WO2014037480A1 - 6-amino acid heteroaryldihydropyrimidines for the treatment and prophylaxis of hepatitis b virus infection - Google Patents

6-amino acid heteroaryldihydropyrimidines for the treatment and prophylaxis of hepatitis b virus infection Download PDF

Info

Publication number
WO2014037480A1
WO2014037480A1 PCT/EP2013/068429 EP2013068429W WO2014037480A1 WO 2014037480 A1 WO2014037480 A1 WO 2014037480A1 EP 2013068429 W EP2013068429 W EP 2013068429W WO 2014037480 A1 WO2014037480 A1 WO 2014037480A1
Authority
WO
WIPO (PCT)
Prior art keywords
carboxylic acid
phenyl
fluoro
dihydro
ylmethyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2013/068429
Other languages
French (fr)
Inventor
Lei Guo
Taishan HU
Yimin Hu
Buelent Kocer
Xianfeng Lin
Haixia Liu
Alexander V. Mayweg
Zongxing Qiu
Hong Shen
Guozhi Tang
Lisha Wang
Guolong Wu
Shixiang YAN
Weixing Zhang
Mingwei Zhou
Wei Zhu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
F Hoffmann La Roche AG
Hoffmann La Roche Inc
Original Assignee
F Hoffmann La Roche AG
Hoffmann La Roche Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=49212746&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2014037480(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to CA2881322A priority Critical patent/CA2881322A1/en
Priority to SG11201500377UA priority patent/SG11201500377UA/en
Priority to ES13763201.4T priority patent/ES2617906T3/en
Priority to MX2015002954A priority patent/MX2015002954A/en
Priority to MA37942A priority patent/MA37942B1/en
Priority to HK15110886.9A priority patent/HK1210152A1/en
Priority to BR112015004113A priority patent/BR112015004113A2/en
Priority to JP2015530405A priority patent/JP6113285B2/en
Application filed by F Hoffmann La Roche AG, Hoffmann La Roche Inc filed Critical F Hoffmann La Roche AG
Priority to EP13763201.4A priority patent/EP2892893B2/en
Priority to KR1020157005893A priority patent/KR20150054795A/en
Priority to AU2013311705A priority patent/AU2013311705A1/en
Priority to EA201590384A priority patent/EA201590384A1/en
Priority to CN201380046738.5A priority patent/CN104603125A/en
Publication of WO2014037480A1 publication Critical patent/WO2014037480A1/en
Priority to IL236691A priority patent/IL236691A0/en
Priority to ZA2015/00580A priority patent/ZA201500580B/en
Priority to CR20150085A priority patent/CR20150085A/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • 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
    • 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
    • C07D403/02—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 two hetero rings
    • C07D403/06—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 two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D417/14—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

  • 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 for the treatment of 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 is shunted to the nucleus, where they are converted to cccDNA.
  • cccDNA covalently closed circular DNA
  • 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. et al. 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 as HBV inhibitors and for the treatment or prophylaxis of HBV infection.
  • the compounds of formula I show superior anti-HBV activity.
  • the compounds of formula I also show high selectivity index, better solubility and mouse SDPK profiles.
  • Ci_ 6 alkyl 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, tert- vXy ⁇ and the like.
  • Particular "Ci_ 6 alkyl” groups are methyl, ethyl, isopropyl and tert-bvXy ⁇ .
  • -C X H2 X - alone or in combination signifies a saturated, linear or branched chain alkyl group containing from 1 to 6 carbon atoms, particularly from 1 to 4 carbon atoms.
  • 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.
  • cyano alone or in combination refers to the group -CN.
  • halogen means fluorine, chlorine, bromine or iodine. Halogen is particularly fluorine, chlorine or bromine.
  • enantiomer denotes two stereoisomers of a compound which are non- superimposable mirror images of one another.
  • diastereomer denotes a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another.
  • the compounds according to the present invention may exist in the form of their pharmaceutically acceptable salts.
  • 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 /?-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 1 is Ci_ 6 alkyl or trifluoromethyl-C x H 2x -, wherein x is 1-6;
  • R 2 and R 3 is phenyl, which is once or twice or three times substituted by Ci_ 6 alkyl, cyano or halogen; and the other one is hydrogen or deuterium;
  • R 4 is phenyl, thiazolyl, oxazolyl, imidazolyl, thienyl or pyridinyl, which is unsubstituted or substituted by Ci_ 6 alkyl, Ci_ 6 alkylsulfanyl, halogen or cycloalkyl, where said Ci_ 6 alkyl can be further optionally substituted with halogen;
  • FIG. 1 is a compound of formula I, wherein R 1 is methyl, ethyl, propyl, isopropyl, tert-butyl or trifluoromethylmethyl;
  • R 2 and R 3 is phenyl, which is once or twice or three times substituted by fluoro, chloro, bromo, iodo, methyl, or cyano; and the other one is hydrogen or deuterium;
  • R 4 is phenyl, thiazolyl, oxazolyl, imidazolyl, thienyl or pyridinyl, which is unsubstituted or substituted by methyl, isopropyl, tert-butyl, bifluoromethyl, trifluoromethyl, cyclopropyl, meth lsulfanyl, fluoro or chloro;
  • Another embodiment of present invention is (iii) a compound of formula I, wherein R 1 is Ci_6alkyl or trif uoromethyl-C x H 2x -, wherein x is 1-6;
  • R 2 and R 3 is phenyl, which is once or twice or three times substituted by C ⁇ aUcyl, cyano or halogen; and the other one is hydrogen or deuterium;
  • R 4 is phenyl, thiazolyl, oxazolyl, imidazolyl, thienyl or pyridinyl, which is unsubstituted or substituted by C ⁇ aUcyl, Ci_ 6 alkylsulfanyl, halogen or cycloalkyl, where said Ci_ 6 alkyl can be further optionally substituted with halogen;
  • A is T or which is unsubstituted or substituted by groups selected from C ⁇ aHcyl, deuterium and halogen;
  • R 2 and R 3 is phenyl, which is once or twice or three times substituted by fluoro, chloro, bromo, iodo, methyl or cyano; and the other one is hydrogen or deuterium;
  • R 4 is phenyl, thiazolyl, oxazolyl, imidazolyl, thienyl or pyridinyl, which is unsubstituted or substituted by methyl, isopropyl, trifluoromethyl, cyclopropyl, methylsulfanyl, fluoro or chloro;
  • A is , b , , T or , which is unsubstituted or substituted by groups selected from methyl, isopropyl, deuterium and fluoro; or pharmaceutically acceptable salts, or enantiomers, or diastereomers thereof.
  • Another embodiment of present invention is (v) a compound of formula I, wherein
  • R 1 is Ci_ 6 alkyl
  • R 2 and R 3 is phenyl, which is once or twice or three times substituted by Ci_ 6 alkyl or halogen; and the other one is hydrogen or deuterium;
  • R 4 is thiazolyl, oxazolyl, imidazolyl, thienyl or pyridinyl, which is unsubstituted or substituted by Ci_ 6 alkyl, halogen or cycloalkyl, where said Ci_ 6 alkyl can be further optionally substituted with halogen;
  • A is , or ; which is unsubstituted or substituted by groups selected from Ci_ 6 alkyl, deuterium and halogen;
  • R 2 and R 3 is phenyl, which is once or twice or three times substituted by fluoro, chloro, bromo, iodo or methyl; and the other one is hydrogen or deuterium;
  • R 4 is thiazolyl, oxazolyl, imidazolyl, thienyl or pyridinyl, which is unsubstituted or substituted by methyl, isopropyl, trifluoromethyl, cyclopropyl or fluoro;
  • A is , or , which is unsubstituted or substituted by groups selected from methyl, isopropyl, deuterium and fluoro;
  • Another embodiment of present invention is (vii) a compound of formula I or pharmaceutically acceptable salts, or enantiomers, or diastereomers thereof, wherein
  • R 1 is Ci_ 6 alkyl
  • R 2 and R 3 is phenyl, which is once or twice or three times substituted by halogen; and the other one is hydrogen;
  • A is , which is unsubstituted or substituted by Ci_ 6 alkyl.
  • a further embodiment of present invention is (viii) a compound of formula I pharmaceutically acceptable salts, or enantiomers, or diastereomers thereof, wherein R 1 methyl or ethyl;
  • R 2 and R 3 is phenyl, which is once or twice or three times substituted by fluoro, chloro or bromo; and the other one is hydrogen;
  • a further embodiment of present invention is (ix) a compound of formula I or pharmaceutically acceptable salts, or enantiomers, or diastereomers thereof, wherein
  • R 1 is methyl or ethyl
  • R 2 and R 3 are and the other one is hydrogen, wherein
  • a 1 is hydrogen or fluoro
  • a 2 is hydrogen or fluoro
  • a 3 is fluoro, chloro or bromo; provided that at least one of A 1 and A 2 is hydrogen;
  • a 4 is hydrogen or methyl
  • Another embodiment of present invention is (x) a compound of formula I, wherein
  • R 1 is Ci_6alkyl or trif uoromethyl-C x H 2x -, wherein x is 1-6;
  • R 2 and R 3 is phenyl, which is once or twice or three times substituted by Ci_6alkyl, cyano or halogen; and the other one is hydrogen or deuterium;
  • R 4 is thiazolyl, oxazolyl, imidazolyl, thienyl or pyridinyl, which is unsubstituted or substituted by Ci_ 6 alkyl, Ci_ 6 alkylsulfanyl, halogen or cycloalkyl, where said Ci_ 6 alkyl can be further optionally substituted with halogen;
  • A is or which is unsubstituted or substituted by groups selected from Ci-ealkyl, deuterium and halogen;
  • R 2 and R 3 is phenyl, which is once or twice or three times substituted by fluoro, chloro, bromo, methyl, or cyano; and the other one is hydrogen or deuterium;
  • R 4 is thiazolyl, oxazolyl, imidazolyl, thienyl or pyridinyl, which is unsubstituted or substituted by methyl, isopropyl, trifluoromethyl, cyclopropyl, methylsulfanyl, fluoro or chloro;
  • A is T or which is unsubstituted or substituted by groups selected from methyl, deuterium and fluoro;
  • Another embodiment of present invention is (xii) a compound of formula I, wherein
  • R 1 is Ci_6alkyl or trifluoromethyl-C x H 2x -, wherein x is 1-6;
  • R 2 and R 3 is phenyl, which is once or twice or three times substituted by Ci_6alkyl or halogen; and the other one is hydrogen or deuterium;
  • R 4 is thiazolyl, oxazolyl, imidazolyl, thienyl or pyridinyl, which is unsubstituted or substituted by C ⁇ aUcyl, Ci_ 6 alkylsulfanyl, halogen or cycloalkyl, where said Ci_ 6 alkyl can be further optionally substituted with halogen;
  • A is , or , which is unsubstituted or substituted by groups selected from Ci_ 6 alkyl, deuterium and halogen;
  • R 2 and R 3 is phenyl, which is once or twice or three times substituted by fluoro, chloro, bromo, iodo or methyl; and the other one is hydrogen or deuterium;
  • R 4 is thiazolyl, oxazolyl, imidazolyl, thienyl or pyridinyl, which is unsubstituted or substituted by methyl, isopropyl, trifluoromethyl, cyclopropyl, methylsulfanyl or fluoro;
  • A is , or , which is unsubstituted or substituted by groups selected from methyl, isopropyl, deuterium and fluoro;
  • Another embodiment of present invention is (xiv) a compound of formula I or
  • R 1 is Ci_ 6 alkyl or trifluoromethyl-C x H 2x -, wherein x is 1-6;
  • R 2 and R 3 is phenyl, which is once or twice or three times substituted by halogen; and the other one is hydrogen or deuterium;
  • R 4 is , which is unsubstituted or substituted by Ci_ 6 alkyl, Ci_ 6 alkylsulfanyl or cycloalkyl, where said Ci_ 6 alkyl can be further optionally substituted with halogen;
  • A is or , which is unsubstituted or substituted by groups selected from Ci_ 6 alkyl, deuterium and halogen.
  • R 1 is methyl, ethyl, propyl, isopropyl or trifluoromethylmethyl
  • R 2 and R 3 is phenyl, which is once or twice or three times substituted by fluoro, chloro, bromo or iodo; and the other one is hydrogen or deuterium;
  • R 4 is , which is unsubstituted or substituted by methyl, isopropyl, trifluoromethyl, cyclopropyl or methylsulfanyl; A is or which is unsubstituted or substituted by groups selected from methyl, isopropyl, deuterium and fluoro.
  • Another embodiment of present invention is (xvi) a compound of formula I or
  • R 1 is Ci_ 6 alkyl
  • R 2 and R 3 is and the other one is hydrogen
  • Ci_ 6 alkyl which is unsubstituted or substituted by Ci_ 6 alkyl;
  • A is b which is substituted by halogen.
  • Another embodiment of present invention is (xvii) a compound of formula I or
  • R 1 is Ci_ 6 alkyl
  • R 2 and R 3 is phenyl, which is substituted by halogen; and the other one is hydrogen;
  • Ci_ 6 alkyl which is substituted by Ci_ 6 alkyl
  • R 1 is methyl or ethyl
  • R 2 and R 3 is phenyl, which is substituted by fluoro or chloro; and the other one is hydrogen;
  • A is or which is unsubstituted or substituted by fluoro.
  • Another embodiment of present invention is (xix) a compound of formula I or
  • R 1 is Ci_ 6 alkyl
  • R 2 and R 3 are henyl, which is substituted by halogen; and the other one is hydrogen
  • R 1 is methyl or ethyl
  • R 2 and R 3 is phenyl, which is substituted by fluoro, chloro or bromo; and the other one is hydrogen;
  • Another embodiment of present invention is (xxi) a compound of formula lb or pharmaceutically acceptable salts, or enantiomers, or diastereomers thereof,
  • R 1 is Ci_ 6 alkyl
  • R 2 and R 3 is phenyl, which is twice or thrice substituted by cyano or halogen; and the other one is hydrogen or deuterium;
  • R 4 is phenyl, thiazolyl, oxazolyl, imidazolyl, thienyl or pyridinyl; which is unsubstituted or once or twice substituted by Ci_ 6 alkyl, halogen, cycloalkyl or trifluoromethyl;
  • R 5 is hydrogen
  • R 6 is hydrogen; A is , , " or which is unsubstituted or twice or four times substituted by deuterium or halogen.
  • R 1 is methyl or ethyl
  • R 2 and R 3 is phenyl, which is twice or thrice substituted by cyano, fluoro, chloro or bromo; and the other one is hydrogen or deuterium;
  • R 4 is phenyl, thiazolyl, oxazolyl, imidazolyl, thienyl or pyridinyl; which is unsubstituted or once or twice substituted by methyl, isopropyl, tert-butyl, fluoro, chloro, cyclopropyl or trif uoromethyl;
  • R 5 is hydrogen
  • R 6 is hydrogen
  • A is , , " or which is unsubstituted or twice or four times substituted by deuterium or fluoro.
  • Another embodiment of present invention is (xxiii) a compound of formula lb or pharmaceutically acceptable salts, or enantiomers, or diastereomers thereof, wherein
  • R 1 is Ci_ 6 alkyl
  • R 2 and R 3 is phenyl, which is twice or thrice substituted by cyano or halogen; and the other one is hydrogen or deuterium;
  • R 4 is thiazolyl or imidazolyl; which is unsubstituted or once or twice substituted by Ci_ 6 alkyl, halogen, cycloalkyl or trifluoromethyl;
  • R 5 is hydrogen
  • R 6 is hydrogen; A is , , " or which is unsubstituted or twice or four times substituted by deuterium or halogen.
  • R 1 is methyl or ethyl
  • R 2 and R 3 is phenyl, which is twice or thrice substituted by cyano, fluoro, chloro or bromo; and the other one is hydrogen or deuterium;
  • R 4 is thiazolyl or imidazolyl; which is unsubstituted or once or twice substituted by methyl, isopropyl, tert-butyl, cyclopropyl or trifluoromethyl;
  • R 5 is hydrogen
  • R 6 is hydrogen
  • A is or which is unsubstituted or twice or four times substituted by deuterium or fluoro.
  • Another embodiment of present invention is (xxv) a compound of formula lb or pharmaceutically acceptable salts, or enantiomers, or diastereomers thereof, wherein
  • R 1 is Ci_ 6 alkyl
  • R 2 and R 3 is phenyl, which is twice substituted by halogen; and the other one is hydrogen;
  • R 4 is phenyl, oxazolyl, thienyl or pyridinyl; which is unsubstituted or once or twice substituted by Ci_ 6 alkyl, halogen, cycloalkyl or trifluoromethyl;
  • R 5 is hydrogen
  • R 6 is hydrogen; ; which is unsubstituted or twice substituted by halogi
  • R 1 is methyl
  • R 2 and R 3 is phenyl, which is twice substituted by fluoro or chloro; and the other one is hydrogen;
  • R 4 is phenyl, oxazolyl, thienyl or pyridinyl; which is once or twice substituted by methyl, fluoro or chloro;
  • R 5 is hydrogen
  • R 6 is hydrogen
  • A is ; which is unsubstituted or twice substituted by fluoro.
  • the compounds of the present invention have good anti- HBV activity, high selectivity index, superior solubility and mouse SDPK profiles compared to the previously reported capsid assembly effectors such as Bay 41-4109.
  • the in-house data of the Bayer compound which is Bay 41-4109 are also shown in Table 3, 4, 5 and 6.
  • Example No. ⁇ € 50 ( ⁇ ) Example No. ⁇ € 50 ( ⁇ )
  • AUC(o-oo) area under the curve from the time of dosing to infinity
  • aqueous solubility is an important physico-chemical property that plays a significant role in various physical and biological processes. It is desirable to have good solubility which enables good permeability and gastric and intestinal absorption, linear dose proportionality, less PK variability, and easy formulation for PD/PK studies. At different stages of the drug disco very/development process solubility has to be determined and especially in the early phases (lead generation to lead optimization) high throughput methods are needed. Lyophilisation solubility assay (Lysa) is a well adopted high throughput assay to measure compound solubility in industry.
  • Example No. Lysa ⁇ /mL Example No. Lysa ⁇ /mL
  • Example No. Lysa ⁇ /mL Example No. Lysa ⁇ /mL
  • selectivity index effectiveness of the compound in inhibiting viral replication compared to inducing cell death. It is desirable to have a high selectivity index giving maximum antiviral activity with minimal cell toxicity.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Virology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Communicable Diseases (AREA)
  • Molecular Biology (AREA)
  • Biotechnology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

The invention provides novel compounds having the general formula:, wherein R1, R2, R3, R4 and A are as described herein, compositions including the compounds and methods of using the compounds.

Description

6-AMINO ACID HETEROARYLDIHYDROPYRIMIDINES 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 for the treatment of 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 is 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. et al. 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 as HBV inhibitors and for the treatment or prophylaxis of HBV infection. The compounds of formula I show superior anti-HBV activity. In addition, the compounds of formula I also show high selectivity index, better solubility and mouse SDPK profiles.
DETAILED DESCRIPTION OF THE INVENTION
DEFINITIONS
As used herein, the term "Ci_6alkyl" 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, tert- vXy\ and the like. Particular "Ci_6alkyl" groups are methyl, ethyl, isopropyl and tert-bvXy\.
The term "-CXH2X-" alone or in combination signifies a saturated, linear or branched chain alkyl group containing from 1 to 6 carbon atoms, particularly from 1 to 4 carbon atoms.
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 "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, chlorine or bromine.
The term "sulfanyl" alone or in combination refers to the group -S-.
The term "enantiomer" denotes two stereoisomers of a compound which are non- superimposable mirror images of one another.
The term "diastereomer" denotes a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another.
The compounds according to the present invention may exist in the form of their pharmaceutically acceptable salts. 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 /?-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 HBV
The present invention provides (i) novel compounds having the general formula I:
Figure imgf000007_0001
wherein
R1 is Ci_6alkyl or trifluoromethyl-CxH2x-, wherein x is 1-6;
One of R2 and R3 is phenyl, which is once or twice or three times substituted by Ci_6alkyl, cyano or halogen; and the other one is hydrogen or deuterium;
R4 is phenyl, thiazolyl, oxazolyl, imidazolyl, thienyl or pyridinyl, which is unsubstituted or substituted by Ci_6alkyl, Ci_6alkylsulfanyl, halogen or cycloalkyl, where said Ci_6alkyl can be further optionally substituted with halogen;
Figure imgf000007_0002
Figure imgf000007_0003
, which is unsubstituted or substituted by groups selected from C^aUcyl, deuterium and halogen;
or pharmaceutically acceptable salts, or enantiomers, or diastereomers thereof.
