophenylsulfonyl)ethyl, 2-(diphenylphosphino)ethyl, nitroethyl, and the like. For a general description of protecting groups and their use, see Greene et al., Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991 and Kocienski et al., Protecting Groups, Thieme, Stuttgart, 2005.
DESCRIPTION OF COMPOUNDS OF THE INVENTION
[0082] Provided herein are compounds and pharmaceutically acceptable compositions thereof, which are useful in inhibiting viral disease, particularly in inhibiting HBV infections.
[0083] In one aspect, provided herein are compounds having Formula (I) or (la) as shown below:
Figure imgf000032_0001
or an enantiomer, a diastereoisomer, a tautomer, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, wherein: each A is a bond, -0-, -S-, or -NR5-; each R is -X-Z;
X is -(CR7R7a)m- or -C(=0)-;
Z has Formula (II) or (Ila):
Figure imgf000033_0002
wherein each B is a bond, -(CR7R7a)m- or -C(=0)-; each W is CR7 or N; each Y is -(CR7R7a)m-, -0-, -S-, -S(=0)q- or -NR6-; each R1 is aryl or heteroaryl; each R2 is H, alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl or alkoxycarbonyl; each R3 is aryl or heteroaryl; each R4 is H, or CM alkyl;
R5 is H, alky], -(CR7R7A)M-C(=0)0-R8, alkenyl or alkynyl; each R6 is alkyl, -(CR7R7a)m-C(=0)0-R8, alkenyl or alkynyl; each R7a and R7 is independently H, F, CI, Br, alkyl, haloalkyl, -(CH2)m-OH or -(CH2)m-C(=0)0-R8; each R8 and RB is independently H, alkyl, haloalkyl, aminoalkyl, Boc-NH-alkyl, alkoxy, -(CH2)m-OH, -(CH2)m-C(=0)0-(CH2)m-H or -(CH2)m-OC(=0)-(CH2)m-H;
Boc is rer/-butyloxycarbonyl; each R9 is independently -(CR7R7a),-OH. -(CR7R7a)m-S(=0)q-R8, -(CR7R7a)m-OS(=0)q-R8, -(CR7R7a)m-S(=0)qO-R8, -(CR7R7a)m-C(=0)-R8,
-(CR7R7a)m-C(=0)0-R8, -(CR7R7a)iT1-C(=0)0-(CR7R7a)m-OC(=0)0-R8, -(CR7R7a)m-C(=0)0-(CR7R7a)m-OC(-0)-R8, -(CR7R7a)m-C(=0)0-(CR7R7a)m-C(-0)0-R8, -(CR7R7a) OC(=0)-R8, triazolyl, tetrazolyl or -(CR7R7a)m-C(=0)N(R8)2, with the proviso that when R9 is -(CR7R7a)t-OH, R3 is aryl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrimidinyl, pyndazinyl, thiazolyl, diazolyl, triazolyl, tetrazolyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyranyl or triazinyl; each n is independently 1 , 2 or 3; each t is independently 1 , 2, 3 or 4; each m is independently 0, 1 , 2, 3 or 4; each q is independently 0, 1 or 2; and optionally each of aryl, heteroaryl, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, alkoxycarbonyl, aralkyl, heteroarylalkyl, aminoalkyl, alkoxy, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrimidinyl, pyndazinyl, thiazolyl, diazolyl, triazolyl, tetrazolyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyranyl, triazinyl, heterocyclyl and heterocyclylalkyl described above, is independently substituted with one or more substituents which are the same or different, wherein the substituent is H, F, CI, Br, I, alkyl, alkoxy, cyano, hydroxy, nitro, alkylamino, amino, trifiuoromethyl, trifiuoromethoxy, -(CR7R7a)m-C(=0)0-R8a, haloalkyl-substituted aryl, -substituted aryl, -(CR7R7a)m-C(=0)N(R8a)2 or trifluoromethylsulfonyl.
[0084] In certain embodiments, Z has Formula (III) or (Ilia):
Figure imgf000035_0001
wherein each B is a bond or -(CR R a)m-; each Y is -(CR7R7a)m-, -0-, -S-, -S(=0)q- or -NR6-; each R6 is C alkyl, -(CR7R7a)m-C(=0)0-R8, C2-4 alkenyl or C2-4 alkynyl; each R7a and R7 is independently H, F, CI, Br, CM alkyl, -(CH2)m-OH, C1 -4 haloalkyl or -(CH2)m-C(=0)0-R8; each R is independently H, Cj.6 alkyl, C haloalkyl, amino-Ci-4-alkyl, Boc-NH-Ci_4-alkyl, C alkoxy, -(CH2)m-OH, -(CH2)m-C(=0)0-(CH2),n-H or -(CH2)m-OC(=0)-(CH2)m-H; each R9 is independently -(CR7R7a),-OH, -(CR7R7a)m-C(=0)-R8, -(CR7R7a)m-C(=0)0-R8, -(CR7R7a)m-C(=0)0-(CR7R7a)m-OC(=0)0-R8, -(CR7R7a)m-C(=0)0-(CR7R7a)m-OC(=0)-R8, -(CR7R7a)m-C(=0)0-(CR7R7a)m-C(=0)0-R8, -(CR7R7a),-OC(=0)-R8, triazolyl, tetrazolyl or -(CR7R7a)m-C(=0)N(R8)2, with the proviso that when R9 is -(CR7R7a),-OH, R3 is C6-io aryl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pynmidinyl, pyridazinyl, thiazolyl, diazolyl, triazolyl, tetrazolyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyranyl or triazinyl; each n is independently 1 or 2; each t is independently 1 , 2, 3 or 4; and each m is independently 0, 1 , 2, 3 or 4. [0085] In other embodiments, Z is
Figure imgf000036_0001
each R7 and R7a is independently H, methyl, ethyl, -(CH2)m-OH, -(CH2)m-C(=0)0-R8 or propyl; each R is independently H, methyl, ethyl, propyl, isopropyl, butyl, 1-methylpropyl, 2-methylpropyl, aminomethyl, 1 -amino-2-methylpropyl, 1 -aminoethyl, 2-aminoethyl, 1 -aminobutyl, 1-aminopropyl, 2-aminopropyl, Boc-NH-methyl, l-Boc-NH-2-methylpropyl, 1-Boc-NH-ethyl, 2-Boc-NH-ethyl, 1-Boc-NH-butyl, 1-Boc-NH-propyl, 2-Boc-NH-propyl, methoxy, ethoxy, -(CH2)m-OH, -(CH2)m-C(=0)0-(CH2)m-H, -(CH2)m-OC(=0)-(CH2)m-H or ter /-butyl; and each R9 is independently triazolyl, tetrazolyl, -(CR7R7a),-OH, -(CR7R7a)m-C(=0)-R8, -(CR7R7a)m-C(=0)0-R8, -(CR7R7a)m-C(=0)0-(CR7R7a)m- OC(=0)0-R8,
-(CR7R7a)m-C(=0)0-(CR7R7a)m-OC(=0)-R8, -(CR7R7a)t-OC(=0)-R8 or
-(CR7R7a)m-C(=0)N(R )2, with the proviso that when R9 is -(CR7R7a),-OH, R3 is phenyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pynmidinyl, pyridazinyl, thiazolyl, diazolyl, triazolyl, tetrazolyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyranyl or triazinyl.
[0086] In certain embodiments, R3 is C6-io aryl or 5-6 membered heteroaryl, and optionally each of the heteroaryl and aryl is independently substituted with one or more substituents which are the same or different, wherein the substituent is H, F, CI, Br, I, methyl, ethyl, propyl, isopropyl, butyl, methoxy, ethoxy, methylamino, ethylamino, cyano, hydroxy, nitro, amino, trifluoromethyl, trifluoromethoxy, -(CR7R7a)m-C(=0)0-R8a, -(CR7R7a)m-C(=0)N(R8a)2 or trifluoromethylsulfonyl; each R7a and R7 is independently H, F, CI, Br, C alkyl, CM haloalkyl, -(CH2)m-OH or -(CH2)m-C(=0)0-R8; and each R8a and R8 is independently H, C] -4 alkyl, Cj.4 haloalkyl, amino-Ci-4-alkyl, Boc-NH-C^-alkyl, C1-4 alkoxy, -(CH2)m-OH, -(CH2)m-C(=0)0-(CH2)m-H or -(CH2)m-OC(=0)-(CH2)m-H.
[0087] In other embodiments, R has one of the following formulae:
Figure imgf000037_0001
wherein each X1 is independently O, S, NR11 or CR12R12a; each X2, X3, X4, X5 and X6 is independently N or CR12; wherein at most three or four of the X2, X3, X4, X5 and X6 are N; each R10 is independently H, F, CI, Br, I, methyl, ethyl, propyl, isopropyl, butyl, methoxy, ethoxy, methylamino, ethylamino, cyano, hydroxy, nitro, amino, trifluoromethyl, trifluoromethoxy, -(CR7R7a)m-C(=0)0-R8a, -(CR7R7a)m-C(=0)N(R8a)2 0r tri fl uoromethylsulfony 1 ; each Rn is independently H, methyl, ethyl, propyl, isopropyl, butyl, trifluoromethyl,
-(CR7R7a)m-C(=0)N(R8a)2 or -(CR7R7a)m-C(=0)0-R8a; each R12 and R12a is independently H, F, CI, Br, 1, methyl, ethyl, propyl, isopropyl, butyl, methoxy, ethoxy, methylamino, ethylamino, cyano, hydroxy, nitro, amino, trifluoromethyl, trifluoromethoxy, -(CR7R7a)m-C(=0)0-R8A, -(CR7R7a)m-C(=0)N(R8A)2 or tri fluoromethylsul fonyl ; each R7A and R7 is independently H, F, CI, Br, CM alkyl, -(CH2)m-OH,
Figure imgf000038_0001
or -(CH2)M-C(=0)0-R8; each R and R is independently H, Ci-4 alkyl, C haloalkyl, amino-C]_4-alkyl, Boc-NH-C^-alkyl, Cl -4 alkoxy, -(CH2)m-OH, -(CH2)m-C(=0)0-(CH2)m-H or -(CH2)m-OC(=0)-(CH2)m-H; each m is independently 0, 1 , 2, 3 or 4; and each p is independently 0, 1 , 2 or 3.
[0088] In other embodiments, R3 has one of the following formulae:
Figure imgf000038_0002
wherein each R is independently H, F, CI, methyl, ethyl, cyano, hydroxy, nitro, amino, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, -(CR7R7a)m-C(=0)0-R8a, -(CR7R7a)m-C(=0)N(R8a)2 or trifiuoromethylsulfonyl; each R11 is independently H, methyl, ethyl, propyl, isopropyl, butyl, trifluoromethyl or -(CR7R7a)m-C(=0)0-R8a; each R7a and R7 is independently H, methyl, ethyl, -(CH2)m-OH, -(CH2)m-C(=0)0-R8 or propyl; each R8 and R8a is independently H, methyl, ethyl, propyl, isopropyl, butyl, 2-methylpropyl, 1 -methylpropyl, aminomethyl, l-amino-2-methylpropyl, 1 -aminoethyl, 2-aminoethyl, 1 -aminobutyl, 1 -amiriopropyl, 2-aminopropyl, Boc-NH-methyl, l -Boc-NH-2-methylpropyl, 1-Boc-NH-ethyl, 2-Boc-NH-ethyl, 1-Boc-NH-butyl, 1 -Boc-NH-propyl, 2-Boc-NH-propyl, methoxy, ethoxy, -(CH2)m-OH, -(CH2)m-C(=0)0-(CH2)m-H, -(CH2)m-OC(=0)-(CH2)m-H or tert-butyl; and each p is independently 0, 1 , 2 or 3.
[0089] In certain embodiments, R1 is C6-10 aryl, and the aryl is independently substituted with one or more substituents which are the same or different, wherein the substituent is H, F, CI, Br, cyano, methyl, ethyl, methoxy, ethoxy, methylamino, ethylamino, nitro, 4-(trifluoromethyl)phenyl, 3,5-frw(trifluoromethyl)phenyl or trifluoromethyl;
R2 is H, or C] .4 alkyl; and
R5 is H, or Ci-4 alkyl.
[0090] In other embodiments, R1 is phenyl or a phenyl substituted with one or more substituents which are the same or different, wherein the substituent is H, F, CI, Br, nitro, 4-(trifluoromethyl)pheny], 3,5-& s(trifluoromethyl)phenyl or trifluoromethyl.
[0091 ] In certain embodiments, Formula (IV) or (IVa) is
Figure imgf000040_0001
or an enantiomer, a diastereoisomer, a tautomer, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, wherein Z has Formula (II) or (lla):
Figure imgf000040_0002
wherein each B is a bond or -(CR7R7a)m-; each W is CR7 or N; each Y is -(CR7R7a)m-, -0-, -S-, -S(=0)q- or -NR6-; each R2 is H, or C alkyl; each R is C6-10 ary' or 5-6 membered heteroaryl, and optionally each of the heteroaryl and aryl is independently substituted with one or more substituents which are the same or different, wherein the substituent is H, F, CI, methyl, ethyl, propyl, cyano, trifluoromethyl, methoxy, -(CR7R7a)m-C(=0)N(R8a)2 or -(CR7R7a)m-C(=0)0-R8a; each R6 is Ci-4 alkyl; each R7a and R7 is independently H, -(CH2)m-OH, -(CH2)m-C(=0)0-R8 or CM alkyl; each R8 and R8a is independently H, amino-Ci-4-alkyl,
Figure imgf000040_0003
C alkoxy, -(CH2)m-OH, -(CH2)m-C(=0)0-(CH2)m-H, -(CH2)m-OC(=0)-(CH2)m-H or C1 -6 alkyl; each R9 is independently triazolyl, tetrazolyl, -(CR7R7a),-OH, -(CR7R7a)m-C(=0)0-(CR7R7a)m-OC(=0)0-R8, -(CR7R7a)m-C(=0)-R8, -(CR7R7a)m-C(=0)0-R8, -(CR7R7a)m-C(=0)0-(CR7R7a)m-OC(=0)-R8, -(CR7R7a),-OC(=0)-R8 or -(CR7R7a)m-C(=0)N(R8)2, with the proviso that when R9 is -(CR7R7a)t-OH, R3 is C6-10 aryl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrimidinyl, pyridazinyl, thiazolyl, diazolyl, triazolyl, tetrazolyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyranyl or triazinyl; each R13 is independently H, F, CI, Br, cyano, nitro, 4-(trifluoromethyl)phenyl, 3,5-£ s(trifluoromethyl)phenyl or trifluoromethyl; each n is independently 1 or 2; each t is independently 1 , 2, 3 or 4; each m is independently 0, 1 , 2, 3 or 4; and each q is independently 0, 1 or 2.
[0092] In certain embodiments, Z has Formula (II) or (Ha):
Figure imgf000041_0001
wherein each B is a bond or -(CR7R7a)m-; each W is CR7 or N; each Y is -(CR7R7a)m-, -0-, -S-, -1 S(=0)q- or -NR6-; each R6 is methyl, ethyl or propyl; each R7a and R7 is independently H, methyl, -(CH2)m-OH, -(CH2)m-C(=0)0-R8, ethyl or propyl; each R is independently H, methyl, ethyl, propyl, isopropyl, butyl, 1 -methylpropyl, 2-methylpropyl, tert-buty\, aminomethyl, l-amino-2-methylpropyl, 1 -aminoethyl, 2-aminoethyl, 1-aminobutyl, 1 -aminopropyl, 2-aminopropyl, Boc-NH-methyl, l -Boc-NH-2-methylpropyl, 1-Boc-NH-ethyl, 2-Boc-NH-ethyl, 1-Boc-NH-butyl, 1 -Boc-NH-propyl, 2-Boc-NH-propyl, methoxy, ethoxy, -(CH2)m-OH, -(CH2)m-C(=0)0-(CH2)m-H or -(CH2)m-OC(=0)-(CH2)m-H; each R8a is independently H, methyl, ethyl, isopropyl or propyl; each R9 is independently -(CR7R7a),-OH, -(CR7R7a)m-C(0)0-R8, -(CR7R7a)m-C(=0)0-(CR7R7a)m-OC(=0)0-R8, -(CR7R7a)m-C(=0)0-(CR7R7a)m- OC(=0)-R8, -(CR7R7a)t-OC(=0)-R8, triazolyl, tetrazolyl or -(CR7R7a)m-C(=0)N(R8)2, with the proviso that when R9 is -(CR7R7a) OH, R3 is phenyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrimidinyl, pyridazinyl, thiazolyl, diazolyl, triazolyl, tetrazolyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyranyl or triazinyl; each m is independently 0, 1 , 2, 3 or 4; and each t is independently 1 , 2, 3 or 4.
[0093] In other embodiments, Z is:
Figure imgf000042_0001
Figure imgf000043_0001
42
Figure imgf000044_0001
43
Figure imgf000045_0001
[0095] In another aspect, provided herein are 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:
Figure imgf000045_0002
Figure imgf000046_0001

Figure imgf000047_0001

Figure imgf000048_0001
Figure imgf000048_0002
47 W
Figure imgf000049_0001
Figure imgf000049_0002
Figure imgf000049_0003
Figure imgf000050_0001
Figure imgf000051_0001
50
Figure imgf000052_0001
51 W
Figure imgf000053_0001
Figure imgf000053_0002
Figure imgf000053_0003
Figure imgf000054_0001
53
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
[0096] In one aspect, provided herein are compounds and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.
[0097] In certain embodiments, provided herein is the pharmaceutical composition further comprising an anti-HBV agent.
[0098] In certain embodiments, the pharmaceutical composition is disclosed herein, wherein the anti-HBV agent is a HBV polymerase inhibitor, immunomodulator or interferon. [0099] In certain embodiments, the pharmaceutical composition is disclosed herein, wherein the anti-HBV agent is lamivudine, telbivudine, tenofovir, entecavir, adefovir dipivoxil, alfaferone, alloferon, celmoleukin, clevudine, emtricitabine, famciclovir, feron, fepatect CP, intefen, interferon a- lb, interferon a, interferon a-2, interferon a-2a, interferon a-2b, interferon β-l a, interleukin-2, mivotilate, nitazoxanide, peginterferon alfa-2a, ribavirin, roferon-A, sizofiran, euforavac, rintatolimod, phosphazid, heplisav, levamisole, or propagermanium.
[001 00] In another aspect, provided herein is use of the compound disclosed herein or the pharmaceutical composition disclosed herein in the manufacture of a medicament for preventing, managing, or treating a viral disease or a HBV disease or lessening the severity of a viral disease or a HBV disease in a patient.
[001 01 ] In another aspect, provided herein are methods for preventing, managing, treating or lessening a viral disease or a HBV disease in a patient, which comprises administering a pharmaceutically effective amount of the compound disclosed herein to the patient.
[00102] In another aspect, provided herein are methods for preventing, managing, treating or lessening a viral disease or a HBV disease in a patient, which comprises administering a pharmaceutically effective amount of the pharmaceutical composition disclosed herein to the patient.
[001 03] In another aspect, provided herein are the compounds disclosed herein or the pharmaceutical compositions disclosed herein for use in preventing, managing or treating a viral disease or a HBV disease or lessening the severity of a viral disease or a HBV disease in a patient.
[00104] In certain embodiments, the viral disease or HBV disease is hepatitis B infection or a disease caused by hepatitis B infection.
[001 05] In other embodiments, the disease caused by hepatitis B infection is cirrhosis or hepatocellular carcinoma.
[001 06] In some embodiments, 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 a HBV therapeutic agent.
[001 07] In another aspect, provided herein is a method of inhibiting HBV infection, comprising contacting a cell or a plurality of cells with an effective HBV inhibiting amount of a compound disclosed herein or a composition thereof. In other embodiments, the method further comprises contacting the cells with a HBV therapeutic agent.
[001 08] In another aspect, provided herein is a method of treating HBV disease in a patient, the method comprises administering to the patient in need of such treatment an effective therapeutic amount of a compound disclosed herein or a composition thereof. In other embodiments, the method further comprises administering to the patient a HBV therapeutic agent.
[001 09] In another aspect, provided herein is a method of inhibiting a HBV infection in a patient, the method comprises administering to the patient in need of an effective therapeutic amount of a compound disclosed herein or a composition disclosed herein. In other embodiments, the method further comprises administering to the patient a HBV therapeutic agent.
[001 10] In another aspect, provided herein include methods of preparing, methods of separating, and methods of purifying the compounds of Formula (I) or (la).
[001 1 1 ] Provided herein includes the use of 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. Also provided herein is a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) or (la) in association with at least one pharmaceutically acceptable carrier, adjuvant or diluent.
[001 12] 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 (la).
[001 13] Unless otherwise stated, all stereoisomers, geometric isomers, tautomers, N-oxides, hydrates, solvates, metabolites, salts, and pharmaceutically acceptable prodrugs of the compounds disclosed herein are within the scope of the invention.
[001 14] In certain embodiments, the salt is a pharmaceutically acceptable salt. The phrase "pharmaceutically acceptable" refers to that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.
[001 15] 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 (la) and/or for separating enantiomers of compounds of Formula (I) or (la).
[001 16] If the compound disclosed herein is a base, 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. Or with 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 / oluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid or trifluoromethanesulfonic acid, and the like.
[001 17] If the compound disclosed herein is an acid, 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 )4 or an alkaline earth metal hydroxide, and the like. Some non-limiting examples of suitable salts include organic salts derived from amino acids, such as glycine and arginine, ammonia (primary, secondary, and tertiary amines), salts of N+(R14)4, such as R14 is H, C alky], Ce-io aryl or C6-io aryl-C^-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. Further salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, C]-8 sulfonate or aryl sulfonate.
COMPOSITION, FORMULATIONS, USES AND ADMINSTRATION OF
COMPOUNDS AND COMPOSITIONS OF THE INVENTION
[001 18] According to another aspect, the invention features pharmaceutical compositions that include a compound of Formula (I) or (la), a compound listed herein, or a compound named in Examples 1 to 157, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The compound disclosed herein can inhibit HBV effectively, and is suitable for use in treating 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.
[001 19] Areas of indication which may be mentioned for the compounds disclosed herein are, for example: the treatment of acute and chronic viral infections which may lead to infectious hepatitis, for example, infections with hepatitis B viruses. The compounds disclosed herein are particularly suitable for the treatment of chronic hepatitis B infections and the treatment of chronic hepatitis B infections and the treatment of acute and chronic hepatitis B viral infections.
[00120] The present invention includes pharmceutical preparations which, besides nontoxic, inert pharmaceutically suitable carriers, comprise one or more compounds (I) or (la) disclosed herein or a combination thereof or which consist of one or more active ingredients (I) or (la) disclosed herein or a combination thereof.
[00121 ] The pharmaceutical preparations mentioned above may also comprise other active pharmaceutical ingredients apart from the compounds (I) or (la).
[00122] It will also be appreciated that certain of the compounds disclosed herein can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable derivative thereof. Some non-limiting examples of the 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.
[00123] As described above, the pharmaceutically acceptable compositions disclosed herein additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, 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. Troy et al., Remington: The Science and Practice of Pharmacy, 21st ed., 2005, Lippincott Williams & Wilkins, Philadelphia, and Swarbrick et al., Encyclopedia of Pharmaceutical Technology, eds. 1988-1999, Marcel Dekker, New York, all of each of which are herein incorporated by referencein their entireties, are disclosed various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except in so far as any conventional carrier medium is incompatible with the compounds disclosed herein, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention.
[00124] 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 com starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; 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; glycols such as propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants. As a matter of convenience, local anesthetics, preservatives, buffering agents and so on, can be dissolved in carriers directly.
[00125] The pharmaceutical composition comprising the compound disclosed herein may be administered in any of the following routes: orally, inhaled by spray, rectally, nasally, vaginally, topically, 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.
[00126] The compound disclosed herein or the pharmaceutical composition comprising the compound 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.
[00127] 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.
[00128] 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 jp-hydroxybenzoate, sorbic acid. If desired, a flavoring agent or a colorant may be added.
[00129] Suppository may comprise a conventional suppository subtrate, such as cocoa butter or other glyceride.
[00130] For non-gastric administration, the liquid dosage form is usually made of the compound and a sterilized carrier. The preferred carrier is water. According to the carrier selected and the drug concentration, the compound can be dissolved in the carrier or made into a suspension. When making an injection solution, the compound is firstly dissolved in water, and then filtered and sterilized before being packaged into an enclosed bottle or ampoule.
[00131 ] For topical application on skin, 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). Some non-limitimg examples of the carriers used for an ointment include mineral oil, liquid vaseline, albolene, propylene glycol, polyoxyethylene, polyoxypropylene, emulsified wax, water, and the like; Some non-limitimg 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.
[00132] In general, it has been proved that, advantageously, whether in human medicine or in veterinary medicine, 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.
[00133] In one aspect, provided herein is the pharmaceutical composition further comprising an anti-HBV agent. And the anti-HBV agent is a HBV polymerase inhibitor, immunomodulator or interferon.
[00134] The anti-HBV agent is lamivudine, telbivudine, tenofovir, entecavir, adefovir dipivoxil, alfaferone, alloferon, celmoleukin, clevudine, emtricitabine, famciclovir, feron, hepatect CP, intefen, interferon a- lb, interferon a, interferon a-2a, interferon β-l a, interferon a-2, interleukin-2, mivotilate, nitazoxanide, peginterferon alfa-2a, ribavirin, roferon-A, sizofiran, euforavac, veldona, rintatolimod, phosphazid, heplisav, interferon a-2b, levamisole or propagermanium.
[00135] In another aspect, provided herein is use of 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 or 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.
[00136] Those additional agents may be administered separately from the compound-containing composition, as part of a multiple dosage regimen. Alternatively, 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.
[00137] The amount of both the compound and the additional therapeutic agent (in those compositions which comprise an additional therapeutic agent as described above) that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Normally, 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. In other embodiment, 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. In those compositions which comprise an additional therapeutic agent, that additional therapeutic agent and the compound disclosed herein may act synergistically.
[00138] 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 vural diseases caused by HBV may lead to various syndromes having different extents of severity. As well known, chronic HBV infection may lead to hepatic cirrhosis and /or liver cell carcinoma.
[00139] Examples of 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.
[00140] 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.
GENERAL SYNTHETIC PROCEDURES
[00141 ] Generally, the compounds disclosed herein may be prepared by methods described herein, wherein the substituents are as defined for Formulas (I) or (la), above, except where further noted. The following non-limiting schemes and examples are presented to further exemplify the invention.
[00142] Persons skilled in the art will recognize that the chemical reactions described may be readily adapted to prepare a number of other compounds disclosed herein, and alternative methods for preparing the compounds disclosed herein are deemed to be within the scope disclosed herein. For example, the synthesis of non-exemplified compounds according to the invention may be successfully performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by utilizing other suitable reagents known in the art other than those described, and/or by making routine modifications of reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds disclosed herein.
[00143] In the examples described below, unless otherwise indicated all 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.
[00144] Column chromatography was conducted using a silica gel column. Silica gel (200 - 300 mesh) was purchased from Qingdao Ocean Chemical Factory. Ή NMR spectra were obtained as CDCI3, c^-DMSO, CD3OD or ί/ή-acetone solutions (reported in ppm), using TMS (0 ppm) or chloroform (7.25 ppm) as the reference standard. When peak multiplicities are reported, the following abbreviations are used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets), br.s (broadened singlet). Coupling constants, when given, are reported in Hertz (Hz).
[00145] Low-resolution mass spectral (MS) data were determined on an Agilent 6320 Series LC-MS spectrometer equipped with G 1312A binary pumps and a G 1316A TCC (Temperature Control of Column, maintained at 30 °C). A G 1329A autosampler and a G 1315B DAD detector were used in the analysis, and an ESI source was used on the LC-MS spectrometer.
[00146] Low-resolution mass spectral (MS) data were determined on an Agilent 6120 Series LC-MS spectrometer equipped with G 1 3 1 1 A quaternary pumps and a G 1 31 6A TCC (Temperature Control of Column, maintained at 30 °C). A G 1329A autosampler and a G 1 31 5D DAD detector were used in the analysis, and an ESI source was used on the LC-MS spectrometer. [00147] Both Spectrographs were equipped with an Agilent Zorbax SB-C18 (2.1 x 30 mm, 5 micron). Injection volume was decided by the sample concentration. The flow rate is 0.6 mL/min. The mobile phase was (0.1 % formic acid in CH3CN as mobile phase A) in (0.1 % formic acid in H20 as mobile phase B) with UV detection at 210/254 nm. The conditions of gradient elution is described in Table 1 :
[00148] Tab. 1
Figure imgf000075_0001
[00149] Purities of compounds were assessed by Agilent 1 100 Series high performance liquid chromatography (HPLC) with UV detection at 210 nm and 254 nm (Zorbax SB-C18, 2.1 x 30 mm, 4 micron), 10 min, 0.6 mL/min flow rate, 5 to 95% (0.1 % formic acid in CH3CN) in (0.1% formic acid in H20). Column was operated at 40 °C.
[00150] The following abbreviations are used throughout the specification:
MeCN, CH3CN acetonitrile
DCM, CH2C12 methylene chloride
CHCI3 chloroform
CDC I 3 chloroform-d
CCI4 carbon tetrachloride
Boc to'i-butyloxycarbonyl
PE petroleum ether (60-90 °C)
EtOAc, EA ethyl acetate HC1 hydrochloric acid
K2CO3 potassium carbonate
NaHC03 sodium bicarbonate
NaOH sodium hydroxide
NaCl sodium chloride
Na2S04 sodium sulfate
Et3N, TEA triethylamine
NBS N-bromosuccinimide
D2O oxide
H20 water
mL milliliter
RT, rt room temperature
Rt retention time
H2 hydrogen
EDCvHCl 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
HOAT 1 -hydroxy-7-azabenzotriazole
DIPEA N,N-diisopropylethylamine
DCC N,N-dicyclohexylcarbodiimide
DMF N,N-dimethylformamide
LiAlH4 lithium aluminum hydride
THF tetrahydrofuran
DMSO dimethylsulfoxide
Pd/C, Pd-C palladium on carbon CuCN copper (I) cyanide
CH3OH methanol
N2 nitrogen
NH4CI ammonium chloride
Ac20 Acetic anhydride tj,2 half-life period
AUC area under the curve
Vss apparent volume of distribution
CL clearance
F absolute bioavailability
Tmax time to peak
Cmax peak concentration hr ng/mL blood concentration time
SYNTHESIS OF INTERMEDIATES
[001 51 ] Synthesis of intermediate 3A
Figure imgf000077_0001
[00152] Intermediate 3A can be prepared by the process disclosed herein. Compound 1 A reacts with compound 2A in an acidic condition to give intermediate 3A.
[00153] Synthesis of intermediate 5A
Figure imgf000078_0001
[00154] Intermediate 5A can be prepared by the process disclosed herein. Compound 4A is hydrolyzed in an alkaline condition to give intermediate 5A.
[00155] Synthesis of intermediate 8A
Figure imgf000078_0002
[00156] Intermediate 8A, wherein R8 is alkylamino, alkoxy or amino, can be prepared by the process disclosed herein. Compound 6A is transformed to an acyl chloride intermediate through acylation. The acyl chloride intermediate reacts with compound 7A to give intermediate 8A.
[00157] Synthesis of intermediate 12A
Figure imgf000078_0003
[00158] Intermediate 12A can be prepared by the process disclosed herein. Compound 9 A reacts with benzyl bromide to afford compound 10A, which can be transformed to compound 11A under the action of borane tetrahydrofuran. Compound 11 A is then reduced through catalytic hydrogenation to give intermediate 12A.
[00159] Synthesis of intermediate 18A
Figure imgf000079_0001
[001 60] Intermediate 18A can be prepared by the process disclosed herein. Compound 13A reacts with benzaldehyde and sodium borohydride to give compound 14A. Compound 14A then reacts with chloroacetyl chloride in an alkaline condition to afford compound 15A followed by reacting with benzyl bromide to afford compound 16A, which can be transformed to compound 17A under the action of borane tetrahydrofuran. Compound 17A is then reduced through catalytic hydrogenation to give intermediate 18A.
[00161 ] Synthesis of intermediate 22 A
Figure imgf000079_0002
[00162] Intermediate 22 A can be prepared by the process disclosed herein. Compound 19A reacts with 2-aminoethanol to afford compound 21 A followed by reacting with hydrochloric acid in ethyl acetate under the action of acetic acid to give intermediate 22A.
[00163] Synthesis of intermediate 25A
Figure imgf000079_0003
[00164] Intermediate 25A, wherein each R13 and n is as defined above, can be prepared by the process disclosed herein. Compound 23A reacts with compound 24A under the action of tetrakis(triphenylphosphine)palladium in an alkaline condition to give intermediate 25A. [00165] Synthesis of intermediate 28A
Figure imgf000080_0001
[00166] Intermediate 28A can be prepared by the process disclosed herein, wherein R3 is as defined herein. Compound 26A can be transformed to compound 27A through the action of copper (I) cyanide. Compound 27A then reacts with hydroxylamine hydrochloride in the presence of Pd/C to give intermediate 28A.
[00167] Synthesis of intermediate 34A
Figure imgf000080_0002
[00168] Intermediate 34A can be prepared by the process disclosed herein. Compound 31A can be prepared by the reduction and bromination of compound 29A. Compound 31A then reacts with compound 32A to afford compound 33A followed by reduction to give intermediate 34A.
[00169] Synthesis of intermediate 36A
Figure imgf000080_0003
[00170] Intermediate 36A can be prepared by the process disclosed herein. Compound 33A is reduced twice by any reduction reaction that can reduce esters into alcohols or amides into amines to give intermidate 36A.
[00171 ] Synthesis of intermediate 44A
Figure imgf000081_0001
[00172] Intermediate 44A can be prepared by the process disclosed herein. Compound 37A reacts with compound 38A to afford compound 39A. A mixture of compound 39A and compound 40A in methanol is refluxed to afford compound 41A, followed by methylation, reduction through catalytic hydrogenation and hydrolyzation in an alkaline condition to give intermediate 44A.
[00173] Synthesis of intermediate 47 A
Figure imgf000081_0002
[00174] Intermediate 47A can be prepared by the process disclosed herein. Compound 45A is reacted with sodium azide and ammonium chloride to afford compound 46A followed by reduction through deprotection to give intermediate 47A. [00175] Synthesis of intermediate 53A
Figure imgf000082_0001
[00176] Intermediate 53A can be prepared by the process disclosed herein. Compound 49A can be prepared through oxidation of compound 48A. Compound 49A then reacts with compound 50A to afford compound 51 A followed by basic hydrolysis, reduction and salt forming reaction to give intermediate 53A.
[00177] Synthesis of intermediate 60A
Figure imgf000082_0002
[00178] Intermediate 60A can be prepared by the process disclosed herein. Compound 49A reacts with compound 50A to afford compound 54A, followed by reduction of the alkenyl and ester groups to give intermediate 60 A.
[00179] Synthesis of intermediate 61 A
Figure imgf000082_0003
[00180] Intennediate 61 A can be prepared by the process disclosed herein. Compound 55A is ammonolyzed to give intermediate 61A. [00181 ] Sythesis of intermediate 69A
Figure imgf000083_0001
[001 82] Intermidiate 69A can be prepared by the process disclosed herein. Compound 62 A reacts with compound 63 A to afford compound 64A. Compound 64A reacts with compound 65A to afford compound 66A. Compound 66A reacts with (bromomethyl)benzene to afford compound 67A, which is reduced twice to give intermediate 69A.
SYNTHESIS OF COMPOUNDS
[001 83] Compounds having Formula (I) or (la) may be prepared by methods described herein.
[00184] Scheme 1
Figure imgf000083_0002
[00185] Pyrimidine 6, wherein each R1 , R2, R3, A and Z is as defined herein, can be prepared by the process illustrated in Scheme 1. Amidines 1 or hydrochloride thereof, aldehydes 2 and compound 3 are cyclized in suitable inert solvent(s) (such as alcohol reagents) to give compound 4.
[00186] Compound 4 reacts with brominating agent in inert solvent(s) to give compound 5. Subsequently, compound 5 reacts with ZH in appropriate inert solvent(s) under an alkaline condition to yield pyrimidine 6.
[00187] Scheme 2
Chlorination
Figure imgf000084_0001
Figure imgf000084_0002
1 2 3
[00188] Alternatively, pyrimidine 6, wherein each R , R , R , A and Z is as defined herein, can be prepared by the process illustrated in Scheme 2. Amidines 7 or hydrochloride thereof, aldehydes 2 and compound 3 can be cyclized in suitable inert solvent(s) (such as alcohol reagents) to give compound 8.
[00189] Compound 8 can be reacted with chlorinating agent to give compound 9. Compound 9 reacts with RJH in suitable inert solvent(s) to yield compound 4. Compound 4 reacts with brominating agent in inert solvent(s) to give compound 5. Subsequently, compound 5 reacts with ZH in appropriate inert solvent(s) under an alkaline condition to yield pyrimidine 6.
[00190] Scheme 3
Figure imgf000085_0001
[00191 ] Pyrimidine 12, wherein each R1, R2, R3, A and Z is as defined above, can be prepared by the process illustrated in Scheme 3. Compound 4 reacts with methylating agent to afford compound 10 followed by reacting with brominating agent in inert solvent(s) to give compound 11. Subsequently, compound 11 reacts with ZH in appropriate inert solvcnt(s) under an alkaline condition to yield pyrimidine 12.
[00192] Scheme 4
Figure imgf000085_0002
[00193] Pyrimidine 14 can be prepared by the process illustrated in Scheme 4, wherein when Z1 is -(CR7R7a),-OH, Z2 is -(CR7R7a),-OC(=0)-R8; when Z1 is -(CR7R7a)m-C(=0)0-R8, Z2 is -(CR7R7a)m-C(=0)N(R8)2, each R1, R2, R3, R7, R7a, R8, m and A is as defined herein. Compound 5 reacts with ΖΉ to afford compound 13 followed by esterification or amidation, and hydrolyzation to give pyrimidine 14.
[00194] Scheme 5
Figure imgf000085_0003
[00195] Pyrimidine 19 can be prepared by the process illustrated in Scheme 5, wherein R3' is heteroaryl substituted with -(CR7R7a)m-C(=0)0-R8a, R3 is heteroaryl substituted with -(CR7R7a)m-C(=0)N(R8a)2, each R1, R2, A, R7, R7a, R8a, m and Z is as defined above. Amidines 15 or hydrochloride thereof, aldehydes 2 and compound 3 are cyclized in suitable inert solvent(s) (such as alcohol reagents) to afford compound 16. Compound 17 can be prepared through amidation of compound 16. Compound 17 then reacts with brominating agent in inert solvent(s) to give compound 18 followed by reacting with ZH under an alkaline condition in appropriate inert solvent(s) to yield pyrimidine 19.
EXAMPLES
The invention is illustrated further by the following examples, which are not be construed as limiting the invention in scope.
[00196] Example 1 :
4-((5-(ethoxycarbonyl)-2-(thiazol-2-yl)-6-(2-(trifluoromethyl)phenyl)-3,6-dihydropyrimi din-4-yl)methyl)morpholine-3-carboxylic acid
Figure imgf000086_0001
[00197] Step A: Ethyl 6-methyl-2-(thiazol-2-yl)-4-(2-(trifluoromethyl)pheny])-l,4- dihydropyrimidine-5-carboxylate
A mixture of 2-(trifluoromethyl)benzaldehyde (8.7 g, 50 mmol), thiazole-2-carboximidamide hydrochloride (8.2 g, 50 mmol), ethyl 3-oxobutanoate (7.8 g, 60 mmol) and sodium acetate (5.33 g, 65 mmol) in ethanol (90 mL) was refluxed at 80 "C for 12 hours under N2. The resulting mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PETROLEUM ETHER/EtOAc (V/V) = 3/1 ) to give the title compound as a yellow solid ( 12.62 g, 64%). The compound was characterized by the following spectroscopic data: MS-ESI: (ESI, pos.ion) m/z: 396.1 [M+l ] ;
1 H NMR (400 MHz, CDC13): δ 7.79 (d, 1 H), 7.77 (d, 1 H), 7.67-7.30 (m, 4H), 6.19 (s, 1H), 5.13 (br.s, 1 H), 3.99 (q, 2H), 2.6 (s, 3H), 1.01 (t, 3H).
[00198] Step B: Ethyl 6-(bromomethyl)-2-(thiazol-2-yl)-4-(2-(trinuoromethyl) phenyl)-l,4-dihydropyrimidine-5-carboxylate
To a solution of ethyl 6-methyl-2-(thiazo]-2-yl)-4-(2-(trifluoromethyl)phenyl)-l ,4- dihydropyrimidine-5-carboxylate (7.9 g, 20 mmol) in carbon tetrachloride ( 100 mL) was added NBS (3.74 g, 21 mmol) under N2 at 60 °C The reaction mixture was stirred at 60 °C for 10 minutes, and cooled to 25 °C. The resulting mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PETROLEUM ETHER/EtOAc (V/V) = 3/1) to give the title compound as a yellow solid (6.64 g, 70%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 474.1 [M+l ;
Ή NMR (400 MHz, CDC13): δ 7.81 (d, 1 H), 7.72 (d, 1H), 7.68-7.31 (m, 4H), 6.18 (s, 1 H), 5.13 (br.s, 1 H), 4.53 (dd, 2H), 3.99 (q, 2H), 1.01 (t, 3H).
[00199] Step C: 4-((5-(ethoxycarbonyl)-2-(thiazol-2-yl)-6-(2-(trinuoromethyl) phenyl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid
A mixture of ethyl 6-(bromomethyl)-2-(thiazol-2-yl)-4-(2-(trifluoromethyl)phenyl)- l ,4-dihydropyrimidine-5-carboxylate (3.8 g, 8 mmol), morpholine-3-carboxylic acid hydrochloride (2.62 g, 16 mmol) and potassium carbonate (4.2 g, 30 mmol) in ethanol ( 130 mL) was stirred at 25 °C for 12 hours. The resulting mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (V/V) = 30/1) to give the title compound as a yellow solid (2.1 g, 50%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 525.2 [M+l ] ÷ ; Ή NMR (400 MHz, CDC13): δ 7.80 (d, 1H), 7.69 (d, 1 H), 7.50-7.41 (m, 3H), 7.35-7.29 (m, 1H), 6.16 (s, 1H), 4.50-4.35 (m, 1H), 4.25-4.02 (m, 3H), 3.99-3.77 (m, 4H), 3.67-3.59 (m, 1 H), 3.45-3.20 (m, 1H), 3.79-3.69 (m, 1H), 1.01 (t, 3H).
[00200] Example 2:
4-((5-(ethoxycarbonyl)-6-(2-nitrophenyI)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)met hyl)morpholine-3-carboxylic aci
Figure imgf000088_0001
[00201 ] Step A: Ethyl 6-methyl-4-(2-nitrophenyl)-2-(thiazol-2-yl)-l,4-dihydro pyrimidine-5-carboxylate
A mixture of 2-nitrobenzaldehyde (10 g, 66 mmol), thiazole-2-carboximidamide hydrochloride (10.8 g, 66 mmol), ethyl 3-oxobutanoate (8.6 g, 66 mmol) and sodium acetate (5.5 g, 66 mmol) in ethanol (250 mL) was stirred at 88 °C for 16 hours, then cooled to 25 °C. The resulting mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PETROLEUM ETHER/EtOAc (V/V) = 3/1 ) to give the title compound as a light yellow solid (12 g, 48%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 373.1 [M+l ]+;
Ή NMR (400 MHz, CDC13): δ 7.80 (d, 1 H), 7.62 (d, 1H), 7.52-7.48 (m, 2H), 7.45-7.40 (m, 1 H), 7.37-7.32 (m, 1H), 6.06 (s, 1 H), 4.01 -3.85 (m, 2H), 2.51 (s, 3H), 1 .13 (t, 3H).
[00202] Step B: Ethyl 6-(bromomethyl)-4-(2-nitrophenyl)-2-(thiazoI-2-yl)-l,4- dihydropyrimidine-5-carboxylate
To a solution of ethyl 6-methyl-4-(2-nitropheny])-2-(thiazol-2-yl)-l ,4- dihydropyrimidine-5-carboxylate (7.45 g, 20 mmol) in carbon tetrachloride (100 mL) was added NBS (3.74 g, 21 mmol) under N2 at 60 °C. The mixture was stirred at 60 °C for 10 minutes, and cooled to 25 °C. The resulting mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PETROLEUM ETHER/EtOAc (V/V) = 3/1 ) to give the title compound as a yellow solid (6.32 g, 70%). The compound was characterized by the following spectroscopic data:
MS-ES1 : (ESI, pos.ion) m/z: 451 .1 [M+l ]+;
]H NMR (400 MHz, CDC13): δ 7.73 (d, IH), 7.63 (d, I H), 7.52-7.49 (m, 2H), 7.45-7.39 (m, I H), 7.37-7.33 (m, I H), 6.07 (s, I H), 4.66 (dd, 2H), 4.01 -3.85 (m, 2H), 1 .13 (t, 3H).
[00203] Step C: 4-((5-(ethoxycarbonyl)-6-(2-nitrophenyl)-2-(thiazol-2-yl)-3,6- dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid
A mixture of ethyl 6-(bromomethyl)-4-(2-nitrophenyl)-2-(thiazol-2-yl)-l ,4-dihydro pyrimidine-5-carboxylate (2.4 g, 5.3 mmol), morpholine-3-carboxylic acid hydrochloride (0.9 g, 5.37 mmol) and potassium carbonate ( 1.48 g, 10.74 mmol) in ethanol (60 mL) was stirred at 25 °C for 12 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (V/V) = 25/1) to give the title compound as a light yellow solid (1.1 g, 41%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 502.2 [M+l ]+;
'H NMR (400 MHz, DMSO-</6): δ 9.88 (s, IH), 8.01 (d, 1 H), 7.93 (d, I H), 7.82-7.80 (m, I H), 7.65-7.61 (m, I H), 7.50-7.45 (m, 2H), 6.23 (s, IH), 4.11 (br.s, I H), 3.97-3.89 (m, 2H), 3.81 -3.79 (m, 2H), 3.70-3.56 (m, 4H), 3.05-2.99 (m, I H), 2.49-2.31 (m, I H), 1 .04 (t, 3H)..
[00204] Example 3:
4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidi n-4-yl)methyl)morpholine-3-carboxylic acid
Figure imgf000090_0001
A mixture of ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-l ,4- dihydropyrimidine-5-carboxylate (3.02 g, 6 mmol) (The compound was synthesized according to the procedure as described in WO2010069147A), morpholine-3-carboxylic acid hydrochloride (1 g, 6 mmol) and triethylamine ( 1.21 g, 12 mmol) in ethanol (40 mL) was stirred at 25 °C for 12 hours under N2. The mixture was concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (V/V) = 25/1) to give the title compound as a yellow solid ( 1 .5 g, 45%). The compound was characterized by the following spectroscopic data:
MS-ES1: (ESI, pos.ion) m/z: 553.1 [M+l ]+;
Ή NMR (400 MHz, DMSO-flf6): δ 12.69 (br.s, 1 H), 9.84 (s, 1H), 8.04 (d, 1H), 7.95 (d, 1 H), 7.58-7.55 (m, 1H), 7.40-7.36 (m, 1H), 7.24-7.19 (m, 1H), 6.02 (s, 1 H), 4.13 (br.s, 2H>, 3.97-3.94 (m, 2H), 3.92-3.81 (m, 2H), 3.74-3.66 (m, 2H), 3.53-3.51 (m, 1 H), 3.08-3.06 (m, 1H), 2.54-2.52 (m, 1 H), 1 .06 (t, 3H).
