WO2013144129A1 - Novel 4-methyl-dihydropyrimidines for the treatment and prophylaxis of hepatitis b virus infection - Google Patents

Novel 4-methyl-dihydropyrimidines for the treatment and prophylaxis of hepatitis b virus infection Download PDF

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Publication number
WO2013144129A1
WO2013144129A1 PCT/EP2013/056371 EP2013056371W WO2013144129A1 WO 2013144129 A1 WO2013144129 A1 WO 2013144129A1 EP 2013056371 W EP2013056371 W EP 2013056371W WO 2013144129 A1 WO2013144129 A1 WO 2013144129A1
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Prior art keywords
methyl
phenyl
fluoro
carboxylic acid
dihydro
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PCT/EP2013/056371
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French (fr)
Inventor
Lei Guo
Xianfeng Lin
Haixia Liu
Zongxing Qiu
Hong Shen
Guozhi Tang
Guolong Wu
Weixing Zhang
Wei Zhu
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F. Hoffmann-La Roche Ag
Hoffmann-La Roche Inc.
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Priority to CA2865259A priority Critical patent/CA2865259A1/en
Priority to CN201380012285.4A priority patent/CN104144924B/en
Priority to RU2014142598A priority patent/RU2014142598A/en
Priority to KR20147027071A priority patent/KR20140143160A/en
Priority to ES13712263.6T priority patent/ES2575398T3/en
Priority to JP2015502296A priority patent/JP6141402B2/en
Priority to EP13712263.6A priority patent/EP2831060B1/en
Priority to MX2014011749A priority patent/MX2014011749A/en
Publication of WO2013144129A1 publication Critical patent/WO2013144129A1/en
Priority to HK15104421.4A priority patent/HK1203944A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • 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
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms 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
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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

Definitions

  • Novel 4-methyl-dihydropyrimidines for the treatment and prophylaxis of hepatitis B virus infection
  • the present invention relates to organic compounds useful for therapy and/or prophylaxis in a human, and in particular to Hepatitis B virus (HBV) inhibitors by targeting on HBV capsid useful for treating HBV infection.
  • HBV Hepatitis B virus
  • HBV is a species of the hepadnaviridae family of viruses. HBV is a serious public health problem worldwide, with more than 400 million people especially in Asia-pacific regions chronically infected by this small enveloped DNA virus. Although most individuals seem to resolve the infection following acute symptoms, 15-40% of HBV patients will finally develop clinical diseases during their lifespan, most notably, hepatitis, liver cirrhosis, and hepatocellular carcinoma. Every year 500,000 to 1 million people die from the end stage of liver diseases caused by HBV infection.
  • HBV lifecycle begins with the binding of the "Dane” particle with an unidentified receptor on the surface of hepatocyte. Following entry, viral genome is delivered into nucleus where a covalently closed circular DNA (cccDNA) is formed through DNA repair of viral relaxed circular DNA. Unlike the mechanisms of most other DNA viruses, HBV cccDNA replicates through the retrotranscription of a 1.1-genome unit-length RNA copy (pregenomic RNA). Viral pregenomic RNA interacts with other two viral components, capsid protein and polymerase, as well as some host factors, to form capsid particles where viral DNA replication occurs. Most copies of the encapsidated genome then efficiently associate with the envelope proteins for virion assembly and secretion; a minority of these genomes are shunted to the nucleus, where they are converted to cccDNA.
  • pregenomic RNA 1.1-genome unit-length RNA copy
  • nucleoside (tide) analogs targeting viral polymerase (lamivudine, adefovir, tenofovir, telbivudine and entecavir) and interferon modulating host immune functions. Mutations in the primary sequence of the polymerase that confer resistance to lamivudine and adefovir have been identified clinically and underlie a rebound of serum virus titers that 70% of treated patients experience within 3 years of the start of lamivudine therapy. Although resistance to telbivudine, adefovir, and entecavir occurs more rarely, it has been recorded.
  • Interferon alpha is the other major therapy available for hepatitis B, but it is limited by a poor long-term response and debilitating side effects. Some viral genotypes do not show good responses to interferon therapy. Now, the standard of clinic cure of HBV infection is the loss and/or seroconversion of HBsAg. The majority (around or more than 90%) of treated patients fail to achieve this goal. This drawback is mainly due to the presence of a stable pool of viral cccDNA in nucleus that doesn't replicate itself, therefore, shows no accessibility to nucleoside (tide) analogs.
  • HBV capsid protein plays essential roles in HBV replication.
  • HBV has an icosahedral core comprising of 240 copies of the capsid (or core) protein.
  • the predominant biological function of capsid protein is to act as a structural protein to encapsidate pre-genomic RNA and form immature capsid particles in the cytoplasm. This step is prerequisite for viral DNA replication.
  • the HBV capsid spontaneously self-assembles from many copies of core dimers present in the cytoplasm. It has been shown that the formation of a trimeric nucleus and the subsequent elongation reactions occur by adding one dimeric subunit at a time until it is complete.
  • capsid protein regulates viral DNA synthesis through different phosphorylation status of its C-terminal phosphorylation sites.
  • capsid protein might facilitate the nuclear translocation of viral relaxed circular genome by means of the nuclear localization signals located in the Arginine-rich domain of the C-terminal region of capsid protein.
  • capsid protein could play a structural and regulatory role in the functionality of cccDNA minichromosomes.
  • Capsid protein also interacts with viral large envelope protein in endoplasmic reticulum and triggers the release of intact viral particles from hepatocytes.
  • capsid related anti-HBV inhibitors There has been a couple of capsid related anti-HBV inhibitors reported. For example, phenylpropenamide derivatives, including compounds named AT-61 and AT-130 (Feld J. et al. Antiviral Research 2007, 168-177), and a class of thiazolidin-4-ones from Valeant R&D
  • HAP Heteroaryldihydropyrimidines or HAP, including compounds named Bay 41-4109, Bay 38-7690 and Bay 39-5493, were discovered in a tissue culture-based screening (Deres K. et al. Science 2003, 893). These HAP analogs act as synthetic allosteric activators and are able to induce aberrant capsid formation that leads to degradation of the core protein.
  • HAP analogs also reorganized core protein from preassembled capsids into noncapsid polymers, presumably by interaction of HAP with dimers freed during capsid 'breathing', the transitory breaking of individual intersubunit bonds.
  • Bay 41-4109 was administered to HBV infected transgenic mouse or humanized mouse models and demonstrated in vivo efficacy with HBV DNA reduction (Deres K. et al. Science 2003, 893; Brezillon N. etal. PLoS ONE 2011, e25096.). It was also shown that bis- ANS, a small molecule that acts as a molecular 'wedge' and interferes with normal capsid- protein geometry and capsid formation (Zlotnick A. et al. J. Virol. 2002, 4848-4854).
  • Objects of the present invention are novel compounds of formula I, their manufacture, medicaments based on a compound in accordance with the invention and their production as well as the use of compounds of formula I for the treatment or prophylaxis of HBV infection.
  • C h alky alone or in combination signifies a saturated, linear- or branched chain alkyl group containing 1 to 6, particularly 1 to 4 carbon atoms, for example methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, ie/t-butyl and the like.
  • Particular "C h alky! groups are methyl, ethyl, isopropyl, ie/t-butyl.
  • cycloalkyl refers to a saturated carbon ring containing from 3 to 7 carbon atoms, particularly from 3 to 6 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Particular cycloalkyl groups are cyclopropyl, cyclopentyl and cyclohexyl.
  • Ci-ealkoxy alone or in combination signifies a group Ci ⁇ alkyl-O-, wherein the "C h alky! is as defined above; for example methoxy, ethoxy, propoxy, isopropoxy, w-butoxy, i- butoxy, 2-butoxy, i-butoxy and the like.
  • Particular Ci ⁇ alkoxy groups are methoxy and ethoxy and more particularly methoxy.
  • C 2 _ 6 alkoxy alone or in combination signifies a group C 2 _ 6 alkyl-0-, wherein the "C 2 _ 6 alkyl” alone or in combination signifies a saturated, linear- or branched chain alkyl group containing 2 to 6, particularly 2 to 4 carbon atoms; for example ethoxy, propoxy, isopropoxy, n- butoxy, j-butoxy, 2-butoxy, i-butoxy and the like.
  • C 1 _ 2 alkoxy alone or in combination refers to methoxy or ethoxy.
  • C y H 2y alone or in combination signifies a saturated, linear- or branched chain alkyl group containing 1 to 6, particularly 1 to 4 carbon atoms.
  • amino alone or in combination, refers to primary (-NH 2 ), secondary (-NH-) or
  • carbonyl alone or in combination refers to the group -C(O)-.
  • cyano alone or in combination refers to the group -CN.
  • halogen means fluorine, chlorine, bromine or iodine. Halogen is particularly fluorine or chlorine, more particularly fluorine.
  • hydroxy alone or in combination refers to the group -OH.
  • tautomers refers to constitutional isomers of organic compounds that readily interconvert by a chemical reaction called tautomerization. This reaction commonly results in the formal migration of a hydrogen atom or proton, accompanied by a switch of a single bond and adjacent double bond.
  • pharmaceutically acceptable salt refers to conventional acid-addition salts or base-addition salts that retain the biological effectiveness and properties of the compounds of formula I and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases.
  • Acid-addition salts include for example those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, and the like.
  • Base-addition salts include those derived from ammonium, potassium, sodium and, quaternary ammonium hydroxides, such as for example, tetramethyl ammonium hydroxide.
  • the chemical modification of a pharmaceutical compound into a salt is a technique well known to pharmaceutical chemists in order to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds. It is for example described in Bastin R.J., et. al., Organic Process Research & Development 2000, 4, 427-435; or in Ansel, H., et. al., In: Pharmaceutical Dosage Forms and Drug Delivery Systems, 6th ed. (1995), pp. 196 and 1456-1457. Particular are the sodium salts of the compounds of formula I.
  • Racemates can be separated according to known methods into the enantiomers.
  • diastereomeric salts which can be separated by crystallization are formed from the racemic mixtures by reaction with an optically active acid such as e.g. D- or L-tartaric acid, mandelic acid, malic acid, lactic acid or camphorsulfonic acid.
  • the present invention provides (i) novel compounds having the general formula I:
  • R is C ⁇ alkoxycarbonyl or cyano
  • R is phenyl, which is substituted by halogen
  • R is thiazolyl, thienyl, imidazolyl, isoxazolyl or pyridinyl; which is unsubstituted or substituted by halogen or Ci-ealkyl;
  • X is oxygen or -NR 7 ;
  • R 4 and R 5 are independently selected from hydrogen, Ci- 6 alkyl and trifluoroCi-ealkyl; or
  • R 4 and R 5 together with the carbon atom to which they are attached, form a 3 to 7 membered cycloalkyl; or when X is -NR 7 , one of R 4 and R 5 is hydrogen or C 1-6 alkyl, and the other one with the carbon atom to which it is attached and -NR , form a pyrrolidinyl, morpholinyl or piperidinyl ring, which ring is unsubstituted or substituted by fluoro;
  • M is Ci-ealkoxycarbonyl, carboxy, diCi-ealkylaminoC ⁇ ealkoxycarbonyl, aminocarbonyl, Ci-ealkylaminocarbonyl, diCi-ealkylaminocarbonyl, Ci-ealkylsulfonylaminocarbonyl, 2- 1 -6 alkyl
  • R is Ci- 6 alkyl or trifluoroCi-ealkyl; y is 1-6; or pharmaceutically acceptable salts, or tautomerism isomers thereof.
  • Another embodiment of present invention is (ii) a compound of formula I, wherein R 1 is Ci ⁇ alkoxycarbonyl or cyano;
  • R is phenyl, which is once or twice substituted by halogen
  • R is 2-thiazolyl, which is unsubstituted or once substituted by Ci-ealkyl or halogen; or 2- thienyl or 2-pyridinyl, which is once substituted by halogen; or 2-imidazolyl, which is once substituted by C ⁇ aUcyl; or 3-isoxazolyl, which is unsubstituted or once substituted by C ⁇ aUcyl;
  • X is oxygen or -NR 7 ;
  • R 4 and R 5 are independently selected from hydrogen, Ci-ealkyl and trifluoroCi-ealkyl; or
  • R 4 and R 5 together with the carbon atom to which they are attached, form a 3 to 7 membered cycloalkyl; or when X is -NR 7 , one of R 4 and R 5 is hydrogen or C 1-6 alkyl, and the other one with the carbon atom to which it is attached and -NR together form a morpholinyl; or pyrrolidinyl or piperidinyl, which is substituted by fluoro;
  • M is Ci-ealkoxycarbonyl, carboxy, diCi-ealkylamino-Ci-ealkoxycarbonyl, aminocarbonyl, Ci-ealkylaminocarbonyl, diCi-ealkylaminocarbonyl, Ci-ealkylsulfonylaminocarbonyl, 2- 1 -6 alkyl
  • R is Ci- 6 alkyl or trifluoroCi-ealkyl; y is 1-6; or pharmaceutically acceptable salts, or tautomerism isomers thereof.
  • Further embodiment of present invention is (iii) a compound of formula I, wherein
  • R 1 is methoxycarbonyl, ethoxycarbonyl or cyano; R is phenyl substituted once or twice by fluoro;
  • X is oxygen or -NR 7 ;
  • R 4 and R 5 are independently selected from hydrogen, methyl and trifluoromethyl; or
  • R 4 and R 5 together with the carbon atom to which they are attached form cyclopropyl; or hen X is -NR 7 , one of R 4 and R 5 is hydrogen or methyl, and the other one with the carbon atom
  • M is methoxycarbonyl, carboxy, dimethylaminoethoxycarbonyl, aminocarbonyl, dimethylaminocarbonyl, methylaminocarbonyl, methylsulfonylaminocarbon l, 2-
  • R is methyl or trifluoroethyl; or pharmaceutically acceptable salts, or tautomerism isomers thereof.
  • Another embodiment of present invention is (iv) a compound of formula I or a pharmaceutically acceptable salt or tautomerism isomers thereof, wherein
  • R 1 is Ci ⁇ alkoxycarbonyl
  • R is phenyl which is once substituted by halogen; R is 2-thiazolyl; X is oxygen; R 4 and R 5 are independently selected from hydrogen, Ci- 6 alkyl and trifluoroCi-ealkyl; M is Ci-ealkoxycarbonyl or carboxy.
  • R 1 is methyoxycarbonyl
  • X is oxygen
  • R 4 and R 5 are independently selected from hydrogen, methyl and trifluoromethyl
  • M is methoxycarbonyl or carboxy.
  • Another embodiment of present invention is (vi) a compound of formula I or a pharmaceutically acceptable salt or tautomerism isomers thereof, wherein
  • R 1 is Ci ⁇ alkoxycarbonyl
  • R is phenyl which is once substituted by halogen;
  • R is 2-thiazolyl;
  • X is -N-Ci-ealkyl or -N-trifluoroC 1-6 alkyl
  • R 4 is hydrogen;
  • R 5 is hydrogen; or R 4 and R 5 , together with the carbon atom to which they are attached, form a 3 to 7 membered cycloalkyl;
  • M is carboxy
  • R 1 is methoxycarbonyl
  • R 4 is hydrogen;
  • R 5 is hydrogen; or R 4 and R 5 , together with the carbon atom to which they are attached, form cyclopropyl;
  • M is carboxy
  • Another embodiment of present invention is (viii) a compound of formula I or a pharmaceutically acceptable salt or tautomerism isomers thereof, wherein
  • R 1 is Ci-ialkoxycarbonyl or cyano
  • R is phenyl which is once or twice substituted by halogen
  • R is 2-thiazolyl; or 2-pyridinyl, which is once substituted by halogen; or 2-imidazolyl, which is once substituted by C 1-6 alkyl;
  • X is -NR 7 ;
  • one of R 4 and R 5 is hydrogen, and the other one with the carbon atom to which it is attached and -NR together form a morpholinyl;
  • M is C 1-6 alkoxycarbonyl, carboxy or hydroxy-C y H2 y -; y is 1-6.
  • Further embodiment of present invention is (ix) a compound of formula I or a pharmaceutically acceptable salt or tautomerism isomers thereof, wherein
  • R 1 is methoxycarbonyl, ethoxycarbonyl or cyano
  • R 4 and R 5 is h drogen, and the other one with the carbon atom to which it is
  • M is methoxycarbonyl, carboxy or hydroxymethyl-.
  • Another embodiment of present invention is (x) a compound of formula I or a pharmaceutically acceptable salt or tautomerism isomers thereof, wherein
  • R 1 is Ci-ialkoxycarbonyl or cyano
  • R is phenyl which is once or twice substituted by halogen
  • R is 2-thiazolyl, which is unsubstituted or once substituted by Ci- 6 alkyl or halogen; or 2- thienyl or 2-pyridinyl, which is once substituted by halogen; or 2-imidazolyl, which is once substituted by C 1-6 alkyl; or 3-isoxazolyl, which is unsubstituted or once substituted by C 1-6 alkyl;
  • X is -NR 7 ; one of R 4 and R 5 is hydrogen or Ci- 6 alkyl, and the other one with the carbon atom to which it is attached and -NR together form a pyrrolidinyl or piperidinyl, which is substituted by fluoro;
  • M is Ci-ealkoxycarbonyl, carboxy, diCi-ealkylaminoCi-ealkoxycarbonyl, aminocarbonyl, Ci-ealkylaminocarbonyl, diCi-ealkylaminocarbonyl, Ci-ealkylsulfonylaminocarbonyl, 2- 1 -6 alkyl
  • R 1 is methoxycarbonyl, ethoxycarbonyl or cyano
  • X is -NR 7 ; one of R 4 and R 5 is h carbon atom to which
  • M is methoxycarbonyl, carboxy, dimethylaminoethoxycarbonyl, aminocarbonyl, dimethylaminocarbonyl, methylaminocarbonyl, methylsulfonylaminocarbonyl, 2- hiazolylaminocarbonyl, hydroxymethyl, hydroxypropyl,
  • Another embodiment of present invention is (xii) a compound of formula ⁇ or a pharmaceutically acceptable salt or tautomerism isomers thereof,
  • R 1 is Ci-ialkoxycarbonyl or cyano
  • R is phenyl, which is substituted by halogen
  • R is 2-thiazolyl which is unsubstituted or substituted by C ⁇ aUcyl or 2-pyridinyl, which is substituted by halogen;
  • X is oxygen or -NR 7 ;
  • R 4 and R 5 are independently selected from hydrogen, Ci-ealkyl and trifluoroCi-ealkyl; or
  • R 4 and R 5 together with the carbon atom to which they are attached, form a 3 to 7 membered cycloalkyl; or when X is -NR 7 , one of R 4 and R 5 is hydrogen or C 1-6 alkyl, and the other one with the carbon atom to which it is attached and -NR together form a morpholinyl; or pyrrolidinyl substituted by fluoro;
  • R 6 is hydrogen or Ci- 6 alkyl
  • R 7 is Ci-ealkyl.
  • Further embodiment of present invention is (xiii) a compound of formula ⁇ or a pharmaceutically acceptable salt or tautomerism isomers thereof, wherein
  • R 1 is methoxycarbonyl or cyano
  • R is phenyl substituted once or twice by fluoro
  • X is oxygen or -NR 7 ;
  • R 4 and R 5 are independently selected from hydrogen, methyl and trifluoromethyl; or
  • R 4 and R 5 together with the carbon atom to which they are attached form cyclopropyl; or X is -NR 7 , one of R 4 and R 5 is hydrogen or methyl, and the other one with the carbon atom
  • R 6 is hydrogen or methyl
  • R is methyl
  • Still further embodiment of present invention is (xiv) a compound of formula ⁇ or a pharmaceutically acceptable salt or tautomerism isomers thereof, wherein
  • R 1 is Ci ⁇ alkoxycarbonyl
  • R is phenyl which is substituted by halogen
  • R is 2-thiazolyl
  • X is oxygen;
  • R 4 and R 5 are independently selected from hydrogen, Ci-6alkyl and trifluoroCi-ealkyl;
  • R 6 is hydrogen or Ci-ealkyl.
  • More further embodiment of present invention is (xv) a compound of formula ⁇ or a pharmaceutically acceptable salt or tautomerism isomers thereof, wherein
  • R 1 is methyoxycarbonyl; oxygen;
  • R 4 and R 5 are independently selected from hydrogen, methyl and trifluoromethyl; R 6 is hydrogen or methyl.
  • Another further embodiment of present invention is (xvi) a compound of formula ⁇ or a pharmaceutically acceptable salt or tautomerism isomers thereof, wherein
  • R 1 is Ci ⁇ alkoxycarbonyl
  • R is phenyl which is substituted by halogen
  • R is 2-thiazolyl
  • X is NCi-ealkyl
  • R 4 and R 5 together with the carbon atom to which they are attached, form a 3 to 7 membered cycloalkyl
  • R 6 is hydrogen
  • R 1 is methoxycarbonyl
  • X is -NCH 3 ;
  • R 4 and R 5 together with the carbon atom to which they are attached, form cyclopropyl; R 6 is hydrogen.
  • More further embodiment of present invention is (xviii) a compound of formula ⁇ or a pharmaceutically acceptable salt or tautomerism isomers thereof, wherein
  • R 1 is Ci ⁇ alkoxycarbonyl or cyano
  • R is phenyl which is substituted by halogen
  • R is 2-thiazolyl; or 2-pyridinyl, which is substituted by halogen;
  • X is -NR 7 ;
  • one of R 4 and R 5 is hydrogen or Ci-6alkyl, and the other one with the carbon atom to which it is attached and -NR together form a morpholinyl;
  • R 6 is hydrogen or Ci-ealkyl.
  • R 1 is methoxycarbonyl or cyano
  • R is , * oonnee ootf R "* aannad ⁇ R ⁇ D i iss n hyyadrroojgen or methyl, and the other one
  • R 6 is hydrogen or methyl.
  • Still further embodiment of present invention is (xx) a compound of formula ⁇ or a pharmaceutically acceptable salt or tautomerism isomers thereof, wherein
  • R 1 is Ci-ialkoxycarbonyl or cyano
  • R is phenyl which is substituted by halogen;
  • R is 2-thiazolyl which is unsubstituted or substituted by Ci- 6 alkyl or 2-pyridinyl, which is substituted by halogen;
  • X is -NR 7 ;
  • one of R 4 and R 5 is hydrogen or Ci- 6 alkyl, and the other one with the carbon atom to which it is attached and -NR together form a pyrrolidinyl which is substituted by fluoro;
  • R 6 is hydrogen or Ci-ealkyl.
  • Another further embodiment of present invention is (xxi) a compound of formula ⁇ or a pharmaceutically acceptable salt or tautomerism isomers thereof, wherein
  • R 1 is methoxycarbonyl or cyano
  • X is -NR 7 ; one of R 4 and R 5 is h methyl, and the other one with the carbon atom to which
  • R 6 is hydrogen or methyl.
  • methyl ester It is very important for a drug to have a moderate or low clearance, as this often lead to a good oral bioavailability and high exposure in target organ. Reducing the clearance of a compound or drug could then potentially reduce drastically the daily dose required for efficacy and therefore give a much better safety profile as well. From the examples below, it has been found a marked increase of metabolic stability and liver exposure of 4-methyldihydropyrimidines of current invention.
  • 4-Hydrogen-dihydropyrimidines such as Bay 41-4109 can be oxidized to pyrimidine product XL VI when treated with human, rat or mouse liver microsomes.
  • pooled liver microsomes (20 mg/ml) from human, male Wister rat and male CD-I mouse were obtained from BD Bioscience (Franklin Lakes, NJ USA).
  • Incubation reaction mixtures contained a final concentration of 0.1M sodium phosphate buffer (pH 7.4), 0.5 mg/ml microsomal protein, 5 ⁇ of the tested compounds and 1 mM NADPH in a total volume of 400 ⁇ .
  • the incubations were done for 60 minutes and 300 ⁇ of the mixtures was transferred to 150 ⁇ of ice cold methanol to terminate reactions. After vortexes for 3 minutes and centrifuged at 4000 rpm at 4°C for 10 minutes, the clear supernatant was used directly for analysis. The samples were analyzed by Applied Biosystems API 3200 Q TRAP LC/MS/MS system using electrospray ionization mode.
  • Pyrimidine product XLVI was the major metabolite in the in vitro clearance tests ( Figure 1), and it was inactive to HBV DNA reduction in HepDE19 cell based assays with EC 50 value above 100 ⁇ .
  • the 4-methyl-dihydropyrimidines series in this invention do not have the aromatization issues of the core structure.
  • HBV viruses infect hepatocyte cells and replicate in the liver. To have effective viral suppression, it is important for an anti-HBV drug to have sufficient exposure in the target organ.
  • the following findings highlight increased metabolic stability and high liver exposure of 4- methyldihydropyrimidine analogs in this invention.