Further embodiment of present invention is (ii) a compound of formula I, wherein R1 is methyl, ethyl, propyl, isopropyl, tert-butyl or trifluoromethylmethyl;
One of R2 and R3 is phenyl, which is once or twice or three times substituted by fluoro, chloro, bromo, iodo, methyl, or cyano; and the other one is hydrogen or deuterium;
R4 is phenyl, thiazolyl, oxazolyl, imidazolyl, thienyl or pyridinyl, which is unsubstituted or substituted by methyl, isopropyl, tert-butyl, bifluoromethyl, trifluoromethyl, cyclopropyl, meth lsulfanyl, fluoro or chloro;
Figure imgf000008_0001
, which is unsubstituted or substituted by groups selected from methyl, isopropyl, deuterium and fluoro;
or pharmaceutically acceptable salts, or enantiomers, or diastereomers thereof.
Another embodiment of present invention is (iii) a compound of formula I, wherein R1 is Ci_6alkyl or trif uoromethyl-CxH2x-, wherein x is 1-6;
One of R2 and R3 is phenyl, which is once or twice or three times substituted by C^aUcyl, cyano or halogen; and the other one is hydrogen or deuterium;
R4 is phenyl, thiazolyl, oxazolyl, imidazolyl, thienyl or pyridinyl, which is unsubstituted or substituted by C^aUcyl, Ci_6alkylsulfanyl, halogen or cycloalkyl, where said Ci_6alkyl can be further optionally substituted with halogen;
Figure imgf000008_0002
A is T or which is unsubstituted or substituted by groups selected from C^aHcyl, deuterium and halogen;
or pharmaceutically acceptable salts, or enantiomers, or diastereomers thereof.
Further embodiment of present invention is (iv) a compound of formula I, wherein R1 is methyl, ethyl, propyl, isopropyl or trifiuoromethylmethyl;
One of R2 and R3 is phenyl, which is once or twice or three times substituted by fluoro, chloro, bromo, iodo, methyl or cyano; and the other one is hydrogen or deuterium;
R4 is phenyl, thiazolyl, oxazolyl, imidazolyl, thienyl or pyridinyl, which is unsubstituted or substituted by methyl, isopropyl, trifluoromethyl, cyclopropyl, methylsulfanyl, fluoro or chloro;
A is
Figure imgf000009_0001
, b , , T or , which is unsubstituted or substituted by groups selected from methyl, isopropyl, deuterium and fluoro; or pharmaceutically acceptable salts, or enantiomers, or diastereomers thereof. Another embodiment of present invention is (v) a compound of formula I, wherein
R1 is Ci_6alkyl;
One of R2 and R3 is phenyl, which is once or twice or three times substituted by Ci_6alkyl or halogen; and the other one is hydrogen or deuterium;
R4 is thiazolyl, oxazolyl, imidazolyl, thienyl or pyridinyl, which is unsubstituted or substituted by Ci_6alkyl, halogen or cycloalkyl, where said Ci_6alkyl can be further optionally substituted with halogen;
A is
Figure imgf000009_0002
, or ; which is unsubstituted or substituted by groups selected from Ci_6alkyl, deuterium and halogen;
or pharmaceutically acceptable salts, or enantiomers, or diastereomers thereof.
Further embodiment of present invention is (vi) a compound of formula I, wherein R1 is methyl or ethyl;
One of R2 and R3 is phenyl, which is once or twice or three times substituted by fluoro, chloro, bromo, iodo or methyl; and the other one is hydrogen or deuterium;
R4 is thiazolyl, oxazolyl, imidazolyl, thienyl or pyridinyl, which is unsubstituted or substituted by methyl, isopropyl, trifluoromethyl, cyclopropyl or fluoro; A is
Figure imgf000010_0001
, or , which is unsubstituted or substituted by groups selected from methyl, isopropyl, deuterium and fluoro;
or pharmaceutically acceptable salts, or enantiomers, or diastereomers thereof.
Another embodiment of present invention is (vii) a compound of formula I or pharmaceutically acceptable salts, or enantiomers, or diastereomers thereof, wherein
R1 is Ci_6alkyl;
One of R2 and R3 is phenyl, which is once or twice or three times substituted by halogen; and the other one is hydrogen;
A
Figure imgf000010_0002
is , which is unsubstituted or substituted by Ci_6alkyl.
A further embodiment of present invention is (viii) a compound of formula I pharmaceutically acceptable salts, or enantiomers, or diastereomers thereof, wherein R1 methyl or ethyl;
One of R2 and R3 is phenyl, which is once or twice or three times substituted by fluoro, chloro or bromo; and the other one is hydrogen;
Figure imgf000010_0003
, which is unsubstituted or substituted by methyl. A further embodiment of present invention is (ix) a compound of formula I or pharmaceutically acceptable salts, or enantiomers, or diastereomers thereof, wherein
R1 is methyl or ethyl;
Figure imgf000011_0001
One of R2 and R3 is and the other one is hydrogen, wherein
A1 is hydrogen or fluoro;
A2 is hydrogen or fluoro;
A3 is fluoro, chloro or bromo; provided that at least one of A1 and A2 is hydrogen;
Figure imgf000011_0002
, wherein A4 is hydrogen or methyl.
Another embodiment of present invention is (x) a compound of formula I, wherein
R1 is Ci_6alkyl or trif uoromethyl-CxH2x-, wherein x is 1-6;
One of R2 and R3 is phenyl, which is once or twice or three times substituted by Ci_6alkyl, cyano or halogen; and the other one is hydrogen or deuterium;
R4 is thiazolyl, oxazolyl, imidazolyl, thienyl or pyridinyl, which is unsubstituted or substituted by Ci_6alkyl, Ci_6alkylsulfanyl, halogen or cycloalkyl, where said Ci_6alkyl can be further optionally substituted with halogen;
A is
Figure imgf000011_0003
or which is unsubstituted or substituted by groups selected from Ci-ealkyl, deuterium and halogen;
or pharmaceutically acceptable salts, or enantiomers, or diastereomers thereof.
Further embodiment of present invention is (xi) a compound of formula I, wherein R1 is methyl, ethyl, propyl, isopropyl or trifluoromethylmethyl;
One of R2 and R3 is phenyl, which is once or twice or three times substituted by fluoro, chloro, bromo, methyl, or cyano; and the other one is hydrogen or deuterium;
R4 is thiazolyl, oxazolyl, imidazolyl, thienyl or pyridinyl, which is unsubstituted or substituted by methyl, isopropyl, trifluoromethyl, cyclopropyl, methylsulfanyl, fluoro or chloro;
Figure imgf000012_0001
A is T or which is unsubstituted or substituted by groups selected from methyl, deuterium and fluoro;
or pharmaceutically acceptable salts, or enantiomers, or diastereomers thereof. Another embodiment of present invention is (xii) a compound of formula I, wherein
R1 is Ci_6alkyl or trifluoromethyl-CxH2x-, wherein x is 1-6;
One of R2 and R3 is phenyl, which is once or twice or three times substituted by Ci_6alkyl or halogen; and the other one is hydrogen or deuterium;
R4 is thiazolyl, oxazolyl, imidazolyl, thienyl or pyridinyl, which is unsubstituted or substituted by C^aUcyl, Ci_6alkylsulfanyl, halogen or cycloalkyl, where said Ci_6alkyl can be further optionally substituted with halogen;
A is
Figure imgf000012_0002
, or , which is unsubstituted or substituted by groups selected from Ci_6alkyl, deuterium and halogen;
or pharmaceutically acceptable salts, or enantiomers, or diastereomers thereof.
Further embodiment of present invention is (xiii) a compound of formula I, wherein R1 is methyl, ethyl, isopropyl or trifluoromethylmethyl;
One of R2 and R3 is phenyl, which is once or twice or three times substituted by fluoro, chloro, bromo, iodo or methyl; and the other one is hydrogen or deuterium;
R4 is thiazolyl, oxazolyl, imidazolyl, thienyl or pyridinyl, which is unsubstituted or substituted by methyl, isopropyl, trifluoromethyl, cyclopropyl, methylsulfanyl or fluoro; A is
Figure imgf000013_0001
, or , which is unsubstituted or substituted by groups selected from methyl, isopropyl, deuterium and fluoro;
or pharmaceutically acceptable salts, or enantiomers, or diastereomers thereof.
Another embodiment of present invention is (xiv) a compound of formula I or
pharmaceutically acceptable salts, or enantiomers, or diastereomers thereof, wherein
R1 is Ci_6alkyl or trifluoromethyl-CxH2x-, wherein x is 1-6;
One of R2 and R3 is phenyl, which is once or twice or three times substituted by halogen; and the other one is hydrogen or deuterium;
Figure imgf000013_0002
R4 is , which is unsubstituted or substituted by Ci_6alkyl, Ci_6alkylsulfanyl or cycloalkyl, where said Ci_6alkyl can be further optionally substituted with halogen;
A is
Figure imgf000013_0003
or , which is unsubstituted or substituted by groups selected from Ci_6alkyl, deuterium and halogen.
Further embodiment of present invention is (xv) a compound of formula I or
pharmaceutically acceptable salts, or enantiomers, or diastereomers thereof, wherein
R1 is methyl, ethyl, propyl, isopropyl or trifluoromethylmethyl;
One of R2 and R3 is phenyl, which is once or twice or three times substituted by fluoro, chloro, bromo or iodo; and the other one is hydrogen or deuterium;
Figure imgf000013_0004
R4 is , which is unsubstituted or substituted by methyl, isopropyl, trifluoromethyl, cyclopropyl or methylsulfanyl; A is
Figure imgf000014_0001
or which is unsubstituted or substituted by groups selected from methyl, isopropyl, deuterium and fluoro.
Another embodiment of present invention is (xvi) a compound of formula I or
pharmaceutically acceptable salts, or enantiomers, or diastereomers thereof, wherein
R1 is Ci_6alkyl;
Figure imgf000014_0002
One of R2 and R3 is and the other one is hydrogen;
, which is unsubstituted or substituted by Ci_6alkyl;
Figure imgf000014_0003
A is b which is substituted by halogen.
Another embodiment of present invention is (xvii) a compound of formula I or
pharmaceutically acceptable salts, or enantiomers, or diastereomers thereof, wherein
R1 is Ci_6alkyl;
One of R2 and R3 is phenyl, which is substituted by halogen; and the other one is hydrogen;
Figure imgf000014_0004
, which is substituted by Ci_6alkyl; a
Figure imgf000015_0001
, which is unsubstituted or substituted by halogen.
Further embodiment of present invention is (xviii) a compound of formula I or pharmaceutically acceptable salts, or enantiomers, or diastereomers thereof, wherein
R1 is methyl or ethyl;
One of R2 and R3 is phenyl, which is substituted by fluoro or chloro; and the other one is hydrogen;
A
Figure imgf000015_0002
is or which is unsubstituted or substituted by fluoro.
Another embodiment of present invention is (xix) a compound of formula I or
pharmaceutically acceptable salts, or enantiomers, or diastereomers thereof, wherein
R1 is Ci_6alkyl;
One of R2 and R3 is henyl, which is substituted by halogen; and the other one is hydrogen
Figure imgf000015_0003
Figure imgf000015_0004
, which is unsubstituted or substituted by halogen. Further embodiment of present invention is (xx) a compound of formula I or pharmaceutically acceptable salts, or enantiomers, or diastereomers thereof, wherein
R1 is methyl or ethyl;
One of R2 and R3 is phenyl, which is substituted by fluoro, chloro or bromo; and the other one is hydrogen;
Figure imgf000016_0001
, which is unsubstituted or substituted by fluoro.
Another embodiment of present invention is (xxi) a compound of formula lb or pharmaceutically acceptable salts, or enantiomers, or diastereomers thereof,
Figure imgf000016_0002
wherein
R1 is Ci_6alkyl;
One of R2 and R3 is phenyl, which is twice or thrice substituted by cyano or halogen; and the other one is hydrogen or deuterium;
R4 is phenyl, thiazolyl, oxazolyl, imidazolyl, thienyl or pyridinyl; which is unsubstituted or once or twice substituted by Ci_6alkyl, halogen, cycloalkyl or trifluoromethyl;
R5 is hydrogen;
R6 is hydrogen; A is
Figure imgf000017_0001
, , " or which is unsubstituted or twice or four times substituted by deuterium or halogen.
Further embodiment of present invention is (xxii) a compound of formula lb or pharmaceutically acceptable salts, or enantiomers, or diastereomers thereof, wherein
R1 is methyl or ethyl;
One of R2 and R3 is phenyl, which is twice or thrice substituted by cyano, fluoro, chloro or bromo; and the other one is hydrogen or deuterium;
R4 is phenyl, thiazolyl, oxazolyl, imidazolyl, thienyl or pyridinyl; which is unsubstituted or once or twice substituted by methyl, isopropyl, tert-butyl, fluoro, chloro, cyclopropyl or trif uoromethyl;
R5 is hydrogen;
R6 is hydrogen;
A is
Figure imgf000017_0002
, , " or which is unsubstituted or twice or four times substituted by deuterium or fluoro.
Another embodiment of present invention is (xxiii) a compound of formula lb or pharmaceutically acceptable salts, or enantiomers, or diastereomers thereof, wherein
R1 is Ci_6alkyl;
One of R2 and R3 is phenyl, which is twice or thrice substituted by cyano or halogen; and the other one is hydrogen or deuterium;
R4 is thiazolyl or imidazolyl; which is unsubstituted or once or twice substituted by Ci_ 6alkyl, halogen, cycloalkyl or trifluoromethyl;
R5 is hydrogen;
R6 is hydrogen; A is
Figure imgf000018_0001
, , " or which is unsubstituted or twice or four times substituted by deuterium or halogen.
Further embodiment of present invention is (xxiv) a compound of formula lb or pharmaceutically acceptable salts, or enantiomers, or diastereomers thereof, wherein
R1 is methyl or ethyl;
One of R2 and R3 is phenyl, which is twice or thrice substituted by cyano, fluoro, chloro or bromo; and the other one is hydrogen or deuterium;
R4 is thiazolyl or imidazolyl; which is unsubstituted or once or twice substituted by methyl, isopropyl, tert-butyl, cyclopropyl or trifluoromethyl;
R5 is hydrogen;
R6 is hydrogen;
A is
Figure imgf000018_0002
or which is unsubstituted or twice or four times substituted by deuterium or fluoro.
Another embodiment of present invention is (xxv) a compound of formula lb or pharmaceutically acceptable salts, or enantiomers, or diastereomers thereof, wherein
R1 is Ci_6alkyl;
One of R2 and R3 is phenyl, which is twice substituted by halogen; and the other one is hydrogen;
R4 is phenyl, oxazolyl, thienyl or pyridinyl; which is unsubstituted or once or twice substituted by Ci_6alkyl, halogen, cycloalkyl or trifluoromethyl;
R5 is hydrogen;
R6 is hydrogen;
Figure imgf000019_0001
; which is unsubstituted or twice substituted by halogi
Further embodiment of present invention is (xxvi) a compound of formula lb or pharmaceutically acceptable salts, or enantiomers, or diastereomers thereof, wherein
R1 is methyl;
One of R2 and R3 is phenyl, which is twice substituted by fluoro or chloro; and the other one is hydrogen;
R4 is phenyl, oxazolyl, thienyl or pyridinyl; which is once or twice substituted by methyl, fluoro or chloro;
R5 is hydrogen;
R6 is hydrogen;
A is
Figure imgf000019_0002
; which is unsubstituted or twice substituted by fluoro.
Particular compounds of formula I, including NMR data and MS data are summarized in the following Table 1 and 2.
Table 1 : Structure and name of particular compounds
Figure imgf000019_0003
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
Figure imgf000034_0001
Figure imgf000035_0001
F
(5)-4-[(i?)-6-(2-Chloro-4-fluoro-phenyl)-5- methoxycarbonyl-2-(5-methyl-oxazol-4-yl)-3,6-
68
dihydro-pyrimidin-4-ylmethyl] -morpho line-3 - carboxylic acid
F
(5)-4-[(i?)-6-(2-Bromo-4-fluoro-phenyl)-5- ethoxycarbonyl-2-(5-methyl-oxazol-4-yl)-3,6-
69
dihydro-pyrimidin-4-ylmethyl] -morpho line-3 -
JL N N ¾- / carboxylic acid
(5)-4-[(i?)-6-(2,3-Difluoro-phenyl)-5- ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-
70
pyrimidin-4-ylmethyl] -morpho line-3 -carboxylic acid
o >r (5)-4-[(i?)-6-(2-Bromo-phenyl)-5- methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-
71
pyrimidin-4-ylmethyl] -morpho line-3 -carboxylic acid
(i?)-4-(2-Bromo-phenyl)-6-((5)-2-carboxy-4,4- difluoro-pyrrolidin- 1 -ylmethyl)-2-thiazol-2-yl-
72
l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
(2i?,35)-4-[(i?)-6-(2-Chloro-3-fluoro-phenyl)-5- ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl] -2-methyl-morpho line-3 - carboxylic acid
(2i?,35)-4-[(i?)-6-(2-Bromo-phenyl)-5- methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl] -2-methyl-morpho line-3 - carboxylic acid
(2i?,35)-4-[(i?)-6-(2-Chloro-4-fluoro-phenyl)-5- methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl] -2-isopropyl-morpho line-3 - carboxylic acid
(S)-4-(((R)-6-(2-Ch ro-4-fluorophenyl)-5- (methoxycarbonyl)-2-(thiazol-2-yl)-3,6- dihydropyrimidin-4-yl)methyl)-3 - methylmorpho line-3 -carboxylic acid
(5)-4-(((i?)-6-(2-Bromo-4-fluorophenyl)-5- (ethoxycarbonyl)-2-(thiazol-2-yl)-3,6- dihydropyrimidin-4-yl)methyl)morpholine-3- carboxylic acid
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Table 2: NMR and MS data of particular compounds
Example
1H NMR data MW data No.