[00205] Example 4:
4-((6-(2-chloro-4-fluorophenyI)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidi n-4-yl)methyl)morpholine-3-carboxylic acid
Figure imgf000091_0001
Ethyl 6-(bromomethyl)-4-(2-chloro-4-iluorophenyl)-2-(thiazol-2-yl)-l ,4-dihydro pyrimidine-5-carboxylate (2.92 g, 6.36 mmol) (The compound was synthesized according to the procedure as described in WO2010069147A) was reacted with morpholine-3-carboxylic acid hydrochloride ( 1.07 g, 6.36 mmol) according to the procedure as described in Example 3 to give the title compound as a yellow solid ( 1.2 g, 37%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlr. 509.2 [M+l]+;
Ή NMR (400 MHz, DMSO-i/6): δ 9.84 (s, 1H), 8.04 (d, 1 H), 7.94 (d, 1 H), 7.43-7.38 (m, 2H), 7.19-7.16 (m, 1 H), 6.05 (s, 1 H), 4.12 (br.s, 2H), 3.97-3.95 (m, 2H), 3.93-3.84 (m, 2H), 3.71 -3.61 (m, 2H), 3.53-3.51 (m, 1H), 3.12-3.05 (m, 1 H), 2.55-2.53 (m, 1 H), 1.07 (t, 3H).
[00206] Example 5:
4-((6-(2,4-dichlorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-y l)methyl)morpholine-3-carboxylic acid
Figure imgf000091_0002
Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-l ,4-dihydropyrimidine- 5-carboxylate (3.56 g, 7.5 mmol) (The compound was synthesized according to the procedure as described in WO2010069147A) was reacted with morpholine-3-carboxylic acid hydrochloride (1.26 g, 7.5 mmol) according to the procedure as described in Example 3 to give the title compound as a yellow solid (1.7 g, 43%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 525.1 [M+l ]+;
Ή NMR (400 MHz, DMSO- 6): δ 9.86 (s, 1H), 8.03 (d, 1H), 7.94 (d, 1 H), 7.60-7.59 (m, 1 H), 7.41 -7.38 (m, 2H), 6.05 (s, 1 H), 4.22-4.00 (m, 2H), 3.98-3.95 (m, 2H), 3.94-3.80 (m, 2H), 3.71 -3.61 (m, 2H), 3.60-3.59 (m, 1 H), 3.10-3.02 (m, 1 H), 2.43-2.38 (m, 1 H), 1 .07 (t, 3H).
[00207] Example 6:
4-((6-(2-bromo-4-fluorophenyl)-5-(methoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimi din-4-yl)methyl)morpholine-3-carboxylic acid
Figure imgf000092_0001
Methyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)- 1 ,4-dihydro pyrimidine-5-carboxylate (4.11 g, 8.4 mmol) (The compound was synthesized according to the procedure as described in WO2010069147A) was reacted with morpholine-3-carboxylic acid hydrochloride (1.4 g, 8.4 mmol) according to the procedure as described in Example 3 to give the title compound as a yellow solid (2.1 g, 46%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 539.1 [M+l ]+;
Ή NMR (400 MHz, DMSO-ί/β): δ 9.89 (s, 1 H), 8.03-8.02 (m, 1 H), 7.94 (d, 1 H), 7.57-7.54 (m, 1 H), 7.39-7.35 (m, 1 H), 7.22-7.17 (m, 1H), 6.01 (s, 1 H), 4.19-4.05 (m, 2H), 3.93-3.82 (m, 2H), 3.75 (s, 3H), 3.70-3.60 (m, 3H), 3.09-3.07 (m, 1 H), 2.55-2.35 (m, 1 H). [00208] Example 7:
4-((6-(2-chloro-4-fluorophenyl)-5-(methoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimi din-4-yl)methyl)morpholine-3-carboxylic acid
Figure imgf000093_0001
Methyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)- 1 ,4-dihydro pyrimidine-5-carboxylate (2.94 g, 6.6 mmol) (The compound was synthesized according to the procedure as described in WO2010069147A) was reacted with morpholine-3-carboxylic acid hydrochloride (1 .1 g, 6.6 mmol) according to the procedure as described in Example 3 to give the title compound as a yellow solid (1.5 g, 46%). The compound was characterized by the following spectroscopic data:
MS-ES1: (ESI, pos.ion) mlz: 495.1 [M+l ]+;
Ή NMR (400 MHz, DMSO-i/6): δ 9.89 (s, 1H), 8.03 (d, 1H), 7.92 (d, 1H), 7.43-7.36 (m, 2H), 7.18-7.13 (m, 1H), 6.03 (s, 1H), 4.1 1 -4.05 (m, 2H), 3.89-3.81 (m, 2H), 3.71 -3.65 (m, 2H), 3.52 (s, 3H), 3.07-3.06 (m, 1H), 2.61 -2.35 (m, 2H).
[00209] Example 8:
4-((6-(2,4-dichlorophenyl)-5-(methoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4 -yl)methyl)morpholine-3-carboxylic acid
Figure imgf000094_0001
Methyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-l ,4-dihydro pyrimidine-5-carboxylate (3.02 g, 6.54 mmol) (The compound was synthesized according to the procedure as described in WO2010069147A) was reacted with morpholine-3-carboxylic acid hydrochloride ( 1 .1 g, 6.54 mmol) according to the procedure as described in Example 3 to give the title compound as a yellow solid ( 1.5 g, 45%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 51 1 .1 [M+l ]+;
Ή NMR (400 MHz, DMSO- 6): δ 9.80 (br.s, 1 H), 7.85 (br.s, 1 H), 7.47 (br.s, 1H), 7.40-7.39 (m, 1H), 7.23-7.21 (m, 1H), 7.19-7.16 (m, 1 H), 6.17 (s, 1 H), 4.42-4.31 (m, 1 H), 4.19-3.95 (m, 3H), 3.86-3.79 (m, 2H), 3.59 (s, 3H), 3.57-3.56 (m, 1 H), 3.25-3.1 1 (m, 1 H), 2.65-2.59 (m, 1H).
[00210] Example 9:
4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidi n-4-yl)methyl)morpholine-2-carboxylic acid
Figure imgf000094_0002
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)- 1 ,4-dihydro pyrimidine-5-carboxylate (0.6 g, 1.2 mmol) was reacted with morpholine-2-carboxylic acid hydrochloride (0.3 g, 1.8 mmol) according to the procedure as described in Example 3 to give the title compound as a yellow solid (0.2 g, 30%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 553.1 [M+l ]+;
Ή NMR (400 MHz, DMSO-c 6): δ 9.56 (s, 1 H), 8.00-7.98 (m, 1 H), 7.92 (d, 1 H), 7.56-7.53 (m, 1H), 7.42-7.35 (m, 1H), 7.25-7.17 (m, 1 H), 6.02 (s, 1 H), 4.17-4.15 (m, 1 H), 4.04-3.87 (m, 4H), 3.64-3.56 (m, 2H), 3.06-2.85 (m, 2H), 2.69-2.39 (m, 2H), 1 .06-1.02 (m, 3H).
[0021 1 ] Example 10:
4-((6-(2-chloro-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidi n-4-yl)methyl)morpholine-2-carboxyIic acid
Figure imgf000095_0001
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)- 1 ,4-dihydro pyrimidine-5-carboxylate (0.69 g, 1.5 mmol) was reacted with morpholine-2-carboxylic acid hydrochloride (0.3 g, 1.8 mmol) according to the procedure as described in Example 3 to give the title compound as a yellow solid (0.32 g, 42%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 509.1 [M+l ]+;
Ή NMR (400 MHz, DMSO-i 6): δ 9.57 (s, 1 H), 8.01 -8.00 (m, 1 H), 7.94 (d, 1H), 7.44-7.41 (m, 2H), 7.19-7.15 (m, I H), 6.06 (s, IH), 4.17-4.16 (m, IH), 4.15-3.93 (m, 4H), 3.65-3.57 (m, 2H), 3.06-2.86 (m, 2H), 2.69-2.45 (m, 2H), 1.07-1.03 (m, 3H).
[00212] Example 11 :
4-((6-(2,4-dichlorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-y l)methyl)morpholine-2-carboxylic acid
Figure imgf000096_0001
Ethyl 6-(bromomethyl)-4-(2,4-dichloropheny])-2-(thiazol-2-yl)-l ,4-dihydropyrimidine- 5-carboxylate ( 1 .43 g, 3 mmol) was reacted with morpholine-2-carboxylic acid hydrochloride (0.5 g, 3 mmol) according to the procedure as described in Example 3 to give the title compound as a yellow solid (0.49 g, 31 %). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 525.1 [M+l ]+;
Ή NMR (400 MHz, DMSO-</6): δ 9.56 (s, IH), 7.99-7.97 (m, I H), 7.92 (d, IH), 7.59-7.58 (m, I H), 7.36-7.35 (m, 2H), 6.02 (s, IH), 4.14-4.11 (m, IH), 3.96-3.88 (m, 4H), 3.63-3.51 (m, 2H), 3.05-2.85 (m, 2H), 2.67-2.35 (m, 2H), 1.05 (t, 3H).
[00213] Example 12:
4-((6-(2-bromo-4-fluorophenyI)-5-(methoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimi din-4-yI)methyl)morpholine-2-carboxylic acid
Figure imgf000097_0001
Methyl 4-(2-bromo-4-iluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)- 1 ,4-dihydro pyrimidine-5-carboxylate (1.22 g, 2.5 mmol) was reacted with morpholine-2-carboxylic acid hydrochloride (0.5 g, 3 mmol) according to the procedure as described in Example 3 to give the title compound as a yellow solid (0.54 g, 40%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 539.1 [M+l ]+;
Ή NMR (400 MHz, DMSO-i/6): δ 9.60 (s, 1 H), 8.01 -7.99 (m, 1 H), 7.94 (d, 1 H), 7.58-7.55 (m, 1 H), 7.40-7.37 (m, 1 H), 7.23-7.1 8 (m, 1H), 6.02 (s, 1 H), 4.20-4.15 (m, 1 H), 4.01 -3.88 (m, 4H), 3.65-3.61 (m, 2H), 3.52 (s, 3H), 2.70-2.39 (m, 2H).
[00214] Example 13:
4-((6-(2-chloro-4-fluorophenyl)-5-(methoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimi din-4-yl)methyl)morpholine-2-carboxylic acid
Figure imgf000097_0002
Methyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)- 1 ,4-dihydro pyrimidine-5-carboxylate (1.11 g, 2.5 mmol) was reacted with morpholine-2-carboxylic acid hydrochloride (0.5 g, 3 mmol) according to the procedure as described in Example 3 to give the title compound as a yellow solid (0.5 g, 40%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 495.1 [M+l]+;
Ή NMR (400 MHz, DMSO-c/6): δ 9.64 (s, 1 H), 8.02-8.01 (m, 1 H), 7.94 (d, 1 H), 7.45-7.39 (m, 2H), 7.20-7.17 (m, 1H), 6.05 (s, 1 H), 4.17-4.16 (m, 1 H), 4.03-3.88 (m, 4H), 3.55 (s, 3H), 3.08-2.86 (m, 2H), 2.72-2.40 (m, 2H).
[00215] Example 14:
4-((6-(2,4-dichlorophenyl)-5-(methoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4 -yl)methyl)morpholine-2-carboxylic acid
Figure imgf000098_0001
Methyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)- 1 ,4-dihydropyrimid ine-5-carboxylate (1.15 g, 2.5 mmol) was reacted with morpholine-2-carboxylic acid hydrochloride (0.5 g, 3 mmol) according to the procedure as described in Example 3 to give the title compound as a yellow solid (0.47 g, 37%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 511.1 [M+l ] ;
Ή NMR (400 MHz, DMSO-i 6): δ 9.60 (br.s, 1 H), 7.85-7.83 (m, 1 H), 7.45-7.43 (m, 1 H), 7.40-7.39 (m, 1 H), 7.25-7.24 (m, 1 H), 7.20-7.16 (m, 1 H), 6.19 (s, 1H), 4.43-4.38 (m, 1H), 4.22-3.95 (m, 2H), 3.93-3.85 (m, 2H), 3.59 (s, 3H), 3.18-3.05 (m, 2H), 2.81 -2.61 (m, 2H). [00216] Example 15:
2-(4-((6-(2,4-dichlorophenyl)-5-(ethoxycarbonyl)-2-(thiazoI-2-yl)-3,6-dihydropyrimidin- 4-yl)methyl)morpholin-3-yl)acetic acid
Figure imgf000099_0001
Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-l ,4-dihydropyrimidine- 5-carboxylate (0.29 g, 0.61 mmol) was reacted with 2-(morpholin-3-yl)acetic acid hydrochloride (0.1 1 g, 0.61 mmol) according to the procedure as described in Example 1 , Step C to give the title compound as a light yellow solid (0.2 g, 60%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 539.1 [M+l f;
Ή NMR (400 MHz, DMSO-i/6): δ 12.12 (br.s, IH), 9.71 (br.s, IH), 8.03 (d, I H), 7.94 (d, IH), 7.59 (br.s, I H), 7.41-7.34 (m, 2H), 6.04 (s, IH), 4.20-3.90 (m, 4H), 3.75-3.45 (m, 4H), 3.10-2.65 (m, 3H), 2.45 (br.s, 2H), 1.05 (t, 3H).
[00217] Example 16:
2-(4-((6-(2-chloro-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrim idin-4-yI)methyl)morpholin-3-yl)acetic acid
Figure imgf000100_0001
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-] ,4-dihydro pyrimidine-5-carboxylate (0.18 g, 0.39 mmol) was reacted with 2-(morpholiri-3-yl)acetic acid hydrochloride (0.07 g, 0.39 mmol) according to the procedure as described in Example 1 , Step C to give the title compound as a light yellow solid (0.14 g, 67%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 523.2 [M+] ]+;
JH NMR (400 MHz, DMSO-c/6): δ 12.10 (br.s, I H), 9.71 (br.s, I H), 8.03 (d, I H), 7.94 (d, I H), 7.43-7.40 (m, 2H), 7.16-7.12 (m, I H), 6.04 (s, I H), 4.15-3.89 (m, 4H), 3.74-3.50 (m, 4H), 3.08-2.65 (m, 3H), 2.40 (br.s, 2H), 1 .05 (t, 3H).
[00218] Example 17:
2-(4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrim idin-4-yI)rnethy])morpholin-3-yl)acetic acid
Figure imgf000100_0002
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-l ,4-dihydro pyrimidine-5-carboxylate (0.7 g, 1 .4 mmol) was reacted with 2-(morpholin-3-yl)acetic acid hydrochloride (0.25 g, 1.4 mmol) according to the procedure as described in Example 1 , Step C to give the title compound as a pale yellow solid (0.57 g, 72%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlr. 567.1 [M+l ]+;
1H NMR (400 MHz, OMSO-d6): δ 12.13 (br.s, 1H), 9.74 (br.s, 1H), 8.03 (d, 1H), 7.94 (d, 1H), 7.58-7.55 (m, 1 H), 7.40-7.36 (m, 1 H), 7.24-7.19 (m, 1 H), 6.01 (s, 1H), 4.18-3.91 (m, 4H), 3.76-3.52 (m, 4H), 3.09-2.66 (m, 3H), 2.41 (br.s, 2H), 1 .07 (t, 3H).
[00219] Example 18:
3-(4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrim idin-4-yl)methyl)morpholin-3-yl)propanoic acid
Figure imgf000101_0001
[00220] Step A: 3-(4-( rt-butoxycarbonyl)morpholin-3-yl)propanoic acid
A mixture of formic acid (2.26 mL, 58.9 mmol) and triethylamine (3.36 mL, 24.11 mmol) was stirred for 5 minutes in an ice bath. To the mixture were added te/ -butyl 3-formylmorpholine-4-carboxylate (0.47 g, 2.2 mmol) and Meldrum's acid (0.32 g, 2.2 mmol) in turn at 0 °C . The reaction mixture was heated at 100 °C for 5 hours, and cooled down in an ice bath. To the resulting mixture was added aqueous NaOH soluiton (2 mol/L, 40 mL). The aqueous layer was extracted with EtOAc (50 mL x 3) and the organic layer was discarded. To the aqueous layer was added EtOAc (80 mL), and the mixture was adjusted to pH 4-5 with HC1 (1 mol/L) under stirring. The aqueous layer was extracted with EtOAc (80 mL). The organic layer was dried over anhydrous Na2S04, then filtered and the filtrate was concentrated in vacuo to give the title compound as a white solid (0.23 g, 40%). The compound was characterized by the following spectroscopic data: MS-ESI: (ESI, pos.ion) mlz: 204.1 [M+l -56]4;
Ή NMR (400 MHz, CDC13): δ 4.13-4.10 (m, 1H), 3.84-3.81 (m, 2H), 3.80-3.74 (m, 1H), 3.71 -3.41 (m, 2H), 3.12-3.10 (m, 1H), 2.38-2.35 (m, 2H), 2.25-2.21 (m, 1H), 1 .90-1.85 (m, 1H), 1 .46 (s, 9H).
[00221 ] Step B: 3-(morphoIin-3-yl)propanoic acid hydrochloride
To a solution of 3-(4-(ter/-butoxycarbonyl)morpholin-3-yl)propanoic acid (0.3 g, 1.2 mmol) in EtOAc (2 mL) was added the solution of HC1 in EtOAc (6 mol/L, 6 mL). The mixture was stirred closedly at 25 °C for 2 hours and filtered. The residue was washed with EtOAc (4 mL) to give the title compound as a white solid (0.21 g, 90%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 160.3 [M+l ]+;
Ή NMR (400 MHz, CDC13): δ 4.06-3.91 (m, 2H), 3.76-3.70 (m, 1H), 3.54-3.51 (m, 1H), 3.48-3.36 (m, 2H), 3.30-3.18 (m, 1H), 2.53-2.48 (m, 2H), 1 .90-1.80 (m, 2H).
[00222] Step C: 3-(4-((6-(2-bromo-4-fluoropheny])-5-(ethoxycarbony])-2-(thiazol-2- yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholin-3-y])propanoic acid
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-l ,4-dihydro pyrimidine-5-carboxylate (1 g, 2 mmol) was reacted with 3-(morpholin-3-yl)propanoic acid hydrochloride (0.39 g, 2 mmol) according to the procedure as described in Example 1 , Step C to give the title compound as a yellow solid (0.55 g, 47%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 581.1 [M+l ]+;
Ή NMR (400 MHz, CDC13): δ 9.68 (s, 1 H), 7.85 (s, 1 H), 7.45 (s, 1 H), 7.32-7.29 (m, 2H), 6.99-6.96 (m, 1H), 6.18 (s, 1H), 4.26-4.07 (m, 1 H), 4.04-4.00 (m, 3H), 3.92-3.88 (m, 1H), 3.85-3.81 (m, 1 H), 3.73-3.68 (m, 1 H), 3.58-3.53 (m, 1H), 2.89-2.86 (m, 1 H), 2.64 (br.s, 1H), 2.52-2.46 (m, 2H), 2.38-2.34 (m, 1H), 1.92-1.89 (m, 1H), 1.28-1.24 (m, 2H), 1.13 (t, 3H).
[00223] Example 19:
3-(4-((6-(2-chloro-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yI)-3,6-dihydropyrim idin-4-y])methy])morpholin-3-yl)propanoic acid
Figure imgf000103_0001
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-l ,4-dihydro pyrimidine-5-carboxylate (0.92 g, 2 mmol) was reacted with 3-(morpholin-3-yl)propanoic acid hydrochloride (0.39 g, 2 mmol) according to the procedure as described in Example 1 , Step C to give the title compound as a yellow solid (0.45 g, 42%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 537.2 [M+l ]+;
Ή NMR (400 MHz, CDC13): δ 12.88 (br.s, 1H), 9.71 (s, 1 H), 7.95 (br.s, 1H), 7.55 (br.s, 1H), 7.39-7.29 (m, 2H), 7.12-7.01 (m, 1 H), 6.12 (s, 1H), 4.26-4.1 1 (m, 1 H), 4.09-4.01 (m, 3H), 3.95-3.87 (m, 1H), 3.84-3.80 (m, 1 H), 3.75-3.69 (m, 1 H), 3.59-3.52 (m, 1H), 2.89-2.83 (m, 1 H), 2.63 (br.s, 1 H), 2.53-2.46 (m, 2H), 2.38-2.32 (m, 1 H), 1.92-1.88 (m, 1H), 1.28-1.23 (m, 2H), 1.13 (t, 3H).
[00224] Example 20:
3- (4-((6-(2,4-dichlorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-
4- yl)methyl)morpholiii-3-yl)propanoic acid
Figure imgf000104_0001
Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-l,4-dihydropyrimidine- 5-carboxylate (0.95 g, 2 mmol) was reacted with 3-(morpholin-3-yl)propanoic acid hydrochloride (0.39 g, 2 mmol) according to the procedure as described in Example 1 , Step C to give the title compound as a yellow solid (0.61 g, 55%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 553.2 [M+l]+;
Ή NMR (400 MHz, CDC13): δ 12.75 (br.s, IH), 9.64 (s, IH), 7.93 (d, IH), 7.55 (d, IH), 7.41-7.28 (m, 2H), 7.09-7.01 (m, IH), 6.13 (s, IH), 4.20-4.07 (m, IH), 4.05-3.94 (m, 3H), 3.92-3.86 (m, IH), 3.84-3.80 (m, IH), 3.75-3.67 (m, IH), 3.58-3.52 (m, IH), 2.89-2.83 (m, IH), 2.63 (br.s, IH), 2.52-2.45 (m, 2H), 2.38-2.33 (m, IH), 1.92-1.86 (m, IH), 1.28-1.23 (m, 2H), 1.13 (t, 3H).
[00225] Example 21:
(3 -4-((6-(2,4-dichlorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidi n-4-yl)methyl)-6,6-dimethylmorpholine-3-carboxylic acid
Figure imgf000104_0002
[00226] Step A: (5)-6,6-dimethyImorpholine-3-carboxylic acid hydrochloride
To a solution of (S)-methyl 6,6-dimethylmorpholine-3-carboxylate (0.2 g, 1.2 mmol) (The compound was synthesized according to the procedure as described in WO2008024692) in anhydrous methanol (4 mL) was added a solution of sodium hydroxide (0.1 g, 2.4 mmol) in water (1 mL). The reaction mixture was stirred at 25 °C for 2 hours, and cooled to 0 °C. The reaction mixture was adjusted to pH 1 -2 with cow.HCl. The mixture was concentrated in vacuo to give the title compound as a white solid (0.19 g, 100%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 1 60.3 [M+l ]+;
Ή NMR (400 MHz, DMSO-c/6): δ 3.76-3.72 (m, 1H), 3.68-3.62 (m, 1 H), 3.41 -3.36 (m, 1 H), 2.66 (d, 1 H), 2.45 (d, 1 H), 1.1 1 (s, 3H), 1.08 (s, 3H).
[00227] Step B: (3S)-4-((6-(2,4-dichlorophenyI)-5-(ethoxycarbonyl)-2-(thiazoI-2-yl) -3,6-dihydropyrimidin-4-yl)methyl)-6,6-dimethylmorpholine-3-carboxyIic acid
Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-2-y])-l ,4-dihydropyrimidine- 5-carboxylate (0.24 g, 0.51 mmol) was reacted with (5)-6,6-dimethyl morpholine-3-carboxylic acid hydrochloride (0.1 g, 0.51 mmol) according to the procedure as described in Example 1 , Step C to give the title compound as a yellow solid (0.19 g, 68%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 553.1 [M+l ]+;
Ή NMR (400 MHz, CDC13): δ 7.81 (br.s, 1H), 7.44 (br.s, 1H), 7.40-7.38 (m, 1H), 7.30-7.26 (m, 1H), 7.18-7.16 (m, 1 H), 6.19 (s, 1H), 4.38-4.21 (m, 2H), 4.12-3.85 (m, 4H), 3.45-3.43 (m, 1H), 2.90-2.79 (m, 1H), 2.37-2.32 (m, 1 H), 1.25 (s, 3H), 1.24 (s, 3H), 1.11 (t, 3H).
[00228] Example 22:
(35)-4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazoI-2-yl)-3,6-dihydropyri midin-4-yI)methyl)-6,6-dimethylmorpholine-3-carboxylic acid
Figure imgf000106_0001
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)- 1 ,4-dihydro pyrimidine-5-carboxylate (0.26 g, 0.51 mmol) was reacted with (5)-6,6-dimethylmorpholine- 3-carboxylic acid hydrochloride (0.1 g, 0.51 mmol) according to the procedure as described in Example 1 , Step C to give the title compound as a yellow solid (0.18 g, 63%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 581.1 [M+l ]+;
Ή NMR (400 MHz, CDC13): δ 9.72 (s, 1 H), 7.82 (d, 1 H), 7.45 (d, 1 H), 7.34-7.30 (m, 2H), 7.01 -6.93 (m, 1H), 6.16 (s, 1 H), 4.39-4.21 (m, 2H), 4.13-3.85 (m, 4H), 3.46-3.43 (m, 1 H), 2.91 -2.79 (m, 1H), 2.38-2.32 (m, 1 H), 1.26 (s, 3H), 1.23 (s, 3H), 1.10 (t, 3H).
[00229] Example 23:
(35)-4-((6-(2-chloro-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyri midin-4-yl)methyl)-6,6-dimethylmorpholine-3-carboxylic acid
Figure imgf000106_0002
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-l ,4-dihydro pyrimidine-5-carboxylate (0.26 g, 0.51 mmol) was reacted with (S)-6,6-dimethylmoφholine- 3-carboxylic acid hydrochloride (0.1 g, 0.51 mmol) according to the procedure described in Example 1 , Step C to give the title compound as a yellow solid (0.16 g, 59%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 537.2 [M+l ]+;
Ή NMR (400 MHz, CDC13): δ 12.65 (br.s, IH), 9.69 (s, I H), 7.93 (br.s, I H), 7.58 (br.s, I H), 7.38-7.28 (m, 2H), 7.15-7.01 (m, I H), 6.15 (s, I H), 4.37-4.20 (m, 2H), 4.14-3.84 (m, 4H), 3.45-3.42 (m, IH), 2.92-2.80 (m, IH), 2.39-2.33 (m, IH), 1.27 (s, 3H), 1.22 (s, 3H), 1.11 (t, 3H).
[00230] Example 24:
Methyl (35)-4-((6-(2,4-dichlorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydro pyrimidin-4-yl)methyl)-6,6-dimethylmorpholine-3-carboxylate
Figure imgf000107_0001
A mixture of ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-l ,4- dihydropyrimidine-5-carboxylate (0.72 g, 1.52 mmol), (5)-methyl 6,6-dimethyl morpholine-3-carboxylate (0.26 g, 1.52 mmol) and potassium carbonate (0.42 g, 3.04 mmol) in acetonitrile (40 mL) was stirred at 25 °C for 3 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PETROLEUM ETHER/EtOAc (V/V) = 3/1 ) to give the title compound as yellow oil (0.55 g, 64%). The compound was characterized by the following spectroscopic data: MS-ES1: (ESI, pos.ion) mlz: 567.2 [M+l ]+;
Ή NMR (400 MHz, DMSO-i/6): δ 9.44 (br.s, I H), 8.02 (d, IH), 7.99 (d, IH), 7.62-7.60 (m, IH), 7.50-7.48 (m, IH), 7.38-7.36 (m, I H), 6.05 (s, I H), 4.38-4.20 (m, 2H), 4.13-3.85 (m, 4H), 3.70 (s, 3H), 3.46-3.43 (m, IH), 2.91-2.79 (m, I H), 2.37-2.31 (m, IH), 1 .26 (s, 3H), 1.23 (s, 3H), 1.09 (t, 3H).
[00231 ] Example 25:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-((3-carbamoylmorpholino)methyl)-2-(thiazol-2-yl)- l,4-dihydropyrimidine-5-carboxylate
Figure imgf000108_0001
[00232] Step A: Morpholine-3-carboxamide
A mixture of methyl morpholine-3-carboxylate hydrochloride (0.55 g, 3.0 mmol) and a solution of NH in methanol (7 mol/L, 20 mL) was stirred at 50 °C for 24 hours in a sealed tube. The mixture was concentrated in vacuo to give the title compound as glutinous semisolid (0.39 g, 99%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 131.1 [M+l ]+;
]H NMR (400 MHz, D20): δ 4.16-4.13 (m, I H), 3.94-3.91 (m, IH), 3.83-3.80 (m, I H), 3.78-3.68 (m, 2H), 3.35-3.31 (m, IH), 3.20-3.15 (m, IH).
[00233] Step B: Ethyl 4-(2-bromo-4-fluorophenyl)-6-((3-carbamoylmorpholino) methyl)-2-(thiazol-2-yl)-l,4-dihydropyrimidine-5-carboxylate
A mixture of ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl) -l ,4-dihydropyrimidine-5-carboxylate (3.02 g, 6 mmol), morpholine-3-carboxamide (0.78 g, 6 mmol) and potassium carbonate (1.66 g, 12 mmol) in anhydrous ethanol (70 mL) was stirred at 25 °C for 12 hours under N2. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (V/V) = 100/1) to give the title compound as a yellow solid (1.66 g, 50%). The compound was characterized by the following spectroscopic data:
MS-ES1: (ESI, pos.ion) mlz: 552.1 [M+l ]+;
Ή NMR (400 MHz, DMSO-i/6): δ 10.05 (s, 1H), 8.01 (d, 1H), 7.92 (d, 1H), 7.57-7.53 (m, 1H), 7.38-7.35 (m, 1H), 7.24-7.21 (m, 1H), 6.01 (s, 1H), 4.13-4.00 (m, 1H), 3.95-3.93 (m, 2H), 3.87-3.67 (m, 3H), 3.63-3.53 (m, 2H), 3.01-2.87 (m, 1H), 2.79-2.69 (m, 1H), 2.60-2.56 (m, 1H), 1.06 (t, 3H).
[00234] Example 26:
Ethyl 6-((3-carbamoylmorpholino)methyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)- l,4-dihydropyrimidine-5-carboxylate
Figure imgf000109_0001
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)- 1 ,4-dihydro pyrimidine-5-carboxylate (2.75 g, 6 mmol) was reacted with morpholine-3-carboxamide (0.78 g, 6 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a yellow solid (1.37 g, 45%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 508.1 [M+l]+; lH NMR (400 MHz, DMSO-t¾): δ 10.04 (s, IH), 8.02 (d, I H), 7.91 (d, IH), 7.43-7.40 (m, IH), 7.39-7.36 (m, IH), 7.24-7.17 (m, IH), 6.04 (s, I H), 4.13-4.05 (m, IH), 3.96-3.93 (m, 2H), 3.89-3.86 (m, IH), 3.67-3.41 (m, 4H), 3.00-2.86 (m, IH), 2.79-2.67 (m, IH), 2.58-2.54 (m, IH), 1.03 (t, 3H).
[00235] Example 27:
Ethyl 6-((3-carbamoylmorpholino)methyl)-4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-l,4- dihydropyrimidine-5-carboxylate
Figure imgf000110_0001
Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)- 1 ,4-dihydropyrimidine- 5-carboxylate (2.85 g, 6 mmol) was reacted with rnorpholine-3-carboxamide (0.78 g, 6 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a yellow solid (1.54 g, 49%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz 524.0 [M+l]+;
!H NMR (400 MHz, DMSO-c/6): δ 10.06 (s, IH), 8.02 (d, IH), 7.91 (d, IH), 7.68-7.62 (m, IH), 7.58-7.38 (m, IH), 7.24-7.20 (m, IH), 6.03 (s, IH), 4.12-4.05 (m, IH), 3.95-3.85 (m, 3H), 3.75-3.66 (m, IH), 3.62-3.57 (m, I H), 3.55-3.35 (m, 2H), 3.00-2.87 (m, IH), 2.79-2.65 (m, IH), 2.57-2.54 (m, IH), 1.03 (t, 3H).
[00236] Example 28:
(3S)-4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyri midin-4-yl)methyl)morpholine-3-carboxylic acid
Figure imgf000111_0001
A mixture of ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazo]-2-yl)-l ,4- dihydropyrimidine-5-carboxylate (7.7 g, 15.3 mmol), (-S)-morpholine-3-carboxylic acid (2 g, 15.3 mmol) and potassium carbonate (4.23 g, 30.6 mmol) in anhydrous ethanol (154 mL) was stirred at 25 °C for 16 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM MeOH (V/V) = 25/1) to give the title compound as a yellow solid (7.26 g, 86%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 553.2 [M+l ]+;
Ή NMR (400 MHz, DMSO-d6): δ 12.90 (s, IH), 9.84 (s, IH), 8.04 (d, I H), 7.95 (d, IH), 7.57-7.55 (m, I H), 7.43-7.37 (m, IH), 7.23-7.19 (m, I H), 6.03 (s, IH), 4.30-3.92 (m, 5H), 3.84-3.82 (m, IH), 3.74-3.52 (m, 3H), 3.1 1-3.07 (m, I H), 2.55-2.39 (m, I H), 1 .06 (t, 3H).
[00237] Example 29:
(3S)-4-((6-(2,4-dichlorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidi n-4-y])methyl)morpholine-3-carboxyIic acid
Figure imgf000111_0002
Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-l ,4-dihydropyrimidine- 5-carboxylate (1.6 g, 3.37 mmol) was reacted with (,!>)-morprioline-3-carboxylic acid (0.44 g, 3.37 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid (1.42 g, 80%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z 525.1 [M+l]+;
Ή NMR (600 MHz, DMSO-4,): δ 12.90 (br.s, 1H), 9.84 (s, 1 H), 8.04 (d, 1 H), 7.95 (d, 1 H), 7.60 (br.s, 1 H), 7.41 -7.37 (m, 2H), 6.06 (s, 1 H), 4.28-4.02 (m, 2H), 4.01 -3.92 (m, 3H), 3.84-3.82 (m, 1 H), 3.73-3.71 (m, 1 H), 3.67-3.64 (m, 1 H), 3.62-3.52 (m, 1 H), 3.10-3.07 (m, 1 H), 2.54-2.40 (m, 1 H), 1 .06 (t, 3H).
[00238] Example 30:
(3S)-4-((6-(2-chloro-4-fluorophenyl)-5-(ethoxycarbonyI)-2-(thiazol-2-yI)-3,6-dihydropyri midin-4-yl)methyl)morpholine-3-carboxylic acid
Figure imgf000112_0001
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)- 1 ,4-dihydro pyrimidine-5-carboxylate (1.55 g, 3.37 mmol) was reacted with (5)-morpholine-3-carboxylic acid (0.44 g, 3.37 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid ( 1.48 g, 86%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 509.1 [M+l ]+;
Ή NMR (600 MHz, OMSO-d6): δ 12.91 (br.s, 1 H), 9.85 (s, 1 H), 8.03 (br.s, 1 H), 7.94 (br.s, 1 H), 7.44-7.39 (m, 2H), 7.1 8-7.1 5 (m, 1 H), 6.05 (s, 1 H), 4.27-4.05 (m, 2H), 4.00-3.92 (m, 3H), 3.84-3.83 (m, IH), 3.75-3.71 (m, I H), 3.66-3.64 (m, IH), 3.61 -3.52 fm, IH), 3.09-3.07 (m, IH), 2.54-2.39 (m, IH), 1.06 (t, 3H).
[00239] Example 31 :
(3S)-4-((6-(2,4-dichlorophenyl)-5-(methoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimi din-4-yl)methyl)morpholine-3-carboxylic acid
Figure imgf000113_0001
Methyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)- 1 ,4-dihydro pyrimidine-5-carboxylate (1 .55 g, 3.37 mmol) was reacted with (S)-morpholine-3-carboxylic acid (0.44 g, 3.37 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid ( 1 .41 g, 82%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 511.1 [M+l ]+;
Ή NMR (600 MHz, DMSO-cfe): δ 12.89 (br.s, IH), 10.05 (br.s, I H), 8.02 (br.s, IH), 7.94 (br.s, IH), 7.60-7.58 (m, IH), 7.43-7.36 (m, 2H), 6.03 (s, IH), 4.19-4.02 (m, 2H), 3.91-3.86 (m, 2H), 3.68 (br.s, 2H), 3.51 (s, 3H), 3.43 (br.s, IH), 3.08-3.02 (m, IH), 2.52-2.44 (m, I H).
[00240] Example 32:
(35)-4-((6-(2-chIoro-4-fluorophenyl)-5-(methoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropy rimidin-4-yl)methyl)morpholine-3-carboxylic acid
Figure imgf000114_0001
Methyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-l ,4-dihydro pyrimidine-5-carboxylate (1.5 g, 3.37 mmol) was reacted with (S)-morpholine-3-carboxylic acid (0.44 g, 3.37 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid ( 1.33 g, 80%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlr. 495.1 [M+] ;
]H NMR (600 MHz, DMSO-c/6): δ 12.90 (br.s, 1H), 9.89 (br.s, 1H), 8.03 (br.s, 1H), 7.94 (br.s, 1H), 7.43-7.37 (m, 2H), 7.18-7.15 (m, 1H), 6.04 (s, 1 H), 4.25-4.01 (m, 2H), 3.99-3.90 (m, 1H), 3.85-3.83 (m, 1H), 3.71-3.61 (m, 2H), 3.51 (s, 3H), 3.44-3.41 (m, 1 H), 3.09-3.07 (m, 1H), 2.51 -2.44 (m, 1 H).
[00241 ] Example 33:
(3S)-4-((6-(2-bromo-4-fluorophenyl)-5-(methoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydrop yrimidin-4-yl)methyl)morpholine-3-carboxyIic acid
Figure imgf000114_0002
Methyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-l ,4-dihydro pyrimidine-5-carboxylate (1.65 g, 3.37 mmol) was reacted with (S)-morpholine-3-carboxylic acid (0.44 g, 3.37 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid ( 1.51 g, 83%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 539.0 [M+l ]+;
Ή NMR (600 MHz, DMSO-</6): δ 12.88 (br.s, 1H), 10.07 (br.s, 1 H), 8.02 (br.s, 1H), 7.93 (br.s, 1 H), 7.56-7.54 (m, 1H), 7.40-7.37 (m, 1 H), 7.22-7.19 (m, 1H), 6.01 (s, 1 H), 4.19-4.03 (m, 2H), 3.88-3.82 (m, 2H), 3.68-3.66 (m, 2H), 3.51 (s, 3H), 3.44-3.40 (m, 1 H), 3.07-2.99 (m, 1 H), 2.42-2.40 (m, 1 H).
[00242] Example 34:
(2/f,3S)-4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydro pyrimidin-4-yl)methyl)-2-methylmorpholine-3-carboxylic acid
Figure imgf000115_0001
[00243] Step A: (2/?,3S)-benzyl 4-benzyl-2-methyI-5-oxomorpholine-3-carboxylate
A mixture of (2/?,3.S)-4-benzyl-2-methyl-5-oxomorpholine-3-carboxylic acid ( 1.07 g, 4.25 mmol) ( The compound was synthesized according to the procedure as described in Helvetica Chimica Acta, 87, 2004), (bromomethyl)benzene (0.87 g, 5.1 mmol) and potassium carbonate ( 1.16 g, 8.5 mmol) in acetonitrile (20 mL) was stirred at 65 °C for 6 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PETROLEUM ETHER/EtOAc (V V) = 4/1) to give the title compound as colorless oil ( 1 .23 g, 85%). The compound was characterized by the following spectroscopic data:
• MS-ESI: (ESI, pos.ion) mlz: 340.3 [M+l ]+; ]H NMR (600 MHz, CDCL,): δ 7.42-7.18 (m, 10H), 5.52 (d, 1H), 5.22 (q, 2H), 4.33 (q, 2H), 4.23-4.21 (m, 1 H), 3.76-3.74 (m, 2H), 1.23 (d, 3H).
[00244] Step B: (2R,35 -benzyl 4-benzyl-2-methylmorphoIine-3-carboxyIate
To a solution of (2i?,35)-benzyl 4-benzyl-2-methyl-5-oxomorpholine-3-carboxylate (15.7 g, 46.1 mmol) in THF (60 mL) was added a solution of borane in THF (1 mol/L, 69.2 mL) dropwise over a period of 1 hour at -10 °C under N2. After the end of addition, the mixture was warmed to 25 °C and stirred for 16 hours, then cooled to -10 °C. And to the mixture was added methanol slowly until gas evolution was ceased, then added water (10 mL). The mixture was concentrated in vacuo and the residue was dissolved in EtOAc ( 150 mL). The organic layer was washed with aqueous NaOH solution (2 mol/L, 50 mL x 2) and birne (50 mL x 2). The organic phase was concentrated in vacuo to give the title compound as colorless oil ( 13 g, 86.7%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 326.3 [M+l ;
Ή NMR (600 MHz, CDC13): δ 7.33-7.27 (m, 10H), 5.22 (s, 2H), 3.80-3.70 (m, 4H), 3.27 (d, 1H), 2.90 (d, 1H), 2.71 (d, 1H), 2.22-2.18 (m, 1H), 1.15 (d, 3H).
[00245] Step C: (2R,3S)-2-methylmorpholine-3-carboxylic acid
A mixture of (27?,3iS -benzyl 4-benzyl-2-methylmo holine-3-carboxylate (10 g, 30.76 mmol) and Pd C ( 10%, 1 g) in anhydrous methanol (100 mL) was stirred at 25 °C for 12 hours under H2. The mixture was filtered and the filtrate was concentrated in vacuo to give the title compound as a white solid (3.8 g, 85%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI. pos.ion) m/z: 146.2 [M+l ]+;
Ή NMR (600 MHz, D20): δ 4.01 -3.98 (m, 1H), 3.82-3.77 (m, 1 H), 3.76-3.72 (m, 1 H), 3.37 (d, 1H), 3.27-3.24 (m, 1 H), 3.19-3.14 (m, 1 H), 1 .26 (d, 3H). [00246] Step D: (2/?,35)-4-f(6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2- (thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)-2-methylmorpholine-3-carboxylic acid
A mixture of ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-l ,4- dihydropyrimidine-5-carboxylate (0.96 g, 1 .9 mmol), (2/?,3S)-2-methylmorpholine-3 -carboxylic acid (0.28 g, 1.9 mmol) and potassium carbonate (0.53 g, 3.8 mmol) in anhydrous ethanol (35 mL) was stirred at 25 °C for 12 hours under N2. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (V/V) = 15/1 ) to give the title compound as a yellow solid (0.48 g, 45%). The compound was characterized by the following spectroscopic data: S-ESI: (ESI, pos.ion) m/z: 567.1 [M+l ;
Ή NMR (400 MHz, DMSO-< 6): δ 13.1 (br.s, 1 H), 9.88 (s, 1 H), 8.03-8.01 (m, 1 H), 7.94-7.92 (m, 1H), 7.58-7.54 (m, 1H), 7.41 -7.33 (m, 1 H), 7.24-7.18 (m, 1 H), 6.03 (s, 1H), 4.18-4.08 (m, 1H), 4.02-3.93 (m, 2H), 3.91-3.70 (m, 2H), 3.68-3.51 (m, 3H), 2.98-2.89 (m, 1H), 2.72-2.47 (m, 1H), 1.26 (br.s, 3H), 1.04 (t, 3H).
[00247] Example 35:
(2R,3S)-4-((6-(2-chloro-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydrop yrimidin-4-yl)methyl)-2-methylmorpholine-3-carboxylic acid
Figure imgf000117_0001
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)- 1 ,4-dihydro pyrimidine-5-carboxylate (0.87 g, 1 .9 mmol) was reacted with (2R,3S)-2-methyl morpholine-3-carboxylic acid (0.28 g, 1 .9 mmol) according to the procedure as described in Example 34, Step D to give the title compound as a yellow solid (0.6 g, 60%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 523.2 [M+l ] ;
Ή NMR (400 MHz, DMSO-i 6): δ 12.93 (br.s, IH), 9.86 (s, I H), 8.03 (d, IH), 7.94 (d, IH), 7.45-7.38 (m, 2H), 7.20-7.16 (m, IH), 6.05 (s, IH), 4.19-4.09 (m, IH), 4.03-3.93 (m, 2H), 3.90-3.71 (m, 2H), 3.69-3.50 (m, 3H), 2.99-2.88 (m, IH), 2.73-2.47 (m, IH), 1 .25 (br.s, 3H), 1 .06 (t, 3H).
[00248] Example 36:
(2R,35)-4-((6-(2,4-dichlorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrim idin-4-yl)methyl)-2-methylmorpholine-3-carboxylic acid
Figure imgf000118_0001
Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)- 1 ,4-dihydropyrimidine- 5-carboxylate (0.9 g, 1.9 mmol) was reacted with (2R,35)-2 -methyl morpholine-3-carboxylic acid (0.28 g, 1 .9 mmol) according to the procedure as described in Example 34, Step D to give the title compound as a yellow solid (0.43 g, 42%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 539.1 [M+l ]+;
Ή NMR (600 MHz, DMSO-J6): δ 12.91 (br.s, IH), 9.85 (s, I H), 8.04 (d, I H), 7.96 (d, IH), 7.58-7.55 (m, I H), 7.42-7.37 (m, 2H), 6.06 (s, I H), 4.17-4.08 (m, I H), 4.02-3.92 (m, 2H), 3.92-3.71 (m, 2H), 3.69-3.52 (m, 3H), 2.99-2.89 (m, I H), 2.71 -2.47 (m, I H), 1 .25 (br.s, 3H), 1 .06 (t, 3H).
[00249] Example 37: (2 f,35')-4-((6-(2-bromo-4-fluorophenyl)-5-(methoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydr opyrimidin-4-yl)methyl)-2-methylmorpholine-3-carboxylic acid
Figure imgf000119_0001
Methyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)- 1 ,4-dihydro pyrimidine-5-carboxylate (0.93 g, 1.9 mmol) was reacted with (2R,35)-2 -methyl morpholine-3-carboxylic acid (0.28 g, 1 .9 mmol) according to the procedure as described in Example 34 to give the title compound as a yellow solid (0.52 g, 49%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 553.1 [M+l ]+;
Ή NMR (400 MHz, DMSO-c ): δ 13.0 (br.s, IH), 9.87 (s, I H), 8.03 (d, IH), 7.93 (d, IH), 7.57-7.53 (m, IH), 7.40-7.32 (m, I H), 7.25-7.17 (m, IH), 6.04 (s, IH), 4.18-4.07 (m, IH), 4.02-3.92 (m, I H), 3.91 -3.85 (m, IH), 3.72 (s, 3H), 3.68-3.50 (m, 3H), 2.98-2.87 (m, IH), 2.73-2.47 (m, IH), 1.27 (br.s, 3H).
[00250] Example 38:
(2R,3S)-4-((6-(2-chloro-4-fluorophenyl)-5-(methoxycarbonyl)-2-(thiazol-2-yI)-3,6-dihydr opyrimidin-4-yl)methyl)-2-methylmorphoHne-3-carboxyIic acid
Figure imgf000119_0002
Methyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-l ,4-dihydro pyrimidine-5-carboxylate (0.85 g, 1.9 mmol) was reacted with (2i?,3S)-2-methylmorpholine- 3-carboxylic acid (0.28 g, 1.9 mmol) according to the procedure as described in Example 34 to give the title compound as a yellow solid (0.5 g, 52%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 509.2 [M+l ]+;
]H NMR (400 MHz, DMSO-i 6): δ 12.94 (br.s, 1 H), 9.87 (s, 1 H), 8.04 (d, 1 H), 7.92 (d, 1 H), 7.46-7.39 (m, 2H), 7.21 -7.15 (m, 1H), 6.04 (s, 1H), 4.19-4.08 (m, 1 H), 4.03-3.94 (m, 1 H), 3.89-3.79 (m, 1 H), 3.71 (s, 3H), 3.69-3.51 (m, 3H), 2.99-2.87 (m, 1 H), 2.74-2.48 (m, 1 H), 1 .25 (br.s, 3H).