  • liver homogenate solutions fresh mouse liver sample was homogenized by adding saline (1 g liver tissue: 5 mL saline) immediately after collection. After centrifuging for 10 minutes at 14000 rpm, the pooled supernatant was used to prepare liver homogenate solutions. The effective compounds concentrations in liver homogenate were 100, 300, and 1000 ng/mL. Then, they were incubated at rt. After incubation time of 0, 15 and 30 minutes, 180 ⁇ aliquots of MeOH was added into 20 ⁇ of homogenate, respectively. All these samples were vortex mixed for 5 minutes at 1500 rpm and centrifuged for 10 minutes at 14000 rpm. The supernatants were transferred into a 96- well plate for LC-MS/MS analysis. The results were summarized and showed in Table 3.
  • Bay41-4109 is not stable in liver homogenate treated with saline. About 2% of compound was detected after 15 minutes room temperature incubation, at three different concentration levels. In samples incubated for 30 minutes, only 0.16% can be found (at 1000 ng/mL. Not detected in 100 ng/mL and 300 ng/mL samples due to instrument sensitivity).
  • Example 13 is stable in in liver homogenate treated with saline.
  • the in vivo DMPK of selected compounds were evaluated in male ICR mice following intravenous (or i.v.) or oral (or p.o.) administration.
  • SDPK single dose pharmacokinetics
  • compounds were dissolved in 6% Solutol solution (Solutol: Ethanol, 1: 1, v/v), and 94% 0.9% saline for i.v. dose.
  • compounds were mixed with 0.89% microcrystalline cellulose and 0.11% carboxymethyl cellulose sodium water solution, or 1% RC591 as suspensions.
  • the single dose exposure levels of Bay 41-4109, Example 6, Example 11, Example 13 and Example 19 in mouse plasma and/or liver are shown as Figure 2-6.
  • the compounds of the present invention can be prepared by any conventional means.
  • R 8 is C ⁇ alkyl
  • Amidine III can be prepared from commercial available nitrile II, ammonium chloride and trimethyl aluminum. The reaction is typically performed by adding trimethyl aluminum to the mixture of ammonium chloride in toluene at 0 °C. After 30 minutes, nitrile II is added into the flask and the reaction mixture is stirred at 80 °C overnight.
  • the indium triflate catalyzed condensation reaction of commercial available ester IV and ethynyl-benzene V gives ⁇ , ⁇ -unsaturated ketone VI.
  • the reaction is typically performed in o- xylene at 120 °C for 2 h.
  • Ketone VIII can be prepared by condensation of ester IV with substituted benzaldehyde VII. The reaction is typically performed in ethanol with catalytic quantity of piperidine and acetic acid at rt overnight.
  • Ketone IX can be prepared by 1,4-Michael addition of methyl group to the ⁇ , ⁇ -unsaturated ketone VIII.
  • the reaction is typically performed by adding methyl lithium solution to cuprous iodide in THF solution at 0 °C and stirred for 1 hour at 0 °C, then the solution of VIII in THF is added into the mixture at -78 °C and stirred for 1 hour at -78 °C.
  • ⁇ , ⁇ -Unsaturated ketone VI can be prepared by oxidative elimination of ketone IX.
  • the reaction is typically performed by adding sodium hydride into the solution of ketone IX in THF, then phenylselenyl chloride is added and stirred at rt for 1 hour. After the mixture is treated with pentene, ether and saturated sodium bicarbonate, the organic layer is treated with H 2 0 2 solution (30%) and stirred at rt for 1 hour.
  • Analogs with general structure Intermediate-1 can be prepared by the condensation reaction of ⁇ , ⁇ -unsaturated ketone VI with amidine III.
  • the reaction is typically carried out by adding a solution of VI in NMP dropwisely into a mixture of amidine III and NaHC0 3 in NMP at 120 °C, after addition the mixture is stirred at 120 °C for half an hour before workup.
  • Compound XI can be obtained by the deprotection of Intermediate-2.
  • the reaction is typically performed in DCM with TFA at rt for 2 hours.
  • Compound XII can be obtained by coupling reaction from XI with ammonia.
  • the reaction is typically performed in DCM with HATU and ammonia of dioxane solution at rt for 1 hour.
  • Cyano compound Intermediate-3 can be obtained by dehydrate reaction from compound XII.
  • the reaction is typically performed in 1,2-dichloroethane with thionyl chloride or trifluoroacetic anhydride under refluxing for 1 hour.
  • the Boc-protected compound XIII can be obtained by treatment of ester Intermediate- 1 or cyano Intermediate-3 with di-iert-butyldicarbonate and DMAP as base in an inert organic solvent such as DCM, typically at rt for 24 hours.
  • the compound XIV can be obtained by the bromination of compound XIII.
  • the reaction is typically performed in tetrachloromethane with NBS and AIBN as catalyst at 80 °C for 2 hours.
  • the amino substituted intermediate XVI can be obtained through substitution reaction of compound XIV with XV.
  • the reaction can be carried out with a suitable organic base such as ⁇ , ⁇ -diisopropylethylamine, inorganic base such as NaH, Na 2 C0 3 , or i-BuOK in an inert organic solvent such as DCM, THF or DMF at rt or 50 °C for 1-10 hours.
  • a suitable organic base such as ⁇ , ⁇ -diisopropylethylamine, inorganic base such as NaH, Na 2 C0 3 , or i-BuOK
  • an inert organic solvent such as DCM, THF or DMF at rt or 50 °C for 1-10 hours.
  • Compound la can be obtained from the deprotection of XVI treated with TFA in DCM or HCI in MeOH as deprotective agent at rt.
  • Compound XVIII can be obtained by substitution reaction of compound XIV with alcohol XVII.
  • the reaction is typically performed by adding NaH to the solution of alcohol XVII in anhydrous THF at rt, then bromide XIV is added into the flask and the mixture is stirred at rt for 3 hours.
  • Compound lb can be obtained by treating XVIII with TFA in DCM or HC1 in MeOH at rt.
  • This invention also relates to a process for the preparation of a compound of formula I comprising the reaction of
  • step (a) the acid can be for example TFA or HC1.
  • the invention also relates to a compound of formula I for use as therapeutically active substance.
  • a compound of formula (I) when manufactured according to the above process is also an object of the invention.
  • compositions or medicaments containing the compounds of the invention and a therapeutically inert carrier, diluent or excipient, as well as methods of using the compounds of the invention to prepare such compositions and medicaments.
  • compounds of formula I may be formulated by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed into a galenical administration form.
  • the pH of the formulation depends mainly on the particular use and the concentration of compound, but preferably ranges anywhere from about 3 to about 8.
  • a compound of formula I is formulated in an acetate buffer, at pH 5.
  • the compounds of formula I are sterile.
  • the compound may be stored, for example, as a solid or amorphous composition, as a lyophilized formulation or as an aqueous solution.
  • compositions are formulated, dosed, and administered in a fashion consistent with good medical practice.
  • Factors for consideration in this context include the particular disorder being treated, the particular human being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners.
  • the "effective amount" of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to the suppression of serum HBV DNA levels, or HBeAg seroconversion to HBeAb, or HBsAg loss, or normalization of alanine aminotransferase levels and improvement in liver histology. For example, such amount may be below the amount that is toxic to normal cells, or the human as a whole.
  • the pharmaceutically effective amount of the compound of the invention administered parenterally per dose will be in the range of about 0.01 to 100 mg/kg, alternatively about 0.1 to 20 mg/kg of patient body weight per day, with the typical initial range of compound used being 0.3 to 15 mg/kg/day.
  • oral unit dosage forms such as tablets and capsules, contain from about 0.1 to about 1000 mg of the compound of the invention.
  • the compounds of the invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and, if desired for local treatment, intralesional administration.
  • Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.
  • the compounds of the present invention may be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc.
  • Such compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents.
  • a typical formulation is prepared by mixing a compound of the present invention and a carrier or excipient.
  • Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., Ansel, Howard C, et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005.
  • the formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).
  • buffers stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing
  • An example of a suitable oral dosage form is a tablet containing about 0.1 mg to 1000 mg of the compound of the invention compounded with about 90 mg to 30 mg anhydrous lactose, about 5 mg to 40 mg sodium croscarmellose, about 5 mg to 30 mg polyvinylpyrrolidone (PVP) K30, and about 1 mg to 10 mg magnesium stearate.
  • the powdered ingredients are first mixed together and then mixed with a solution of the PVP.
  • the resulting composition can be dried, granulated, mixed with the magnesium stearate and compressed to tablet form using conventional equipment.
  • An example of an aerosol formulation can be prepared by dissolving the compound, for example 5 mg to 400 mg, of the invention in a suitable buffer solution, e.g.
  • An embodiment includes a pharmaceutical composition comprising a compound of Formula I, or a stereoisomer or pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising a compound of Formula I, or a stereoisomer or pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or excipient.
  • the compounds of the invention can inhibit HBV's de novo DNA synthesis and reduce HBV DNA levels. Accordingly, the compounds of the invention are useful for the treatment or prophylaxis of HBV infection.
  • the invention relates to the use of a compound of formula I for the treatment or prophylaxis of HBV infection.
  • the use of a compound of formula I for the preparation of medicaments useful in the treatment or prophylaxis diseases that are related to HBV infection is an object of the invention.
  • the invention relates in particular to the use of a compound of formula I for the preparation of a medicament for the treatment or prophylaxis of HBV infection.
  • Another embodiment includes a method of treating or prophylaxising HBV infection in a human in need of such treatment, wherein the method comprises administering to said human a therapeutically effective amount of a compound of Formula I, a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof.
  • the compounds of the invention can be used together with interferon, pegylated interferons, Lamivudine, Adefovir dipivoxil, Entecavir, Telbivudine, and Tenofovir disoproxil for the treatment or prophylaxis of HBV.
  • FIG. 1 Mean + SD Plasma Concentration-Time Curve of Bay41-4109 in Male ICR Mice Following Intravenous and Oral Administration* * Drug exposure in liver is not available due to instability of Bay 41-4109 in liver homogenate.
  • CC 50 cytotoxic concentration 50%
  • CDCI 3 deuterated chloroform
  • CDI N, N'-Carbonyldiimidazole
  • CMV cytomegalovirus
  • DIPEA N,N-diisopropylethylamine
  • DNA deoxyribonucleic acid
  • EDTA ethylenediaminetetraacetic acid
  • FBS fetal bovine serum
  • EC 50 concentration required for 50% induction of acetylated tubulin
  • FBS fetal bovine serum
  • HAP heteroaryldihydropyrimidine
  • HATU 2-(7- Aza- IH-benzotriazole- 1-yl)- 1 , 1 ,3,3-tetramethyluronium hexafluorophosphate
  • HBeAb hepatitis B e antibody
  • HBeAg hepatitis B e antigen
  • HBsAg hepatitis B surface antigen
  • NBS N-bromosuccinimide
  • PBS Phosphate buffered saline
  • SSC saline- sodium citrate buffer
  • Acidic condition A: 0.1% formic acid in H 2 0; B: 0.1% formic acid in acetonitrile;
  • LC-MS/MS instrument on liver homogenate stability test An Agilent 1290 series LC system composited of a binary pump, a degasser, a CTCPAL autosampler and a thermostatted column was applied. The Chromatographic separation was achieved on a Chromolith Performance RP-18 endcapped (3 x 100 mm) at room temperature.
  • Mass spectrometric detection was performed on an Agilent 6530 Q-TOF instrument in full scan mode with an AJS ESI interface in positive ionization mode. Data processing was performed with Agilent MassHunter Workstation Data Acquisition B.04.00 and Agilent MassHunter Workstation Qualitative Analysis B.04.00.
  • the microwave assisted reactions were carried out in a Biotage Initiator Sixty microwave synthesizer.
  • Example 3 6- ⁇ [(l-Carboxy-cyclopropyl)-methyl-amino]-methyl ⁇ -4-(4-fluoro- phenyl)-4-methyl-2-thiazol-2-yl- l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester
  • the title compound was prepared according to the synthesis method shown in Scheme 1 and Scheme 3. A detailed synthesis route is provided as shown in Scheme 6.
  • the crude product XXV from above step was dissolved in DCM and then TFA was added. The mixture was stirred at rt for 2 hours. LC-MS indicated that the reaction was finished. The solvent was removed and the residue was used in the next step without further purification.
  • the crude product XXVI from above step was dissolved in MeOH (5 mL) and LiOH in water (2 mL) was added to the mixture. The mixture was stirred at rt for 2 h and LC-MS indicated that the reaction was finished. The solvent was removed and the mixture was adjusted to pH (3-5) with diluted hydrochloric acid. The mixture was purified by prep-HPLC to afford Example 3 as yellow solid (0.63 g, yield for 3 steps: 73%).
  • Example 7 ( l S')-4-[6-(4-Fluoro-phenyl)-5-methoxycarbonyl-6-methyl-2-thiazol-2-yl- 3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-( l S')-3-carboxylic acid
  • the chiral intermediate compound XXVII was separated from XXI by SFC and the absolute stereochemistry was determined by X-ray diffraction study (please see Figure 7).
  • the title compound was prepared in analogy to Example 3 in Scheme 6 by using morpholine-( l S')-3- carboxylic acid methyl ester XXVIII instead of 1-methylamino-cyclopropanecarboxylic acid methyl ester in the replacement reaction.
  • Example 11 6-(2-( l S')-Carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(4-fluoro-phenyl)- 4-methyl-2-thiazol-2-yl- l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester
  • the title compound was prepared in analogy to Example 3 in Scheme 6 by using 4,4- difluoro-pyrrolidine-( l S')-2-carboxylic acid methyl ester instead of 1-methylamino- cyclopropanecarboxylic acid methyl ester.
  • Example 17 6-(4,4-Difluoro-2-methoxycarbonyl-pyrrolidin-l-ylmethyl)-4-(4-fluoro- phenyl)-2-(5-fluoro-pyridin-2-yl)-4-methyl- 1 ,4-dihydro-pyrimidine-5-carboxylic acid methyl ester
  • the title compound was prepared in analogy to Example 9 in Scheme 8 by using 4,4- difluoro-pyrrolidine-( l S')-2-carboxylic acid methyl ester instead of morpholine-(R)-3-carboxylic acid methyl ester XXXVIII in the replacement reaction.
  • Example 20 6-(2-Carboxy-4,4-difluoro-2-methyl-pyrrolidin-l-ylmethyl)-4-(4-fluoro- phenyl)-4-methyl-2-thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester
  • the title compound was prepared in analogy to Example 3 in Scheme 6 by using 4,4- difluoro-2-methyl-pyrrolidine-2-carboxylic acid methyl ester instead of morpholine-3-carboxylic acid methyl ester.
  • Example 21 ( l S')-l-[( l S , )-5-Cyano-6-(4-fluoro-phenyl)-6-methyl-2-thiazol-2-yl-3,6- dihydro-pyrimidin-4-ylmethyl]-4,4-difluoro-pyrrolidine-2-carboxylic acid
  • the title compound was prepared according to the synthesis method shown in Scheme 2 and Scheme 3. A detailed synthesis route is provided as shown in Scheme 13.
  • the chiral intermediate XLII was separated from XLI by SFC.
  • Example 21 was prepared from XLII in analogy to Example 3 in Scheme 6.
  • Example 22 was prepared in the same method as shown in Scheme 5 and Scheme 6 by using morpholine-( l S')-3-carboxylic acid methyl ester XXVIII in the replacement reaction.
  • Example 25 Preparation of ( l S , )-6-(2-carboxy-5,5-difluoro-piperidin-l-ylmethyl)-4-(4- fluoro-phenyl)-4-methyl-2-thiazol-2-yl- l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester
  • the title compound was prepared in analogy to Example 7 in Scheme 7 by using5,5- difluoro-piperidine-2-carboxylic acid instead of (S)-morpholine-3-carboxylic acid methyl ester.
  • Example 26 Preparation of ( l S , )-6-(2-carboxy-4,4-difluoro-piperidin-l-ylmethyl) 4-(4- fluoro-phenyl)-4-methyl-2-thiazol-2-yl- l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester
  • the title compound was prepared in analogy to Example 7 in Scheme 7 by using 4,4- difluoro-piperidine-2-carboxylic acid instead of (S)-morpholine-3-carboxylic acid methyl ester.
  • Example 30 Preparation of ( l S')-4-[( l S , )-6-(4-fluoro-phenyl)-5-methoxycarbonyl-6- methyl-2-(l-methyl- lH-imidazol-2-yl)-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3- carboxylic acid
  • Example 35 Preparation of 6-(( l S , )-2-carboxy-4,4-difluoro-pyrrolidin- l-ylmethyl)-4-(4- fluoro-phenyl)-2-isoxazol-3-yl-4-methyl-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester
  • the title compound was prepared in analogy to Example 11 by using isoxazole-3- carbonitrile instead of thiazole-2-carbonitrile.
  • Example 40 Preparation of 6-(( l S , )-2-carboxy-4,4-difluoro-pyrrolidin- l-ylmethyl)-4-(4- fluoro-phenyl)-4-methyl-2-(5-methyl-isoxazol-3-yl)- 1 ,4-dihydro-pyrimidine-5-carboxylic acid methyl ester
  • Example 51 Preparation of ( l S')-6-((S)-4,4-difluoro-2-methanesulfonylaminocarbonyl- pyrrolidin- l-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl- l,4-dihydro-pyrimidine-5- carboxylic acid methyl ester
  • Example 60 HBV inhibition assays (biochemical assay) Cells and culture conditions: HepDE19 (Haitao Guo et al, Journal of Virology, 81, Nov.
  • cells were derived from HepG2 (ATCC, American Type Culture Collection) cells through transfection with pTet-off plasmid (Clontech) that expresses the Tet-responsive transcriptional activator and pTREHBVDE plasmid in which HBV pgRNA expression is controlled by a CMV early promoter with a tetracycline-responsive element.
  • the transfected cells were selected with G418 (also known as Genticin, purchased from Invitrogen). In tetracycline-free medium, cells support high levels of HBV DNA replication and HBV virus secretion.
  • DMEM Dulbecco's modified Eagle's medium
  • Invitrogen 10% fetal bovine serum, 100 U/ml penicillin, and 100 ⁇ g/ml streptomycin, 0.5 mg/ml of G418 and ⁇ g/ml tetracycline.
  • HepDE19 cells were seeded into 96- well plates (3xl0 4 cells/well) with tetracyc line-free medium and incubated overnight at 37 °C.
  • the test or control compounds were serially half-log diluted with medium and added into the plates (the final concentration of DMSO kept at 0.5% in each well).
  • HepDE19 cells (5x10 J cells/well) were seeded into 96-well plates and compounds were treated as described above. Five days after treatment, cell viability was measured by addition of 20 ⁇ of CCK-8 reagent. Four hours after incubation at 37 °C, the absorbance at wavelengths of 450 nm and 630 nm (OD 450 and ⁇ 6 3 ⁇ ) was recorded by a plate reader. The 50% cytotoxic concentration (CC 50 ) of each compounds were determined accordingly.
  • the compounds of the present invention were tested for their capacity to inhibit a HBV activity and activation as described herein.
  • the Examples were tested in the above assay and found to have EC 50 of about 0.01 ⁇ to about 50 ⁇ .
  • Particular compounds of formula I were found to have EC 50 of about ⁇ . ⁇ to about 30 ⁇ .
  • a compound of formula I can be used in a manner known per se as the active ingredient for the production of tablets of the following composition:
  • a compound of formula I can be used in a manner known per se as the active ingredient for the production of capsules of the following composition:

Abstract

The invention provides novel compounds having the general formula (I): wherein R1, R2, R3, R4, R5, M and X are as described herein, compositions including the compounds and methods of using the compounds.

Description

Novel 4-methyl-dihydropyrimidines for the treatment and prophylaxis of hepatitis B virus infection
The present invention relates to organic compounds useful for therapy and/or prophylaxis in a human, and in particular to Hepatitis B virus (HBV) inhibitors by targeting on HBV capsid useful for treating HBV infection.
FIELD OF THE INVENTION
HBV is a species of the hepadnaviridae family of viruses. HBV is a serious public health problem worldwide, with more than 400 million people especially in Asia-pacific regions chronically infected by this small enveloped DNA virus. Although most individuals seem to resolve the infection following acute symptoms, 15-40% of HBV patients will finally develop clinical diseases during their lifespan, most notably, hepatitis, liver cirrhosis, and hepatocellular carcinoma. Every year 500,000 to 1 million people die from the end stage of liver diseases caused by HBV infection.
HBV lifecycle begins with the binding of the "Dane" particle with an unidentified receptor on the surface of hepatocyte. Following entry, viral genome is delivered into nucleus where a covalently closed circular DNA (cccDNA) is formed through DNA repair of viral relaxed circular DNA. Unlike the mechanisms of most other DNA viruses, HBV cccDNA replicates through the retrotranscription of a 1.1-genome unit-length RNA copy (pregenomic RNA). Viral pregenomic RNA interacts with other two viral components, capsid protein and polymerase, as well as some host factors, to form capsid particles where viral DNA replication occurs. Most copies of the encapsidated genome then efficiently associate with the envelope proteins for virion assembly and secretion; a minority of these genomes are shunted to the nucleus, where they are converted to cccDNA.
Currently, there are two types of anti-HBV agents on the market, nucleoside (tide) analogs targeting viral polymerase (lamivudine, adefovir, tenofovir, telbivudine and entecavir) and interferon modulating host immune functions. Mutations in the primary sequence of the polymerase that confer resistance to lamivudine and adefovir have been identified clinically and underlie a rebound of serum virus titers that 70% of treated patients experience within 3 years of the start of lamivudine therapy. Although resistance to telbivudine, adefovir, and entecavir occurs more rarely, it has been recorded. Interferon alpha is the other major therapy available for hepatitis B, but it is limited by a poor long-term response and debilitating side effects. Some viral genotypes do not show good responses to interferon therapy. Now, the standard of clinic cure of HBV infection is the loss and/or seroconversion of HBsAg. The majority (around or more than 90%) of treated patients fail to achieve this goal. This drawback is mainly due to the presence of a stable pool of viral cccDNA in nucleus that doesn't replicate itself, therefore, shows no accessibility to nucleoside (tide) analogs.
Hence, there is certainly a medical need for treatments with improved characteristics, and for a diversity of approaches in the development of therapies for HBV infection.
HBV capsid protein plays essential roles in HBV replication. HBV has an icosahedral core comprising of 240 copies of the capsid (or core) protein. The predominant biological function of capsid protein is to act as a structural protein to encapsidate pre-genomic RNA and form immature capsid particles in the cytoplasm. This step is prerequisite for viral DNA replication. The HBV capsid spontaneously self-assembles from many copies of core dimers present in the cytoplasm. It has been shown that the formation of a trimeric nucleus and the subsequent elongation reactions occur by adding one dimeric subunit at a time until it is complete. Besides this function, capsid protein regulates viral DNA synthesis through different phosphorylation status of its C-terminal phosphorylation sites. When a near full-length relaxed circular DNA is formed through reverse-transcription of viral pregenomic RNA, an immature capsid becomes a mature capsid. On one hand, capsid protein might facilitate the nuclear translocation of viral relaxed circular genome by means of the nuclear localization signals located in the Arginine-rich domain of the C-terminal region of capsid protein. In nucleus, as a component of viral cccDNA minichromosome, capsid protein could play a structural and regulatory role in the functionality of cccDNA minichromosomes. Capsid protein also interacts with viral large envelope protein in endoplasmic reticulum and triggers the release of intact viral particles from hepatocytes.
There has been a couple of capsid related anti-HBV inhibitors reported. For example, phenylpropenamide derivatives, including compounds named AT-61 and AT-130 (Feld J. et al. Antiviral Research 2007, 168-177), and a class of thiazolidin-4-ones from Valeant R&D
(WO2006/033995), have been shown to inhibit pgRNA packaging. A recent study suggested that phenylpropenamides are, in fact, accelerators of HBV capsid assembly, and their actions result in the formation of empty capsids. These very interesting results illustrate the importance of the kinetic pathway in successful virus assembly. Heteroaryldihydropyrimidines or HAP, including compounds named Bay 41-4109, Bay 38-7690 and Bay 39-5493, were discovered in a tissue culture-based screening (Deres K. et al. Science 2003, 893). These HAP analogs act as synthetic allosteric activators and are able to induce aberrant capsid formation that leads to degradation of the core protein. HAP analogs also reorganized core protein from preassembled capsids into noncapsid polymers, presumably by interaction of HAP with dimers freed during capsid 'breathing', the transitory breaking of individual intersubunit bonds. Bay 41-4109 was administered to HBV infected transgenic mouse or humanized mouse models and demonstrated in vivo efficacy with HBV DNA reduction (Deres K. et al. Science 2003, 893; Brezillon N. etal. PLoS ONE 2011, e25096.). It was also shown that bis- ANS, a small molecule that acts as a molecular 'wedge' and interferes with normal capsid- protein geometry and capsid formation (Zlotnick A. et al. J. Virol. 2002, 4848-4854).