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.94-7.93 (m, 1H), 7.75- 7.73 (m, 1H), 7.50-7.44 (m, 1H), 7.25-7.21 (m, 1H), 7.10-7.05 MS: calc'd (MH+)
1 (m, 1H), 6.17 (s, 0.5H), 6.15 (s, 0.5H), 4.49-4.39 (m, 1H), 4.17- 515, measured 4.13 (m, 1H), 3.90-3.83 (m, 1H), 3.65-3.55 (m, 4H), 3.25-3.08 (MH+) 515 (m, 1H), 2.86-2.73 (m, 1H), 2.62-2.51 (m, 1H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 8.21 (s, 2H), 7.63-7.60
MS: calc'd (MH+) (m, 1H), 7.38-7.35 (m, 1H), 7.22-7.18 (m, 1H), 6.29 (s, 1H),
2 515, measured 4.57 (d, m, J = 16 Hz), 4.13-4.08 (m, 2H), 3.70-3.67 (m, 4H),
(MH+) 515 3.33-3.28 (m, 1H), 2.92-2.82 (m, 1H), 2.63-2.56 (m, 1H)
1H NMR (CDCl3-d, 400 MHz): δ ppm 7.85 (br. s., 1H), 7.50- MS: calc'd 514
3
7.55 (m, 1H), 7.29-7.35 (m, 1H), 7.16 (ddd, J = 8.34, 5.96, 2.51 (MH~), measured Hz, IH), 6.93-7.02 (m, IH), 4.56-4.69 (m, IH), 3.91 (dd, J = 514 (MH~) 11.80, 2.76 Hz, IH), 3.78 (d, J = 14.81 Hz, IH), 3.63 (s, 3H),
3.46-3.59 (m, IH), 3.06-3.29 (m, IH), 2.72-2.86 (m, IH), 2.49- 2.64 (m, IH)
1H NMR (MeOD-d4, 400 MHz): δ ppm 8.71 (d, J = 2.01 Hz,
IH), 7.98 (d, J = 2.01 Hz, IH), 7.65-7.80 (m, IH), 7.41-7.56 (m, MS: calc'd (MH+) IH), 7.33 (br. s., IH), 6.47 (s, IH), 4.65 (br. s., IH), 4.37 (br. s., 545, measured IH), 4.12 (br. s., IH), 3.74-3.90 (m, 4H), 3.31-3.50 (m, IH), (MH+) 545 2.92-3.09 (m, IH), 2.64-2.86 (m, IH)
1H NMR (DMSO-dg, 400 MHz): δ ppm 12.88 (br. s, IH), 9.87
(s, IH), 8.04 (d, IH, J = 4 Hz), 7.95 (d, IH, J = 4 Hz), 7.44- MS: calc'd (MH+) 7.39 (m, 2H), 7.19-7.14 (m, IH), 6.04 (s, IH), 4.25 (d, IH, J = 495, measured 20 Hz), 4.07-3.97 (m, 2H), 3.86-3.61 (m, 4H), 3.51 (s, 3H), (MH+) 495 3.12-3.07 (m, IH), 2.45-2.39 (m, IH)
1H NMR (MeOD-d4, 400 MHz): δ ppm 8.51 (s, IH), 8.47 (s,
2H), 7.73-7.72 (m, IH), 7.50-7.46 (m, IH), 7.25-7.22 (m, IH),
MS: calc'd (MH+) 7.08-7.04 (m, IH), 6.22 (s, IH), 4.24 (d, IH, J = 16 Hz), 4.12
525, measured (d, IH, J = 16 Hz), 4.07-4.04 (m, IH), 3.89-3.79 (m, 3H), 3.62
(MH+) 525 (s, 3H), 3.47-3.44 (m, IH), 3.25-3.19 (m, IH), 2.67-2.65 (m,
IH)
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.93 (d, J = 3.01 Hz,
IH), 7.73 (d, J = 3.01 Hz, IH), 7.45 (dd, J = 8.66, 6.15 Hz, IH),
MS: calc'd (MH+) 7.23 (dd, J = 8.78, 2.51 Hz, IH), 7.06 (td, J = 8.41, 2.51 Hz,
529, measured IH), 6.16 (s, IH), 4.13-4.39 (m, 2H), 3.66 (d, J = 8.78 Hz, 2H),
(MH+) 529 3.60 (s, 3H), 2.88 (d, J = 10.04 Hz, IH), 2.23 (d, J = 5.02 Hz,
2H), 1.89-2.16 (m, 2H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 8.70 (s, IH), 8.30 (d, J
= 8.28 Hz, IH), 7.95 (d, J = 7.03 Hz, IH), 7.62 (dd, J = 8.66,
5.90 Hz, IH), 7.38 (dd, J = 8.66, 2.64 Hz, IH), 7.21 (td, J = MS: calc'd (MH+) 8.34, 2.64 Hz, IH), 6.32 (s, IH), 4.59 (d, J = 16.06 Hz, IH), 523, measured 4.01 (t, J = 8.41 Hz, IH), 3.94 (d, J = 16.31 Hz, IH), 3.69 (s, (MH+) 523 3H), 3.49-3.65 (m, IH), 3.21 (td, J = 14.62, 11.17 Hz, IH),
2.76-2.93 (m, IH), 2.43-2.61 (m, 4H) 1H NMR (MeOD-d4, 400 MHz): δ ppm 8.74 (s, 1H), 8.20 (d, J
= 8.28 Hz, 1H), 7.96 (d, J = 7.28 Hz, 1H), 7.62 (dd, J = 8.66,
5.90 Hz, 1H), 7.37 (dd, J = 8.53, 2.51Hz, 1H), 7.19 (td, J = MS: calc'd (MH+) 8.28, 2.51 Hz, 1H), 6.35 (s, 1H), 4.23-4.34 (m, 1H), 4.05-4.22 503, measured (m, 2H), 3.99 (d, J = 6.27 Hz, 1H), 3.85-3.93 (m, 1H), 3.74-3.83 (MH+) 503 (m, 1H), 3.64-3.73 (s, 3H), 3.11-3.27 (m, 2H), 2.64-2.76 (m,
1H), 2.52 (s, 3H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.69 (s, 1H), 7.53-7.62
(m, 1H), 7.30-7.38 (m, 1H), 7.08-7.23 (m, 1H), 6.23-6.27 (m, MS: calc'd (MH+) 1H), 4.43-4.55 (m, 1H), 3.96-4.12 (m, 1H), 3.65 (s, 4H), 3.14- 555, measured 3.30 (m, 1H), 2.74-2.97 (m, 1H), 2.45-2.64 (m, 1H), 2.09-2.25 (MH+) 555 (m, 1H), 0.94-1.10 (m, 4H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.67-7.73 (m, 1H), 7.53-
7.63 (m, 1H), 7.28-7.37 (m, 1H), 7.11-7.22 (m, 1H), 6.22-6.28 MS: calc'd (MH+) (m, 1H), 4.44-4.52 (m, 1H), 4.08-4.18 (m, 1H), 3.99-4.07 (m, 571, measured 1H), 3.65 (s, 4H), 3.16-3.30 (m, 1H), 2.77-2.95 (m, 1H), 2.46- (MH+) 571
2.64 (m, 1H), 1.41 (s, 9H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.67 (d, J = 1.3 Hz, 1H),
7.42 (dd, J = 8.7, 6.1 Hz, 1H), 7.21 (dd, J = 8.8, 2.5 Hz, 1H), MS: calc'd (MH+) 6.98-7.11 (m, 2H), 6.07 (s, 1H), 4.61 (d, J = 15.8 Hz, 2H), 3.79 532, measured (d, J = 15.8 Hz, 1H), 3.60-3.69 (m, 4H), 2.93-3.19 (m, 1H), (MH+) 532 2.63-2.77 (m, 1H), 2.35-2.54 (m, 1H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.39 (ddd, J = 14.18,
8.41, 6.02 Hz, 1H), 7.24 (dd, J = 8.66, 2.13 Hz, 1H), 7.19 (d, J
= 2.51 Hz, 1H), 6.99-7.11 (m, 2H), 6.17 (d, J = 1.76 Hz, 1H), MS: calc'd (MH+) 4.18-4.35 (m, 2H), 3.97-4.14 (m, 2H), 3.94 (s, 1.5H), 3.77-3.91 492, measured (m, 3.5H), 3.62 (d, J = 2.01 Hz, 3H), 3.44-3.53 (m, 0.5H), 3.39 (MH+) 492 (dd, J = 7.65, 3.39 Hz, 0.5H), 3.21-3.30 (m, 0.5H), 3.07 (d, J =
12.30 Hz, 0.5H), 2.52-2.65 (m, 1H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.94 (d, 1¾ J = 4 Hz),
MS: calc'd (MH+) 7.74 (d, IH, J = 4 Hz), 7.46-7.43 (m, 1H), 7.25-7.22 (m, 1H),
529, measured 7.09-7.06 (m, IH), 6.18 (s, IH), 4.11 (dd, 2H, J = 56 Hz, J2 =
(MH+) 529 16 Hz), 3.62 (s, 3H), 3.21-3.01 (m, 3H), 2.79-2.43 (m, 3H), 2.11-1.98 (m, 1H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.93 (s, 1H), 7.56- 7.52(m, 1H), 7.33-7.30 (m, 1H), 7.18-7.15 (m, 1H), 6.24 (s, 1H), MS: calc'd (MH+) 4.47(d, m, J = 16 Hz), 4.05 (d, 1¾ J = 16 Hz), 3.99 (t, 1¾ J = 513, measured 8 Hz), 3.64-3.58 (m, 4H), 3.27-3.15 (m, 1H), 2.85-2.79 (m, 1H), (MH+) 513 2.68-2.51 (m, 1H), 2.26 (s, 3H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.69 (d, J = 0.75 Hz,
1H), 7.54-7.63 (m, 1H), 7.28-7.38 (m, 1H), 7.10-7.20 (m, 1H), MS: calc'd (MH+) 6.27 (s, 1H), 4.52-4.61 (m, 1H), 4.12-4.21 (m, 1H), 4.03-4.12 529, measured (m, 1H), 3.66 (s, 4H), 3.17-3.29 (m, 1H), 2.78-2.98 (m, 1H), (MH+) 529 2.53 (d, J = 0.75 Hz, 4H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.51-7.59 (m, 2H), 7.28-
MS: calc'd (MH+) 7.34 (m, 1H), 7.09-7.18 (m, 1H), 6.19-6.26 (m, 1H), 4.71-4.79
509, measured (m, 1H), 4.44-4.53 (m, 1H), 4.08-4.23 (m, 3H), 3.90-4.04 (m,
(MH+) 509 2H), 3.66 (s, 4H), 3.07-3.18 (m, 1H), 2.51 (s, 3H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 8.10-8.19 (m, 2H), 7.47-
MS: calc'd (MH+) 7.60 (m, 2H), 6.22-6.26 (m, 1H), 4.53-4.60 (m, 1H), 4.09-4.23
533, measured (m, 2H), 3.68 (s, 4H), 3.27-3.38 (m, 1H), 2.80-2.98 (m, 1H),
(MH+) 533 2.52-2.66 (m, 1H)
1H NMR (CDCl3-d, 400 MHz): δ ppm 10.62 (s, 1H), 8.02 (s,
1H), 7.81 (br. s., 1H), 7.36 (dd, J = 8.53, 5.77 Hz, 1H), 7.21 (dd,
MS: calc'd 516 J = 8.16, 2.38 Hz, 1H), 7.05 (td, J = 8.09, 2.38 Hz, 1H), 6.25 (s,
(MH+), measured 1H), 4.62 (d, J = 15.56 Hz, 1H), 3.93-4.00 (m, 1H), 3.88 (d, J =
516 (MH+) 15.56 Hz, 1H), 3.68 (s, 3H), 3.57-3.65 (m, 1H), 3.16-3.29 (m,
1H), 2.49-2.63 (m, 1H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.36-7.48 (m, 1H), 7.17- 7.29 (m, 1H), 7.02-7.13 (m, 1H), 6.91 (s, 1H), 6.16 (s, 1H), MS: calc'd (MH+) 4.30-4.53 (m, 1H), 4.02-4.25 (m, 1H), 3.73-3.86 (m, 5H), 3.62 526, measured (d, J = 3.01 Hz, 3H), 2.95-3.24 (m, 1H), 2.71 (s, 1H), 2.45-2.62 (MH+) 526 (m, 1H), 2.08-2.28 (m, 3H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 8.02-8.07 (m, 1H), 7.91- MS: calc'd (MH+) 7.97 (m, 1H), 7.39-7.54 (m, 2H), 6.16-6.23 (m, 1H), 4.81- 513, measured 4.85(m, 1H), 4.48-4.58 (m, 1H), 4.13-4.29 (m, 3H), 3.91-4.07 (MH+) 513 (m, 2H), 3.70-3.81 (m, 1H), 3.67 (s, 3H), 3.12-3.25 (m, 1H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 8.56 (d, J = 4.5 Hz, 1H),
7.80-7.91 (m, 1H), 7.73 (dt, J = 8.5, 4.2 Hz, 1H), 7.57 (dd, J =
8.8, 6.0 Hz, 1H), 7.30 (dd, J = 8.8, 2.5 Hz, 1H), 7.12 (td, J = MS: calc'd (MH+) 8.4, 2.5 Hz, 1H), 6.25-6.35 (m, 1H), 4.52 (d, J = 17.3 Hz, 1H), 527, measured 4.14 (d, J = 17.3 Hz, 1H), 3.92 (t, J = 8.3 Hz, 1H), 3.54-3.73 (MH+) 527 (m, 4H), 3.13 (td, J = 14.7, 11.2 Hz, 1H), 2.80 (t, J = 9.7 Hz,
1H), 2.42-2.63 (m, 1H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.71 (d, J = 11.3 Hz,
2H), 7.50 (dd, J = 8.5, 6.0 Hz, 1H), 7.29 (dd, J = 8.5, 2.5 Hz, MS: calc'd (MH+) 1H), 7.11 (td, J = 8.4, 2.5 Hz, 1H), 6.16 (s, 1H), 4.69 (d, J = 548, measured 16.3 Hz, 1H), 3.89-4.08 (m, 2H), 3.52-3.70 (m, 4H), 3.13-3.28 (MH+) 548 (m, 1H), 2.87 (dd, J = 14.4, 9.4 Hz, 1H), 2.43-2.64 (m, 1H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 8.59 (d, J = 4.5 Hz, 1H),
7.91 (d, J = 8.0 Hz, 1H), 7.58-7.74 (m, 2H), 7.43 (dd, J = 8.5,
MS: calc'd (MH+) 2.3 Hz, 1H), 7.28 (td, J = 8.3, 2.3 Hz, 1H), 6.39 (s, 1H), 4.44 (d,
523, measured J = 16.1 Hz, 1H), 4.12 (d, J = 15.8 Hz, 1H), 3.89-4.01 (m, 1H),
(MH+) 523 3.66-3.77 (m, 3H), 3.51-3.63 (m, 1H), 3.16-3.28 (m, 1H), 2.70- 2.88 (m, 1H), 2.42-2.57 (m, 4H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 8.36 (s, 1H), 7.41-7.54
MS: calc'd (MH+) (m, 1H), 7.23 - 7.29 (m, 1H), 7.01 - 7.14 (m, 1H), 6.19 (s, 1H),
583, measured 4.40 (s, 1H), 4.28 (s, 1H), 3.97-4.09 (m, 1H), 3.65-3.74 (m, 1H),
(MH+) 583 3.62 (s, 3H), 3.37 (s, 2H), 2.73-2.91 (m, 1H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.93 (br. s, 1H), 7.74
(br. s, 1H), 7.48 (dt, J = 8.53, 6.02 Hz, 1H), 7.23 (dt, J = 8.66,
2.82 Hz, 1H), 7.07 (qd, J = 8.53, 2.26 Hz, 1H), 6.17 (d, J = 8.28 MS: calc'd (MH+) Hz, 1H), 4.39-4.56 (m, 1H), 4.17 (d, J = 17.07 Hz, 1H), 4.06 (q, 529, measured J = 7.03 Hz, 2H), 3.93 (q, J = 7.95 Hz, 1H), 3.52-3.72 (m, 1H), (MH+) 529 3.08-3.29 (m, 1H), 2.71-2.89 (m, 1H), 2.48-2.68 (m, 1H), 1.15
(t, J = 7.15 Hz, 3H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.89 (s, 1H), 7.78 (s, MS: calc'd (MH+) 1H), 7.59 (dd, J= 5.90, 8.66 Hz, 1H), 7.39 (dd, J= 2.51, 8.53 528, measured Hz, 1H), 7.19 (dt, J= 2.51, 8.28 Hz, 1H), 6.26 (s, 1H), 4.71 (d, J (MH+) 528 = 17.32 Hz, 1H), 3.88-4.13 (m, 2H), 3.69 (s, 3H), 3.45-3.63 (m,
2H), 3.08-3.26 (m, 1H), 2.90 (dd, J= 9.66, 15.18 Hz, 1H), 2.45- 2.63 (m, 1H), 2.36 (s, 3H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.69 (s, 1H), 7.58 (dd, J
= 8.78, 6.02 Hz, 1H), 7.34 (dd, J = 8.78, 2.26 Hz, 1H), 7.17 (td,
MS: calc'd (MH+) J = 8.34, 2.13Hz, 1H), 6.25 (s, 1H), 4.50 (d, J = 16.81 Hz, 1H),
557, measured 4.13 (d, J = 16.81 Hz, 1H), 4.04 (t, J = 8.16Hz, 1H), 3.59 - 3.69
(MH+) 557 (m, 4H), 3.13 - 3.29 (m, 2H), 2.76 -2.94 (m, 1H), 2.46 - 2.65 (m,
1H), 1.36 (d, J = 6.78 Hz, 6H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 8.10 (d, J = 3.01Hz,
1H), 8.04 (d, J = 3.01 Hz, 1H), 7.70 (s, 1H), 7.55 (d, J = 8.28
MS: calc'd (MH+) Hz, 1H), 7.45 (d, J = 8.53Hz, 1H), 6.23 (s, 1H), 4.52 (d, J =
557, measured 16.31 Hz, 1H), 4.15 (d, J = 16.06 Hz, 1H), 4.07 (t, J = 8.16 Hz,
(MH+) 557 1H), 3.61-3.73 (m, 4H), 3.21-3.31 (m, 1 H)2.78-2.94 (m, 1H),
2.48-2.66 (m, 1H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 8.04 (d, J = 3.01 Hz,
1H), 7.88-7.94 (m, 2H), 7.70 (s, 2H), 6.30 (s, 1H), 4.56 (d, J = MS: calc'd (MH+) 17.07 Hz, 1H), 4.20 (d, J = 16.81 Hz, 1H), 4.04 (t, J = 8.28 Hz, 522, measured 1H), 3.57-3.68 (m, 4H), 3.14-3.28 (m, 1H) 2.77-2.93 (m, 1H), (MH+) 522 2.50-2.66 (m, 1H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 8.08 (d, J = 3.01 Hz,
1H), 8.01 (d, J = 3.01 Hz, 1H), 7.60 (dd, J = 8.53, 6.02 Hz, 1H),
7.31 (dd, J = 8.66,2.38 Hz, 1H), 7.15 (td, J = 8.34, 2.38 Hz,
MS: calc'd (MH+) 1H), 6.26 (s, 1H), 4.88 (d, J = 16.31 Hz, 1H), 4.59 (d, J = 16.56
509, measured Hz, 1H), 4.26-4.33 (m, 1H), 4.22 (d, J = 4.02Hz, 2H), 4.11 (q, J
(MH+) 509 = 6.94 Hz, 2H), 3.93-4.05 (m, 2H), 3.78 (ddd, J = 12.42, 8.28,
3.64 Hz, 1H), 3.27 (d, J = 13.05 Hz, 1H), 1.16 (t, J = 7.15 Hz,
3H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.51-7.66 (m, 2H), 7.38
(t, J = 5.27 Hz, 2H), 7.15-7.25 (m, 1H), 6.29 (s, 1H), 4.42 (d, J MS: calc'd (MH+) = 15.81 Hz, 1H), 4.24 (d, J = 15.81 Hz, 1H), 3.95-4.11 (m, 4H), 512, measured 3.59-3.78 (m, 4H), 2.76-2.95 (m, 1H), 2.53 (td, J = 17.63, 7.40 (MH+) 512 Hz, 1H) 1H NMR (MeOD-d4, 400 MHz): δ ppm 7.95 (m, 1H), 7.62 (dd,
MS: calc'd (MH+) J= 5.9, 8.7 Hz, 1H), 7.42 (m, 1H), 7.29 (m, 3H), 6.29 (s, 1H),
544, measured 4.49 (d, J= 16.0 Hz, 1H), 4.00 (d, J= 16.0 Hz, 1H), 3.69 (s,
(MH+) 544 3H), 3.57 (m, 1H), 3.20 (m, 1H), 2.79 (m, 1H), 2.45 (m, 1H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 8.09 (d, J = 3.01 Hz,
1H), 8.02 (d, J = 3.01 Hz, 1H), 7.57 (dd, J = 8.78, 6.02 Hz, 1H),
MS: calc'd 529 7.32 (dd, J = 8.78,2.51 Hz, 1H), 7.16 (td, J = 8.41, 2.51 Hz,
(MH+), exp 529 1H), 6.25 (s, 1H), 4.53 (d, J = 16.06 Hz, 1H), 4.00 - 4.18 (m,
(MH+).
4H), 3.68 (q, J = 11.13 Hz, 1H), 3.20 - 3.30 (m,lH), 2.77 - 2.94
(m, 1H), 2.49 - 2.65 (m, 1H), 1.17 (t, J = 7.15 Hz, 3 H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 8.09 (s, 1H), 7.44 (dd, J
= 6.0, 8.5 Hz, 1H), 7.32 - 7.23 (m, 2H), 7.17 - 7.03 (m, 2H),
MS: calc'd 506 6.21 (s, 1H), 4.57 - 4.45 (m, 1H), 4.38 - 4.27 (m, 1H), 4.19 - (MH+), exp 506 4.05 (m, 3H), 4.00 (s, 3H), 3.97 - 3.80 (m, 2H), 3.75 (t, J = 4.1
(MH+).
Hz, 1H), 3.49 - 3.36 (m, 1H), 2.84 - 2.72 (m, 1H), 1.16 (t, J =
7.2 Hz, 3H).
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.63 (dd, J = 8.78, 5.77
Hz, 1 H), 7.57 (s, 1 H), 7.39 (dd, J = 8.53, 2.51 Hz, 1 H), 7.33
(d, J = 1.00 Hz, 1 H), 7.20 (td, J = 8.41, 2.51 Hz, 1 H), 6.32 (s, MS: calc'd 526 1 H), 4.63 (d, J = 17.32 Hz, 1 H), 4.14 (qd, J = 6.86, 3.01 Hz, 3 (MH+), exp 526 H), 4.01 - 4.07 (m, 1 H), 4.00 (s, 3 H), 3.67 (td, J = 11.54, 7.78 (MH+).
Hz, 1 H), 3.13 - 3.28 (m, 1 H), 2.88 (dd, J = 14.43, 9.41 Hz, 1
H), 2.45 - 2.61 (m, 1 H), 1.17 (t, J = 7.03 Hz, 3 H).
1H NMR (MeOD-d4, 400 MHz): δ ppm 8.09 - 8.28 (m, 1 H),
7.85 (t, J = 7.78 Hz, 1 H), 7.38 - 7.57 (m, 2 H), 7.27 (dd, J =
8.53, 2.51 Hz, 1 H), 7.09 (d, J = 2.51 Hz, 1 H), 6.24 (s, 1 H), MS: calc'd 517 4.36 (d, J = 4.52 Hz, 2 H), 3.99 - 4.20 (m, 4 H), 3.92 (br. s., 1 (MH+), exp 517 H), 3.86 (d, J = 2.76 Hz, 1 H), 3.63 (t, J = 4.39 Hz, 1 H), 3.35 (MH+).