[00251 ] Example 39:
(2R,35)-4-((6-(2,4-dichlorophenyl)-5-(methoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyri midin-4-yl)methyl)-2-methylmorpholine-3-carboxylic acid
Figure imgf000120_0001
Methyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-l ,4-dihydro pyrimidine-5-carboxylate (0.88 g, 1.9 mmol) was reacted with (2/?,3S)-2-methylmorpholine- 3-carboxylic acid (0.28 g, 1.9 mmol) according to the procedure as described in Example 34 to give the title compound as a yellow solid (0.51 g, 51 %). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 525.1 [M+l ]+;
Ή NMR (400 MHz, DMSO- ): δ 12.93 (br.s, 1 H), 9.84 (s, 1 H), 8.04 (d, 1H), 7.96 (d, 1 H), 7.59-7.56 (m, IH), 7.43-7.38 (m, 2H), 6.05 (s, IH), 4.18-4.09 (m, IH), 4.03-3.93 fm, IH), 3.91 -3.80 (m, IH), 3.72 (s, 3H), 3.68-3.51 (m, 3H), 2.99-2.89 (m, IH), 2.69-2.47 (m, IH), 1 .27 (br.s, 3H).
[00252] Example 40:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(((S)-3-(hydroxymethyl)morphoIino)methyl)-2- (thiazol-2-yl)-l,4-dihydropyrimidine-5-carboxylate
Figure imgf000121_0001
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-l ,4-dihydro pyrimidine-5-carboxylate (1 g, 2 mmol) was reacted with (5)-morpholin-3-ylmethanol (0.24 g, 2 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a pale yellow solid (0.6 g, 55%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 539.2 [M+l ;
Ή NMR (400 MHz, DMSO-flfc): δ 9.86 (br.s, I H), 8.04 (d, IH), 7.95 (d, IH), 7.58-7.56 (m, I H), 7.43-7.38 (m, IH), 7.25-7.19 (m, I H), 6.03 (s, IH), 4.83-4.74 (m, IH), 4.37-4.24 (m, IH), 4.01-3.89 (m, 3H), 3.82-3.69 (m, 2H), 3.59-3.38 (m, 4H), 2.86-2.69 (m, IH), 2.57-2.43 (m, IH), 1.06 (t, 3H).
[00253] Example 41 :
Ethyl 4-(2-chloro-4-fluorophenyl)-6-(((5)-3-(hydroxymethyl)morpholino)methyl)-2- (thiazol-2-yl)-l,4-dihydropyrimidine-5-carboxylate
Figure imgf000122_0001
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-l ,4-dihydro pyrimidine-5-carboxylate (0.92 g, 2 mmol) was reacted with (S)-morpholin-3-ylmethanol (0.24 g, 2 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a pale yellow solid (0.6 g, 61 %). The compound was characterized by the following spectroscopic data: S-ESI: (ESI, pos.ion) m/z: 495.2 [M+l ]+;
]H NMR (400 MHz, DMSO-i¾: δ 9.86 (br.s, IH), 8.04 (d, IH), 7.94 (d, IH), 7.46-7.38 (m, 2H), 7.20-7.16 (m, I H), 6.04 (s, IH), 4.83-4.74 (m, IH), 4.38-4.25 (m, IH), 4.03-3.88 (m, 3H), 3.83-3.68 ( , 2H), 3.61 -3.38 (m, 4H), 2.87-2.68 (m, I H), 2.58-2.43 (m, IH), 1 .06 (t, 3H).
[00254] Example 42:
Ethyl 4-(2,4-dichIorophenyl)-6-(((S)-3-(hydroxymethyI)morpholino)methyl)-2-(thiazol- 2-yl)-l,4-dihydropyrimidine-5-carboxylate
Figure imgf000122_0002
Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-] ,4-dihydropyrimidine- 5-carboxylate (0.95 g, 2 mmol) was reacted with (5)-morpholin-3-ylmethanol (0.24 g, 2 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a pale yellow solid (0.42 g, 41 %). The compound was characterized by the following spectroscopic data:
MS-ES1: (ESI, pos.ion) m/z: 511.2 [M+l ]+;
Ή NMR (400 MHz, DMSO-i¾: δ 9.85 (br.s, 1 H), 8.03 (d, 1H), 7.94 (d, 1H), 7.60-7.58 (m, 1 H), 7.39-7.37 (m, 2H), 6.05 (s, 1 H), 4.81 (br.s, 1H), 4.35-4.22 (m, 1 H), 3.99-3.92 (m, 3H), 3.87-3.77 (m, 2H), 3.59-3.40 (m, 4H), 2.84-2.66 (m, 1 H), 2.60-2.56 (m, 1 H), 2.48-2.40 (m, 1 H), 1 .05 (t, 3H).
[00255] Example 43:
Methyl 4-(2-bromo-4-fluorophenyl)-6-(((5)-3-(hydroxymethyl)morpholino)methyl)-2- (thiazol-2-yl)-l,4-dihydropyrimidine-5-carboxylate
Figure imgf000123_0001
Methyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)- 1 ,4-dihydro pyrimidine-5-carboxylate (0.98 g, 2 mmol) was reacted with (5)-morpholin-3-ylmethanol (0.24 g, 2 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a pale yellow solid (0.56 g, 53%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 525.1 [M+ l ]+;
Ή NMR (400 MHz, DMSO-dfi): δ 9.87 (br.s, 1 H), 8.04 (d, 1 H), 7.94 (d, 1 H), 7.59-7.56 (m, 1 H), 7.44-7.38 (m, 1 H), 7.25-7.18 (m, 1 H), 6.04 (s, 1 H), 4.83-4.73 (m, 1 H), 4.37-4.25 (m, 1 H), 4.03-3.89 (m, 1 H), 3.83-3.76 (m, 1 H), 3.69 (s, 3H), 3.59-3.37 (m, 4H), 2.87-2.69 (m, I H), 2.57-2.42 (m, IH). [00256] Example 44:
Methyl 4-(2-chloro-4-fluorophenyl)-6-(((S)-3-(hydroxymethyl)morpholino)methyl)-2- (thiazol-2-yl)-l,4-dihydropyrimidine-5-carboxylate
Figure imgf000124_0001
Methyl 6-(bromomethyl)-4-(2-chloro-4-fluoropheny])-2-(thiazol-2-yl)- 1 ,4-dihydro pyrimidine-5-carboxylate (0.89 g, 2 mmol) was reacted with (.S morpholin-S-ylmethanol (0.24 g, 2 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a pale yellow solid (0.38 g, 39%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 481.2 [M+l f;
Ή NMR (400 MHz, DMSO- 6): δ 9.83 (br.s, I H), 8.02 (d, IH), 7.92 (d, IH), 7.48-7.36 (m, 2H), 7.21 -7.16 (m, I H), 6.03 (s, I H), 4.82-4.74 (m, IH), 4.38-4.26 (m, IH), 4.05-3.88 (m, 2H), 3.83-3.75 (m, IH), 3.71 (s, 3H), 3.62-3.35 (m, 4H), 2.88-2.67 (m, IH), 2.58-2.44 (m, IH).
[00257] Example 45:
Methyl 4-(2,4-dichlorophenyl)-6-(((5)-3-(hydroxymethyl)morpholino)methyl)-2-(thiazol -2-yl)-l,4-dihydropyrimidine-5-carboxylate
Figure imgf000125_0001
Methyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-l ,4-dihydropyrimidine -5-carboxylate (0.92 g, 2 mmol) was reacted with (S)-morpholin-3-ylmethanol (0.24 g, 2 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a pale yellow solid (0.44 g, 44%). The compound was characterized by the following spectroscopic data:
MS-ES1: (ESI, pos.ion) mlr. 497.1 [M+l ]+;
Ή NMR (400 MHz, DMSO-i 6): δ 9.84 (br.s, I H), 8.04 (d, IH), 7.92 (d, IH), 7.61-7.59 (m, I H), 7.38-7.36 (m, 2H), 6.03 (s, I H), 4.81 (br.s, I H), 4.35-4.24 (m, I H), 3.99-3.91 (m, 2H), 3.87-3.78 (m, IH), 3.71 (s, 3H), 3.58-3.39 (m, 4H), 2.85-2.66 (m, IH), 2.61-2.56 (m, IH), 2.49-2.41 (m, IH).
[00258] Example 46:
(3S)-4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-y])-3,6-dihydropyri midin-4-yl)methyl)-2,2-dimethylmorpholine-3-carboxylic acid
Figure imgf000125_0002
[00259] Step A: (£)-2-(benzylamino)-3-hydroxy-3-methylbutanoic acid A mixture of (S)-2-amino-3-hydroxy-3-methylbutanoic acid ( 18.6 g, 140 mmol), aqueous NaOH solution (2 mol/L, 70 mL) and benzaldehyde ( 14.56 g, 137 mmol) was stirred at 25 °C for 1 hour and cooled to 0 °C. Then to the mixture was added sodium borohydride (3 g, 80 mmol) portion wise with the temperature maintained below 10 °C. Then the mixture was wanned to 25 °C and stirred for another 12 hours. The aqueous layer was washed with DCM (30 mL x 3) and the organic layer was discarded. The aqueous layer was cooled to 5 °C, and adjusted to pH 1 -2 with con.HCl. The mixture was stirred at 5 °C for 4 hours, and filtered to give the title compound as a white solid (18.8 g, 60%). The compound was characterized by the following spectroscopic data:
MS-ESl: (ESI, pos.ion) m/z: 224.1 [M+l ]+;
!H NMR (400 MHz, D20): δ 7.35 (s, 5H), 4.24 (q, 2H), 3.63-3.61 (m, 1H), 1.25-1 .23 (m, 6H).
[00260] Step B: (5)-4-benzyI-2,2-dimethyl-5-oxomorphoIine-3-carboxylic acid
To a mixture of (S)-2-(benzylamino)-3-hydroxy-3-methylbutanoic acid (22.86 g, 102.4 mmol), tetrahydrofuran ( 1 10 mL), potassium carbonate (42.5 g, 307.2 mmol) and water (70 mL) was added chloroacetyl chloride slowly ( 17.8 g, 157.7 mmol) at 0 °C over a period of 1 hour, then the mixture was stirred at 0 °C for 3 hours. To the reaction mixture was added a solution of sodium hydroxide (16.4 g, 409.6 mmol) in water (40 mL) over a period of 1 hour. At the end of addition, the mixture was cooled to 3 °C-5 °C, and the mixture was stirred at the temprarure for 4 hours. Then the reaction mixture was warmed to room temperature, and washed with Petroleum ether (50 mL x 2). The aqueous layer was cooled to 3 °C below and adjusted to pH 2 with con.HCl. The mixture was stirred at 6 °C below for 12 hours, then filtered. The filter cake was washed with water to give the title compound as a white solid (18.6 g, 69%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mix: 264.1 [M+l ;
Ή NMR (600 MHz, DMSO-</6): δ 12.83 (br.s, 1 H), 7.36-7.26 (m, 5H), 5.29 (d, 1 H), 4.32-4.10 (m, 3H), 3.73 (d, 1 H), 1.21 -1.17 (m, 6H).
[00261 ] Step C: (5)-benzyI 4-benzyl-2,2-dimethyl-5-oxomorpholine-3-carboxylate
(S)-4-benzyl-2,2-dimethyl-5-oxomorpholine-3-carboxylic acid (11 .2 g, 42.5 mmol) was reacted with benzyl bromide (8.72 g, 51 mmol) according to the procedure as described in Example 34, Step A to give the title compound as a white solid (8.11 g, 54%). The compound was characterized by the following spectroscopic data: S-ESI: (ESI, pos.ion) mlz: 354.2 [M+l ]+;
]H NMR (400 MHz, CDC13): δ 7.36-7.31 (m, 5H), 7.30-7.20 (m, 5H), 5.60 (d, 1 H), 1 H), 5.26 (q, 2H), 4.40-4.37 (m, 1H), 4.33-4.08 (m, 3H), 1.24-1.19 (m, 6H).
[00262] Step D: (5)-benzyl 4-benzyl-2,2-dimethylmorpholine-3-carboxylate
(S)-benzyl 4-benzyl-2,2-dimethyl-5-oxomorpholine-3-carboxylate ( 163 g, 461 mmol) was reacted with a solution of borane in THF (1 mol/L, 692 mL) according to the procedure as described in Example 34, Step B to give the title compound as colorless oil ( 133 g, 85%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 340.2 [M+l ;
Ή NMR (600 MHz, CDCI3): δ 7.33-7.27 (m, 10H), 5.25 (s, 2H), 3.89-3.70 (m, 4H), 3.24 (d, 1H), 2.72 (d, 1 H), 2.25-2.18 (m, 1H), 1.25-1 .17 (m, 6H).
[00263] Step E: (S)-2,2-dimethylmorpholine-3-carboxylic acid
(5)-benzyl 4-benzyl-2,2-dimethylmoφholine-3-carbo ylate (10.4 g, 30.8 mmol) was reacted with H2 by Pd/C catalysis ( 10%, 1 g) according to the procedure as described in Example 34, Step C to give the title compound as a white solid (3.4 g, 70%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 160.1 [M+l ]+; Ή NMR (600 MHz, D20): δ 4.06-3.98 fm, I H), 3.85-3.77 (m, I H), 3.76-3.75 (m, IH), 3.27-3.26 (m, IH), 3.19-3.13 (m, I H), 1.26-1.19 (m, 6H).
[00264] Step F: (35)-4-((6-(2-bromo-4-fluorophenyI)-5-(ethoxycarbonyl)-2-(thiazol- 2-yI)-3,6-dihydropyrimidin-4-yl)raethyl)-2,2-dimethylmorpholine-3-carboxylic acid
A mixture of ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-
2- yl)-l ,4-dihydropyrimidine-5-carboxylate (7.7 g, 15.3 mmol), (5)-2,2-dimethylmorpholine-
3- carboxylic acid (2.44 g, 15.3 mmol) and potassium carbonate (4.23 g, 30.6 mmol) in anhydrous ethanol (154 mL) was stirred at 25 °°C for 16 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (V/V) = 25/1) to give the title compound as a yellow solid (5.8 g, 65%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 581.1 [M+l ]+;
Ή NMR (400 MHz, DMSO- ): δ 12.90 (s, I H), 9.87 (s, I H), 8.06 (d, IH), 7.92 (d, I H), 7.58-7.55 (m, IH), 7.43-7.37 (m, I H), 7.25-7.19 (m, I H), 6.06 (s, I H), 4.20-4.07 (m, IH), 4.02-3.93 (m, 2H), 3.90-3.70 (m, 2H), 3.68-3.49 (m, 3H), 2.69-2.47 (m, I H), 1.27-1.21 (m, 6H).
[00265] Example 47:
(35)-4-((6-(2-chloro-4-fluorophenyl)-5-(methoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropy rimidin-4-yl)methyl)-2,2-dimethyImorphoIine-3-carboxylic acid
Figure imgf000128_0001
Methyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-l ,4-dihydro pyrimidine-5-carboxylate (6.8 g, 15.3 mmol) was reacted with (S -2,2-dimethylmorpholine-
3- carboxylic acid (2.44 g, 15.3 mmol) according to the procedure as described in Example 46, Step F to give the title compound as a yellow solid (4.4 g, 55%). The compound was characterized by the following spectroscopic data:
MS-ES1: (ESI, pos.ion) m/z: 523.1 [M+l]+;
Ή NMR (400 MHz, DMSO-</6): 6 12.93 (s, 1 H), 9.83 (s, 1H), 8.04 (d, 1H), 7.94 (d, 1H), 7.59-7.55 (m, 1 H), 7.44-7.37 (m, 1 H), 7.26-7.1 9 (m, 1 H), 6.05 (s, 1 H), 4.20-4.09 (m, 1 H), 3.95-3.70 (m, 2H), 3.71 (s, 3H), 3.68-3.48 (m, 3H), 2.69-2.49 (m, 1H), 1 .27-1.22 (m, 6H).
[00266] Example 48:
4- ((6-(2-chloro-4-fluorophenyl)-5-(ethoxycarbonyl)-3-methyl-2-(thiazol-2-yl)-3,6-dihydr opyrimidin-4-yl)methyl)morpholine-3-carboxylic acid
Figure imgf000129_0001
[00267] Step A: Ethyl 4-(2-chloro-4-fluorophenyl)-l,6-dimethyl-2-(thiazol-2-yl)-l,4- dihydropyrimidine-5-carboxylate
A mixture of ethyl 4-(2-chloro-4-fluorophenyl)-6-methyl-2-(thiazol-2-yl)-l ,4-dihydro pyrimidine-5-carboxylate (2 g, 5.3 mmol), iodomethane (0.97 g, 6.84 mmol) and potassium carbonate ( 1.47 g, 10.6 mmol) in acetonitrile (50 mL) was stirred at 70 °C for 12 hours, and cooled to 25 °C . The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PETROLEUM ETHER/EtOAc (V V) = 3/1) to give the title compound as a tawny solid (1 .0 g, 48%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 394.0 [M+lf; H NMR (400 MHz, CDC13): δ 7.86 (d, IH), 7.54-7.50 (m, IH), 7.48 (d. I H), 7.09-7.07 (m, IH), 6.95-6.90 (m, IH), 5.92 (s, IH), 4.09 (q, 2H), 3.54 (s, 3H), 2.49 (s, 3H), 1.19 (t, 3H).
[00268] Step B: Ethyl 6-(bromomethyl)-4-(2-chIoro-4-fluorophenyl)-l-methyl-2- (thiazol-2-yl)-l,4-dihydropyrimidine-5-carboxylate
Ethyl 4-(2-chloro-4-fluorophenyl)-l ,6-dimethyl-2-(thiazol-2-yl)- 1.4-dihydropyrimidine -5-carboxylate (0.4 g, 1.02 mmol) was reacted with NBS (0.2 g, 1.12 mmol) according to the procedure as described in Example 1 , Step B to give the title compound as yellow oil (0.19 g, 40%). The compound was characterized by the following spectroscopic data:
MS-ES1: (ESI, pos.ion) m/z: 472.10 [M+l ]+;
Ή NMR (400 MHz, CDC13): δ 7.86 (d, I H), 7.54-7.50 (m, I H), 7.48 (d, I H), 7.09-7.07 (m, I H), 6.95-6.90 (m, I H), 5.92 (s, I H), 4.84 (d, I H), 4.60 (d, I H), 4.09 (q, 2H), 3.54 (s, 3H), 1 .19 (t, 3H).
[00269] Step C: 4-((6-(2-chloro-4-nuoropheny])-5-(ethoxycarbonyl)-3-methyl-2- (thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)- 1 -methyl-2-(thiazol-2-yl)- 1 ,4-di hydropyrimidine-5-carboxylate (0.48 g, 1.02 mmol) was reacted with morpholine-3- carboxylic acid (0.4 g, 3.06 mmol) according to the procedure as described in Example 1 , Step C to give the title compound as a yellow solid (0.1 g, 20%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 523.2 [M+l ]+;
Ή NMR (400 MHz, D20): δ 8.08 (d, 2H), 7.60-7.56 (m, I H), 7.33-7.31 (m, I H), 7.12-7.10 (m, I H), 6.23 (s, I H), 4.38 (d, I H), 4.21 (d, I H), 4.08-3.80 (m, 6H), 3.69-3.57 (m, 2H), 3.41 (s, 3H), 3.26-3.22 (m, I H), 1 .10 (t, 3H).
[00270] Example 49:
Ethyl 6-(((5)-3-((((5)-2-amino-3-methylbutanoyl)oxy)methyl)morpholino)methyl)-4-(2- bromo-4-fluoropbenyl)-2-(thiazo]-2-yl)-l,4-dihydropyrimidine-5-carboxylate
Figure imgf000131_0001
To a solution of ethyl 4-(2-bromo-4-fluorophenyl)-6-(((S)-3-(hydroxymethyl) mo holino)methyl)-2-(thiazol-2-yl)-l ,4-dihydro yΓimidine-5-carboxylate ( 1 g, 1.9 mmol), (5)-2-((/f?r/-butoxycarbonyl)amino)-3-methylbutanoic acid (0.83 g, 3.8 mmol) and 4-dimethylaminopyridine (23 mg, 0.19 mmol) in DCM (30 mL) was added a solution of DCC (0.59 g, 2.85 mmol) in DCM ( 10 mL) dropwise over a period of 15 minutes at rt, then the mixture was stirred at rt for 12 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in a solution of HCl in EtOAc (6 mol/L, 40 mL), and the mixture was stirred at 25 °C for 12 hours. The reaction mixture was diluted with EtOAc (200 mL) and water (100 mL), and the mixture was adjusted to pH 8-9 with aqueous ammonia. The organic layer was dried over Na2S04, and the mixture was filtered and concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (V/V) = 30/1 ) to give the title compound as a yellow solid (0.65 g, 54%). The compound was characterized by the following spectroscopic data:
MS-ES1: (ESI, pos.ion) mlr. 638.1 [M+l f;
Ή NMR (400 MHz, DMSO- ): δ 11.22 (br.s, 1 H), 8.82 (br.s, 2H), 8.12-8.08 (m, 1 H), 7.62-7.55 (m, 1 H), 7.30-7.26 (m, 1H), 6.03 (s, 1H), 4.30-4.21 (m, 3H), 4.06-3.94 (m, 3H), 3.88-3.72 (m, 4H), 3.68-3.52 (m, 2H), 2.89-2.74 (m, 2H), 2.06-1.98 (m, 1 H), 1 .08-1.04 (m, 3H), 0.82-0.74 (m, 6H).
[00271 ] Example 50: Ethyl 6-(((5)-3-((((S)-2-amino-3-methylbutanoyl)oxy)methyl)morpholino)methyl)-4-(2, 4-dichlorophenyl)-2-(thiazoI-2-yl)-l,4-dihydropyrimidine-5-carboxylate
Figure imgf000132_0001
Ethyl 4-(2,4-dichlorophenyl)-6-(((5)-3-(hydroxymethyl)moφholino)methyl)-2-(thiazol- 2-yl)-l ,4-dihydropyrimidine-5-carboxylate (1 g, 1 .96 mmol) was reacted with (S)-2-((/er/-butoxycarbonyl)amino)-3-methylbutanoic acid (0.83 g, 3.8 mmol) according to the procedure as described in Example 49 to give the title compound as a yellow solid (0.43 g, 36%). The compound was characterized by the following spectroscopic data:
MS-ES1: (ESI, pos.ion) m!z: 610.1 [M+l ]+;
Ή NMR (400 MHz, DMSO-</6): δ 9.85 (br.s, 1 H), 8.74 (br.s, 2H), 8.05 (br.s, 2H), 7.61 (s, 1H), 7.48-7.41 (m, 2H), 6.04 (s, 1 H), 4.29-4.20 (m, 3H), 4.07-3.94 (m, 3H), 3.89-3.72 (m, 4H), 3.68-3.52 (m, 2H), 2.89-2.75 (m, 2H), 2.06-1.96 (m, 1H), 1.08-1.04 (m, 3H), 0.82-0.74 (m, 6H).
[00272] Example 51 :
Methyl 4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydro pyrimidin-4-yl)methyl)morpholine-3-carboxylate
Figure imgf000133_0001
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)- 1 ,4-dihydro pyrimidine-5-carboxylate ( 1.1 g, 2.2 mmol) was reacted with methyl morpholine-3- carboxylate (0.4 g, 2.2 mmol) according to the procedure as described in Example 24 to give the title compound as a yellow solid (0.62 g, 50%). The compound was characterized by the following spectroscopic data:
MS-ES1: (ESI, pos.ion) ml . 567.1 [M+l ]+ ;
]H NMR (400 MHz, DMSO-i 6): δ 9.74 (s, IH), 8.03 (d, I H), 7.94 (d, IH), 7.57-7.54 (m, IH), 7.41-7.37 (m, IH), 7.24-7.18 (m, IH), 6.02 (s, I H), 4.32-4.09 (m, 2H), 4.05-4.00 (m, IH), 3.99-3.92 (m, 2H), 3.83-3.73 (m, 3H), 3.70 (s, 3H), 3.65-3.52 (m, IH), 3.10-3.04 (m, IH), 2.58-2.42 (m, I H), 1.06 (t, 3H).
[00273] Example 52:
Ethyl 4-(2-bromo-4-fluorophenyI)-6-(((S)-3-(hydroxycarbamoyl)morphoIino)methyl)-2- (thiazol-2-yl)-l,4-dihydropyrimidine-5-carboxylate
Figure imgf000133_0002
A solution of (35)-4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)- 3,6-dihydropyrimidin-4-yl)rnethyl)morpholine-3-carboxylic acid (0.74 g. 1.36 mmol), EDC HCl (0.31 g, 1.62 mmol), HOAt ( 185 mg, 1.36 mmol) and DIPEA (210 mg, 1.62 mmol) in DCM (20 mL) was stirred at -10 °C for 30 minutes. Then to the mixmre was added a solution of 0-(rer?-butyldimethylsilyl)hydroxylamine (0.2 g, 1.36 mmol) in DCM (2.0 mL) slowly at -10 "C. Then the mixture was warmed to 25 °C and stirred for 12 hours. The mixture was concentrated in vacuo and the residue was dissolved in a solution of HCl in EtOAc (6 mol/L, 10 mL), then the mixture was stirred at 25 °C for 2 hours. The reaction mixture was diluted with EtOAc (200 mL) and water ( 100 mL), and the mixture was adjusted to pH 7 with aqueous ammonia. The organic layer was dried over Na2S04, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH ( V) = 30/1 ) to give the title compound as a yellow solid (0.05 g, 6.5%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 568.2 [M+l ]+;
Ή NMR (400 MHz, DMSO-c/6): δ 1 1 .30 (br.s, 1 H), 9.86 (br.s, 1 H), 8.04 (d, 1 H), 7.95 (d, 1H), 7.57-7.55 (m, 1 H), 7.43-7.37 (m, 1 H), 7.23-7.19 (m, 1 H), 6.02 (s, 1 H), 4.32-4.15 (m, 3H), 4.10-3.91 (m, 2H), 3.84-3.82 (m, 1H), 3.74-3.52 (m, 3H), 3.11 -3.07 (m, 1H), 2.55-2.39 (m, 1H), 1.05 (t, 3H).
[00274] Example 53:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(((S)-3-(methoxycarbamoyl)morpholino)methyl)-2- (thiazol-2-yl)-l,4-dihydropyrimidine-5-carboxylate
Figure imgf000134_0001
A mixture of (35)-4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)- 3,6-dihydropyrirnidin-4-yl)methyl)morpholine-3-carboxylic acid (0.5 g, 0.9 mmol), O-methylhydroxyl amine hydrochloride (0.2 g, 2.25 mmol), EDC HCl (1 g, 5.2 mmol), HOAt (1 g, 7.3 mmol) and TEA (1.45 g, 14.3 mmol) in DCM (30 mL) was stirred at 0 °C for 1 hour. Then the mixture was warmed to 25 °C and stirred for another 10 hours. The mixture was concentrated in vacuo and the residue was purified by a silica gel column chromatography (DCM/MeOH (V/V) = 30/1) to give the title compound as a yellow solid (0.4 g, 76%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 582.0 [M+l ;
Ή NMR (400 MHz, CDC13): δ 7.98 (d, 1H), 7.71 (d, 1 H), 7.40-7.33 (m, 2H), 7.09-7.05 (m, 1H), 6.1 8 (s, 1 H), 4.72-4.65 (m, 1 H), 4.55-4.44 (m, 1 H), 4.31-4.21 (m, 2H), 4.11 -4.00 (m, 3H), 3.94-3.84 (m, 2H), 3.80 (s, 3H), 3.56-3.40 (m, 2H), 3.35-3.27 (m, 1 H), 1 .12 (t, 3H).
[00275] Example 54:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(((S)-3-((2-hydroxyethyl)carbamoyl)morpholino) methyl)-2-(thiazol-2-yl)-l,4-dihydropyrimidine-5-carboxylate
Figure imgf000135_0001
(35)-4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropy rimidin-4-yl)methyl)morpholine-3-carboxylic acid (0.5 g, 0.9 mmol) was reacted with 2-aminoethanol (72 mg, 1.2 mmol) according to the procedure as described in Example 53 to give the title compound as a yellow solid (0.3 g, 56%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 596.0 [M+l f; Ή NMR (400 MHz, DMSO-^): δ 9.93 (s, 1 H), 8.27 (br.s, 1H), 8.04 (d, 1 H), 7.92 (d, 1H), 7.57-7.54 (m, 1H), 7.41-7.37 (m, 1H), 7.24-7.19 (m, 1H), 6.02 (s, 1H), 4.73-4.68 (m, 1H), 4.14-4.00 (m, 2H), 3.95-3.88 (m, 2H), 3.86-3.71 (m, 2H), 3.68-3.50 (m, 2H), 3.45-3.38 (m, 1H), 3.33-3.27 (m, 1H), 3.22-3.14 (m, 2H), 3.00-2.81 (m, 1 H), 2.48-2.41 (m, I H), 1.06 (t, 3H).
[00276] Example 55:
Ethyl 6-(((5)-3-((2-acetoxyethyl)carbamoyl)morpholino)methyI)-4-(2-bromo-4-fluoro phenyl)-2-(thiazol-2-yl)-l,4-dihydropyrimidine-5-carboxyIate
Figure imgf000136_0001
[00277] Step A: (S)-tert-buty\ 3-((2-hydroxyethyl)carbamoyl)morphoIine-4- carboxylate
A mixture of (iS)-4-ter/-butyl 3-methyl morpholine-3,4-dicarboxylate (0.93 g, 3.8 mmol) and 2-aminoethanol (5 g, 81.9 mmol) in methanol (2 mL) was stirred at 80 °C for 7 hours under N2. The mixture was concentrated in vacuo, diluted with EtOAc (100 mL) and acetic acid (5 mL). The organic layer was washed with brine (80 mL x 6), dried over Na2S04, and filtered. The filtrate was concentrated in vacuo to give the title compound as a white solid (0.8 g, 77%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 1 75.1 [M+ M OOf;
Ή NMR (400 MHz, DMSO- /6): δ 12.01 (br.s, IH), 7.89 (s, IH), 4.69 (br.s, IH), 4.28-4.12 (m, 2H), 3.77-3.69 (m, I H), 3.57-3.51 (m, 2H), 3.40-3.30 (m, 3H), 3.25-3.14 (m, 2H), 1.37 (s, 9H).
[00278] Step B: (5)-2-(morpholine-3-carboxamido)ethyl acetate hydrochloride To a solution of (S)-tert-buty\ 3-((2-hydroxyethyl)carbamoyl)mo holine-4-carboxylate (0.33 g, 1.2 mmol) in glacial acetic acid (0.5 mL) was added a solution of HCl in EtOAc (6 mol/L, 15 mL), then the mixture was stirred closedly at 25 °C for 12 hours. The mixture was concentrated in vacuo to give the title compound as glutinous semisolid (0.21 g, 70%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 217.1 [M+l ]+;
Ή NMR (400 MHz, D20): δ 4.65 (br.s, I H), 4.31 -4.18 (m, 2H), 3.82-3.71 (m, I H), 3.60-3.50 (m, 2H), 3.46-3.35 (m, 3H), 3.23-3.1 1 (m, 2H), 1.98 (s, 3H).
[00279] Step C: Ethyl 6-(((5)-3-((2-acetoxyethyl)earbamoyl)morpholino)methyl)-4- (2-bromo-4-fluorophenyl)-2-(thiazol-2-yl)-l,4-dihydropyrimidine-5-carboxylate
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-l ,4-dihydro pyrimidine-5-carboxylate (0.6 g, 1.2 mmol) was reacted with (.^^-(morpholine-S- carboxamido)ethyl acetate hydrochloride (0.3 g, 1 .2 mmol) according to the procedure as described in Example 24 to give the title compound as a yellow solid (0.2 g, 26%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 638.1 [M+l ]+;
Ή NMR (400 MHz, DMSO-i/6): δ 9.96 (s, IH), 8.41 (d, I H), 8.33 (d, I H), 7.57-7.54 (m, IH), 7.39-7.36 (m, IH), 7.25-7.18 (m, IH), 6.03 (s, IH), 4.13-4.03 (m, 2H), 4.02-3.90 (m, 2H), 3.86-3.77 (m, 2H), 3.74-3.56 (m, 2H), 3.55-3.50 (m, I H), 3.40-3.36 (m, IH), 3.31 -3.25 (m, 2H), 3.00-2.80 (m, IH), 2.48-2.31 (m, 2H), 1.96 (s, 3H), 1.03 (t, 3H).
[00280] Example 56:
(3S)-4-((5-(ethoxycarbonyl)-6-(5-nuoro-4'-(trinuoromethyl)-[l,l'-bipheny]]-2-yl)-2-(thia zol-2-yl)-3,6-dihydropyrimidin-4-yI)methyl)morpholine-3-carboxylic acid
Figure imgf000138_0001
[00281] Step A: 5-nuoro-4'-(trifluoromethyl)-[l,l'-biphenyl]-2-carbaldehyde
A mixture of 2-bromo-4-fluorobenzaldehyde (2 g, 9.85 mmol), (4-(trifluoromethyl)phenyl)boronic acid (2.25 g, 11.82 mmol), potassium acetate (2.42 g, 24.63 mmol) and Pd(PPh3)4 ( 1.14 g, 0.98 mmol) in DMF (40 mL) and water ( 13 mL) was stirred at 100 °C for 3 hours under N2, then cooled to 25 °C. To the mixture was added EtOAc (250 mL). The organic layer was washed with brine (200 mL x 3), dried over Na2S04 and filtered. The filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PETROLEUM ETHER/EtOAc (V/V) = 70/1) to give the title compound as colorless oil (2.1 1 g, 79%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 269.1 [M+l ]+;
Ή NMR (400 MHz, DMSO-< ): δ 9.81 (s, 1H), 8.07-8.03 (m, 1H), 7.88 (dd, 4H), 7.52-7.47 (m, 1H), 7.45-7.42 (m, 1H).
[00282] Step B: Ethyl 4-(5-fluoro-4'-(trifluoromethyl)-[l,l ,-biphenyl]-2-yl)-6- methyl-2-(thiazol-2-yl)-l,4-dihydropyrimidine-5-carboxylate
5-fluoro-4'-(trifluoromethyl)-[ l , l '-biphenyl]-2-carbaldehyde (2.1 1 g, 7.87 mmol) was reacted with thiazole-2-carboximidamide hydrochloride (1.29 g, 7.87 mmol) and ethyl 3-oxobutanoate ( 1.23 g, 9.44 mmol) according to the procedure as described in Example 1 , Step A to give the title compound as a yellow solid ( 1.22 g, 32%). The compound was characterized by the following spectroscopic data: MS-ESI: (ESI, pos.ion) mlz: 490.1 [M+l ]+;
Ή NMR (400 MHz, DMSO- 6): δ 9.90 (s, 1H), 7.99 (d, 1 H), 7.93 (d, 1H), 7.89 (s, 4H),
7.46- 7.42 (m, 1 H), 7.28-7.23 (m, 1H), 7.17-7.14 (m, 1H), 5.50 (s, 1H), 3.84 (q, 2H), 2.45 (s, 3H), 0.87 (t, 3H).
[00283] Step C: Ethyl 6-(bromomethyl)-4-(5-nuoro-4'-(trinuoromethy])-[l,r-bi phenyl]-2-yl)-2-(thiazol-2-yI)-l,4-dihydropyrimidine-5-carboxylate
Ethyl 4-(5-f uoro-4'-(trifluoromethyl)-[l ,r-biphenyl]-2-yl)-6-methyl-2-(thiazol-2-yl)- l ,4-dihydropyrimidine-5-carboxylate (5 g, 10.2 mmol) was reacted with NBS (2.2 g, 12.2 mmol) according to the procedure as described in Example 1 , Step B to give the title compound as a yellow solid (3.48 g, 60%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 568.1 [M+l ]+;
Ή NMR (400 MHz, DMSO-i/6): δ 9.98 (s, 1H), 7.96 (d, 1H), 7.90 (d, 1H), 7.80 (s, 4H),
7.47- 7.41 (m, 1 H), 7.28-7.21 (m, 1 H), 7.16-7.1 1 (m, 1H), 5.58 (s, 1H), 4.66 (dd, 2H), 3.94 (q, 2H), 0.93 (t, 3H).
[00284] Step D: (3S)-4-((5-(ethoxycarbonyl)-6-(5-fluoro-4*-(trinuoromethyl)-[l,l '-bi phenyl]-2-yl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morphoIine-3-carboxyli c acid
Ethyl 6-(bromomethyl)-4-(5-fluoro-4'-(trifluoromethyl)-[ 1 , 1 '-biphenyl]-2-yl)-2-(thiazol-
2- yl)-l ,4-dihydropyrimidine-5-carboxylate (3 g, 5.3 mmol) was reacted with (5)-morpholine-
3- carboxylic acid (0.69 g, 5.3 mmol) according to the procedure as described in Example 1 , Step C to give the title compound as a yellow solid ( 1.64 g, 50%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 619.3 [M+l ]' ;
Ή NMR (400 MHz{ DMSO-</6): δ 12.96 (br.s, 1 H), 9.87 (br.s, 1 H), 8.04 (d, 1 H), 7.96 (d, 1 H), 7.89 (s, 4H), 7.51 -7.46 (m, I H), 7.25-7.22 (m. I H), 7.18-7.15 (m, I H), 5.56 (s, I H), 4.23-4.10 (m, IH), 4.08-4.04 (m, I H), 4.02-3.96 (m, IH), 3.88-3.83 (m, 3H), 3.75-3.63 (m, 2H), 3.57-3.45 (m, I H), 3.07-3.04 (m, I H), 2.38-2.36 (m, IH), 0.90 (t, 3H).
[00285] Example 57:
(3S)-4-((5-(ethoxycarbonyl)-6 541uoro-3S5'-6i^
(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid
Figure imgf000140_0001
[00286] Step A: 5 1uoro-3\5'-WA(trifluoromethyl)-|l,l '-biphenyl]-2-carbaldehyde
2-bromo-4-fluorobenzaldehyde ( 1 .53 g, 7.5 mmol) was reacted with (3,5-6w(trifluoromethyl)phenyl)boronic acid (2.3 g, 9 mmol) according to the procedure as described in Example 56, Step A to give the title compound as a white solid (2.34 g, 92%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 337.0 [M+l ]+;
!H NMR (400 MHz, DMSO-i ): δ 9.82 (s, I H), 8.23 (s, 3H), 8.12-8.08 (m, IH), 7.58-7.52 (m, 2H).
[00287] Step B: Ethyl 4-(5-fluoro-3',5,-*«(trifluoromethyl)-Il,r-biphenyl]-2-yl)-6- methyl-2-(thiazol-2-yl)-l,4-dihydropyrimidine-5-carboxylate
5-fluoro-3',5'-6w(trifluoromethyl)-[ l, -biphenyl]-2-carbaldehyde (2.34 g, 6.96 mmol) was reacted with thiazole-2-carboximidamide hydrochloride ( 1 .14 g, 6.96 mmol) and ethyl 3-oxobutanoate ( 1.1 g, 8.35 mmol) according to the procedure as described in Example 1 , Step A to give the title compound as a yellow solid ( 1 g, 26%). The compound was characterized by the following spectroscopic data: MS-ESI: (ESI, pos.ion) m/z: 558.1 [ +l]+;
Ή NMR (400 MHz, DMSO-i/6): δ 9.97 (s, IH), 8.42 (s, 2H), 8.23 (s, IH), 7.99 (d, IH), 7.95 (d, IH), 7.47-7.43 (m, I H), 7.34-7.29 (m, 2H), 5.34 (s, IH), 3.80 (q, 2H), 2.46 (s, 3H), 0.87 (t, 3H).
[00288] Step C: Ethyl e-ib omomethylH-iS-nuoro-S S'-Awttrinuoromethy -ll,! '- bi phenyl]-2-yl)-2-(thiazol-2-y])-l,4-dihydropyrimidine-5-carboxylate
Ethyl 4-(5-fluoro-3\5'-to(trifluoromethyl)-[l ,1 '-biphenyl]-2-yl)-6-methyl-2-(thiazol-2- yl)-l ,4-dihydropyrimidine-5-carboxylate (5.69 g, 10.2 mmol) was reacted with NBS (2.2 g, 12.2 mmol) according to the procedure as described in Example 1 , Step B to give the title compound as a yellow solid (3.57 g, 55%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 636.0 [M+l ]+;
1H NMR (400 MHz, DMSO- 6): δ 9.98 (s, IH), 8.43 (s, 2H), 8.24 (s, IH), 7.98 (d, IH), 7.96 (d, IH), 7.48-7.44 (m, IH), 7.35-7.28 (m, 2H), 5.40 (s, I H), 4.62 (dd, 2H), 3.88 (q, 2H), 0.89 (t, 3H).
[00289] Step D: (3S)-4-((5-(ethoxycarbony])-6-(5-fluoro-3',5'-A«(trifluoromethyl)- [1 '-biphenyl]-2-yl)-2-(thiazoI-2-yI) ,6-dihydropyrimidin-4-yl)rnethyl)morpholine-3-ca rboxylic acid
Ethyl 6-(bromomethyl)-4-(5-fluoro-3',5'-fc;'5(trifluoromethyl)-[l ,1 '-biphenyl]-2-yl)-2- (thiazol-2-yl)-l ,4-dihydropyrimidine-5-carboxylate (3.37 g, 5.3 mmol) was reacted with (,S)-morpholine-3-carboxylic acid (0.69 g, 5.3 mmol) according to the procedure described in Example 1 , Step C to give the title compound as a yellow solid (2.1 1 g, 58%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 687.1 [M+l ]+; Ή NMR (400 MHz, OMSO-de): δ 9.94 (br.s, I H), 8.44 (s, 2Η), 8.24 (s, IH), 8.04 (d, I H), 7.97 (d, IH), 7.51 -7.46 (m, IH), 7.37-7.27 (m, 2H), 5.38 (s, I H), 4.26-4.12 (m, I H), 4.05-3.96 (m, I H), 3.85-3.76 (m, 3H), 3.67-3.57 (m, 2H), 3.50-3.42 (m, 2H), 3.07-3.03 (m, I H), 2.47-2.38 (m, IH), 0.89 (t, 3H).
[00290] Example 58:
2-(4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrim idin-4-yl)methyl)morphoIine-3-carboxamido)acetic acid
Figure imgf000142_0001
[00291 ] Step A: Ethyl 4-(2-bromo-4-fluorophenyl)-6-((3-((2-ethoxy-2-oxoethyI) carbamoyl)morpholino)methyl)-2-(thiazol-2-yl)-l,4-dihydropyrimidine-5-carboxylate
4-((6-(2-brorno-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimid in-4-y])methyl)moφholine-3-carboxylic acid (0.5 g, 0.9 mmol) was reacted with ethyl 2-aminoacetate hydrochloride (0.15 g, 1.1 mmol) according to the procedure as described in Example 53 to give the title compound as a yellow solid (0.27 g, 47%). The compound was characterized by the following spectroscopic data:
MS-ES1: (ESI, pos.ion) mlz: 638.2 [M+l ]+;
Ή NMR (400 MHz, CDC13): δ 7.89-7.84 (m, IH), 7.54-7.46 (m, IH), 7.39-7.30 (m, 2H), 7.07-6.92 (m, IH), 6.22 (s, I H), 4.45-4.18 (m, 2H), 4.16-4.03 (m, 6H), 4.01 -3.81 (m, 3H), 3.78-3.50 (m, IH), 3.42-3.36 (m, I H), 3.08-2.85 (m, IH), 2.75-2.51 (m, I H), 1 .31 -1.23 (m, 3H), 1 .17-1 .13 (m, 3H).
[00292] Step B: 2-(4-((6-(2-bromo-4-fluorophenyI)-5-(ethoxycarbonyl)-2-(thiazol-2 -yl)-3,6-dihydropyrimidin-4-yl)methyI)morphoIine-3-carboxamido)acetic acid A mixture of ethyl 4-(2-bromo-4-fluorophenyl)-6-i(3-((2-ethoxy-2-oxoethyl)carbamoyl) morpholino)methyl)-2-(thiazol-2-yl)-l ,4-dihydropyrimidine-5-carboxylate (0.2 g, 0.31 mmol) and sodium hydroxide (0.13 g, 3.1 mmol) in ethanol (6 mL) and water (1 mL) was stirred at 25 °C for 20 minutes. The reaction solution was adjusted to pH 6-7 with con.UCl, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (V/V) = 25/1 ) to give the title compound as a yellow solid (0.14 g, 74%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m!z 610.0 [M+l ]+;
Ή NMR (400 MHz, D SO-cfe): 5 12.41 (br.s, 1H), 9.94 (br.s, 1 H), 8.60 (br.s, Ί Η), 8.04 (d, 1H), 7.93 (d, 1H), 7.57-7.54 (m, 1H), 7.38-7.33 (m, 1 H), 7.25-7.21 (m, 1H), 5.99 (s, 1H), 4.16-3.96 (m, 2H), 3.94-3.84 (m, 2H), 3.82-3.71 (m, 3H), 3.60-3.51 (m, 2H), 3.39-3.35 (m, 2H), 2.99-2.77 (m, 1 H), 2.46-2.40 (m, 1 H), 1 .07-1.02 (m, 3H).
[00293] Example 59:
l-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yI) ,6-dihydropyrimidi n-4-yl)methyl)-4-hydroxypyrroiidine-2-carboxylic acid
Figure imgf000143_0001
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)- 1 ,4-dihydro pyrimidine-5-carboxylate ( 1.92 g, 3.81 mmol) was reacted with 4-hydroxypyrrolidine- 2-carboxylic acid (0.5 g, 3.81 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid (1 .37 g, 65%). The compound was characterized by the following spectroscopic data: MS-ESI: (ESI, pos.ion) mlz: 553.2 [M+l ] ;
Ή NMR (400 MHz, DMSO- 6): δ 12.41 (br.s, 1H), 9.86 (br.s, 1H), 7.99 (d, 1 H), 7.92 (d, 1H), 7.59-7.54 (m, 1 H), 7.45-7.35 (m, 1H), 7.28-7.20 (m, 1H), 6.02 (s, 1H), 5.09-5.01 (m, 1 H), 4.40-4.30 (m, 3H), 3.99-3.94 (m, 3H), 3.76-3.66 (m, 1 H), 2.07 (br.s, 2H), 1 .06 (t, 3H).
[00294] Example 60:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(((5)-3-(methoxy(methyl)carbamoyl)morpholino) methyl)-2-(thiazol-2-yl)-l,4-dihydropyrimidine-5-carboxyIate
Figure imgf000144_0001
(35)-4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropy rimidin-4-yl)methyl)mo holine-3-carboxylic acid (4 g, 7.2 mmol) was reacted with N,0-dimethylhydroxylamine hydrochloride (0.84 g, 8.64 mmol) according to the procedure as described in Example 53 to give the title compound as a yellow solid (1.5 g, 35%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 596.0 [M+l f;
JH NMR (400 MHz, DMSO-</6): δ 9.93 (br.s, 1 H), 8.04 (d, 1 H), 7.95 (d, 1H), 7.58-7.55 (m, 1 H), 7.43-7.38 (m, 1H), 7.26-7.20 (m, 1H), 6.02 (s, 1H), 4.20-4.05 (m, 1H), 3.98-3.88 (m, 4H), 3.82-3.79 (m, 1 H), 3.76 (s, 3H), 3.70-3.56 (m, 3H), 3.25-3.15 (m, 1H), 3.13 (s, 3H), 2.65-2.58 (m, 1H), 1.07 (t, 3H).