SUMMARY OF THE INVENTION
Objects of the present invention are novel compounds of formula I, their manufacture, medicaments based on a compound in accordance with the invention and their production as well as the use of compounds of formula I for the treatment or prophylaxis of HBV infection.
DETAILED DESCRIPTION OF THE INVENTION
DEFINITIONS
As used herein, the term "Chalky!" alone or in combination signifies a saturated, linear- or branched chain alkyl group containing 1 to 6, particularly 1 to 4 carbon atoms, for example methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, ie/t-butyl and the like. Particular "Chalky!" groups are methyl, ethyl, isopropyl, ie/t-butyl. The term "cycloalkyl", alone or in combination, refers to a saturated carbon ring containing from 3 to 7 carbon atoms, particularly from 3 to 6 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Particular cycloalkyl groups are cyclopropyl, cyclopentyl and cyclohexyl.
The term "Ci-ealkoxy" alone or in combination signifies a group Ci^alkyl-O-, wherein the "Chalky!" is as defined above; for example methoxy, ethoxy, propoxy, isopropoxy, w-butoxy, i- butoxy, 2-butoxy, i-butoxy and the like. Particular Ci^alkoxy groups are methoxy and ethoxy and more particularly methoxy.
The term "C2_6alkoxy" alone or in combination signifies a group C2_6alkyl-0-, wherein the "C2_6alkyl" alone or in combination signifies a saturated, linear- or branched chain alkyl group containing 2 to 6, particularly 2 to 4 carbon atoms; for example ethoxy, propoxy, isopropoxy, n- butoxy, j-butoxy, 2-butoxy, i-butoxy and the like.
The term "C1_2alkoxy" alone or in combination refers to methoxy or ethoxy.
The term "CyH2y" alone or in combination signifies a saturated, linear- or branched chain alkyl group containing 1 to 6, particularly 1 to 4 carbon atoms. The term "amino", alone or in combination, refers to primary (-NH2), secondary (-NH-) or
/
N
tertiary amino ( ).
The term "carbonyl" alone or in combination refers to the group -C(O)-.
The term "carboxy" alone or in combination refers to the group -COOH.
The term "cyano" alone or in combination refers to the group -CN.
The term "halogen" means fluorine, chlorine, bromine or iodine. Halogen is particularly fluorine or chlorine, more particularly fluorine.
The term "hydroxy" alone or in combination refers to the group -OH.
The term "sulfonyl" alone or in combination refers to the group -S(0)2-.
The term "morpholinyl" alone or in combination refers to the group
The term "pyrrolidinyl" alone or in combination refers to the group
Figure imgf000005_0001
The term "piperidinyl" alone or in combination refers to the group The term "tautomers isomers" refers to constitutional isomers of organic compounds that readily interconvert by a chemical reaction called tautomerization. This reaction commonly results in the formal migration of a hydrogen atom or proton, accompanied by a switch of a single bond and adjacent double bond. For example, compounds of general formular (I)
Figure imgf000006_0001
The term "pharmaceutically acceptable salt" refers to conventional acid-addition salts or base-addition salts that retain the biological effectiveness and properties of the compounds of formula I and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases. Acid-addition salts include for example those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, and the like. Base-addition salts include those derived from ammonium, potassium, sodium and, quaternary ammonium hydroxides, such as for example, tetramethyl ammonium hydroxide. The chemical modification of a pharmaceutical compound into a salt is a technique well known to pharmaceutical chemists in order to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds. It is for example described in Bastin R.J., et. al., Organic Process Research & Development 2000, 4, 427-435; or in Ansel, H., et. al., In: Pharmaceutical Dosage Forms and Drug Delivery Systems, 6th ed. (1995), pp. 196 and 1456-1457. Particular are the sodium salts of the compounds of formula I.
Compounds of the general formula I which contain one or several chiral centers can either be present as racemates, diastereomeric mixtures, or optically active single isomers. The racemates can be separated according to known methods into the enantiomers. Particularly, diastereomeric salts which can be separated by crystallization are formed from the racemic mixtures by reaction with an optically active acid such as e.g. D- or L-tartaric acid, mandelic acid, malic acid, lactic acid or camphorsulfonic acid.
INHIBITORS OF HEPATITIS B VIRUS
The present invention provides (i) novel compounds having the general formula I:
Figure imgf000007_0001
wherein
R is C^alkoxycarbonyl or cyano;
R is phenyl, which is substituted by halogen;
R is thiazolyl, thienyl, imidazolyl, isoxazolyl or pyridinyl; which is unsubstituted or substituted by halogen or Ci-ealkyl;
X is oxygen or -NR7;
R4 and R5 are independently selected from hydrogen, Ci-6alkyl and trifluoroCi-ealkyl; or
R4 and R5, together with the carbon atom to which they are attached, form a 3 to 7 membered cycloalkyl; or when X is -NR7, one of R4 and R5 is hydrogen or C1-6alkyl, and the other one with the carbon atom to which it is attached and -NR , form a pyrrolidinyl, morpholinyl or piperidinyl ring, which ring is unsubstituted or substituted by fluoro;
M is Ci-ealkoxycarbonyl, carboxy, diCi-ealkylaminoC^ealkoxycarbonyl, aminocarbonyl, Ci-ealkylaminocarbonyl, diCi-ealkylaminocarbonyl, Ci-ealkylsulfonylaminocarbonyl, 2- 1 -6alkyl
Figure imgf000007_0002
thiazolylaminocarbonyl, hydroxy-CyH2y-, or
Figure imgf000007_0003
7
R is Ci-6alkyl or trifluoroCi-ealkyl; y is 1-6; or pharmaceutically acceptable salts, or tautomerism isomers thereof.
Another embodiment of present invention is (ii) a compound of formula I, wherein R1 is Ci^alkoxycarbonyl or cyano;
R is phenyl, which is once or twice substituted by halogen;
R is 2-thiazolyl, which is unsubstituted or once substituted by Ci-ealkyl or halogen; or 2- thienyl or 2-pyridinyl, which is once substituted by halogen; or 2-imidazolyl, which is once substituted by C^aUcyl; or 3-isoxazolyl, which is unsubstituted or once substituted by C^aUcyl;
X is oxygen or -NR7;
R4 and R5 are independently selected from hydrogen, Ci-ealkyl and trifluoroCi-ealkyl; or
R4 and R5, together with the carbon atom to which they are attached, form a 3 to 7 membered cycloalkyl; or when X is -NR7, one of R4 and R5 is hydrogen or C1-6alkyl, and the other one with the carbon atom to which it is attached and -NR together form a morpholinyl; or pyrrolidinyl or piperidinyl, which is substituted by fluoro;
M is Ci-ealkoxycarbonyl, carboxy, diCi-ealkylamino-Ci-ealkoxycarbonyl, aminocarbonyl, Ci-ealkylaminocarbonyl, diCi-ealkylaminocarbonyl, Ci-ealkylsulfonylaminocarbonyl, 2- 1 -6alkyl
thiazolylaminocarbonyl, hydroxy-C
Figure imgf000008_0001
yH2y-, , or
Figure imgf000008_0002
7
R is Ci-6alkyl or trifluoroCi-ealkyl; y is 1-6; or pharmaceutically acceptable salts, or tautomerism isomers thereof. Further embodiment of present invention is (iii) a compound of formula I, wherein
R1 is methoxycarbonyl, ethoxycarbonyl or cyano; R is phenyl substituted once or twice by fluoro;
Figure imgf000009_0001
X is oxygen or -NR7;
R4 and R5 are independently selected from hydrogen, methyl and trifluoromethyl; or
R4 and R5 together with the carbon atom to which they are attached form cyclopropyl; or hen X is -NR7, one of R4 and R5 is hydrogen or methyl, and the other one with the carbon atom
Figure imgf000009_0002
M is methoxycarbonyl, carboxy, dimethylaminoethoxycarbonyl, aminocarbonyl, dimethylaminocarbonyl, methylaminocarbonyl, methylsulfonylaminocarbon l, 2-
Figure imgf000009_0003
thiazol laminocarbonyl, hydroxymethyl, hydroxypropyl,
Figure imgf000009_0004
R is methyl or trifluoroethyl; or pharmaceutically acceptable salts, or tautomerism isomers thereof.
Another embodiment of present invention is (iv) a compound of formula I or a pharmaceutically acceptable salt or tautomerism isomers thereof, wherein
R1 is Ci^alkoxycarbonyl;
R is phenyl which is once substituted by halogen; R is 2-thiazolyl; X is oxygen; R4 and R5 are independently selected from hydrogen, Ci-6alkyl and trifluoroCi-ealkyl; M is Ci-ealkoxycarbonyl or carboxy.
Further embodiment of present invention is (v) a compound of formula I or a pharmaceutically acceptable salt or tautomerism isomers thereof, wherein
R1 is methyoxycarbonyl;
Figure imgf000010_0001
X is oxygen;
R4 and R5 are independently selected from hydrogen, methyl and trifluoromethyl;
M is methoxycarbonyl or carboxy.
Another embodiment of present invention is (vi) a compound of formula I or a pharmaceutically acceptable salt or tautomerism isomers thereof, wherein
R1 is Ci^alkoxycarbonyl;
R is phenyl which is once substituted by halogen; R is 2-thiazolyl;
X is -N-Ci-ealkyl or -N-trifluoroC1-6alkyl;
R4 is hydrogen; R5 is hydrogen; or R4 and R5, together with the carbon atom to which they are attached, form a 3 to 7 membered cycloalkyl;
M is carboxy.
Further embodiment of present invention is (vii) a compound of formula I or a pharmaceutically acceptable salt or tautomerism isomers thereof, wherein
R1 is methoxycarbonyl;
Figure imgf000011_0001
R4 is hydrogen; R5 is hydrogen; or R4 and R5, together with the carbon atom to which they are attached, form cyclopropyl;
M is carboxy.
Another embodiment of present invention is (viii) a compound of formula I or a pharmaceutically acceptable salt or tautomerism isomers thereof, wherein
R1 is Ci-ialkoxycarbonyl or cyano;
R is phenyl which is once or twice substituted by halogen;
R is 2-thiazolyl; or 2-pyridinyl, which is once substituted by halogen; or 2-imidazolyl, which is once substituted by C1-6alkyl; X is -NR7; one of R4 and R5 is hydrogen, and the other one with the carbon atom to which it is attached and -NR together form a morpholinyl;
M is C1-6alkoxycarbonyl, carboxy or hydroxy-CyH2y-; y is 1-6. Further embodiment of present invention is (ix) a compound of formula I or a pharmaceutically acceptable salt or tautomerism isomers thereof, wherein
R1 is methoxycarbonyl, ethoxycarbonyl or cyano;
Figure imgf000012_0001
one of R4 and R5 is h drogen, and the other one with the carbon atom to which it is
attached and -NR form
Figure imgf000012_0002
M is methoxycarbonyl, carboxy or hydroxymethyl-.
Another embodiment of present invention is (x) a compound of formula I or a pharmaceutically acceptable salt or tautomerism isomers thereof, wherein
R1 is Ci-ialkoxycarbonyl or cyano;
R is phenyl which is once or twice substituted by halogen;
R is 2-thiazolyl, which is unsubstituted or once substituted by Ci-6alkyl or halogen; or 2- thienyl or 2-pyridinyl, which is once substituted by halogen; or 2-imidazolyl, which is once substituted by C1-6alkyl; or 3-isoxazolyl, which is unsubstituted or once substituted by C1-6alkyl;
X is -NR7; one of R4 and R5 is hydrogen or Ci-6alkyl, and the other one with the carbon atom to which it is attached and -NR together form a pyrrolidinyl or piperidinyl, which is substituted by fluoro;
M is Ci-ealkoxycarbonyl, carboxy, diCi-ealkylaminoCi-ealkoxycarbonyl, aminocarbonyl, Ci-ealkylaminocarbonyl, diCi-ealkylaminocarbonyl, Ci-ealkylsulfonylaminocarbonyl, 2- 1 -6alkyl
thiazolylaminocarbonyl, hydroxy-CyH2y-,
Figure imgf000013_0001
Figure imgf000013_0002
y is 1-6.
Further embodiment of present invention is (xi) a compound of formula I or a pharmaceutically acceptable salt or tautomerism isomers thereof, wherein
R1 is methoxycarbonyl, ethoxycarbonyl or cyano;
Figure imgf000013_0003
X is -NR7; one of R4 and R5 is h carbon atom to which
it is attached and -NR form
Figure imgf000013_0004
M is methoxycarbonyl, carboxy, dimethylaminoethoxycarbonyl, aminocarbonyl, dimethylaminocarbonyl, methylaminocarbonyl, methylsulfonylaminocarbonyl, 2- hiazolylaminocarbonyl, hydroxymethyl, hydroxypropyl,
Figure imgf000014_0001
Figure imgf000014_0002
Another embodiment of present invention is (xii) a compound of formula Γ or a pharmaceutically acceptable salt or tautomerism isomers thereof,
Figure imgf000014_0003
wherein
R1 is Ci-ialkoxycarbonyl or cyano;
R is phenyl, which is substituted by halogen;
R is 2-thiazolyl which is unsubstituted or substituted by C^aUcyl or 2-pyridinyl, which is substituted by halogen;
X is oxygen or -NR7;
R4 and R5 are independently selected from hydrogen, Ci-ealkyl and trifluoroCi-ealkyl; or
R4 and R5, together with the carbon atom to which they are attached, form a 3 to 7 membered cycloalkyl; or when X is -NR7, one of R4 and R5 is hydrogen or C1-6alkyl, and the other one with the carbon atom to which it is attached and -NR together form a morpholinyl; or pyrrolidinyl substituted by fluoro;
R6 is hydrogen or Ci-6alkyl;
R7 is Ci-ealkyl. Further embodiment of present invention is (xiii) a compound of formula Γ or a pharmaceutically acceptable salt or tautomerism isomers thereof, wherein
R1 is methoxycarbonyl or cyano;
R is phenyl substituted once or twice by fluoro;
Figure imgf000015_0001
X is oxygen or -NR7;
R4 and R5 are independently selected from hydrogen, methyl and trifluoromethyl; or
R4 and R5 together with the carbon atom to which they are attached form cyclopropyl; or X is -NR7, one of R4 and R5 is hydrogen or methyl, and the other one with the carbon atom
to which it is attached and -NR form
Figure imgf000015_0002
R6 is hydrogen or methyl;
7
R is methyl.
Still further embodiment of present invention is (xiv) a compound of formula Γ or a pharmaceutically acceptable salt or tautomerism isomers thereof, wherein
R1 is Ci^alkoxycarbonyl;
R is phenyl which is substituted by halogen;
R is 2-thiazolyl;
X is oxygen; R4 and R5 are independently selected from hydrogen, Ci-6alkyl and trifluoroCi-ealkyl;
R6 is hydrogen or Ci-ealkyl.
More further embodiment of present invention is (xv) a compound of formula Γ or a pharmaceutically acceptable salt or tautomerism isomers thereof, wherein
R1 is methyoxycarbonyl;
Figure imgf000016_0001
oxygen;
R4 and R5 are independently selected from hydrogen, methyl and trifluoromethyl; R6 is hydrogen or methyl.
Another further embodiment of present invention is (xvi) a compound of formula Γ or a pharmaceutically acceptable salt or tautomerism isomers thereof, wherein
R1 is Ci^alkoxycarbonyl;
R is phenyl which is substituted by halogen;
R is 2-thiazolyl;
X is NCi-ealkyl;
R4 and R5, together with the carbon atom to which they are attached, form a 3 to 7 membered cycloalkyl;
R6 is hydrogen.
Further embodiment of present invention is (xvii) a compound of formula Γ or a pharmaceutically acceptable salt or tautomerism isomers thereof, wherein
R1 is methoxycarbonyl;
Figure imgf000016_0002
X is -NCH3;
R4 and R5, together with the carbon atom to which they are attached, form cyclopropyl; R6 is hydrogen.
More further embodiment of present invention is (xviii) a compound of formula Γ or a pharmaceutically acceptable salt or tautomerism isomers thereof, wherein
R1 is Ci^alkoxycarbonyl or cyano;
R is phenyl which is substituted by halogen;
R is 2-thiazolyl; or 2-pyridinyl, which is substituted by halogen;
X is -NR7; one of R4 and R5 is hydrogen or Ci-6alkyl, and the other one with the carbon atom to which it is attached and -NR together form a morpholinyl;
R6 is hydrogen or Ci-ealkyl.
Further embodiment of present invention is (xix) a compound of formula Γ or a pharmaceutically acceptable salt or tautomerism isomers thereof, wherein
R1 is methoxycarbonyl or cyano;
R
Figure imgf000017_0001
is , * oonnee ootf R"* aannad κ R~D i iss n hyyadrroojgen or methyl, and the other one
with the carbon atom to which it is attached and -NR7 form
Figure imgf000017_0002
; R6 is hydrogen or methyl.
Still further embodiment of present invention is (xx) a compound of formula Γ or a pharmaceutically acceptable salt or tautomerism isomers thereof, wherein
R1 is Ci-ialkoxycarbonyl or cyano;
R is phenyl which is substituted by halogen; R is 2-thiazolyl which is unsubstituted or substituted by Ci-6alkyl or 2-pyridinyl, which is substituted by halogen;
X is -NR7; one of R4 and R5 is hydrogen or Ci-6alkyl, and the other one with the carbon atom to which it is attached and -NR together form a pyrrolidinyl which is substituted by fluoro;
R6 is hydrogen or Ci-ealkyl.
Another further embodiment of present invention is (xxi) a compound of formula Γ or a pharmaceutically acceptable salt or tautomerism isomers thereof, wherein
R1 is methoxycarbonyl or cyano;
Figure imgf000018_0001
X is -NR7; one of R4 and R5 is h methyl, and the other one with the carbon atom to which
7
it is attached and -NR form
Figure imgf000018_0002
R6 is hydrogen or methyl.
Particular compounds of formula I, including their activity data, NMR data and MS data are summarized in the following Table 1 and 2.
Table 1 : Structure, name and activity data of particular compounds
HepDel9
Example CC50
Structure Name EC50 No. (μΜ)
(μΜ)
Figure imgf000019_0001
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
Table 2: NMR and MS data of particular compounds
Example
IH NMR data MW
No.
IH NMR (MeOD-d4, 400MHz), 7.95 (d, IH, J = 3.2
Hz), 7.75 (d, IH, J = 3.2 Hz), 7.49-7.45 (m, 2H), 7.04 MS: calc'd 462 (MH+),
1
(t, 2H, J = 8.8 Hz), 4.71-4.62 (m, 2H), 3.80 (s, 3H), exp 462 (MH+).
3.43 (s, 3H), 1.92 (s, 3H), 1.57 (s, 6H).
IH NMR (MeOD-d4, 400MHz), 7.94 (d, IH, J = 2.8 MS: calc'd 488 (MH+),
2 Hz), 7.93 (d, IH, J = 2.8 Hz), 7.53-7.49 (m, 2H), 7.07- exp 488 (MH+).
7.03 (m, 2H), 4.85-4.78 (m, 2H), 4.40-4.37 (m, IH), 3.44 (s, 3H), 1.94 (s, 3H).
IH NMR (MeOD-d4, 400MHz), 8.12 (d, IH, J = 3.2
Hz), 8.06 (d, IH, J = 3.2 Hz), 7.63-7.60 (m, 2H), 7.15
MS: calc'd 459 (MH+), (t, 2H, J = 8.8 Hz), 4.30 (s, 2H), 3.51 (s, 3H), 2.79 (s,
exp 459 (MH+).
3H), 2.10 (s, 3H), 1.52-1.51 (m, 2H), 1.38-1.37 (m,
2H).
IH NMR (CD30D, 500 MHz) δ 8.10 (d, IH), 8.03 (d,
IH), 7.64-7.61 (m, 2H), 7.15-7.12 (m, 2H), 4.32-4.31 LC-MS: calc'd 475 (m, 2H), 4.18-4.14 (m, 2H), 3.99-3.72 (m, 3H), 3.51- (MH+), exp 475 (MH+). 3.49 (m, 4H), 3.02 (m, IH), 2.11 (d, 3H).
IH NMR (MeOD-d4, 400 MHz), 7.95 (d, IH, J = 3.2
Hz), 7.74 (d, IH, J = 3.2 Hz), 7.48-7.45 (m, 2H), 7.03
MS: calc'd (MH+) 489 (t, 2H, J = 8.8 Hz), 4.05-3.87 (m, 4H), 3.78-3.71 (m,
exp (MH+) 489.
5H), 3.49-3.45 (m, IH), 3.42 (s, 3H), 3.14-3.07 (m,
IH), 2.52-2.42 (m, IH), 1.99 (s, 3H).
IH NMR (MeOD-d4, 400 MHz), 7.95 (d, IH, J = 3.2
Hz), 7.74 (d, IH, J = 3.2 Hz), 7.48-7.45 (m, 2H), 7.03
MS: calc'd (MH+) 475 (t, 2H, J = 8.8 Hz), 4.35-4.21 (m, 2H), 4.17-4.05 (m,
exp (MH+) 475.
2H), 3.96-3.84 (m, 2H), 3.75-3.70 (m, IH), 3.58- 3.47 (m, 4H), 2.97-2.89 (m, IH), 1.99 (s, 3H).
IH NMR (MeOD-d4, 400 MHz), 8.07 (d, IH, J = 3.2
Hz), 7.97 (d, IH, J = 3.2 Hz), 7.62-7.59 (m, 2H), 7.13
MS: calc'd (MH+) 475 (t, 2H, J = 8.8 Hz), 4.31 (s, 2H), 4.17-4.05 (m, 2H),
exp (MH+) 475.
3.96-3.84 (m, 3H), 3.62-3.55 (m, IH), 3.51 (s, 3H),
3.03-2.99 (m, IH), 2.09 (s, 3H).
IH NMR (MeOD-d4, 400 MHz), 8.07 (d, IH, J = 3.2
Hz), 7.97 (d, IH, J = 3.2 Hz), 7.62-7.59 (m, 2H), 7.13
MS: calc'd (MH+) 475 (t, 2H, J = 8.8 Hz), 4.28 (dd, 2H, Jl = 33.4 Hz, J2 =
exp (MH+) 475.
16.4 Hz), 4.17-4.05 (m, 2H), 3.96-3.84 (m, 3H), 3.62- 3.50 (m, 4H), 3.03-2.99 (m, IH), 2.09 (s, 3H).
IH NMR (MeOD-d4, 400 MHz), 8.60 (d, IH, J = 2.8
Hz), 8.53-8.50 (m, IH), 7.80-7.78 (m, IH), 7.59-7.56
(m, 2H), 7.11-7.07 (m, 2H), 4.11-4.01 (m, 3H), 3.99- MS: calc'd (MH+) 487 3.97 (m, IH), 3.88-3.84 (m, IH), 3.82-3.80 (m, IH), exp (MH+) 487.
3.59-3.56 (m, IH), 3.49 (s, 3H), 3.44-3.38 (m, IH),
2.89-2.80 (m, IH), 2.05 (s, 3H).
IH NMR (MeOD-d4, 400 MHz), 8.60 (d, IH, J = 2.8
Hz), 8.55-8.53 (m, IH), 7.83-7.79 (m, IH), 7.60-7.57
(m, 2H), 7.13-7.08 (m, 2H), 4.17-4.08 (m, 3H), 4.01- MS: calc'd (MH+) 487 3.97 (m, IH), 3.91-3.84 (m, IH), 3.82-3.80 (m, IH), exp (MH+) 487.
3.60-3.58 (m, IH), 3.50 (s, 3H), 3.44-3.38 (m, IH),
2.89-2.80 (m, IH), 2.06 (s, 3H).
IH NMR (CD30D, 500 MHz) δ 8.15-8.15 (m, 2H),
7.67-7.62 (m, 2H), 7.19-7.14 (m, 2H), 4.16-3.90 (m, LC-MS: calc'd 495 3H), 3.65-3.61 (m, IH), 3.51 (d, 3H), 3.25-3.20 (m, (MH+), exp 495 (MH+). IH), 2.86-2.82 (m, IH), 2.63-2.61 (m, IH), 2.15 (d, 3H).
IH NMR (CD30D, 500 MHz) δ 7.96 (s, IH), 7.77 (s,
IH), 7.52 (d, 2H), 7.06 (d, 2H), 4.00-3.95 (m, 3H), LC-MS: calc'd 495 3.63-3.61 (m, IH), 3.46 (s, 3H), 3.20-3.18 (m, (MH+), exp 495 (MH+). 1H),2.79 (m, IH), 2.67 (m, IH), 1.95 (s, 3H).