(br. s., 1 H), 2.69 - 2.82 (m, 1 H), 2.63 (s, 3 H), 1.17 (t, J = 7.15
Hz, 3 H).
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.93 - 8.06 (m, 1 H), MS: calc'd 545 7.82 - 7.90 (m, 1 H), 7.43 - 7.57 (m, 2 H), 7.37 (dd, J = 8.53, (MH+), exp 545 2.01 Hz, 1 H), 6.20 (s, 1 H), 4.48 (d, J = 16.31 Hz, 1 H), 4.18 (MH+). (d, J = 16.31 Hz, 1 H), 4.08 (q, J = 7.11 Hz, 2 H), 4.01 (t, J =
8.16 Hz, 1 H), 3.65 (s, 1 H), 3.18 - 3.29 (m, 2 H), 2.75 - 2.91 (m,
1 H), 2.50 - 2.67 (m, 1 H), 1.16 (t, J = 7.15 Hz, 3 H).
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.97 (d, J = 3.01 Hz, 1
H), 7.78 (d, J = 3.01 Hz, 1 H), 7.49 (d, J = 2.01 Hz, 1 H), 7.44
MS: calc'd 525 (d, J = 8.28 Hz, 1 H), 7.32 (dd, J = 8.28, 2.01 Hz, 1 H), 6.18 (s,
(MH+), exp 525 1 H), 4.33 - 4.49 (m, 1 H), 4.17 - 4.30 (m, 1 H), 4.07 (d, J =
(MH+).
7.03 Hz, 5 H), 3.78 - 3.96 (m, 2 H), 3.61 (br. s., 1 H), 2.62 - 2.79
(m, 1 H), 1.16 (t, J = 7.15 Hz, 3 H).
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.66 (s, 1 H), 7.42 (dd, J
= 8.66, 6.15 Hz, 1 H), 7.25 (dd, J = 8.78, 2.51 Hz, 1 H), 7.07
MS: calc'd 594 (td, J = 8.41, 2.51 Hz, 1 H), 6.20 (s, 1 H), 4.41 (d, J = 16.31 Hz,
(MH+), exp 594 1 H), 4.20 - 4.28 (m, 1 H), 4.06 (q, J = 7.11 Hz, 2 H), 3.97 (m, 4
(MH+).
H), 3.53 - 3.69 (m, 1 H), 3.16 - 3.32 (m, 1 H), 2.68 - 2.88 (m, 1
H), 2.47 - 2.65 (m, 1 H), 1.15 (t, J = 7.03 Hz, 3 H).
1H NMR (MeOD-d4, 400 MHz): δ ppm 8.15 (d, J = 3.01 Hz, 1
H), 8.10 (d, J = 3.01 Hz, 1 H), 7.24 - 7.46 (m, 3 H), 5.80 (s, 1 MS: calc'd 513 H), 4.52 (d, J = 16.06 Hz, 1 H), 4.13 - 4.25 (m, 3 H), 4.04 - 4.11 (MH+), exp 513 (m, 1 H), 3.67 (d, J = 11.04 Hz, 1 H), 3.22 - 3.31 (m, 1 H), 2.74 (MH+).
- 2.96 (m, 1 H), 2.45 - 2.69 (m, 1 H), 1.23 (t, J = 7.15 Hz, 3 H).
1H NMR (MeOD-d4, 400 MHz): δ ppm 8.00 (d, J = 3.26 Hz, 1
H), 7.83 (d, J = 3.01 Hz, 1 H), 7.14 - 7.31 (m, 3 H), 5.71 (s, 1 MS: calc'd 493 H), 4.54 (d, J = 17.07 Hz, 1 H), 4.02 - 4.30 (m, 5 H), 3.78 - 3.98 (MH+), exp 493 (m, 2 H), 3.67 (t, J = 3.89 Hz, 1 H), 3.41 (br. s., 1 H), 2.70 - (MH+).
2.86 (m, 1 H), 1.24 (t, J = 7.15 Hz, 3 H).
1H NMR (MeOD-d4, 400 MHz): δ ppm 8.01 (d, J = 3.26 Hz, 1
H), 7.83 (d, J = 3.26 Hz, 1 H), 7.13 (dd, J = 8.66, 6.65 Hz, 2 H), MS: calc'd 511 5.72 (s, 1 H), 4.55 (d, J = 17.32 Hz, 1 H), 4.01 - 4.26 (m, 5 H), (MH+), exp 511 3.78 - 3.96 (m, 2 H), 3.67 (t, J = 3.76 Hz, 1 H), 3.35 - 3.47 (m, 1 (MH+).
H), 2.61 - 2.79 (m, 1 H), 1.25 (t, J = 7.03 Hz, 3 H).
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.93 - 8.08 (m, 1 H), MS: calc'd 511 7.76 - 7.90 (m, 1 H), 7.19 - 7.31 (m, 1 H), 7.04 - 7.16 (m, 1 H), (MH+), exp 511 6.02 (br. s., 1 H), 4.35 - 4.54 (m, 1 H), 4.10 (d, J = 4.77 Hz, 4 (MH+). H), 3.79 - 3.97 (m, 2 H), 3.56 - 3.70 (m, 1 H), 2.61 - 2.81 (m, 1
H), 1.09 - 1.30 (m, 3 H).
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.99 (d, J = 3.26 Hz, 1
H), 7.80 (d, J = 2.76 Hz, 1 H), 7.35 - 7.45 (m, 1 H), 7.14 (t, J = MS: calc'd 557 6.90 Hz, 1 H), 6.03 (s, 1 H), 4.39 (br. s., 1 H), 4.14 - 4.27 (m, 1 (MH+), exp 557 H), 4.08 (br. s., 3 H), 3.87 (d, J = 12.80 Hz, 3 H), 3.65 (s, 3 H), (MH+).
2.68 (br. s., 1 H).
1H NMR (MeOD-d4, 400 MHz): δ ppm 8.01 (d, J = 3.26 Hz, 1
H), 7.83 (d, J = 3.01 Hz, 1 H), 7.43 - 7.57 (m, 2 H), 7.32 (dd, J MS: calc'd 525 = 8.41, 2.13 Hz, 1 H), 5.71 (s, 1 H), 4.44 (d, J = 14.81 Hz, 1 H), (MH+), exp 525 4.02 - 4.31 (m, 5 H), 3.78 - 3.98 (m, 3 H), 3.60 (br. s., 1 H), 2.68 (MH+).
(br. s., 1 H), 1.25 (t, J = 7.15 Hz, 3 H).
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.97 (d, J = 2.76 Hz, 1
MS: calc'd 495 H), 7.78 (br. s., 1 H), 7.24 - 7.38 (m, 2 H), 7.10 - 7.21 (m, 1 H),
(MH+), exp 495 6.23 (s, 1 H), 4.40 (m, 1H), 4.25 (m, 1 H), 4.07 (m, 2 H), 3.87
(MH+).
(m, 2 H), 3.62 (m, 4 H), 2.70 (m, 2 H).
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.97 (d, J = 3.3 Hz, 1H),
7.78 (d, J = 3.0 Hz, 1H), 7.75 - 7.68 (m, 2H), 7.59 (d, J = 8.3
MS: calc'd 502 Hz, 2H), 5.78 (s, 1H), 4.35 (d, J = 16.3 Hz, 1H), 4.14 (q, J = 7.0
(MH+), exp 502 Hz, 3H), 3.81 (t, J = 7.8 Hz, 1H), 3.60 - 3.49 (m, 1H), 3.16 - (MH+).
3.05 (m, 1H), 2.74 (dd, J = 7.9, 13.2 Hz, 1H), 2.53 (dd, J = 7.9,
14.9 Hz, 1H), 1.22 (t, J = 7.0 Hz, 3H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.99 (d, J = 3.3 Hz, 1H),
7.81 (d, J = 3.3 Hz, 1H), 7.40 (t, J = 8.3 Hz, 1H), 7.26 - 7.15
MS: calc'd 509 (m, 2H), 5.99 (s, 1H), 4.43 (d, J = 17.1 Hz, 1H), 4.26 (d, J =
(MH+), exp 509 14.3 Hz, 1H), 4.10 (dq, J = 2.3, 7.1 Hz, 4H), 3.96 - 3.78 (m,
(MH+).
2H), 3.65 (br. s., 1H), 3.36 (d, J = 8.3 Hz, 1H), 2.75 (br. s., 1H),
1.19 (t, J = 7.2 Hz, 3H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.95 (d, J = 3.3 Hz, 1H),
7.77 (d, J = 3.0 Hz, 1H), 7.29 - 7.06 (m, 3H), 6.04 (s, 1H), 4.43 MS: calc'd 513 (d, J = 16.3 Hz, 1H), 4.17 (d, J = 16.3 Hz, 1H), 4.12 - 4.03 (m, (MH+), exp 513 2H), 4.00 - 3.85 (m, 2H), 3.62 (q, J = 11.3 Hz, 1H), 3.28 - 3.13 (MH+).
(m, 2H), 2.87 - 2.73 (m, 1H), 2.65 - 2.50 (m, 1H), 1.17 (t, J = 7.2 Hz, 3H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.98 (d, J = 3.3 Hz, 1H),
7.77 (d, J = 3.0 Hz, 1H), 7.45 (dd, J = 6.0, 8.5 Hz, 1H), 7.24
MS: calc'd 563 (dd, J = 2.6, 8.7 Hz, 1H), 7.06 (dt, J = 2.8, 8.4 Hz, 1H), 6.20 (s,
(MH+), exp 563 1H), 4.62 - 4.46 (m, 2H), 4.35 (br. s., 1H), 4.20 (br. s., 1H), 4.06
(MH+).
(d, J = 4.3 Hz, 2H), 3.98 - 3.79 (m, 3H), 3.60 (d, J = 11.0 Hz,
1H), 2.66 (d, J = 17.8 Hz, 1H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 8.01 (d, J = 3.3 Hz, 1H),
7.83 (d, J = 3.0 Hz, 1H), 7.59 (dd, J = 7.3, 8.3 Hz, 1H), 7.22
MS: calc'd 553 (dd, J = 2.0, 9.8 Hz, 1H), 7.15 (dd, J = 2.0, 8.3 Hz, 1H), 5.73 (s,
(MH+), exp 553 1H), 4.53 (d, J = 16.8 Hz, 1H), 4.27 - 4.01 (m, 5H), 3.98 - 3.80
(MH+).
(m, 2H), 3.67 (br. s., 1H), 3.36 (d, J = 6.0 Hz, 1H), 2.73 (br. s.,
1H), 1.24 (t, J = 7.2 Hz, 3H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 8.01 (d, J = 3.0 Hz, 1H),
7.83 (d, J = 3.3 Hz, 1H), 7.35 (dt, J = 6.0, 7.9 Hz, 1H), 7.22 (d,
MS: calc'd 475 J = 7.5 Hz, 1H), 7.10 (td, J = 2.0, 9.9 Hz, 1H), 7.01 (dt, J = 2.0,
(MH+), exp 475 8.4 Hz, 1H), 5.74 (s, 1H), 4.53 (d, J = 14.1 Hz, 1H), 4.34 - 4.02
(MH+).
(m, 5H), 3.98 - 3.80 (m, 2H), 3.66 (br. s., 1H), 3.47 - 3.36 (m,
1H), 2.77 (br. s., 1H), 1.24 (t, J = 7.2 Hz, 3H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 8.00 (d, J = 3.0 Hz, 1H),
7.84 (d, J = 3.0 Hz, 1H), 7.41 (dd, J = 5.4, 8.7 Hz, 2H), 7.07 (t,
MS: calc'd 475 J = 8.8 Hz, 2H), 5.71 (s, 1H), 4.58 (d, J = 16.1 Hz, 1H), 4.31
(MH+), exp 475 (br. s., 1H), 4.21 - 4.03 (m, 4H), 3.98 - 3.81 (m, 2H), 3.71 (br. s.,
(MH+).
1H), 3.50 (dd, J = 1.6, 3.4 Hz, 1H), 2.85 (br. s., 1H), 1.23 (t, J =
7.2 Hz, 3H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.93 (d, J = 3.0 Hz, 1H),
7.74 (d, J = 3.3 Hz, 1H), 7.34 - 7.20 (m, 2H), 6.16 (s, 1H), 4.43
MS: calc'd 547 (d, J = 16.6 Hz, 1H), 4.17 (d, J = 16.6 Hz, 1H), 4.06 (q, J = 7.0
(MH+), exp 547 Hz, 2H), 3.91 (t, J = 8.0 Hz, 1H), 3.70 - 3.57 (m, 1H), 3.23 - (MH+).
3.14 (m, 1H), 2.85 - 2.73 (m, 1H), 2.65 - 2.50 (m, 1H), 1.15 (t, J
= 7.2 Hz, 3H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.36 - 7.13 (m, 4H), MS: calc'd 510 7.04 (d, J = 0.8 Hz, 1H), 5.73 (s, 1H), 4.29 (d, J = 15.8 Hz, 1H), (MH+), exp 510 4.14 (q, J = 7.2 Hz, 2H), 3.96 (d, J = 15.8 Hz, 1H), 3.89 (s, 3H), (MH+).
3.55 - 3.46 (m, 2H), 3.01 - 2.82 (m, 1H), 2.68 - 2.52 (m, 1H),
2.50 - 2.33 (m, 1H), 1.23 (t, J = 7.2 Hz, 3H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 8.57 (s, 1H), 7.33 - 7.15
(m, 4H), 7.06 (d, J = 1.0 Hz, 1H), 5.74 (s, 1H), 4.19 - 4.09 (m,
MS: calc'd 490 2H), 4.08 - 4.02 (m, 1H), 4.01 - 3.95 (m, 1H), 3.93 (s, 3H), 3.87
(MH+), exp 490 - 3.71 (m, 2H), 3.19 (dd, J = 3.5, 8.0 Hz, 1H), 3.05 - 2.97 (m,
(MH+).
1H), 2.43 (ddd, J = 3.8, 8.3, 11.7 Hz, 1H), 1.24 (t, J = 7.2 Hz,
3H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.98 (d, J = 2.8 Hz, 1H),
7.79 (d, J = 2.8 Hz, 1H), 7.50 - 7.36 (m, 1H), 7.04 - 6.87 (m, MS: calc'd 493 2H), 6.02 - 5.93 (m, 1H), 4.38 - 4.19 (m, 2H), 4.17 - 4.00 (m, (MH+), exp 493 4H), 3.97 - 3.78 (m, 3H), 3.58 (br. s., 1H), 2.71 (br. s., 1H), 1.19 (MH+).
(t, J = 7.0 Hz, 3H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.95 (d, J = 3.0 Hz, 1H),
7.73 (d, J = 3.0 Hz, 1H), 7.47 - 7.38 (m, 1H), 6.95 (t, J = 8.7
MS: calc'd 513 Hz, 2H), 5.96 (s, 1H), 4.36 (d, J = 15.8 Hz, 1H), 4.13 - 3.99 (m,
(MH+), exp 513 3H), 3.68 (t, J = 8.4 Hz, 1H), 3.59 (q, J = 11.1 Hz, 1H), 3.03
(MH+).
(dt, J = 11.0, 15.2 Hz, 1H), 2.76 - 2.62 (m, 1H), 2.56 - 2.41 (m,
1H), 1.18 (t, J = 7.2 Hz, 3H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.97 (d, J = 3.3 Hz, 1H),
7.78 (d, J = 3.0 Hz, 1H), 7.35 - 7.19 (m, 2H), 6.18 (s, 1H), 4.48 MS: calc'd 527 (d, J = 17.3 Hz, 1H), 4.31 - 4.19 (m, 1H), 4.16 - 4.01 (m, 4H), (MH+), exp 527 3.97 - 3.82 (m, 2H), 3.67 (br. s., 1H), 3.36 (d, J = 6.0 Hz, 1H), (MH+).
2.80 - 2.63 (m, 1H), 1.16 (t, J = 7.0 Hz, 3H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.44 (dd, J = 6.0, 8.5
Hz, 1H), 7.35 (s, 1H), 7.24 (dd, J = 2.5, 8.8 Hz, 1H), 7.06 (d, J MS: calc'd (MH+) = 2.5 Hz, 1H), 6.15 (s, 1H), 4.51 - 4.35 (m, 1H), 4.27 - 4.15 (m, 541, measured 1H), 4.14 - 4.02 (m, 2H), 3.96 - 3.79 (m, 2H), 3.76 - 3.65 (m, (MH+) 541 1H), 3.61 (s, 3H), 2.78 - 2.66 (m, 1H), 2.62 (s, 3H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.58 - 7.52 (m, 2H), MS: calc'd (MH+) 7.30 (dd, J = 2.6, 8.7 Hz, 1H), 7.16 - 7.07 (m, 1H), 6.24 (s, 1H), 561, measured 4.58 (d, J = 17.1 Hz, 1H), 4.21 - 3.94 (m, 2H), 3.64 (s, 4H), 3.23 (MH+) 561 (s, 1H), 2.87 (dd, J = 8.9, 12.7 Hz, 1H), 2.63 (s, 3H), 2.57 - 2.44
(m, 1H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 8.05 (d, J = 3.01 Hz,
1H), 7.95 (d, J = 3.26 Hz, 1H), 7.33 - 7.42 (m, 2H), 7.22 - 7.29
MS: calc'd (MH+) (m, 1H), 6.29 (s, 1H), 4.83 (d, J = 16.56 Hz, 1H), 4.52 (d, J =
509, measured 16.56 Hz, 1H), 4.15 - 4.27 (m, 3H), 4.10 (q, J = 6.94 Hz, 2H),
(MH+) 509 3.92 - 4.06 (m, 2H), 3.72 (ddd, J = 12.55, 8.28, 4.02 Hz, 1H),
3.11 - 3.21 (m, 1H), 1.15 (t, J = 7.15 Hz, 3 H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 8.10 - 8.15 (m, 1H),
8.03 - 8.08 (m, 1H), 7.35 - 7.45 (m, 2H), 7.24 - 7.32 (m, 1H), MS: calc'd (MH+) 6.32 (s, 1H), 4.55 (d, J = 16.06 Hz, 1H), 4.04 - 4.19 (m, 4H), 529, measured 3.63 - 3.73 (m, 1H), 3.23 - 3.31 (m, 1H), 2.79 - 2.94 (m, 1H), (MH+) 529 2.51 - 2.65 (m, 1H), 1.15 (t, J = 7.15 Hz, 3 H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 8.07 (s, 1H), 7.35 - 7.48
(m, 2H), 7.12 (td, J = 8.34, 2.64 Hz, 1H), 6.12 (s, 1H), 4.35 -
MS: calc'd (MH+) 4.50 (m, 2H), 4.02 - 4.15 (m, 2H), 3.92 - 3.99 (m, 1H), 3.83
538, measured (ddd, J = 12.05, 6.15, 3.14 Hz, 1H), 3.70 (br. s., 1H), 3.63 - 3.64
(MH+) 537&539 (s, 3H), 3.44 (br. s., 1H), 2.84 (d, J = 11.80 Hz, 1H), 2.66 (s, 3
H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.93 - 8.00 (m, 1H),
7.78 (d, J = 3.26 Hz, 1H), 7.32 - 7.40 (m, 1H), 7.25 - 7.30 (m,
MS: calc'd (MH+) 1H), 7.14 (td, J = 8.22, 1.38 Hz, 1H), 6.25 (s, 1H), 4.50 (d, J =
554, measured 17.32 Hz, 1H), 4.26 (d, J = 11.54 Hz, 1H), 4.00 - 4.16 (m, 4H),
(MH+) 553&555 3.81 - 3.96 (m, 2H), 3.68 (br. s., 1H), 3.39 (br. s., 1H), 2.75 (br.