[00295] Example 61 :
(35)-4-((6-(2-bromo-4-fluorophenyI)-5-(ethoxycarbonyl)-2-(4-(2-methoxy-2-oxoethyl)thi azol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid
Figure imgf000145_0001
[00296] Step A: Ethyl 2-(2-cyanothiazol-4-yl)acetate
To a mixture of /<?r/-butyl nitrite (10 mL, 80 mmol) and CuCN (7.28 g, 80 mmol) in anhydrous acetonitrile (30 mL) was added a solution of ethyl 2-(2-aminothiazol-4-yl)acetate (7.5 g, 40 mmol) in anhydrous acetonitrile (20 mL) dropwise over a period of 1 hour at 50 °C, then the mixture was stirred at the temperature for 2.5 hours. The mixture was concentrated in vacuo and the residue was purified by a silica gel column chromatography (PETROLEUM ETHER/EtOAc (V/V) = 25/1) to give the title compound as yellowish liquid (2 g, 25%). The compound was characterized by the following spectroscopic data:
Ή NMR (400 MHz, DMSO-d6): δ 4.01 (q, 2H), 3.72 (s, 2H), 1 .16 (t, 3H).
[00297] Step B: Methyl 2-(2-carbamiraidoylthiazol-4-yl)acetate hydrochloride
A mixture of ethyl 2-(2-cyanothiazol-4-yl)acetate (2.17 g, 11 mmol), sodium methylate (0.84 g, 15.5 mmol) and ammonium chloride (0.88 g, 16.5 mmol) in anhydrous methanol (50 mL) was stirred at 25 °C for 24 hours under N2. The reaction mixture was filtered and the filtrate was concentrated in vacuo. Then to the the residue was added acetone (12 mL). The mixture was stirred for 3 hours and filtered. The filter cake was washed with a little of acetone to give the title compound as a yellowish solid ( 1.63 g, 63%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 200.1 [M+l ]+;
Ή NMR (400 MHz, D20): δ 6.76 (s, 1 H), 3.77 (s, 3H), 3.68 (s, 2H).
[00298] Step C: Ethyl 4-(2-bromo-4-fluorophenyl)-2-(4-(2-methoxy-2-oxoethyl) thiazol-2-yl)-6-methy]-l,4-dihydropyrimidine-5-carboxylate
Methyl 2-(2-carbamimidoylthiazol-4-yl)acetate hydrochloride (2.35 g, 10 mmol) was reacted with 2-bromo-4-f1uorobenzaldehyde (2.03 g, 10 mmol) and ethyl 3-oxobutanoate ( 1 .56 g, 12 mmol) according to the procedure as described in Example 1 , Step A to give the title compound as a yellow solid (2.48 g, 50%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 496.2 [M+l ;
Ή NMR (400 MHz, DMSO-</6): δ 9.84 (br.s, 1H), 7.77 (s, 1H), 7.55-7.20 (m, 3H), 5.89 (s, 1 H), 3.92 (q, 2H), 3.90 (s, 2H), 3.62 (s, 3H), 2.47 (s, 3H), 1.03 (t, 3H).
100299] Step D: Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(4-(2- methoxy-2-oxoethyl) thiazol-2-yl)-l,4-dihydropyrimidine-5-carboxylate
Ethyl 4-(2-bromo-4-fluorophenyl)-2-(4-(2-methoxy-2-oxoethyl)thiazol-2-yl)-6-methyl- 1 ,4-dihydropyrimidine-5-carboxylate ( 1 g, 2 mmol) was reacted with NBS (0.39 g, 2.2 mmol) according to the procedure as described in Example 1 , Step B to give the title compound as a yellow solid (0.81 g, 70%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 574.1 [M+lf;
Ή NMR (400 MHz, DMSO-i 6): δ 9.88 (br.s, 1H), 7.78 (s, 1H), 7.56-7.23 (m, 3H), 6.01 (s, 1 H), 4.68 (dd, 2H), 3.98 (q, 2H), 3.91 (s, 2H), 3.62 (s, 3H), 1.06 (t, 3H).
[00300] Step E: (35 -4-((6-(2-bromo-4-fluorophenyI)-5-(ethoxycarbonyl)-2-(4-(2- methoxy-2-oxoethyl)thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carb oxylic acid
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(4-(2-methoxy-2-oxoethyl) thiazol-2-yl)-l ,4-dihydropyrimidine-5-carboxylate (1 .15 g, 2 mmol) was reacted with (Symorpholine-3-carboxylic acid (0.39 g, 3 mmol) according to the procedure as described in Example 1 , Step C to give the title compound as a yellow solid (0.75 g, 60%). The compound was characterized by the following spectroscopic data:
MS-ES1: (ESI, pos.ion) mlz: 625.0 [M+l ]+;
Ή NMR (400 MHz, DMSO-i 6): δ 9.93 (br.s, 1 H), 7.72 (s, 1 H), 7.56-7.54 (m, 1H), 7.43-7.37 (m, 1H), 7.21-7.17 (m, 1H), 6.02 (br.s, 1H), 4.37-4.09 (m, 2H), 4.06-3.94 (m, 3H), 3.91 (s, 2H), 3.83-3.74 (m, 2H), 3.65 (s, 3H), 3.55-3.49 (m, 2H), 3.11 -3.08 (m, 1H), 2.50-2.34 (m, 1 H), 1 .06 (t, 3H).
[00301 ] Example 62:
(35 -4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(4-(2-(methylamino)-2-oxoeth yl)thiazol-2-yl)-3,6-dihydropyrimidin-4-y])methyl)morpholine-3-carboxyIic acid
Figure imgf000147_0001
[00302] Step A: 2-(2-(4-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-6-methyl-l,4- dihydropyrimidin-2-y])thiazoI-4-yl)acetic acid
Ethyl 4-(2-bromo-4-fluorophenyl)-2-(4-(2-methoxy-2-oxoethyl)thiazol-2-yl)-6-methyl- 1 ,4-dihydropyrimidine-5-carboxylate (1 g, 2 mmol) was reacted with sodium hydroxide (0.24 g, 6 mmol) according to the procedure as described Example 58, Step B to give the title compound as a yellow solid (0.87 g, 90%). The compound was characterized by the following spectroscopic data:
MS-ES1: (ESI, pos.ion) mlz: 482.0 [M+l ]+;
Ή NMR (400 MHz, DMSO-i/6): δ 9.87 (br.s, 1 H), 7.79 (s, 1H), 7.53-7.21 (m, 3H), 5.99 (s, 1 H), 4.01 (q, 2H), 3.92 (s, 2H), 2.49 (s, 3H), 1 .08 (t. 3H).
[00303] Step B: Ethyl 4-(2-bromo-4-fluorophenyI)-6-methyl-2-(4-(2-(methylamino)- 2-oxoethyl)thiazoI-2-yl)-l,4-dihydropyrimidine-5-carboxylate
A solution of 2-(2-(4-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-6-methyl-l ,4- dihydropyrimidin-2-yl)thiazol-4-yl)acetic acid (3 g, 6.2 mmol), EDC HCl (1.55 g, 8.06 mmol), HOAt (0.84 g, 6.2 mmol) and D1PEA ( 1.6 g, 12.4 mmol) in DMF (60 mL) was cooled to 10 °C and then stirred at -10 °C for 30 minutes. Then methanamine hydrochloride (0.63 g, 9.3 mmol) was added and the mixture was stirred for another 1 hour. The mixture was warmed to 50 °C and stirred for 4 hours. The reaction solution was diluted with EtOAc ( 150 mL), and washed with brine ( 100 mL x 6). The organic layer was dried over Na2S04, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PETROLEUM ETHER/EtOAc (V V) = 3/1 ) to give the title compound as a yellow solid (1 .2 g, 39%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 496.2 [M+l]+;
Ή NMR (400 MHz, DMSO-</6): δ 9.84 (br.s, 1 H), 7.77 (s, 1H), 7.55-7.20 (m, 3H), 5.89 (s, 1H), 3.92 (q, 2H), 3.90 (s, 2H), 3.51 (s, 3H), 2.44 (s, 3H), 1.08 (t, 3H).
[00304] Step C: Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyI)-2-(4-(2-(methyl amino)-2-oxoethyl)thiazoI-2-yl)-l,4-dihydropyrimidine-5-carboxylate
Ethyl 4-(2-bromo-4-fluorophenyl)-6-methyl-2-(4-(2-(methylamino)-2-oxoethyl)thiazol- 2-yl)-l ,4-dihydropyrimidine-5-carboxylate (1 g, 2 mmol) was reacted with NBS (0.39 g, 2.2 mmol) according to the procedure as described in Example 1 , Step B to give the title compound as a yellow solid (0.63 g, 55%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 573.0 [M+l ]+;
Ή NMR (400 MHz, DMSO-i/6): δ 9.83 (br.s, 1 H), 7.79 (s, 1H), 7.56-7.21 (m, 3H), 6.04 (s, I H), 4.65 (dd, 2H), 3.99 (q, 2H), 3.90 (s, 2H). 3.52 (s, 3H), 1.07 (t. 3H).
[00305] Step D: (3S)-4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyI)-2-(4-(2- (methylamino)-2-oxoethyl)thiazoI-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3 -carboxylic acid
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(4-(2-(methylamino)-2-oxoethyl) thiazol-2-yl)-l ,4-dihydropyrimidine-5-carboxylate (1.15 g, 2 mmol) was reacted with (5")-morpholine-3-carboxylic acid (0.39 g, 3 mmol) according to the procedure as described in Example 1 , Step C to give the title compound as a yellow solid (0.66 g, 53%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 624.1 [M+l ]+;
Ή NMR (400 MHz, DMSO-i/6): δ 12.86 (br.s, I H), 9.93 (br.s, I H), 7.76 (s, I H), 7.56-7.47 (m, IH), 7.43-7.35 (m, IH), 7.21 -7.15 (m, IH), 6.02 (s, IH), 4.37-4.1 1 (m, 2H), 4.06-3.96 (m, 3H), 3.91 (s, 2H), 3.85-3.74 (m, 2H), 3.56 (s, 3H), 3.54-3.45 (m, 2H), 3.11-3.08 (m, IH), 2.50-2.38 (m, IH), 1.06 (t, 3H).
[00306] Example 63:
4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(4-(2-(isopropylamino)-2-oxo ethyl)thiazol-2-yI)-3,6-dihydropyrimidin-4-yI)methy])morpholine-3-carboxylic acid
Figure imgf000149_0001
[00307] Step A: Ethyl 4-(2-bromo-4-nuorophenyl)-2-(4-(2-(isopropylamino)-2- oxoethyl)thiazol-2 -yl)-6-methyI-l,4-dihydropyrimidine-5-carboxylate
2-(2-(4-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-6-methyl- l ,4-dihydropyrimidin-2 -yl)thiazol-4-yl)acetic acid {3 g, 6.2 mmol) was reacted with isopropylamine (0.55 g, 9.3 mmol) according to the procedure as described in Example 62, Step B to give the title compound as a yellow solid (1.46 g, 45%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 523.1 [M+l]+;
Ή NMR (400 MHz, DIVISOR): δ 9.88 (br.s, I H), 7.75 (s, IH), 7.51-7.20 (m, 3H), 5.92 (s, I H). 4.01 (q, 2H), 3.90 (s, 2H), 3.86-3.82 (m, I H), 2.49 (s, 3H), 1 .08 (t, 3H), 0.97-0.89 (m, 6H).
[00308] Step B: Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(4-(2- (isopropylamino)-2-oxoethyl)thiazoI-2-yl)-l,4-dihydropyrimidine-5-carboxylate
Ethyl 4-(2-bromo-4-fluorophenyl)-2-(4-(2-(isopropylamino)-2-oxoethyl)thiazol-2-yl)- 6-methyl-l ,4-dihydropyrimidine-5-carboxylate ( 1 .05 g, 2 mmol) was reacted with NBS (0.39 g, 2.2 mmol) according to the procedure as described in Example 1 , Step B to give the title compound as a yellow solid (0.6 g, 50%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 601.0 [M+l ]+;
1H NMR (400 MHz, DMSO-<¾: δ 9.88 (br.s, IH), 7.76 (s, IH), 7.51-7.24 (m, 3H), 6.01 (s, IH), 4.68-4.57 (m, 2H), 4.06 (q, 2H), 3.94 (s, 2H), 3.85-3.80 (m, IH), 1.05 (t, 3H), 0.97-0.84 (m, 6H).
[00309] Step C: 4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyI)-2-(4-(2-(iso propyIamino)-2-oxoethyl)thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3- carboxylic acid
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(4-(2-(isopropylamino)-2-oxo ethyl)thiazol-2-y])- l ,4-dihydropyrimidine-5-carboxylate ( 1 .2 g, 2 mmol) was reacted with morpholine-3-carboxylic acid (0.39 g, 3 mmol) according to the procedure as described in Example 1 , Step C to give the title compound as a yellow solid (0.64 g, 49%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlr. 652.2 [M+l ;
Ή NMR (400 MHz, DMSO-i/6): δ 12.83 (br.s, 1H), 9.96 (br.s, 1 H), 7.78 (s, 1H), 7.56-7.46 (m, 1H), 7.45-7.35 (m, 1H), 7.21 -7.15 (m, 1H), 6.05 (s, 1H), 4.38-4.12 (m, 2H), 4.09-3.94 (m, 3H), 3.93 (s, 2H), 3.89-3.75 (m, 3H), 3.50-3.45 (m, 2H), 3.12-3.08 (m, 1H), 2.53-2.38 (m, 1 H), 1 .06 (t, 3H), 0.95-0.83 (m, 6H).
[00310] Example 64:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-((2-((2-hydroxyethyl)carbamoyl)morpholino) methyl)-2-(thiazol-2-yl)-l,4-dihydropyrimidine-5-carboxylate
Figure imgf000151_0001
4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimid in-4-yl)methyl)morpholine-2-carboxylic acid (0.5 g, 0.9 mmol) was reacted with 2-aminoethanol (72 mg, 1.2 mmol) according to the procedure as described in Example 53 to give the title compound as a yellow solid (0.32 g, 60%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlr. 596.1 [M+l ] ;
Ή NMR (400 MHz, DMSO- 6): δ 9.63 (s, 1 H), 8.01 (d, 1 H), 7.95 (d, 1 H), 7.59-7.56 (m, 1 H), 7.42-7.38 (m, 1 H), 7.25-7.19 (m, 1 H), 6.03 (s, 1 H), 4.72-4.68 (m, 1H), 4.03-3.92 (m, 5H), 3.71 -3.61 (m, 1H), 3.43-3.39 (m, 2H), 3.17-3.14 (m, 2H), 2.99-2.81 (m, 1 H), 2.67-2.39 (m, 1 H), 2.34-2.21 (m, 2H), 1.05 (t, 3H). [0031 1 ] Example 65:
2-(4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrim idin-4-yl)methyl)morpholine-2-carboxamido acetic acid
Figure imgf000152_0001
[00312] Step A: Ethyl 4-(2-bromo-4-fluorophenyl)-6-((2-((2-ethoxy-2-oxoethyl) carbamoyl)morpholino)methyl)-2-(thiazol-2-yl)-l,4-dihydropyrimidine-5-carboxylate
4-((6-(2-brorao-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrirnid in-4-yl)methyl)mo holine-2-carboxylic acid (0.8 g, 1 .45 mmol) was reacted with ethyl 2-aminoacetate hydrochloride (0.31 g, 2.17 mmol) according to the procedure as described in Example 53 to give the title compound as a yellow solid (0.76 g, 82%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 638.2 [M+l]+;
Ή NMR (400 MHz, DMSO-i 6): δ 9.62 (br.s, 1 H), 8.19 (br.s, 1H), 8.02 (d, 1 H), 7.95 (d, 1H), 7.59 (dd, 1 H), 7.42-7.39 (m, 1 H), 7.25-7.19 (m, 1 H), 6.04 (s, 1 H), 4.12-4.07 (m, 2H), 4.06-4.03 (m, 1H), 4.02-3.99 (m, 2H), 3.98-3.89 (m, 3H), 3.83 (t, 2H), 3.73-3.64 (m, 1H), 3.17-2.97 (m, 1H), 2.86-2.69 (m, 1H), 2.46-2.22 (m, 2H), 1.21-1.16 (m, 3H), 1.06 (t, 3H).
[00313] Step B: 2-(4-((6-(2-bromo-4-fluorophenyI)-5-(ethoxycarbonyl)-2-(thiazol-2- yl)-3,6- dihydropyrimidin-4-yl)methyl)morpholine-2-carboxamido)acetic acid
Ethyl 4-(2-bromo-4-fluoro henyl)-6-((2-((2-ethoxy-2-oxoethyl)carbamoyl)mo holino) methyl)-2-(thiazol-2-yl)-l ,4-dihydropyrimidine-5-carboxylate (0.5 g, 0.8 mmol) was reacted with sodium hydroxide (0.32 g, 8 mmol) according to the procedure as described in Example 58, Step B to give the title compound as a yellow solid (0.43 g, 88%). The compound was characterized by the following spectroscopic data: MS-ES1: (ESI, pos.ion) mlz: 610.2 [M+l]+;
Ή NMR (400 MHz, DMSO- 6): δ 12.27 (br.s, IH), 9.63 (s, IH), 8.01 (d, I H), 7.95 (d, I H), 7.58-7.56 (m, IH), 7.42-7.39 (m, IH), 7.25-7.20 (m, IH), 6.04 (s, IH), 4.06-3.89 (m, 6H), 3.77-3.64 (m, 3H), 3.17-2.98 (m, IH), 2.86-2.69 (m, IH), 2.46-2.22 (m, 2H), 1.06 (t, 3H).
[00314] Example 66:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(((S)-2-(hydroxymethyl)morpholino)methyl)-2- (thiazol-2-yI)-l,4-dihydropyriraidine-5-carboxylate
Figure imgf000153_0001
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)- 1 ,4-dihydro pyrimidine-5-carboxylate (1 g, 2 mmol) was reacted with (S)-morpholin-2-ylmethanol hydrochloride (0.34 g, 2.2 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a yellow solid (0.25 g, 23%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 539.1 [M+l ]+;
Ή NMR (400 MHz, CDC13): δ 9.66 (d, IH), 8.01 (d, I H), 7.94 (d, I H), 7.56-7.48 (m, IH), 7.40-7.32 (m, I H), 7.20-7.13 (m, I H), 6.02 (s, IH), 3.98-3.34 (m, 7H), 2.95-2.62 (m, 4H), 2.45-2.00 (m, 2H), 1 .05 (t, 3H).
[00315] Example 67:
2-((4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyri midin-4-yI)methyl)morphoIin-3-yl)methyl)-3-ethoxy-3-oxopropanoic acid
Figure imgf000154_0001
[00316] Step A: Diethyl 2-((4-benzylmorpholin-3-yI)methyl)maIonate
Diethyl malonate (1.78 g, 11.1 mmol), DMF (25 mL), sodium hydroxide (0.22 g, 5.55 mmol) and 4-benzyl-3-(bromomethyl)morpholine ( 1 g, 3.7 mmol) (The compound was synthesized according to the procedure as described in Helvetica Chimica Acta, 87, 2004) were added to a dried flask in turn. The mixture was stirred at 80 °C for 4 hours under N2, and cooled to 25 °C . The reaction mixture was diluted with EtOAc (200 mL). The organic layer was washed with brine (100 mL x 6), dried over unhydrous Na2S04. The crude product was purified by a silica gel column chromatography (PETROLEUM ETHER/EtOAc (V V) = 15/1) to give the title compound as colorless oil (1.15 g, 89%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 350.3 [M+l ]+;
Ή NMR (400 MHz, CDC13): δ 7.35-7.24 (m, 5H), 4.20-4.15 (m, 4H), 4.04 (d, I H), 3.81 -3.79 (m, IH), 3.70-3.68 (m, IH), 3.60-3.54 (m, 2H), 3.46-3.43 (m, IH), 3.35 (d, IH), 2.74-2.71 (m, I H), 2.51 (br.s, I H), 2.39-2.35 (m, IH), 2.26 (m, I H), 2.20-2.15 (m, IH), 1.29-1.25 (m, 6H).
[00317] Step B: Diethyl 2-(morpholin-3-ylmethyl)malonate
Diethyl 2-((4-benzylmo holin-3-yl)methyl)malonate (1 g, 2.86 mmol) was reacted with Pd C ( 10%, 0.1 g) according to the procedure as described in Example 34, Step C to give the title compound as colorless oil (0.66 g, 89%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 260.2 [M+l ]+;
Ή NMR (400 MHz, DMSO-c 6): δ 4.17-4.06 (m, 4H), 4.01-3.66 (m, 2H), 3.55-3.42 (m, 2H), 3.31-3.15 (m, 1H), 3.08-2.87 (m, 2H), 2.54-2.50 (m, 1H), 2.47-2.23 (m, 1 H), 1 .86-1.69 (m, 1H), 1.23-1.16 (m, 6H).
[00318] Step C: Diethyl 2-((4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2- (thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morphoIin-3-yl)methyl)maIonate
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromornethy])-2-(thiazol-2-yl)-] ,4-dihydropyrirni dine-5-carboxylate (0.77 g, 1 .53 mmol) was reacted with diethyl
Figure imgf000155_0001
malonate (0.4 g, 1.53 mmol) according to the procedure as described in Example 24 to give the title compound as a pale yellow solid (0.32 g, 47%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 681.1 [M+l ]+;
Ή NMR (400 MHz, DMSO-t/6): δ 9.67 (br.s, 1H), 8.01 (d, 1H), 7.95 (d, 1H), 7.58-7.56 (m, 1H), 7.42-7.37 (m, 1H), 7.24-7.18 (m, 1H), 6.04 (m, 1H), 4.25-4.04 (m, 5H), 4.02-3.89 (m, 4H), 3.72-3.60 (m, 4H), 2.96-2.62 (m, 5H), 1.17-1.04 (m, 9H).
[00319] Step D: 2-((4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyI)-2-(thiazoI-2- yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholin-3-yl)methyl)-3-ethoxy-3-oxopropanoic acid
Diethyl 2-((4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-di hydropyrimidin-4-yl)methyl)mo holin-3-yl)methyl)malonate (0.3 g, 0.44 mmol), anhydrous ethanol (6 mL) and a solution of sodium hydroxide (17.6 mg, 0.44 mmol) in water (1 mL) were added to a dried flask in turn, then the mixture was stirred at 25 °C for 4 hours. The mixture was concentrated in vacuo and the residue was purified by a silica gel column chromatography (DCM/MeOH (V/V) = 25/1 ) to give the title compound as a yellow solid (0.22 g, 75%). The compound was characterized by the following spectroscopic data: MS-ES1: (ESI, pos.ion) mlr. 653.1 [M+l]+;
Ή NMR (400 MHz, DMSO-c/6): δ 13.03 (br.s, 1H), 9.72 (br.s, 1H), 8.07 (d, 1 H), 7.94 (d, 1H), 7.58-7.55 (m, 1 H), 7.41-7.38 (m, 1H), 7.25-7.21 (m, lH), 6.02 (s, 1H), 4.23-4.10 (m, 2H), 4.04-3.87 (m, 5H), 3.75-3.59 (m, 3H), 2.97-2.90 (m, 1 H), 2.81-2.66 (m, 3H), 2.60 (br.s, 1H), 1.18-1.04 (m, 6H).
[00320] Example 68:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-((3-(3-hydroxy-2-(hydroxymethyl)propyl)morpho lino)methyl)-2-(thiazol-2-yI)-l,4-dihydropyrimidine-5-carboxyIate
Figure imgf000156_0001
[00321 ] Step A: 2-((4-benzylmorpholin-3-yl)methy])propane-l,3-diol
LiAlH (0.35 g, 9.32 mmol) in a dried flask was cooled to 0 °C, and then anhydrous THF (15 mL) was added. The mixture was stirred thoroughly and a solution of diethyl 2-((4-benzylmo holin-3-yl)methyl)malonate (0.93 g, 2.66 mmol) in anhydrous THF (5 mL) was added, then the mixture was stirred at 70 °C for 6 hours and cooled to 30 °C. To the reaction mixture were added water (0.5 mL), sodium hydroxide aqueous solution ( 10%, 0.5 mL) and water (3 mL) in turn, then the mixture was stirred at 25 °C for 10 minutes and filtered. The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (PETROLEUM ETHER/EtOAc (V V) = 3/1 ) to give the title compound as colorless oil (0.38 g, 54%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlr 266.3 [M+l ]+; Ή NMR (400 MHz, CDC1 ): δ 7.33-7.29 (m, 5H), 4.25 (d, 1 H), 3.85-3.83 (m. 1 H), 3.76-3.59 (m, 7H), 3.33 (d, 1 H), 2.77-2.74 (m, 1 H), 2.66 (br.s, 1 H), 2.31 -2.27 (m, 1 H), 1.93-1.89 (m, 1H), 1.84-1.80 (m, 1 H), 1.74-1 .69 (m, 2H).
[00322] Step B: 2-(morpholin-3-ylmethyl)propane-l,3-diol
2-((4-benzylmo holin-3-yl)methyl)propane-l ,3-diol (0.18 g, 0.68 mmol) was reacted with Pd/C ( 10%, 25 mg) according to the procedure as described in Example 34, Step C to give the title compound as colorless oil (0.1 g, 83%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 176.3 [M+l ] ;
Ή NMR (400 MHz, CH3OH-c/4): δ 4.38-4.18 (m, 1H), 4.14-3.91 (m, 2H), 3.74-3.57 (m, 5H), 3.55-3.50 (m, 1 H), 3.45-3.36 (m, 2H), 3.25 (br.s, 1 H), 3.13-3.07 (m, 1 H), 2.99-2.83 (m, 1 H), 2.17-2.14 (m, 1 H), 1 .77-1.61 (m, 2H).
[00323] Step C: Ethyl 4-(2-bromo-4-fluorophenyl)-6-((3-(3-hydroxy-2-(hydroxy methyl)propyI)morpholino)methyl)-2-(thiazoI-2-y])-l,4-dihydropyrimidine-5-carboxylat e
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)- 1 ,4-dihydro pyrimidine-5-carboxylate (0.34 g, 0.68 mmol) was reacted with 2-(morpholin-3-ylmethyl)propane-l ,3-diol (0.12 g, 0.68 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a yellow solid (0.18 g, 44%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 597.2 [M+ l ]+;
Ή NMR (400 MHz, DMSO-rf6): δ 9.86 (br.s, 1H), 8.03 (d, 1H), 7.95 (d, 1 H), 7.58-7.55 (m, 1 H), 7.39-7.36 (m, 1 H), 7.23-7.17 (m, 1 H), 6.02 (s, 1 H), 4.45-4.36 (m, 2H), 4.20-4.13 (m, 1 H), 3.99 (q, 2H), 3.89-3.79 (m, 2H), 3.75-3.68 (m, 1 H), 3.64-3.57 (m, 1 H), 3.46-3.35 (m, 3H), 3.26-3.21 (m, 1 H), 2.82-2.62 (m, 2H), 1.54-1.30 (m, 3H), 1.07 (t, 3H). [00324] Example 69:
4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(5-methyl-l,3,4-thiadiazol-2-yl)-3, 6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxyIic acid
Figure imgf000158_0001
[00325] Step A: 5-methyl-l,3,4-thiadiazole-2-carbonitrile
5-methyl-l ,3.4-thiadiazol-2-amine ( 11 .5 g, 100 mmol) was reacted with CuCN (10.75 g, 120 mmol) according to the procedure as described in Example 61 , Step A to give the title compound as a white solid (1.6 g, 13%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 126.2 [M+l ]+; Ή NMR (400 MHz, CDC13): δ 2.94 (s, 3H).
[00326] Step B: 5-methyl-l,3,4-thiadiazole-2-carboximidamide hydrochloride
5-methyl-l ,3,4-thiadiazole-2-carbonitrile (1.25 g, 10 mmol) was reacted with sodium methoxide (0.54 g, 10 mmol) and ammonium chloride (0.64 g, 12 mmol) according to the procedure as described in Example 61 , Step B to give the title compound as a yellowish solid ( 1 .25 g, 70%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 143.1 [M+l ]' ;
Ή NMR (400 MHz, D20): δ 2.99 (s, 3H).
[00327] Step C: Ethyl 4-(2-bromo-4-fluorophenyl)-6-methyl-2-(5-methyl-l,3,4-thia diazol-2-yl)-l,4 -dihydropyrimidine-5-carboxylate 5-methyl-l ,3,4-thiadiazole-2-carboximidamide hydrochloride (1.8 g, 10 mmol) was reacted with 2-bromo-4-fluorobenzaldehyde (2.03 g, 10 mmol) and ethyl 3-oxobutanoate (1.56 g, 12 mmol) according to the procedure as described in Example 1 , Step A to give the title compound as a yellow solid ( 1.0 g, 25%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 440.9 [M+l ]+;
JH NMR (400 MHz, DMSO-< 6): δ 10.24 (br.s, 1 H), 7.56-7.21 (m, 3H), 5.98 (s, 1 H), 3.93 (q, 2H), 2.72 (s, 3H), 2.46 (s, 3H), 1 .10 (t, 3H).
[00328] Step D: Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(5-methyl- l,3,4-thiadiazol-2-yl)-l,4-dihydropyrimidine-5-carboxylate
Ethyl 4-(2-bromo-4-fIuorophenyl)-6-methyl-2-(5-methyl-l ,3,4-thiadiazol-2-yl)-l ,4- dihydropyrimidine-5-carboxylate (0.88 g, 2 mmol) was reacted with NBS (0.36 g, 2 mmol) according to the procedure as described in Example 1 , Step B to give the title compound as a yellow solid (0.73 g, 70%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 517.2 [M+l ]+;
Ή NMR (400 MHz, DMSO-c/6): δ 10.25 (br.s, 1H), 7.57-7.20 (m, 3H), 6.01 (s, 1H), 4.65-4.43 (m, 2H), 3.92 (q, 2H), 2.78 (s, 3H), 1.08 (t, 3H).
[00329] Step E: 4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyI)-2-(5-methyI-l,3, 4-thiadiazol-2-yI)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(5-methyl-l ,3,4-thiadiazol-2-yl)- l ,4-dihydropyrimidine-5-carboxylate ( 1.04 g, 2 mmol) was reacted with morpholine-3- carboxylic acid (0.26 g, 2 mmol) according to the procedure as described in Example 1 , Step C to give the title compound as a yellow solid (0.63 g, 55%). The compound was characterized by the following spectroscopic data: MS-ESI: (ESI. pos.ion) mlz: 568.1 [M+l ]+;
Ή NMR (400 MHz, CDC13): δ 9.85 (br.s, IH), 7.33-6.98 (m, 3H), 6.18 (s, IH), 4.11 -4.09 (m, I H), 4.06 (q, 2H), 4.02-4.01 (m, IH), 3.95-3.88 (m, I H), 3.83-3.65 (m, 3H), 3.58-3.45 (m, I H), 3.23-3.13 (m, I H), 2.74 (s, 3H), 2.63-2.57 (m, IH), 1 .13 (t, 3H).
[00330] Example 70:
4-((6-(2,4-dichlorophenyl)-5-(ethoxycarbonyI)-2-(l ,3,4-thiadiazol-2-yI)-3,6-dihydropyri midin-4-yl)methyl)morphoIine-3-carboxylic acid
Figure imgf000160_0001
[00331 ] Step A: l,3,4-thiadiazoIe-2-carbonitrile l ,3,4-thiadiazol-2-amine (4.05 g, 40 mmol) was reacted with CuCN (7.2 g, 80 mmol) according to the procedure as described in Example 61 , Step A to give the title compound as red liquid (1 .78 g, 40%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 112.0 [M+l]+; Ή NMR (400 MHz, DMSCW6): δ 9.56 (s, I H).
[00332] Step B: l,3,4-thiadiazole-2-carboximidamide hydrochloride l ,3,4-thiadiazole-2-carbonitrile (1 .1 1 g, 10 mmol) was reacted with sodium methoxide (0.81 g, 15 mmol) and ammonium chloride (0.96 g, 18 mmol) according to the procedure as described in Example 61 , Step B to give the title compound as an offwhite solid ( 1.15 g, 70%). The compound was characterized by the following spectroscopic data: S-ESI: (ESI, pos.ion) mlz: 129.0 [M+l ]+; Ή NMR (400 MHz, D20): δ 9.52 (s, 1 H).
[00333] Step C: Ethyl 4-(2,4-dichlorophenyI)-6-methyl-2-(l,3,4-thiadiazoI-2-yl)-l,4- dihydro pyrimidine-5-carboxylate
1 ,3,4-thiadiazole-2-carboximidamide hydrochloride (1.43 g, 8.69 mmol) was reacted with 2,4-dichlorobenzaldehyde ( 1 .52 g, 8.69 mmol) and ethyl 3-oxobutanoate ( 1 .36 g, 10.5 mmol) according to the procedure as described in Example 1 , Step A to give the title compound as a yellow solid (1.83 g, 53%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 397.1 [M+ l ]+;
Ή NMR (400 MHz, DMSO-c ): δ 10.36 (br.s, 1 H), 9.71 (s, 1H), 7.62-7.40 (m, 3H), 6.06 (s, 1 H), 3.99 (q, 2H), 2.53 (s, 3H), 1.06 (t, 3H).
[00334] Step D: Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(l,3,4-thiadiazol- 2-yl)-l,4-dihydropyrimidine-5-carboxylate
Ethyl 4-(2,4-dichlorophenyl)-6-methyl-2-(l ,3,4-thiadiazol-2-yl)-l ,4-dihydropyrimidine -5-carboxylate (1 g, 2.5 mmol) was reacted with NBS (0.5 g, 2.8 mmol) according to the procedure as described in Example 1 , Step B to give the title compound as a yellow solid (0.71 g, 60%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 475.1 [M+l ]+;
Ή NMR (400 MHz, DMSO-i ): δ 10.38 (br.s, 1H), 9.70 (s, 1H), 7.61 -7.38 (m, 3H), 6.05 (s, 1 H), 4.65-4.48 (m, 2H), 4.01 (q, 2H), 1.06 (t, 3H).
[00335] Step E: 4-((6-(2,4-dichlorophenyl)-5-(ethoxycarbonyl)-2-(l,3,4-thiadiazol-2- yl)-3,6-dihydro pyrimidin-4-yl)methyl)morpholine-3-carboxylic acid
Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(l ,3,4-thiadiazol-2-yl)- l ,4-dihydro pyrimidine-5-carboxylate (0.7 g, 1.5 mmol) was reacted with morpholine-3-carboxylic acid (0.2 g, 1.5 mmol) according to the procedure as described in Example 1 , Step C to give the title compound as a yellow solid (0.44 g, 56%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlr. 526.0 [M+l ]+;
Ή NMR (400 MHz. CDC13): δ 9.17 (s, 1 H), 7.41-7.39 (m, 1 H), 7.29-7.26 (m, 1H), 7.21 -7.17 (m, 1 H), 6.23 (s. 1 H), 4.35-4.15 (m, 2H), 4.10-3.92 (m, 4H), 3.85-3.78 (m, 2H), 3.62-3.51 (m, 1 H), 3.25-3.15 (m, 1 H), 2.65-2.59 (m, 1 H), 1.10 (t, 3H).
[00336] Example 71 :
4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(l,3,4-thiadiazol-2-yl)-3,6-dihydro pyrimidin-4-yl)methyl)morpholine-3-carboxylic acid
Figure imgf000162_0001
[00337] Step A: Ethyl 4-(2-bromo-4-fluorophenyl)-6-methyl-2-(l,3,4-thiadiazol- 2-yl)-l,4-dihydropyrimidine-5-carboxylate l ,3,4-thiadiazole-2-carboximidamide hydrochloride (1.43 g, 8.69 mmol) was reacted with 2-bromo-4-fluorobenzaldehyde (1.76 g, 8.69 mmol) and ethyl 3-oxobutanoate (1.36 g, 10.5 mmol) according to the procedure as described in Example 1 , Step A to give the title compound as a yellow solid (1.74 g, 47%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlr. 425.0 [M+l ]+;
Ή NMR (400 MHz. DMSO-rf6): δ 10.37 (br.s, 1 H), 9.68 (s, 1 H), 7.57-7.23 (m, 3H), 6.01 (s, 1 H), 4.03 (q, 2H), 2.51 (s, 3H), 1 .06 (t. 3H).
[00338] Step B: Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(l,3,4-thia diazol-2-yl)-l,4-dihydropyrimidine-5-carboxylate
Ethyl 4-(2-bromo-4-fluorophenyl)-6-methyl-2-( 1 ,3,4-thiadiazol-2-yl)-l ,4-dihydro pyrimidine-5-carboxylate (1.06 g, 2.5 mmol) was reacted with NBS (0.5 g, 2.8 mmol) according to the procedure as described in Example 1 , Step B to give the title compound as a yellow solid (0.89 g, 71 %). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 503.1 [M+l ]" ;
Ή NMR (400 MHz, DMSO-i/6): δ 10.38 (br.s, 1 H), 9.69 (s, 1 H), 7.56-7.22 (m, 3H), 6.00 (s, 1 H), 4.65-4.47 (m, 2H), 4.03 (q, 2H), 1 .08 (t, 3H).
[00339] Step C: 4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(l,3,4-thia diazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(l ,3,4-thiadiazol-2-yl)-l ,4- dihydropyrimidine-5-carboxylate (0.76 g, 1.5 mmol) was reacted with morpholine-3-carboxylic acid (0.2 g, 1 .5 mmol) according to the procedure as described in Example 1 , Step C to give the title compound as a yellow solid (0.6 g, 72%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 554.0 [M+l ]+;
Ή NMR (400 MHz, CDC13): δ 9.17 (s, 1 H), 7.35-7.26 (m, 2H), 7.01 -6.97 (m, 1 H), 6.22 (s, 1 H), 4.32-4.13 (m, 2H), 4.1 1 -3.91 (m, 4H), 3.86-3.76 (m, 2H), 3.61 -3.49 (m, 1 H), 3.26-3.14 (m, 1 H), 2.66-2.58 (m, 1 H), 1.13 (t, 3H).
[00340] Example 72:
4-((6-(2-chloro-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(l,3,4-thiadiazol-2-yl)-3,6-dihydro pyrimidin-4-yl)methyl)morpholine-3-carboxylic acid
Figure imgf000164_0001
[00341 ] Step A: Ethyl 4-(2-chloro-4-fluoropheny])-6-metbyl-2-(l,3,4-thiadiazol- 2-yl)-l,4-dihydropyrimidine-5-carboxylate l ,3,4-thiadiazole-2-carboximidamide hydrochloride ( 1.43 g, 8.69 mmol) was reacted with 2-chloro-4-fluorobenzaldehyde ( 1.38 g, 8.69 mmol) and ethyl 3-oxobutanoate ( 1 .36 g, 10.5 mmol) according to the procedure as described in Example 1 , Step A to give the title compound as a yellow solid ( 1.82 g, 55%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 381.0 [M+l ]+;
Ή NMR (400 MHz, DMSO-i/6): δ 10.36 (br.s, 1 H), 9.71 (s, 1 H), 7.62-7.40 (m, 3H), 6.03 (s, 1 H), 3.99 (q, 2H), 2.52 (s, 3H), 1.10 (t, 3H).
[00342] Step B: Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(l,3,4-thia diazol-2-yl)-l,4-dihydropyrimidine-5-carboxylate
Ethyl 4-(2-chloro-4-fluorophenyl)-6-methyl-2-(l ,3,4-thiadiazol-2-yl)-l ,4-dihydro pyrimidine-5-carboxylate (0.76 g, 2 mmol) was reacted with NBS (0.36 g, 2 mmol) according to the procedure as described in Example 1 , Step B to give the title compound as a yellow solid (0.46 g, 50%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 459.0 [M+l ]+;
Ή NMR (400 MHz, DMSO-i 6): δ 9.96 (br.s, 1 H), 9.71 (s, 1 H), 7.60-7.39 (m, 3H), 6.01 (s, 1 H), 4.59-4.41 (m, 2H), 4.01 (q, 2H), 1.03 (t, 3H). [00343] Step C: 4-i(6-i2-chloro-4-nuorophenyl)-5-(ethoxycarbonyI)-2-(l ,3,4-thia diazol-2-yI)-3,6-dihydropyrimidin-4-yl)methyi)morpholine-3-carboxylic acid
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-( 1 ,3, ,·4-thiadiazol-2-yl)-l ,4- dihydropyrimidine-5-carboxylate (0.69 g, 1.5 mmol) was reacted with morpholine-3- carboxylic acid (0.2 g, 1.5 mmol) according to the procedure as described in Example 1 , Step C to give the title compound as a yellow solid (0.47 g, 61 %). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 510.1 [M+l ]+;
Ή N R (400 MHz, CDC13): δ 9.18 (s, I H), 7.34-7.26 (m, IH), 7.15-7.11 (m, IH), 6.96-6.92 (m, I H), 6.23 (s, I H), 4.35-4.1 1 (m, 2H), 4.09-3.98 (m, 4H), 3.90-3.79 (m, 2H), 3.61 -3.50 (m, I H), 3.26-3.13 (m, 1H), 2.61 (br.s, I H), 1 .12 (t, 3H).
[00344] Example 73:
4-((6-(2,4-difluorophenyI)-5-(ethoxycarbonyl)-2-(ly3,4-thiadiazoI-2-yI)-3,6-dihydropyrim idin-4-yl)methyI)morphoIine-3-carboxylic acid
Figure imgf000165_0001
[00345] Step A: Ethyl 4-(2,4-difluorophenyI)-6-methyl-2-(l,3,4-thiadiazoI-2-yl)-l,4- dihydropyrimidine-5-carboxylate l ,3,4-thiadiazole-2-carboximidamide hydrochloride ( 1.43 g, 8.69 mmol) was reacted with 2,4-difluorobenzaldehyde ( 1.23 g, 8.69 mmol) and ethyl 3-oxobutanoate ( 1.36 g, 10.5 mmol) according to the procedure as described in Example 1 , Step A to give the title compound as a yellow solid ( 1.3 g, 41 %). The compound was characterized by the following spectroscopic data: MS-ESI: (ESI, pos.ion) m/z: 365.1 [M+l ] ;
Ή NMR (400 MHz, CDC13): δ 9.15 (s, 1H), 7.85 (br.s, 1H), 7.30-7.27 (m, 1H), 6.83-6.78 (m, 2H), 6.06 (s, 1H), 4.08 (q, 2H), 2.48 (s, 3H), 1.17 (t, 3H).
[00346] Step B: Ethyl 6-(bromomethyl)-4-(2,4-difluorophenyl)-2-(l,3,4-thiadiazol- 2-yl)-l,4-dihydropyrimidine-5-carboxylate
Ethyl 4-(2,4-difluorophenyl)-6-methyl-2-( l ,3,4 hiadiazol-2-yl)- l ,4-dihydropyrimidine- 5-carboxylate (0.73 g. 2 mmol) was reacted with NBS (0.36 g, 2 mmol) according to the procedure as described in Example 1 , Step B to give the title compound as a yellow solid (0.53 g, 60%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 443.0 [M+l ;
Ή NMR (400 MHz, CDC13): δ 9.17 (s, 1H), 7.86 (br.s, 1H), 7.30-7.27 (m, 1H), 6.83-6.78 (m, 2H), 6.05 (s, 1H), 4.61 -4.49 (m, 2H), 4.06 (q, 2H), 1.17 (t, 3H).
[00347] Step C: 4-((6-(2,4-difluorophenyl)-5-(ethoxycarbonyl)-2-(l,3,4-thiadiazol-2- yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid
Ethyl 6-(bromomethyl)-4-(2,4-difluorophenyl)-2-( 1 ,3,4-thiadiazol-2-yl)-l ,4-dihydro pyrimidine-5-carboxylate (0.66 g, 1.5 mmol) was reacted with morpholine-3-carboxylic acid (0.2 g, 1.5 mmol) according to the procedure as described in Example 1 , Step C to give the title compound as a yellow solid (0.3 g, 41 %). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 494.1 [M+l ]+;
]U NMR (400 MHz, CDC13): δ 9.17 (s, 1H), 7.31 -7.28 (m, 1 H), 6.82-6.79 (m, 2H), 6.05 (s, 1 H), 4.21 -4.11 (m, 1H), 4.09-3.92 (m, 5H), 3.85-3.78 (m, 2H), 3.56-3.45 (m, 1H), 3.19-3.09 (m, 1 H), 2.62-2.56 (m, 1 H), 1 .12 (t, 3H).
[00348] Example 74: 2-(4-ii6-(2-bromo-4-fluorophenyl)-5-iethoxycarbonyl)-2-ithiazo]-2-yl)-3,6-dihydropyrim idin-4-yl)methyl)morpholin-2-yI)acetic acid
Figure imgf000167_0001
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)- 1 ,4-dihydropyrimi dine-5-carboxylate (0.69 g, 1.37 rnmol) was reacted with 2-(mo holin-2-yl)acetic acid hydrochloride (0.3 g, 1.65 mmol) according to the procedure as described in Example 3 to give the title compound as a yellow solid (0.46 g, 60%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 567.1 [M+l ]+ :
Ή NMR (400 MHz, CDC13): 5 9.57 (br.s, 1 H), 7.85 (d, 1 H), 7.44 (d, 1 H), 7.32-7.27 (m, 2H), 6.98-6.94 (m, 1H), 6.19 (s, 1 H), 4.14-3.84 (m, 7H), 2.78-2.35 (m, 6H), 1 .13 (t, 3H).
[00349] Example 75:
2-(4-((6-(2-chloro-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yI)-3,6-dihydropyrim idin-4-y])methy])morpholin-2-yl)acetic acid
Figure imgf000167_0002
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)- 1 ,4-dihydro pyrimidine-5-carboxylate (0.63 g, 1.37 mmol) was reacted with 2-(morpholin-2-yl)acetic acid hydrochloride (0.3 g. 1 .65 mmol) according to the procedure as described in Example 3 to give the title compound as a yellow solid (0.38 g, 53%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 523.2 [M+l ]+;
Ή NMR (400 MHz, CDC13): δ 9.57 (br.s, 1H), 7.85 (d, 1H), 7.44 (d, 1H), 7.31 -7.27 (m, 1H), 7.13-7.11 (m, 1H), 6.93-6.89 (m, 1H), 6.21 (s, 1H), 4.08-3.82 (m, 7H), 2.90-2.24 (m, 6H), 1 .13 (t, 3H).
[00350] Example 76:
2-(4-((6-(2,4-dichlorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin- 4-yl)methyl)morpholin-2-yI)acetic acid
Figure imgf000168_0001
Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-l ,4-dihydropyrimidine- 5-carboxylate (0.65 g, 1.37 mmol) was reacted with 2-(morpholin-2-yl)acetic acid hydrochloride (0.3 g, 1.65 mmol) according to the procedure as described in Example 3 to give the title compound as a yellow solid (0.36 g, 49%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 539.2 [M+l ]+;
Ή NMR (400 MHz, CDC13): δ 9.60 (br.s, 1 H), 7.83 (d, 1 H), 7.59-7.54 (m, 1 H), 7.42 (d, 1 H), 7.41 -7.35 (m, 2H), 6.19 (s, 1 H), 4.08-3.93 (m, 3H), 3.91 -3.85 (m, 2H), 3.84-3.79 (m, 2H), 2.90-2.75 (m, 2H), 2.73-2.56 (m, 2H), 2.43-2.24 (m, 2H), 1 .08 (t, 3H).
[00351 ] Example 77: Isopropyl 4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihy dropyrimidin-4-yl)methyI)morpholine-3-carboxyIate
Figure imgf000169_0001
[00352] Step A: Isopropyl morpholine-3-carboxyIate hydrochloride
To a suspension of morpholine-3-carboxylic acid hydrochloride (2 g, 12 mmol) in isopropanol (30 mL) was added SOCI2 U .9 g, 15.6 mmol) at 5 °C, then the mixture was stirred at 80 °C for 6 hours. The mixture was concentrated in vacuo to give the title compound as pale brown oil (2.39 g, 95%). The compound was characterized by the following spectroscopic data:
MS-ES1: (ESI. pos.ion) mlr. 174.1 [M+l ]+.