IH NMR (MeOD-d4, 400 MHz), 8.21 (s, 2H), 7.67- 7.65 (m, 2H), 7.21-7.17 (m, 2H,), 4.16 (d, IH, J = 15.6
MS: calc'd (MH+) 495 Hz), 4.02 (t, IH, J = 8.0 Hz), 3.93 (d, IH, J = 15.6 Hz),
exp (MH+) 495.
3.72-3.61 (m, IH), 3.53 (s, 3H), 3.29-3.19 (m, IH),
2.91-2.78 (m, IH), 2.59-2.55 (m, IH), 2.17 (s, 3H).
IH NMR (MeOD-d4, 400 MHz), 8.11 (d, IH, J = 3.2
Hz), 8.04 (d, IH, J = 3.2 Hz), 7.55-7.49 (m, IH), 7.40- 7.38 (m, IH), 7.34-7.29 (m, IH,), 4.15 (d, IH, J = 15.6 MS: calc'd (MH+) 513.1, Hz), 4.02 -3.98(m, 2H), 3.74-3.61 (m, IH), 3.53 (s, exp (MH+) 513.1 3H), 3.30-3.23 (m, IH), 2.91-2.78 (m, IH), 2.65-2.49
(m, IH), 2.08 (s, 3H).
IH NMR (MeOD-d4, 400 MHz), 8.17 (d, IH, J = 3.2
Hz), 8.10 (d, IH, J = 3.2 Hz), 7.62-7.53 (m, IH), 7.45- 7.39 (m, IH), 7.37-7.25 (m, IH,), 4.25-4.18 (m, 2H), MS: calc'd (MH+) 507, 4.10-4.06(m, 2H), 3.96-3.94 (m, IH), 3.89-3.86 (m, exp (MH+) 507.
2H), 3.84 (s, 3H), 3.55 (s, 3H), 3.50-3.40 (m, IH),
2.90-2.87 (m, IH), 2.08 (s, 3H).
IH NMR (MeOD-d4, 400 MHz), 8.06 (d, IH, J = 3.2
Hz), 7.95 (d, IH, J = 3.2 Hz), 7.53-7.51 (m, IH), 7.40-
MS: calc'd (MH+) 493 7.37 (m, IH), 7.31-7.25 (m, IH,), 4.39-4.28 (m, 2H),
exp (MH+) 493.
4.15-4.12 (m, 2H), 3.58-3.50 (m, 4H), 3.05-3.01 (m,
IH), 2.05 (s, 3H).
IH NMR (MeOD-d4, 400 MHz), 8.80 (d, IH, J = 2.8
Hz), 8.43-8.40 (m, IH), 8.01-7.98 (m, IH), 7.70-7.66
(m, 2H), 7.24-7.18 (m, 2H), 4.16-3.94 (m, 3H), 3.84- MS: calc'd (MH+) 521 3.83 (m, 3H), 3.61-3.55 (m, 4H), 3.22-3.18 (m, IH), exp (MH+) 521
2.91-2.78 (m, IH), 3.61-3.48 (m, IH), 2.24-2.21 (m,
3H).
IH NMR (MeOD-d4, 400 MHz), 8.77 (d, IH, J = 2.8
Hz), 8.46-8.42 (m, IH), 8.00-7.95 (m, IH), 7.70-7.66
(m, 2H), 7.23-7.19 (m, 2H), 4.16 (d, IH, J = 16 Hz), MS: calc'd (MH+) 507 3.98 (t, IH, J = 8.8 Hz), 3.88 (d, IH, J = 16 Hz), 3.60- exp (MH+) 507.
3.56 (m, 4H), 3.28-3.15 (m, IH), 2.93-1.79 (m, IH),
2.58-44 (m, IH), 2.21 (s, 3H).
lH NMR (400 MHz, MeOH-d4) 7.87 (s, 1 H), 7.47 - 7.51 (m, 2 H), 7.01 - 7.06 (m, 2 H), 3.92 - 4.30 (m, 2 MS: calc'd (MH+) 509 H), 3.49 (s, 3 H), 3.40 (m, 2H), 2.35 - 2.90 (m, 3 H), exp (MH+) 509.
2.36 (s, 3 H), 1.85 (s, 3 H).
1H NMR (400 MHz, MeOH-d4) 8.02 - 8.18 (m, 2 H), MS: calc'd (MH+) 509 7.54 - 7.65 (m, 2 H), 7.08 - 7.20 (m, 2 H), 3.88 - 4.14 exp (MH+) 509.
(m, 2 H), 3.49 (s, 3 H), 2.75 - 2.90 (m, 2 H), 2.41 - 2.57 (m, 2 H), 2.09 (s, 3 H), 1.56 (s, 3 H).
IH NMR (MeOD-d4, 400 MHz), 7.98 (d, IH, J = 3.2
Hz), 7.81 (d, IH, J = 3.2 Hz), 7.57-7.53 (m, 2H), 7.14
MS: calc'd (M++H) 462, (t, 2H, J = 8.8 Hz), 3.92-3.74 (m, 3H), 3.49-3.41 (m,
exp (M++H) 462.
IH), 3.18-3.08 (m, IH), 2.81-2.69 (m, IH), 2.55- 2.49 (m, IH), 1.89 (s, 3H).
IH NMR (MeOD-d4, 400 MHz), 8.03 (d, IH, J = 3.2
Hz), 7.88 (d, IH, J = 3.2 Hz), 7.45-7.42 (m, IH), 7.36- MS: calc'd (MH+) 460 7.30 (m, 2H), 4.16-4.01(m, 4H), 3.96-3.82 (m, 3H), exp (MH+) 460.
3.43-3.37 (m, IH), 2.93-2.86 (m, IH), 1.92 (s, 3H).
IH NMR (MeOD-d4, 400 MHz), 7.98 (d, IH, J = 3.2
Hz), 7.81 (d, IH, J = 3.2 Hz), 7.44-7.39 (m, IH), 7.35-
MS: calc'd (MH+) 480 7.27 (m, 2H), 3.92-3.74 (m, 3H), 3.49-3.41 (m, IH),
exp (MH+) 480.
3.18-3.08 (m, IH), 2.81-2.69 (m, IH), 2.52-2.46 (m,
IH), 1.86 (s, 3H).
1H NMR (MeOD-d4, 400 MHz), 7.95 (d, / = 3.01 Hz,
1 H), 7.73 (d, / = 3.26 Hz, 1 H), 7.37 (ddd, / = 12.17,
7.78, 1.88 Hz, 1 H), 7.28 (br. s., 1 H), 7.17- 7.26 (m, 1
MS: calc'd (MH+) 527 H), 3.85 - 4.06 (m, 4 H) 3.69 (t, J=8.16 Hz, 1 H) 3.48 - exp (MH+) 527.
3.61 (m, 1 H) 2.99 - 3.18 (m, 1 H) 2.61 - 2.78 (m, 1 H)
2.39 - 2.58 (m, 1 H) 1.89 (s, 3 H)1.04 (t, / = 7.03 Hz, 3
H).
1H NMR (MeOD-d4, 400 MHz), 8.25 (s, 2 H), 7.58 - 7.75 (m, 2 H), 7.19 (t, / = 8.66 Hz, 2 H), 3.93 - 4.19
MS: calc'd (MH+) 509 (m, 2 H), 3.75 (d, / = 1.25 Hz, 1 H), 3.53 (s, 3 H), 3.35
exp (MH+) 509.
-3.46 (m, 1 H), 2.88 - 3.10 (m, 1 H), 1.85 - 2.41 (m, 7
H).
lH NMR (MeOD-d4, 400 MHz), 7.97 (d, / = 3.01 Hz,
1 H), 7.72 (d, / = 3.01 Hz, 1 H), 7.49 (dd, / = 8.66,
5.40 Hz, 2 H), 7.04 (t, / = 8.78 Hz, 2 H), 3.72- 3.87 MS: calc'd (MH+) 509 (m, 2 H), 3.44 (s, 3 H), 3.25 - 3.31 (m, 1 H), 3.14 (d, / exp (MH+) 509.
= 12.05 Hz, 1 H), 2.47 - 2.60 (m, 1 H), 1.97 - 2.41 (m,
4 H), 1.89 (s, 3 H).
lH NMR (MeOD-d4, 400 MHz), 7.53 (dd, / = 8.66,
5.40 Hz, 2 H), 7.19 (s, 1 H), 6.98 - 7.11 (m, 3 H), 3.77
- 3.96 (m, 5 H), 3.51 - 3.65 (m, 2 H), 3.46(s, 3 H), 3.01 MS: calc'd (MH+) 492 (td, / = 15.12, 11.42 Hz, 1 H), 2.64 (qd, / = 12.84, exp (MH+) 492.
8.16 Hz, 1 H), 2.32 - 2.50 (m, 1 H), 1.84 - 2.00 (m, 3
H). lH NMR (MeOD-d4, 400 MHz), 7.95 (d, J = 3.01 Hz,
1 H), 7.72 (d, J = 3.26 Hz, 1 H), 7.36 (ddd, J = 12.30,
7.78, 2.26 Hz, 1 H), 7.27 (br. s., 1 H), 7.21(dd, J =
MS: calc'd (MH+) 527 10.29, 8.28 Hz, 1 H), 3.80 - 4.02 (m, 4 H), 3.44 - 3.58
exp (MH+) 527.
(m, 2 H), 2.87 (td, J = 15.56, 11.04 Hz, 1 H), 2.54 - 2.73 (m, 1 H), 2.35 - 2.52 (m, 1 H), 1.89 (s, 3 H), 1.03
(t, J = 7.03 Hz, 3 H).
1H NMR (MeOD-d4, 400 MHz), 8.10 (d, J = 2.76 Hz,
1 H), 7.99 - 8.06 (m, 1 H), 7.52 - 7.63 (m, 1 H), 7.44
(d, J = 7.03 Hz, 1 H), 7.22 - 7.38 (m, 1 H), 5.36 (t, J = MS: calc'd (MH+) 507 4.64 Hz, 1 H), 4.30 - 4.54 (m, 2 H), 4.09 - 4.22 (m, 3 exp (MH+) 507.
H), 3.86 - 4.06 (m, 4 H), 3.55 - 3.73 (m, 1 H), 1.98 - 2.15 (m, 3 H), 0.92 (t, J = 6.78 Hz, 3 H).
1H NMR (MeOD-d4, 400 MHz), 7.52 (dd, J = 8.66,
5.40 Hz, 2 H), 7.21 (s, 1 H), 6.98 - 7.11 (m, 3 H), 3.72 MS: calc'd (MH+) 472 - 4.06 (m, 10 H) 3.48 (s, 3 H), 3.12 - 3.23 (m, 1 H), exp (MH+) 472.
2.61 (ddd, J = 11.54, 8.16, 3.14 Hz, 1 H), 1.93 (s, 3 H). lH NMR (CDC13, 400 MHz), 7.47 - 7.59 (m, 2 H),
7.18 (s, 1 H), 7.01 - 7.12 (m, 2 H), 4.12 (d, J = 14.56
Hz, 1 H), 3.98 (dd, J = 9.79, 6.02 Hz, 1 H), 3.61 (d, J = MS: calc'd (MH+) 509 14.31 Hz, 1 H), 3.53 (d, J = 10.54 Hz, 1 H), 3.47 (s, 3 exp (MH+) 509.
H), 3.12 (br. s., 1 H), 2.71 - 2.90 (m, 1 H), 2.50 - 2.67
(m, 1 H), 2.46 (s, 3 H), 1.98 - 2.07 (m, 3 H).
lH NMR (CDCI3, 400 MHz), 7.49 - 7.61 (m, 2 H),
7.17 (s, 1 H), 7.05 - 7.13 (m, 2 H), 4.14 (d, J = 14.31
Hz, 1 H), 3.92 (dd, J = 9.66, 6.15 Hz, 1 H), 3.49 - 3.58 MS: calc'd (MH+) 509 (m, 2 H), 3.47 (s, 3 H), 3.18 - 3.33 (m, 1 H), 2.81 (dd, exp (MH+) 509.
J = 14.68, 9.66 Hz, 1 H), 2.57 (dd, J = 12.30, 6.02 Hz,
1 H), 2.46 (s, 3 H), 2.01 (s, 3 H).
1H NMR (CDCI3, 400 MHz), 7.71 (s, 1 H), 7.41 - 7.58
(m, 2 H), 7.00 - 7.17 (m, 2 H), 4.12 - 4.21 (m, 1 H),
MS: calc'd (MH+) 529 3.93 - 4.03 (m, 1 H), 3.70 - 3.78 (m, 1 H), 3.54 (s, 4
exp (MH+) 529.
H), 3.15 - 3.30 (m, 1 H), 2.75 - 2.90 (m, 1 H), 2.52 - 2.69 (m, 1 H), 2.15 (s, 3 H).
1H NMR (MeOD-d4, 400 MHz), 7.93 - 8.01 (m, 1 H),
7.79 - 7.89 (m, 1 H), 7.55 - 7.67 (m, 2 H), 7.06 - 7.17
MS: calc'd (MH+) 477 (m, 2 H), 5.45 - 5.58 (m, 1 H), 5.31 - 5.45 (m, 1 H),
exp (MH+) 477.
3.81 - 4.12 (m, 2 H), 3.48 (s, 3 H), 2.70 - 2.94 (m, 2
H), 2.31 - 2.55 (m, 2 H), 1.96 - 2.10 (m, 3 H). 1H NMR (MeOD-d4, 400 MHz), 8.80 - 8.87 (m, 1 H),
7.48 - 7.59 (m, 2 H), 7.10 (s, 3 H), 3.77 - 4.10 (m, 3
MS: calc'd (MH+) 479 H), 3.48 - 3.62 (m, 1 H), 3.46 (d, J = 4.27 Hz, 3 H),
exp (MH+) 479.
3.00 - 3.23 (m, 1 H), 2.70 - 2.87 (m, 1 H), 2.42 - 2.64
(m, 1 H), 1.98 (d, J = 3.51 Hz, 3 H).
1H NMR (MeOD-d4, 400 MHz), 8.14 - 8.17 (m, 1 H),
8.10 - 8.13 (m, 1 H), 7.58 - 7.65 (m, 2 H), 7.11 - 7.19
MS: calc'd (MH+) 509 (m, 2 H), 3.99 - 4.06 (m, 2 H), 3.52 (s, 4 H), 3.35 - exp (MH+) 509.
3.38 (m, 1 H), 2.75 - 2.89 (m, 1 H), 2.41 - 2.56 (m, 1
H), 2.12 (s, 3 H), 1.56 (s, 3 H).
1H NMR (MeOD-d4, 400 MHz), 7.62 (s, IH), 7.50 (dd,
J = 5.40, 8.66 Hz, 2H), 7.05 (t, J = 8.78 Hz, 2H), 3.90
MS: calc'd (MH+) 509 (d, J = 5.77 Hz, 2H), 3.65 (t, J = 8.28 Hz, IH), 3.39 - exp (MH+)509.
3.58 (m, 7H), 3.05 (d, J = 11.54 Hz, IH), 2.68 (dd, J =
7.91, 13.18 Hz, IH), 2.48 - 2.58 (m, 4H).
1H NMR (MeOD-d4, 400MHz), 7.62 (t, J = 3.9 Hz, 1
H), 7.46 (dd, J = 8.7, 5.4 Hz, 2 H), 7.02 (t, J = 8.8 Hz,
2 H), 6.59 (dd, J = 4.3, 1.8 Hz, 1 H),3.86 (d, J = 14.3 MS: calc'd (MH+)512 Hz, 2 H), 3.75 (t, J = 6.5 Hz, 1 H), 3.41 - 3.62 (m, 6 exp (MH+) 512 . H), 3.06 (q, J = 7.3 Hz, 2 H), 2.61 (dd, J = 16.1, 7.5
Hz, 1 H), 2.26 - 2.45 (m, 1 H).
1H NMR (MeOD-d4, 400MHz), 7.96 (d, J = 3.0 Hz, 1
H), 7.85 (d, J = 3.3 Hz, 1 H), 7.65 (dd, J = 8.8, 5.3 Hz,
2 H), 7.13 (t, J = 8.8 Hz, 2 H), 5.29 - 5.52 (m, 1 H), MS: calc'd (MH+)477 4.62 (d, J = 14.1 Hz, 1 H), 4.39 (d, J = 9.5 Hz, 1 H), exp (MH+) 477 . 4.08 - 4.27 (m, 2 H), 3.44 - 3.69 (m, 5 H), 2.54 - 2.97
(m, 3 H).
1H NMR (MeOD-d4, 400MHz), 7.51 (dd, J = 8.2, 5.4
Hz, 2 H), 7.06 (q, J = 8.8 Hz, 2 H), 6.61 (d, J = 4.0 Hz,
MS: calc'd (MH+)493 1 H), 3.72 - 3.96 (m, 2 H), 3.40 - 3.63 (m, 6 H), 2.82 - exp (MH+) 493 . 3.12 (m, 2 H), 2.57 - 2.76 (m, 1 H), 2.35 - 2.52 ppm
(m, 5 H).
1H NMR (CDC13, 400 MHz), 7.53 (m, 2H), 7.43 (m,
IH), 7.08 (m, 2H), 6.85 (d, IH, J = 5.6 Hz), 4.08 (d,
MS: calc'd (MH+) 512 IH, J = 14.2 Hz), 3.86 (IH, m), 3.57 (d, IH, J = 14.2
exp (MH+) 512.
Hz), 3.50 (IH, m), 3.45 (3H, s), 3.20 (IH, m), 2.77
(IH, m), 2.54 (IH, m), 1.97 (3H, s). 1H NMR (CDC13, 400 MHz), 7.52 (m, 2H), 7.42
(m,lH), 7.06 (m, 2H), 6.84 (d, IH, J = 5.6 Hz), 4.05
MS: calc'd (MH+) 512 (d, IH, J = 14.2 Hz), 3.91 (m, IH), 3.64 (d, IH, J =
exp (MH+) 512.
14.2 Hz), 3.47 (m, IH), 3.45 (3H, s), 3.10 (m, IH),
2.78 (m, IH), 2.55 (m, IH), 1.98 (s, 3H).
1H NMR (CDCI3, 400 MHz), 7.70 (s, IH), 7.45 (m,
2H), 7.00 (m, 3H), 4.07 (d, IH, J = 15.0 Hz), 3.72 (m, MS: calc'd (MH+) 512 IH), 3.55 (s, 3H), 3.54-3.34 (m, 2H), 3.07 (m, IH), exp (MH+) 512.
2.68 (m, IH), 2.32 (m, IH), 2.01 (s, 3H).
1H NMR (MeOD-d4, 400 MHz),7.95 (d, J = 3.26 Hz, 1
H), 7.75 (d, J = 3.26 Hz, 1 H), 7.44 - 7.54 (m, 2 H), MS: calc'd (MH+) 501 7.05 (t, J = 8.78 Hz, 2 H), 3.90 - 4.09 (m, 2H), 3.63 (s, exp (MH+) 501.
2 H), 3.45 (s, 3 H), 1.91 (s, 3 H).
1H NMR (MeOD-d4, 400 MHz), 8.23 (d, J = 0.75 Hz,
2 H), 7.61 - 7.70 (m, 2 H) ,7.19 (t, J = 8.66 Hz, 2 H),
4.06 - 4.16 (m, 1 H), 4.02 (t, J = 8.03 Hz, IH), 3.92 (d, MS: calc'd (MH+) 509 J = 15.81 Hz, 1 H), 3.82 (s, 3 H), 3.59 (d, J = 10.79 exp (MH+) 509.
Hz, 1 H), 3.53 (s, 3 H), 3.12 - 3.28 (m, 1 H), 2.72 - 2.89 (m, 1 H), 2.43 - 2.61 (m, 1 H), 2.16 (s, 3 H).
1H NMR (MeOD-d4, 400 MHz), 7.94 (d, J = 3.01 Hz,
1 H), 7.74 (d, J = 3.01 Hz, 1 H), 7.49 (br. s., 2 H), 7.05
MS: calc'd (MH+) 566 (t, J = 8.78 Hz, 2 H), 4.33 (t, J = 5.65 Hz, 2 H), 3.94
exp (MH+) 566.
(s, 3 H), 3.42 - 3.56 (m, 5 H), 2.66 - 2.82 (m, 4 H),
2.33 (s, 6 H), 1.90 (s, 3 H).
1H NMR (MeOD-d4, 400 MHz), 7.95 (br. s., 1 H) 7.69
- 7.84 (m, 1 H) 7.61 (dd, J = 8.28, 5.52 Hz, 1 H) 7.48
MS: calc'd (MH+) 494 (dd, J = 8.03, 5.52 Hz, 1 H) 6.99 - 7.17(m, 2 H) 3.39 - exp (MH+) 494.
3.88 (m, 6 H) 2.91 - 3.30 (m, 2 H) 2.62 - 2.86 (m, 1 H)
2.22 - 2.53 (m, 1 H) 1.81 - 2.02 (m, 3 H).
1H NMR(MeOD-d4, 400 MHz), 8.13 - 8.00 (m, 1 H)
7.98 - 7.82 (m, 1 H) 7.59 (br. s., 2 H) 7.13 (s, 2 H)
MS: calc'd (MH+) 494 3.96 - 3.82 (m, 1 H) 3.80 -3.64 (m, 2 H) 3.62 - 3.44
exp (MH+) 494.1. (m, 4 H) 3.24 - 3.07 (m, 1 H) 2.84 - 2.66 (m, 1 H) 2.49
- 2.26 (m, 1 H) 2.02 (s, 3 H). 1H NMR(MeOD-d4, 400 MHz), 8.10 -7.98 (m, 1 H)
7.94 - 7.76 (m, 1 H) 7.62 - 7.43 (m, 2 H) 7.10 (s, 2 H)
MS: calc'd (MH+) 522 4.27 (s, 1 H) 3.95 (s, 1 H) 3.76 -3.53 (m, 2 H) 3.47 (s,
exp (MH+) 522.0. 3 H) 3.09 (s, 4 H) 3.00 (s, 3 H) 2.91 - 2.75 (m, 1 H)
2.43 - 2.21 (m, 1 H) 1.97 (s, 3 H).
1H NMR(MeOD-d4, 400 MHz), 8.05 - 7.89 (m, 1 H)
7.87 - 7.69 (m, 1 H) 7.66 - 7.33 (m, 2 H) 7.07 (br. s., 2
MS: calc'd (MH+) 508 H) 3.92 - 3.59 (m, 3 H) 3.57 - 3.39 (m, 4 H) 3.27 - exp (MH+) 508.2. 2.95 (m, 1 H) 2.90 - 2.58 (m, 4 H) 2.39 -2.23 (m, 1 H)
2.02 - 1.77 (m, 3 H). lH NMR(MeOD-d , 400 MHz), 8.14 - 8.03 (m, 1 H)
8.00 - 7.91(m, 1 H) 7.65 - 7.51 (m, 2 H) 7.11 (s, 2 H)
4.03 - 3.81 (m, 3 H) 3.63 (d, J = 11.04 Hz, 1 H) 3.50 MS: calc'd (MH+) 572 (s, 3 H) 3.28 - 3.10 (m, 1 H) 291 - 2.73 (m, 1 H) 2.68 exp (MH+) 572.2. (s, 3 H) 2.49 (qd, J = 14.01, 7.15 Hz, 1 H) 2.06 (s, 3
H).
1H NMR(MeOD-d4, 400 MHz), 8.00 -7.84 (m, 1 H)
7.82 - 7.62 (m, 1 H) 7.60 - 7.29(m, 3 H) 7.13 (br. s., 1
MS: calc'd (MH+) 577 H) 7.03 (br. s., 2 H) 4.10 - 3.76 (m, 3 H) 3.72 -3.55 (m,
exp (MH+) 577.3. 1 H) 3.45 (s, 3 H) 3.25 - 3.08 (m, 1 H) 2.95 - 2.73 (m,
1 H) 2.63 - 2.35 (m, 1 H) 1.97 - 1.64 (m, 3 H).
1H NMR (MeOD-d4, 400 MHz), 7.86 - 8.06 (m, 2 H)
7.63 (dd, J = 8.53, 5.27 Hz, 2 H) 7.13 (t, J = 8.16 Hz, 2
MS: calc'd (MH+) 461 H) 4.41 - 4.73 (m, 2 H) 4.02 - 4.24 (m,2 H) 3.87 - 3.98
exp (MH+) 461.
(m, 3 H) 3.72-3.65 (m, 2 H) 3.35 - 3.55 (m, 5 H) 2.09
(d, J = 4.52 Hz, 3 H).
1H NMR (CDC13, 400 MHz), 7.81 - 7.91 (m, 1 H),
7.38 - 7.66 (m, 3 H), 7.03 (br. s., 2 H), 4.10 - 4.28 (m,
1 H), 3.88 - 4.09 (m, 1 H), 3.45 - 3.59 (m, 3 H), 3.29 - MS: calc'd (MH+) 509 3.45 (m, 1 H), 3.23 (t, J = 8.41 Hz, 1 H), 2.87 - 3.09 exp (MH+) 509.