s., 1H), 1.14 (t, J = 7.03 Hz, 3 H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.95 (d, J = 3.26 Hz,
1H), 7.77 (d, J = 3.26 Hz, 1H), 7.33 - 7.41 (m, 1H), 7.26 - 7.32
(m, 1H), 7.14 (td, J = 8.28, 1.51 Hz, 1H), 6.21 - 6.27 (m, 1H), MS: calc'd (MH+) 4.46 (d, J = 16.56 Hz, 1H), 4.20 (d, J = 16.31 Hz, 1H), 4.02 - 574, measured 4.08 (m, 2H), 3.97 (t, J = 8.03 Hz, 1H), 3.65 (q, J = 11.29 Hz, (MH+) 573&575 1H), 3.19 - 3.30 (m, 1H), 2.75 - 2.89 (m, 1H), 2.51 - 2.66 (m,
1H), 1.13 (t, J = 7.15 Hz, 3 H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 8.32 (s, 1H), 7.57 (dd, J MS: calc'd (MH+) = 8.66, 5.90 Hz, 1H), 7.39 (dd, J = 8.53, 2.51 Hz, 1H), 7.20 (td, 493, measured J = 8.34, 2.64 Hz, 1H), 6.27 (s, 1H), 4.18 - 4.29 (m, 2H), 4.07 (MH+) 493 (dd, J = 11.42, 3.64 Hz, 1H), 3.85 - 3.94 (m, 2H), 3.73 - 3.81
(m, 1H), 3.63 - 3.71 (m, 4H), 3.21 (ddd, J = 11.98, 5.84, 3.01
Hz, 1H), 2.67 - 2.79 (m, 4 H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 8.07 (s, 1H), 7.40 - 7.48
(m, 2H), 7.13 (td, J = 8.38, 2.57 Hz, 1H), 6.14 (s, 1H), 4.34 -
MS: calc'd (MH+) 4.50 (m, 2H), 4.03 - 4.13 (m, 4H), 3.91 - 4.00 (m, 1H), 3.83
552, measured (ddd, J = 12.11, 6.15, 3.07 Hz, 1H), 3.70 (t, J = 4.45 Hz, 1H),
(MH+) 551&553 3.40 - 3.52 (m, 1H), 2.86 (br. s., 1H), 2.66 (s, 3H), 1.15 (t, J =
7.09 Hz, 3 H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 8.34 - 7.89 (m, 1H),
7.82 - 7.60 (m, 1H), 7.30 - 7.01 (m, 3H), 6.08 (s, 1H), 4.29 (d, J MS: calc'd (MH+) = 16.8 Hz, 1H), 4.13 - 3.97 (m, 4H), 3.90 - 3.75 (m, 3H), 3.42 - 493, measured 3.40 (m, 1H), 3.02 (d, J = 11.9 Hz, 1H), 2.57 (ddd, J = 4.0, 8.0, (MH+) 493 11.9 Hz, 1H), 1.21 (t, 3H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.99-8.28 (m, 1H), 7.92- 8.00 (m, 1H), 7.74-7.81 (m, 1H), 7.61 (m, 1H), 7.44 (m, 1H), MS: calc'd (MH+) 7.33 (m, 1H), 7.17 (m, 1H), 6.19 (s, 1H), 4.53 (d, 1H), 4.31 (d, 521 measured 1H), 4.04-4.17 (m, 2H), 3.82-3.98 (m, 2H), 3.67-3.74 (m, 1H), (MH+) 521 3.71 (br. s., 1H), 3.61 (s, 3H), 3.44 (d, 1H), 2.81 (br. s., 1H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.90-7.97 (m, 1H), 7.72- 7.78 (m, 1H), 7.57-7.66 (m, 1H), 7.45 (m, 1H), 7.35 (m, 1H), MS: calc'd (MH+) 7.17 (m, 1H), 6.18 (s, 1H), 4.45 (d, 1H), 4.20 (d, 1H), 3.98 (m, 541 measured 1H), 3.63-3.72 (m, 1H), 3.61 (m, 3H), 3.20-3.30 (m, 1H), 2.82 (MH+) 541 (tm, 1H), 2.49-2.65 (m, 1H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.99-8.08 (m, 1H), 7.93
MS: calc'd (MH+) (d, 1H), 7.20-7.41 (m, 2H), 6.13-6.30 (m, 1H), 6.22 (s, 1H), 4.84
513 measured (d, 2H), 4.77 (br. s., 2H), 4.51 (d, 1H), 4.11-4.27 (m, 3H), 3.89- (MH+) 513 4.07 (m, 2H), 3.72 (m, 1H), 3.65 (s, 3H), 3.10-3.23 (m, 1H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 8.09-8.16 (m, 1H), 7.99- MS: calc'd (MH+) 8.09 (m, 1H), 7.25-7.43 (m, 2H), 6.19-6.30 (m, 1H), 4.54 (d, 533 measured 1H), 4.18 (d, 1H), 4.10 (m, 1H), 3.67-3.76 (m, 1H), 3.66 (s, 3H), (MH+) 533 3.22-3.31 (m, IH), 2.88 (tm, IH), 2.48-2.66 (m, IH)
1H NMR (MeOD-d4, 400 MHz): δ ppm 8.04-8.12 (m, IH), 7.95- 8.03 (m, IH), 7.47 (m, IH), 7.21-7.31 (m, 2H), 6.03 (s, IH), MS: calc'd (MH+)
75 4.81 (d, IH), 4.58 (d, IH), 4.23-4.29 (m, IH), 4.15-4.23 (m, 495 measured 2H), 3.92-4.06 (m, 2H), 3.75 (m, IH), 3.69 (s, 3H), 3.19-3.29 (MH+) 495 (m, IH)
lH NMR (MeOD-d4, 400 MHz): δ ppm 8.14-8.17 (m, IH), 8.12
MS: calc'd (MH+) (d, IH), 7.49 (m, IH), 7.26-7.35 (m, 2H), 6.04 (s, IH), 4.54 (d,
76 515 measured IH), 4.04-4.16 (m, 2H), 3.69 (s, 3H), 3.58-3.67 (m, IH), 3.19- (MH+) 515 3.30 (m, IH), 2.80-2.94 (m, IH), 2.50-2.65 (m, IH)
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.99-8.10 (m, IH), 7.95
MS: calc'd (MH+) (d, IH), 7.48 (m, IH), 7.15-7.34 (m, 2H), 5.75 (s, IH), 4.75-4.82
77 495 measured (m, IH), 4.48 (d, IH), 4.08-4.26 (m, 3H), 3.90-4.03 (m, 2H),
(MH+) 495 3.72 (s, 3H), 3.68 (d, IH), 3.14 (d, IH)
1H NMR (MeOD-d4, 400 MHz): δ ppm 8.10 (d, IH), 7.93-8.02
MS: calc'd (MH+) (m, IH), 7.22-7.41 (m, 2H), 6.17-6.29 (m, IH), 4.60 (d, IH),
78 527 measured 4.37 (d, IH), 4.13 (d, IH), 3.89-4.02 (m, 2H), 3.84 (d, IH), 3.65
(MH+) 527 (s, 3H), 3.41 (m, IH), 3.15 (m, IH), 1.60 (s, 3H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 8.03-8.13 (m, IH), 7.96
MS: calc'd (MH+) (d, IH), 7.20-7.36 (m, 2H), 6.14-6.28 (m, IH), 4.35-4.56 (m,
79 527 measured 2H), 4.11-4.22 (m, IH), 3.85-4.03 (m, 2H), 3.78 (d, IH), 3.65 (s,
(MH+) 527 3H), 3.39-3.46 (m, IH), 3.00 (d, IH), 1.57 (s, 3H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.56-7.52 (m, 2H), 7.31-
MS: calc'd (MH+) 7.29 (m, IH), 7.14-7.10 (m, IH), 6.23 (s, IH), 4.31 (dd, 2H, Jl
80 543exp (MH+) = 32 Hz, J2 = 16 Hz), 3.65 (s, 3H), 3.51-2.92 (m, 5H), 2.52- 543
2.22(m, 5H).
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.97 (d, J = 3.01Hz,
IH), 7.78 (d, J = 3.01 Hz, IH), 7.47-7.40 (m, 2H), 7.14-7.09 (m, MS: calc'd (MH+)
81 IH), 6.14 (s, IH), 4.52 (d, J = 16.31 Hz, IH), 4.15 (d, J = 16.06 539 exp (MH+) Hz, IH), 4.07 (t, J = 8.16 Hz, IH), 3.61 - 3.73 (m, 4H), 3.21 - 539.
3.31 (m, 1 H)2.78 - 2.94 (m, IH), 2.48 - 2.66 (m, IH)
1H NMR (MeOD-d4, 400 MHz): δ ppm 10.00(br, IH), 8.02 (d, J MS: calc'd (MH+)
82
= 3.3 Hz, IH), 7.93 (d, J = 3.0 Hz, IH), 7.55 - 7.35 (m, 2H), 491, measured 7.28 (dt, J = 2.0, 7.4 Hz, 2H), 6.09 (s, 1H), 4.32 - 3.77 (m, 6H), (MH+) 491 3.77 - 3.45 (m, 3H), 3.14 - 2.97 (m, 1H), 2.41 (d, J = 12.3 Hz,
1H), 1.05 (t, J = 7.2 Hz, 3H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 8.06-8.04 (m, 1H), 7.97-
MS: calc'd (MH+) 7.95 (m, 1H), 7.46-7.42 (m, 1H), 7.25-7.20 (m, 2H), 5.73 (s,
83 509, measured 1H), 4.25-4.09 (m, 5H), 3.95-3.81 (m, 3H), 3.75-3.61 (m, 3H),
(MH+) 509 1.25 (t, J = 7.2 Hz, 3H).
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.93 (d, J = 3.01Hz, 1
H)7.72(d, J = 3.01 Hz, 1H), 7.47-7.39 (m, 2H), 7.15-7.10 (m, MS: calc'd (MH+)
84 1H), 6.13 (s, 1H), 4.42 (d, J = 16.31 Hz, 1H), 4.15 (d, J = 16.06 559exp (MH+) Hz, 1H), 4.07 (t, J = 8.16 Hz, 1H), 3.61 - 3.73 (m, 4H), 3.21 - 559
3.31 (m, 1 H)2.78 - 2.94 (m, 1H), 2.48 - 2.66 (m, 1H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 8.05 (d, J = 3.01Hz, 1
H)7.93(d, J = 3.01 Hz, 1H), 7.54-7.36 (m, 3H), ) 6.20 (s, 1H), MS: calc'd (MH+)
85 4.48(d, J = 16.31 Hz, 1H), 4.16 (d, J = 16.06 Hz, 1H), 4.07 (t, J 531exp (MH+) = 8.16 Hz, 1H), 3.61 - 3.73 (m, 4H), 3.21 - 3.31 (m, 1 H)2.78 - 531
2.94 (m, 1H), 2.48 - 2.66 (m, 1H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 8.01 - 8.18 (m, 2 H),
7.51 - 7.68 (m, 1 H), 7.26 - 7.40 (m, 1 H), 7.08 - 7.19 (m, 1 H), MS: calc'd (MH+)
86 6.28 (s, 1 H), 5.02 - 5.15 (m, 1 H), 4.92 - 4.99 (m, 1 H), 4.25 - 511 exp (MH+) 4.53 (m, 2 H), 4.05 - 4.25 (m, 1 H), 3.68 (s, 3 H), 2.81 - 3.09 (m, 511.
2 H), 2.30 - 2.47 (m, 1 H), 2.08 - 2.28 (m, 1 H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.61 - 7.64 (m, 1 H),
7.53 - 7.61 (m, 1 H), 7.29 - 7.34 (m, 1 H), 7.10 - 7.19 (m, 1 H),
MS: calc'd (MH+) 6.24 (s, 1 H), 4.57 - 4.70 (m, 1 H), 4.39 - 4.52 (m, 1 H), 4.04 -
87 535 exp (MH+) 4.24 (m, 3 H), 3.83 - 4.04 (m, 2 H), 3.66 (s, 3 H), 3.51 - 3.63 (m,
535.
1 H), 3.01 - 3.15 (m, 1 H), 2.12 - 2.27 (m, 1 H), 0.90 - 1.11 (m,
4 H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 8.17 - 8.25 (m, 1 H),
7.47 - 7.61 (m, 1 H), 7.23 - 7.33 (m, 1 H), 7.02 - 7.16 (m, 1 H), MS: calc'd (MH+)
88 6.73 - 6.94 (m, 1 H), 6.21 (s, 1 H), 4.54 - 4.72 (m, 1 H), 4.42 - 545 exp (MH+) 4.54 (m, 1 H), 4.16 (s, 3 H), 3.88 - 4.07 (m, 2 H), 3.67 - 3.81 (m, 545.
1 H), 3.65 (d, J = 1.51 Hz, 3 H), 3.10 - 3.24 (m, 1 H) 1H NMR (MeOD-d4, 400 MHz): δ ppm 8.03 - 8.18 (m, 2 H),
7.57 (dd, J = 8.66, 5.90 Hz, 1 H), 7.34 (dd, J = 8.53, 2.51 Hz, 1
MS: calc'd (MH+) H), 7.18 (td, J = 8.41, 2.51 Hz, 1 H), 6.20 - 6.31 (m, 1 H), 4.58
89 543 exp (MH+) (d, J = 16.31 Hz, 1 H), 3.69 - 3.93 (m, 3 H), 3.66 (s, 3 H), 3.20 - 543.
3.31 (m, 1 H), 1.34 (d, J = 2.26 Hz, 3 H), 1.22 (d, J = 2.26 Hz,
3H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 8.09 (d, J = 3.01 Hz, 1
H), 8.01 (d, J = 3.26 Hz, 1 H), 7.54 (s, 1 H), 7.31 (dd, J = 8.78, MS: calc'd (MH+)
90 2.51 Hz, 1 H), 7.03 - 7.20 (m, 1 H), 6.24 (s, 1 H), 4.17 - 4.31 (m, 539 exp (MH+) 2 H), 3.92 (s, 1 H), 3.70 (ddd, J = 11.54, 6.15, 2.89 Hz, 1 H), 539.
3.64 (s, 3 H), 2.85 - 3.12 (m, 3 H), 1.53 - 1.69 (m, 6 H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 8.02 - 8.09 (m, 1 H),
7.86 - 8.00 (m, 1 H), 7.46 - 7.60 (m, 1 H), 7.24 - 7.36 (m, 1 H), MS: calc'd (MH+)
91 6.99 - 7.19 (m, 1 H), 6.12 - 6.31 (m, 1 H), 4.80 - 4.87 (m, 1 H), 511 exp (MH+) 4.38 - 4.52 (m, 2 H), 3.80 - 3.99 (m, 1 H), 3.66 (s, 3 H), 3.36 - 511.
3.51 (m, 2 H), 3.10 - 3.29 (m, 2 H), 2.76 - 2.89 (m, 1 H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 8.16 (br. s., 1H), 7.38
MS: calc'd (dd, J = 8.7, 6.1 Hz, 1H), 7.26 (dd, J = 8.8, 2.5 Hz, 1H), 7.06
507(MH+) ,
92 (td, J = 8.3, 2.6 Hz, 1H), 6.95 (s, 1H), 6.16 (s, 1H), 4.28-4.55
measured
(m, 2H), 4.01-4.21 (m, 2H), 3.80-3.99 (m, 4H), 3.56-3.74 (m,
507(MH+) 3H), 3.38-3.51 (m, 1H), 2.77 (br. s., 1H), 2.19 ppm (s, 3H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.99 (d, J = 3.0 Hz, 1H),
MS: calc'd 7.81 (d, J = 3.3 Hz, 1H), 7.27-7.40 (m, 3H), 5.99 (s, 1H), 4.46
554(MH+) ,
93 (d, J = 16.3 Hz, 1H), 4.27 (br. s., 1H), 4.03-4.16 (m, 4H), 3.79- measured
3.99 (m, 2H), 3.67 (br. s., 1H), 3.35-3.51 (m, 1H), 2.64-2.84 (m,
554(MH+) 1H), 1.19 ppm (t, J = 7.2 Hz, 3H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 8.00 (d, J = 3.0 Hz, 1H),
MS: calc'd 7.84 (d, J = 2.8 Hz, 1H), 7.27-7.42 (m, 3H), 5.99 (s, 1H), 4.53
540(MH+) ,
94 (d, J = 17.6 Hz, 1H), 4.30 (d, J = 15.3 Hz, 1H), 4.05-4.18 (m,
measured
2H), 3.74-3.99 (m, 3H), 3.66 (s, 3H), 3.39-3.55 (m, 1H), 2.83
540(MH+) ppm (br. s., 1H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 8.46 (s, 1H), 7.53 (dd, J MS: calc'd
95
= 8.5, 6.0 Hz, 1H), 7.28 (dd, J = 8.7, 2.6 Hz, 1H), 7.10 (td, J = 563(MH+) , 8.4, 2.8 Hz, 1H), 6.21 (s, 1H), 4.48 (d, J = 16.6 Hz, 1H), 4.11- measured
4.30 (m, 3H), 3.90-4.05 (m, 2H), 3.73 (ddd, J = 12.7, 8.4, 3.8 563(MH+) Hz, 2H), 3.65 (s, 3H), 3.07-3.23 ppm (m, 1H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.97 (d, J = 3.3 Hz, 1H),
MS: calc'd 7.79 (br. s., 1H), 6.97-7.24 (m, 2H), 5.93 (s, 1H), 4.21-4.60 (m,
507(MH+) ,
96 3H), 4.09 (q, J = 7.1 Hz, 3H), 3.87 (br. s., 2H), 3.66 (br. s., 1H),
measured
2.79 (br. s., 2H), 2.56 (d, J = 2.5 Hz, 3H), 1.16 ppm (t, J = 7.0
507(MH+) Hz, 3H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.09-7.35 (m, 4H), 7.06 MS: calc'd (d, J = 1.3 Hz, 1H), 6.24 (s, 1H), 4.20-4.49 (m, 2H), 3.98-4.14 506(MH+) ,
97
(m, 3H), 3.81-3.94 (m, 5H), 3.55 (br. s., 1H), 3.17-3.29 (m, 2H), measured
2.69 (br. s., 1H), 1.15 ppm (t, J = 7.2 Hz, 3H) 506(MH+)
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.97 (d, J = 3.0 Hz, 1H),
7.80 (d, J = 2.8 Hz, 1H), 7.49 (dd, J = 6.1, 8.7 Hz, 1H), 7.26
(dd, J = 2.6, 8.7 Hz, 1H), 7.08 (dt, J = 2.6, 8.3 Hz, 1H), 6.17 (s, MS: calc'd (MH+)
98 1H), 4.96 - 4.90 (m, 1H), 4.51 (br. s., 1H), 4.39 - 4.19 (m, 1H), 523, measured 4.19 - 4.04 (m, 2H), 3.88 (br. s., 2H), 3.70 (br. s., 1H), 3.36 - (MH+) 523 3.34 (m, 1H), 2.72 (br. s., 1H), 1.24 (d, J = 6.3 Hz, 3H), 0.99 (d,
J = 6.3 Hz, 3H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.97 (dd, J = 1.6, 3.1
Hz, 1H), 7.79 (d, J = 3.0 Hz, 1H), 7.54 - 7.43 (m, 1H), 7.25 (td,
MS: calc'd (MH+) J = 2.5, 8.8 Hz, 1H), 7.12 - 7.03 (m, 1H), 6.19 (s, 1H), 4.43 (d, J
99 523, measured = 17.6 Hz, 1H), 4.29 (br. s., 1H), 4.16 - 3.80 (m, 6H), 3.65 (d, J
(MH+) 523 = 19.3 Hz, 1H), 3.35 (br. s., 1H), 2.78 (br. s., 1H), 1.62 - 1.51
(m, 2H), 0.84 - 0.76 (m, 3H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 8.06 (d, J = 3.0 Hz, 1H),
7.95 (d, J = 3.0 Hz, 1H), 7.40 - 7.21 (m, 3H), 5.72 (s, 1H), 5.02
MS: calc'd (MH+) (quin, J = 6.2 Hz, 1H), 4.84 (d, J = 16.8 Hz, 1H), 4.48 (d, J =
100 507, measured 16.8 Hz, 1H), 4.27 - 4.08 (m, 3H), 4.05 - 3.92 (m, 2H), 3.76 - (MH+) 507 3.65 (m, 1H), 3.19 - 3.09 (m, 1H), 1.28 (d, J = 6.3 Hz, 3H), 1.11
(d, J = 6.3 Hz, 3H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.97 (d, J = 3.0 Hz, 1H), MS: calc'd (MH+)
101
7.78 (d, J = 2.8 Hz, 1H), 7.39 - 7.27 (m, 2H), 7.22 - 7.12 (m, 523, measured 1H), 6.23 (s, 1H), 4.92 (d, J = 6.3 Hz, 1H), 4.46 (d, J = 17.1 Hz, (MH+) 523 1H), 4.26 (d, J = 16.1 Hz, 1H), 4.10 (d, J = 7.5 Hz, 2H), 3.95 - 3.81 (m, 2H), 3.64 (d, J = 6.8 Hz, 1H), 3.39 (br. s., 1H), 2.74
(br. s., 1H), 1.23 (d, J = 6.0 Hz, 3H), 0.96 (d, J = 6.3 Hz, 3H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 8.08 (s, 1H), 7.45 (dd, J
= 8.8, 6.0 Hz, 1H), 7.28 (dd, J= 8.8, 2.5 Hz, 1H), 7.11 (td, J =
MS: calc'd (MH+) 8.4, 2.5 Hz, 1H), 6.14 (s, 1H), 4.51 (d, J= 16.1 Hz, 1H), 4.05 (d,
102 513, measured J= 16.1 Hz, 1H), 3.84 (t, J= 8.2 Hz, 1H), 3.65 (m, 1H), 3.63 (s,
(MH+) 513 3H), 3.09-3.30 (m, 1H), 2.68-2.90 (m, 1H), 2.60 (s, 3H), 2.40- 2.56 (m, 1H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 8.30 (s, 1H), 7.22-7.59
MS: calc'd (MH+) (m, 3H), 6.31 (s, 1H), 4.27 (m, 2H), 4.08 (dd, J= 11.5, 3.5 Hz,
103 493, measured 1H), 3.92 (m, 2H), 3.79 (m, 1H), 3.71 (m, 1H), 3.69 (s, 3H),
(MH+) 493 3.23 (m, 1H), 2.73-2.80 (m, 1H), 2.72 (s, 3H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 8.03 (d, J = 3.01 Hz,
1H), 7.87-7.92 (m, 1H), 7.51 (dd, J = 8.78 Hz, 6.02Hz, 1H),
MS: calc'd (MH+) 7.28(dd, J = 8.78, 2.5 lHz, 1H), 7.11(td, J = 8.41Hz, 2.76Hz,
104 509, measured 1H) 6.19 (s, 1H), 4.42-4.20 (m, 2H), 4.00-4.13 (m, 1H), 3.71- (MH+) 509 3.97 (m, 2H), 3.63 (s, 3H), 3.51 (d, J = 8.78Hz, 1H) 3.06 (td, J
= 11.73, 3.64 Hz, 2H), 1.30-1.44 (d, J = 8.0Hz, 3 H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.96 (s, 1H), 7.79(s,
MS: calc'd (MH+) 1H), 7.47 (m, 1H) 7.27 (m, 1H), 7.09 (m, 1H), 6.12 (s, 1H),
105 537, measured 4.37-4.58 (m, 2 Hz), 3.99-4.23 (m, 2H), 3.80-3.97 (m, 2H), 3.68
(MH+) 537 (m, 1H), 3.45(m, 1H) 2.82 (m, 1H), 1.35 (s, 9H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.97 (s, 1H), 7.78 (s,
MS: calc'd (MH+) 1H), 7.36-7.52 (m, 2H), 7.12 (m, 1H), 6.13 (s, 1H), 4.33 (m,
106 554, measured 1H), 3.95-4.23 (m, 2H), 3.68-3.95 (m, 3H), 3.61 (s, 3H), 3.29- (MH+) 554 3.36 (m, 2H), 2.87 (m, 1H), 1.27-1.45(m, 3H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.92 (s, 1H), 7.73 (s,
MS: calc'd (MH+) 1H), 7.31-7.50 (m, 2H), 7.11 (m, 1H), 6.16 (s, 1H), 4.30 (m,
107 588, measured 2H), 4.05 (m, 2H), 3.70 (m, 2H), 2.89 (m, 2H), 2.24 (m, 1H),
(MH+) 588 2.08 (m, 2H), 1.16(t, J = 7.15Hz, 3H)
108 1H NMR (MeOD-d4, 400 MHz): δ ppm 7.93 (s, 1H), 7.74 (s, MS: calc'd (MH+) 1H), 7.39-7.59 (m, 2H), 7.12 (m, 1H), 6.16 (s, 1H), 4.30 (m, 588, measured 2H), 4.05 (m, 2H), 3.63 (m, 2H), 2.95(m, 2H), 2.08-2.24(m, (MH+) 588 3H), 1.16(t, J = 7.03Hz, 3H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.92 (s, 2H), 7.73 (s,
MS: calc'd (MH+) 1H), 7.25-7.31 (m, 2H), 7.13-7.17 (m, 1H), 6.22 (s, 1H), 4.19-
109 529, measured 4.34 (m, 2H), 3.70 (m, 1H), 3.60 (s, 3H), 3.36-3.48 (m, 1H),
(MH+) 529 2.92-2.88 (m, 1H), 2.00-2.23 (m, 4H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.94 (s, 2H), 7.74 (s,