[00353] Step B: Isopropyl 4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2- (thiazol-2-yl)-3,6-dihydropyrimidin-4-yI)methyl)morphoIine-3-carboxylate
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-l ,4-dihydro pyrimidine-5-carboxylate (2.52 g, 5 mmol) was reacted with isopropyl morpholine-3-carboxylate hydrochloride ( 1.05 g, 5 mmol) according to the procedure as described in Example 24 to give the title compound as a yellow solid (1.79 g, 60%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlr. 595.0 [M+l ]+;
] H NMR (400 MHz, CDC13): δ 9.78 (br.s, 1 H), 7.85 (d, 1 H), 7.43 (d, 1H), 7.34-7.26 (m, 2H), 6.96-6.94 (m, 1 H), 6.18 (s, 1 H), 5.14-5.08 (m, 1 H), 4.29-4.19 (m, 1 H), 4.08-3.99 (m, 4H), 3.95-3.91 (m, 1 H), 3.89-3.80 (m, 2H), 3.47-3.40 (m, 1 H), 3.17-3.07 (m, 1 H), 2.54-2.48 (m, 1 H), 1 .30-1.25 (m, 6H), 1.13 (t, 3H). [00354] Example 78:
Isopropyl 4-((6-(2,4-dichlorophenyl)-5-(ethoxycarbonyI)-2-(thiazoI-2-yI)-3,6-dihydro pyrimidin-4-y])methyl)morpholine-3-carboxylate
Figure imgf000170_0001
Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-l ,4-dihydropyrimidine- 5-carboxylate (2.38 g, 5 mmol) was reacted with isopropyl morpholine-3-carboxylate hydrochloride (1.05 g, 5 mmol) according to the procedure as described in Example 24 to give the title compound as a yellow solid (1.79 g, 63%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 567.1 [M+l]+;
Ή NMR (400 MHz, CDC13): δ 9.79 (br.s, 1H), 7.86-7.84 (m, 1 H), 7.43-7.41 (m, 1 H), 7.40-7.38 (m, 1H), 7.30-7.24 (m, 1H), 7.17-7.14 (m, 1H), 6.21 (s, 1 H), 5.15-5.07 (m, 1 H), 4.28-4.18 (m, 1H), 4.10-3.99 (m, 4H), 3.94-3.91 (m, 1H), 3.89-3.80 (m, 2H), 3.46-3.41 (m, 1 H), 3.19-3.08 (m, 1 H), 2.53-2.49 (m, 1 H), 1.29-1.23 (m, 6H), 1.15 (t, 3H).
[00355] Example 79:
(Pivaloyloxy)methyl 4-((6-(2,4-dichlorophenyI)-5-(ethoxycarbonyI)-2-(thiazol-2-yI)-3,6- dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylate
Figure imgf000171_0001
To a solution of 4-((6-(2,4-dichlorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6- dihydropyΓimidin-4-yl)methyl)mo holine-3-carboxy]ic acid (0.12 g, 0.23 mmol) and TEA (0.06 g, 0.6 mmol) in DMF (6 mL) was added chloromethyl pivalate (0.12 g, 0.8 mmol). And the mixture was stirred at 60 °C for 3 hours, and cooled to 25 °C. To the reaction mixture was added DCM ( 100 mL). The organic layer was washed with brine (80 mL x 6) and dried over unhydrous Na2S0 . The crude product was purified by a silica gel column chromatography (PETROLEUM ETHER/EtOAc (V V) = 8/1 ) to give the title compound as yellow oil (0.09 g, 62%). The compound was characterized by the following spectroscopic data:
MS-ES1: (ESI, pos.ion) mlz: 539.1 [M+l ]+;
Ή NMR (400 MHz, CDC13): 5 9.71 (br.s, 1H), 7.85-7.83 (m, 1H), 7.43 (d, 1H), 7.39 (d, 1H), 7.30-7.23 (m, 1H), 7.18-7.14 (m, 1H), 6.20 (s, 1 H), 5.87-5.79 (m, 2H), 4.30-4.21 (m, 1H), 4.09-3.98 (m, 5H), 3.83-3.81 (m, 2H), 3.55-3.49 (m, 1 H), 3.25-3.15 (m, 1 H), 2.57-2.48 (m, 1 H), 1 .25 (s, 9H), 1.18 (t, 3H).
[00356] Example 80:
((Isopropoxycarbonyl)oxy)methyl 4-((6-(2,4-dichlorophenyl)-5-(ethoxycarbonyl)-2- (thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylate
Figure imgf000172_0001
4-((6-(2,4-dichlorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4- yl)methyl)morpholine-3-carboxylic acid (0.22 g, 0.4 mmol) was reacted with chloromethyl isopropyl carbonate (0.25 g, 1.64 mmol) according to the procedure as described in Example 79 to give the title compound as yellow oil (0.12 g, 47%). The compound was characterized by the following spectroscopic data:
MS-ES1: (ESI, pos.ion) mlz: 641 .1 [M+l ]+;
'H NMR (400 MHz, CDC13): δ 9.67 (br.s, 1H), 7.84 (br.s, 1H), 7.43 (d, 1H), 7.38 (d, 1H), 7.3 1 -7.23 (m, 1 H), 7.1 8-7.14 (m, 1 H), 6.20 (s, 1 H), 5.82 (s, 2H), 4.92-4.88 (m, 1 H), 4.33-4.1 8 (m, 2H), 4.15-4.03 (m, 3H), 3.82 (br.s, 2H), 3.56-3.52 (m, 1 H), 3.23-3.15 (m, 1 H), 2.56-2.46 (m, 1 H), 1.42-1.25 (m, 6H), 1.13 (t, 3H).
[00357] Example 81 :
Ethyl 4-(2,4-dichIorophenyl)-6-((3-(isopropylcarbamoyl)morpholino)methyl)-2-(thiazol- 2-yl)-l,4-dihydropyrimidine-5-carboxylate
Figure imgf000172_0002
[00358] Step A: -isopropylmorpholine-3-carboxamide
A mixture of methyl morpholine-3-carboxylate hydrochloride (0.22 g, 1 .2 mmol) and propan-2-amine (2.78 g. 47 mmol) was stirred at 60 °C for 12 hours under N2. The mixture was concentrated in vacuo to give the title compound as brownish sticky oil (0.2 g, 95%). The compound was characterized by the following spectroscopic data:
MS-ES1: (ESI, pos.ion) mlz: 173.2 [M+l]+.
[00359] Step B: Ethyl 4-(2,4-dichlorophenyl)-6-((3-(isopropylcarbamoyl)morpholino) methyl)-2-(thiazol-2-yl)-l,4-dihydropyrimidine-5-carboxylate
Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-l ,4-dihydropyrimidine- 5-carboxylate (0.57 g, 1 .2 mmol) was reacted with N-isopropylmorpholine-3-carboxamide (0.21 g, 1 .2 mmol) according to the procedure as described in Example 24 to give the title compound as a yellow solid (0.2 g, 30%). The compound was characterized by the following spectroscopic data:
MS-ES1: (ESI, pos.ion) mlz: 566.1 [M+l ;
Ή NMR (400 MHz, CDC13): δ 9.59 (s, IH), 7.89-7.86 (m, IH), 7.49-7.39 (m, 2H), 7.27-7.18 (m, 2H), 6.22 (s, I H), 4.31 -4.18 (m, I H), 4.1 5-3.99 (m, 4H), 3.95-3.83 (m, 2H), 3.76-3.66 (m, 2H), 3.30-3.27 (m, I H), 2.95-2.89 (m, IH), 2.65-2.49 (m, IH), 1.26-1 .1 1 (m, 6H), 1 .07 (t, 3H).
[00360] Example 82:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-((3-(isopropylcarbamoyI)morpholino)methyl)-2- (thiazol-2-yl)-l,4-dihydropyrimidine-5-carboxylate
Figure imgf000173_0001
Ethyl . 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-l ,4-dihydro pyrimidine-5-carboxylate (0.6 ε, 1 .2 mmol) was reacted with N-isopropylmorpholine-3- carboxamide (0.21 g, 1.2 mmol) according to the procedure as described in Example 24 to give the title compound as a yellow solid (0.25 g, 35%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 594.1 [M+l ]+;
Ή NMR (400 MHz, CDC13): δ 9.58 (s, 1H), 7.88-7.85 (m, 1 H), 7.48 (d, 1 H), 7.35 (d, 1H), 7.31 -7.25 (m, 1 H), 6.98-6.93 (m, 1 H), 4.33-4.15 (m, 1 H), 4.12-3.99 (m, 4H), 3.93-3.82 (m, 2H), 3.78-3.67 (m, 2H), 3.29-3.22 (m, 1 H), 2.94-2.81 (m, 1H), 2.66-2.62 (m, 1 H), 1.20-1.12 (m, 3H), 1 .08 (d, 3H), 0.98 (d, 3H).
[00361 ] Example 83:
4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(l-methyl-lH-l,2,4-triazol-3-yl)-3, 6-dihydropyrimidin-4-yI)methyl)morpholine-2-carboxylic acid
Figure imgf000174_0001
[00362] Step A: l-methyl-lH-l,2,4-triazo]e-3-carbonitrile lH-l ,2,4-triazole-3-carbonitrile (2.35 g, 25 mmol) was reacted with iodomethane (3.53 g, 25 mmol) according to the procedure as described in Example 48, Step A to give the title compound as a white solid (2.3 g, 85%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 109.0 [M+l ]+.
Ή NMR (400 MHz, CDCh): δ 8.29 (s, 1H), 3.19 (s, 3H).
[00363] Step B: l-methyl-1H-l,2,4-triazole-3-carboximidamide hydrochloride l -methyl-lH-l ,2,4-triazole-3-carbonitrile (20 g, 185 mmol) was reacted with sodium methoxide ( 14 g, 295 mmol) and ammonium chloride ( 14.8 g, 277.5 mmol) according to the procedure as described in Example 61, Step B to give the title compound as a white solid (23.44 g, 78.8%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 126.1 [M+l]+;
Ή NMR (400 MHz, D20): δ 8.40 (s, 1 H), 3.89 (s, 3H).
[00364] Step C: Ethyl 4-(2-bromo-4-fluorophenyl)-6-methyl-2-(l-methyl-lH-l,2,4- triazol-3-yl)-l,4-dihydropyrimidine-5-carboxylate
1 -methyl- lH-l ,2,4-triazole-3-carboximidamide hydrochloride (3.3 g, 20 mmol) was reacted with 2-bromo-4-fluorobenzaldehyde (4 g, 20 mmol) and ethyl 3-oxobutanoate (2.6 g, 20 mmol) according to the procedure as described in Example 1 , Step A to give the title compound as a white solid (5.3 g, 63%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 422 A [M+l ]+;
Ή NMR (400 MHz, CDC13): δ 8.03 (s, 1H), 7.39-6.93 (m, 3H), 6.15 (s, 1H), 4.07-4.02 (m, 2H), 3.96 (s, 3H), 2.53 (s, 3H), 1.14 (t, 3H).
[00365] Step D: Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(l-methyl- lH-l,2,4-triazol-3-yI)-l,4-dihydropyrimidine-5-carboxylate
Ethyl 4-(2-bromo-4-fluorophenyl)-6-methyl-2-( l -methyl-lH-l ,2,4-triazol-3-yl)-l ,4- dihydropyrimidine-5-carboxylate (5 g, 12 mmol) was reacted with NBS (2.1 g, 12 mmol) in chloroform ( 1 0 mL) according to the procedure as described in Example 1 , Step B to give the title compound as a yellow solid (2.4 g, 40%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 501 .0 [M+l ]+; Ή NMR (400 MHz, DMSO-^): δ 9.81 (br.s, I H), 8.06 (s, IH), 7.35-6.90 (m, 3H), 6.11 (s, I H), 4.23 (q, 2H), 4.01 (q, 2H), 3.92 (s, 3H), 1.15 (t, 3H).
[00366] Step E: 4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbony])-2-(l-methyl-lH- l,2,4-triazoI-3-yl)-3,6-dihydropyrimidin-4-yl)methyl)inorpholine-2-carboxylic acid
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(l -methyl-lH-l ,2,4-triazol-3- yl)-l ,4-dihydropyrimidine-5-carboxylate ( 1 g, 2 mmol) was reacted with morpholine-2- carboxylic acid hydrochloride (0.34 g, 2 mmol) according to the procedure as described in Example 1 , Step C to give the title compound as a yellow solid (0.42 g, 38%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 551.1 [M+l ]+;
!H NMR (400 MHz, CDC13): δ 8.09 (s, I H), 7.36-6.93 (m, 3H), 6.20 (s, I H), 4.20-3.99 (m, 4H), 3.95 (s, 3H), 3.93-3.80 (m, 3H), 2.73-2.36 (m, 4H), 1.09 (t, 3H).
[00367] Example 84:
2-(4-((6-(2-bromo-4-fluoropheny])-5-(ethoxycarbonyl)-2-(l-methyl-lH-l,2,4-triazol-3-yl) -3,6-dihydropyrimidin-4-yl)methyl)morpholin-2-yl)acetic acid
Figure imgf000176_0001
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-( l-methyl-lH-l ,2,4-triazol-3-yl)- l ,4-dihydropyrimidine-5-carboxylate ( 1 g, 2 mmol) was reacted with 2-(morpholin-2-yl) acetic acid hydrochloride (0.36 g, 2 mmol) according to the procedure as described in Example 1 , Step C to give the title compound as a yellow solid (0.47 g, 42%). The compound was characterized by the following spectroscopic data: MS-ESI: (ESI, pos.ion) mlr. 565.1 [M+l ]+;
Ή NMR (400 MHz, CDC13): δ 8.09 (s, 1H), 7.34-6.94 (m, 3H), 6.22 (s, 1 H), 4.13-3.84 (m, 7H), 3.95 (s, 3H), 2.94-2.1 8 (m, 6H), 1.14-1.11 (m, 3H).
[00368] Example 85:
2-(4-((6-(2-bromo-4-fluorophenyl)-2-(3-cyano-lH-l,2,4-triazol-l-yl)-5-(ethoxycarbonyl)- 3,6-dihydropyrimidin-4-yl)methyl)morpholin-2-yl)acetic acid
Figure imgf000177_0001
[00369] Step A: Ethyl 4-(2-bromo-4-fluorophenyl)-6-methyI-2-oxo-l,2,3,4-tetra hydropyrimidine-5-carboxyIate
A mixture of urea (2.90 g, 48 mmol), ethyl 3-oxobutanoate (5.22 g, 40 mmol), 2-bromo-4-fluorobenzaldehyde (8.12 g, 40 mmol), chlorotnmethylsilane (3.75 g, 35 mmol) and sodium iodide (4.85 g, 35 mmol) in anhydrous acetonitrile (50 mL) was stirred at 25 °C for 12 hours in the dark. The mixture was filtered and the filter cake was washed with a little acetonitrile to give the title compound as a white solid (5.72 g, 40%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlr. 357.0 [M+l ]+;
Ή NMR (400 MHz, DMSO-i/6): δ 9.80 (br.s, 1H), 9.22 (br.s, 1 H), 6.97-6.85 (m, 3H), 6.10 (s, 1 H), 4.06 (q, 2H), 2.52 (s, 3H), 1.12 (t, 3H).
[00370] Step B: Ethyl 4-(2-bromo-4-fluorophenyl)-2-chloro-6-methyl-l,4-dihydro pyrimidine-5-carboxylate
A mixture of ethyl 4-(2-bromo-4-fluorophenyl)-6-methyl-2-oxo-l ,2,3,4-tetrahydrp pyrimidine-5-carboxylate (3.56 g, 10 mmol) and POCl3 (15 mL) was stirred at 110 °C for 4 hours under N2, then cooled to 25 °C. POCl3 was removed in vacuo and the residue was dissolved in chloroform (100 mL). Then the mixture was adjusted to pH 6-8 with strong ammonia. The organic phase was washed with brine (80 mL x 3), dried over Na2S04 and filtered. The filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PETROLEUM ETHER/EtOAc (V/V) = 5/1) to give the title compound as a white solid ( 1.73 g, 46%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 375.0 [M+l ]+;
Ή NMR (400 MHz, DMSO-d6): δ 9.82 (br.s, 1 H), 6.92-6.83 (m, 3H), 6.12 (s, 1 H), 4.08 (q, 2H), 2.52 (s, 3H), 1 .08 (t, 3H).
[00371 ] Step C: Ethyl 4-(2-bromo-4-fluorophenyl)-2-(3-cyano-lH-l,2,4-triazol-l-yl)- 6-methyl-l,4-dihydropyrimidine-5-carboxylate
Ethyl 4-(2-bromo-4-fluorophenyl)-2-chloro-6-methyl-l ,4-dihydropyrimidine-5- carboxylate (3.77 g, 10 mmol) was reacted with lH-l ,2,4-triazole-3-carbonitrile (2.82 g, 30 mmol) according to the procedure as described in Example 48, Step A to give the title compound as a pale yellow solid (2.16 g, 50%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 433.0 [M+l ;
!H NMR (400 MHz, DMSO-i/6): δ 9.68 (br.s, 1 H), 8.14 (s, 1H), 7.53-7.19 (m, 3H), 6.12 (s, 1 H), 4.06 (q, 2H), 2.46 (s, 3H), 1.12 (t, 3H).
[00372] Step D: Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyI)-2-(3-cyano-lH- l,2,4-triazol-l-yl)-l,4-dihydropyrimidine-5-carboxylate
Ethyl 4-(2-bromo-4-fluorophenyl)-2-(3-cyano-lH-l ,2,4-triazo]-l -yl)-6-methyl-l ,4- dihydropyrimidine-5-carboxylate (0.35 g, 0.8 mmol) was reacted with NBS (0.14 g, 0.81 mmol) in chloroform (15 mL) according to the procedure as described in Example 1 , Step B to give the title compound as pale yellow oil (0.33 g, 80%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 51 1.0 [M+l ]+;
]H NMR (400 MHz, DMSO-i/6): δ 9.67 (br.s, 1 H), 8.15 (s, 1H), 7.52-7.18 (m, 3H), 6.10 (s, 1H), 4.59-4.40 (m, 2H), 4.09 (q, 2H), 1.10 (t, 3H).
[00373] Step E: 2-(4-((6-(2-bromo-4-nuorophenyl)-2-(3-cyano-lH-l,2,4-triazol-l-yl)- 5-(ethoxycarbonyl)-3,6-dihydropyrimidin-4-yl)methyl)morphoIin-2-yl)acetic acid
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(3-cyano-lH-l ,2,4-triazol-l -yl)- l ,4-dihydropyrimidine-5-carboxylate (0.32 g, 0.62 mmol) was reacted with 2-(morpholin-2-yl)acetic acid hydrochloride (0.2 g, 1 .1 mmol) according to the procedure as described in Example 1 , Step C to give the title compound as a pale yellow solid (0.14 g, 40%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 576.1 [M+l ]+;
Ή NMR (400 MHz, DMSO-< ): δ 12.3 (br.s, 1H), 9.46 (br.s, 1H), 7.75 (s, 1H), 7.59-7.57 (m, 1H), 7.50-7.39 (m, 1H), 7.28-7.24 (m, 1 H), 6.08 (s, 1 H), 4.14-4.02 (m, 1H), 4.07-3.88 (m, 4H), 3.83-3.52 (m, 2H), 2.92-2.62 (m, 2H), 2.48-2.35 (m, 2H), 2.32-2.05 (m, 2H), 1.04 (t, 3H).
[00374] Example 86:
4-((6-(2-bromo-4-fluorophenyl)-2-(3-cyano-lH-l,2,4-triazol-l-yI)-5-(ethoxycarbonyl)-3,6 -dihydropyrimidin-4-yl)methyl)morpholine-2-carboxylic acid
Figure imgf000180_0001
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(3-cyano-lH-l ,2,4-triazol-l -yl)- l ,4-dihydropyrimidine-5-carboxylate (0.32 g, 0.63 mmol) was reacted with morpholine-2- carboxylic acid hydrochloride (0.13 g, 0.75 mmol) according to the procedure as described in Example 3 to give the title compound as a pale yellow solid (0.15 g, 42%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 562.1 [M+l ]+;
!H NMR (400 MHz, CDC13): δ 9.17 (s, 1H), 8.03 (s, 1H), 7.85 (s, 1H), 7.58-7.22 (m, 3H), 6.07 (s, 1H), 4.11 -3.97 (m, 2H), 3.86-3.71 (m, 2H), 3.67-3.41 (m, 4H), 3.25-2.91 (m, 3H), 1 .05 (t, 3H).
[00375] Example 87:
4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(lH-l,2,4-triazol-l-yl)-3,6-dihydro pyrimidin-4-yI)methyl)morpholine-3-carboxylic acid
Figure imgf000180_0002
[00376] Step A: Ethyl 4-(2-bromo-4-nuorophenyl)-6-methyl-2-(lH-l ,2,4-triazoI-l- yl)-l,4-dihydropyrimidine-5-carboxylate
Ethyl 4-(2-bromo-4-fluorophenyl)-2-chloro-6-methyl- 1 ,4-dihydropyrimidine-5 - carboxylate ( 1 5.04 e, 40 mmol) was reacted with lH-1 ,2,4-triazole (8.28 g, 120 mmol) according to the procedure as described in Example 48, Step A to give the title compound as a yellow solid (9.8 g, 60%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 408.1 [M+l ]+;
Ή NMR: (400 MHz, CDC13): δ 9.80 (s, 1 H), 8.93 (s, 1 H), 8.03 (s, 1 H), 7.29-6.97 (m, 3H), 6.12 (s, 1 H). 4.06 (q, 2H). 2.52 (s, 3H), 1.08 (t, 3H).
[00377] Step B: Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(lH-l,2,4- triazol-l-yl)-l,4-dihydropyrimidine-5-carboxylate
Ethyl 4-(2-bromo-4-fluorophenyl)-6-methyl-2-(] H-l ,2,4-triazol-l -yl)-l ,4-dihydro pyrimidine-5-carboxylate ( 1.23 g, 3 mmol) was reacted with NBS (0.54 g, 3 mmol) according to the procedure as described in Example 1 , Step B to give the title compound as a yellow solid (1.02 g, 70%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 486.0 [M+l ]+;
Ή NMR: (400 MHz, CDC13): δ 9.82 (s, 1H), 8.90 (s, 1H), 8.01 (s, 1H), 7.27-6.95 (m, 3H), 6.10 (s, 1H), 4.56-4.41 (m, 2H), 4.05 (q, 2H), 1.07 (t, 3H).
[00378] Step C: 4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(lH-l,2,4- triazol-l-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxyIic acid
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-( 1H- 1 ,2,4-triazol- 1 -yl)- 1 ,4- dihydropyrimidine-5-carboxylate (1 .75 g, 3.6 mmol) was reacted with morpholine-3- carboxylic acid hydrochloride (0.6 g, 3.6 mmol) according to the procedure as described in Example 1 , Step C to give the title compound as a pale yellow solid (0.6 g, 31 %). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI. pos.ion) mlz: 537.1 [M+l ]+; Ή NMR (400 MHz, CDC13): δ 9.80 (s, I H), 8.93 (s, I H), 8.03 (s,l H), 7.36-6.97 (m, 3H), 6.17 (s, I H), 4.20-4.00 (m, 4H), 3.85-3.62 (m, 4H), 3.58-3.45 (m, I H), 3.22-3.1 1 (m, IH), 2.62-2.56 (m, IH), 1.12 (t, 3H).
[00379] Example 88:
4-((6-(2-bromo-4-fluorophenyI)-5-(ethoxycarbonyl)-2-(lH-l,2,4-triazol-l-yl)-3,6-dihydro pyrimidin-4-yI)methyl)morpholine-2-carboxylic acid
Figure imgf000182_0001
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(lH-l ,2,4-triazol-l-yl)-l ,4- dihydropyrimidine-5-carboxylate (0.5 g, 1.03 mmol) was reacted with morpholine-2- carboxylic acid hydrochloride (0.21 g, 1 .23 mmol) according to the procedure as described in Example 1 , Step C to give the title compound as a pale yellow solid (0.18 g, 33%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 537.1 [M+l ]+;
Ή NMR (400 MHz, CDCI3): δ 9.60 (s, I H), 9.08 (s, IH), 8.31 (s, IH), 7.58-7.23 (m, 3H), 6.06 (s, IH), 4.16-3.88 (m, 7H), 2.68-2.32 (m, 4H), 1.19 (t, 3H).
[00380] Example 89:
2-(4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(lH-l,2,4-triazol-l-yl)-3,6-dihy dropyrimidin-4-yl)methyl)morpholin-2-yl)acetic acid
Figure imgf000183_0001
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-( lH-1 ,2,4-triazol-l -yl)-l ,4- dihydropyrimidine-5-carboxylate (0.5 g, 1.03 mmol) was reacted with 2-(morpholin-2-yl)acetic acid hydrochloride (0.19 g, 1.03 mmol) according to the procedure as described in Example 1 , Step C to give the title compound as a yellow solid (0.22 g, 39%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 551.1 [M+l ]+;
Ή NMR (400 MHz, CDC13): δ 9.55 (s, 1 H), 8.89 (s, 1 H), 8.04 (s, 1 H), 7.35-6.98 (m, 3H), 6.17 (s, 1 H), 4.15-3.82 (m, 7H), 2.67-2.37 (m, 6H), 1.12 (t, 3 H).
[00381] Example 90:
2-(4-((6-(2-bromo-4-nuorophenyl)-2-(l-(2-ethoxy-2-oxoethyl)-lH-l,2,4-triazol-3-yl)-5- (ethoxycarbonyl)-3,6-dihydro rimidin-4-yl)methyl)morpholin-2-yl)acetic acid
Figure imgf000183_0002
[00382] Step A: Ethyl 2-(3-cyano-lH-l,2,4-triazol-l -yl)acetate
Ethyl 2-bromoacetate (8.88 g, 53.15 mmol) was reacted lH-1 ,2.4-triazole-3-carbonitrile (5 g, 53.15 mmol) according to the procedure as described in Example 48, Step A to give the title compound as a white solid (8 g, 84%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 181.2 [M+l ]+;
1 Η NMR (400 MHz, CDC13): δ 8.34 (s, 1H), 5.06 (s, 2H), 4.31 (q, 2H), 1.32 (t, 3H).
[00383] Step B: Methyl 2-(3-carbamimidoyl-lH-l,2,4-triazol-l-yl)acetate hydrochloride
Ethyl 2-(3-cyano-lH-l ,2,4-triazol-l -yl)acetate (2 g, 1 1.2 mmol) was reacted with sodium methoxide (0.85 g, 15.68 mmol) and ammonium chloride (0.89 g, 16.8 mmol) according to the procedure as described in Example 61 , Step B to give the title compound as a white solid ( 1.35 g, 55%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 184.2 [M+l ]+;
Ή NMR (400 MHz, D20): δ 8.60 (s, 1H), 8.34 (s, 1H), 5.26 (s, 2H), 3.73 (s, 3H).
[00384] Step C: Ethyl 4-(2-bromo-4-fluorophenyl)-2-(l-(2-ethoxy-2-oxoethyl)-l /- l,2,4-triazol-3-yl)-6-methyl-l,4-dihydropyrimidine-5-carboxyIate
Methyl 2-(3-carbamimidoyl-lH-l ,2,4-triazol-l-yl)acetate hydrochloride (0.6 g, 2.73 mmol) was reacted with 2-bromo-4-fluorobenzaldehyde (0.55 g, 2.73 mmol) and ethyl 3-oxobutanoate (0.35 g, 2.73 mmol) according to the procedure as described in Example 1 , Step A to give the title compound as a yellow solid (0.6 g, 45%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 494.1 [M+l f;
Ή NMR (400 MHz, CDC13): δ 8.21 (s, 1 H), 7.39-7.35 (m, 1 H), 7.28-7.26 (m, 1 H), 6.97-6.94 (m, 1 H), 6.16 (s, 1 H), 5.05 (s, 2H), 4.25 (q, 2H), 4.05 (q, 2H), 2.52 (br.s, 3H), 1 .28 (t, 3H), 1.12 (t, 3H).
[00385] Step D: Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(l-(2-ethoxy- 2-oxoethyl)-lH-l,2,4-triazoI-3-y])-l,4-dihydropyrimidine-5-carboxyIate
Ethyl 4-(2-bromo-4-ftuorophenyl)-2-( 1 -(2-ethoxy-2-oxoethyl)-lH-l ,2,4-triazol-3-yl)-6- methyl-l ,4-dihydropyrimidine-5-carboxylate (0.45 g, 0.91 mmol) was reacted with NBS (0.16 g, 0.91 mmol) according to the procedure as described in Example 1 , Step B to give the title compound as a yellow solid (0.36 g, 69%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 572.0 [M+l ]+;
Ή NMR (400 MHz, CDC13): δ 8.23 (s, I H), 7.45-7.41 (m, I H), 7.31 -7.27 (m, I H), 7.03-6.99 (m, l H), 6.10 (s, I H), 5.03 (s, 2H), 4.99 (d, 1 H), 4.67 (d, 1 H), 4.26 (q, 2H), 4.13 (q, 2H), 1 .29 (t, 3H), 1.17 (t, 3H).
[00386] Step E: 2-(4-((6-(2-bromo-4-fluorophenyl)-2-(l-(2-ethoxy-2-oxoethyI)-lH-l, 2,4-triazoI-3-yl)-5-(ethoxycarbonyl)-3,6-dihydropyrimidin-4-yl)methyl)morpholin-2-yI) acetic acid
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(l -(2-ethoxy-2-oxoethyl)-lH- l ,2,4-triazol-3-yl)-l ,4-dihydropyrimidine-5-carboxylate (0.57 g, 1 mmol) was reacted with 2-(morpholin-2-yl)acetic acid hydrochloride (0.3 g, 1 .65 mmol) according to the procedure as described in Example 1 , Step C to give the title compound as a yellow solid (0.34 g, 53%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 637.2 [M+l ]+;
Ή NMR (400 MHz, CDC13): δ 8.23 (s, IH), 7.34-7.30 (m, I H), 7.28-7.26 (m, IH), 6.96-6.92 (m, I H), 6.24 (s, I H), 5.3 (s, 2H), 4.24 (q, 2H), 4.13-3.82 (m, 7H), 2.80-2.15 (m, 6H), 1 .28 (t, 3H), 1 .14 (t, 3H).
[00387] Example 91 : 4-((6-i2-bromo-4-fluorophenyl)-2-il-(2-ethoxy-2-oxoethyl)-lH-l,2,4-triazoI-3-yl)-5-(etho xycarbonyl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-2-carboxylic acid
Figure imgf000186_0001
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-( 1 -(2-ethoxy-2-oxoethyl)-lH- l ,2,4-triazol-3-yl)-l ,4-dihydropyrimidine-5-carboxylate (0.57 g, 1 mmol) was reacted with morpholine-2-carboxylic acid hydrochloride (0.2 g, 1.2 mmol) according to the procedure as described in Example 1 , Step C to give the title compound as a yellow solid (0.13 g, 20%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 623.1 [M+l ]+;
Ή NMR (400 MHz, CDC13): δ 8.21 (s, 1 H), 7.34-7.26 (m, 2H), 6.97-6.96 (m, 1 H), 6.22 (s, 1 H), 5.03 (s, 2H), 4.42-4.35 (m, 1H), 4.30-4.22 (m, 4H), 4.04-3.99 (m, 2H), 3.97-3.72 (m, 2H), 2.92-2.69 (m, 4H), 1.30 (t, 3H), 1 .12 (t, 3H).
[00388] Example 92:
l-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidi n-4-yl)methyl)pyrrolidine-2-carboxylic acid
Figure imgf000186_0002
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-l ,4-dihydro pyrimidine-5-carboxylate (1 g, 2 mmol) was reacted with pyrrolidine-2-carboxylic acid (0.23 g, 2 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid (0.27 g, 25%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 537.1 [M+l ]+;
Ή NMR (400 MHz, CDC13): δ 7.85 (br.s, 1 H), 7.63-7.56 (m, 2H), 7.40-7.33 (m, 2H), 7.09-7.07 (m, 1 H), 6.15 (s, 1H), 4.81 -4.64 (m, 1 H), 4.22-4.12 (m, 1 H), 4.07 (q, 2H), 3.95-3.68 (m, 2H), 2.95-2.86 (m, 1H), 2.44-2.34 (m, 2H), 2.09-1 .92 (m, 2H), 1.10 (t, 3H).
[00389] Example 93:
l-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidi n-4-yI)methyl)piperidine-2-carb
Figure imgf000187_0001
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)- 1 ,4-dihydro pyrimidine-5-carboxylate (1 g, 2 mmol) was reacted with piperidine-2-carboxylic acid (0.26 g, 2 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid (0.3 g, 27%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 551.0 [M+l ]+;
Ή NMR (400 MHz, CDC13): 5 7.84-7.80 (m, 2H), 7.50 (br.s, 1 H), 7.33-7.26 (m, 2H), 7.05-6.95 (m, 1 H), 6.14 (s, 1 H), 4.45-4.35 (m, 1 H), 4.05 (q, 2H), 3.75-3.45 (m, 4H), 2.1 5-1 .95 (m, 2H). 1 .78-1.45 (m, 4H). 1 .10 (t, 3H). [00390] Example 94:
(25)-l-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(lH-l,2,4-triazoI-l-yl)-3,6-dih ydropyrimidin-4-yl)methyI)pyrrolidine-2-carbox lic acid
Figure imgf000188_0001
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(broniomethyl)-2-(lH-l ,2,4-triazol- l -yl)-l ,4- dihydropyrimidine-5-carboxylate (0.5 g, 1 .03 mmol) was reacted with (S)-pyrrolidine-2- carboxylic acid (0.12 g, 1 .03 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid (0.18 g, 33%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlr. 521.1 [M+l ;
Ή NMR (400 MHz, CDC13): δ 9.23 (s, 1H), 7.94 (s, 1H), 7.37-7.02 (m, 3H), 6.15 (d, 1 H), 4.63-4.62 (m, 1 H), 4.35-4.25 (m, 2H), 4.05 (q, 2H), 3.83-3.75 (m, 1 H), 2.95-2.85 (m, 1 H), 2.45-2.34 (m, 2H), 2.09-1.95 (m, 2H), 1 .12 (t, 3H).
[00391 ] Example 95:
4-((6-(2-chloro-4-fluorophenyl)-2-(3,5-difluoropyridin-2-yI)-5-(ethoxycarbonyl)-3,6-dihy dropyrimidin-4-yI)methyl)morpholine-3-carboxyHc acid
Figure imgf000189_0001
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(3,5-diiluoropyridin-2-yl)-l ,4- dihydropyrimidine-5-carboxylate (0.75 g, 1.53 mmol) (The compound was synthesized according to the procedure as described in US7074784) was reacted with morpholine-3-carboxylic acid (0.2 g, 1 .53 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid (0.54 g, 65%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 539.1 [M+l ] ;
Ή NMR (400 MHz, DMSO^): δ 9.75 (s, I H), 8.55 (d, I H), 8.05-7.95 (m, IH), 7.45-7.35 (m, 2H), 7.25-7.15 (m, I H), 6.0 (s, I H), 4.30-4.04 (m, 2H), 4.02-3.92 (m, 3H), 3.84-3.72 (m, 2H), 3.68-3.52 (m, 2H), 3.1 1 -3.07 (m, IH), 2.55-2.39 (m, IH), 1.06 (t, 3H).
[00392] Example 96:
2-(4-((6-(2-bromo-4-fluorophenyl)-2-(3,5-difluoropyridin-2-yl)-5-(ethoxycarbonyl)-3,6-di hydropyrimidin-4-yI)methyl)morpholin-3-yl)acetic acid
Figure imgf000189_0002
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(3,5-difluoropyridin-2-yl)-l ,4- dihydropyrimidine-5-carboxylate (0.82 g, 1.53 mmol) (The compound was synthesized according to the procedure as described in US7074784) was reacted with 2-(morpholin-3-yl)acetic acid hydrochloride (0.28 g, 1.53 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid (0.38 g, 42%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 597.1 [M+l ]+;
Ή NMR (400 MHz, DMSO-c/6): δ 9.75 (s, 1 H), 8.55 (d, 1 H), 8.05-7.95 (m, 1H), 7.58-7.55 (m, 1 H), 7.44-7.38 (m, 1 H), 7.24-7.1 8 (m, 1 H), 4.19-3.90 (m, 4H), 3.77-3.53 (m, 4H), 3.1 1 -2.69 (m, 3H), 2.51 -2.41 (m, 2H), 1.07 (t, 3H).
[00393] Example 97:
2-(4-((6-(2-chloro-4-f!uorophenyl)-5-(ethoxycarbonyl)-2-(3-fluoropyridin-2-yl)-3,6-dihyd ropyrimidin-4-yl)methyl)morpholin-3-yl)acetic acid
Figure imgf000190_0001
[00394] Step A: Ethyl 4-(2-chloro-4-fluorophenyl)-2-(3-fluoropyridin-2-yl)-6- methyl-l,4-dihydropyrimidine-5-carboxylate
3-fluoropicolinimidamide hydrochloride (5.53 g, 31.5 mmol) was reacted with 2- chloro-4-fluorobenzaldehyde (5 g, 31.5 mmol) and ethyl 3-oxobutanoate (4.1 g, 31.5 mmol) according to the procedure as described in Example 1 , Step A to give the title compound as a yellow solid (5.56 g, 45%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 392.1 [M+l ]+;
Ή NMR (400 MHz, DMSO- ): δ 10.03 (s, 1 H), 8.80-8.16 (m, 1 H), 7.78 (dd, 1 H), 7.67-7.44 (m, 2H), 7.36 (dd, 1 H). 7.04-6.92 (m, 1 H), 6.27 (s, 1 H), 4.08 (q, 2H), 2.51 (s, 3H), 1.10 (t, 3H).
[00395] Step B: Ethyl 6-(bromomethyl)-4-(2-chloro-4-nuorophenyl)-2-(3-fluoro pyridin-2-y])-l,4-dihydropyrimidine-5-carboxylate
Ethyl 4-(2-chloro-4-fluorophenyl)-2-(3 -fluoropyridin-2-yl)-6-methyl- 1 ,4-dihydro pyrimidine-5-carboxylate (3 g, 7.7 mmol) was reacted with NBS (1.51 g, 8.47 mmol) according to the procedure as described in Example 1 , Step B to give the title compound as a yellow solid (2.2 g, 62%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 470.0 [M+l]+;
Ή N R (400MHz, DMSO-i/6): 6 10.75 (s, 1 H), 8.50-8.32 (m, 1 H), 7.78 (dd, 1 H), 7.65-7.43 (m, 2H), 7.36-7.26 (m, 1H), 7.04-6.91 (m, 1 H), 6.19 (s, 1H), 4.89-4.67 (m, 2H), 4.18 (q, 2H),
1 .10 (t, 3H).
[00396] Step C: 2-(4-((6-(2-chloro-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(3-fluoro pyridin-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morphoIin-3-yl)acetic acid
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(3-fluoropyridin-2-yl)- 1 ,4- dihydropyrimidine-5-carboxylate (0.72 g, 1.53 mmol) was reacted with 2-(morpholin-3-yl)acetic acid hydrochloride (0.28 g, 1.53 mmol) according to the procedure as described in Example 1 , Step C to give the title compound as a yellow solid (0.39 g, 48%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 535.2 [M+l ]+;
Ή NMR (400 MHz, DMSO-i/6): δ 9.80 (s, 1 H), 8.59-8.51 (m, 1 H), 7.62-7.51 (m, 2H), 7.42-7.35 (m, 2H), 7.17-7.12 (m, 1 H), 6.15 (s, 1 H), 4.20-3.91 (m, 4H), 3.81 -3.52 (m, 4H),
3.1 1 -2.65 (m, 3H), 2.56-2.45 (m, 2H), 1 .05 (t, 3H).
[00397] Example 98: 4-((6-(2,4-dich]orophenyl)-5-(ethoxycarbonyl)-2-(3-fluoropyridin-2-yl)-3,6-dihydropyri midin-4-yl)methyl)morpholine-3-carboxyIic acid
Figure imgf000192_0001
[00398] Step A: Ethyl 4-(2,4-dichlorophenyl)-2-(3-fluoropyridin-2-yl)-6-methyl-l,4- dihydropyrimidine-5-carboxylate
3-fluoropicolinimidamide hydrochloride (5.53 g, 31.5 mmol) was reacted with 2,4-dichlorobenzaldehyde (5.51 g, 31.5 mmol) and ethyl 3-oxobutanoate (4.1 g, 31.5 mmol) according to the procedure as described in Example 1 , Step A to give the title compound as a yellow solid (6.94 g, 54%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 408.1 [M+l ]+;
Ή NMR (400 MHz, DIVISOR): δ 10.02 (s, 1 H), 8.78-8.25 (m, 1 H), 7.72 (d, 1H), 7.65-7.42 (m, 2H), 7.25-7.11 (m, 2H), 6.31 (s, 1 H), 4.08 (q, 2H), 2.46 (s, 3H), 1.16 (t, 3H).
[00399] Step B: Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(3-fluoropyridin- 2-yl)-l,4-dihydropyrimidine-5-carboxylate
Ethyl 4-(2,4-dichlorophenyl)-2-(3-fluoropyridin-2-yl)-6-methyl- 1 ,4-dihydropyrimidine- 5-carboxylate (3.14 g, 7.7 mmol) was reacted with NBS (1.51 g, 8.47 mmol) according to the procedure as described in Example 1 , Step B to give the title compound as a yellow solid (2.44 g, 65%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 486.0 [M+l ]+;
]H NMR (400 MHz, DMSO-c 6): δ 10.08 (s, I H), 8.71 -8.49 (m, 1 H), 7.72 (d, 1 H), 7.65-7.42 (m, 2H), 7.25-7.11 (m, 2H), 6.23 (s, IH), 4.65-4.56 (m, 2H), 4.10 (q, 2H), 1.10 (t, 3H).
[00400] Step C: 4-((6-(2,4-dichlorophenyI)-5-(ethoxycarbonyl)-2-(3-nuoropyridin- 2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid
Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(3-fluoropyridin-2-yl)- 1 ,4-dihydro pyrimidine-5-carboxylate (0.75 g, 1.53 mmol) was reacted with morpholine-3-carboxylic acid (0.2 g, 1 .53 mmol) according to the procedure as described in Example 1 , Step C to give the title compound as a yellow solid (0.34 g, 41 %). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 537.1 [M+l ]+;
Ή NMR (400 MHz, DMSO-i/6): δ 9.83 (s, I H), 8.59-8.50 (m, I H), 7.62-7.50 (m, 3H), 7.42-7.37 (m, 2H), 6.07 (s, I H), 4.29-4.04 (m, 2H), 4.01 -3.91 (m, 3H), 3.85-3.82 (m, I H), 3.74-3.71 (m, I H), 3.66-3.64 (m, I H), 3.61 -3.52 (m, IH), 3.11 -3.07 (m, I H), 2.54-2.41 (m, IH), 1.07 (t, 3H).
[00401 ] Example 99:
4-((6-(2-chloro-4-nuorophenyI)-5-(ethoxycarbonyl)-2-(pyridin -yl)-3,6-dihydropyrimidi n-4-yl)methyl)morpholine-3-carboxylic acid
Figure imgf000193_0001
[00402] Step A: Ethyl 4-(2-chloro-4-fluorophenyl)-6-methyl-2-(pyridin-3-yl)-l,4- dihydropyrimidine-5-carboxylate
Nicotinimidamide hydrochloride (4.97 g, 31.5 mmol) was reacted with 2-chloro-4-fluorobenzaldehyde (5 g, 31.5 mmol) and ethyl 3-oxobutanoate (4.1 g, 31.5 mmol) according to the procedure as described in Example 1 , Step A to give the title compound as a yellow solid (5.89 g, 50%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z 374.1 [M+l ]+;
Ή NMR (400 MHz, DMSO-i/6): δ 9.88 (s, 1 H). 9.08 (d, 1H), 8.75-8.65 (m, 1 H), 8.30-8.20 (m, 1 H), 7.78-7.68 (m, 1H), 7.58 (t, 1H), 7.36 (dd, 1 H), 7.04-6.92 (m, 1H), 6.23 (s, 1 H), 4.08 (q, 2H). 2.26 (s, 3H), 1.16 (t, 3H).
[00403] Step B: Ethyl 6-(bromomethy])-4-(2-chloro-4-nuorophenyI)-2-(pyridin-3- yl)-l ,4-dihydropyrimidine-5-carboxylate
Ethyl 4-(2-chloro-4-fluorophenyl)-6-methyl-2-(pyridin-3-yl)- 1 ,4-dihydropyrimidine-5- carboxylate (5 g, 13.4 mmol) was reacted with NBS (2.87 g, 16.1 mmol) according to the procedure as described in Example 1 , Step B to give the title compound as a yellow solid (4.25 g, 70%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 452.0 [M+l ]+;
Ή NMR (400 MHz, DMSO-< ): δ 11.03 (s, 1 H), 9.08 (d, 1H), 8.75-8.65 (m, 1H), 8.30-8.19 (m, 1H), 7.78-7.68 (m, 1 H), 7.58-7.47 (m, 1 H), 7.36-7.26 (m, 1 H), 7.04-6.94 (m, 1H), 6.18 (s, 1H), 4.85-4.65 (m, 2H), 4.06 (q, 2H), 1.12 (t, 3H).
[00404] Step C: 4-((6-(2-chloro-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(pyridin-3-yl)- 3,6-dihydropyrimidin-4-yI)methyl)morphoIine-3-carboxylic acid
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(pyridin-3-y])-l ,4-dihydro pyrimidine-5-carboxylate (1 g, 2.2 mmol) was reacted with morpholine-3-carboxylic acid (0.29 g, 2.2 mmol) according to the procedure as described in Example 1 , Step C to give the title compound as a yellow solid (0.39 g, 35%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 503.2 [M+l ]+; ]H NMR (400 MHz, DMSO- fi): δ 12.39 (s, 1H), 9.90 (s, 1H), 9.30-8.94 (m, 1H), 8.75 (dd, 1H), 8.30-8.21 (m, 1 H), 7.78 (dd, 1 H), 7.58-7.45 (m, 1H), 7.36-7.24 (m, 1 H), 7.04-6.93 (m, 1 H), 6.03 (s, 1H), 4.41 -3.87 (m, 4H), 3.82-3.16 (m, 3H), 2.91-2.34 (m. 4H), 1.10 (t, 3H).
[00405] Example 100:
4-((6-(2-chloro-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(pyrazin-2-yl)-3,6-dihydropyrimid in-4-yI)methyl)morpholine-3-carboxyIic acid
Figure imgf000195_0001
[00406] Step A: Ethyl 4-(2-chlor -4-fluorophenyl)-6-methyl-2-(pyrazin-2-yl)-l,4- dihydropyrimidine-5-carboxylate
Pyrazine-2-carboximidamide hydrochloride (5 g, 31.5 mmol) was reacted with 2-chloro-4-fluorobenzaldehyde (5 g, 31.5 mmol) and ethyl 3-oxobutanoate (4.1 g, 31 .5 mmol) according to the procedure as described in Example 1 , Step A to give the title compound as a yellow solid (4.84 g, 41 %). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 375.1 [M+l]+;
]H NMR (400 MHz, DMSO-rf6): δ 9.88 (s, 1H), 9.34 (s, 1H), 8.94-8.66 (m, 2H), 7.78 (dd, 1H), 7.36 (dd, 1 H), 7.04-6.99 (m, 1H), 6.21 (s, 1H), 4.03 (q, 2H), 2.51 (s, 3H), 1.12 (t, 3H).
[00407] Step B: Ethyl 6-(bromoinethyl)-4-(2-chloro-4-nuorophenyl)-2-(pyrazin-2- yl)-l,4-dihydropyrimidine-5-carboxylate
Ethyl 4-(2-chloro-4-fluorophenyl)-6-methyl-2-(pyrazin-2-yl)-l ,4-dihydropyrimidine-5- carboxylate (5.02 g, 13.4 mmol) was reacted with NBS (2.87 g, 16.1 mmol) according to the procedure as described in Example 1 , Step B to give the title compound as a yellow solid (3.95 g, 65%). The compound was characterized by the following spectroscopic data:
MS-ES1: (ESI, pos.ion) m/z: 453.0 [M+l ]+;
Ή NMR (400 MHz, DMSO-i 6): 6 10.52 (s, 1 H), 9.34 (s, 1H), 9.00-8.48 (m, 2H), 7.78-7.60 (m, 1 H), 7.36-7.21 (m, 1H), 7.04-6.92 (m, 1 H), 6.25 (s, 1H), 4.61-4.50 (m, 2H), 4.09 (q, 2H), 1 .16 (t, 3H).