(m, 1 H), 2.41 (dd, J = 14.31, 7.28 Hz, 1 H), 2.19 (s, 1
H), 1.86 - 2.00 (m, 3 H), 1.18 - 1.33 (m, 6 H).
1H NMR (CDCI3, 400 MHz), 7.86 (d, 1H, J = 3.1 Hz),
7.52 (m, 3H), 7.02 (m, 2H), 4.04 (m, 1H), 3.79 (m, MS: calc'd (MH+) 481 2H), 3.52 (s, 3H), 3.52 (m, 2H), 3.16 (m, 1H), 3.00 (m, exp (MH+) 481.
1H), 2.40 (m, 2H), 1.98 (s, 3H). lH NMR (MeOD-d4, 400 MHz), 7.95 (d, J = 4.0 Hz,
1H), 7.75 (d, J = 4.0 Hz, 1H), 7.51-7.47 (m, 2H), 7.05
(t, J = 8.0 Hz, 2H), 3.96 (d, J = 16 Hz, 1H), 3.74 (d, J
MS: calc'd (MH+) 509
56 = 16 Hz, 1H), 3.58 (t, J = 6.0 Hz, 2H), 3.50-3.40 (m,
exp (MH+) 509.
1H), 3.48 (s, 3H), 2.98-2.85 (m, 2H), 2.57-2.45 (m,
1H), 2.13-2.05 (m, 1H), 1.92- 1.85 (m, 1H), 1.90 (s,
3H), 1.63-1.49 (m, 3H).
1H NMR(MeOD-d4, 400 MHz), 7.97 (br. s., 1 H) 7.83
- 7.68 (m, 1 H) 7.44 (br. s., 2 H) 7.03 (br. s., 2 H) 4.55
MS: calc'd (MH+) 533
57 - 4.37 (m, 1 H) 3.97 (d, J = 3.26 Hz, 2 H) 3.67 - 3.53
exp (MH+) 533.2. (m, 1 H) 3.45 (s, 3 H) 3.27 - 3.13(m, 1 H) 2.96 - 2.66
(m, 2 H) 2.36 (s, 3 H) 1.84 (s, 3 H).
1H NMR(MeOD-d4, 400 MHz), 8.02 - 7.92 (m, 1 H)
7.77 (d, J = 3.01 Hz, 1 H) 7.48 (dd, J = 8.53, 5.27 Hz,
MS: calc'd (MH+) 519
58 2 H) 7.05 (t, J = 8.66 Hz, 2 H) 4.50 (t, J = 8.28 Hz, 1
exp (MH+) 519.1. H) 3.72 - 3.57(m, 2 H) 3.41 (s, 3 H) 3.24 - 3.08 (m, 2
H) 2.80 (td, J = 15.75, 7.15 Hz, 2 H) 1.85 (s, 3 H).
1H NMR(MeOD-d4, 400 MHz), 7.95 (d, J = 3.01 Hz, 1
H) 7.74 (d, J = 3.26 Hz, 1 H) 7.47 (dd, J = 8.66, 5.40
Hz, 2 H) 7.04 (t, J = 8.78 Hz, 2 H) 4.53 (t, J = 7.91 Hz,
MS: calc'd (MH+) 533
59 1 H) 3.95 (d, J = 8.53 Hz, 2 H) 3.60 (d, J = 10.79 Hz, 1
exp (MH+) 533.2. H) 3.50 -3.39 (m, 3 H) 3.26 (br. s., 1 H) 2.99 - 2.85(m,
1 H) 2.78 - 2.64 (m, 1 H) 2.35 (s, 3 H) 1.90 - 1.81 (m,
3 H).
More particular compounds of formula I include the following:
4-[6-(4-fluoro-phenyl)-5-methoxycarbonyl-6-methyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid; 4-[6-(4-fluoro-phenyl)-5-methoxycarbonyl-6-methyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl]-morpholine-(lS')-3-carboxylic acid;
(5)-4-[6-(4-fluoro-phenyl)-5-methoxycarbonyl-6-methyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl]-morpholine-(lS')-3-carboxylic acid;
(5)-4-[6-(4-fluoro-phenyl)-5-methoxycarbonyl-6-methyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl]-morpholine-(R)-3-carboxylic acid;
4-[6-(4-fluoro-phenyl)-2-(5-fluoro-pyridin-2-yl)-5-methoxycarbonyl-6-methyl-3,6- dihydro-pyrimidin-4-ylmethyl]-morpholine-(R)-3-carboxylic acid; 4-[6-(4-fluoro-phenyl)-2-(5-fluoro-pyridin-2-yl)-5-methoxycarbonyl-6-methyl-3,6- di ydro-pyrimidin-4-ylmethyl]-morpholine-(lS')-3-carboxylic acid;
6-(2-(lS')-carboxy-4,4-difluoro-pyrrolidin- l-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2- thiazol-2-yl- l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester; 6-(2-(R)-carboxy-4,4-difluoro-pyrrolidin- l-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2- thiazol-2-yl- l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
(lS,)-6-((5,)-2-carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(4-fluoro-phenyl)-4- methyl-2-thiazol-2-yl- l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
(lS,)-6-((5,)-2-carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(3,4-difluoro-phenyl)-4- methyl-2-thiazol-2-yl- l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
4-[6-(3,4-difluoro-phenyl)-5-methoxycarbonyl-6-methyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;
6-(4,4-difluoro-2-methoxycarbonyl-pyrrolidin-l-ylmethyl)-4-(4-fluoro-phenyl)-2-(5- fluoro-pyridin-2-yl)-4-methyl- l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester; 6-(2-carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(4-fluoro-phenyl)-2-(5-fluoro- pyridin-2-yl)-4-methyl- l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
6-((5,)-2-carboxy-4,4-difluoro-pyrrolidin- l-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2- (5-methyl-thiazol-2-yl)-l ,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
6-(2-carboxy-4,4-difluoro-2-methyl-pyrrolidin-l-ylmethyl)-4-(4-fluoro-phenyl)-4- methyl-2-thiazol-2-yl- l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
(lS,)-l-[(5,)-5-cyano-6-(3,4-difluoro-phenyl)-6-methyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl]-4,4-difluoro-pyrrolidine-2-carboxylic acid;
(lS,)-6-((5,)-2-Carboxy-4,4-difluoro-pyrrolidin- l-ylmethyl)-4-(3,4-difluoro-phenyl)-4- methyl-2-thiazol-2-yl- l,4-dihydro-pyrimidine-5-carboxylic acid ethyl ester; (lS,)-6-(2-Carboxy-5,5-difluoro-piperidin- l-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2- thiazol-2-yl- l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
(5,)-6-(2-Carboxy-4,4-difluoro-piperidin- l-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2- thiazol-2-yl- l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester; (lS,)-6-((5,)-2-Carboxy-4,4-difluoro-pyrrolidin- l-ylmethyl)-4-(4-fluoro-phenyl)-4- methyl-2-(l-methyl- lH-imidazol-2-yl)- l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
(lS,)-6-((5,)-2-Carboxy-4,4-difluoro-pyrrolidin- l-ylmethyl)-4-(4-fluoro-phenyl)-4- methyl-2-(4-methyl-thiazol-2-yl)-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
(lS,)-6-((5,)-2-Carboxy-4,4-difluoro-pyrrolidin- l-ylmethyl)-2-(5-chloro-thiazol-2-yl)-4- (4-fluoro-phenyl)-4-methyl-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
(lS,)-6-((5,)-2-Carboxy-4,4-difluoro-pyrrolidin- l-ylmethyl)-4-(4-fluoro-phenyl)-4- methyl-2-(5-methyl-thiazol-2-yl)-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
(lS,)-6-((5,)-2-Carboxy-4,4-difluoro-pyrrolidin- l-ylmethyl)-4-(4-fluoro-phenyl)-2-(5- fluoro-thiophen-2-yl)-4-methyl-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
(lS,)-6-((5,)-2-Carboxy-4,4-difluoro-pyrrolidin- l-ylmethyl)-4-(4-fluoro-phenyl)-2-(3- fluoro-thiophen-2-yl)-4-methyl-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
(lS,)-6-((5,)-2-Carboxy-4,4-difluoro-pyrrolidin- l-ylmethyl)-4-(4-fluoro-phenyl)-2-(4- fluoro-thiophen-2-yl)-4-methyl-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
(lS,)-6-((5,)-4,4-Difluoro-2-methoxycarbonyl-pyrrolidin-l-ylmethyl)-4-(4-fluoro-phenyl)- 4-methyl-2-thiazol-2-yl- l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester; (lS,)-6-(2-Carbamoyl-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl- 2-thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
(lS,)-6-((lS,)-2-Dimethylcarbamoyl-4,4-difluoro-pyrrolidin- l-ylmethyl)-4-(4-fluoro- phenyl)-4-methyl-2-thiazol-2-yl- l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
(lS,)-6-[(5,)-4,4-Difluoro-2-(thiazol-2-ylcarbamoyl)-pyrrolidin-l-ylmethyl]-4-(4-fluoro- phenyl)-4-methyl-2-thiazol-2-yl- l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
(5 6-[(5 4,4-Difluoro-2-( 1 -hydroxy- 1 -methyl-ethyl)-pyrrolidin- 1 -ylmethyl] -4-(4- fluoro-phenyl)-4-methyl-2-thiazol-2-yl- 1 ,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
(lS,)-6-((5,)-4,4-Difluoro-2-hydroxymethyl-pyrrolidin- l-ylmethyl)-4-(4-fluoro-phenyl)-4- methyl-2-thiazol-2-yl- l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester; (5)-6-[(5)-4,4-Difluoro-2-(5-methyl-[l,3,4]oxadiazol-2-yl)-pyrrolidin-l-ylmethyl]-4-(4- fluoro-phenyl)-4-methyl-2-thiazol-2-yl- 1 ,4-dihydro-pyrimidine-5-carboxylic acid
methyl ester;
(lS,)-6-[(lS,)-4,4-Difluoro-2-(lH-tetrazol-5-yl)-pyrrolidin-l-ylmethyl]-4-(4-fluoro- phenyl)-4-methyl-2-thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
and
(lS,)-6-[(lS,)-4,4-Difluoro-2-(3-methyl-[l,2,4]oxadiazol-5-yl)-pyrrolidin-l-ylmethyl]-4-(4- fluoro-phenyl)-4-methyl-2-thiazol-2-yl- 1 ,4-dihydro-pyrimidine-5-carboxylic acid
methyl ester. It is very important for a drug to have a moderate or low clearance, as this often lead to a good oral bioavailability and high exposure in target organ. Reducing the clearance of a compound or drug could then potentially reduce drastically the daily dose required for efficacy and therefore give a much better safety profile as well. From the examples below, it has been found a marked increase of metabolic stability and liver exposure of 4-methyldihydropyrimidines of current invention.
4-Hydrogen-dihydropyrimidines such as Bay 41-4109 can be oxidized to pyrimidine product XL VI when treated with human, rat or mouse liver microsomes. In this experiment, pooled liver microsomes (20 mg/ml) from human, male Wister rat and male CD-I mouse were obtained from BD Bioscience (Franklin Lakes, NJ USA). Incubation reaction mixtures contained a final concentration of 0.1M sodium phosphate buffer (pH 7.4), 0.5 mg/ml microsomal protein, 5 μΜ of the tested compounds and 1 mM NADPH in a total volume of 400 μΐ. The incubations were done for 60 minutes and 300 μΐ of the mixtures was transferred to 150 μΐ of ice cold methanol to terminate reactions. After vortexes for 3 minutes and centrifuged at 4000 rpm at 4°C for 10 minutes, the clear supernatant was used directly for analysis. The samples were analyzed by Applied Biosystems API 3200 Q TRAP LC/MS/MS system using electrospray ionization mode.
Pyrimidine product XLVI was the major metabolite in the in vitro clearance tests (Figure 1), and it was inactive to HBV DNA reduction in HepDE19 cell based assays with EC50 value above 100 μΜ. On the other hand, the 4-methyl-dihydropyrimidines series in this invention do not have the aromatization issues of the core structure.
HBV viruses infect hepatocyte cells and replicate in the liver. To have effective viral suppression, it is important for an anti-HBV drug to have sufficient exposure in the target organ. The following findings highlight increased metabolic stability and high liver exposure of 4- methyldihydropyrimidine analogs in this invention.
In this experiment, fresh mouse liver sample was homogenized by adding saline (1 g liver tissue: 5 mL saline) immediately after collection. After centrifuging for 10 minutes at 14000 rpm, the pooled supernatant was used to prepare liver homogenate solutions. The effective compounds concentrations in liver homogenate were 100, 300, and 1000 ng/mL. Then, they were incubated at rt. After incubation time of 0, 15 and 30 minutes, 180 μΐ aliquots of MeOH was added into 20 μΐ of homogenate, respectively. All these samples were vortex mixed for 5 minutes at 1500 rpm and centrifuged for 10 minutes at 14000 rpm. The supernatants were transferred into a 96- well plate for LC-MS/MS analysis. The results were summarized and showed in Table 3.
Table 3. The percentage of Bay 41-4109 and Example 13 remaining in mouse liver homogenate.
Concentration Peak Incubation Time Percentage to 0
Compound
(ng/mL) Area* (min) min
Figure imgf000045_0001
7868 30 0.16%
1000 93431 15 1.90%
4930207 100%
E
Figure imgf000045_0002
368388 30 86.0%
1000
375366 15 87.6% 428458 0 100%
*: the data directly calculated by LC/MS/MS, the relative standard variation is at 20%. **: not detected
By comparing the peak area of individual samples at 15 and 30 min to the one at 0 min from same concentration level, the stability of Bay41-4109 and Example 13 in CD-I mouse liver homogenate was evaluated.
It can be obviously concluded that Bay41-4109 is not stable in liver homogenate treated with saline. About 2% of compound was detected after 15 minutes room temperature incubation, at three different concentration levels. In samples incubated for 30 minutes, only 0.16% can be found (at 1000 ng/mL. Not detected in 100 ng/mL and 300 ng/mL samples due to instrument sensitivity).
It can be concluded that Example 13 is stable in in liver homogenate treated with saline.
The in vivo DMPK of selected compounds were evaluated in male ICR mice following intravenous (or i.v.) or oral (or p.o.) administration. In single dose pharmacokinetics (SDPK) studies, compounds were dissolved in 6% Solutol solution (Solutol: Ethanol, 1: 1, v/v), and 94% 0.9% saline for i.v. dose. For p.o. administration, compounds were mixed with 0.89% microcrystalline cellulose and 0.11% carboxymethyl cellulose sodium water solution, or 1% RC591 as suspensions. The single dose exposure levels of Bay 41-4109, Example 6, Example 11, Example 13 and Example 19 in mouse plasma and/or liver are shown as Figure 2-6. SYNTHESIS
The compounds of the present invention can be prepared by any conventional means.
Suitable processes for synthesizing these compounds as well as their starting materials are provided in the schemes below and in the examples. All substituents, in particular, R1 to R5, M and X are as defined above unless otherwise indicated. Furthermore, and unless explicitly otherwise stated, all reactions, reaction conditions, abbreviations and symbols have the meanings well known to a person of ordinary skill in organic chemistry.
General synthetic scheme for 4-methyl-5-ester-6-methyl-dihydropyrimidine based analogues Intermediate- 1 (Scheme 1) One category of the compounds described herein relates to 4-methyl-5-ester-6-methyl- dihydropyrimidine based analogues with the formula Intermediate- 1 wherein R8 is Chalky!.
Figure imgf000047_0001
lntermediate-1
Compound of interest Intermediate- 1 can be prepared according to the general synthesis method shown in Scheme 1.
Scheme 1
NhLCI, AIMe, NH
H2N X R3
Figure imgf000048_0001
IV V VI or
Figure imgf000048_0002
IV VII VIII
MeCuLi
h
Figure imgf000048_0003
IX X
Figure imgf000048_0004
VI
Figure imgf000048_0005
VI lntermediate-1
R8 is C^alkyl.
Amidine III can be prepared from commercial available nitrile II, ammonium chloride and trimethyl aluminum. The reaction is typically performed by adding trimethyl aluminum to the mixture of ammonium chloride in toluene at 0 °C. After 30 minutes, nitrile II is added into the flask and the reaction mixture is stirred at 80 °C overnight.
The indium triflate catalyzed condensation reaction of commercial available ester IV and ethynyl-benzene V gives α,β-unsaturated ketone VI. The reaction is typically performed in o- xylene at 120 °C for 2 h.
As an alternative method to synthesize tetra-substituted α,β-unsaturated ketone VI, especially when R is ie/t-butyl group. Ketone VIII can be prepared by condensation of ester IV with substituted benzaldehyde VII. The reaction is typically performed in ethanol with catalytic quantity of piperidine and acetic acid at rt overnight. Ketone IX can be prepared by 1,4-Michael addition of methyl group to the α,β-unsaturated ketone VIII. The reaction is typically performed by adding methyl lithium solution to cuprous iodide in THF solution at 0 °C and stirred for 1 hour at 0 °C, then the solution of VIII in THF is added into the mixture at -78 °C and stirred for 1 hour at -78 °C. α,β-Unsaturated ketone VI can be prepared by oxidative elimination of ketone IX. The reaction is typically performed by adding sodium hydride into the solution of ketone IX in THF, then phenylselenyl chloride is added and stirred at rt for 1 hour. After the mixture is treated with pentene, ether and saturated sodium bicarbonate, the organic layer is treated with H202 solution (30%) and stirred at rt for 1 hour.
Analogs with general structure Intermediate-1 can be prepared by the condensation reaction of α,β-unsaturated ketone VI with amidine III. The reaction is typically carried out by adding a solution of VI in NMP dropwisely into a mixture of amidine III and NaHC03 in NMP at 120 °C, after addition the mixture is stirred at 120 °C for half an hour before workup.
General synthetic scheme for 4-methyl-5-cyano-6-nitrogen-substituted-2,4- dihydro-pyrimidine based analogues Intermediate-3 (Scheme-2)
Figure imgf000049_0001
lntermediate-3 Compounds of interest Intermediate-3 can be prepared according to the general synthesis method shown in Scheme 2.
Scheme 2
Figure imgf000050_0001
Yl l lntermediate-2
Figure imgf000050_0002
XI XI I Intermediate-3
Compound XI can be obtained by the deprotection of Intermediate-2. The reaction is typically performed in DCM with TFA at rt for 2 hours.
Compound XII can be obtained by coupling reaction from XI with ammonia. The reaction is typically performed in DCM with HATU and ammonia of dioxane solution at rt for 1 hour.
Cyano compound Intermediate-3 can be obtained by dehydrate reaction from compound XII. The reaction is typically performed in 1,2-dichloroethane with thionyl chloride or trifluoroacetic anhydride under refluxing for 1 hour.
General synthetic scheme for 4-methyl-5-ester or cyano-6-aminoalkyl-dihydropyrimidine based analogues la (Scheme 3)
Figure imgf000050_0003
Compounds of interest la can be prepared according to the general synthesis method shown in Scheme 3.
Scheme 3
Figure imgf000051_0001
XIV XV XVI
Figure imgf000051_0002
The Boc-protected compound XIII can be obtained by treatment of ester Intermediate- 1 or cyano Intermediate-3 with di-iert-butyldicarbonate and DMAP as base in an inert organic solvent such as DCM, typically at rt for 24 hours.
The compound XIV can be obtained by the bromination of compound XIII. The reaction is typically performed in tetrachloromethane with NBS and AIBN as catalyst at 80 °C for 2 hours.
The amino substituted intermediate XVI can be obtained through substitution reaction of compound XIV with XV. The reaction can be carried out with a suitable organic base such as Ν,Ν-diisopropylethylamine, inorganic base such as NaH, Na2C03, or i-BuOK in an inert organic solvent such as DCM, THF or DMF at rt or 50 °C for 1-10 hours.
Compound la can be obtained from the deprotection of XVI treated with TFA in DCM or HCI in MeOH as deprotective agent at rt.
General synthetic scheme for 4-methyl-5 -ester or cyano-6-alkoxymethyl- dihydropyrimidine based analogue lb (Scheme 4)
Figure imgf000052_0001
l b
Compound of interest lb can be prepared according to the general synthesis method shown in Scheme 4.
Scheme 4
Figure imgf000052_0002
XIV XVI I XVI I I
Figure imgf000052_0003
lb Compound XVIII can be obtained by substitution reaction of compound XIV with alcohol XVII. The reaction is typically performed by adding NaH to the solution of alcohol XVII in anhydrous THF at rt, then bromide XIV is added into the flask and the mixture is stirred at rt for 3 hours. Compound lb can be obtained by treating XVIII with TFA in DCM or HC1 in MeOH at rt.
This invention also relates to a process for the preparation of a compound of formula I comprising the reaction of
(a) a compound of formula (A)
Figure imgf000053_0001
in the presence of an acid; wherein R1 to R5, M and X are defined above unless otherwise indicated. In step (a), the acid can be for example TFA or HC1. PHARMACEUTICAL COMPOSITIONS AND ADMINISTRATION
The invention also relates to a compound of formula I for use as therapeutically active substance.
A compound of formula (I) when manufactured according to the above process is also an object of the invention.
Another embodiment provides pharmaceutical compositions or medicaments containing the compounds of the invention and a therapeutically inert carrier, diluent or excipient, as well as methods of using the compounds of the invention to prepare such compositions and medicaments. In one example, compounds of formula I may be formulated by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed into a galenical administration form. The pH of the formulation depends mainly on the particular use and the concentration of compound, but preferably ranges anywhere from about 3 to about 8. In one example, a compound of formula I is formulated in an acetate buffer, at pH 5. In another embodiment, the compounds of formula I are sterile. The compound may be stored, for example, as a solid or amorphous composition, as a lyophilized formulation or as an aqueous solution.
Compositions are formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular human being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners. The "effective amount" of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to the suppression of serum HBV DNA levels, or HBeAg seroconversion to HBeAb, or HBsAg loss, or normalization of alanine aminotransferase levels and improvement in liver histology. For example, such amount may be below the amount that is toxic to normal cells, or the human as a whole.
In one example, the pharmaceutically effective amount of the compound of the invention administered parenterally per dose will be in the range of about 0.01 to 100 mg/kg, alternatively about 0.1 to 20 mg/kg of patient body weight per day, with the typical initial range of compound used being 0.3 to 15 mg/kg/day. In another embodiment, oral unit dosage forms, such as tablets and capsules, contain from about 0.1 to about 1000 mg of the compound of the invention.
The compounds of the invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and, if desired for local treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.
The compounds of the present invention may be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents.
A typical formulation is prepared by mixing a compound of the present invention and a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., Ansel, Howard C, et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament). An example of a suitable oral dosage form is a tablet containing about 0.1 mg to 1000 mg of the compound of the invention compounded with about 90 mg to 30 mg anhydrous lactose, about 5 mg to 40 mg sodium croscarmellose, about 5 mg to 30 mg polyvinylpyrrolidone (PVP) K30, and about 1 mg to 10 mg magnesium stearate. The powdered ingredients are first mixed together and then mixed with a solution of the PVP. The resulting composition can be dried, granulated, mixed with the magnesium stearate and compressed to tablet form using conventional equipment. An example of an aerosol formulation can be prepared by dissolving the compound, for example 5 mg to 400 mg, of the invention in a suitable buffer solution, e.g. a phosphate buffer, adding a tonicifier, e.g. a salt such sodium chloride, if desired. The solution may be filtered, e.g., using a 0.2 micron filter, to remove impurities and contaminants. An embodiment, therefore, includes a pharmaceutical composition comprising a compound of Formula I, or a stereoisomer or pharmaceutically acceptable salt thereof. In a further embodiment includes a pharmaceutical composition comprising a compound of Formula I, or a stereoisomer or pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or excipient. INDICATIONS AND METHODS OF TREATMENT
The compounds of the invention can inhibit HBV's de novo DNA synthesis and reduce HBV DNA levels. Accordingly, the compounds of the invention are useful for the treatment or prophylaxis of HBV infection.
The invention relates to the use of a compound of formula I for the treatment or prophylaxis of HBV infection.
The use of a compound of formula I for the preparation of medicaments useful in the treatment or prophylaxis diseases that are related to HBV infection is an object of the invention. The invention relates in particular to the use of a compound of formula I for the preparation of a medicament for the treatment or prophylaxis of HBV infection.
Another embodiment includes a method of treating or prophylaxising HBV infection in a human in need of such treatment, wherein the method comprises administering to said human a therapeutically effective amount of a compound of Formula I, a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof.
COMBINATION THERAPY
The compounds of the invention can be used together with interferon, pegylated interferons, Lamivudine, Adefovir dipivoxil, Entecavir, Telbivudine, and Tenofovir disoproxil for the treatment or prophylaxis of HBV.