MS: calc'd (MH+) 1H), 7.24-7.45 (m, 2H), 7.06-7.21 (m, 1H), 6.22 (s, 1H), 4.21-
110 529, measured 4.38 (m, 2H), 3.63 (m, 1H), 3.60 (s, 3H), 3.38-3.46 (m, 1H),
(MH+) 529 2.92-2.98 (m, 1H), 2.00-2.33 (m, 4H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 8.14 (d, J = 4.0 Hz, 1H),
8.08 (d, J = 4.0 Hz, 1H), 7.57-7.49 (m, 2H), 7.38-7.36 (m, 2H), MS: calc'd (MH+)
111 6.31 (s, 1H), 4.27-4.26 (m, 2H), 4.10 - 4.06 (m, 2H), 3.75 (m, 525 measured 1H), 3.40-3.37 (m, 1H), 2.98 - 2.96 (m, 1H), 2.27-2.06 (m,4H), (MH+) 525 1.15 (t, J = 8.0 Hz, 3H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 8.06 (d, J = 3.26Hz,
1H), 7.94 (d, J = 3.26Hz, 1H), 7.11-7.36 (m, 3H), 5.72 (s, 1H),
MS: calc'd (MH+) 4.42 (d, J = 16.5 Hz, 1H), 4.27 (d, J = 16.8 Hz, 1H), 4.17 (m,
112 506, measured 3H), 4.06 (d, J = 12.5 Hz, 1H), 3.73-3.98 (m, 2H), 3.58 (d, J =
(MH+) 507 9.3 Hz, 1H), 3.01-3.20 (m, 2H), 1.36(d, J = 6.3 Hz, 3H), 1.22 (t,
J = 7.1 Hz, 3H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 8.02 (d, J = 3.01Hz,
1H), 7.86 (brs, 1H), 7.15-7.30 (m, 3H), 5.69 (s, 1H), 4.34 (d, J = MS: calc'd (MH+)
113 15.6 Hz, 1H), 4.12(brs, 1H), 4.03 (d, J = 12.5 Hz, 1H), 4.77-3.95 492, measured (m, 2H), 3.70(s, 3H), 3.43-3.60 (m, 1H), 3.22 (brs, 1H), 3.08- (MH+) 493 3.19 (m, 1H), 1.35(d, J = 6.3 Hz, 3H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 8.04 (d, J = 3.01Hz,
1H), 7.90 (d, J = 3.01Hz, 1H), 7.24 (d, J = 7.78 Hz, 1H), 7.06-
MS: calc'd (MH+) 7.19 (m, 1H), 6.01 (s, 1H), 4.37-4.42 (d, J = 16.3Hz, 1H), 3.89-
114 511, measured 3.90 (d, J = 11.0Hz, 1H), 3.87-3.89 (m, 2H), 3.67 (s, 3H), 3.52- (MH+) 511 3.54 (d, J = 9.0Hz, 1H), 3.02-3.08 (m, 1H), 1.36 (d, J = 6.0 Hz,
3H) 1H NMR (MeOD-d4, 400 MHz): δ ppm 8.05 (d, J = 3.26Hz,
1H), 7.94 (d, J = 3.01Hz, 1H), 7.35-7.37 (m, 1H), 7.23-7.34 (m,
MS: calc'd (MH+) 1H), 6.26 (s, 1H), 4.43-4.47 (d, J = 16.0Hz, 1H), 4.30-4.34 (d, J
115 508, measured = 16.0Hz, 1H), 4.08 (d, J = 12.4Hz, 1H), 3.78-3.98 (m, 2H),
(MH+) 509 3.61-3.69 (m, 4H), 3.42-3.45 (d, J = 12.3Hz, 1H), 3.15-3.19 (m,
1H), 1.36 (d, J = 6.0 Hz, 3H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.99-8.00 (d, J =
3.01Hz, 1H), 7.83-7.84 (d, J = 3.01Hz, 1H), 7.43-7.50 (m, 2H), MS: calc'd (MH+)
116 7.13-7.15 (m, 1H), 6.17 (s, 1H), 4.36-4.41 (d, J = 17.3Hz, 1H), 567, measured 4.04-4.13 (m, 5H), 3.84-3.89 (m, 2H), 2.97-3.15 (m, 2H), 1.34- (MH+) 568 1.36 (d, J = 6.0 Hz, 3H), 1.15(t, J = 7.15Hz, 3H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 8.06-8.07 (d, J =
3.01Hz, 1H), 7.96-7.97(d, J = 3.01Hz, 1H), 7.40-7.46 (m, 2H),
MS: calc'd (MH+) 7.25-7.29 (m, 2H), 6.18 (s, 1H), 4.26-4.49 (m, 2H), 4.06 (d, J =
117 505, measured 12.5Hz, 1H), 3.78-3.97 (m, 4H), 3.72 (s, 3H), 3.65 (d, J =
(MH+) 505 8.8Hz, 1H), 3.37-3.44 (m, 2H), 1.36 (d, J = 6.3 Hz, 3H), 1.11- 1.14 (t, J = 6.0Hz, 3H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.98 (d, J = 4.0Hz, 1H),
7.79 (d, J = 4.0Hz, 1H), 7.35-7.27 (m, 2H), 7.20-7.16 (m, 1H), MS: calc'd (MH+)
118 6.22 (s, 1H), 4.36-4.34 (m, 1H), 4.08-4.03 (m, 3H), 3.90-3.83 523 measured (m, 2H), 3.30-2.78 (m, 4H), 1.35 (d, J = 8.0 Hz, 3H), 1.15 (t, J = (MH+) 523 8.0Hz, 3H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 8.0 (d, J = 4.0Hz, 1H),
7.81 (d, J = 4.0Hz, 1H), 7.63-7.61 (m, 1H), 7.45-7.33(m, 2H), MS: calc'd (MH+)
119 7.17 (m, 1H), 6.17 (s, 1H), 4.41-4.38 (m, 2H), 4.06-4.03 (m, 536 measured 2H), 3.92-3.84 (m, 3H), 3.61 (s, 3H), 3.01-2.89 (m, lh), 1.36 (d, (MH+) 536 J = 8.0 Hz, 3H), 1.15 (t, J = 8.0Hz, 3H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 8.01-8.02 (d, J =
3.01Hz, 1H), 7.48-7.52 (dd, J = 8.7Hz, 6.0Hz 1H), 7.26-7.30 MS: calc'd (MH+)
120 (dd, J = 8.7Hz, 2.7Hz, 1H), 7.10 (m, 1H), 6.18 (s, 1H), 4.20- 537, measured 4.35 (m, 1H), 4.11 (d, J = 12.3Hz, 1H), 3.81-3.84 (m, 3H), 3.01 (MH+) 537 (m, 2H), 2.01-2.10 (m, 1H), 1.06-1.09 (m, 6H)
121 1H NMR (MeOD-d4, 400 MHz): δ ppm 8.06 (d, J = 3.01 Hz, MS: calc'd (MH+) IH), 7.85 (d, J = 2.76 Hz, IH), 7.36 (dd, J = 8.66, 5.90 Hz, IH), 509 measured
7.20 (dd, J = 8.28, 2.51 Hz, IH), 7.03 (td, J = 8.16, 2.51 Hz, (MH+) 511 IH), 6.30 (s, IH), 4.46 (d, J = 17.07 Hz, IH), 4.21 (d, J = 17.32
Hz, IH), 3.95 - 4.09 (m, 2H), 3.80 - 3.89 (m, 2H), 3.66 (s, 3H),
3.21 - 3.30 (m, IH), 2.98 - 3.08 (m, IH), 1.58 (s, 3 H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.89 (d, J = 3.0 Hz, IH),
7.55 (d, J = 3.0 Hz, IH), 7.33-7.42 (m, 2H), 6.97-7.09 (m, IH), MS: calc'd (MH+)
122 6.21 (s, IH), 4.36 (d, J = 16.1 Hz, IH), 3.97-4.18 (m, 5H), 3.92 554, measured (d, J = 6.0 Hz, IH), 3.78-3.86 (m, IH), 3.70 (br. s., IH), 3.26 (MH+) 555 (br. s., IH), 2.76 (br. s., IH), 1.16 (t, J = 7.0 Hz, 3H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.95 (s, IH), 7.64 (br. s.,
IH), 7.46 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 8.3 Hz, 2H), 5.87 (s, MS: calc'd (MH+)
123 IH), 4.37 (d, J = 16.8 Hz, IH), 4.14 (d, J = 7.3 Hz, 2H), 4.01 536, measured (d, J = 18.3 Hz, 2H), 3.84 (d, J = 19.3 Hz, 2H), 3.62 (br. s., (MH+) 537 IH), 3.11 (br. s., IH), 2.66 (br. s., IH), 1.21 (t, J = 7.2 Hz, 3H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.98 (br. s., IH), 7.62-
MS: calc'd (MH ) 7.69 (m, 2H), 7.35-7.45 (m, 3H), 5.88 (br. s., IH), 4.23-4.38 (m,
124 568, measured IH), 4.15 (br. s., 4H), 3.87 (br. s., 2H), 3.62 (br. s., IH), 3.11
(MH~) 567 (br. s., IH), 2.66 (br. s., IH), 1.20-1.26 (m, 3H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.93 (s, IH), 7.57 (br. s.,
MS: calc'd (MH+) IH), 7.18 (s, IH), 6.95-7.06 (m, 2H), 5.84 (s, IH), 4.04-4.28 (m,
125 509, measured 5H), 3.84 (br. s., 2H), 3.60 (br. s., IH), 3.17 (br. s., IH), 2.56
(MH+) 509 (br. s., IH), 1.26 (t, J = 7.2 Hz, 3H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 8.10 (s, IH), 7.83-7.94 MS: calc'd (MH+)
126 (m, IH), 7.47 (d, J = 4.0 Hz, 2H), 7.38 (d, J = 7.5 Hz, 2H), 6.16 491, measured (br. s, IH), 3.73-4.53 (m, 11H), 1.22 (t, J = 7.2 Hz, 3H) (MH+) 491
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.84-7.91 (m, IH), 7.58- 7.65 (m, IH), 7.54 (d, J = 2.5 Hz, IH), 7.34-7.40 (m, IH), 7.32
(d, J = 6.8 Hz, IH), 7.17 (t, J = 7.5 Hz, IH), 6.20-6.26 (m, IH), MS: calc'd (MH+)
127 4.44 (d, J = 14.6 Hz, IH), 4.03-4.18 (m, 3H), 3.83-3.97 (m, 2H), 536, measured 3.72-3.82 (m, 2H), 3.61 (d, J = 3.8 Hz, IH), 3.22 (d, J = 11.5 (MH+) 537 Hz, 1H), 2.03 (d, J = 5.5 Hz, IH), 1.98-2.08 (m, IH), 1.13 (q, J
= 7.0 Hz, 3H) 1H NMR (MeOD-d4, 400 MHz): δ ppm 10.01 (br. s., 1H), 8.03
(d, J = 3.0 Hz, 1H), 7.94 (d, J = 3.3 Hz, 1H), 7.40-7.49 (m, 1H),
MS: calc'd (MH+) 7.25 (ddd, J = 8.8, 5.3, 1.9 Hz, 1H), 6.05 (s, 1H), 4.17-4.26 (m,
128 571 measured 1H), 4.05 (d, J = 17.3 Hz, 1H), 3.95 (q, J = 7.0 Hz, 3H), 3.79- (MH+) 571 3.86 (m, 1H), 3.68 (td, J = 7.8, 3.4 Hz, 2H), 3.56 (br. s., 1H),
3.02-3.12 (m, 1H), 2.36-2.45 (m, 1H), 1.05 (t, J = 7.0 Hz, 3H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.83-7.93 (m, 2H), 7.53
(d, J = 3.0 Hz, 1H), 7.34 (d, J = 3.8 Hz, 2H), 6.93-7.04 (m, 1H),
MS: calc'd (MH+) 6.07 (d, J = 7.5 Hz, 1H), 4.41 (d, J = 15.6 Hz, 1H), 4.14 (dd, J
129 583 measured = 11.4, 3.9 Hz, 1H), 4.02-4.11 (m, 2H), 3.86-3.97 (m, 2H),
(MH+) 583 3.75-3.84 (m, 1H), 3.62 (d, J = 4.3 Hz, 1H), 3.07-3.31 (m, 2H),
2.73 (br. s., 1H), 1.13 (q, J = 7.0 Hz, 3H)
1H NMR (MeOD-d4, 400 MHz): δ ppm 7.98 (d, J = 3.0 Hz, 1H),
7.75 (d, J = 3.0 Hz, 1H), 7.48-7.57 (m, 2H), 7.26 (d, J = 8.5 Hz,
MS: calc'd (MH+) 2H), 5.85 (s, 1H), 4.59 (d, J = 15.6 Hz, 1H), 4.16 (q, J = 7.0 Hz,
130 555 measured 2H), 3.78-3.94 (m, 2H), 3.54 (q, J = 10.8 Hz, 1H), 3.10-3.24 (m,
(MH+) 555 1H), 2.73-2.89 (m, 1H), 2.55 (qd, J = 14.7, 9.0 Hz, 1H), 1.22 (t,
J = 7.2 Hz, 3H)
More particular compounds of formula I include the following:
(i?)-6-((5)-2-carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2- thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
(5)-6-((5)-2-carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-[4- 2H]-2-thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
(i?)-6-((5)-2-carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2- (3,5-difluoro-pyridin-2-yl)-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
(5)-4-[(i?)-6-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl] -morpho line-3 -carboxylic acid;
(5)-4-[(i?)-6-(2-chloro-4-fluoro-phenyl)-2-(3,5-difluoro-pyridin-2-yl)-5-methoxycarbonyl- 3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;
(i?)-6-((5)-2-carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2- (4-cyclopropyl-thiazol-2-yl)-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester; (i?)-6-((5)-2-Carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2- (4-fluoro-thiophen-2-yl)-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
(i?)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidm^
(4-methyl-thiazol-2-yl)-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
(5)-4-[(i?)-6-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-(4-methyl-thiazol-2-yl)-3,6- dihydro-pyrimidin-4-ylmethyl] -morpho line-3 -carboxylic acid;
(i?)-6-((5)-2-carboxy-[3,3-2H2]-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2-chloro-4-fluoro- phenyl)-2-thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
(i?)-6-((5)-2-Carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2- (4-trifluoromethyl-thiazol-2-yl)-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
(i?)-6-((5)-2-carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2- (4-isopropyl-thiazol-2-yl)-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
(5)-4-[(i?)-6-(2-chloro-4-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl] -morpho line-3 -carboxylic acid;
(i?)-6-((5)-2-Carboxy-4,4-difluoro-pyrrolidin- 1 -ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-
(l-methyl-lH-imidazol-2-yl)-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
(i?)-6-((5)-2-Carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2- thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid ethyl ester;
(5)-4-[(i?)-6-(2-Chloro-4-fluoro-phenyl)-5-ethoxycarbonyl-2-(l -methyl- lH-imidazol-2-yl)- 3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;
(i?)-6-((5)-2-Carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2- (l-methyl-lH-imidazol-2-yl)-l,4-dihydro-pyrimidine-5-carboxylic acid ethyl ester;
(i?)-6-((5)-2-Carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2,4-dichloro-phenyl)-2- thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid ethyl ester;
(5)-4-[(i?)-6-(2,4-Dichloro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl] -morpho line-3 -carboxylic acid;
(5)-6-((5)-2-Carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(3,4-difluoro-phenyl)-2- thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid ethyl ester;
(5)-4-[(5)-6-(3,4-Difluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin- 4-ylmethyl] -morpho line-3 -carboxylic acid;
(5)-4-[(5)-5-Ethoxycarbonyl-2-thiazol-2-yl-6-(3,4,5-trifluoro-phenyl)-3,6-dihydro- pyrimidin-4-ylmethyl] -morpho line-3 -carboxylic acid; (5)-4-[(i?)-5-Ethoxycarbonyl-2-thiazol-2-yl-6-(2,3,4-trifluoro-phenyl)-3,6-dihydro- pyrimidin-4-ylmethyl] -morpho line-3 -carboxylic acid;
(5)-4-[(5)-6-(3,4-Dichloro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl] -morpho line-3 -carboxylic acid;
(5)-4-[(i?)-6-(2-Chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl] -morpho line-3 -carboxylic acid;
(5)-4-[(i?)-6-(4-Chloro-2-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl] -morpho line-3 -carboxylic acid;
(i?)-6-((5)-2-Carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2,3-difluoro-phenyl)-2- thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid ethyl ester;
(5)-4-[(i?)-6-(2-Chloro-4-fluoro-phenyl)-2-thiazol-2-yl-5-(2,2,2-trifluoro-ethoxycarbonyl)- 3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;
(5)-4-[(5)-6-(4-Bromo-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl] -morpho line-3 -carboxylic acid;
(5)-4-[(5)-5-Ethoxycarbonyl-6-(3-fluoro-phenyl)-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4- ylmethyl] -morpho line-3 -carboxylic acid;
(5)-4-[(5)-5-Ethoxycarbonyl-6-(4-fluoro-phenyl)-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4- ylmethyl] -morpho line-3 -carboxylic acid;
(i?)-6-((5)-2-Carboxy-4,4-difluoro-pyrrolidin- 1 -ylmethyl)-4-(2-chloro-3 ,4-difluoro- phenyl)-2-thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid ethyl ester;
(5)-6-((5)-2-Carboxy-4,4-difluoro-pyrro lidin- 1 -ylmethyl)-4-(3 ,4-difluoro-phenyl)-2-( 1 - methyl- lH-imidazol-2-yl)-l,4-dihydro-pyrimidine-5-carboxylic acid ethyl ester;
(5)-4-[(5)-6-(3,4-Difluoro-phenyl)-5-ethoxycarbonyl-2-(l-methyl-lH-imidazol-2-yl)-3,6- dihydro-pyrimidin-4-ylmethyl] -morpho line-3 -carboxylic acid;
(5)-4-[(i?)-6-(2,4-Difluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl] -morpho line-3 -carboxylic acid;
(i?)-6-((5)-2-Carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2,4-difluoro-phenyl)-2- thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid ethyl ester;
(5)-4-[(i?)-6-(2-Chloro-3,4-difluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl] -morpho line-3 -carboxylic acid;
(3S)-4-[[(4R)-4-(2-Chloro-4-fluorophenyl)-5-methoxycarbonyl-2-(4-methylsulfanyl-l,3- thiazol-2-yl)- 1 ,4-dihydropyrimidin-6-yl]methyl]morpholine-3-carboxylic acid; (2S)- 1 -[[(4i?)-4-(2-Chloro-4-fluorophenyl)-5-methoxycarbonyl-2-(4-methylsulfanyl- 1 ,3- thiazol-2-yl)- 1 ,4-dihydropyrimidin-6-yl]methyl]-4,4-difluoropyrrolidine-2-carboxylic acid;
(5)-4-[(i?)-6-(2-Chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl] -morpho line-3 -carboxylic acid;
(i?)-6-((5)-2-Carboxy-4,4-difluoro-pyrrolidin- 1 -ylmethyl)-4-(2-chloro-3-fluoro-phenyl)-2- thiazol-2-yl-l ,4-dihydro-pyrimidine-5-carboxylic acid ethyl ester;
(5)-4-[(i?)-6-(2-Bromo-4-fluoro-phenyl)-5-methoxycarbonyl-2-(5-methyl-oxazol-4-yl)-3,6- dihydro-pyrimidin-4-ylmethyl] -morpho line-3 -carboxylic acid;
(5)-4-[(i?)-6-(2-Bromo-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl] -morpho line-3 -carboxylic acid;
(5)-4-[(i?)-6-(2-Chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-(5-methyl-oxazol-4-yl)-3,6- dihydro-pyrimidin-4-ylmethyl] -morpho line-3 -carboxylic acid;
(5)-4-[(i?)-6-(2-Bromo-4-fluoro-phenyl)-5-ethoxycarbonyl-2-(5-methyl-oxazol-4-yl)-3,6- dihydro-pyrimidin-4-ylmethyl] -morpho line-3 -carboxylic acid;
(5)-4-[(i?)-6-(2,3-Difluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl] -morpho line-3 -carboxylic acid;
(5)-4-[(i?)-6-(2-Bromo-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin- 4-ylmethyl] -morpho line-3 -carboxylic acid
(5)-4-[(i?)-6-(2-Chloro-3,4-difluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6- dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;
(i?)-6-((5)-2-Carboxy-4,4-difluoro-pyrrolidin- 1 -ylmethyl)-4-(2-chloro-3 ,4-difluoro- phenyl)-2-thiazol-2-yl-l ,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
(5)-4-[(i?)-6-(4-Chloro-2-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl] -morpho line-3 -carboxylic acid;
(5)-4-[(5)-6-(4-Chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl] -morpho line-3 -carboxylic acid;