[00408] Step C: 4-((6-(2-chloro-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(pyrazin-2- yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(pyrazin-2-yl)- 1 ,4-dihydro pyrimidine-5-carboxylate (1 g, 2.2 mmol) was reacted with morpholine-3-carboxylic acid (0.29 g, 2.2 mmol) according to the procedure as described in Example 1 , Step C to give the title compound as a yellow solid (0.32 g, 29%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 504.2 [M+l ]+;
Ή NMR (400 MHz, DMSO-c/6): δ 12.65 (br.s, 1H), 10.41 (s, 1 H), 9.34 (s, 1 H), 8.98-8.41 (m, 2H), 7.70-7.58 (m, 1H), 7.36-7.19 (m, 1H), 7.14-7.08 (m, 1H), 6.01 (s, 1H), 4.28-4.15 (m, 1H), 4.04 (q, 2H), 3.91-3.75 (m, 2H), 3.70-3.43 (m, 3H), 3.37 (s, 1 H), 3.02-2.21 (m, 2H), 1.15 (t, 3H).
[00409] Example 101 :
4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(2,4,6-trifluorophenyl)-3,6-dihydr opyrimidin-4-yI)methyl)morpholine-3-carboxylic acid
Figure imgf000197_0001
[00410] Step A: Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(2,4,6-tri fluorophenyl)-l,4-dihydropyrimidine-5-carboxylate
Ethyl 4-(2-bromo-4-fluorophenyl)-6-methyl-2-(2,4,6-trifluorophenyl)- 1 ,4-dihydro pyrimidine-5-carboxylate (6.31 g, 13.4 mmol) (The compound was synthesized according to the procedure as described in CN200610098646.3) was reacted with NBS (2.87 g, 16.1 mmol) according to the procedure as described in Example 1 , Step B to give the title compound as a yellow solid (4.1 g, 55%). The compound was characterized by the following spectroscopic data:
MS-ES1: (ESI, pos.ion) m/z: 549.0 [M+l]+;
Ή NMR (400 MHz, DMSC ,): δ 10.23 (s, 1 H), 7.35-7.10 (m, 2H), 7.09-6.98 (m, 1 H), 6.63-6.49 (m, 2H), 6.33 (s, 1 H), 4.89-4.59 (m, 2H), 4.12 (q, 2H), 1.09 (t, 3H).
[0041 1] Step B: 4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyI)-2-(2,4,6- trifluorophenyl)-3,6-dihydropyrimidin-4-yl)methyI)morpholine-3-carboxylic acid
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(2,4,6-trifluorophenyl)- 1 ,4- dihydropyrimidine-5-carboxylate ( 1 .21 g, 2.2 mmol) was reacted with morpholine-3- carboxylic acid (0.29 g, 2.2 mmol) according to the procedure as described in Example 1 , Step C to give the title compound as a yellow solid (0.44 g, 33%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 600.1 [M+l ]+; Ή NMR (400 MHz, DMSO-cfe): δ 12.98 (br.s. 1 H), 10.26 (s, 1 H), 7.34-7.24 (m, 2H), 7.19-6.99 (m, 1H), 6.64-6.44 (m, 2H), 6.05 (s, 1 H), 4.02-3.89 (m, 3H), 3.82-3.40 (m, 4H), 3.02-2.27 (m, 4H), 1.19 (t, 3H).
[00412] Example 102:
4-((6-(2,4-dichlorophenyl)-5-(ethoxycarbonyl)-2-(3-fluoropyridin-2-yl)-3,6-dihydropyri midin-4-yl)methyl)morpholine-2-carboxyIic acid
Figure imgf000198_0001
Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(3-fluoropyridin-2-yl)- 1 ,4-dihydro pyrimidine-5-carboxylate (0.75 g, 1 .53 mmol) was reacted with morpholine-2-carboxylic acid (0.26 g, 1.53 mmol) according to the procedure as described in Example 1 , Step C to give the title compound as a yellow solid (0.35 g, 43%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 537.1 [M+l ]+;
Ή NMR (400 MHz, DMSO-c/6): δ 9.83 (s, 1H), 8.59-8.50 (m, 1 H), 7.62-7.50 (m, 3H), 7.42-7.37 (m, 2H), 6.02 (s, 1H), 4.14-4.10 (m, 1 H), 3.97-3.88 (m, 4H), 3.64-3.51 (m, 2H), 3.06-2.85 (m, 2H), 2.63-2.35 (m, 2H), 1 .05 (t, 3H).
[00413] Example 103:
4-((6-(2-chloro-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(pyridin-2-yl)-3,6-dihydropyrimidi n-4-yl)methyl)morpholine-3-carboxylic acid
Figure imgf000199_0001
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(pyridin-2-yl)-l ,4-dihydro pyrimidine-5-carboxylate (0.69 g, 1 .53 mmol) (The compound was synthesized according to the procedure as described in WO2010069147) was reacted with morpholine-3 -carboxylic acid (0.2 g, 1.53 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid (0.42 g, 55%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 503.2 [M+l ]+;
]H NMR (400 MHz, DMSO-</6): δ 12.69 (s, 1 H), 10.12 (s, 1 H), 8.72 (dd, 1 H), 8.34 (dd, 1H), 8.13-7.99 (m, 1 H), 7.78-7.67 (m, 1 H), 7.57-7.28 (m, 2H), 7.04-6.89 (m, 1 H), 5.98 (s, 1 H), 4.41 -3.87 (m, 4H), 3.77-3.32 (m, 3H), 2.98-2.25 (m, 4H), 1.10 (t, 3H).
[00414] Example 104:
4-((6-(2-bromo-4-fluorophenyl)-2-(3-chloropyridin-2-yl)-5-(ethoxycarbonyl)-3,6-dihydro pyrimidin-4-yl)methyl)morpholine-3-carboxyIic acid
Figure imgf000199_0002
[00415] Step A: Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(3-chloro pyridin-2-yl)-l ,4-dihydropyrimidine-5-earboxylate Ethyl 4-(2-bromo-4-fluorophenyl)-2-(3-chloropyridin-2-yl)-6-methyl-l ,4-dihydro pyrimidine-5-carboxylate (6.07 g, 13.4 mmol) (The compound was synthesized according to the procedure as described in WO0058302) was reacted with NBS (2.87 g, 16.1 mmol) according to the procedure as described in Example 1 , Step B to give the title compound as a yellow solid (3.5 g, 49%). The compound was characterized by the following spectroscopic data:
MS-ES1: (ESI. pos.ion) m/z: 530.0 [M+l ]+;
Ή NMR (400 MHz, DMSO-</6): δ 11.04 (s, 1 H), 8.80 (dd, 1H), 8.16 (dd, 1H), 7.78-7.65 (m, 1 H), 7.35-7.23 (m, 2H), 7.19-6.97 (m, 1 H), 6.60 (s, 1 H), 4.97-4.79 (m, 2H), 4.02 (q, 2H), 1 .12 (t, 3H).
[00416] Step B: 4-((6-(2-bromo-4-fluorophenyl)-2-(3-chloropyridin-2-yl)-5-(ethoxy carbonyl)-3,6-dihydropyrimidin-4-yl)methyl)morphoIine-3-carboxylic acid
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(3-chloropyridin-2-yl)-l ,4- dihydropyrimidine-5-carboxylate (0.81 g, 1.53 mmol) was reacted with morpholine-3- carboxylic acid (0.2 g, 1.53 mmol) according to the procedure as described in Example 1 , Step C to give the title compound as a yellow solid (0.36 g, 40%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 581 .1 [M+l ]+;
Ή NMR (400 MHz, OMSO-d6): δ 12.48 (s, 1 H), 9.88 (s, 1H), 8.80 (dd, 1H), 8.43-7.98 (m, 1 H), 7.68-7.57 (m, 1H), 7.32-7.27 (m, 2H), 7.19-6.97 (m, 1 H), 5.94 (s, 1H), 4.66-3.87 (m, 4H), 3.85-3.23 (m, 3H), 2.91 -2.21 (m, 4H), 1 .13 (t, 3H).
[00417] Example 105:
2-(4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-phenyl-3,6-dihydropyrimidin-4 -yl)methyl)morpholin-3-yl)acetic acid
Figure imgf000201_0001
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-phenyl-l ,4-dihydropyrimidine-5- carboxylate (0.76 g, 1.53 mmol) (The compound was synthesized according to the procedure as described in WO2010069147) was reacted with 2-(morpholin-3-yl)acetic acid hydrochloride (0.28 g, 1.53 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid (0.42 g, 49%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 560.1 [M+l ]' ;
Ή NMR (400 MHz, DMSO-c 6): δ 12.31 (s, I H), 10.17 (s, I H), 7.85-7.67 (m, 2H), 7.56-7.44 (m, 3H), 7.38-7.28 (m, I H), 7.31 -7.26 (m, I H), 7.10-6.99 (m, I H), 6.25 (s, IH), 4.21 -3.94 (m, 3H), 3.76-3.43 (m, 2H), 3.27-3.06 (m, I H), 3.00-2.95 (m, 2H), 2.72-2.65 (m, IH), 2.62-2.58 (m, 2H), 2.52-2.47 (m, I H), 2.33-2.1 1 (m, I H), 1.08 (t, 3H).
[00418] Example 106:
4-((6-(2,4-dichlorophenyl)-5-(ethoxycarbonyl)-3,6-dihydro-[2,2'-bipyrimidin]-4-yl) methyl)morpholine-2-carboxylic acid
Figure imgf000201_0002
Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-l ,4-dihydro-[2,2'-bipyrimidine]-5- carboxylate (0.72 g, 1.53 mmol) (The compound was synthesized according to the procedure as described in WO2010069147) was reacted with morpholine-2-carboxylic acid hydrochloride (0.26 g, 1.53 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid (0.45 g, 56%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI. pos.ion) mlz: 520.1 [M+l ]+;
Ή N R (400 MHz, DMSO-</6): δ 12.86 (s, 1 H), 9.84 (s, 1 H), 9.09 (d, 2H), 7.87-7.80 (m, 1 H), 7.72 (d, 1 H), 7.25-7.09 (m, 2H), 6.23 (s, 1H), 4.01 (q, 2H), 3.81 -3.76 (m, 1 H), 3.72-3.39 (m, 3H), 3.05-2.88 (m, 1 H), 2.79-2.57 (m, 3H), 2.50-2.45 (m, 1 H), 1 .06 (t, 3H).
[00419] Example 107:
3-(4-((6-(2-chloro-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(3-fluoropyridin-2-yl)-3,6-dihyd ropyrimidin-4-yI)methyl)morpholin-3-yl)propanoic acid
Figure imgf000202_0001
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(3-fluoropyridin-2-yl)-l,4- dihydropyrimidine-5-carboxylate (0.72 g, 1.53 mmol) was reacted with 3-(morpholin-3-yl) propanoic acid hydrochloride (0.3 g, 1.53 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid (0.3 g, 36%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 549.3 [M+l ]+;
Ή NMR (400 MHz, DMSO-i 6): δ 9.80 (s, 1 H), 8.59-8.51 (m, 1 H). 7.62-7.51 (m, 2H), 7.42-7.35 (m, 2H), 7.17-7.12 (m, I H), 6.13 (s. I H), 4.26-4.10 (m, I H), 4.09-4.02 (m, 3H), 3.95-3.88 (m, I H), 3.84-3.81 (m, IH), 3.76-3.69 (m, IH), 3.59-3.53 (m, IH), 2.89-2.82 (m, I H), 2.63 (br.s, I H), 2.54-2.45 (m, 2H), 2.38-2.33 (m, I H), 1.93-1.88 (m, I H), 1.29-1.23 (m, 2H), 1.13 (t, 3H).
[00420] Example 108:
3- (4-((6-(2,4-dichlorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-4-yl)-3,6-dihydropyrimidin-
4- yl)methyl)morpholin-2-yl)propanoic acid
Figure imgf000203_0001
[00421 ] Step A: Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-4-yl)-l,4- dihydropyrimidine-5-carboxylate
Ethyl 4-(2,4-dichlorophenyl)-6-methyl-2-(thiazol-4-yl)-l ,4-dihydropyrimidine-5- carboxylate (5.31 g, 13.4 mmol) (The compound was synthesized according to the procedure as described in CN200610098646.3) was reacted with NBS (2.87 g, 16.1 mmol) according to the procedure as described in Example 1 , Step B to give the title compound as a yellow solid (3.63 g, 57%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 474.0 [M+l ]+;
Ή NMR (400 MHz, DMSO-</6): δ 10.06 (s, I H), 9.1 1 (d, IH), 8.44 (d, I H), 7.96-7.60 (m, I H), 7.25-7.15 (m, 2H), 6.27 (s, IH), 4.56-4.43 (m, 2H), 4.08 (q, 2H), 1.1 1 (t, 3H).
[00422] Step B: 3-(4-((6-(2,4-dichlorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-4-yl)- 3,6-dihydropyrimidin-4-yl)methyl)morpholin-2-yl)propanoic acid
Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-4-yl)-l ,4-dihydropyrimidine- 5-carboxylate (0.73 g, 1.53 mmol) was reacted with 3-(morpholin-2-yl)propanoic acid hydrochloride (0.3 g, 1.53 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid (0.38 g, 45%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 553.1 [M+l ]+;
Ή NMR (400 MHz, DMSO-c/6): 5 12.71 (s, 1H), 10.04 (s, 1H), 9.11 (d, 1 H), 8.44 (d, 1 H), 7.94-7.48 (m, 1 H), 7.35-7.27 (m, 2H), 6.35 (s, 1 H), 3.98 (q, 2H), 3.78-3.44 (m, 3H), 3.37-3.22 (m, 2H), 2.83-2.54 (m, 3H), 2.33-2.13 (m, 2H), 2.12-2.09 (m, 1 H), 1.67-1.57 (m, 2H), 1 .06 (t, 3H).
[00423] Example 109:
4-((2-(5-chlorothiazol-4-yl)-6-(2,4-dichlorophenyl)-5-(ethoxycarbonyl)-3,6-dihydropyrim idin-4-yl)methyl)morpholine-3-carboxylic acid
Figure imgf000204_0001
[00424] Step A: Ethyl 6-(bromomethyl)-2-(5-chlorothiazol-4-yl)-4-(2,4-dichloro phenyl)-l,4-dihydropyrimidine-5-carboxylate
Ethyl 2-(5-chlorothiazol-4-yl)-4-(2,4-dichlorophenyl)-6-methyl-l ,4-dihydropyrimidine- 5-carboxylate (5.77 g, 13.4 mmol) (The compound was synthesized according to the procedure as descnbed in CN200610098646.3) was reacted with NBS (2.87 g, 16.1 mmol) according to the procedure as described in Example 1 , Step B to give the title compound as a yellow solid (3.3 g, 48%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 508.0 [M+l f; 1H NMR (400 MHz, DMSO-A): δ 10.03 (s, 1 H), 8.89 (s, 1H), 7.94-7.48 (m, 1H), 7.29-7.12 (m, 2H), 6.31 (s, 1H), 5.03-4.87 (m, 2H), 4.08 (q, 2H), 1.16 (t, 3H).
[00425] Step B: 4-((2-(5-chlorothiazol-4-yl)-6-(2,4-dichlorophenyl)-5-(ethoxy carbonyl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid
Ethyl 6-(bromomethyl)-2-(5-chlorothiazol-4-yl)-4-(2,4-dichlorophenyl)-l ,4-dihydro pyrimidine-5-carboxylate (0.78 g, 1 .53 mmol) was reacted with morpholine-3-carboxylic acid (0.2 g, 1.53 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid (0.29 g, 34%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 559.1 [M+ l ]+;
Ή NMR (400 MHz, DMSO-c 6): δ 12.69 (s, 1 H), 1 1.30 (s, 1 H), 8.89 (s, 1 H), 8.00-7.50 (m, 1 H), 7.20-7.10 (m, 2H), 6.31 (s, 1 H), 4.39-3.96 (m, 4H), 3.91 -3.30 (m, 3H), 3.02-2.32 (m, 4H), 1.03 (t, 3H).
[00426] Example 110:
4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbony!)-2-(furan-2-yl)-3,6-dihydropyrimidin -4-yl)methyl)morphoIine-3-carboxylic acid
Figure imgf000205_0001
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(furan-2-yl)- 1 ,4-dihydropy rimidine-5-carboxylate (0.74 g, 1.53 mmol) (The compound was synthesized according to the procedure as described in WO2010069147) was reacted with morpholine-3-carboxylic acid (0.2 g, 1.53 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid (0.31 g, 38%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 536.1 [M+l ]+;
Ή NMR (400 MHz, DMSO-c/6): δ 12.39 (s, 1H), 10.10 (s, 1H), 7.98 (dd, 1H), 7.48-7.19 (m, 3H), 7.17-7.00 (m, 1 H), 6.75-6.63 (m, 1H), 6.25 (s, 1 H), 4.09 (q, 2H), 3.96-3.91 (m, 1H), 3.90-3.41 (m, 4H), 2.85-2.35 (m, 4H), 1.06 (t, 3H).
[00427] Example 111 :
4-((6-(2-chloro-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiophen-2-yl)-3,6-dihydropyrimi din-4-yl)methy1)morpholine-3-carboxylic acid
Figure imgf000206_0001
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiophen-2-yl)- 1 ,4-dihydro pyrimidine-5-carboxylate (0.7 g, 1.53 mmol) (The compound was synthesized according to the procedure as described in WO2010069147) was reacted with morpholine-3-carboxylic acid (0.2 g, 1.53 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid (0.33 g, 43%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 508.1 [M+l ;
Ή NMR (400 MHz, DMSO- 6): δ 12.59 (s, 1 H), 10.1 1 (s, 1H), 7.78 (dd, 1 H), 7.67 (dd, 1 H), 7.45 (dd, 1 H), 7.36 (dd, 1 H), 7.21 -6.95 (m, 2H), 5.89 (s, l H), 4.19 (s, 1 H), 4.09-3.83 (m, 3H), 3.75-3.40 (m, 3H), 2.88-2.44 (m, 4H), 1 .18 (t, 3H).
[00428] Example 112: 4-((6-f2-bromo-4-fluorophenyl)-5-iethoxycarbonyl)-2-(oxazol-2-yl)-3,6-dihydropyrimidi n-4-yl)methyl)morpholine-3-carboxylic acid
Figure imgf000207_0001
[00429] Step A: Oxazole-2-carboximidamide hydrochloride
Oxazole-2-carbonitrile (0.94 g, 1 0 mmol) was reacted with sodium methoxide (0.81 g, 1 5 mmol) and ammonium chloride (0.96 g, 1 8 mmol) according to the procedure as described in Example 61 , Step B to give the title compound as an oifwhite solid (1 .25 g, 70%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlr. 1 12.0 [M+l ]+;
'H NMR (400 MHZ, DMSO-i/6): δ 1 0.67 (s, 1 H), 7.59 (d, lH), 7.14 (d, 1 H), 6.89 (s, 2H).
[00430] Step B: Ethyl 4-(2-bromo-4-fluorophenyl)-6-methyl-2-(oxazoI-2-yI)-l,4- dihydropyrimidine-5-carboxylate
Oxazole-2-carboximidamide hydrochloride (1 .28 g, 8.69 mmol) was reacted with 2-bromo-4-fluorobenzaldehyde (1 .76 g, 8.69 mmol) and ethyl 3-oxobutanoate ( 1 .36 g, 10.5 mmol) according to the procedure as described in Example 1 , Step A to give the title compound as a yellow solid ( 1 .35 g, 38%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlr. 408.0 [M+l ]+;
Ή NMR (400 MHz, DMSO-i 6): δ 9.82 (s, 1 H), 7.58 (d, 1 H), 7.33-7.25 (m. 2H), 7.19-7.00 (m, 2H), 6.13 (s, 1 H), 4.07 (q, 2H), 2.45 (s, 3H), 1.19 (t, 3H). [00431 ] Step C: Ethyl 4-i2-bromo-4-fluorophenyl)-6-ibromomethy])-2-ioxazoI-2-yI)- l,4-dihydropyrimidine-5-carboxylate
Ethyl 4-(2-bromo-4-fluorophenyl)-6-methyl-2-(oxazol-2-yl)-l ,4-dihydropyrimidine-5- carboxylate (5.47 g, 13.4 mmol) was reacted with NBS (2.87 g, 16.1 mmol) according to the procedure as described in Example 1 , Step B to give the title compound as a yellow solid (3.3 g, 51 %). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z 486.0 [M+l f;
Ή NMR (400 MHz, DMSO- 6): δ 10.10 (s, 1H), 7.60 (d, 1 H), 7.33-7.25 (m, 2H), 7.20-7.03 (m, 2H), 6.03 (s, 1 H), 4.95-4.69 (m, 2H), 4.02 (q, 2H), 1.04 (t, 3H).
[00432] Step D: 4-((6-(2-bromo-4-fIuorophenyl)-5-(ethoxycarbonyl)-2-(oxazol-2-yl)- 3,6-dihydropyrimidin-4-yl)methy])morpholine-3-carboxyIic acid
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(oxazol-2-yl)- 1 ,4-dihydro pyrimidine-5-carboxylate (0.75 g, 1 .53 mmol) was reacted with morpholine-3-carboxylic acid (0.2 g, 1.53 mmol) according to the procedure as described in Example 1 , Step C to give the title compound as a yellow solid (0.29 g, 35%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 537.1 [M+l ]+;
Ή NMR (400 MHz, DMSO- 6): δ 12.79 (s, 1H), 9.95 (s, 1H), 7.58 (d, 1H), 7.32-7.23 (m, 2H), 7.21-7.07 (m, 2H), 6.09 (s, 1 H), 4.24-4.13 (m, 1H), 4.08-3.85 (m, 3H), 3.79 -3.39 (m, 3H), 2.96-2.41 (m, 4H), 1.06 (t, 3H).
[00433] Example 113:
2-(4-((6-(2-bromo-4-lluorophenyl)-5-(ethoxycarbonyl)-2-(l,2,4-thiadiazol-5-yl)-3,6-dihyd ropyrimidin-4-yl)methyl)morpholin-3-yl)acetic acid
Figure imgf000209_0001
[00434] Step A: l,2,4-thiadiazole-5-carbonitrile l ,2,4-thiadiazol-5-amine (4.05 g, 40 mmol) was reacted with CuCN (7.2 g, 80 mmol) according to the procedure as described in Example 61 , Step A to give the title compound as pink liquid (2.04 g, 46%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 1 12.0 [M+ l ]+; 1H NMR (400 MHz, DMSO-d6): δ 6.46 (s, 1 H).
[00435] Step B: l,2,4-thiadiazole-5-carboximidamide hydrochloride l ,2,4-thiadiazole-5-carbonitrile ( 1.1 1 g, 10 mmol) was reacted with sodium methoxide (0.81 g, 15 mmol) and ammonium chloride (0.96 g, 18 mmol) according to the procedure as described in Example 61 , Step B to give the title compound as an offwhite solid (1.32 g, 80%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 129.0 [M+l f;
Ή NMR (400 MHz, DMSO-i 6): δ 7.12 (s, 1H), 6.90 (s, 2H), 6.32 (s, 1H).
[00436] Step C: Ethyl 4-(2-bromo-4-fluorophenyl)-6-methyl-2-(l,2,4-thiadiazol-5- yI)-l,4-dihydropyrimidine-5-carboxylate l ,2,4-thiadiazole-5-carboximidamide hydrochloride ( 1.43 g, 8.69 mmol) was reacted with 2-bromo-4-fluorobenzaldehyde ( 1 .76 g, 8.69 mmol) and ethyl 3-oxobutanoate (1 .36 g, 10.5 mmol) according to the procedure as. described in Example 1 , Step A to give the title compound as a yellow solid fl .3 g, 35%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 425.0 [M+l ]+;
Ή NMR (400 MHz, DMSO-c/6): δ 9.70 (s, 1 H), 7.31-7.28 (m, 2H), 7.20-7.12 (m, 1H), 6.25 (s, 1 H), 6.10 (s, 1H), 4.08 (q, 2H), 2.51 (s, 3H), 1.12 (t, 3H).
[00437] Step D: Ethyl 4-(2-bromo-4-nuorophenyl)-6-(bromomethyl)-2-(l,2,4-thia diazol-5-yl)-l,4-dihydropyrimidine-5-carboxylate
Ethyl 4-(2-bromo-4-fluorophenyl)-6-methyl-2-( 1 ,2,4-thiadiazol-5-yl)-l ,4-dihydro pyrimidine-5-carboxylate (5.7 g, 13.4 mmol) was reacted with NBS (2.87 g, 16.1 mmol) according to the procedure as described in Example 1 , Step B to give the title compound as a yellow solid (2.7 g, 40%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 503.0 [M+l ]+;
Ή NMR (400 MHz, DMSO-c 6): δ 10.04 (s, 1 H), 7.30-7.20 (m, 2H), 7.17-7.02 (m, 1 H), 6.26 (s, 1H), 6.13 (s, 1H), 4.73 (s, 2H), 4.08 (q, 2H), 1.16 (t, 3H).
[00438] Step E: 2-(4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(l,2,4-thia diazol-5-yl)-3,6-dihydropyrimidin-4-yl)methyI)morpholin-3-yl)acetic acid
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-( 1 ,2,4-thiadiazol-5-yl)- 1 ,4- dihydropyrimidine-5-carboxylate (0.77 g, 1.53 mmol) was reacted with 2-(morpholin-3- yl)acetic acid hydrochloride (0.28 g, 1 .53 mmol) according to the procedure as described in Example 1 , Step C to give the title compound as a yellow solid (0.29 g, 33%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 568.1 [M+l f;
Ή NMR (400 MHz, DMSO- ): δ 12.41 (s, 1 H), 9.68 (s, 1 H), 7.38 (dd, 1 H), 7.31 (dd, 1 H), 7.10-6.99 (m, I H), 6.18 (s, IH), 5.91 (s, I H), 4.04 (q, 2H), 3.76-3.48 (m, 2H), 3.43-3.26 (m, 2H), 3.21-3.03 (m, I H), 2.99-2.89 (m, I H), 2.82-2.53 (m, 4H), 2.29-2.04 (m, IH), 1.16 (t, 3H).
[00439] Example 114:
2-(4-((6-(2,4-dichlorophenyl)-5 ethoxycarbonyl)-2-(thiazoI-2-yl)-3,6-dihydropyrimidin- 4-yl)methyl)morpholin-3-yl)propanoic acid
Figure imgf000211_0001
Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-l ,4-dihydropyrimidine- 5-carboxylate (0.73 g, 1 .53 mmol) was reacted with 2-(morpholin-3-yl)propanoic acid hydrochloride (0.3 g, 1.53 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid (0.34 g, 40%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 553.1 [M+l ]+;
Ή NMR (400 MHz, DMSO- 6): δ 10.63 (s, IH), 9.88 (s, IH), 8.10 (d, IH), 7.93 (d, I H), 7.72 (d, I H), 7.25-7.09 (m, 2H), 6.09 (s, IH), 4.19-3.98 (m, 3H), 3.73-3.47 (m, 2H), 3.40-3.25 (m, IH), 3.15-3.08 (m, IH), 3.00-2.92 (m, I H), 2.84-2.48 (m, 3H), 2.37-2.28 (m, I H), 1 .46-0.82 (m, 6H).
[00440] Example 115:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(((S)-2-(hydroxymethyl)pyrrolidin-l-yl)methyl)-2- (lH-l,2,4-triazol-3-yl)-l ,4-dihydropyrimidine-5-carboxylate
Figure imgf000212_0001
[00441] Step A: lH-l,2,4-triazoIe-3-carboximidamide hydrochloride lH-l ,2,4-triazole-3-carbonitrile (0.94 g, 10 mmol) was reacted with sodium methoxide (0.81 g, 15 mmol) and ammonium chloride (0.96 g, 18 mmol) according to the procedure as described in Example 61 , Step B to give the title compound as an offwhite solid (0.59 g, 40%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 1 12.0 [M+l]+;
Ή NMR (400 MHz, D20): δ 8.52 (s, IH), 2.65 (br.s, 2H).
[00442] Step B: Ethyl 4-(2-bromo-4-fluoropheny])-6-methyI-2-(lH-l,2,4-triazol-3- yl)-l,4-dihydro pyrimidine-5-carboxylate lH-l ,2,4-triazole-3-carboximidamide hydrochloride (1.28 g, 8.69 mmol) was reacted with 2-bromo-4-fIuorobenzaldehyde (1.76 g, 8.69 mmol) and ethyl 3-oxobutanoate (1.36 g, 10.5 mmol) according to the procedure as described in Example 1 , Step A to give the title compound as a yellow solid (1.06 g, 30%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 408.0 [M+l]+;
Ή NMR (400 MHz, DMSO- ): δ 9.62 (s, IH), 8.50 (s, IH), 7.42-7.15 (m, 3H), 6.06 (s, IH), 4.01 (q, 2H), 2.52 (s, 3H), 1.08 (t, 3H).
[00443] Step C: Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(lH-l,2,4- triazoJ-3-yl)-l,4-dihydropyrimidine-5-carboxylate Ethyl 4-(2-bromo-4-fluorophenyl)-6-methyl-2-( lH-1 ,2,4-triazol-3-yl)-l ,4-dihydro pyrimidine-5-carboxylate (0.82 g, 2 mmol) was reacted with NBS (0.39 g, 2.2 mmol) in chloroform (40 mL) according to the procedure as described in Example 1 , Step B to give the title compound as a yellow solid (0.44 g, 45%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 486.0 [M+l ]+;
'H NMR (400 MHz, DMSO- 6): δ 9.63 (s, I H), 8.51 (s, I H), 7.40-7.16 (m, 3H), 6.03 (s, I H), 4.65-4.49 (m, 2H), 4.03 (q, 2H), 1.06 (t, 3H).
[00444] Step D: Ethyl 4-(2-bromo-4-fluorophenyl)-6-(((S)-2-(hydroxymethyl) pyrroIidin-l-yI)methyl)-2-(lH-l,2,4-triazoI-3-yl)-l,4-dihydropyrimidine-5-carboxylate
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-( lH-1 ,2,4-triazol-3-yl)-l ,4- dihydropyrimidine-5-carboxylate (0.75 g, 1.53 mmol) was reacted with (5 pyrrolidin-2-ylmethanol hydrochloride (0.21 g, 1.53 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a yellow solid (0.25 g, 32%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 507.1 [M+l ]+;
Ή NMR (400 MHz, DMSO-i/6): δ 10.77 (s, I H), 8.27 (s, IH), 7.32-7.23 (m, 2H), 7.17-6.98 (m, IH), 5.97 (s, IH), 4.48 (s, IH), 4.32 (s, IH), 4.07 (q, 2H), 3.67 (s, IH), 3.46-3.00 (m, 2H), 3.00-2.73 (m, IH), 2.63-2.26 (m, 2H), 1.88-1 .25 (m, 4H), 1.16 (t, 3H).
[00445] Example 116:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(((5)-2-(2-hydroxypropan-2-yl)pyrrolidin-l-yl) methyl)-2-(lH-l,2,4-triazol-3-yl)-l,4-dihydropyrimidine-5-carboxylate
Figure imgf000214_0001
Ethyl 4-(2-bromo-4-iluoropheny])-6-(bromomethyl)-2-( l H-l ,2,4-triazol-3-yl)-l ,4- dihydropyrimidine-5-carboxylate (0.75 g, 1.53 mmol) was reacted with (S)-2-(pyrrolidin-2-yl)propan-2-ol hydrochloride (0.25 g, 1.53 mmol) acc rding to the procedure as described in Example 25, Step B to give the title compound as a yellow solid (0.21 g, 26%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 535.2 [M+l ]+;
Ή NMR (400 MHz, DMSO-d6): δ 9.97 (s, 1H), 8.30 (s, 1H), 7.35-7.22 (m, 2H), 7.17 -7.03 (m, 1 H), 6.12 (s, 1H), 5.08-4.92 (m, 2H), 4.01 (q, 2H), 3.10-2.71 (m, 1 H), 2.64 -2.19 (m, 2H), 1 .80-1.33 (m, 5H), 1 .26-1 .08 (m, 9H).
[00446] Example 117:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(((R)-2-(hydroxymethyl)morpholino)methyl)-2- (lH-l,2,4-triazol-3-yl)-l,4-dihydropyrimidine-5-carboxylate
Figure imgf000214_0002
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-( lH-1 ,2,4-triazol-3-yl)-l ,4- dihydropyrimidine-5-carboxylate (0.75 g, 1.53 mmol) was reacted with (i^-morpholin^-ylmethanol hydrochloride (0.24 g, 1 .53 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a yellow solid (0.41 g, 51%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 523.1 [M+lf ;
]U NMR (400 MHz, OMSO-d6): δ 9.64 (s, 1H), 8.50 (s, 1H), 7.41-7.17 (m, 3H), 6.06 (s, 1H), 4.23-4.03 (m, 3H), 3.98-3.34 (m, 6H), 2.95-2.62 (m, 2H), 2.45-2.23 (m, 2H), 1.05 (t, 3H).
[00447] Example 118:
Ethyl 6-((3-(5H-tetrazol-5-yl)morpholino)methyI)-4-(2-bromo-4-fluorophenyl)-2- (thiazol-2-yl)-l,4-dihydropyrimidine-5-carboxylate
Figure imgf000215_0001
[00448] Step A: Tert-buty\ 3-(5H-tetrazol-5-yl)morpholine-4-carboxylate
A mixture of /e -butyl 3-cyanomorpholine-4-carboxylate (5 g, 23.6 mmol, the compound was synthesized according to the procedure as described in J.Med.Chem. 2007, 50(20), 4953-4975), sodium azide (1.53 g, 23.6 mmol) and ammonium chloride (0.63 g, 11.8 mmol) in anhydrous DMF (30 mL) was stirred at 100 °C for 72 hours and cooled to 25 °C. The reaction mixture was diluted with EtOAc (300 mL), then washed with brine (150 mL x 6). The organc phase was concentrated in vacuo and the residue was purified by a silica gel column chromatography (PETROLEUM ETHER/EtOAc (V V) = 1/1) to give the title compound as a brownish solid (2.5 g, 41%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 200.1 [M+l-56]+;
Ή NMR (400 MHz, DMSO-t/6): δ 3.93-3.86 (m, 1 H), 3.83-3.73 (m, 1H), 3.70-3.60 (m, 2H), 3.58-3.46 (m, 2H), 3.45-3.34 (m, 1 H), 1 .41 (s, 9H).
[00449] Step B: 3-(5H-tetrazol-5-yl)morpholine hydrochloride
Tert-butyl 3-(5H-tetrazo]-5-yl)morpholine-4-carboxylate (2 g, 7.8 mmol) was reacted with a solution of HCl in EtOAc (6 mol/L, 30 mL) according to the procedure as described in Example 18, Step B to give the title compound as a grey solid (1.05 g, 70%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/r. 156.1 [M+l ]' ;
Ή NMR (400 MHz, DMSO-c/6): δ 3.68-3.50 (m, 2H), 3.28-3.15 (m, 1 H), 3.14-2.99 (m, 2H), 2.96-2.90 (m, 1 H), 2.87-2.78 (m, 1 H), 1.92 (br.s, 1 H).
[00450] Step C: Ethyl 6-((3-(5H-tetrazol-5-yl)morphoHno)methyl)-4-(2-bromo-4- fluorophenyl)-2- (thiazol-2-yI)-l,4-dihydropyrimidine-5-carboxylate
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-l ,4-dihydro pyrimidine-5-carboxylate (0.5 g, 1 mmol) was reacted with 3-(5H-tetrazol-5-yl)morpholine hydrochloride (0.19 g, 1 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid (0.24 g, 42%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/r. 577.1 [M+l ]+;
Ή NMR (400 MHz, DMSO-</6): δ 10.01 (s, 1H), 8.10 (d, 1H), 7.93 (d, 1H), 7.34-7.23 (m, 2H), 7.19-6.93 (m, 1H), 6.09 (s, 1 H), 4.18-3.86 (m, 3H), 3.72-3.41 (m, 3H), 3.17-3.08 (m, 1 H), 2.86-2.46 (m, 3H), 2.14-2.05 (m, 1 H), 1 .06 (t, 3H).
[00451] Example 119:
4-((6-(2,4-dichlorophenyl)-5-(ethoxycarbonyl)-2-(4-(trifluoromethyl)thiazol-2-yl)-3,6-dih ydropyrimidin-4-yl)methyl)morphoIine-3-carboxylic acid
Figure imgf000217_0001
[00452] Step A: 4-(trifluoromethyl)thiazole-2-carbonitrile
4-(trifluoromethyl)thiazol-2-amine (2.52 g, 15 mmol) was reacted with CuCN (2.95 g, 33 mmol) according to the procedure as described in Example 61 , Step A to give the title compound as brown oil (0.90 g, 34%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 179.0 [M+l ]+; Ή NMR (400 MHz, CDC13): δ 8.15 (s, 1H).
[00453] Step B: 4-(trifluoromethyl)thiazole-2-carboximidamide acetate
To a solution of 4-(trifluoromethyl)thiazole-2-carbonitrile (0.9 g, 5 mmol) and TEA (1.1 mL, 7.5 mmol) in DCM (20 mL) was added hydroxylamine hydrochloride (0.35 g, 5 mmol), then the mixture was stirred at 25 °C for 2 hours. The mixture was concentrated in vacuo and the residue was purified by a silica gel column chromatography (PETROLEUM ETHER/EtOAc (V/V) = 10/1 ) to give the crude product as a white solid. To the white solid in acetic acid (25 mL) were added Ac20 (0.32 mL, 3.33 mmol) and Pd-C (10%, 0.2 g), then the mixture was stirred at 25 °C for 12 hours under N2. The reaction mixture was filtered and the filtrate was concentrated in vacuo. Then the residue was crystalized from EtOAc (2 mL) and ether ( 10 mL) to give the title compound as a white solid (0.74 g, 58%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 196.0 [M+l ]+; Ή NMR (400 MHz, DMSO-Λ): δ 7.44 (s, 1 H), 3.12 (br.s, 2H), 1 .99 (s, 3H).
[00454] Step C: Ethyl 4-(2,4-dichlorophenyl)-6-methyl-2-(4-(trifluoromethyl) thiazol-2-yl)-l,4-dihydropyrimidine-5-carboxylate
4-(trifluoromethyl)thiazole-2-carboximidamide acetate (0.38 g, 1.49 mmol) was reacted with 2,4-dichlorobenzaldehyde (0.26 g, 1.49 mmol) and ethyl 3-oxobutanoate (0.2 g, 1.49 mmol) according to the procedure as described in Example 1 , Step A to give the title compound as a yellow solid (0.44 g, 64%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 464.0 [M+l ]+;
Ή NMR (400 MHz, CDC13): δ 7.33 (d, 1 H), 7.17 (d, 1 H), 7.08-7.01 (m, 1 H), 6.96 (s, 1 H), 5.99 (br.s, l H), 4.16 (q, 2H), 2.53 (s, 3H), 1 .25 (t, 3H).
[00455] Step D: Ethyl 6-(bromomethyl)-4-(2,4-dichloropheny])-2-(4-(trifluoromethyl) thiazol-2-yl)-l,4-dihydropyrimidine-5-carboxylate
Ethyl 4-(2,4-dichlorophenyl)-6-methyl-2-(4-(trifluoromethyl)thiazol-2-yl)-l ,4-dihydro pyrimidine-5-carboxylate (0.44 g, 0.94 mmol) was reacted with NBS (0.21 g, 0.94 mmol) according to the procedure as described in Example 1 , Step B to give the title compound as a yellow solid (0.36 g, 70%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 541 .9 [M+l ]+;
Ή NMR (400 MHz, CDC13): δ 7.33 (s, 1 H), 7.1 1 -7.07 (m, 1 H), 7.00 (s, 1 H), 6.72 (s, 1 H), 5.99 (d, 1 H), 4.76 (dd, 2H), 4.21 (q, 2H), 1.07 (t, 3H).
[00456] Step E: 4-((6-(2,4-dichIorophenyl)-5-(ethoxycarbonyl)-2-(4-(trifluoromethyl) thiazol-2-yl)-3,6-dihydropyrimidin-4-yI)methyl)morpholine-3-carboxylic acid
Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(4-(trifluoromethyl)thiazol-2-yl)- 1 ,4- dihydropyrimidine-5-carboxylate (0.1 g, 0.18 mmol) was reacted with morpholine-3-carboxylic acid hydrochloride (0.03 g, 0.18 mmol) according to the procedure as described in Example 1 , Step C to give the title compound as a yellow solid (0.09 g, 80%). The compound was characterized by the following spectroscopic data:
MS-ES1: (ESI, pos.ion) m/z: 593.1 [M+l]+;
!H NMR (400 MHz, DMSO-fife): δ 12.67 (br.s, 1H), 7.32 (s, 1H), 7.69-7.59 (m, 1H), 7.23-7.07 (m, 2H), 6.17 (s, 1 H), 4.30-3.92 (m, 5H), 3.84-3.82 (m, 1 H), 3.74-3.52 (m, 3H), 3.1 1 -3.07 (m, 1 H), 2.55-2.39 (m, 1 H), 1.06 (t, 3H).
[00457] Example 120:
4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(5-fluorothiazol-2-yl)-3,6-dihydro pyrimidin-4-yl)methyl)morpholine-3-carboxyIic acid
Figure imgf000219_0001
[00458] Step A: 5-fluorothiazoIe-2-carbonitrile
5-fluorothiazol-2-amine (2.36 g, 20 mmol) (The compound was synthesized according to the procedure as described in Chinese Journal of Synthetic Chemistry, 2011, 19( 1), 139-141 ) was reacted with CuCN (3.94 g, 44 mmol) according to the procedure as described in Example 61 , Step A to give the title compound as brownish liquid (0.51 g, 20%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 129.0 [M+l ]+.
[00459] Step B: 5-fluorothiazole-2-carboximidamide acetate
5-fluorothiazole-2-carbonitrile (0.52 g, 4 mmol) was reacted with hydroxylamine hydrochloride (0.56 g, 8 mmol) according to the procedure as described in Example 119, Step B to give the title compound as a white solid (0.5 g, 63%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 146.0 [M+l ]+;
Ή NMR (400 MHz, CDC13): δ 7.72 (d, 1 H), 3.23 (br.s, 2H), 1.89 (s, 3H).
[00460] Step C: Ethyl 4-(2-bromo-4-nuorophenyl)-2-(5-nuorothiazol-2-yl)-6-methyl- l ,4-dihydropyrimidine-5-carboxylate
5-fluorothiazole-2-carboximidamide acetate (0.22 g, 1.07 mmol) was reacted with 2-bromo-4-fluorobenzaldehyde (0.22 g, 1.07 mmol) and ethyl 3-oxobutanoate (0.14 g, 1.07 mmol) according to the procedure as described in Example 1 , Step A to give the title compound as a yellow solid (0.21 g, 45%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 442.0 [M+l]+;
JH NMR (400 MHz, CDC13): δ 7.86 (d, 1H), 7.60-7.51 (m, 1H), 7.40-7.29 (m, 1H), 7.19-7.10 (m, 1H), 5.98 (br.s, 1H), 4.16 (q, 2H), 2.53 (s, 3H), 1.25 (t, 3H).
[00461 ] Step D: Ethyl 4-(2-bromo-4-nuorophenyl)-6-(bromomethyl)-2-(5-fluoro thiazol-2-yl)-l,4-dihydropyrimidine-5-carboxy]ate
Ethyl 4-(2-bromo-4-fluorophenyl)-2-(5-fluorothiazol-2-yl)-6-methyl-l,4-dihydro pyrimidine-5-carboxylate (0.51 g, 1.16 mmol) was reacted with NBS (0.21 g, 1.16 mmol) according to the procedure as described in Example 1 , Step B to give the title compound as a yellow solid (0.52 g, 86%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 5 19.9 [M+l ]+;
Ή NMR (400 MHz, CDC13): 7.86 (d, 1H), 7.60-7.52 (m, 1 H), 7.40-7.25 (m, 1H), 7.19-7.08 (m, ] H), 5.98 (br.s, 1 H), 5.74 (d, 1 H). 4.64 (d, 1 H), 4.21 (q, 2H), 1.27 (t, 3H). [00462] Step E: 4-i(6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbony])-2-(5-fluoro thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morphoIine-3-carboxylic acid
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(5-fIuorothiazol-2-yl)-l ,4- dihydropyrimidine-5-carboxylate (0.63 g, 1 .2 mmol) was reacted with morpholine-3-carboxylic acid hydrochloride (0.23 g, 1.4 mmol) according to the procedure as described in Example 28 to give the title compound as a yellowish solid (0.41 g, 60%). The compound was characterized by the following spectroscopic data:
MS-ES1: (ESI, pos.ion) m/z: 571.0 [M+l ]+;
1H NMR (400 MHz, CDC13): δ 9.82 (s, 1H), 7.86 (4. 1 H), 7.59-7.50 (m, 1 H), 7.41 -7.22 (m, 1 H), 7.19-7.07 (m, 1 H), 5.98 (br.s, 1H), 4.33-3.91 (m, 5H), 3.86-3.82 (m, 1 H), 3.75-3.51 (m, 3H), 3.14-3.08 (m, 1 H), 2.58-2.37 (m, 1H), 1 .06 (t, 3H).
[00463] Example 121 :
4-((6-(2-chloro-4-fluoropheny])-5-(ethoxycarbonyl)-2-(5-fluorothiazoI-2-yl)-3,6-dihydro pyrimidin-4-yl)methyl)morpholine-3-carboxylic acid
Figure imgf000221_0001
[00464] Step A: Ethyl 4-(2-chloro-4-fluorophenyl)-2-(5-fluorothiazol-2-yl)-6-methyl- l,4-dihydropyrimidine-5-carboxylate
5-fluorothiazole-2-carboximidamide acetate (0.22 g, 1 .07 mmol) was reacted with 2-chloro-4-fluorobenzaldehyde (0.17 g, 1 .07 mmol) and ethyl 3-oxobutanoate (0.14 g, 1.07 mmol) according to the procedure as described in Example 1 , Step A to give the title compound as a yellow solid (0.17 g, 39%). The compound was characterized by the following spectroscopic data:
MS-ES1: (ESI, pos.ion) m/z 398.0 [ +l ]+;
Ή NMR (400 MHz, CDC13): δ 7.88 (d, IH), 7.40-7.28 (m, 2H), 7.17-7.09 (m, IH), 6.00 (d, 1 Η), 4.16 (q, 2Η), 2.47 (s, 3Η), 1 .20 (t, 3Η).
[00465] Step B: Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluoropheny))-2-(S-fluoro thiazol-2-yl)-l,4-dihydropyrimidine-5-carboxylate
Ethyl 4-(2-chloro-4-fluorophenyl)-2-(5-fluorothiazol-2-yl)-6-methyl- 1 ,4-dihydro pyrimidine-5-carboxylate (0.17 g, 0.41 mmol) was reacted with NBS (0.07 g, 0.41 mmol) according to the procedure as described in Example 1 , Step B to give the title compound as a yellow solid (0.13 g, 65%). The compound was characterized by the following spectroscopic data:
MS-ES1: (ESI, pos.ion) m/z: 476.0 [M+l]+;
!H NMR (400 MHz, CDC13): δ 7.81 (d, IH), 7.40-7.22 (m, 2Η), 7.17-7.10 (m, IH), 6.03 (d, I H), 5.74 (d, IH), 4.64 (d, I H), 4.21 (q, 2H), 1.17 (t, 3H).