Brief description of the Figures
Figure 1. Bay 41-4109 was converted to XLVI in human liver microsomes.
Figure 2. Mean + SD Plasma Concentration-Time Curve of Bay41-4109 in Male ICR Mice Following Intravenous and Oral Administration* * Drug exposure in liver is not available due to instability of Bay 41-4109 in liver homogenate.
Figure 3. Mean + SD Plasma and Tissue Concentration-Time Curve of Example 6 in Male ICR Mice Following Intravenous and Oral Administration
Figure 4. Mean + SD Plasma and Tissue Concentration-Time Curve of Example 11 in Male ICR Mice Following Intravenous and Oral Administration Figure 5. Mean + SD Plasma and Tissue Concentration-Time Curve of Example 13 in Male ICR Mice Following Intravenous and Oral Administration
Figure 6. Mean + SD Plasma and Tissue Concentration-Time Curve of Example 19 in Male ICR Mice Following Intravenous and Oral Administration
Figure 7. X-ray structure of compound XXVII
EXAMPLES
The invention will be more fully understood by reference to the following examples. They should not, however, be construed as limiting the scope of the invention.
Abbreviations used herein are as follows: AIBN: azobisisobutyronitrile
Boc: iert-butoxycarbonyl
i-BuOK: potassium ie/t-butoxide
calc'd: calculated
CC50: cytotoxic concentration 50%
CC14: tetrachloromethane
CDCI3: deuterated chloroform
CCK-8: cell counting kit- 8
CDI: N, N'-Carbonyldiimidazole
CMV: cytomegalovirus
d: day
DIPEA: N,N-diisopropylethylamine
DCM: dichloromethylene
DMAP: N,N'-dimethylaminopyridine
DMF: dimethylformamide
DMSO: dimethylsulfoxide
DNA: deoxyribonucleic acid
EDCI: l-ethyl-3-(3-dimethylaminopropyl)carbodiimide
EDTA: ethylenediaminetetraacetic acid
exp: expected
EtOAc: ethyl acetate
FBS: fetal bovine serum
g: gram
EC50: concentration required for 50% induction of acetylated tubulin FBS: fetal bovine serum
h: hour or hours
HAP: heteroaryldihydropyrimidine
HATU: 2-(7- Aza- IH-benzotriazole- 1-yl)- 1 , 1 ,3,3-tetramethyluronium hexafluorophosphate HBeAb: hepatitis B e antibody
HBeAg: hepatitis B e antigen
HBsAg: hepatitis B surface antigen
HC1: hydrogen chloride
HPLC: high performance liquid chromatography
Hz: Hertz
In(OTf)3: indium (III) trifluoromethanesulfonate
IPA: isopropanol
KOH: potassium
LC/MS: liquid chromatography mass spectrometer
LiOH: lithium hydroxide
LDA: lithium diisopropylamide
MeOD-d4 or CD30D:deuterated methanol
MeOH: methanol
mg: milligram
MHz: megahertz
min: minute or minutes
mL: milliliter
mM: milliliter
NMP: l-methyl-piperidin-2-one
mmol: millimole
NaCl: sodium chloride
NaOH: sodium hydroxide
NBS: N-bromosuccinimide
NEt : triethylamine
NMR: nuclear magnetic resonance
PBS: Phosphate buffered saline
prep-HPLC: preparative high performance liquid chromatography
RP-HPLC: reverse phase high performance liquid chromatography rt: room temperature
SDPK: single dose pharmacokinetics
SFC: supercritical fluid chromatography
SSC: saline- sodium citrate buffer
TEA: triethylamine
TFA: trifluoroacetic acid
TFAA: trifluoroacetic acid anhydride
THF: tetrahydrofuran
μΐ: microliter
μΜ: micromole
General Experimental Conditions
Intermediates and final compounds were purified by flash chromatography using one of the following instruments: i) Biotage SPl system and the Quad 12/25 Cartridge module, ii) ISCO combi-flash chromatography instrument. Silica gel brand and pore size: i) KP-SIL 60 A, particle size: 40-60 μΜ; ii) CAS registry NO: Silica Gel: 63231-67-4, particle size: 47-60 micron silica gel; iii) ZCX from Qingdao Haiyang Chemical Co., Ltd, pore: 200-300 or 300-400.
Intermediates and final compounds were purified by preparative HPLC on reversed phase column using XBridge™Prep-C18 (5 μπι, OBD™ 30 x 100 mm) column or SunFire™ Prep-C18 (5 μιη, OBD™ 30 x 100 mm) column. Waters AutoP purification System (Column: XBridge™ Prep-Ci8, 30 x 100 mm, Sample Manager 2767, Pump 2525, Detector: Micromass ZQ and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water). For SFC chiral separation, intermediates were separated by chiral column (Daicel chiralpak IC, 5 μιη, 30 x 250 mm) column using Mettler Toledo SFC-Multigram III system, solvent system: 95% C02 and 5% IPA (0.5% TEA in IPA), back pressure lOObar, detection UV@ 254nm.
LC/MS spectra of compounds were obtained using a LC/MS (Waters™ Alliance 2795- Micromass ZQ). LC/MS conditions were as follows (running time 6 min):
Acidic condition: A: 0.1% formic acid in H20; B: 0.1% formic acid in acetonitrile;
Basic condition: A: 0.01% NH3 H20 in H20; B: acetonitrile; Neutral condition: A: H20; B: acetonitrile. Mass spectra (MS): generally only ions which indicate the parent mass are reported, and unless otherwise stated the mass ion quoted is the positive mass ion (M+H)+.
LC-MS/MS instrument on liver homogenate stability test: An Agilent 1290 series LC system composited of a binary pump, a degasser, a CTCPAL autosampler and a thermostatted column was applied. The Chromatographic separation was achieved on a Chromolith Performance RP-18 endcapped (3 x 100 mm) at room temperature.
Mass spectrometric detection was performed on an Agilent 6530 Q-TOF instrument in full scan mode with an AJS ESI interface in positive ionization mode. Data processing was performed with Agilent MassHunter Workstation Data Acquisition B.04.00 and Agilent MassHunter Workstation Qualitative Analysis B.04.00.
The microwave assisted reactions were carried out in a Biotage Initiator Sixty microwave synthesizer.
NMR Spectra were obtained using Bruker Avance 400MHz.
All reactions involving air-sensitive reagents were performed under an argon atmosphere.
Reagents were used as received from commercial suppliers without further purification unless otherwise noted.
The following examples were prepared by the general methods outlined in the schemes above. They are intended to illustrate the meaning of the present invention but should by no means represent a limitation within the meaning of the present invention.
PREPARATIVE EXAMPLES
Example 1 4-(4-Fluoro-phenyl)-6-(l-methoxycarbonyl-l-methyl-ethoxymethyl)-4- methyl-2-thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester
The title compound was prepared according to the general synthesis methods shown in Scheme 1 and Scheme 4. A detailed synthesis route is provided as shown in Scheme 5.
Scheme 5
Figure imgf000061_0001
XXIII XXIV
Figure imgf000062_0001
XXIV Example 1
To a stirred suspension of NH4C1 in toluene (400 mL) was added A1(CH3)3 solution (1.0 M, 56 mL) at 0 °C over 30 minutes. After the mixture solution was stirred at rt for 30 minutes, the solution of thiazole-2-carbonitrile (5.24 g, 47.6 mmol) in toluene (10 mL) was added into the flask. The reaction mixture was stirred at 80 °C for 16 hours before cooling to rt and then the mixture was poured into a slurry of silica gel in DCM. After stirring for 20 minutes, the slurry was filtered and washed with MeOH three times and concentrated in vacuo to afford crude product of thiazole-2-carboxamidine XIX that was used in next step reaction without further purification. MS: calc'd (MH+) 128.2, exp (MH+) 128.1. A mixture of 3-oxo-butyric acid methyl ester (5.0 g, 43.1 mmol), l-ethynyl-4-fluoro- benzene (5.0 g, 41.7mmol) and In(OTf) (400 mg, 0.71 mmol) in o-xylene (20 ml) was heated to 120 °C for 1 to 2 h. After solvent removal, the residue was purified by column chromatography (EtOAc/petroleum ether: 1/10) to afford XX as light yellowish oil (4.0 g, yield: 40.8%).
To a mixture of thiazole-2-carboxamidine XIX (1.7g, 10.5 mmol) and NaHC03 (2.5 g, 29.8 mmol) in NMP (10 mL) which was preheated to 120 °C was added dropwisely (E)-2-acetyl- 3-(4-fluoro-phenyl)-but-2-enoic acid methyl ester XX (2.4 g, 10.2 mmol) in NMP (10 mL) in about 1 h. The mixture was stirred at 120 °C for 0.5 h before reaction workup with EtOAc (200 mL) and water. The organic layer was dried and concentrated, and the residue was purified by column chromatography (EtOAc/petroleum ether 1/4 to 1/2) to afford 4-(4-fluoro-phenyl)-4,6- dimethyl-2-thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester XXI as yellow viscous oil (1.7 g, yield: 48.3%). MS: calc'd (MH+) 346, exp (MH+) 346. 1H NMR (MeOD-d4, 400 MHz) 7.93 (d, 1H, J = 3.2 Hz), 7.72 (d, 1H, J = 3.2 Hz), 7.51-7.47 (m, 2H), 7.04 (t, 2H, J = 8.8 Hz), 3.45 (s, 3H), 2.28 (s, 3H), 1.90 (s, 3H).
To a solution of XXI (1.0 g, 2.9 mmol) in DCM (20 mL) was added DMAP (0.15 g, 1.2 mmol) and Boc20 (0.94 g, 4.3 mmol), and the mixture was stirred overnight. The mixture was washed with water (15 mL) and brine (15 mL). The organic layer was separated, dried over anhydrous Na2S04 and concentrated, and the residue was purified by column chromatography (EtO Ac/petroleum ether from 1/4 to 1/3) to afford 4-(4-fluoro-phenyl)-4,6-dimethyl-2-thiazol-2- yl-4H-pyrimidine-l,5-dicarboxylic acid 1-iert-butyl ester 5-methyl ester XXII as yellow solid (0.91 g, yield: 70.5%).
A solution of XXII (0.90 g, 2.02 mmol) and NBS (0.54 g, 3.03 mmol) in CC14 (30 mL) was heated to 50 °C, then AIBN (30 mg) was added to initiate the reaction. The mixture was stirred for 2 h. The mixture was purified by column chromatography (EtO Ac/petroleum ether from 1/4 to 1/3) to afford 6-bromomethyl-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-4H-pyrimidine- l,5- dicarboxylic acid l-ie/t-butyl ester 5-methyl ester XXIII as yellow solid (1.03 g, yield: 97.3%).
Sodium hydride (12 mg, 0.5 mmol) was added to a solution of 2-hydroxy-2-methyl- propionic acid methyl ester (59 mg, 0.5 mmol) in THF at rt. Then the mixture was stirred at rt for 30 min. Compound XXIII (105 mg, 0.2 mmol) was added and stirred at rt overnight. Then the mixture was partitioned between water and EtOAc. The organic phase was dried, concentrated and used in the next step without further purification.
The crude product XXIV from above step was dissolved in DCM and then TFA was added. The mixture was stirred at rt for 2 hours. The solvent was removed and the residue was purified by prep-HPLC to afford Example 1 as yellow solid (40 mg, yield: 43% for 2 steps). MS: calc'd 462 (MH+), exp 462 (MH+). 1H NMR (MeOD-d4, 400MHz), 7.95 (d, 1H, J = 3.2 Hz), 7.75 (d, 1H, J = 3.2 Hz), 7.49-7.45 (m, 2H), 7.04 (t, 2H, J = 8.8 Hz), 4.71-4.62 (m, 2H), 3.80 (s, 3H), 3.43 (s, 3H), 1.92 (s, 3H), 1.57 (s, 6H).
Example 2 6-(l-Carboxy-2,2,2-trifluoro-ethoxymethyl)-4-(4-fluoro-phenyl)-4- methyl-2-thiazol-2-yl- l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester
The title compound was prepared in analogy to Example 1 in Scheme 5 by using 3,3,3- trifluoro-2-hydroxy-propionic acid methyl ester instead of 2-hydroxy-2-methyl-propionic acid methyl ester, the so-obtained methyl ester was hydrolyzed by LiOH as indicated in Scheme 3. MS: calc'd 488 (MH+), exp 488 (MH+). 1H NMR (MeOD-d4, 400MHz), 7.94 (d, 1H, J = 2.8 Hz), 7.93 (d, 1H, J = 2.8 Hz), 7.53-7.49 (m, 2H), 7.07-7.03 (m, 2H), 4.85-4.78 (m, 2H), 4.40-4.37 (m, 1H), 3.44 (s, 3H), 1.94 (s, 3H). Example 3 6-{ [(l-Carboxy-cyclopropyl)-methyl-amino]-methyl}-4-(4-fluoro- phenyl)-4-methyl-2-thiazol-2-yl- l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester The title compound was prepared according to the synthesis method shown in Scheme 1 and Scheme 3. A detailed synthesis route is provided as shown in Scheme 6.
Scheme 6
Figure imgf000064_0001
XXVI Example 3
To a solution of 6-bromomethyl-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-4H- pyrimidine-l,5-dicarboxylic acid l-ie/t-butyl ester 5-methyl ester XXIII (1.00 g, 1.90 mmol) and potassium carbonate in DMF was added 1-methylamino-cyclopropanecarboxylic acid methyl ester (258 mg, 2.00 mmol), the mixture was stirred at 40 °C for 3 hours and LC-MS indicated that the reaction was finished. The mixture was partitioned between water and ethyl acetate. The organic phase was dried and concentrated to afford the crude product used in the next step without further purification.
The crude product XXV from above step was dissolved in DCM and then TFA was added. The mixture was stirred at rt for 2 hours. LC-MS indicated that the reaction was finished. The solvent was removed and the residue was used in the next step without further purification. The crude product XXVI from above step was dissolved in MeOH (5 mL) and LiOH in water (2 mL) was added to the mixture. The mixture was stirred at rt for 2 h and LC-MS indicated that the reaction was finished. The solvent was removed and the mixture was adjusted to pH (3-5) with diluted hydrochloric acid. The mixture was purified by prep-HPLC to afford Example 3 as yellow solid (0.63 g, yield for 3 steps: 73%). MS: calc'd 459 (MH+), exp 459 (MH+). 1H NMR (MeOD-d4, 400MHz), 8.12 (d, IH, J = 3.2 Hz), 8.06 (d, IH, J = 3.2 Hz), 7.63- 7.60 (m, 2H), 7.15 (t, 2H, J = 8.8 Hz), 4.30 (s, 2H), 3.51 (s, 3H), 2.79 (s, 3H), 2.10 (s, 3H), 1.52- 1.51 (m, 2H), 1.38-1.37 (m, 2H).
Example 4 4-[6-(4-Fluoro-phenyl)-5-methoxycarbonyl-6-methyl-2-thiazol-2-yl-3,6- dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid
The title compound was prepared in analogy to Example 3 in Scheme 6 by using morpholine-3-carboxylic acid methyl ester instead of 1-methylamino-cyclopropanecarboxylic acid methyl ester. LC-MS: calc'd 475 (MH+), exp 475 (MH+). 1H NMR (MeOD-d4, 400 MHz) δ 8.10 (d, IH), 8.03 (d, IH), 7.64-7.61 (m, 2H), 7.15-7.12 (m, 2H), 4.32-4.31 (m, 2H), 4.18-4.14 (m, 2H), 3.99-3.72 (m, 3H), 3.51-3.49 (m, 4H), 3.02 (m, IH), 2.11 (d, 3H).
Example 5 4-[6-(4-Fluoro-phenyl)-5-methoxycarbonyl-6-methyl-2-thiazol-2-yl-3,6- dihydro-pyrimidin-4-ylmethyl]-morpholine-(lS')-3-carboxylic acid methyl ester
The title compound was prepared in analogy to Example 3 in Scheme 6 by using morpholine-(S)-3-carboxylic acid methyl ester instead of 1-methylamino- cyclopropanecarboxylic acid methyl ester.
Example 6 4-[6-(4-Fluoro-phenyl)-5-methoxycarbonyl-6-methyl-2-thiazol-2-yl-3,6- dihydro-pyrimidin-4-ylmethyl]-morpholine-(lS')-3-carboxylic acid
The title compound was prepared by from the hydrolysis of Example 5 with LiOH in MeOH as shown in Scheme 6. Example 7 (lS')-4-[6-(4-Fluoro-phenyl)-5-methoxycarbonyl-6-methyl-2-thiazol-2-yl- 3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-(lS')-3-carboxylic acid
The title compound was prepared according to the synthesis method shown in Scheme 1 and Scheme 3. A detailed synthesis route is provided as shown in Scheme 7.
Scheme 7
Figure imgf000066_0001
Figure imgf000066_0002
XXVIII Example 7
The chiral intermediate compound XXVII was separated from XXI by SFC and the absolute stereochemistry was determined by X-ray diffraction study (please see Figure 7). The title compound was prepared in analogy to Example 3 in Scheme 6 by using morpholine-(lS')-3- carboxylic acid methyl ester XXVIII instead of 1-methylamino-cyclopropanecarboxylic acid methyl ester in the replacement reaction.
Example 8 (lS')-4-[6-(4-Fluoro-phenyl)-5-methoxycarbonyl-6-methyl-2-thiazol-2-yl- 3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-(R)-3-carboxylic acid
The title compound was prepared in analogy to Example 7 in Scheme 7 by using morpholine-(R)-3-carboxylic acid methyl ester instead of 1-methylamino- cyclopropanecarboxylic acid methyl ester.
Example 9 4-[6-(4-Fluoro-phenyl)-2-(5-fluoro-pyridin-2-yl)-5-methoxycarbonyl-6- methyl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-(R)-3-carboxylic acid
The title compound was prepared according to the methods shown in Scheme 8.
Scheme 8
Figure imgf000067_0001
Figure imgf000067_0002
Example 9
5-Fluoro-pyridine-2-carbonitrile was used in the synthesis of Compound XXIX in the same methods as shown in Scheme 5. Following similar procedures to Scheme 5 and Scheme 6, XXIX was converted to Example 9 by using morpholine-(R)-3-carboxylic acid methyl ester XXX in the replacement reaction.
Example 10 4-[6-(4-Fluoro-phenyl)-2-(5-fluoro-pyridin-2-yl)-5-methoxycarbonyl-6- methyl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-(lS')-3-carboxylic acid
The title compound was prepared in analogy to Example 9 in Scheme 8 by using morpholine-^-S-carboxylic acid methyl ester instead of morpholine-(R)-3-carboxylic acid methyl ester in the replacement reaction.
Example 11 6-(2-(lS')-Carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(4-fluoro-phenyl)- 4-methyl-2-thiazol-2-yl- l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester The title compound was prepared in analogy to Example 3 in Scheme 6 by using 4,4- difluoro-pyrrolidine-(lS')-2-carboxylic acid methyl ester instead of 1-methylamino- cyclopropanecarboxylic acid methyl ester.
Example 12 6-(2-(R)-Carboxy-4,4-difluoro-pyrrolidin- l-ylmethyl)-4-(4-fluoro- phenyl)-4-methyl-2-thiazol-2-yl- l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester
The title compound was prepared in analogy to Example 3 in Scheme 6 by using 4,4- difluoro-pyrrolidine-(R)-2-carboxylic acid methyl ester instead of 1-methylamino- cyclopropanecarboxylic acid methyl ester.
Example 13 (lS')-6-((lS,)-2-Carboxy-4,4-difluoro-pyrrolidin- l-ylmethyl)-4-(4-fluoro- phenyl)-4-methyl-2-thiazol-2-yl- l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester
The title compound was prepared in analogy to Example 7 in Scheme 7 by using 4,4- difluoro-pyrrolidine-(lS')-2-carboxylic acid methyl ester instead of using morpholine-(lS')-3- carboxylic acid methyl ester XXVIII in the replacement reaction.
Example 14 (lS')-6-((lS,)-2-Carboxy-4,4-difluoro-pyrrolidin- l-ylmethyl)-4-(3,4-difluoro- phenyl)-4-methyl-2-thiazol-2-yl- l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester
The title compound was prepared according to the synthesis method shown in Scheme 1 and Scheme 3. A detailed synthesis route is provided as shown in Scheme 9.
Scheme 9
Figure imgf000069_0001
Figure imgf000069_0002
Figure imgf000069_0003
Figure imgf000069_0004
λλνι" Example 14
A mixture of 3,4-difluoro-benzaldehyde (8.96 g , 63.1 mmol), 3-oxo-butyric acid methyl ester (7.32 g, 63.1 mmol), piperidine (0.27 g, 3.16 mmol) and acetic acid (0.19 g, 3.16 mmol) in anhydrous ethanol (200 mL) was stirred for 12 hours at room temperature. After removal of the solvent, the residue was purified by flash column chromatography (EtOAc : hexane = 1 : 10) to afford the product of 2-[l-(3,4-difluoro-phenyl)-meth-(Z)-ylidene]-3-oxo-butyric acid methyl ester XXXI as yellow solid ( 13.6 g). Yield: 90%. MS: calc'd (M++H) 241.0, exp (M++H) 241.1. A solution of methylithium (1.6 M in ether, 48.7 mL, 78 mmol) was added to a suspension of copper(I) iodide (14.9 g, 78 mmol) in 200 mL of anhydrous THF under argon at 0 °C and the mixture was stirred for 1 hour at 0 °C. A solution of XXXI (8.0 g, 31.2 mmol) in 50 mL of anhydrous THF was added dropwisely into the mixture at -78 °C. After stirring at -78 °C for 1 hour, the reaction mixture was quenched with saturated ammonium chloride solution, extracted with EtOAc, washed with brine and dried over anhydrous sodium sulfate. After removal of organic solvent, the residue was purified by flash column chromatography (EtOAc : hexane = 1: 10) to afford 6.39 g of XXXII as oil. Yield: 80%. MS: calc'd (M++H) 257.1.
NaH (60%, 1.10 g, 27.5 mmol) was added into a solution of XXXII (5.0 g, 18.3 mmol) in anhydrous THF (100 mL) under argon. A solution of phenylselenyl chloride (5.3 g, 27.5 mmol) in THF (20 mL) was added into the flask at rt through syringe and the mixture was stirred at rt for 1 h. 60 mL of pentene/ether mixture (v/v =1/1) and 30 mL of saturated NaHC03 solution were added into the reaction mixture. The organic layer was separated and washed with brine, and treated with H202 solution (30%, 4 mL) in DCM (50 mL). The mixture was stirred at rt (for 0.5 ~2 hours) and diluted with DCM (100 mL). The organic phase was separated, washed with saturated sodium bicarbonate, sodium sulfite, water and brine in sequential and dried over anhydrous sodium sulfate. After removal of organic solvent, the residue was purified by flash column chromatography (EtOAc : hexane = 1: 10) to afford 3.97 g of XXXIII as yellow oil. MS: calc'd (M++H) 255.1, exp (M++H) 255.1 A mixture of XXXIII (2.54 g, 10 mmol), thiazole-2-carboxamidine hydrochloride XIX
(1.6g, 10 mmol) and sodium bicarbonate (1.68 g, 20 mmol) in NMP (15 mL) was stirred for 3 hours at 120 °C. After cooling, the mixture was separated between water and ethyl acetate. The organic phase was dried and concentrated. The residue was purified to afford the product of 4- (3,4-difluoro-phenyl)-4,6-dimethy l-2-thiazol-2-yl- 1 ,4-dihydro-pyrimidine-5-carboxylic acid methyl ester XXXIV as yellow solid (2.00 g). Yield: 55%. MS: calc'd (M++H) 363.1, exp (M++H) 363.1.
The chiral intermediate XXXV was separated from XXXIV by SFC and the absolute configuration was assigned through comparing its retention time on SFC with that of the stereochemistry known compound XXVII. The title compound Example 14 was prepared in analogy to Example 7 in Scheme 7 from
Compound XXXV. Example 15 ^[(^-G-iS^-Difluoro-pheny^-S-methoxycarbonyl-G-methyl-l-thiazol-l- yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid methyl ester
The title compound was prepared by the methods shown in Scheme 10 by using XXXIV in the bromination and following replacement reactions, which were carried out in the same procedures as Scheme 5 and Scheme 6.
Scheme 10
Figure imgf000071_0001
XXXIV Example 15
Example 16 4-[6-(3,4-Difluoro-phenyl)-5-methoxycarbonyl-6-methyl-2-thiazol-2-yl- 3,6-dihydro-pyrimidin-4-ylmethyl] -morpholine-3-carboxylic acid
The title compound was obtained by hydrolysis of Example 15 with LiOH in MeOH.