(i?)-4-[(i?)-6-(2-Chloro-3,4-difluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6- dihydro-pyrimidin-4-ylmethyl] -3 -methyl-morpho line-3 -carboxylic acid;
(5)-4-[(i?)-6-(2-Bromo-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl] -morpho line-3 -carboxylic acid;
(5)-4-[(i?)-6-(2-Chloro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4- ylmethyl] -morpho line-3 -carboxylic acid; (5)-4-[(5)-6-(4-Chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl] -morpho line-3 -carboxylic acid;
(i?)-4-(2-Bromo-4-fluoro-phenyl)-6-((5)-2-carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-2- thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
(i?)-6-((5)-2-Carboxy-4,4-difluoro-pyrrolidin- 1 -ylmethyl)-4-(2,4-dichloro-phenyl)-2- thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
(5)-4-[(5)-6-(2-Chloro-4-fluoro-phenyl)-2-(l,4-dimethyl-lH-imidazol-2-yl)-5- methoxycarbonyl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;
(5)-4-[(i?)-6-(4-Bromo-2-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl] -morpho line-3 -carboxylic acid;
(5)-4-[(i?)-6-(2-Chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-(4-trifluoromethyl-thiazol- 2-yl)-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;
(5)-4-[(5)-6-(3,4-Difluoro-2-methyl-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl] -morpho line-3 -carboxylic acid;
(5)-4-[(i?)-6-(2-Chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-(l -methyl- lH-imidazo 1-2-yl)-
3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;
(5)-4-[(i?)-6-(2-Chloro-4-fluoro-phenyl)-5-isopropoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl] -morpho line-3 -carboxylic acid;
(5)-4-[(i?)-6-(2-Chloro-3-fluoro-phenyl)-5-isopropoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl] -morpho line-3 -carboxylic acid;
(i?)-6-((5)-2-Carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2- (5-methyl-oxazol-4-yl)-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
(5)-4-[(i?)-6-(2-Chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-(5-methyl-oxazol-4-yl)-3,6- dihydro-pyrimidin-4-ylmethyl] -morpho line-3 -carboxylic acid;
(2i?,35)-4-[(i?)-6-(2-Chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6- dihydro-pyrimidin-4-ylmethyl] -2-methyl-morpho line-3 -carboxylic acid;
(2i?,35)-4-[(i?)-6-(2-Bromo-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6- dihydro-pyrimidin-4-ylmethyl] -2-methyl-morpho line-3 -carboxylic acid;
(i?)-4-(2-Bromo-4-fluoro-phenyl)-6-((5)-2-carboxy-5,5-difluoro-piperidin-l-ylmethyl)-2- thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid ethyl ester;
(i?)-4-(2-Bromo-4-fluoro-phenyl)-6-((i?)-2-carboxy-5,5-difluoro-piperidin-l-ylmethyl)-2- thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid ethyl ester; (i?)-6-((5)-2-Carboxy-5,5-difluoro-piperidin-l-ylmethyl)-4-(2-chloro-3-fluoro-phenyl)-2- thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
(i?)-6-((5)-2-Carboxy-5,5-difluoro-piperidin-l-ylmethyl)-4-(2-chloro-phenyl)-2-thia^ yl-l,4-dihydro-pyrimidine-5-carboxylic acid ethyl ester;
(2i?,35)-4-[(5)-6-(3,4-Difluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl] -2-methyl-morpho line-3 -carboxylic acid;
(2i?,35)-4-[(5)-6-(3,4-Difluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl] -2-methyl-morpho line-3 -carboxylic acid;
(2i?,35)-4-[(i?)-5-Methoxycarbonyl-2-thiazol-2-yl-6-(2,3,4-trifluoro-phenyl)-3,6-dihydro- pyrimidin-4-ylmethyl] -2-methyl-morpho line-3 -carboxylic acid;
(2i?,35)-4-[(i?)-6-(2-Chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6- dihydro-pyrimidin-4-ylmethyl] -2-methyl-morpho line-3 -carboxylic acid;
(2i?,35)-4-[(i?)-6-(2-Bromo-4-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl] -2-methyl-morpho line-3 -carboxylic acid;
(2i?,35)-4-[(i?)-6-(2-Chloro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl] -2-methyl-morpho line-3 -carboxylic acid;
(2i?,35)-4-[(i?)-6-(2-Chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl] -2-methyl-morpho line-3 -carboxylic acid;
(2i?,35)-4-[(i?)-6-(2-Bromo-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl] -2-methyl-morpho line-3 -carboxylic acid;
(2i?,35)-4-[(i?)-6-(2-Chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6- dihydro-pyrimidin-4-ylmethyl]-2-isopropyl-morpholine-3-carboxylic acid;
(5)-4-(((i?)-6-(2-Chloro-4-fluorophenyl)-5-(methoxycarbonyl)-2-(thiazol-2-yl)-3,6- dihydropyrimidin-4-yl)methyl)-3 -methylmorpho line-3 -carboxylic acid;
(5)-4-(((i?)-6-(2-Bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6- dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid;
(35)-4-[[(45)-4-(4-Bromophenyl)-5-ethoxycarbonyl-2-(l,3-thiazol-2-yl)-l,4- dihydropyrimidin-6-yl]methyl]morpholine-3-carboxylic acid;
(5)-4-(((i?)-6-(2-Bromophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin- 4-yl)methyl)morpho line-3 -carboxylic acid;
(35)-4-[[(4i?)-4-(2-Bromo-3,4-difluorophenyl)-5-ethoxycarbonyl-2-(l,3-thiazol-2-yl)-l,4- dihydropyrimidin-6-yl]methyl]morpholine-3-carboxylic acid; (35)-4-[[(4i?)-5-Ethoxycarbonyl-4-(2-iodophenyl)-2-(l ,3-thiazol-2-yl)-l ,4- dihydropyrimidin-6-yl]methyl]morpholine-3-carboxylic acid; and
(2S)- 1 -[[(4S)-4-(4-Bromophenyl)-5-ethoxycarbonyl-2-(l ,3-thiazol-2-yl)- 1 ,4- dihydropyrimidin-6-yl]methyl]-4,4-difluoropyrrolidine-2-carboxylic acid.
The compounds of the present invention have good anti- HBV activity, high selectivity index, superior solubility and mouse SDPK profiles compared to the previously reported capsid assembly effectors such as Bay 41-4109. As a reference, the in-house data of the Bayer compound which is Bay 41-4109, are also shown in Table 3, 4, 5 and 6.
Table 3 : Anti-HBV activity data of particular compounds in HepG2.2.15 cells
Example No. Ε€50 (μΜ) Example No. Ε€50 (μΜ)
Bay 41-4109 0.087 (0.050)*
2 0.0027 3 0.001 1
4 0.0015 5 0.0031
6 0.0075 10 0.0073
12 0.0093 14 0.041
16 0.0020 17 0.0070
19 0.0057 23 0.025
24 0.026 25 0.0050
28 0.0044 29 0.028
31 0.002 32 0.013
33 0.023 34 0.010
35 0.0077 36 0.018
38 0.0033 39 0.001 1
41 0.017 42 0.0100
43 0.018 44 0.0046
45 0.028 46 0.016
47 0.0044 48 0.028
49 0.0047 50 0.014
51 0.013 52 0.0030
53 0.014 54 0.014
55 0.0010 56 0.015 57 0.015 58 0.014
59 0.013 60 0.0006
61 0.018 62 0.014
63 0.0008 64 0.0030
65 0.0076 66 0.0007
68 0.014 69 0.0060
70 0.0089 71 0.0048
73 0.0012 74 0.0021
75 0.0180 77 0.0070
78 0.026 79 0.0045
80 0.027 81 0.0060
82 0.014 83 0.0015
84 0.0024 85 0.0062
87 0.022 91 0.038
92 0.014 93 0.0043
94 0.020 95 0.0025
96 0.0006 97 0.0050
98 0.017 99 0.012
100 0.035 101 0.014
102 0.0090 103 0.015
104 0.0070 106 0.0021
107 0.0015 108 0.018
109 0.0044 110 0.042
111 0.0058 112 0.0052
113 0.016 114 0.0093
115 0.0023 116 0.0018
117 0.0015 118 0.0005
119 0.0030 120 0.0048
121 0.020 122 0.0013
123 0.0028 124 0.029
125 0.030 127 0.0067
128 0.0006 129 0.0076 130 0.0060
Literature data, see: Deres K. et al. Science 2( 103, 893-896
Compound with favorable pharmacokinetics is more likely to be efficacious and safe. It is very important for a drug to have a moderate or low clearance and a reasonable half-life, as this often leads to a good oral bioavailability and high systemic exposure. Reducing the clearance of a compound or drug could reduce the daily dose required for efficacy and therefore give a better efficacy and safety profile. It is also very important for HBV infection treatment compound to show good liver exposure since this is the targeted organ. As shown in Table 4, compounds of the present invention exhibit good mouse SDPK profiles: low to moderate clearance, good exposure at low dose in both plasma and liver, and good bioavailability. As shown in Table 5, compounds of the present invention also exhibit low clearance in in vitro human hepatic microsome stability assay.
The single dose PK parameters of Bay 41-4109, Example 2, Example 5 and Example 16 in mouse plasma and liver are shown in Table 4.
Table 4: Pharmacokinetics of particular compounds in male ICR mice
Figure imgf000077_0001
Figure imgf000078_0001
1 Literature data, please see Deres K. et al. Science 2003 , 893-896
2 Not detectable in liver.
CI: clearance;
AUC(o-oo) : area under the curve from the time of dosing to infinity
Normalized AUC(o-∞)= AUC(o_∞)/Dose
F: bioavailability.
Table 5 Metabolic stability in human microsome
Human Human Human
Example Hepatic Example Hepatic Example Hepatic number Clearance number Clearance number Clearance
(mL/min/kg) (mL/min/kg) (mL/min/kg)
1 7.51 2 3.65 3 9.21
4 5.11 5 2.7 6 6.28
7 6.12 8 6.33 9 10.07
10 8.76 12 5.55 13 2.33
14 1.41 15 3.53 16 6.35
17 0.74 18 3.38 19 3.65
20 10.74 21 3.08 22 4.82
23 8.8 24 3.19 25 9.34
26 10.02 27 8.79 29 7.65
30 6.56 31 4.68 32 5.04
33 4.15 34 7.46 35 8.86
36 6.22 37 7 38 9.3
39 7.18 40 8.45 41 6.83
42 5.56 43 1.2 44 4.46
45 4.69 46 0 47 1.46
48 3.12 49 0 50 0
51 0 52 4.03 53 0
54 0 56 2.44 57 0
58 1.26 59 3.5 60 4.8
62 9.06 63 1.71 64 0
65 1.67 66 1.64 67 6.42
68 0.23 69 0 70 2.22
71 2.81 72 5.16 73 0
74 0.51 75 0 76 1.72
77 1.43 78 3.22 79 2.18
80 4.27 81 5.33 82 0
83 1.77 84 9.3 85 6.91
86 6.8 87 6.86 88 6.46
89 6.13 90 5.52 91 1.62
92 1.26 93 1.24 94 0.61 95 3.04 96 4.8 97 1.63
98 0 99 2.13 100 0.1
101 4.18 102 0.97 103 2.81
104 5.42 105 8.13 106 6.32
107 1.89 108 4.88 109 1.25
110 2.41 111 5.31 112 1.95
113 0 114 0 115 1.55
116 0 117 0 118 0.1
119 0.85 120 2.58 121 1.42
122 1.58 123 3.14 124 2.17
125 1.32 126 0 127 2.44
128 0.26 129 4.25 130 3.92
The aqueous solubility is an important physico-chemical property that plays a significant role in various physical and biological processes. It is desirable to have good solubility which enables good permeability and gastric and intestinal absorption, linear dose proportionality, less PK variability, and easy formulation for PD/PK studies. At different stages of the drug disco very/development process solubility has to be determined and especially in the early phases (lead generation to lead optimization) high throughput methods are needed. Lyophilisation solubility assay (Lysa) is a well adopted high throughput assay to measure compound solubility in industry.
Results of Lysa are given in Table 6.
Table 6: Solubility data of particular compounds
Example No. Lysa ^ /mL) Example No. Lysa ^ /mL) Example No. Lysa ^ /mL)
Bay 41-4109 38.0
2 >698 3 >644 4 >700
5 >660 6 >100 7 398
8 >620 9 >645 10 246
12 488 13 594 14 >644
15 >627 16 >622 17 >673
18 >659 19 >654 20 683
21 828 22 630 23 172
24 656 25 546 26 668
28 247 29 420 30 667
31 630 32 632 34 531
35 >599 36 >637 37 >593 38 291 39 >654 40 409
41 >630 42 >613.0 43 >606
44 >626 45 >695 46 >655
47 >660 48 >635 49 >679
50 >580 51 >695 52 >665
53 >621 54 >606 55 >670
56 >645 57 >613 58 >638
59 >630 60 >703 61 495
63 >679 64 >620 65 >678
66 >669 67 590 68 >627
69 >658 70 >611 71 >642
72 >670 73 >656 74 >655
75 >632 76 >630 77 >631
78 >653 79 >660 80 518
81 >691 82 >618 83 >652
84 >668 85 >599 86 >596
87 >600 88 >665 89 >525
90 >610 91 584 92 >602
93 >690 94 >677 95 >705
96 >628 97 >640 98 >650
99 >677 100 >656 101 >571
102 >635 103 >643 104 >667
106 >730 107 510 108 410
109 >657 110 >661 111 >620
113 >615 114 >617 115 >642
116 >735 117 >628 118 >630
121 600 122 >722 123 >666
124 >655 125 >636 127 >672
128 >710 130 >625
Based on FDA guidance, in order to support clinical testing in humans, the assessment of acceptable risk-benefit has to be achieved by providing clear evidence of in vitro antiviral activity (EC50) and cytotoxicity (CC50). It is important to establish that an investigational product has antiviral activity at concentrations that can be achieved in vivo without inducing toxic effects to cells. Furthermore, in a cell culture model, apparent antiviral activity of an investigational product can be the result of host cell death after exposure to the product. The relative
effectiveness of the compound in inhibiting viral replication compared to inducing cell death is defined as the selectivity index (CC50 value/ECso value). It is desirable to have a high selectivity index giving maximum antiviral activity with minimal cell toxicity.
Results of CC50 and the corresponding selectivity index are given in Table 7.
Table 7: CC50 and selectivity index of particular compounds
Selectivity index Selectivity index
Example No. CCso (μΜ) Example No. CCso (μΜ)
(CCso/ECso) (CCso/ECso)
Bay 41-4109 13 149
2 85 31481 3 97 88182
5 >100 >32258 6 27 3600
10 39 5342 12 >100 >10753
16 30 15000 17 >100 >14286
19 89 15614 25 >100 >20000
28 31 7045 31 >100 >50000
32 40 3125 34 >100 >10000
35 >100 12987 36 23 1251
38 21 6315 39 44 40227
41 40 2372 42 >100 >10000
43 >100 >5556 44 49 10748
46 36 2212 47 >100 >2273
49 42 8936 50 26 1905
51 27 21 17 52 14 4693
53 69 4769 54 62 4293
57 35 2384 58 >100 >7353
59 52 3935 60 29 47783
61 56 3133 63 >100 >125000
64 47 15667 65 >100 >13157
66 95 135714 68 >100 >7407
69 57 9500 70 >100 >1 1236 71 >100 >20833 73 >100 >83333
74 72 34286 75 >100 5556
77 >100 14286 79 76 16889
81 >100 >16667 82 >100 >7194
83 25 16440 84 >100 >41667
85 66 10694 87 100 >4545
93 30 6977 94 92 4600
95 >100 40000 96 97 161667
97 44 8800 98 72 4224
101 91 6741 102 23 2599
103 >100 >6803 104 >100 >14286
106 >100 >47619 107 24 16000
108 33 1784 109 55 12500
111 >100 17241 112 73 14123
113 >100 >6061 114 >100 >10753
115 >100 >43478 116 77 42739
117 >100 66667 118 >100 >200000
119 >100 >33333 120 81 16875
121 >100 >5000 122 73 55769
123 56 19900 127 >100 >14925
128 51 85000 129 >100 >13158
130 17 2833
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 R4, and A 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. A. General synthetic route for Compound la, Iaa, and lab (Scheme 1)
Scheme 1
Figure imgf000083_0001
Figure imgf000083_0002
Figure imgf000083_0003
laa lab
Compounds of interest la, Iaa and lab can be prepared according to Scheme 1. Starting with acetyl acetate Ila, aldehyde III and amidine IV, dihydropyrimidine Va can be synthesized through a one-pot condensation reaction. Bromination of Compound Va provides bromide Via. Coupling bromide Via with cyclic amino acid VII generates compound of interest la. Further chiral separation of la affords two enantiomerically pure compounds of interest Iaa and lab.
Dihydropyrimidine Va can be prepared from condensation and cyclization sequence of acetyl acetate II, aldehyde III and amidine IV. The reaction can be carried out in a suitable alcoholic solvent such as trifluoroethanol in the presence of a base like potassium acetate under a heating condition over several hours. Bromide Via can be prepared by reaction of Va with a bromination reagent, such as N- bromosuccinimide, in a suitable inert solvent such as carbon tetrachloride at 80-100 degrees Celsius for about 1 hour.
Compound of interest la can be obtained by coupling bromide Via with cyclic amino acid VII. The reaction is typically performed in a suitable solvent like 1,2-dichloroethane at room temperature over several hours in the presence of an organic base such as N,N- diisopropylethy lamine .