[00466] Step C: 4-((6-(2-chloro-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(5-fluoro thiazoI-2-y])-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxyIic acid
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(5-fluorothiazol-2-yl)-l ,4- dihydropyrimidine-5-carboxylate (0.2 g, 0.41 mmol) was reacted with morpholine-3-carboxylic acid hydrochloride (0.07 g, 0.41 mmol) according to the procedure as described in Example 1 , Step C to give the title compound as a yellow solid (0.2 g, 90%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 527.1 [M+l ]+;
Ή NMR (400 MHz, CDC13): δ 7.88 (d, IH), 7.40-7.24 (m, 2H), 7.17-7.10 (m, I H), 6.00 (s, I H), 4.33-3.92 (m, 5H), 3.87-3.82 (m, I H), 3.72-3.52 (m, 3H), 3.13-3.07 (m. I H), 2.52-2.39 (m, 1H), 1 .03 (t, 3H). [00467] Example 122:
4-((6-(2,4-dichlorophenyl)-5-(ethoxycarbonyl)-2-(5-fluorothiazol-2-yl)-3,6-dihydropyrim idin-4-yl)methyl)morpholine-3-carboxylic acid
Figure imgf000223_0001
[00468] Step A: Ethyl 4-(2,4-dichlorophenyl)-2-(5-fluorothiazol-2-yl)-6-methyl-l,4- dihydropyrimidine-5-carboxylate
5-fluorothiazole-2-carboximidamide acetate (0.25 g, 1 .22 mmol) was reacted with 2,4-dichlorobenzaldehyde (0.21 g, 1.22 mmol) and ethyl 3-oxobutanoate (0.16 g, 1.22 mmol) according to the procedure as described in Example 1 , Step A to give the title compound as a yellow solid (0.41 g, 80%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 414.0 [M+l ;
Ή NMR (400 MHz, CDC13): δ 7.87 (s, 1H), 7.59 (s, 1H), 7.36 (s, 2H), 6.00 (s, 1H), 4.16 (q, 2H), 2.43 (s, 3H), 1.05 (t, 3H).
[00469] Step B: Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(5-fluorothiazol- 2-yl)-l,4-dihydropyrimidine-5-carboxylate
Ethyl 4-(2,4-dichlorophenyl)-2-(5-fluorothiazol-2-yl)-6-methyl-l ,4-dihydropyrimidine- 5-carboxylate (0.44 g, 1 .06 mmol) was reacted with NBS (0.19 g, 1.06 mmol) according to the procedure as described in Example 1 , Step B to give the title compound as a yellow solid (0.36 g, 70%). The compound was characterized by the following spectroscopic data: MS-ESI: (ESI, pos.ion) m/z: 491 .9 [M+l ] ;
Ή NMR (400 MHz, CDC13): δ 7.87 (s, I H), 7.59 (s, IH), 7.36 (s, 2H), 6.00 (s, I H), 5.68 (d, I H), 4.60 (d, I H), 4.11 (q, 2H), 1.07 (t, 3H).
[00470] Step C: 4-((6-(2,4-dichlorophenyl)-5-(ethoxycarbonyl)-2-(5-fluorothiazol- 2-yl)-3,6-dihydropyrimidiii-4-yl)methyl)morpholine-3-carboxylic acid
Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(5-fluorothiazol-2-yl)-l ,4-dihydro pyrimidine-5-carboxylate (0.52 g, 1 .06 mmol) was reacted with morpholine-3-carboxylic acid hydrochloride (0.21 g, 1.28 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellowish solid (0.35 g, 60%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 543.1 [M+l ]+;
Ή NMR (400 MHz, DMSO-<¾: δ 9.89 (s, IH), 7.87 (s, IH), 7.59 (s, IH), 7.36 (s, 2H), 6.00 (s, I H), 4.28-3.92 (m, 5H), 3.85-3.82 (m, I H), 3.71 -3.52 (m, 3H), 3.09-3.07 (m, IH), 2.52-2.37 (m, I H), 1 .09 (t, 3H).
[00471 ] Example 123:
4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(l-methyl-lH-l,2,4-triazoI-3-yl)-3, 6-dihydropyrimidin-4-yl)methy])morpholine-3-carboxylic acid
Figure imgf000224_0001
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-( l -methyl-lH-l ,2,4-triazol-3-yl)- l ,4-dihydropyrimidine-5-carboxylate (0.5 g. 1 mmol) was reacted with morpholine-3-carboxylic acid hydrochloride (0.17 g, 1 mmol) according to the procedure as described in Example 1 , Step C to give the title compound as a yellow solid (0.25 g, 45%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 551.1 [M+l ]+;
Ή NMR (400 MHz, CDC13): δ 8.03 (s, IH), 7.60 (s, I H), 7.37-7.29 (m, IH), 7.26-7.13 (m, IH), 6.95-6.84 (m, IH), 6.21 (s, IH), 4.33-3.99 (m, 5H), 3.96 (s, 3H), 3.81-3.78 (m, IH), 3.71 -3.52 (m, 3H), 3.11 -3.07 (m, I H), 2.52-2.39 (m, I H), 1 .06 (t, 3H).
[00472] Example 124:
l-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazoI-2-yl)-3,6-¾hydropyrimidi n-4-yl)methyI)-4-methylpiperazine-2-carboxylic acid
Figure imgf000225_0001
[00473] Step A: Ethyl l,4-dibenzylpiperazine-2-carboxylate
To a solution of N'^-dibenzyl ethane- 1 ,2-diamine (24 g, 100 mmol) in toluene (100 mL) was added TEA (24.2 g, 240 mmol). The mixture was heated to 80 °C, and a solution of ethyl 2,3-dibromopropanoate (27.3 g, 105 mmol) in toluene (100 mL) was added dropwise over a period of 0.5 hour at 80 °C. Then the mixture was stirred at the temperature for 12 hours and cooled to 25 °C The reaction mixture was washed with saturated NaHC03 aqueous solution. The organic layer was dried over Na2S04, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PETROLEUM ETHER/EtOAc (V/V) = 5/1 ) to give the title compound as yellow oil (22.7 g, 67%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 339.2 [M+l ]+; Ή NMR (400 MHz, CDC1 ): δ 7.34-7.22 (m, 10Η), 4.20-4.08 (m. 2H), 3.92 (d, IH), 3.62-3.48 (m, 2H), 3.38 (d, IH), 3.35-3.24 (m, IH), 3.12-3.02 (m, IH), 2.80-2.59 (m, 2H), 2.57-2.38 (m, 3H), 1.24 (t, 3H).
[00474] Step B: Ethyl l-benzylpiperazine-2-carboxylate
To a solution of ethyl l ,4-dibenzylpiperazine-2-carboxylate (6.76 g, 20 mmol) in 1 ,2-dichloroethane (20 mL) was added 1 -chloroethyl carbonochloridate (3.15 g, 22 mmol) dropwise over a period of 30 minutes at 0 °C, and the mixture was stirred at the temperature for another 15 minutes. Then the mixture was stirred at 90 °C for 1 hour. The mixture was concentrated in vacuo, and to the residue was added methanol (15 mL). The mixture was stirred at 70 °C for 1 hour and concentrated in vacuo. The residue was diluted with water and washed with DCM. The aqueous layer was adjusted to pH 9 with NaHC03 aqueous solution and extracted with DCM. The organic layer was dried over Na2S04, and concentrated in vacuo to give the title compound as yellow oil (3.06 g, 60%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 249.2 [M+l]+;
Ή NMR (400 MHz, CDC13): δ 7.26-7.15 (m, 5H), 4.15 (q, 2H), 3.60 (dd, 2H), 3.15-3.02 (m, 3H), 2.91-2.72 (m, 3H), 2.24-2.17 (m, IH), 1.68 (br.s, IH), 1.23 (t, 3H).
[00475] Step C: Ethyl l-benzyl-4-methylpiperazine-2-carboxylate
Ethyl l -benzylpiperazine-2-carboxylate (3.03 g, 12.2 mmol) was reacted with iodomethane (1.73 g, 12.2 mmol) according to the procedure as described in Example 48, Step A to give the title compound as yellow oil (2.33 g, 73%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI. pos.ion) m/z: 263.2 [M+l f;
Ή NMR (400 MHz, CDC13): δ 7.34-7.24 (m, 5H), 4.21 (q, 2H), 3.90 (d, I H), 3.52-3.45 (m, I H), 3.30 (t, I H), 3.02 (br.s, I H), 2.64 (br.s, 2H), 2.36-2.26 (m, 3H), 2.25 (s, 3H), 1.27 (t, 3H).
[00476] Step D: Ethyl 4-methylpiperazine-2-carboxylate
Ethyl l-benzyI-4-methylpiperazine-2-carboxylate ( 1 1.54 g, 44 mmol) was reacted with Pd-C (10%, 1 g) according to the procedure as described in Example 34, Step C to give the title compound as colorless oil (6.2 g, 82%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI. pos.ion) m/z: 173.1 [M+l ]+;
Ή NMR (400 MHz, CDC13): δ 4.21 (q, 2H), 3.69 (d, 1 H), 3.52-3.46 (m, 1 H), 3.30 (t, 1 H), 3.02 (br.s, 1 H), 2.36-2.28 (m, 3H), 2.26 (s, 3H), 1.29 (t, 3H).
[00477] Step E: 4-methylpiperazine-2-carboxylic acid
Ethyl 4-methylpiperazine-2-carboxylate (1 .03 g, 6 mmol) was reacted with NaOH (0.48 g, 12 mmol) according to the procedure as described in Example 21 , Step A to give the title compound as colorless oil (0.86 g, 100%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 145.1 [M+l ]+;
Ή NMR (400 MHz, CDC13): δ 3.69 (d, 1H), 3.54-3.48 (m, 1 H), 3.30 (t, 1H), 3.02 (br.s, 1H), 2.36-2.27 (m, 3H). 2.26 (s, 3H).
[00478] Step F: l-((6-(2-bromo-4-fluorophenyI)-5-(ethoxycarbony])-2-(thiazol-2-yl)- 3,6-dihydropyrimidin-4-yl)methyl)-4-methylpiperazine-2-carboxylic acid
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazoI-2-yI)-] ,4-dihydro pyrimidine-5-carboxyIate ( 1 .5 g, 3 mmol) was reacted with 4-methylpiperazine-2-carboxylic acid (0.43 g, 3 mmol) according to the procedure as described in Example 1 , Step C to give the title compound as a yellow solid ( 1 .00 g, 59%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 566.1 [M+l f; Ή N R (400 MHz, D SO-Λ): δ 10.90 (br.s, IH), 8.00-7.96 (m, IH), 7.87-7.82 (m, IH), 7.52-7.48 (m, IH), 7.39-7.31 (m, I H), 7.24-7.1 8 (m, IH), 6.01 (s, IH), 4.30-3.92 (m, 2H), 3.69-3.56 (m, 2H), 3.52-3.39 (m, 2H), 3.30-3.15 (m, IH), 3.02 (br.s, IH), 2.36-2.29 (m, 3H), 2.26 (s, 3H), 1.06 (t, 3H).
[00479] Example 125:
4-((6-(2-bromo-4-fIuorophenyl)-5-(ethoxycarbonyl)-2-(l-methyl-lH-imidazol-2-yl)-3,6- dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid
Figure imgf000228_0001
Ethyl 4-(2-bromo-4-fluoropheny])-6-(bromomethyl)-2-(l -methyl-lH-imidazol-2-yl)-] ,4- dihydropyrimidine-5-carboxylate ( 1 g, 2 mmol) (The compound was synthesized according to the procedure as described in WO2010069147) was reacted with morpholine-3-carboxylic acid (0.26 g, 2 mmol) according to the procedure as described in Example 28 to give the title compound as a yellowish solid (0.49 g, 45%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z 550.1 [M+l ]+;
Ή NMR (400 MHz, DMSO-</6): δ 9.83 (s, IH), 7.69-7.48 (m, 2H), 7.32-7.28 (m, IH), 7.23-7.12 (m, 2H), 6.17 (s, IH), 4.30-3.88 (m, 5H), 3.84-3.78 (m, IH), 3.74-3.50 (m, 3H), 3.49 (s, 3H), 3.11 -3.03 (m, IH), 2.55-2.34 (m, I H), 1.06 (t, 3H).
[00480] Example 126:
Ethyl 6-(((5 -2-((((5)-2-amino-3-methylbutanoyl)oxy)methyl)morpholino)methyl)-4-(2- bromo-4-fluorophenyl)-2-(thiazol-2-yl)-l,4-dihydropyrimidine-5-carboxylate
Figure imgf000229_0001
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(((S)-2-(hydroxymethy])moφholino)methyl)-2- (thiazol-2-yl)-l ,4-dihydropyrimidine-5-carboxylate (1 g. 1.9 mmol) was reacted with (S)-2-((fer/-butoxycarbonyl)amino)-3-methylbutanoic acid (0.63 g, 2.9 mmol) according to the procedure as described in Example 49 to give the title compound as a yellow solid (0.57 g, 47%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 638.1 [M+l ]+;
1H NMR (400 MHz, D20): δ 7.92-7.87 (m, 2H), 7.49-7.41 (m, 2H), 7.13-7.09 (m, 1 H), 6.15 (br.s, 1 H), 4.51 -4.35 (m, 4H), 4.34-4.19 (m, 2H), 4.1 1 -3.98 (m, 4H), 3.79-3.66 (m, 2H), 3.44-3.28 (m, 2H), 2.31 -2.25 (m, I H), 1 .07-1.03 (m, 3H), 0.98-0.91 (m, 6H).
[00481 ] Example 127:
Ethyl 4-(2-chloro-4-fluorophenyl)-6-(((5)-2-(hydroxymethyl)morpholino)methyl)-2- (thiazol-2-yl)-l,4-dihydropyrimidine-5-carboxylate
Figure imgf000229_0002
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-l ,4-dihydro pyrimidine-5-carboxylate (0.92 g, 2 mmol) was reacted with (S)-morpholin-2-ylmethanol (0.34 g, 2.2 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a yellow solid (0.30 g, 30%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 495.1 [M+l ]+;
Ή NMR (400 MHz, CDC13): δ 9.68 (d, 1 H), 7.96 (d, 1 H), 7.80 (d, 1 H), 7.56-7.50 (m, 1 H), 7.40-7.35 (m, 1 H), 7.20-7.16 (m, 1 H), 6.00 (s, 1H), 3.98-3.30 (m, 7H), 2.97-2.61 (m, 4H), 2.45-2.05 (m, 2H), 1 .05 (t, 3H).
[00482] Example 128:
Ethyl 4-(2,4-dichlorophenyl)-6-(((5)-2-(hydroxymethyl)morpholino)methyl)-2-(thiazol- 2-yl)-l,4-dihydropyrimidine-5-carboxylate
Figure imgf000230_0001
Ethyl 6-(bromomethyl)-4-(2 ,4-dichlorophenyl)-2-(thiazol-2-yl)- 1 ,4-dihydropyrimidine- 5-carboxylate (0.95 g, 2 mmol) was reacted with (^-morpholin^-ylmethanol (0.34 g, 2.2 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a yellow solid (0.34 g, 33%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 51 1.1 [M+l ]+;
Ή NMR (400 MHz, CDC13): δ 9.64 (d, 1 H), 8.00 (d, 1H), 7.90 (d, 1 H), 7.56-7.46 (m, 1 H), 7.38-7.29 (m, 1H), 7.20-7.13 (m, 1H), 6.02 (s, 1H), 3.98-3.29 (m, 7H), 2.99-2.62 (m, 4H), 2.45-2.01 (m, 2H), 1.05 (t, 3H).
[00483] Example 129:
3-(4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydro pyrimidin-4-yl)methyl)morphoIin-2-yl)propanoic acid
Figure imgf000231_0001
[00484] Step A: Benzyl 2-(3-methoxy-3-oxoprop-l-en-l-yl)morpholine-4- carboxylate
A mixture of benzyl 2-formylmorpholine-4-carboxylate (1.5 g, 6 mmol) and methyl 2-(triphenylphosphoranylidene)acetate (2.01 g, 6 mmol) in DCM (30 mL) was stirred at 25 °C for 12 hours under N2. The mixture was concentrated in vacuo, and the residue was purified by a silica gel column chromatography (PETROLEUM ETHER/EtOAc (V V) = 3/1) to give the title compound as colorless oil (0.88 g, 48%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 306.1 [M+l]+;
Ή NMR (400 MHz, CDC13): δ 7.35-7.29 (m, 5H), 6.82-6.78 (m, 1H), 6.09-6.01 (m, 1H), 5.15-5.10 (m, 2H), 4.20-4.11 (q, 2H), 3.94-3.88 (m, 2H), 3.77-3.65 (m, 3H), 3.60-3.58 (m, 1H), 3.02 (br.s, 1H), 2.74 (br.s, 1H).
[00485] Step B: 3-(4-((benzyloxy)carbonyl)morpholin-2-yl)acrylic acid
Benzyl 2-(3-methoxy-3-oxoprop-l -en-l -yl)morpholine-4-carboxylate (0.86 g, 2.82 mmol) was reacted with NaOH ( 1.12 g, 28.2 mmol) according to the procedure as described in Example 21 , Step A to give the title compound as colorless oil (0.79 g, 96%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 292.1 [M+l ]+;
Ή NMR (400 MHz, CDC13): δ 7.37-7.19 (m, 5H), 6.82-6.79 (m, I H), 6.09-6.02 (m, IH), 5.15-5.08 (m, 2H), 4.10-4.01 (m, 2H), 3.94-3.80 (m, 2H), 3.60-3.55 (m, IH), 3.02 (br.s, IH), 2.74 (br.s, I H).
[00486] Step C: 3-(morpholin-2-yl)propanoic acid
3-(4-((benzyloxy)carbonyl)morpholin-2-yl)acrylic acid (0.52 g, 1 .8 mmol) was reacted with Pd-C (10%, 0.05 g) according to the procedure as described in Example 34, Step C to give the title compound as a white solid (0.2 g, 70%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 160.1 [M+l ]+;
*H NMR (400 MHz, CDC13): δ 3.66-3.52 (m, 3H), 2.96-2.69 (m, 4H), 2.33-2.21 (m, 2H), 1.69-1.54 (m, 2H).
[00487] Step D: 3-(4-((6-(2-bromo-4-nuoropheny])-5-(ethoxycarbonyl)-2-(thiazol-2- yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholin-2-y])propanoic acid
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-l ,4-dihydro pyrimidine-5-carboxylate (0.7 g, 1.4 mmol) was reacted with 3-(morpholin-2-yl)propanoic acid (0.22 g, 1.4 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid (0.40 g, 50%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 581.1 [M+l ]+;
!H NMR (400 MHz, DMSO- ): δ 9.81 (s, I H), 7.84 (d, I H), 7.43-7.36 (m, IH), 7.33 (d, I H), 7.28 (d, I H), 6.95-6.87 (m, I H), 6.19 (s. I H), 4.30-3.92 (m, 5H), 3.84-3.82 (m, I H), 3.74-3.52 (m, 3H), 2.82-2.69 (m, 3H), 2.55-2.14 (m, 3H). 1 .06 (t, 3H). [00488] Example 130:
3-(4-((6-(2-chloro-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydro pyrimidin-4-yI)methyl)morpholin-2-yl)propanoic acid
Figure imgf000233_0001
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-l ,4-dihydro pyrimidine-5-carboxylate (0.64 g, 1.4 mmol) was reacted with 3-(morpholin-2-yl)propanoic acid (0.22 g, 1 .4 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid (0.45 g, 60%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 537.1 [M+l ;
Ή NMR (400 MHz, DMSO-i/6): δ 12.91 (br.s, IH), 9.82 (s, IH), 7.89 (d, IH), 7.42-7.37 (m, I H), 7.30 (d, IH), 7.26 (d, IH), 6.99-6.89 (m, IH), 6.20 (s, I H), 4.33-3.92 (m, 5H), 3.84-3.80 (m, IH), 3.71-3.52 (m, 3H), 2.82-2.65 (m, 3H), 2.55-2.19 (m, 3H), 1.05 (t, 3H).
[00489] Example 131 :
3- (4-((6-(2,4-dichlorophenyl)-5-(ethoxycarbonyl)-2-(thiazoI-2-yl)-3,6-dihydropyrimidin-
4- yl)methyl)morpholin-2-yI)propanoic acid
Figure imgf000234_0001
Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-l ,4-dihydropyrimidine -5-carboxylate (0.67 g, 1 .4 mmol) was reacted with 3-(morpholin-2-yl)propanoic acid (0.22 g, ] .4 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid (0.35 g, 45%). The compound was characterized by the following spectroscopic data:
MS-ES1: (ESI, pos.ion) m/z: 553.1 [M+l ]+;
]H NMR (400 MHz, DMSO-c/6): δ 12.90 (br.s, 1 H), 9.86 (br.s, I H), 7.79 (d, 1 H,), 7.41 -7.39 (m, I H), 7.32 (d, I H), 7.26 (d, IH), 7.00-6.89 (m, IH), 6.09 (s, I H), 4.30-3.92 (m, 5H), 3.88-3.82 (m, IH), 3.78-3.52 (m, 3H), 2.89-2.69 (m, 3H), 2.57-2.14 (m, 3H), 1.05 (t, 3H).
[00490] Example 132:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-((2-(3-methoxy-3-oxopropyl)morpholino)methyl)- 2-(thiazol-2-yl)-l,4-dihydropyrimidine-5-carboxylate
Figure imgf000234_0002
[00491 ] Step A: Methyl 3-(morpholin-2-yl)propanoate
Benzyl 2-(3-methoxy-3-oxoprop-l -en-l -yl)mo holine-4-carboxylate (6.47 g, 21 .2 mmol) was reacted with Pd-C ( 10%, 0.65 g) according to the procedure as described in Example 34, Step C to give the title compound as colorless oil (3.21 g, 87%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 174.1 [M+l]+;
Ή NMR (400 MHz, CDC13): δ 3.66-3.49 (m, 3H), 2.96-2.78 (m, 4H), 2.33-2.21 (m, 2H), 1.69-1.55 (m, 2H), 1.29-1.21 (m, 3H).
[00492] Step B: Ethyl 4-(2-bromo-4-fluorophenyl)-6-((2-(3-methoxy-3-oxopropyl) morpholino)methyl)-2-(thiazol-2-yl)-l,4-dihydropyrimidine-5-carboxylate
Ethyl 4-(2-bromo-4-fiuorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-l ,4-dihydro pyrimidine-5-carboxylate (1 g, 2 mmol) was reacted with methyl 3-(mor 10ijn_2-yl) propanoate (0.38 g, 2.2 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a yellow solid (0.53 g, 45%). The compound was characterized by the following spectroscopic data:
MS (ESI, pos.ion) m/z: 595.1 [M+l f ;
Ή NMR (600 MHz, CDC13): .63 (s> I H), 7.84 (t, 1H), 7.43 (d, 1H), 7.30-7.27 (m, 1H), 6.96-6.83 (m, 1H), 6.20 (s, 1H), 4.00-3.85 (m, 5H), 3.65 (s, 1H), 3.63-3.51 (m, 2H), 2.92-2.82 (m, IH), 2.79-2.65 (m, 3H), 2.39-2.14 (m, 4H), 1.65-1.58 (m, 2H), 1.09 (t, 3H).
[00493] Example 133:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-((2-(3-hydroxypropyl)morpholino)methyl)-2- (thiazol-2-yl)-l,4-dihydropyrimidine-5-carboxylate
Figure imgf000235_0001
[00494] Step A: 3-(morpholin-2-yl)propan-l-oI
Methyl 3-(morpholin-2-yl)propanoate (0.69 g, 4 mmol) was reacted with LiAlH4 (0.23 g, 6 mmol) according to the procedure as described in Example 68, Step A to give the title compound as colorless oil (0.43 g, 75%). The compound was characterized by the following spectroscopic data:
MS-ES1: (ESI, pos.ion) m/z: 146.1 [M+l]+.
[00495] Step B: Ethyl 4-(2-bromo-4-nuorophenyl)-6-((2-(3-hydroxypropyl) morpholino)methyl)-2-(thiazol-2-yl)-l,4-dihydropyrimidine-5-carboxylate
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethy])-2-(thiazol-2-yl)-l ,4-dihydro pyrimidine-5-carboxylate (1.26 g, 2.5 mmol) was reacted with 3-(morpholin-2-yl)propan-] -ol (0.43 g, 3 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a yellow solid (1.0 g, 70%). The compound was characterized by the following spectroscopic data:
MS (ESI, pos.ion) m/z: 567.1 [M+l f ;
Ή NMR (600 MHz, CDC13): δ 9.68 (s, IH), 8.01-7.99 (m, IH), 7.92-7.89 (m, IH), 7.53-7.49 (m, IH), 7.41 -7.38 (m, IH), 7.20-7.16 (m, IH), 6.04 (s, IH), 4.03-3.73 (m, 5H), 3.62-3.59 (m, 4H), 2.78-2.65 (m, 2H), 2.46-2.33 (m, 3H), 2.23-2.07 (m, I H), 1.82-1.70 (m, 2H), 1.23 (t, 3H).
[00496] Example 134:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-((2-(3-(methylamino)-3-oxopropyl)morpholino) methyl)-2-(thiazol-2-yl)-l,4-dihydropyrimidine-5-carboxylate
Figure imgf000237_0001
3-(4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyri midln-4-yl)methyl)mo holin-2-yl)propanoic acid (0.69 g, 1.19 mmol) was reacted with methanamine hydrochloride (0.12 g, 1.8 mmol) according to the procedure as described in Example 62, Step B to give the title compound as a yellow solid (0.27 g, 38%). The compound was characterized by the following spectroscopic data:
MS (ESI, pos.ion) m/z: 594.1 [M+l ]+;
Ή NMR (600 MHz, CDC13): δ 9.65 (s, I H), 8.04 (d, I H), 7.94 (d, I H), 7.70-7.68 (m, IH), 7.55-7.50 (m, IH), 7.39-7.31 (m, IH), 7.23-7.19 (m, IH), 6.03 (s, I H), 4.00-3.85 (m, 3H), 3.63-3.51 (m, 2H), 3.05 (s, 3H), 2.92-2.82 (m, I H), 2.79-2.65 (m, 3H), 2.39-2.14 (m, 4H), 1 .65-1 .48 (m, 2H), 1.09 (t, 3H).
[00497] Example 135:
Ethyl 6-((2-(3-amino-3-oxopropyl)morpholino)methyl)-4-(2-bromo-4-fluorophenyl)-2- (thiazol-2-yl)-l,4-dihydropyrimidine-5-carboxylate
Figure imgf000237_0002
[00498] Step A: 3-(morpholin-2-yJ)propanamide Methyl 3-(morpholin-2-yl)propanoate (0.58 g, 3.35 mmol) was reacted with a solution of NH3 in methanol (7 mol/L, 10 mL) according to the procedure as described in Example 25, Step A to give the title compound as brownish oil (0.41 g, 78%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 159.1 [M+l ]+.
[00499] Step B: Ethyl 6-((2-(3-amino-3-oxopropyl)morpholino)methyl)-4-(2-bromo- 4-fluorophenyl)-2-(thiazol-2-yI)-l,4-dihydrop rimidine-5-carboxylate
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-l,4-dihydrn pyrimidine-5-carboxylate (1.51 g, 3 mmol) was reacted with
Figure imgf000238_0001
(0.47 g, 3 mmol) according to the procedure as described in Example 2 , Step B to give the title compound as a yellow solid (1.5 g, 86%). The compound, was characterized by the following spectroscopic data:
MS (ESI, pos.ion) m/z: 580.1 (M+l)+;
Ή NMR (600 MHz, CDClj): δ 9.69 (d, I H), 8.06-8.01 (m, IH), 7.97-7.90 (m, IH), 7.60-7.54 (m, I H), 7.42-7.39 (m, I H), 7.27-7.16 (m, 2H), 6.72 (d, I H), 6.07 (d, I H), 4.00-3.85 (m, 5H), 3.63-3.51 (m, 2H), 2.92-2.82 (m, I H), 2.79-2.65 (m, I H), 2.39 -2.14 (m, 4H), 1.65-1.60 (m, 2H), 1 .09 (t, 3H).
[00500] Example 136:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-((3-(methylcarbamoyl)morpholino)methyl)-2- (thiazol-2-yl)-l,4-dihydropyrimidine-5-carboxylate
Figure imgf000238_0002
4-((6-(2-bromo-4-fiuorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimi in-4-yl)methyl)moφholine-3-carboxyIic acid (2 g, 3.6 mmol) was reacted with methanamine hydrochloride (0.49 g, 7.2 mmol) according to the procedure as described in Example 62, Step B to give the title compound as a yellow solid (0.69 g, 34%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/∑: 566.1 [M+l ;
Ή NMR (400 MHz, DMSO-c76): δ 9.95 (d, I H), 8.15-8.08 (m, I H), 8.02 (t, I H), 7.91 -7.87 (m, I H), 7.54-7.51 (m, I H), 7.38-7.31 (m, I H), 7.21 -7.18 (m, I H), 6.00 (d, IH), 4.28-3.92 (m, 5H), 3.86-3.82 (m, I H), 3.74-3.50 (m, 3H), 3.1 1 -3.07 (m, I H), 3.07 (s, 3H), 2.55-2.39 (m, I H), 1 .06 (t, 3H).
[00501 ] Example 137:
4-((6-(2-bromo-4-fluorophenyI)-2-(6-methoxybenzo[<flthiazoI-2-yI)-5-(methoxycarbony]) -3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid
Figure imgf000239_0001
[00502] Step A: 6-methoxybenzo[i |thiazole-2-carbonitriIe
6-methoxybenzo[< jthiazol-2-amine (9 g, 50 mmol) was reacted with CuCN (8.96 g, 100 mmol) according to the procedure as described in Example 61 , Step A to give the title compound as a white solid (2.1 g, 22%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 191.0 [M+l] ;
Ή NMR (400 MHz, CDCU): δ 8.08 (d, IH), 7.36 (q, I H), 7.24 (dd, I H), 3.65 (s, 3H). [00503] Step B: 6-methoxybenzo|if)thiazole-2-carboximidamide hydrochloride
6-methoxybenzo[_/]thiazole-2-carbonitrile ( 1 g, 5.26 mmol) was reacted with sodium methoxide (0.28 g, 5.26 mmol) and ammonium chloride (0.6 g, 1 1 mmol) according to the procedure as described in Example 61 , Step B to give the title compound as a white solid (0.96 g, 75%). The compound was characterized by the following spectroscopic data:
MS-ES1: (ESI, pos.ion) m/z: 208.0 [M+lf.
[00504] Step C: Methyl 4-(2-bromo-4-fluorophenyl)-2-(6-methoxybenzo|t ]thiaxo"i_2- yl)-6-methyl-l,4-dihydropyrimidine-5-carboxylate
6-methoxybenzo[i/]thiazole-2-carboximidamide hydrochloride (2.4 g, 10 mmol) was reacted with 2-bromo-4-fluorobenzaldehyde (2.03 g, 10 Tnmol) and methyl 3-oxobutanoate (1 .16 g, 10 mmol) according to the procedure as described in Example 1 , Step A to give the title compound as a yellow solid (2.7 g, 55%). The compound was characterized by the following spectroscopic data:
MS-ES1: (ESI, pos.ion) m/z: 490.0 [M+l f ;
Ή NMR (400 MHz, CDC13): δ 8.06-7.85 (m, 2H), 7.59-7.29 (m, 2H), 7.17-6.93 (m, 2H), 6.19-6.05 (m, 1H), 3.88-3.87 (m, 3H), 3.63-3.60 (m, 3H), 2.59-2.55 (m, 3H).
[00505] Step D: Methyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyI)-2-(6-methoxy benzo[i/Jthiazol-2-yl)-l,4-dihydropyrimidine-5-carboxylate
Methyl 4-(2-bromo-4-fluorophenyl)-2-(6-methoxybenzo[c ]thiazol-2-yl)-6-methyl-l ,4- dihydropyrimidine-5-carboxylate (1 .29 g, 2.63 mmol) was reacted with NBS (0.47 g, 2.63 mmol) in DCM (50 mL) according to the procedure as described in Example 1 , Step B to give the title compound as a yellow solid (0.82 g, 55%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESE pos.ion) m/z: 567.9 [M+l ; Ή NMR (400 MHz, DMSO- 6): δ 7.97 (d, I H), 7.69 (d, IH), 7.58 (dd, IH), 7.41 (m, IH), 7.25 (m, I H), 7.17 (dd, I H). 5.99 (m, IH), 4.86 (br.s, 2H), 3.85 (s, 3H), 3.57 (s, 3H).
[00506] Step E: 4-((6-(2-bromo-4-fluorophenyl)-2-(6-methoxybenzo[i/lthiazol-2-y])- 5-(methoxycarbonyl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid
Methyl 4-(2-bromo-4-fIuorophenyl)-6-(bromomethyl)-2-(6-methoxybenzo[i ]thiazol- 2-yl)-l ,4-dihydropyrimidine-5-carboxylate (0.46 g, 0.8 mmol) was reacted with morpholine-3-carboxylic acid (0.21 g, 1.6 mmol) according to the procedure as described in Example 1. Step C to give the title compound as a yellowish solid (0.3 g, 60%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 619.1 [M+l ]+;
Ή NMR (400 MHz, DMSO-</6): δ 12.9 (br.s, I H), 9.85 (s, I H), 7.97 (d, I H), 7.69 (d, IH), 7.58 (dd, I H), 7.41 -7.38 (m, I H), 7.25-7.21 (m, I H), 7.17 (dd, I H), 5.99 (s, I H), 4.27-3.92 (m, 4H), 3.84-3.79 (m, IH), 3.75 (s, 3H), 3.74-3.65 (m, 2H), 3.57 (s, 3H), 3.11-3.07 (m, IH), 2.55-2.39 (m, I H).
[00507] Example 138:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-((3-(hydroxymethyl)morpholino)methyl)-2-(6- methoxybenzo[i |thiazol-2-yl)-l,4-dihydropyriinidine-5-carboxylate
Figure imgf000241_0001
[00508] Step A: Ethyl 4-(2-bromo-4-fluorophenyl)-2-(6-methoxybenzoI< lthiazol-2- yl)-6-methyl-l,4-dihydropyrimidine-5-carboxylate
6-methoxybenzo[c/]thiazole-2-carboximidamide hydrochloride (2.4 g, 10 mmol) was reacted with 2-bromo-4-fluorobenzaldehyde (2.03 g, 10 mmol) and ethyl 3-oxobutanoate (1 .3 g, 10 mmol) according to the procedure as described in Example 1 , Step A to give the title compound as a yellow solid (3.1 g, 62%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/r. 504.0 [M+l]+;
Ή NMR (400 MHz, CDCh): 5 8.06-7.85 (m, 2H), 7.59-7.29 (m, 2H), 7.17-6.93 (m, 2H), 6.19-6.05 (m. 1 H), 3.88-3.87 (m, 2H), 3.63-3.60 (m, 3H), 2.59-2.55 (m, 3H), 1 .05 (t, 3H).
[00509] Step B: Ethyl 4-(2-bromo-4-nuorophenyl)-6-(bromomethyI)-2-(6-methoxy benzo[</|thiazol -2-yl)-l,4-dihydropyrimidine-5-carboxylate
Ethyl 4-(2-bromo-4-fluorophenyl)-2-(6-methoxybenzo[i ]thiazol-2-yl)-6-methy]-l ,4- dihydropyrimidine-5-carboxylate ( 1 .26 g, 2.5 mmol) was reacted with NBS (0.47 g, 2.63 mmol) in DCM (50 mL) according to the procedure as described in Example 1 , Step B to give the title compound as a yellow solid (0.82 g, 55%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/r. 581.9 [M+l ]+; lU NMR (400 MHz, DMSOc/6): δ 8.02-7.82 (m, 2H), 7.56-7.29 (m, 2H), 7.18-6.93 (m, 2H), 6.09-6.05 (m, 1 H), 4.99 (dd, 2H), 3.88-3.83 (m, 2H), 3.65-3.60 (m, 3H), 2.59-2.55 (m, 3H), 1.05 (t, 3H).
[00510] Step C: 4-(2-bromo-4-fluorophenyl)-6-((3-(hydroxymethyl)morpholino) methyl)-2-(6-methoxybenzo|< ]thiazol-2-yl)-l,4-dihydropyrimidine-5-carboxylate
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(6-methoxybenzo[i ]thiazol-2- yl)-l ,4-dihydropyrimidine-5-carboxylate (0.58 g, 1 mmol) was reacted with morpholin-3- ylmethanol hydrochloride (0.1 8 g, 1 .2 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a yellowish solid (0.50 g, 80%). The compound was characterized by the following spectroscopic data: MS-ESI: (ESI, pos.ion) mlz: 619.1 [M+l ] ;
Ή NMR (400 MHz, CDC13): δ 7.99 (d, IH), 7.69-7.60 (m, IH), 7.57-7.50 (m, IH), 7.40-7.38 (m, I H), 7.25-7.20 (m, I H), 7.17-7.10 (m, I H), 5.99 (s, I H), 4.31 -3.99 (m, 4H), 3.92 (s, 3H), 3.84-3.81 (m, I H), 3.79-3.53 (m, 4H), 3.1 1-3.07 (m, 3H), 2.55-2.39 (m, I H), 1 .05 (t, 3H).
[0051 1 ] Example 139:
4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(5-methoxythiazol-2-yI)-3,6-dihyd ropyrimidin-4-yI)methyl)morpholine-3-carboxylic acid
Figure imgf000243_0001
[00512] Step A: 5-methoxythiazole-2-carbonitrile
5-methoxythiazol-2-amine (2.6 g, 20 mmol) was reacted with CuCN (4 g, 44 mmol) according to the procedure as described in Example 61 , Step A to give the title compound as brownish oil (0.84 g, 30%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 141.0 [M+l ]+;
Ή NMR (400 MHz, CDCI3): δ 7.04 (s, I H), 3.83 (s, 3H).
[00513] Step B: 5-methoxythiazole-2-carboximidamide hydrochloride
5-methoxythiazole-2-carbonitrile (0.74 g, 5.26 mmol) was reacted with sodium methoxide (0.28 g, 5.26 mmol) and ammonium chloride (0.6 g, 1 1 mmol) according to the procedure as described in Example 61 , Step B to give the title compound as a white solid (0.51 g, 50%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 158.2.[M+1 ]\ [00514] Step C: Ethyl 4-(2-bromo-4-fluorophenyl)-2-(5-methoxythiazol-2-y])-6- methyl-l,4-dihydropyrimidine-5-carboxylate
5-methoxythiazole-2-carboximidamide hydrochloride (3.3 g, 17 mmol) was reacted with 2-bromo-4-fluorobenzaldehyde (3.46 g, 17 mmol) and ethyl 3-oxobutanoate (2.2 g, 17 mmol) according to the procedure as described in Example 1 , Step A to give the title compound as a yellow solid (4.56 g, 59%). The compound was characterized by the following spectroscopic data:
MS-ES1: (ESI, pos.ion) m/z: 454.0 [M+l ]+;
Ή NMR (400 MHz, CDC13): δ 7.37-7.35 (m, 1H), 7.32-7.17 (m, 2H), 7.1 1 (s, 1 H), 6.03 (s, 1 H), 4.12 (q, 2H), 3.87 (s, 3H), 2.46 (s, 3H), 1.14 (t, 3H).
[00515] Step D: Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(5-methoxy thiazol-2-yI)-l,4-dihydropyrimidine-5-carboxylate
Ethyl 4-(2-bromo-4-fluorophenyl)-2-(5-methoxythiazol-2-yl)-6-methyl- 1 ,4-dihydro pyrimidine-5-carboxylate (2 g, 4.4 mmol) was reacted with NBS (0.78 g, 4.4 mmol) in DCM (50 mL) according to the procedure as described in Example 1 , Step B to give the title compound as a yellow solid (0.80 g, 34%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 532.0 [M+lf;
Ή NMR (400 MHz, DMSO-i/6): 5 7.39-7.36 (m, 1H), 7.31-7.28 (m, 1H), 7.08 (s, 1H), 6.99-6.91 (m, 1H), 6.03 (s, 1H), 4.90-4.82 (m, 1H), 4.56-4.51 (m, 1H), 4.12 (q, 2H), 3.95 (s, 3H), 1.14 (t, 3H).
[00516] Step E: 4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(5-methoxy thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid
Ethyl 4-(2-bromo-4-fIuorophenyl)-6-(bromomethyl)-2-(5-methoxythiazol-2-yl)-l ,4- dihydropyrimidine-5-carboxylate (0.53 g, 1 mmol) was reacted with morpholine-3-carboxylic acid hydrochloride (0.2 g, 1.2 mmol) according to the procedure as described in Example 1 , Step C to give the title compound as a yellowish solid (0.30 g, 52%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/r.583.1 [M+l]+;
Ή NMR (400 MHz, DMSO-</6): δ 12.23 (br.s, 1H), 9.79 (br.s, 1H), 7.53-7.50 (m, 1H), 7.40 (s, 1 H), 7.35-7.31 (m, 1 H), 7.19-7.15 (m, 1H), 5.95 (s, 1 H), 4.24-3.92 (m, 4H), 3.90 (s, 3H), 3.86-3.81 (m, 4H), 3.72-3.52 (m, 2H), 3.1 1 -3.07 (m, 1 H), 1 .14 (t, 3H).
[00517] Example 140:
4-((6-(2-bromo-4-fIuorophenyl)-5-(ethoxycarbonyl)-2-(5-(trifluoromethyl)thiazol-2-yl)-3,
6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid
Figure imgf000245_0001
[00518] Step A: 5-(trifluoromethyl)thiazole-2-carbonitrile
5-(trifluoromethyl)thiazol-2 -amine (2.52 g, 15 mmol) was reacted with CuCN (2.7 g, 30.2 mmol) according to the procedure as described in Example 61 , Step A to give the title compound as oil (1.25 g, 47%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/r 179.0 [M+l ]+; Ή NMR (600 MHz, CDC13): δ 7.19 (s, 1 H).
[00519] Step B: 5-(trifluoromethyl)thiazole-2-carboximidamide hydrochloride
5-(trifluoromethyl)thiazole-2-carbonitrile (1 .25 g, 7 mmol) was reacted with sodium methoxide (0.38 g, 7 mmol) and ammonium chloride (0.76 g, 14 mmol) according to the procedure as described in Example 61 , Step B to give the title compound as an offwhite solid (1.3 g, 80%). The compound was characterized by the following spectroscopic data:
MS-ESl: (ESI, pos.ion) m/z: 196.0 [M+l ]+.
[00520] Step C: Ethyl 4-(2-bromo-4-fluorophenyl)-6-methyl-2-(5-(trinuoromethyl) thiazol-2-yl)-l,4-dihydropyrimidine-5-carboxylate
5-(trifluoromethyl)thiazole-2-carboximidamide hydrochloride (0.93 g, 4 mmol) was reacted with 2-bromo-4-fluorobenzaldehyde (0.81 g. 4 mmol) and ethyl ,-oxobutanoate (0.55 g, 4.2 mmol) according to the procedure as described in Example 1 , Step A to give the title compound as a yellow solid (0.45 g, 23%). The compound was characterized by the following spectroscopic data:
MS-ESl: (ESI, pos.ion) m/z: 492.0 [ +l ]+;
Ή NMR (600 MHz, CDC13): δ 8.06 (s, 1H), 7.30-7.18 (m, 2H), 6.99-6.91 (m, 2H), 6.15 (s, 1H), 4.06 (q, 2H), 2.54 (s, 3H), 1.13 (t, 3H).
[00521 ] Step D: Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(5-(trifluoro methyl)thiazol-2-yl)-l,4-dihydropyrimidine-5-carboxylate
Ethyl 4-(2-bromo-4-fluoropheny])-6-methyl-2-(5-(trifluoromethy])thiazol-2-yl)- 1 ,4- dihydropyrimidine-5-carboxylate (0.44 g, 0.89 mmol) was reacted with NBS (0.17 g, 0.94 mmol) in DCM (30 mL) according to the procedure as described in Example 1 , Step B to give the title compound as a yellow solid (0.37 g, 72%). The compound was characterized by the following spectroscopic data:
MS-ESl: (ESI, pos.ion) m/z: 569.9 [M+l ]+;
Ή NMR (600 MHz, CDC13): δ 8.06 (s, 1 H), 7.34-7.28 (m, 2H), 6.98-6.90 (m, 2H), 6.15 (s, 1 H), 4.88 (dd, 2H), 3.97 (s, 2H), 1 .12 (t, 3H).
[00522] Step E: 4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(5-(trifluoro methyl)thiazol-2-yl)-3,6-dihydropyrimidin^-y acid
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(5-(trifluoromethyl)thiazol-2-yl)- l ,4-dihydropyrimidine-5-carboxylate (0.37 g, 0.65 mmol) was reacted with morpholine-3-carboxyIic acid (0.1 g, 0.71 mmol) according to the procedure as described in Example 1 , Step C to give the title compound as a yellow solid (0.26 g, 65%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 621.0 [M+ l f;
1H NMR (400 MHz, DMSO-c 6): δ 12.31 (br.s, 1H), 9.82 (s, 1H), 8.66 (s, 1H), 7.58-7.51 (m, 1H), 7.39-7.31 (m, 1H), 7.22-7.17 (m, l H), 6.05 (br.s, 1H), 4.28-3.90 (m, 5H), 3.88-3.82 (m, I H), 3.77-3.52 (m, 3H), 3.16-3.07 (m. 1 H), 2.59-2.39 (m, 1 H), 1.06 (t, 3H).
[00523] Example 141 :
4-((6-(2-chlorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yI)-3,6-dihydropyrimidin-4-yl) methyl)morpholine-3-carboxylic acid
Figure imgf000247_0001
[00524] Step A: Ethyl 4-(2-chlorophenyI)-6-methyl-2-(thiazol-2-yl)-l,4-dihydro pyrimidine-5-carboxylate
Thiazole-2-carboximidamide hydrochloride ( 1 1 .63 g, 71.1 mmol) was reacted with 2-chlorobenzaldehyde ( 10 g, 71.1 mmol) and ethyl 3-oxobutanoate ( 1 1 .1 g, 85.3 mmol) according to the procedure as described in Example 1 , Step A to give the title compound as a yellow solid ( 14.2 g, 55%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 362.1 [M.+ l ]+; Ή NMR (400 MHz, DMSO-</6): δ 9.67 (s, IH), 8.14 (d, I H), 7.83 (d, I H), 7.35-7.07 (m, 4H), 6.24 (s, I H), 3.98 (q, 2H), 2.53 (s, 3H), 1.10 (t, 3H).
[00525] Step B: Ethyl 6-(bromomethyl)-4-(2-chlorophenyl)-2-(thiazol-2-yI)-l,4- dihydropyrimidine-5-carboxylate
Ethyl 4-(2-chlorophenyl)-6-methyl-2-(thiazol-2-yl)-l ,4-dihydropyrimidine-5- carboxylate ( 10 g, 27.6 mmol) was reacted with NBS ( 5.41 g, 30.4 mmol) according to the procedure as descnbed in Example 1 , Step B to give the title compound as a yellow solid (7.3 g, 60%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 440.0 [M+l ]+;
Ή NMR (400 MHz, DMSO-c 6): δ 9.73 (s, IH), 8.04 (d, I H), 7.89 (d, I H), 7.39-7.07 (m, 4H), 6.14 (s, I H), 4.92 (dd, 2H), 4.02 (q, 2H), 1.12 (t, 3H).