Example 17 6-(4,4-Difluoro-2-methoxycarbonyl-pyrrolidin-l-ylmethyl)-4-(4-fluoro- phenyl)-2-(5-fluoro-pyridin-2-yl)-4-methyl- 1 ,4-dihydro-pyrimidine-5-carboxylic acid methyl ester The title compound was prepared in analogy to Example 9 in Scheme 8 by using 4,4- difluoro-pyrrolidine-(lS')-2-carboxylic acid methyl ester instead of morpholine-(R)-3-carboxylic acid methyl ester XXXVIII in the replacement reaction.
Example 18 (lS')-6-((lS,)-2-Carboxy-4,4-difluoro-pyrrolidin- l-ylmethyl)-4-(4-fluoro- phenyl)-2-(5-fluoro-pyridin-2-yl)-4-methyl- 1 ,4-dihydro-pyrimidine-5-carboxylic acid methyl ester
The title compound was prepared in the methods as shown in Scheme 11.
Scheme 11
Figure imgf000072_0001
Figure imgf000072_0002
Example 9
Compound XXXVI was obtained by SFC chiral separation of intermediate XXIX and the absolute configuration was assigned through comparing its retention time on SFC with that of the stereochemistry known compound XXVII. Example 9 was prepared from XXXVI by following the procedures in Scheme 5 and Scheme 6, except that 4,4-difluoro-pyrrolidine-(lS')-2- carboxylic acid methyl ester XXXVII was used in the replacement reaction.
Example 19 6-((lS,)-2-Carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(4-fluoro-phenyl)- 4-methyl-2-(5-methyl-thiazol-2-yl)-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester
The title compound was prepared in the methods as shown in Scheme 12 by using 5- methyl-thiazole-2-carbonitrile in the preparation of ammidine. Compound XXXVIII was obtained by following the procedures in Scheme 5. And 4,4-difluoro-pyrrolidine-(lS')-2- carboxylic acid methyl ester XXXVII was used in the preparation of Example 19, in methods similar to Scheme 5 and Scheme 6.
Scheme 12
Figure imgf000073_0001
Example 19
Example 20 6-(2-Carboxy-4,4-difluoro-2-methyl-pyrrolidin-l-ylmethyl)-4-(4-fluoro- phenyl)-4-methyl-2-thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester The title compound was prepared in analogy to Example 3 in Scheme 6 by using 4,4- difluoro-2-methyl-pyrrolidine-2-carboxylic acid methyl ester instead of morpholine-3-carboxylic acid methyl ester.
Example 21 (lS')-l-[(lS,)-5-Cyano-6-(4-fluoro-phenyl)-6-methyl-2-thiazol-2-yl-3,6- dihydro-pyrimidin-4-ylmethyl]-4,4-difluoro-pyrrolidine-2-carboxylic acid The title compound was prepared according to the synthesis method shown in Scheme 2 and Scheme 3. A detailed synthesis route is provided as shown in Scheme 13.
Scheme 13 O O I
Figure imgf000074_0001
XXXIX
Figure imgf000074_0002
XL
XLI
Figure imgf000074_0003
XLII XXXVII
Example 21
Compound 4-(4-fluoro-phenyl)-4,6-dimethyl-2-thiazol-2-yl- 1 ,4-dihydro-pyrimidine-5- carboxylic acid iert-butyl ester XXXIX was prepared in analogy to XXXIV in Scheme 9 by using 3-oxo-butyric acid iert-butyl ester and 4-fluoro-benzaldehyde instead of 3-oxo-butyric acid methyl ester and 3,4-difluoro-benzaldehyde in the condensation reaction.
To a solution of 4-(4-fluoro-phenyl)-4,6-dimethyl-2-thiazol-2-yl-l,4-dihydro-pyrimidine-5- carboxylic acid iert-butyl ester XXXIX (1.0 g, 2.58mmol) in DCM (15 mL) was added TFA (2 mL), and the mixture was stirred for 3 hr. After that, the solvent and excess TFA was removed in vacuum. The residue XL was dissolved in DCM (15 mL), to which was added HATU (1.21 g,3.70 mmol) and NH3 in dioxane (10 mL, 0.5 M), and the mixture was stirred overnight. The mixture was diluted with DCM (50 mL), and washed with aqueous NaHC03 and brine. The organic layer was separated, dried over anhydrous Na2S04 and concentrated to give 0.89 g of 4- (4-fluoro-phenyl)-4,6-dimethyl-2-thiazol-2-yl- 1 ,4-dihydro-pyrimidine-5-carboxylic acid amide as light yellow solid which was directly for next use without purification.
The above crude intermediate (0.89g) was dissolved in THF (10 mL), TFAA (3 mL) was added and the mixture was stirred for 3 hr. After removal of THF and excess TFAA, the residue was dissolved in MeOH (20 mL). To the solution, K2C03 (2.0 g, 14.5 mmol) was added, and the mixture was stirred at rt for 3 hr. Then the mixture was filtered, the solid was washed with EtOAc (10 mL X 2). The combined filtrate was concentrated, the residue was purified by column chromatography (EtOAc/petroleum ether 1/3 to 1/2) to afford XLI as yellow solid (700 mg, totally yield: 87.0%).
The chiral intermediate XLII was separated from XLI by SFC.
The title compound Example 21 was prepared from XLII in analogy to Example 3 in Scheme 6.
Example 22 (lS')-4-[5-Cyano-6-(3,4-difluoro-phenyl)-6-methyl-2-thiazol-2-yl-3,6- dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid
The title compound was prepared according to the synthesis method shown in Scheme 2 and Scheme 3. A detailed synthesis route is provided as shown in Scheme 14.
Scheme 14
Figure imgf000076_0001
Figure imgf000076_0002
Example 22
Compound 4-(3,4-difluoro-phenyl)-4,6-dimethyl-2-thiazol-2-yl- 1 ,4-dihydro-pyrimidine-5- carboxylic acid iert-butyl ester XLIII was prepared in analogy to XXXIV in Scheme 9 by using 3-oxo-butyric acid iert-butyl ester and 3,4-difluorobenzaldehyde as starting material.
Compound 4-(3,4-difluoro-phenyl)-4,6-dimethyl-2-thiazol-2-yl- 1 ,4-dihydro-pyrimidine-5- carbonitrile XLIV was prepared from ie/t-butyl ester XLIII in the same method as XLI in Scheme 13.
The title compound Example 22 was prepared in the same method as shown in Scheme 5 and Scheme 6 by using morpholine-(lS')-3-carboxylic acid methyl ester XXVIII in the replacement reaction.
Example 23 (lS')-l-[(lS,)-5-Cyano-6-(3,4-difluoro-phenyl)-6-methyl-2-thiazol-2-yl-3,6- dihydro-pyrimidin-4-ylmethyl]-4,4-difluoro-pyrrolidine-2-carboxylic acid
The title compound was prepared according to the synthesis method shown in Scheme 2 and Scheme 3. A detailed synthesis route is provided as shown in Scheme 15.
Scheme 15
Figure imgf000077_0001
Example 23
Compound XLV was chiral separated from racemate XLIV by SFC and the absolute configuration was assigned through comparing its retention time on SFC with that of the stereochemistry known compound XXVII. The title compound was prepared in the same method as shown in Scheme 5 and Scheme 6 by using XXXVII in the replacement reaction.
Example 24 Preparation of (lS,)-6-((lS,)-2-carboxy-4,4-difluoro-pyrrolidin- l-ylmethyl)-4-
(3,4-difluoro-phenyl)-4-methyl-2-thiazol-2-yl- 1 ,4-dihydro-pyrimidine-5-carboxylic acid ethyl ester
The title compound was prepared in analogy to Example 7 in Scheme 7 by using 4-ethynyl-
1,2-difluoro-benzene instead of (S)-morpholine-3-carboxylic acid methyl ester.
Example 25 Preparation of (lS,)-6-(2-carboxy-5,5-difluoro-piperidin-l-ylmethyl)-4-(4- fluoro-phenyl)-4-methyl-2-thiazol-2-yl- l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester The title compound was prepared in analogy to Example 7 in Scheme 7 by using5,5- difluoro-piperidine-2-carboxylic acid instead of (S)-morpholine-3-carboxylic acid methyl ester.
Example 26 Preparation of (lS,)-6-(2-carboxy-4,4-difluoro-piperidin-l-ylmethyl) 4-(4- fluoro-phenyl)-4-methyl-2-thiazol-2-yl- l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester The title compound was prepared in analogy to Example 7 in Scheme 7 by using 4,4- difluoro-piperidine-2-carboxylic acid instead of (S)-morpholine-3-carboxylic acid methyl ester.
Example 27 Preparation of (lS,)-6-((lS,)-2-carboxy-4,4-difluoro-pyrrolidin- l-ylmethyl)-4-
(4-fluoro-phenyl)-4-methyl-2-(l-methyl- lH-imidazol-2-yl)- l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester The title compound was prepared in analogy to Example 7 in Scheme 7 by using 1-methyl- lH-imidazole-2-carbonitrile instead of thiazole-2-carbonitrile.
Example 28 Preparation of (R)-6-((lS')-2-carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4- (3,4-difluoro-phenyl)-4-methyl-2-thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid ethyl ester
The title compound was prepared in analogy to Example 7 in Scheme 7 by using 4-ethynyl- 1,2-difluoro-benzene instead of l-ethynyl-4-fluoro-benzene. Example 29 Preparation of (S)-4-[6-(3,4-difluoro-phenyl)-5-ethoxycarbonyl-6-methyl-
2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl] -morpholine-3-carboxylic acid
The title compound was prepared in analogy to Example 28 by using (S)-morpholine-3- carboxylic acid instead of (S)-4,4-difluoro-pyrrolidine-2-carboxylic acid. Example 30 Preparation of (lS')-4-[(lS,)-6-(4-fluoro-phenyl)-5-methoxycarbonyl-6- methyl-2-(l-methyl- lH-imidazol-2-yl)-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3- carboxylic acid
The title compound was prepared in analogy to Example 27 by using (S)-morpholine-3- carboxylic acid instead of (S)-4,4-difluoro-pyrrolidine-2-carboxylic acid.
Example 31 Preparation of (R)-6-((lS')-2-carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-
(4-fluoro-phenyl)-4-methyl-2-(4-methyl-thiazol-2-yl)- 1 ,4-dihydro-pyrimidine-5-carboxylic acid methyl ester
The title compound was prepared in analogy to Example 13 by using 4-methyl-thiazole-2- carbonitrile instead of thiazole-2-carbonitrile.
Example 32 Preparation of (lS,)-6-((lS,)-2-carboxy-4,4-difluoro-pyrrolidin- l-ylmethyl)-4-
(4-fluoro-phenyl)-4-methyl-2-(4-methyl-thiazol-2-yl)- 1 ,4-dihydro-pyrimidine-5-carboxylic acid methyl ester
The title compound was prepared in analogy to Example 13 by using 4-methyl-thiazole-2- carbonitrile instead of thiazole-2-carbonitrile. Example 33 Preparation of (lS,)-6-((lS,)-2-carboxy-4,4-difluoro-pyrrolidin- l-ylmethyl)-2-
(5-chloro-thiazol-2-yl)-4-(4-fluoro-phenyl)-4-methyl- 1 ,4-dihydro-pyrimidine-5-carboxylic acid methyl ester
The title compound was prepared in analogy to Example 13 by using 5-chloro-thiazole-2- carbonitrile instead of thiazole-2-carbonitrile.
Example 34 Preparation of (lS')-6-((2lS,,4R)-2-Carboxy-4-fluoro-pyrrolidin-l-ylmethyl)-
4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl- 1 ,4-dihydro-pyrimidine-5-carboxylic acid methyl ester
The title compound was prepared in analogy to Example 7 in Scheme 7 by using (2S,4R)-4- fluoro-pyrrolidine-2-carboxylic acid instead of (S)-morpholine-3-carboxylic acid methyl ester.
Example 35 Preparation of 6-((lS,)-2-carboxy-4,4-difluoro-pyrrolidin- l-ylmethyl)-4-(4- fluoro-phenyl)-2-isoxazol-3-yl-4-methyl-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester The title compound was prepared in analogy to Example 11 by using isoxazole-3- carbonitrile instead of thiazole-2-carbonitrile.
Example 36 Preparation of (R)-6-((lS')-2-carboxy-4,4-difluoro-2-methyl-pyrrolidin-l- ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl- l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester
The title compound was prepared in analogy to Example 7 in Scheme 7 by using (S)-4,4- difluoro-2-methyl-pyrrolidine-2-carboxylic acid instead of (S)-morpholine-3-carboxylic acid methyl ester. Example 37 Preparation of (lS,)-6-((lS,)-2-carboxy-4,4-difluoro-pyrrolidin- l-ylmethyl)-4-
(4-fluoro-phenyl)-4-methyl-2-(5-methyl-thiazol-2-yl)- 1 ,4-dihydro-pyrimidine-5-carboxylic acid methyl ester
The title compound was prepared in analogy to Example 13 by using 5-methyl-thiazole-2- carbonitrile instead of thiazole-2-carbonitrile.
Example 38 Preparation of (lS,)-6-((lS,)-2-carboxy-4,4-difluoro-pyrrolidin- l-ylmethyl)-4-
(4-fluoro-phenyl)-2-(5-fluoro-thiophen-2-yl)-4-methyl- 1 ,4-dihydro-pyrimidine-5-carboxylic acid methyl ester The title compound was prepared in analogy to Example 13 by using 5-fluoro-thiophene-2- carbonitrile instead of thiazole-2-carbonitrile.
Example 39 Preparation of (lS,)-6-((2lS,,4lS,)-2-carboxy-4-fluoro-pyrrolidin-l-ylmethyl)- 4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl- l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester
The title compound was prepared in analogy to Example 7 in Scheme 7 by using (2S,4S)-4- fluoro-pyrrolidine-2-carboxylic acid instead of (S)-morpholine-3-carboxylic acid methyl ester. Example 40 Preparation of 6-((lS,)-2-carboxy-4,4-difluoro-pyrrolidin- l-ylmethyl)-4-(4- fluoro-phenyl)-4-methyl-2-(5-methyl-isoxazol-3-yl)- 1 ,4-dihydro-pyrimidine-5-carboxylic acid methyl ester
The title compound was prepared in analogy to Example 11 by using 5-methyl-isoxazole-3- carbonitrile instead of thiazole-2-carbonitrile.
Example 41 Preparation of (lS,)-6-((lS,)-2-carboxy-4,4-difluoro-pyrrolidin- l-ylmethyl)-4-
(4-fluoro-phenyl)-2-(3-fluoro-thiophen-2-yl)-4-methyl- 1 ,4-dihydro-pyrimidine-5-carboxylic acid methyl ester
The title compound was prepared in analogy to Example 13 by using 3-fluoro-thiophene-2- carbonitrile instead of thiazole-2-carbonitrile.
Example 42 Preparation of (R)-6-((lS')-2-carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-
(4-fluoro-phenyl)-2-(3-fluoro-thiophen-2-yl)-4-methyl- 1 ,4-dihydro-pyrimidine-5-carboxylic acid methyl ester
The title compound was prepared in analogy to Example 13 by using 3-fluoro-thiophene-2- carbonitrile instead of thiazole-2-carbonitrile.
Example 43 Preparation of (lS,)-6-((lS,)-2-carboxy-4,4-difluoro-pyrrolidin- l-ylmethyl)-4-
(4-fluoro-phenyl)-2-(4-fluoro-thiophen-2-yl)-4-methyl- 1 ,4-dihydro-pyrimidine-5-carboxylic acid methyl ester
The title compound was prepared in analogy to Example 13 by using 4-fluoro-thiophene-2- carbonitrile instead of thiazole-2-carbonitrile. Example 44 Preparation of (S)-6-{ [carboxymethyl-(2,2,2-trifluoro-ethyl)-amino]- methyl}-4-(4-fluoro-phenyl)-4-methyl-2-m^ acid methyl ester
The title compound was prepared in analogy to Example 7 in Scheme 7 by using (2,2,2- trifluoro-ethylamino)-acetic acid instead of (S)-morpholine-3-carboxylic acid methyl ester.
Example 45 Preparation of (lS,)-6-((lS,)-4,4-difluoro-2-methoxycarbonyl-pyrrolidin- l- ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl- l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester
The title compound was prepared in analogy to Example 7 in Scheme 7 by using (S)-4,4- difluoro-pyrrolidine-2-carboxylic acid methyl ester instead of (S)-morpholine-3-carboxylic acid methyl ester.
Example 46 Preparation of (lS')-6-[(lS,)-2-(2-dimethylamino-ethoxycarbonyl)-4,4- difluoro-pyrrolidin- 1 -ylmethyl] -4- (4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl- 1 ,4-dihydro- pyrimidine-5-carboxylic acid methyl ester
The title compound was prepared in analogy to Example 7 in Scheme 7 by using (S)-4,4- difluoro-pyrrolidine-2-carboxylic acid 2-dimethylamino-ethyl ester instead of (S)-morpholine-3- carboxylic acid methyl ester.
Example 47 Preparation of (lS,)-6-(2-carbamoyl-4,4-difluoro-pyrrolidin- l-ylmethyl)-4-
(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl- 1 ,4-dihydro-pyrimidine-5-carboxylic acid methyl ester
The title compound was prepared in analogy to Example 7 in Scheme 7 by using 4,4- difluoro-pyrrolidine-2-carboxylic acid amide instead of (S)-morpholine-3-carboxylic acid methyl ester.
Example 48 Preparation of (lS,)-6-((lS,)-2-carbamoyl-4,4-difluoro-pyrrolidin-l- ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl- l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester
The title compound was prepared in analogy to Example 7 in Scheme 7 by using (S)-4,4- difluoro-pyrrolidine-2-carboxylic acid amide instead of (S)-morpholine-3-carboxylic acid methyl ester. Example 49 Preparation of (S)-6-((S)-2-dimethylcarbamoyl-4,4-diflu^ ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl- l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester
The title compound was prepared in analogy to Example 7 in Scheme 7 by using (S)-4,4- difluoro-pyrrolidine-2-carboxylic acid dimethylamide instead of (S)-morpholine-3-carboxylic acid methyl ester.
Example 50 Preparation of 6-((lS,)-4,4-difluoro-2-methylcarbamoyl-pyrrolidin-l- ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester
The title compound was prepared in analogy to Example 7 in Scheme 7 by using (S)-4,4- difluoro-pyrrolidine-2-carboxylic acid methylamide instead of (S)-morpholine-3-carboxylic acid methyl ester. Example 51 Preparation of (lS')-6-((S)-4,4-difluoro-2-methanesulfonylaminocarbonyl- pyrrolidin- l-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl- l,4-dihydro-pyrimidine-5- carboxylic acid methyl ester
The title compound was prepared in analogy to Example 7 in Scheme 7 by using N-((S)- 4,4-difluoro-pyrrolidine-2-carbonyl)-methanesulfonamide instead of (S)-morpholine-3- carboxylic acid methyl ester.
Example 52 Preparation of (lS,)-6-[(lS,)-4,4-difluoro-2-(thiazol-2-ylcarbamoyl)- pyrrolidin- l-ylmethyl]-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl- l,4-dihydro-pyrimidine-5- carboxylic acid methyl ester
The title compound was prepared in analogy to Example 7 in Scheme 7 by using (S)-4,4- difluoro-pyrrolidine-2-carboxylic acid thiazol-2-ylamide instead of (S)-morpholine-3-carboxylic acid methyl ester.
Example 53 Preparation of 4-(4-fluoro-phenyl)-6-((R)-3-hydroxymethyl-morpholin-4- ylmethyl)-4-methyl-2-thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester
The title compound was prepared in analogy to Example 7 in Scheme 7 by using (R)-l- morpholin-3-yl-methaol instead of (lS')-morpholine-3-carboxylic acid methyl ester. Example 54 Preparation of (S)-6-[(S)-4,4-difluoro-2-(l-hydroxy- l-m
pyrrolidin- l-ylmethyl]-4-(4-fluoro-phenyl)-4-m
carboxylic acid methyl ester
The title compound was prepared in analogy to Example 7 in Scheme 7 by using 2-((S)- 4,4-difluoro-pyrrolidin-2-yl)-propan-2-ol instead of (S)-morpholine-3-carboxylic acid methyl ester.
Example 55 Preparation of (lS,)-6-((lS,)-4,4-difluoro-2-hydroxymethyl-pyrrolidin- l- ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl- l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester
The title compound was prepared in analogy to Example 7 in Scheme 7 by using ((S)-4,4- difluoro-pyrrolidin-2-yl)-methanol instead of (S)-morpholine-3-carboxylic acid methyl ester.
Example 56 Preparation of (lS,)-6-[4,4-difluoro-2-(3-hydroxy-propyl)-pyrrolidin- l- ylmethyl]-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl- l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester
The title compound was prepared in analogy to Example 7 in Scheme 7 by using 3-(4,4- difluoro-pyrrolidin-2-yl)-propan-l-ol instead of (S)-morpholine-3-carboxylic acid methyl ester. Example 57 Preparation of (lS')-6-[(lS,)-4,4-difluoro-2-(5-methyl-[l,3,4]oxadiazol-2-yl)- pyrrolidin- l-ylmethyl]-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl- l,4-dihydro-pyrimidine-5- carboxylic acid methyl ester
The title compound was prepared in analogy to Example 7 in Scheme 7 by using 2-((S)- 4,4-difluoro-pyrrolidin-2-yl)-5-methyl-[l,3,4]oxadiazole instead of (S)-morpholine-3-carboxylic acid methyl ester.
Example 58 Preparation of (lS,)-6-[(lS,)-4,4-difluoro-2-(lH-tetrazol-5-yl)-pyrrolidin-l- ylmethyl]-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl- l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester
The title compound was prepared in analogy to Example 7 in Scheme 7 by using 5-((S)-
4,4-difluoro-pyrrolidin-2-yl)-lH-tetrazole instead of (S)-morpholine-3-carboxylic acid methyl ester. Example 59 Preparation of (S)-6-[(S)-4,4-difluoro-2-(3-methyl-[l,2,4]oxadiazol-5-yl)- pyrrolidin- l-ylmethyl]-4-(4-fluoro-phenyl^
carboxylic acid methyl ester
The title compound was prepared in analogy to Example 7 in Scheme 7 by using 5-((S)- 4,4-difluoro-pyrrolidin-2-yl)-3-methyl-[l,2,4]oxadiazole instead of (S)-morpholine-3-carboxylic acid methyl ester.
BIOLOGICAL EXAMPLES
Example 60 HBV inhibition assays (biochemical assay) Cells and culture conditions: HepDE19 (Haitao Guo et al, Journal of Virology, 81, Nov.
2007, 12472- 12484; Richeng Mao etal, Journal of Virology, 85, Jan. 2011 , 1048-1057) cells were derived from HepG2 (ATCC, American Type Culture Collection) cells through transfection with pTet-off plasmid (Clontech) that expresses the Tet-responsive transcriptional activator and pTREHBVDE plasmid in which HBV pgRNA expression is controlled by a CMV early promoter with a tetracycline-responsive element. The transfected cells were selected with G418 (also known as Genticin, purchased from Invitrogen). In tetracycline-free medium, cells support high levels of HBV DNA replication and HBV virus secretion. These cells were maintained in Dulbecco's modified Eagle's medium (DMEM)-F12 medium (Invitrogen) supplemented with 10% fetal bovine serum, 100 U/ml penicillin, and 100 μg/ml streptomycin, 0.5 mg/ml of G418 and ^g/ml tetracycline.
Anti-HBV activity and cytotoxicity: HepDE19 cells were seeded into 96- well plates (3xl04 cells/well) with tetracyc line-free medium and incubated overnight at 37 °C. The test or control compounds were serially half-log diluted with medium and added into the plates (the final concentration of DMSO kept at 0.5% in each well). Five days after compound treatment, cells were washed with PBS and lysed with 50 mM Tris- lmM EDTA-0.2% CA-630 (pH 8.0) at 37°C for 20 min. After centrifugation to remove nuclei and other debris, the supernatant was transferred into a new plate and incubated with 2M NaOH/20xSSC (3M NaCl, 0.3M Sodium citrate, pH7.0) at rt for 30 min. Then the samples were transferred to nylon membrane and neutralized withlM Tris (pH7.4)/2M NaCl. The presence of HBV DNA was detected by dot-blot with DIG-labeled HBV specific DNA probe and quantified by dot density. The compound concentrations that inhibited HBV DNA by 50% (EC50) were determined (See Table 1).
To determine if the anti-HBV effect of compound is due to cytotoxicity, HepDE19 cells (5x10J cells/well) were seeded into 96-well plates and compounds were treated as described above. Five days after treatment, cell viability was measured by addition of 20 μΐ of CCK-8 reagent. Four hours after incubation at 37 °C, the absorbance at wavelengths of 450 nm and 630 nm (OD450 and Οϋ63ο) was recorded by a plate reader. The 50% cytotoxic concentration (CC50) of each compounds were determined accordingly.
The compounds of the present invention were tested for their capacity to inhibit a HBV activity and activation as described herein. The Examples were tested in the above assay and found to have EC50 of about 0.01 μΜ to about 50 μΜ. Particular compounds of formula I were found to have EC50 of about Ο. ΙμΜ to about 30 μΜ.
Results of HepDel9 EC50 (μΜ) and CC50 (μΜ) are given in Table 1. Example A
A compound of formula I can be used in a manner known per se as the active ingredient for the production of tablets of the following composition:
Per tablet
Active ingredient 200 mg
Microcrystalline cellulose 155 mg
Corn starch 25 mg
Talc 25 mg
Hydroxypropylmethylcellulose 20 mg
425 mg
Example B
A compound of formula I can be used in a manner known per se as the active ingredient for the production of capsules of the following composition:
Per capsule
Active ingredient 100.0 mg
Corn starch 20.0 mg
Lactose 95.0 mg
Talc 4.5 mg
Magnesium stearate 0.5 mg
220.0 mg

Claims

Claims
Compounds of formula (I)
Figure imgf000086_0001
wherein,
R1 is Ci^alkoxycarbonyl or cyano;
R is phenyl, which is substituted by halogen;
R is thiazolyl, thienyl, imidazolyl, isoxazolyl or pyridinyl; which is unsubstituted or substituted by halogen or C1-6alkyl;
X is oxygen or -NR7;
R4 and R5 are independently selected from hydrogen, Ci-ealkyl and trifluoroCi-ealkyl; or
R4 and R5, together with the carbon atom to which they are attached, form a 3 to 7 membered cycloalkyl; or when X is -NR7, one of R4 and R5 is hydrogen or Ci-6alkyl, and the other one with the carbon atom to which it is attached and -NR , form a pyrrolidinyl, morpholinyl or piperidinyl ring, which ring is unsubstituted or substituted by fluoro;
M is C1-6alkoxycarbonyl, carboxy, diC1-6alkylaminoC2-6alkoxycarbonyl, aminocarbonyl, C1-6alkylaminocarbonyl, diC1-6alkylaminocarbonyl, C1-6alkylsulfonylaminocarbonyl, 2- 1 6alkyl
Figure imgf000086_0002
azo y am nocar ony , y roxy- y 2y-, or
Figure imgf000086_0003
R is Ci-6alkyl or trifluoroCi-ealkyl; y is 1-6; or pharmaceutically acceptable salts, or tautomerism isomers thereof. 2. A compound according to claim 1, wherein, R1 is Ci^alkoxycarbonyl or cyano;
R is phenyl, which is once or twice substituted by halogen;
R is 2-thiazolyl, which is unsubstituted or once substituted by Ci-ealkyl or halogen; or 2- thienyl or 2-pyridinyl, which is once substituted by halogen; or 2-imidazolyl, which is once substituted by Ci-6alkyl; or 3-isoxazolyl, which is unsubstituted or once substituted by Ci-6alkyl; X is oxygen or -NR ;
R4 and R5 are independently selected from hydrogen, Ci-ealkyl and trifluoroCi-ealkyl; or
R4 and R5, together with the carbon atom to which they are attached, form a 3 to 7 membered cycloalkyl; or when X is -NR7, one of R4 and R5 is hydrogen or C1-6alkyl, and the other one with the
7
carbon atom to which it is attached and -NR together form a morpholinyl; or pyrrolidinyl or piperidinyl, which is substituted by fluoro;
M is Ci-ealkoxycarbonyl, carboxy, diCi-ealkylamino-Ci-ealkoxycarbonyl, aminocarbonyl, Ci-ealkylaminocarbonyl, diCi-ealkylaminocarbonyl, Ci-ealkylsulfonylaminocarbonyl,
2- 1 -6alkyl
Figure imgf000087_0001
thiazolylaminocarbonyl, hydroxy-CyH2y-, , or
Figure imgf000087_0002
7
R is Ci-6alkyl or trifluoroCi-ealkyl; y is 1-6; or pharmaceutically acceptable salts, or tautomerism isomers thereof.
3. A compound according to claim 1 or 2, wherein R is methoxycarbonyl, ethoxycarbonyl or cyano;
R is phenyl substituted once or twice by fluoro;
Figure imgf000088_0001
X is oxygen or -NR7;
R4 and R5 are independently selected from hydrogen, methyl and trifluoromethyl; or
R4 and R5 together with the carbon atom to which they are attached form cyclopropyl; or when X is -NR7, one of R4 and R5 is h drogen or methyl, and the other one with the carbon atom
to which it is attached and -NR7 form
Figure imgf000088_0002
M is methoxycarbonyl, carboxy, dimethylaminoethoxycarbonyl, aminocarbonyl, dimethylaminocarbonyl, methylaminocarbonyl, methylsulfon laminocarbon l, 2-
thiazolylaminocarbonyl, hydroxymethyl, hydroxypropyl,
Figure imgf000088_0003
or
Figure imgf000088_0004
R is methyl or trifluoroethyl; or pharmaceutically acceptable salts, or tautomerism isomers thereof.
4. A compound according to claim 1 or 2, wherein. R1 is Ci^alkoxycarbonyl;
R is phenyl which is once substituted by halogen; R is 2-thiazolyl; X is oxygen; R4 and R5 are independently selected from hydrogen, Ci_6alkyl and trifluoroCi-ealkyl; M is Ci_6alkoxycarbonyl or carboxy.
5. A compound according to any one of claims 1 to 4, wherein R1 is methyoxycarbonyl;
Figure imgf000089_0001
X is oxygen;
R4 and R5 are independently selected from hydrogen, methyl and trifluoromethyl; M is methoxycarbonyl or carboxy.
6. A compound according to claim 1 or 2, wherein R1 is Ci-2alkoxycarbonyl;
R2 is phenyl which is once substituted by halogen; R3 is 2-thiazolyl;
X is -N-C1-6alkyl or
Figure imgf000089_0002
R4 is hydrogen;
R5 is hydrogen; or R4 and R5, together with the carbon atom to which they are attached, form a 3 to 7 membered cycloalkyl;
M is carboxy.
7. A compound according to any one of claims 1, 2, 3 or 6, wherein R1 is methoxycarbonyl;
Figure imgf000090_0001
R4 is hydrogen; R5 is hydrogen; or R4 and R5, together with the carbon atom to which they are attached, form cyclopropyl;
M is carboxy.
8. A compound according to claim 1 or 2, wherein R1 is Ci^alkoxycarbonyl or cyano;
R is phenyl which is once or twice substituted by halogen;
R is 2-thiazolyl; or 2-pyridinyl, which is once substituted by halogen; or 2-imidazolyl, which is once substituted by Ci-6alkyl;
X is -NR7; one of R4 and R5 is hydrogen, and the other one with the carbon atom to which it is attached and -NR together form a morpholinyl;
M is Ci-ealkoxycarbonyl, carboxy or hydroxy-CyH2y-; y is 1-6.
9. A compound according to any one of claims 1, 2, 3 or 8, wherein R1 is methoxycarbonyl, ethoxycarbonyl or cyano;
Figure imgf000091_0001
one of R4 and R5 is h drogen, and the other one with the carbon atom to which it is
attached and -NR form
Figure imgf000091_0002
M is methoxycarbonyl, carboxy or hydroxymethyl-.
10. A compound according to claim 1 or 2, wherein R1 is Ci^alkoxycarbonyl or cyano;
R is phenyl which is once or twice substituted by halogen;
R is 2-thiazolyl, which is unsubstituted or once substituted by Ci-ealkyl or halogen; or 2- thienyl or 2-pyridinyl, which is once substituted by halogen; or 2-imidazolyl, which is once substituted by Ci-6alkyl; or 3-isoxazolyl, which is unsubstituted or once substituted by Ci-6alkyl;
X is -NR7; one of R4 and R5 is hydrogen or Ci-ealkyl, and the other one with the carbon atom to which it is attached and -NR together form a pyrrolidinyl or piperidinyl, which is substituted by fluoro;
M is Ci-ealkoxycarbonyl, carboxy, diCi-ealkylaminoCi-ealkoxycarbonyl, aminocarbonyl, Ci-ealkylaminocarbonyl, diCi-ealkylaminocarbonyl, Ci-ealkylsulfonylaminocarbonyl, 2- ^alkyl
thiazolylaminocarbonyl, hydroxy-C
Figure imgf000091_0003
yH2y-, , or y is 1-6.
11. A compound according to any one of claims 1, 2, 3 or 10, wherein R is methoxycarbonyl, ethoxycarbonyl or cyano;
Figure imgf000092_0001
X is -NR7; one of R4 and R5 is h drogen or methyl, and the other one with the carbon atom to which
it is attached and -NR
Figure imgf000092_0002
M is methoxycarbonyl, carboxy, dimethylaminoethoxycarbonyl, aminocarbonyl, dimethylaminocarbonyl, methylaminocarbonyl, methylsulfonylaminocarbon l, 2-
Figure imgf000092_0003
thiazol laminocarbonyl, hydroxymethyl, hydroxypropyl,
Figure imgf000092_0004
12. A compound according to claim 1 of formula (Γ)
Figure imgf000093_0001
wherein,
R1 is Ci-ialkoxycarbonyl or cyano;
R is phenyl, which is substituted by halogen;
R is 2-thiazolyl which is unsubstituted or substituted by Ci-6alkyl or 2-pyridinyl, which is substituted by halogen;
X is oxygen or -NR7;
R4 and R5 are independently selected from hydrogen, Ci-6alkyl and trifluoroCi-ealkyl; or
R4 and R5, together with the carbon atom to which they are attached, form a 3 to 7 membered cycloalkyl; or when X is -NR7, one of R4 and R5 is hydrogen or C1-6alkyl, and the other one with the carbon atom to which it is attached and -NR together form a morpholinyl; or pyrrolidinyl substituted by fluoro;
R6 is hydrogen or Ci-ealkyl;
R7 is Ci-ealk l; or pharmaceutically acceptable salts, or tautomerism isomers thereof.
13. A compound according to claim 12, wherein R1 is methoxycarbonyl or cyano;
R is phenyl substituted once or twice by fluoro;
Figure imgf000093_0002
X is oxygen or -NR7;
R4 and R5 are independently selected from hydrogen, methyl and trifluoromethyl; or R4 and R5 together with the carbon atom to which they are attached form cyclopropyl; or when X is -NR7, one of R4 and R5 is hydrogen or methyl, and the other one with the carbon atom
to which it is attached and -NR7 form
Figure imgf000094_0001
or R6 is hydrogen or methyl; R7 is methyl; or pharmaceutically acceptable salts, or tautomerism isomers thereof.
14. A compound according to claim 12, wherein R1 is Ci^alkoxycarbonyl or cyano; R is phenyl which is substituted by halogen; R is 2-thiazolyl or 2-pyridinyl, which is substituted by halogen;
X is -NR7; one of R4 and R5 is hydrogen or Ci-6alkyl, and the other one with the carbon atom to which it is attached and -NR together form a morpholinyl;
R6 is hydrogen or Ci-ealkyl.
15. A compound according to any one of claims 12, 13 or 14, wherein
R1 is methoxycarbonyl or cyano;
Figure imgf000094_0002
one of R"* and RD is hydrogen or methyl, and the other one
Figure imgf000094_0003
with the carbon atom to which it is attached and -NR7 form ; R6 is hydrogen or methyl.
16. A compound according to claim 12, wherein R1 is Ci-ialkoxycarbonyl or cyano; R is phenyl which is substituted by halogen;
R is 2-thiazolyl which is unsubstituted or substituted by Ci-6alkyl or 2-pyridinyl, which is substituted by halogen;
X is -NR7; one of R4 and R5 is hydrogen or Ci-ealkyl, and the other one with the carbon atom to which it is attached and -NR together form a pyrrolidinyl which is substituted by fluoro;
R6 is hydrogen or Ci-ealkyl.
17. A compound according to any one of claims 12, 13 and 16, wherein
R1 is methoxycarbonyl or cyano;
Figure imgf000095_0001
X is -NR7; one of R4 and R methyl, and the other one with the carbon atom to which
7
Figure imgf000095_0002
it is attached and -NR orm
R6 is hydrogen or methyl.
18. A compound according to any one of claims 1 to 17, selected from
4-(4-fluoro-phenyl)-6-(l-methoxycarbonyl-l-methyl-ethoxymethyl)-4-methyl-2-thiazol-2-yl-l,4- dihydro-pyrimidine-5-carboxylic acid methyl ester; 6-(l-carboxy-2,2,2-trifluoro-ethoxymethyl)- 4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl- 1 ,4-dihydro-pyrimidine-5-carboxylic acid methyl ester; 6- { [(l-carboxy-cyclopropyl)-methyl-amino] -methyl }-4-(4-fluoro-phenyl)-4-methyl-2- thiazol-2-yl- l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester; 4-[6-(4-fluoro-phenyl)-5- methoxycarbonyl-6-methyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3- carboxylic acid; 4-[6-(4-fluoro-phenyl)-5-methoxycarbonyl-6-methyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl]-morpholine-(lS')-3-carboxylic acid methyl ester; 4-[6-(4-fhioro-phenyl)-5- methoxycarbonyl-6-methyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-(lS')-3- carboxylic acid; (lS,)-4-[6-(4-fluoro-phenyl)-5-methoxycarbonyl-6-methyl-2-thiazol-2-yl-3,6- dihydro-pyrimidin-4-ylmethyl]-morpholine-(lS')-3-carboxylic acid; (lS,)-4-[6-(4-fluoro-phenyl)-5- methoxycarbonyl-6-methyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-(R)-3- carboxylic acid; 4-[6-(4-fluoro-phenyl)-2-(5-fluoro-pyridin-2-yl)-5-methoxycarbonyl-6-methyl- 3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-(R)-3-carboxylic acid; 4-[6-(4-fluoro-phenyl)-2- (5-fluoro-pyridin-2-yl)-5-methoxycarbonyl-6-methyl-3,6-dihydro-pyrimidin-4-ylmethyl]- morpholine-^-S-carboxylic acid; 6-(2-(lS,)-carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(4- fluoro-phenyl)-4-methyl-2-thiazol-2-yl- l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester; 6-(2-(R)-carboxy-4,4-difluoro-pyrrolidin- l-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2- yl-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester; (lS,)-6-((5,)-2-carboxy-4,4-difluoro- pyrrolidin- l-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl- l,4-dihydro-pyrimidine-5- carboxylic acid methyl ester; (lS,)-6-((5,)-2-carboxy-4,4-difluoro-pyrrolidin- l-ylmethyl)-4-(3,4- difluoro-phenyl)-4-methyl-2-thiazol-2-yl- l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester; 4-[(lS,)-6-(3,4-difluoro-phenyl)-5-methoxycarbonyl-6-methyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid methyl ester; 4-[6-(3,4-difluoro-phenyl)-5- methoxycarbonyl-6-methyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3- carboxylic acid; 6-(4,4-difluoro-2-methoxycarbonyl-pyrrolidin-l-ylmethyl)-4-(4-fluoro-phenyl)- 2-(5-fluoro-pyridin-2-yl)-4-methyl- l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester; 6-(2- carboxy-4,4-difluoro-pyrrolidin- l-ylmethyl)-4-(4-fluoro-phenyl)-2-(5-fluoro-pyridin-2-yl)-4- methyl- l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester; 6-((5,)-2-carboxy-4,4-difluoro- pyrrolidin- l-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-(5-methyl-thiazol-2-yl)-l,4-dihydro- pyrimidine-5-carboxylic acid methyl ester; 6-(2-carboxy-4,4-difluoro-2-methyl-pyrrolidin- l- ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl- l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester; (S)- l-[(S)-5-cyano-6-(4-fluoro-phenyl)-6-methyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl]-4,4-difluoro-pyrrolidine-2-carboxylic acid; (lS')-4-[5-cyano-6-(3,4- difluoro-phenyl)-6-methyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3- carboxylic acid; (lS,)- l-[(5,)-5-cyano-6-(3,4-difluoro-phenyl)-6-methyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl]-4,4-difluoro-pyrrolidine-2-carboxylic acid; (lS,)-6-((5,)-2-carboxy-4,4- difluoro-pyrrolidin- 1 -ylmethyl^
pyrimidine-5-carboxylic acid ethyl ester; (lS,)-6-(2-carboxy-5,5-difluoro-piperidin-l-ylmethyl)-4- (4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl- 1 ,4-dihydro-pyrimidine-5-carboxylic acid methyl ester; (lS,)-6-(2-carboxy-4,4-difluoro-piperidin-l-ylmethyl)4-(4-fluoro-phenyl)-4-methyl-2- thiazol-2-yl- l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester; (lS,)-6-((5,)-2-carboxy-4,4- difluoro-pyrrolidin-l-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-(l -methyl- lH-imidazol-2-yl)- l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester; (R)-6-((5,)-2-carboxy-4,4-difluoro- pyrrolidin- l-ylmethyl)-4-(3,4-difluoro-phenyl)-4-methyl-2-thiazol-2-yl-l,4-dihydro-pyrimidine- 5-carboxylic acid ethyl ester; (S)-4-[6-(3,4-difluoro-phenyl)-5-ethoxycarbonyl-6-methyl-2- thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl] -morpholine-3-carboxylic acid; (5)-4-[(5')-6-(4- fluoro-phenyl)-5-methoxycarbonyl-6-methyl-2-(l-methyl-lH-imidazol-2-yl)-3,6-dihydro- pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid; (R)-6-((5,)-2-carboxy-4,4-difluoro- pyrrolidin- l-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-(4-methyl-thiazol-2-yl)-l,4-dihydro- pyrimidine-5-carboxylic acid methyl ester; (S)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-l- ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-(4-methyl-thiazol-2-yl)-l,4-dihydro-pyrimidine-5- carboxylic acid methyl ester; (lS,)-6-((5,)-2-carboxy-4,4-difluoro-pyrrolidin- l-ylmethyl)-2-(5- chloro-thiazol-2-yl)-4-(4-fluoro-phenyl)-4-methyl- 1 ,4-dihydro-pyrimidine-5-carboxylic acid methyl ester; (S)-6-((2S,4R)-2-carboxy-4-fluoro-pyrrolidin- l-ylmethyl)-4-(4-fhioro-phenyl)-4- methyl-2-thiazol-2-yl- l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester; 6-((5,)-2-carboxy- 4,4-difluoro-pyrrolidin- 1 -ylmethyl)-4-(4-fluoro-phenyl)-2-isoxazol-3-yl-4-methyl- 1 ,4-dihydro- pyrimidine-5-carboxylic acid methyl ester; (R)-6-((5,)-2-carboxy-4,4-difluoro-2-methyl- pyrrolidin- l-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl- l,4-dihydro-pyrimidine-5- carboxylic acid methyl ester; (lS,)-6-((5,)-2-carboxy-4,4-difluoro-pyrrolidin- l-ylmethyl)-4-(4- fluoro-phenyl)-4-methyl-2-(5-methyl-thiazol-2-yl)- 1 ,4-dihydro-pyrimidine-5-carboxylic acid methyl ester; (S)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin- l-ylmethyl)-4-(4-fhioro-phenyl)-2-(5- fluoro-thiophen-2-yl)-4-methyl-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester; (5)-6- ((2lS,,4lS,)-2-carboxy-4-fluoro-pyrrolidin-l-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl- l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester; 6-((5,)-2-carboxy-4,4-difluoro-pyrrolidin- l-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-(5-methyl-isoxazol-3-yl)- l,4-dihydro-pyrimidine-5- carboxylic acid methyl ester; (lS,)-6-((5,)-2-carboxy-4,4-difluoro-pyrrolidin- l-ylmethyl)-4-(4- fluoro-phenyl)-2-(3-fluoro-thiophen-2-yl)-4-methyl- 1 ,4-dihydro-pyrimidine-5-carboxylic acid methyl ester; (R)-6-((5,)-2-carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(4-fluoro-phenyl)-2-(3- fluoro-thiophen-2-yl)-4-methyl-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester; (S)-6- ((lS')-2-carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(4-fluoro-phenyl)-2-(4-fluoro-thiophen-2- yl)-4-methyl-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester; (^^-{ [carboxymethyl- (2,2,2-trifluoro-ethyl)-amino] -methyl }-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl- l,4-dihydro- pyrimidine-5-carboxylic acid methyl ester; (lS,)-6-((5,)-4,4-difluoro-2-methoxycarbonyl- pyrrolidin- l-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl- l,4-dihydro-pyrimidine-5- carboxylic acid methyl ester; (lS')-6-[(lS,)-2-(2-dimethylamino-ethoxycarbonyl)-4,4-difluoro- pyrrolidin- l-ylmethyl]-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl- l,4-dihydro-pyrimidine-5- carboxylic acid methyl ester; (lS,)-6-(2-carbamoyl-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(4- fluoro-phenyl)-4-methyl-2-thiazol-2-yl- l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester; (lS,)-6-((5,)-2-carbamoyl-4,4-difluoro-pyrrolidin- l-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2- thiazol-2-yl- l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester; (5)-6-((5')-2- dimethylcarbamoyl-4,4-difluoro-pyrrolidin- l-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol- 2-yl- l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester; 6-((5,)-4,4-difluoro-2- methylcarbamoyl-pyrrolidin-l-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl- l,4- dihydro-pyrimidine-5-carboxylic acid methyl ester; (lS,)-6-((5,)-4,4-difluoro-2- methanesulfonylaminocarbonyl-pyrrolidin-l-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol- 2-yl- l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester; (lS,)-6-[(5,)-4,4-difluoro-2-(thiazol-2- ylcarbamoyl)-pyrrolidin- 1 -ylmethyl] -4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-l,4-dihydro- pyrimidine-5-carboxylic acid methyl ester; 4-(4-fluoro-phenyl)-6-((R)-3-hydroxymethyl- morpholin-4-ylmethyl)-4-methyl-2-thiazol-2-yl- 1 ,4-dihydro-pyrimidine-5-carboxylic acid methyl ester; (lS,)-6-[(5,)-4,4-difluoro-2-(l -hydroxy- l-methyl-ethyl)-pyrrolidin- 1 -ylmethyl] -4- (4- fluoro-phenyl)-4-methyl-2-thiazol-2-yl- l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester; (lS,)-6-((5,)-4,4-difluoro-2-hydroxymethyl-pyrrolidin- l-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2- thiazol-2-yl- l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester; (lS,)-6-[4,4-difluoro-2-(3- hydroxy-propyl)-pyrrolidin- 1 -ylmethyl] -4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl- 1 ,4- dihydro-pyrimidine-5-carboxylic acid methyl ester; (lS,)-6-[(5,)-4,4-difluoro-2-(5-methyl- [l,3,4]oxadiazol-2-yl)-pyrrolidin- l-ylmethyl]-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl- l,4- dihydro-pyrimidine-5-carboxylic acid methyl ester; (lS,)-6-[(5,)-4,4-difluoro-2-(lH-tetrazol-5-yl)- pyrrolidin- l-ylmethyl]-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl- l,4-dihydro-pyrimidine-5- carboxylic acid methyl ester; and (lS,)-6-[(5,)-4,4-difluoro-2-(3-methyl-[l,2,4]oxadiazol-5-yl)- pyrrolidin- l-ylmethyl]-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl- l,4-dihydro-pyrimidine-5- carboxylic acid methyl ester.
19. A process for the preparation of a compound according to any one of claims 1 to 18 comprising the reaction of
(a) a compound of formula (A)
Figure imgf000099_0001
in the presence of an acid; wherein R1 to R5, M and X are defined as in any one of claims 1 to 17.
20. A compound according to any one of claims 1 to 18 for use as therapeutically active substance.
21. A pharmaceutical composition comprising a compound in accordance with any one of claims 1 to 18 and a therapeutically inert carrier.
22. The use of a compound according to any one of claims 1 to 18 for the treatment or prophylaxis of hepatitis B virus infection.
23. The use of a compound according to any one of claims 1 to 18 for the preparation of a medicament for the treatment or prophylaxis of hepatitis B virus infection.
24. A compound according to any one of claims 1 to 18 for the treatment or prophylaxis of hepatitis B virus infection.
25. A compound according to any one of claims 1 to 18, when manufactured according to a process of claim 19.
26. A method for the treatment or prophylaxis of hepatitis B virus infection, which method comprises administering an effective amount of a compound as defined in any one of claims 1 to
18.
27. The invention as hereinbefore described.
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RU2014142598A (en) 2016-05-27
CN104144924B (en) 2016-02-24
EP2831060B1 (en) 2016-05-04
ES2575398T3 (en) 2016-06-28
CN104144924A (en) 2014-11-12
CA2865259A1 (en) 2013-10-03
KR20140143160A (en) 2014-12-15
JP2015511614A (en) 2015-04-20
EP2831060A1 (en) 2015-02-04

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