[00526] Step C: 4-((6-(2-chloropheny!)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6- dihydropyrimidin-4-yl)methyl)morphoIine-3-carboxyIic acid
Ethyl 6-(bromomethyl)-4-(2-chlorophenyl)-2-(thiazol-2-yl)-l ,4-dihydropyrimidine-5- carboxylate (2 g, 4.5 mmol) was reacted with morpholine-3-carboxylic acid hydrochloride (0.75 g, 4.5 mmol) according to the procedure as described in Example 1 , Step C to give the title compound as a yellow solid (0.99 g, 45%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 491 .0 [M+l ]+;
Ή NMR (400 MHz, DMSO- 6): δ 12.83 (s, I H), 9.75 (s, I H), 8.02 (d, I H), 7.91 (d, IH), 7.49-7.1 1 (m, 4H), 6.03 (s,l H), 4.23-3.98 (m, 5H), 3.91 -3.87 (m, I H), 3.78-3.54 (m, 3H), 3.17-3.07 (m, I H), 2.57-2.39 (m, IH), 1.09 (t, 3H).
[00527] Example 142:
4-((6-(2-chIoro-4-fluorophenyI)-5-(ethoxycarbonyl)-2-(l,3,4-thiadiazol-2-yI)-3,6-dihydro pyrimidin-4-yl)methyl)morpholine-2-carboxylic acid
Figure imgf000249_0001
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-( l ,3,4-thiadiazol-2-yl)-] ,4-di hydropyrimidme-5-carboxylate (0.69 g, 1 .5 mmol) was reacted with morpholine-2-carboxylic acid hydrochloride (0.25 g, 1.5 mmol) according to the procedure as described in Example 1 , Step C to afford the title compound as a yellow solid (0.43 g, 56%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 510.1 [M+ l ] + ;
Ή NMR (400 MHz, DMSO-rf6): δ 12.86 (br.s, IH), 9.90 (s, IH), 9.00 (s, IH), 7.78 (dd, IH), 7.36 (dd, I H), 7.04-6.97 (m, I H), 5.97 (s, I H), 4.08 (q, 2H), 3.94 (s, I H), 3.80 (t, IH), 3.59-3.43 (m, 2H), 3.19-3.10 (m, I H), 2.77-2.56 (m, 3H), 2.54 (s, IH), 1.16 (t, 3H).
[00528] Example 143:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(((S)-2-(2-hydroxypropan-2-yl)morpholino) methyl)-2-(lH-l,2,4-triazol-3-yl)-l,4-dihydropyrimidine-5-carboxyIate
Figure imgf000249_0002
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(lH-l ,2,4-tnazol-3-yl)-l ,4-di hydropyrimidine-5-carboxylate (0.75 g, 1.53 mmol) was reacted with (^^-(morpholin^-yl) propan-2-ol hydrochloride (0.28 g, 1 .53 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a yellow solid (0.19 g, 22%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 551 .1 [M+l ]+;
Ή NMR (400 MHz, DMSO-< 6): δ 10.44 (s, IH), 8.30 (s, IH), 7.63-6.71 (m, 3H), 6.22 (s, IH), 4.47 (s, I H), 4.08 (q, 2H), 3.83-3.78 (m, IH), 3.59-3.41 (m, 2H), 3.37 (d, 2H), 2.82-2.79 (m, I H), 2.67-2.56 (m, 2H), 2.23-2.17 (m, I H), 1.42-0.92 (m, 9H).
[00529] Example 144:
2-(4-((6-(2-chloro-4-fluorophenyl)-5-(ethoxycarbonyI)-2-(pyrazin-2-yI)-3,6-dihydropyri midin-4-yl)methyl)morpholin-2-yl)acetic acid
Figure imgf000250_0001
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(pyrazin-2-yl)- 1 ,4-dihydro pyrimidine-5-carboxylate ( 1 g, 2.2 mmol) was reacted with 2-(morpholin-2-yl)acetic acid hydrochloride (0.4 g, 2.2 mmol) according to the procedure as described in Example 1 , Step C to give the title compound as a yellow solid (0.36 g, 32%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI. pos.ion) m/z: 518.2 [M+l ]+;
!H NMR (400 MHz, DMSO-</6): δ 12.90 (br.s, I H), 9.99 (s, IH), 9.55-9.17 (m, IH), 9.01 -8.41 (m, 2H), 7.78 (dd, I H), 7.36 (dd, I H), 7.04-6.97 (m, I H), 6.32 (s, I H), 4.23-3.84 (m, 3H), 3.75 (s, I H), 3.59-3.46 (m, 2H), 2.77-2.56 (m, 4H), 2.50-2.45 (m, I H), 2.22-2.10 (m, 2H). 1 .16 (t, 3H). [00530] Example 145:
2-(4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(2,4,6-trifluorophenyl)-3,6-dihy dropyrimidin-4-yl)methyl)morphoIin-3-yl)acetic acid
Figure imgf000251_0001
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(2,4,6-trifluorophenyl)-l ,4-di hydropyrimidine-5-carboxylate ( 1 .21 g, 2.2 mmol) was reacted with 2-(morpholin-3-yl)acetic acid hydrochloride (0.4 g, 2.2 mmol) according to the procedure as described in Example 1 , Step C to give the title compound as a yellow solid (0.58 g, 43%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 614.1 [M+l ]+;
Ή NMR (400 MHz, DMSO-^): δ 12.01 (br.s, IH), 1 1 .06 (s, IH), 7.35-7.24 (m, 2H), 7.17-7.02 (m, IH), 6.80-6.37 (m, 2H), 5.89 (s, I H), 4.08 (q, 2H), 3.73 (s, I H), 3.70 -3.43 (m, 3H), 3.41 (s, I H), 3.29 (dd, IH), 3.02-2.81 (m, IH), 2.80-2.48 (m, 3H), 2.24-2.16 (m, IH), 1 .16 (t, 3H).
[00531 ] Example 146:
2-(4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrim idin-4-yl)methyl)morpholin-3-yl)-2-methylpropanoic acid
Figure imgf000252_0001
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-l ,4-dihydro pyrimidine-5-carboxylate (3.02 g, 6 mmol) was reacted with
2- methyl-2-(morpholin-3-yl)propanoic acid hydrochloride ( 1.26 g, 6 mmol) according to the procedure as described in Example 1 , Step C to give the title compound as a yellow solid ( 1 .39 g, 39%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 595.1 [M+l ]+;
Ή NMR (400 MHz, DMSO-i/6): δ 12.38 (br.s, 1H), 10.02 (s, 1H), 8.10 (d, 1 H), 7.93 (d, 1 H), 7.34-7.26 (m, 2H), 7.18-7.05 (m, 1H), 6.04 (s, 1H), 4.08 (q, 2H), 3.91 (s, 1H), 3.72-3.50 (m, 2H), 3.40 (dd, 1 H), 2.71 -2.59 (m, 3H), 2.39-2.25 (m, 2H), 1.33-0.99 (m, 9H).
[00532] Example 147:
3- (4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrim idin-4-yl)methyl)morpholin-3-yl)-3-methylbutanoic acid
Figure imgf000252_0002
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-l ,4-dihydro pyrimidine-5-carboxylate (3.02 g, 6 mmol) was reacted with 3-methyl-3-(morpholin-3-yl) butanoic acid hydrochloride (1.34 g, 6 mmol) according to the procedure as described in Example 1 , Step C to give the title compound as a yellow solid (1.5 g, 41 %). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 609.1 [M+l ]+;
Ή NMR (400 MHz, DMSO-i/6): δ 1 1.99 (br.s, IH), 10.81 (s, IH), 8.09 (d, I H), 7.92 (d, IH), 7.34-7.15 (m, 2H), 7.1 1 - 6.99 (m, IH), 6.23 (s, IH), 4.07 (q, 2H), 3.82 (s, IH), 3.71 -3.48 (m, 2H), 3.46-3.31 (m, 2H), 3.27-3.04 (m, 2H), 2.67-2.51 (m, 2H), 2.52 (s, 2H), 1.16 (t, 3H), 0.92 (s, 6H).
[00533] Example 148:
3-(4-((6-(2-bromo-4-fluorophenyI)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrim idin-4-yl)methyI)morpholin-3-yl)-2-methylpropanoic acid
Figure imgf000253_0001
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)- 1 ,4-dihydro pyrimidine-5-carboxylate (3.02 g, 6 mmol) was reacted with 2-methyl-3-(morpholin-3-yl)propanoic acid hydrochloride (1.26 g, 6 mmol) according to the procedure as described in Example 1 , Step C to give the title compound as a yellow solid (0.89 g, 25%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 595.1 [M+l ]+;
Ή NMR (400 MHz, DMSO-c/6): δ 1 1.86 (br.s, I H), 10.63 (s, I H), 8.10 (d, I H), 7.93 (d, I H), 7.35-7.19 (m, 2H), 7.15-7.02 (m, I H), 6.37 (s, I H), 4.08 (q, 2H), 3.81 (s, I H), 3.72-3.46 (m, 2H), 3.43-3.02 (m, 3H), 2.86 (t, I H), 2.67-2.56 (m, 2H), 2.50-2.19 (m, 2H), 1 .59 (t, I H), 1 .1 6 (t, 3H), 1.07 (d, 3H). [00534] Example 149:
(3S)-methyl 4-((6-(2-chloro-4-fluorophenyl)-5-(ethoxycarbonyI)-2-(thiazol-2-yI)-3,6- dihydropyrimidin-4-yl)methyl)-6,6-dimethylmorpholine-3-carboxylate
Figure imgf000254_0001
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)- 1 ,4-dihydro pyrimidine-5-carboxylate (0.7 g, 1.52 mmol) was reacted with (5)-methyl 6,6-dimethylmorpholine-3-carboxylate (0.26 g, 1.52 mmol) according to the procedure as described in Example 24 to give the title compound as yellow oil (0.17 g, 20%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 551.2 [M+lf;
!H NMR (400 MHz, DMSO-</6): δ 10.15 (s, I H), 8.01 (dd, 2H), 7.78 (dd, IH), 7.36 (dd, IH), 7.04-7.01 (m, IH), 5.99 (s, I H), 4.32 (dd, I H), 4.08 (dd, 3H), 3.66 (s, 3H), 3.60 (dd, IH), 2.88-2.47 (m, 3H), 2.26 (d, IH), 1.25 (s, 6H), 1.16 (t, 3H).
[00535] Example 150:
(35)-methyl 4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6- dihydropyrimidin-4-yl)methyl)-6,6-dimethylmorpholine-3-carboxylate
Figure imgf000255_0001
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-l ,4-dihydro pyrimidine-5-carboxylate (0.76 g, 1.52 mmol) was reacted with (S)-methyl 6,6-dimethylmo holine-3-carboxylate (0.26 g, 1.52 mmol) according to the procedure as described in Example 24 to give the title compound as yellow oil (0.24 g, 27%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 595.1 [M+l ]" ;
1H NMR (400 MHz, DMSO-<¾: δ 10.15 (s, IH), 8.02 (dd, 2H), 7.35-7.21 (m, 2H), 7.19-6.98 (m, I H), 5.95 (s, I H), 4.33 (dd, I H), 4.18-3.91 (m, 3H), 3.66 (s, 3H), 3.60 (dd, I H), 2.91 -2.43 (m, 3H), 2.27 (d, 1 H), 1.27 (s, 6H), 1.13 (t, 3H).
[00536] Example 151:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(((R)-2-((propionyIoxy)methyl)morphoIino)methyl) -2-(l -l,2,4-triazol-3-yl)-l,4-dihydropyrimidine-5-carboxylate
Figure imgf000255_0002
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(((R)-2-(hydroxymethyl)moφholino)methyl)-2- ( lH-1.2,4-triazol-3-yl)-l ,4-dihydropyrimidine-5-carboxylate (2 g, 3.8 mmol) was reacted with propionic acid (0.37 g, 5 mmol) according to the procedure as described in Example 49 to give the title compound as yellow oil (0.84 g, 38%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 579.1 [M+l ]+;
Ή NMR (400 MHz, DMSO- 6): δ 10.78 (s, 1H), 8.30 (s, 1H), 7.34-7.23 (m, 2H), 7.19-6.97 (m, 1 H), 5.89 (s, 1 H), 4.52-4.1 8 (m, 2H), 4.17-3.95 (m, 3H), 3.79-3.41 (m, 3H), 3.21 (s, 1 H), 2.94-2.54 (m, 3H), 2.41 (q, 2H), 2.29-2.02 (m, 1H), 1.18-1.16 (m , 6H).
[00537] Example 152:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(((i?)-2-((isobutyryloxy)methyl)morpholino) methyl)-2-(lH-l,2,4-triazo]-3-yl)-l,4-dihydropyrimidine-5-carboxylate
Figure imgf000256_0001
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(((R)-2-(hyα,ro ymethyl)mo holino)methyl)-2- ( lH-l ,2,4-triazol-3-yl)-l ,4-dihydropyrimidine-5-carboxylate (2 g, 3.8 mmol) was reacted with isobutyric acid (0.44 g, 5 mmol) according to the procedure as described in Example 49 to give the title compound as yellow oil (0.79 g, 35%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 593.1 [M+l ]+;
Ή NMR (400 MHz, DMSO-*4): δ 10.85 (s, 1 H), 8.30 (s, 1 H), 7.35-7.24 (m, 2H), 7.20-7.01 (m, 1 H), 5.91 (s, 1 H), 4.40-4.17 (m, 2H), 4.15-4.00 (m, 3H), 3.59-3.43 (m, 2H), 3.37 (d, 2H), 2.92-2.42 (m, 4H), 2.31 - 1 .92 (m, IH), 1.33-0.98 (m, 9H). [00538] Example 153:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(((R)-2-((pivaloyloxy)methyl)morpholino)methyl)- 2-(lH-l,2,4-triazol-3-yl)-l,4-dihydropyrimidine-5-carboxylate
Figure imgf000257_0001
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(((R)-2-(hydroxymethyl)mo holino)methyl)-2- ( ] H-l ,2,4-triazol-3-yl)-] ,4-dihydropyrimidine-5-carboxylate (2 g, 3.8 mmol) was reacted with pivalic acid (0.51 g, 5 mmol) according to the procedure as described in Example 49 to give the title compound as yellow oil (0.99 g, 43%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z 607.2 [M+l ]+;
Ή NMR (400 MHz, DMSO-</6): δ 10.76 (s, IH), 8.32 (s, IH), 7.33-7.23 (m, 2H), 7.19-7.00 (m, IH), 6.51 (s, I H), 4.47-4.18 (m, 2H), 4.16-3.97 (m, 3H), 3.57-3.48 (m, 2H), 3.43 (d, 2H), 2.81-2.59 (m, 3H), 2.47 (dd, IH), 1.26 (s, 9H), 1.16 (t, 3H).
[00539] Example 154:
Ethyl 4-(2-bromo-4-f!uorophenyl)-6-((3-(hydroxymethyl)morpholino)methyl)-2-(5- methoxythiazol-2-yl)-l ,4-dihydropyrimidine-5-carboxylate
Figure imgf000258_0001
Ethyl 4-(2-bromo-4-f uorophenyl)-6-(bromomethyl)-2-(5-methoxythiazol-2-yl)-l ,4-di hydropyrimidine-5-carboxylate (0.53 g, 1 mmol) was reacted with morpholin-3-ylmethanol hydrochloride (0.18 g, 1.2 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a yellowish solid (0.27 g, 48%). The compound was characterized by the following spectroscopic data:
MS-ES1: (ESI, pos.ion) m/z: 569.1 [M+l ]+ ;
Ή NMR (400 MHz, DMSO-</6): δ 10.22 (s, IH), 7.33-7.20 (m, 2H), 7.24 (s, I H), 7.18-6.99 (m, I H), 5.54 (s, I H), 4.47 (d, 2H), 4.08 (q, 2H), 3.83 (s, 3H), 3.68-3.45 (m, 2H), 3.34 (dd, I H), 3.24-2.95 (m, 3H), 2.64-2.58 (m, 2H), 2.51 (s, IH), 1.90-1 .88 (m, IH), 1.16 (t, 3H).
[00540] Example 155:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-((3-(hydroxymethyl)morpholino)methyl)-2-(5-
(trifluoromethyl)thiazol-2-yl)-l,4-dihydropyrimidine-5-carboxyIate
Figure imgf000258_0002
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(5-(trifluoromethyl)thiazol-2- yl)-l ,4-dihydropyrimidine-5-carboxylate (0.74 g, 1.3 mmol) was reacted with morpholin-3-ylmethanol hydrochloride (0.23 g, 1.5 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a yellowish solid (0.34 g, 43%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 607.1 [M+l ]+;
JH NMR (400 MHz, DMSO-c/6): δ 10.09 (s, 1H), 7.32-7.27 (m, 2H), 7.25 (s, 1H), 7.16-7.06 (m, 1H), 6.12 (s, 1H), 4.49 (s, 1H), 4.33 (s, 1H), 4.08 (q, 2H), 3.81 -3.47 (m, 2H), 3.34 (dd, 1 H). 3.25-2.97 (m, 3H), 2.61 -2.56 (m, 2H), 2.45 (s, 1 H), 1.88-1 .79 (m, 1 H), 1.16 (t, 3H).
[00541 ] Example 156:
Ethyl 6-(((i?)-3-((((S)-2-aminobutanoyl)oxy)methyl)morpholino)methyI)-4-(2-bromo-4- fluorophenyl)-2-(thiazol-2-yl)-l,4-dihydropyrimidine-5-carboxylate
Figure imgf000259_0001
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(((5)-3-(hydroxymethyl)morpholino)methyl)-2- (thiazol-2-yl)-l ,4-dihydropyrimidine-5-carboxylate (1 g, 1.9 mmol) was reacted with (S)-2-((feri-butoxycarbonyl)amino)butanoic acid (0.61 g, 3 mmol) according to the procedure as described in Example 49 to give the title compound as yellow oil (0.37 g, 31%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 624.1 [M+l] ;
Ή NMR (400 MHz, DMSO- 6): δ 10.17 (s, 1 H), 8.90 (br.s, 2H), 8.10 (d, 1H), 7.93 (d, 1 H), 7.37-7.28 (m, 2H), 7.19-7.01 (m, 1 H), 6.28 (s, 1 H), 4.35 (dd, 1 H), 4.22-3.86 (m, 4H), 3.74-3.44 (m, 2H), 3.25 (dd, 1 H), 3.16-2.96 (m, 2H), 2.71 -2.63 (m, 2H), 2.48 (s, 1 H), 2.36-2.23 (m, 1 H), 2.06- 1 .68 (m, 2H), 1.16 (t, 3H), 0.86 (t, 3H). [00542] Example 157:
(3S)-4-((6-(2-bromo-4-fluorophenyI)-5-(ethoxycarbonyl)-2-(thiazoI-2-yl)-3,6-dihydropyri midin-4-yI)methyl)-3-methylmorpholine-3-carboxylic acid
Figure imgf000260_0001
[00543] Step A: (. )-2-(benzylamino)-3-hydroxy-2-methylpropanoic acid
(S)-2-amino-3-hydroxy-2-methylpropanoic acid (1.2 g, 10 mmol) was reacted with bcnzaldehyde (1.06 g, 10 mmol) according to the procedure as described in Example 46, Step A to give the title compound as a gray solid ( 1.05 g, 50%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 210.1 [M+] ]+;
Ή NMR (400 MHz, DMSO-d6): δ 12.19 (s, 1 H), 7.38-7.26 (m, 5H), 4.90 (s, 1 H), 3.98-3.77 (m, 4H), 2.78 (br.s, 1H), 1 .49 (s, 3H).
[00544] Step B: (S)-4-benzyl-3-methyl-5-oxomorpholine-3-carboxylic acid
(S)-2-(benzylamino)-3-hydroxy-2-methylpropanoic acid (2.09 g, 10 mmol) was reacted with chloroacetyl chloride ( 1.74 g, 15.4 mmol) according to the procedure as described in Example 46, Step B to give the title compound as a gray solid ( 1.62 g, 65%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) mlz: 250.1 [M+l ]+;
Ή NMR (400 MHz, DMSO-c 6): δ 12.03 (s, 1 H), 7.41-7.21 (m, 5H), 4.86 (s, 1 H), 4.54 (d, 1 H), 4.31 (s, 2H), 4.15 (s, lH), 4.00 (d, 1 H), 1.69 (s, 3H). [00545] Step C: (5)-benzyl 4-benzyl-3-methyI-5-oxomorpholine-3-carboxyIate
(5)-4-benzyl-3-methyl-5-oxomorpholine-3-carboxylic acid (2.49 g, 10 mmol) was reacted with benzyl bromide (2.05 g, 12 mmol) according to the procedure as described in Example 34, Step A to give the title compound as colorless oil (2.38 g, 70%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) /z: 340.1 [M+l f ;
Ή NMR (400 MHz, DMSCW6): δ 7.41 -7.24 (m, 10H), 5.24 (s, 2H), 4.40 (d, 2H), 4.24 (s, 2H), 3.86 (dd, 2H), 1 .74 (s, 3H).
[00546] Step D: ( )-benzyl 4-benzyl-3-methyJmorpholine-3-carboxylate
(5)-benzyl 4-benzyl-3-methyl-5-oxomorpholine-3-carboxylate (3.4 g, 10 mmol) was reacted with a solution of borane in THF (1 mol/L, 20 mL) according to the procedure as described in Example 34, Step B to give the title compound as colorless oil (2.3 g, 70%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 326.1 [M+l ]+;
Ή NMR (400 MHz, DMSO-c/6): δ 7.30-7.16 (m, 10H), 5.26 (s, 2H), 3.68-3.51 (m, 5H), 3.23 (d, 1 H), 2.77-2.55 (m, 2H), 1.54 (s, 3H).
[00547] Step E: (S)-3-rnethylrnorpholine-3-carboxylic acid
(S)-benzyl 4-benzyl-3-methylmorphoHne-3-carboxylate (3.26 g, 10 mmol) was reacted with H2 by Pd/C catalysis (10%, 0.33 g) according to the procedure as described in Example 34, Step C to give the title compound as a gray solid (0.97 g, 67%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 146.1 [M+l ]+;
Ή NMR (400 MHz, DMSCW6): δ 12.1 1 (s, 1 H), 3.72-3.52 (m, 3H), 3.17 (d, 1 H), 3.01 -2.78 (m, 2H), 2.06 (s, 1 H), 1 .49 (s, 3H). [00548] Step F: i3S)-4-(i6-i2-bromo-4-fluorophenyI)-5-(ethoxycarbonyl)-2-ithiazol- 2-yl)-3,6-dihydropyrimidin-4-yI)methyl)-3-methylmorpholine-3-carboxylic acid
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)- 1 ,4-dihydro pyrimidine-5-carboxylate (0.77 g, 1.53 mmol) was reacted with (S)-3-methylmorpholine-3- carboxylic acid (0.22 g, 1.53 mmol) according to the procedure as described in Example 46, Step F to give the title compound as a yellow solid (0.52 g, 60%). The compound was characterized by the following spectroscopic data:
MS-ESI: (ESI, pos.ion) m/z: 567.1 [M+l ]+;
Ή NMR (400 MHz, DMSO-</6): δ 12.45 (s, 1 H), 9.87 (s, 1 H), 8.10 (d, 1 H), 7.93 (d, 1H), 7.34-7.10 (m, 3H), 5.94 (s, 1 H), 4.08 (q, 2H). 3.92-3.50 (m, 6H), 3.21 -2.98 (m, 2H), 1 .49 (s, 3H), 1 .16 (s, 3H).
[00549] Example 158:
In-vitr anti-HBV activity of compounds in stable HBV-producing cell line (HepG2.2.15) I. Assay Method
[00550] HBV DNA contents in cell culture fluid were detected by the qPCR-based assay and percents of HBV inhibition by compounds (% Inh) were calculated. Specific procedures are as follows:
[00551 ] HepG2.2.15 cells were seeded into each well of 96-well plates, 40,000 cells per well. Cells were treated with cell culture medium containing compounds 24 hours after cell seeding. Each compound to detected percent inhibition was in duplicate and the final concentration of each compound was 500 nmol in each well. The compound-containing mediums were refreshed on day 4 post cell seeding. Culture media were collected from the HepG2.2.15 plates on day 7 post cell seeding followed by HBV DNA extraction.
[00552] HBV DNA extraction: using QIAamp 96 DNA Blood Kit (QIAGEN 51 161 ). [00553] PCR for quantification: PCR mix was prepared according to PCR system; PCR mix was dispensed to 384-well optical reaction plates (special for quantification); The standard diluted proportionally was added; The sample was added; The plates were sealed with optical adhesive film; PCR system was performed according to programs.
[00554] Percent of HBV inhibition of DNA replication by compound was calculated using the following equation:
% Inh. =[ 1 -HBV DNA quantity of sample/ HBV DNA quantity of DMSO control 1* 100. II. Assay Results
[00555] Percents of HBV inhibition of DNA replication by compounds disclosed herein were detected with the methods above. The results are shown in Table 2:
[00556] Tab. 2
Figure imgf000263_0001
Example 24 56.1 Example 83 36.0
Example 25 91.9 Example 119 94
Example 26 96.0 Example 121 48.5
Example 27 91.9 Example 122 46.2
Example 34 94.35 Example 123 37.55
Example 40 95 Example 125 92.55
Example 42 91 .9 Example 126 94.65
Example 49 96.2 Example 129 92
Example 51 91.3 Example 133 92.61
Example 52 89.51 Example 135 93.35
Example 53 92.62 Example 136 95.85
Example 54 91.05
III. Conclusions
[00557] The compounds disclosed herein showed potent inhibitory effect on HBV. Such compounds have surprising antiviral activity and can be applied in the treatment of various kinds of disorders by HBV infection.
[00558] Example 159:
Test compounds' P assay in ICR mice
I. Assay Method
[00559] The test compounds were poured into ICR mice stomach through mouth with 10 mg/kg or administered 2 mg/kg or 10 mg/kg to ICR mice by tail-intravenous injection. Blood sample of orbital vein was taken at 0.083, 0.25, 0.5, 1 , 2, 4, 6, 8 and 24 hours after administration, and collected in anticoagulation tube added with EDTA-K2. The test compounds were extracted from plasma samples and chromatographed on a tandem mass spectrometer. Quantitation was performed using multiple reaction monitoring ( RM). Pharmacokinetic parameters were calculated using WinNonlin 6.1 software with non compartment model. II. Assay Results
[00560] Test compounds' PK were detected with the methods above. The results are shown in Table 3 :
[00561 ] Tab. 3
Figure imgf000265_0001
E.— Examples; R.— Reference; A.R.—Administration Routes;
Reference— Ethyl 4-(2-bromo-4-fluorophenyl)-2-(thiazol-2-yl)-6-((4-mo holino)methyl) -1 ,4-dihydropyrimidine-5-carboxylate (The compound was synthesized according to the procedure as described in WO2008154817);
N/A— There is no detection;
AUCias. -AUC in 0-24 hours;
AUCJNF—AUC in 0 hour to infinite time. III. Conclusions
[00562] After intragastric administration of drugs in ICR mice, Example 74 and Example 129 were rapidly absorbed and the peak time in plasma were 0.25 hour and 0.08 hour respectively. The AUClast of Example 74 was 7892 hr*ng/mL, and the AUC)as, of Example 129 was 5332.25 hr*ng/mL. Both compounds have better exposure, which are apparently higher than reference. It showed that compounds were absorbed well in ICR mice. After administration by intravenous injection, the CL of Example 74 and Example 129 were 0.93 L/h/Kg and 1.22 L/h/Kg respectively, and Vss of Example 74 and Example 129 were 0.82 L/Kg and 0.9 L/Kg. Caculated by the AUC)asl of Example 74 and Example 129, F were 74.2% and 65.24% respectively when the test compounds were poured into ICR mice stomach through mouth with 10 mg/kg. Both compounds have better bioavailability, which are much higher than reference (7.75%).
[00563] Activity data comparison showed that the acitivity of most compounds disclosed herein were higher than reference, and thus it will show a good prospect in anti-HBV.
Although the present invention has been described by a way of a detailed description in which genaral description, examples and assays have been described, it will be obvious to one skilled in the art that certain changes and modifications may be made without departing from the invention, and therefore, all such changes and modifications are within the scope of the invention.

Claims

1 . A compound of Formula (I) or (la)
Figure imgf000267_0001
or an enantiomer, a diastereoisomer, a tautomer, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, wherein: each A is a bond, -0-, -S-, or -NR.5-; each R is -X-Z;
X is -(CR7R7a)m- or -C(=0)-;
Z has Formula (II) or (Ila):
Figure imgf000267_0002
wherein each B is a bond, -(CR7R7a)m- or -C(=0)-; each W is CR7 or N; each Y is -(CR7R7a)m-, -0-, -S-, -S(=0)q- or -NR6-; each R1 is aryl or heteroaryl; each R2 is H, alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl or alkoxycarbonyl; each R3 is aryl or heteroaryl; each R4 is H, or C alkyl;
R5 is H, alkyl, -(CR7R7a)m-C(=0)0-R8, alkenyl or alkynyl; each R6 is alkyl, -(CR7R7a)m-C(=0)0-R8, alkenyl or alkynyl; each R7a and R7 is independently H, F, CI, Br, alkyl, haloalkyl, -(CH2)m-OH or -(CH2)m-C(=0)0-R8; each R8 and R8a is independently H, alkyl, haloalkyl, aminoalkyl, Boc-NH-alkyl, alkoxy, -(CH2)m-OH, -(CH2)m-C(=0)0-(CH2)m-H or -(CH2)m-OC(=0)-(CH2)m-H;
Boc is /erf-butyl oxycarbonyl; each R9 is independently -(CR7R7a),-OH, -(CR7R7a)m-S(=0)q-R8, -(CR7R7a)m-OS(=0)q-R8, -(CR7R7a)m-S(=0)qO-R8, -(CR7R7a)m-C(=0)-R8,
-(CR7R'a)m-C(=0)0-R8, -(CR7R7a)m-C(=0)0-(CR7R7a)m-OC(=0)0-R . -(CR7R7a)m-C(=0)0-(CR7R7a)m-OC(=0)-R8, -(CR7R7a)m-C(=0)0-(CR7R7a)m-C(=0)0-R8, -(CR7R7a) OC(=0)-R8, triazolyl, tetrazolyl or -(CR7R7a)m-C(=0)N(R8)2, with the proviso that when R9 is -(CR7R7a)t-OH, R3 is aryl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrimidiny], pyridazinyl, thiazolyl, diazolyl, triazolyl, tetrazolyl, thienyl, pyrazolyl, isothiazolyl. oxadiazolyl, thiadiazolyl, pyrazinyl, pyranyl or triazinyl; each n is independently 1 , 2 or 3; each t is independently 1 , 2, 3 or 4; each m is independently 0, 1 , 2, 3 or 4; each q is independently 0, 1 or 2; and optionally each of aryl, heteroaryl, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, alkoxycarbonyl, aralkyl, heteroarylalkyl, aminoalkyl, alkoxy, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrimidinyl, pyridazinyl, thiazolyl, diazolyl, triazolyl, tetrazolyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyranyl, triazinyl, heterocyclyl and heterocyclylalkyl described above, is independently substituted with one or more substituents which are the same or different, wherein the substituent is H, F, CI, Br, I, alkyl, alkoxy, cyano, hydroxy, nitro, alkylamino, amino, trifhiorornethyl, trifluoromethoxy, -(CR7R7a)m-C(=0)0-R8a, haloalkyl-substituted aryl, halogen-substituted aryl, -(CR7R7a)m-C(=0)N(R8a)2 or trifluoromethylsulfonyl.
2. The compound according to claim 1 , wherein Z has Formula (III) or (Ilia):
Figure imgf000268_0001
wherein each B is a bond or -(CR7R7a)m-; each Y is -(CR7R7a)m-, -0-, -S-, -S(=0)q- or -NR6-; each R6 is CM alkyl, -(CR7R7a)m-C(=0)0-R8, C2-4 alkenyl or C2-4 alkynyl; each R7a and R7 is independently H, F, CI, Br, C]-4 alkyl, -(CH2)m-OH, C haloalkyl or -(CH2)m-C(=0)0-R8; each R is independently H, Ci-6 alkyl, C1-4 haloalkyl, ammo-Ci-4-alkyl, Boc-NH-Ci-4-alkyl, CM alkoxy, -(CH2)m-OH, -(CH2)m-C(=0)0-(CH2)m-H or -(CH2)m-OC(=0)-(CH2)m-H; each R9 is independently -(CR7R7a) OH, -(CR7R7a)m-C(=0)-R8, -(CR7R7a)m-C(=0)0-R8, -(CR7R7a)m-C(=0)0-(CR7R7a)m-OC(=0)0-R8, -(CR7R7a)m-C(=0)0-(CR7R7a)m-OC(=0)-R8, -(CR7R7a)m-C(=0)0-(CR7R7a)m-C(=0)0-R8, -(CR7R7a)t-OC(=0)-R8, triazolyl, tetrazolyl or -(CR7R7a)m-C(=0)N(R8)2, with the proviso that when R9 is -(CR7R7a)t-OH, R3 is C6-]0 aryl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrimidinyl, pyridazinyl, thiazolyl, diazolyl, triazolyl, tetrazolyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyranyl or triazinyl; each n is independently 1 or 2; each t is independently 1 , 2, 3 or 4; and each m is independently 0, 1 , 2, 3 or 4.
3. The compound according to claim 2, wherein Z is
Figure imgf000269_0001
each R7 and R7a is independently H, methyl, ethyl, -(CH2)m-OH, -(CH2)m-C(=0)0-R8 or propyl; each R8 is independently H, methyl, ethyl, propyl, isopropyl, butyl, l-methylpropyl, 2-methylpropyl, aminomethyl, l-amino-2-methylpropyl, 1 -aminoethyl, 2-aminoethyl, 1 -aminobutyl, 1 -aminopropyl, 2-aminopropyl, Boc-NH-methyl, l-Boc-NH-2-methylpropyl, 1 -Boc-NH-ethyl, 2-Boc-NH-ethyl, 1 -Boc-NH-butyl, 1 -Boc-NH-propyl, 2-Boc-NH-propyl, methoxy, ethoxy, -(CH2)m-OH, -(CH2)m-C(=0)0-(CH2)m-H, -(CH2)m-OC(=0)-(CH2)m-H or tert-butyl; and each R9 is independently triazolyl, tetrazolyl, -(CR7R7a)t-OH, -(CR7R7a)m-C(=0)-R8, -(CR7R7a)m-C(=0)0-R8, -(CR7R7a)m-C(=0)0-(CR7R7a)m-OC(=0)0-R8, -(CR7R7a)m-C(=0)0-(CR7R7a)m-OC(=0)-R8, -(CR7R7a),-OC(=0)-R8 or
-(CR7R7a)m-C(=0)N(R8)2, with the proviso that when R9 is -(CR7R7a)rOH, R3 is phenyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrimidinyl, pyridazinyl, thiazolyl, diazolyl, triazolyl, tetrazolyl, thienyl, pyrazolyl, isothiazolyl. oxadiazolyl, thiadiazolyl, pyrazinyl, pyranyl or triazinyl.
4. The compound according to claim 1 , wherein R3 is Ce-io aryl or 5-6 membered heteroaryl, and optionally each of the heteroaryl and aryl is independently substituted with one or more substituents which are the same or different, wherein the substituent is H, F, CI, Br, 1, methyl, ethyl, propyl, isopropyl, butyl, methoxy, ethoxy, methylamino, ethylamino, cyano, hydroxy, nitro, amino, trifluoromethyl, trifluoromethoxy, -(CR7R7a)m-C(=0)0-R a, -(CR7R7a)m-C(=0)N(R8a)2 or trifluoromethylsulfonyl; each R7a and R7 is independently H, F, CI, Br, CM alkyl, C1 -4 haloalkyl, -(CH2)m-OH or -(CH2)m-C(=0)0-R8; and each R8a and R8 is independently H, C] -4 alkyl, C1-4 haloalkyl, amino-C -alkyl, Boc-NH-C -alkyl, CM alkoxy, -(CH2)m-OH, -(CH2)m-C(=0)0-(CH2)m-H or -(CH2)m-OC(=0)-(CH2)m-H.
5. The compound according to claim 4, wherein R3 has one of the following formulae:
Figure imgf000270_0001
wherein each X1 is independently O, S, NR11 or CR12R12a; each X2, X3, X4, X5 and X6 is independently N or CR12; wherein at most three or four of the X2, X3, X4, X5 and X6 are N; each R10 is independently H, F, CI, Br, I, methyl, ethyl, propyl, isopropyl, butyl, methoxy, ethoxy, methylamino, ethylamino, cyano, hydroxy, nitro, amino, trifluoromethyl, trifluoromethoxy, -(CR7R7a)m-C(=0)0-R8a. -(CR7R7a)m-C(=0)N(R8a)2 or trifluoromethylsulfonyl; each R1 1 is independently H, methyl, ethyl, propyl, isopropyl, butyl, trifluoromethyl,
-(CR'R7 a)m-C(=0)N(Ri5a)2 or -(CR7R'a)m-C(=0)0-R8a; each R12 and R12a is independently H, F, CI, Br, I, methyl, ethyl, propyl, isopropyl, butyl, methoxy, ethoxy, methylamino, ethylamino, cyano, hydroxy, nitro, amino, trifluoromethyl, trifluoromethoxy, -(CR7R7a)m-C(=0)0-Rea, -(CR7R7A)M-C(=0)N(R8A)2 trifluoromethylsulfonyl; each R7A and R7 is independently H, F, CI, Br, C)-4 alkyl, -(CH2)M-OH, C,-4 haloalkyl or -(CH2)M-C(=0)0-R8; each R8A and R8 is independently H, C alkyl, CM haloalkyl, amino-C] _4-alky], Boc-NH-C M-alkyl, C 1 -4 alkoxy, -(CH2)M-OH, -(CH2)M-C(=0)0-(CH2)M-H or -(CH2)M-OC(=0)-(CH2)M-H; each m is independently 0, 1 , 2, 3 or 4; and each p is independently 0, 1 , 2 or 3.
6. The compound according to claim 5, wherein R3 has one of the following formulae:
Figure imgf000271_0001
wherein each R is independently H, F, CI, methyl, ethyl, cyano, hydroxy, nitro, amino, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, -(CR7R7a)m-C(=0)0-R8a, -(CR7R7a)m-C(=0)N(R8a)2 or trifluoromethylsulfonyl; each RH is independently H, methyl, ethyl, propyl, isopropyl, butyl, trifluoromethyl or -(CR7R7a)m-C(=0)0-R8a; each R7a and R7 is independently H, methyl, ethyl, -(CH2)m-OH, -(CH2)m-C(=0)0-R8 or propyl;
8 8s
each R and R is independently H, methyl, ethyl, propyl, isopropyl, butyl, 2-methylpropyl, 1 -methylpropyl, aminomethyl, l -amino-2-methylpropyl, 1-aminoethyl, 2-aminoethyl, 1 -aminobutyl, 1 -aminopropyl, 2-aminopropyl, Boc-NH-methyl, l-Boc-NH-2-methylpropyl, 1 -Boc-NH-ethyl, 2-Boc-NH-ethyl, 1-Boc-NH-butyl, 1-Boc-NH-propyl, 2-Boc-NH-propyl, methoxy, ethoxy, -(CH )m-OH, -(CH2)m-C(=0)0-(CH2)m-H, -(CH2)m-OC(=OMCH2)m-H or /erf-butyl; and each p is independently 0, 1 , 2 or 3.
7. The compound according to claim 1 , wherein R1 is C -\o aryl, and the aryl is independently substituted with one or more substituents which are the same or different, wherein the substituent is H, F, CI, Br, cyano, methyl, ethyl, methoxy, ethoxy, methylamino, ethylamino, nitro, 4-(trifluoromethyl)phenyl, 3,5-6is(trifluoromethyl)phenyl or trifluoromethyl;
R2 is H, or Ci-4 alkyl; and
R5 is H, or CM alkyl.
8. The compound according to claim 7, wherein R1 is phenyl or a phenyl substituted with one or more substituents which are the same or different, wherein the substituent is H, F, CI, Br, nitro, 4-(trifluoromethyl)phenyl, 3,5-&«(trifiuoromethyl)pheny] or trifluoromethyl.
9. The compound according to claim 1 having Formula (IV) or (IVa),
Figure imgf000272_0001
or an enantiomer, a diastereoisomer, a tautomer, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, wherein Z has Formula (II) or (lla):
Figure imgf000272_0002
wherein each B is a bond or -(CR7R7a)m-; each W is CR7 or N; each Y is -(CR7R7A)M-, -0-, -S-, -S(=0)q- or -NR6-;
2
each R is H, or C alkyl; each R is C6-io aryl or 5-6 membered heteroaryl, and optionally each of the heteroaryl and aryl is independently substituted with one or more substituents which are the same or different, wherein the substituent is H, F, CI, methyl, ethyl, propyl, cyano, trifluoromethyl, methoxy, -(CR7R7a)m-C(=0)N(R8a)2 or -(CR7R7a)m-C(=0)0-R8a; each R6 is C alkyl; each R7a and R7 is independently H, -(CH2)m-OH, -(CH2)m-C(=0)0-R8 or C alkyl; each R8 and R8a is independently H, amino-Ci_4-alkyl,
Figure imgf000273_0001
C alkoxy, -(CH2)m-OH, -(CH2)m-C(=0)0-(CH2)m-H, -(CH2)m-OC(=0)-(CH2)m-H or C,.6 alkyl; each R9 is independently triazoly], tetrazolyl, -(CR7R7a)rOH, -(CR7R7a)m-C(=0)0-(CR7R7a)m-OC(=0)0-R8, -(CR7R7a)m-C(=0)-R8, -(CR7R7a)m-C(=0)0-R8, -(CR7R7a)m-C(=0)0-(CR7R7a)m-OC(=0)-R8, -(CR7R7a),-0C(O)-R8 or -(CR7R7a)m-C(=0)N(R8)2, with the proviso that when R9 is -(CR7R7a)t-OH, R3 is C6-io aryl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrimidinyl, pyridazinyl, thiazolyl, diazolyl, triazoly], tetrazolyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyranyl or triazinyl; each R13 is independently H, F, CI, Br, cyano, nitro, 4-(trifluoromethyl)phenyl, 3,5-Z>«(trifluoromethyl)phenyl or trifluoromethyl; each n is independently 1 or 2; each t is independently 1 , 2, 3 or 4; each m is independently 0, 1 , 2, 3 or 4; and each q is independently 0, 1 or 2.
10. The compound according to claim 9, wherein Z has Formula (II) or (Ila):
Figure imgf000273_0002
wherein each B is a bond or -(CR7R7a)m-; each W is CR' or N; each Y is -(CR7R7a)m-, -0-, -S-, -S(=0)q- or -NR6-; each R6 is methyl, ethyl or propyl; each R7a and R7 is independently H, methyl, -(CH2)m-OH, -(CH2)m-C(=0)0-R8, ethyl or propyl; each R is independently H, methyl, ethyl, propyl, isopropyl, butyl, 1-methylpropyl, 2-methylpropyl, tert-buty\, aminomethyl, 1 -amino-2-methylpropyl, 1 -aminoethyl, 2-aminoethyl, 1 -aminobutyl, 1 -aminopropyl, 2-aminopropyl, Boc-NH-methyl, l -Boc-NH-2-methylpropyl, 1 -Boc-NH-ethyl, 2-Boc-NH-ethyl, 1 -Boc-NH-butyl, 1 -Boc-NH-propyl, 2-Boc-NH-propyl, methoxy, ethoxy, -(CH2)m-OH, -(CH2)m-C(=0)0-(CH2)m-H or -(CH2)m-OC(=0)-(CH2)m-H; each R8a is independently H, methyl, ethyl, isopropyl or propyl; each R9 is independently -(CR7R7a)t-OH, -(CR7R7a)m-C(=0)0-R8, -(CR7R7a)m-C(=0)0-(CR7R7a)m-OC(=0)0-R8, -(CR7R7a)m-C(=0)0-(CR7R7a)m- OC(=0)-R8, -(CR7R7a) OC(=0)-R8, tnazolyl, tetrazolyl or -(CR7R7a)m-C(=0)N(R8)2, with the proviso that when R9 is -(CR7R7a),-OH, R3 is phenyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pynmidinyl, pyridazinyl, thiazolyl, diazolyl, triazolyl, tetrazolyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyranyl or tnazinyl; each m is independently 0, 1 , 2, 3 or 4; and each t is independently 1 , 2, 3 or 4.
1 1. The compound according to claim 10, wherein Z is:
Figure imgf000274_0001
Figure imgf000275_0001
274
Figure imgf000276_0001
Figure imgf000276_0002
275
Figure imgf000277_0001
Figure imgf000277_0002
276
Figure imgf000278_0001
Figure imgf000278_0002
277
Figure imgf000279_0001
Figure imgf000279_0002
Figure imgf000279_0003
278
Figure imgf000280_0001
Figure imgf000280_0002
279
Figure imgf000281_0001
Figure imgf000281_0002
Figure imgf000281_0003
280
Figure imgf000282_0001
281
Figure imgf000283_0001
Figure imgf000283_0002
Figure imgf000283_0003
282
Figure imgf000284_0001
Figure imgf000284_0002
283
Figure imgf000285_0001
Figure imgf000285_0002
Figure imgf000285_0003
284
Figure imgf000286_0001
Figure imgf000286_0002
Figure imgf000286_0003
285
Figure imgf000287_0001
Figure imgf000287_0002
286
Figure imgf000288_0001
287
Figure imgf000289_0001
Figure imgf000289_0002
288
Figure imgf000290_0001
Figure imgf000291_0001
Figure imgf000292_0001
Figure imgf000293_0001
153 154 155
Figure imgf000294_0001
Figure imgf000294_0002
Figure imgf000294_0003
Figure imgf000294_0004
Figure imgf000295_0001
or an enantiomer, a diastereoisomer, a tautomer, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof.
14. A pharmaceutical composition comprising the compound according to any one of claims 1 - 13; and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.
15. The pharmaceutical composition according to claim 14 further comprises an anti-HBV agent.
16. The phannaceutical composition according to claim 15, wherein the anti-HBV agent is a HBV polymerase inhibitor, immunomodulator or interferon.
17. The pharmaceutical composition according to claim 15, wherein the anti-HBV agent is lamivudine, telbivudine, tenofovir, entecavir, adefovir dipivoxil, alfaferone, alloferon, celmoleukin, clevudine, emtricitabine, famciclovir, feron, hepatect CP, intefen, interferon a-lb, interferon a, interferon a-2a, interferon β-l a, interferon a-2, interleukin-2, mivotilate, nitazoxanide, peginterferon alfa-2a, ribavirin, roferon-A, sizofiran, euforavac, veldona, rintatolimod, phosphazid, heplisav, interferon a-2b, levamisole, or propagermanium.
18. Use of the compound according to any one of claims 1 -13 or the pharmaceutical composition according to any one of claims 14-17 in the manufacture of a medicament for preventing, managing, treating or lessening a viral disease or a HBV disease in a patient.
19. The use according to claim 18, wherein the viral disease or HBV disease is hepatitis B infection or a disease caused by hepatitis B infection.
20. The use according to claim 19, wherein the disease caused by hepatitis B infection is cirrhosis or hepatocellular carcinoma.
21 . A method for preventing, managing, treating or lessening a viral disease or a HBV disease in a patient, comprising administering to the patient with a therapeutically effective amount of the compound according to any one of claims 1 -13 or the pharmaceutical composition according to any one of claims 14-17.
22. The method according to claim 21 , wherein the viral disease or HBV disease is hepatitis B infection or a disease caused by hepatitis B infection.
23. The method according to claim 22, wherein the disease caused by hepatitis B infection is cirrhosis or hepatocellular carcinoma.
24. The compound according to any one of claims 1 -13 or the pharmaceutical composition according to any one of claims 14-17 for use in preventing, managing, treating or lessening a viral disease or a HBV disease.
25. The compound or the pharmaceutical composition according to claim 24, wherein the viral disease or HBV disease is hepatitis B infection or a disease caused by hepatitis B infection.
26. The compound or the pharmaceutical composition according to claim 25, wherein the disease caused by hepatitis B infection is cirrhosis or hepatocellular carcinoma.
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