Compounds of further interest laa and lab are obtained by preparative HPLC separation of diastereomeric mixture la. The stereochemistry of laa is determined by comparing its 1H NMR data and SFC retention time with the same compound made by synthetic route B.
B. An alternative general synthetic route for Compound laa (Scheme 2)
Scheme 2
Figure imgf000084_0001
Vaa Vlaa laa
R3 is hydrogen or deuterium.
Alternatively, compound of interest laa can be prepared according to Scheme 2. A one-pot reaction between acetyl acetate II, aldehyde III and amidine IV gives dihydropyrimidine Va. (-)- Enatiomer Vaa is then obtained by SFC chiral separation of Va and its stereochemistry is determined by comparing its SFC retention time with one of its particular Compound E which stereochemistry is determined by X-ray diffraction study (Figure 1).
Bromination of Vaa then affords Vlaa. Coupling Vlaa with a suitable cyclic amino acid VII gives the compound of interest Iaa.
The synthetic procedure from Vaa to Iaa is identical to what is described in Scheme 1 except that chiral intermediate Vaa is used instead of racemic Va.
C. General synthetic route for Compound IV (Scheme 3)
Scheme 3
1 . NaOMe NH
R4-^N
2. NH4CI R' NH2 ■ HCI
VII I IV
Any commercial unavailable amidine building block IV can be prepared from the corresponding nitrile VIII by first reacting with sodium methoxide followed by treatment with ammonium chloride as described in Scheme 3.
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 (XZ)
Figure imgf000085_0001
e of a base;
(b) a compound of formula (YZ)
Figure imgf000086_0001
In step (a), the base can be for example N,N-diisopropylethylamine.
A compound of formula I when manufactured according to the above process is also an object of the invention.
PHARMACEUTICAL COMPOSITIONS AND ADMINISTRATION
The invention also relates to a compound of formula I for use as therapeutically active substance.
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 compounds of inventions are useful as inhibitors of HBV.
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. 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:
[α]ο : optical rotation at 20 degrees Celsius
calc'd: calculated
CC50: concentration results in the death of 50 percent of the cells
CCK-8 : cell counting kit-8
CCI4: carbon tetrachloride
CDCl3-d: deuterated chloroform
CLh: hepatic clearance
CMV: cytomegalovirus
CuOAc copper acetate
d: day
DIG: digoxigenin
DIPEA: N,N-diisopropylethylamine
DCM: dichloromethylene
DM Ac: dimethylacetamide D20: deuterium water
FDA: Food and Drug Administration
PE: petroleum ether
DMSO: dimethy lsulfo xide
DMSO-dg: deuterated dimethylsulfoxide
DNA: deoxyribonucleic acid
EDTA: ethylenediammetetraacetic acid
EtOH: ethanol
EtOAc or EA: ethyl acetate
g: gram
EC50: concentration required for 50% induction of acetylated tubulin h or hr: hour
hrs: hours
HAP: hetero aryldihydropyrimidine
HBeAb: hepatitis B e antibody
HBeAg: hepatitis B e antigen
HBsAg: hepatitis B surface antigen
HC1: hydrogen chloride
HPLC: high performance liquid chromatography
HPLC-UV: high performance liquid chromatography with ultraviolet detector
Hz: hertz
IPA: isopropanol
KCN: potassium cyanide
MeOD-d4: deuterated methanol
MeOH: methanol
mg: milligram
MHz: megahertz
min: minute
mins: minutes
mL: milliliter
mm: millimeter
mM: milliliter
mmol: millimole MS: mass spectrometry
MW: molecular weight
NaCl: sodium chloride
Na2S04: sodium sulfate
NaOH: sodium hydroxide
NBS: N-bromosuccinimide
NMR: nuclear magnetic resonance
PBS: phosphate buffered saline
PD: pharmaco dynamic
PK: pharmacokinetic
prep-HPLC: preparative high performance liquid chromatography
Prep-TLC: preparative thin layer chromatography
rpm: round per minute
rt: room temperature
sat. saturated
SDPK: single dose pharmacokinetics
SFC: supercritical fluid chromatography
SSC: saline- sodium citrate buffer
TEA: triethylamine
Tet: tetracycline
TFA: trifluoro acetic acid
THF: tetrahydro furan
Tris: tris(hydroxymethyl)aminomethane
μ& microgram
μΐ,: microliter
μΜ: micromole
UV: ultraviolet detector
ETV: entecavir
mpk: mg/kg
OD: optical density
pgR A: pre-genom RNA
qPCR: quantitative polymerase chain reaction General Experimental Conditions
Intermediates and final compounds were purified by flash chromatography using one of the following instruments: i) Biotage SP1 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 μιη, OBDTM 30 100 mm) column or SunFire™ Prep- CIS (5 μιη, OBDTM 30 x 100 mm) column. Waters AutoP purification System (Column:
XBridgeTM Prep-C18, 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 IP A), 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%> ΝΗ3Ή20 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 (MH)+.
NMR Spectra were obtained using Bruker Avance 400 MHz.
The microwave assisted reactions were carried out in a Biotage Initiator Sixty microwave synthesizer.
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 and 2: 6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2- thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester (Example 1) and (R)-6- ((S)-2-carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-
2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester (Example 2)
Figure imgf000093_0001
1 2
Procedure A:
The title compounds were prepared according to the general synthetic routes shown in Scheme 1 and Scheme 3. A detailed synthetic route is provided in Scheme 4.
Figure imgf000093_0002
Scheme 4 Preparation of Compound Ai:
To a stirred solution of thiazole-2-carbonitrile (1.5 g, 14 mmol) in 5 mL of dry MeOH was added dropwise a solution of sodium methoxide (0.74 g, 14 mmol) in 10 mL of dry methanol. The reaction mixture was stirred at room temperature until the disappearance of starting material which was checked by LC/MS. After that, ammonium chloride (1.5 g, 28 mmol) was added in one portion and the reaction mixture was stirred overnight. The undissolved material was removed by filtration and the filtrate was concentrated to afford thiazole-2-carboxamidine hydrochloride (Compound Ai) as a grey solid which was used directly in the next step without further purification. MS: calc'd 128 (MH+), measured 128 (MH+).
Preparation of Compound B:
To a stirred solution of thiazole-2-carboxamidine hydrochloride (0.13 g, 1.0 mmol), methyl acetoacetate (0.12 g, 1.0 mmol) and 2-chloro-5-fluorobenzaldehyde (0.16 g, 1.0 mmol) in CF3CH2OH (8 mL) was added potassium acetate (0.20 g, 2.0 mmol). The reaction mixture was either refluxed for 16 hrs or heated at 150 °C in microwave oven for 2 hours. After it was cooled to room temperature, the reaction mixture was concentrated and the residue was dissolved in ethyl acetate and washed with brine. The organic layer was dried over sodium sulfate and concentrated, and the residue was purified by column chromatography (ethyl acetate/petroleum ether is from 1/4 to 1/2) to afford 4-(2-chloro-4-fluoro-phenyl)-6-methyl-2-thiazol-2-yl-l,4- dihydro-pyrimidine-5-carboxylic acid methyl ester (Compound B) as a yellow solid. MS: calc'd (MH+) 366, measured (MH+) 366. 1H NMR (DMSO-d6, 400 MHz): δ ppm 9.98 (s, 1H), 7.97 (d, J = 4.0 Hz, 1H), 7.90 (d, J = 4.0 Hz, 1H), 7.41 (dd, J = 8.0, 4.0 Hz, 1H), 7.35 (dd, J = 8.0, 8.0 Hz, 1H), 7.18 (td, J = 8.0, 4.0 Hz, 1H), 5.98 (s, 1H), 3.53 (s, 3H), 2.47 (s, 3H).
Preparation of Compound C:
To a stirred solution of 4-(2-chloro-4-fluoro-phenyl)-6-methyl-2-thiazol-2-yl-l,4-dihydro- pyrimidine-5-carboxylic acid methyl ester (0.37 g, 1.0 mmol) in CCI4 (5 mL) was added NBS (0.20 g, 1.1 mmol) in portions. After the reaction mixture was stirred at room temperature for 1 hour, the solvent was removed in vacuo and the residue was purified by column chromatography to give 6-bromomethyl-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl- 1 ,4-dihydro-pyrimidine-5- carboxylic acid methyl ester (Compound C) as a yellow solid. MS: calc'd 429 (MH+), measured 429 (MH+).
Preparation of Example 1 :
To a stirred solution of 6-bromomethyl-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-l,4- dihydro-pyrimidine-5-carboxylic acid methyl ester (0.049 g, 0.11 mmol) and (S)-4,4-difluoro- pyrrolidine-2-carboxylic acid (0.044 g, 0.17 mmol) in 1,2-dichloroethane (5 mL) was added dropwise DIPEA (0.078 mL, 0.45 mmol). The reaction mixture was stirred at room temperature until the disappearance of starting material which was checked by LC/MS. The mixture was diluted with EtOAc (50 mL) and washed successively with saturated aqueous NH4C1 solution and brine. The organic layer was separated and dried over Na2S04. The solvent was concentrated in vacuo and the crude product was purified by prep-HPLC to give 6-((5)-2-carboxy-4,4- difluoro-pyrrolidin- 1 -ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl- 1 ,4-dihydro- pyrimidine-5-carboxylic acid methyl ester (Example 1).
Preparation of Example 2:
The enantiopure (i?)-6-((5)-2-carboxy-4,4-difluoro-pyrrolidin- 1 -ylmethyl)-4-(2-chloro-4- fluoro-phenyl)-2-thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester (Example 2) was obtained through the separation of diastereomeric mixture of 6-((5)-2-carboxy-4,4-difluoro- pyrrolidin- 1 -ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl- 1 ,4-dihydro-pyrimidine-5- carboxylic acid methyl ester (Example 1) by reverse preparative HPLC (Waters, SunFire™ Prep- C18) eluting with a mixed solvent of 15%-35% acetonitrile in water plus 0.1% TFA at 40 mL/min eluting rate. (+)-Compound D was separated as a diastereomer of Example 2.
Procedure B:
Preparation of Example 2:
In an alternative synthetic route, Example 2 was synthesized by using chiral intermediate E, which was obtained through SFC chiral separation of the stereomixture of dihydropyrimidine B. A detailed synthetic route is provided in Scheme 5.
Figure imgf000096_0001
Scheme 5
Preparation of Compound E:
The enantiopure (i?)-4-(2-chloro-4-fluoro-phenyl)-6-methyl-2-thiazol-2-yl-l,4-dihydro- pyrimidine-5-carboxylic acid methyl ester (Compound E) was obtained through SFC (SFC- Multigram; IC: 5 x 250 mm, 5μ) chiral separation of the stereomixture of 4-(2-chloro-4-fluoro- phenyl)-6-methyl-2-oxazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester (Compound B) eluting with a mixed solvent of 85% supercritical C02 / 15% EtOH at 100 mL/min rate. The desired (-)-enantiomer E has a relatively short retention time. The absolute stereochemistry of (-)-enantiomer E was determined by X-ray diffraction study (Figure 1). Compound E: [a]D 20 -55.0 (c 0.845, MeOH).
Compound F: [a]D 20 +44.6 (c 0.175, MeOH).
Preparation of Compound G:
To a stirred solution of (R)-4-(2-chloro-4-fluoro-phenyl)-6-methyl-2-thiazol-2-yl-l ,4- dihydro-pyrimidine-5-carboxylic acid methyl ester (0.37 g, 1.0 mmol) in CC (5 mL) was added NBS (0.20 g, 1.1 mmol) in portions. After the reaction mixture was stirred at room temperature for 1 hour, the solvent was removed in vacuo and the residue was purified by column chromatography to give (i?)-6-bromomethyl-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-l ,4- dihydro-pyrimidine-5-carboxylic acid methyl ester (Compound G) as a yellow solid. MS: calc'd 445 (MH+), measured 445 (MH+).
Preparation of Example 2:
To a stirred solution of (i?)-6-bromomethyl-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl- l ,4-dihydro-pyrimidine-5-carboxylic acid methyl ester (0.049 g, 0.1 1 mmol) and (S)-4,4- difluoro-pyrrolidine-2-carboxylic acid (0.044 g, 0.17 mmol) in 1 ,2-dichloroethane (5 mL) was added dropwise DIPEA (0.078 mL, 0.45 mmol). The reaction mixture was stirred at room temperature until the disappearance of starting material which was checked by LC/MS. The mixture was diluted with EtOAc (50 mL) and washed successively with saturated aqueous NH4CI solution and brine. The organic layer was separated and dried over Na2S04. The solvent was concentrated in vacuo and the crude product was purified by prep-HPLC to give (R)-6-((S)- 2-carboxy-4,4-difluoro-pyrrolidin- 1 -ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl- 1 ,4- dihydro-pyrimidine-5-carboxylic acid methyl ester (Example 2) as a light yellow solid.
Example 3:
(S)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2-chloro-4-fluoro- phenyl)- [4-2H]-2-thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester
The title compound was prepared in analogy to Example 2 with Procedure A shown in Scheme 4 by using 2-chloro-4-fluoro-[2Hl]-benzaldehyde instead of 2-chloro-4- fluorobenzaldehyde. The stereochemistry of Example 3 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Preparation of 2-chloro-4-fluoro-[2Hl]-benzaldehyde (Compound H):
Figure imgf000098_0001
H
2-Chloro-4-fluorobenzaldehyde (1.6 g, 4.2 mL, 10 mmol,) in diethyl ether (4 mL) was added to a stirred solution of KCN (0.70 g, 11 mmol) in D20 (4.0 mL) at room temperature. After the reaction mixture was vigorously stirred for 3 days, it was extracted twice with diethyl ether (50 mL). The aqueous layer was back-extracted with diethyl ether (1 x 20 mL). The organic layers were dried over Na2S04 and concentrated in vacuo to give 2-chloro-4-fluoro- [2Hl]-benzaldehyde as a yellow solid (1.7 g) which was used as is for the next step. Isotopical purity is determined as 90% by 1H NMR. 1H NMR (CDCl3-d, 400 MHz): δ ppm 7.99 (dd, J = 8.78, 6.27 Hz, 1H), 7.1-7.24 (m, 1H), 7.13 (td, J = 8.16, 2.26 Hz, 1H).
Example 4:
(R)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2-chloro-4-fluoro- phenyl)-2-(3,5-difluoro-pyridin-2-yl)-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester
The title compound was prepared in analogy to Example 2 with Procedure A shown in Scheme 4 by using 3,5-difluoro-pyridine-2-carboxamidine (for its synthesis, please see: Stolting J. et al. PCTInt. Appl. 2000, WO 2000058302 Al 20001005) instead of thiazole-2- carboxamidine. The stereochemistry of Example 4 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 5:
(S)-4-[(R)-6-(2-Chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6- dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid
The title compound was prepared in analogy to Example 2 with Procedure B shown in Scheme 5 by using (5)-morpholine-3-carboxylic acid (Aldrich, CAS: 106825-79-0) instead of (5)-4,4-difluoro-pyrrolidine-2-carboxylic acid.
Example 6: (S)-4-[(R)-6-(2-Chloro-4-fluoro-phenyl)-2-(3,5-difluoro-pyridin-2-yl)-5- methoxycarbonyl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid
The title compound was prepared in analogy to Example 2 with Procedure A shown in Scheme 4 by using 3,5-difluoro-pyridine-2-carboxamidine and (5)-morpholine-3-carboxylic acid instead of thiazole-2-carboxamidine and (5)-4,4-difluoro-pyrrolidine-2-carboxylic acid. The stereochemistry of Example 6 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 7:
(R)-6-(2-Carboxy-5,5-difluoro-piperidin-l-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2- thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester
The title compound was prepared in analogy to Example 2 with Procedure B shown in Scheme 5 by using 5,5-difluoro-piperidine-2-carboxylic acid (for its synthesis, please see:
Golubev, A. et al. Tetrahedron Lett. 2004, 45, 1445-1447) instead of (S)-4,4-difluoro- pyrrolidine-2-carboxylic acid.
Example 8:
(R)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2-chloro-4-fluoro- phenyl)-2-(4-methyl-pyridin-2-yl)-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester The title compound was prepared in analogy to Example 2 with Procedure A shown in
Scheme 4 by using 4-methyl-pyridine-2-carboxamidine instead of thiazole-2-carboxamidine. The stereochemistry of Example 8 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Preparation of 4-methyl-pyridine-2-carboxamidine (Compound A2):
Figure imgf000099_0001
4-Methyl-pyridine-2-carboxamidine (Compound A2) was prepared in analogy to compound thiazole-2-carboxamidine with the procedure shown in Scheme 5 by using 4-methyl- pyridine-2-carbonitrile instead of thiazole-2-carbonitrile. MS: calc'd (MH+) 136, measured
(MH+) 136. Example 9:
(S)-4-[(R)-6-(2-Chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-(4-methyl-pyridin-2- yl)-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid
The title compound was prepared in analogy to Example 2 with Procedure A shown in Scheme 4 by using 4-methyl-pyridine-2-carboxamidine and (5)-morpholine-3-carboxylic acid instead of thiazole-2-carboxamidine and (5)-4,4-difluoro-pyrrolidine-2-carboxylic acid. The stereochemistry of Example 9 was determined by comparing its 1H NMR data and HPLC retention time with Example 2. Example 10:
(R)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2-chloro-4-fluoro- phenyl)-2-(4-cyclopropyl-thiazol-2-yl)- 1 ,4-dihydro-py rimidine-5-carboxylic acid methyl ester
The title compound was prepared in analogy to Example 2 with Procedure A shown in Scheme 4 by using 4-cyclopropyl-thiazole-2-carboxamidine (Compound M ) instead of thiazole- 2-carboxamidine. The stereochemistry of Example 10 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Preparation of 4-cyclopropyl-thiazole-2-carboxamidine (Compound M):
Figure imgf000100_0001
To a stirred solution of 2-bromo-l-cyclopropyl-ethanone (16 g, 100 mmol) in EtOH (150 mL) was added successively thiourea (8.0 g, 105 mmol) and Cu(OAc)2 (0.90 g, 5.0 mmol) at room temperature. After the mixture was heated at 80 °C for 1 hour, the solvent was removed under reduced pressure. The residue was neutralized with saturated NaHC03 (100 mL) to pH = 8-9, and then DCM (200 mL) was added. The organic layer was separated and the aqueous layer was further extracted with DCM (200 mL x 2). The combined organic layers were washed with sat. NaHC03 (100 mL), brine (100 mL) and dried over anhydrous Na2S04. After filtration and concentration, the residue was purified by column chromatography (eluent: EA: PE = 1 :4) to afford the desired product J (1 1 g) as a yellow solid. 1H NMR (CDCl3-d, 400 MHz): δ ppm 6.06 (s, 1H), 4.86 (br s, 2H), 1.85-1.79 (m, 1H), 0.84-0.74 (m, 4H).
To a stirred solution of Compound J (5.6 g, 40 mmol) and CuBr (8.5 g, 60 mmol) in CH3CN (100 mL) was added dropwise t-BuONO (6.2 g, 7.2 mL, 60 mmol) at 0 °C. Then the reaction mixture was warmed to room temperature and further stirred for additional 30 mins. After that, the precipitate was filtered and the solvent was removed under reduced pressure. The residue was purified by column chromatography (eluent: 100% petroleum ether) to afford the desired product K (3.5 g, 43 %) as a light yellow oil containing small amount of petroleum ether. 1H NMR (400 MHz, CDC13): δ 6.77 (s, 1H), 2.00-1.95 (m, 1H), 0.94-0.85 (m, 4H).
A mixture of Compound K (3.3 g, 16 mmol) and CuCN (4.3 g, 49 mmol) in DMAc (15 mL) was heated to 135 °C for 3 hours. The reaction mixture was extracted with PE and dried over Na2S04. The solvent was removed under reduced pressure to afford the crude product L (0.9 g, 38%) as a yellow oil, which was used as it in the next step.
Compound M was prepared in analogy to thiazole-2-carboxamidine (Compound Ai) with the procedure shown in Scheme 5 by using 4-cyclopropyl-thiazole-2-carbonitrile instead of thiazole-2-carbonitrile. 1H NMR (CDCl3-d, 400 MHz): δ 9.68 (br, 1H), 9.56 (br, 1H), 2.23-2.19 (m, 1H), 1.01-0.92 (m, 4H).
Example 11:
(R)-2-(4-tert-Butyl-thiazol-2-yl)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)- 4-(2-chloro-4-fluoro-phenyl)-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester
The title compound was prepared in analogy to Example 2 with Procedure A shown in Scheme 4 by using 4-tert-butyl-thiazole-2-carboxamidine instead of thiazole-2-carboxamidine. The stereochemistry of Example 11 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Preparation of 4-terf-butyl-thiazole-2-carboxamidine (Compound N):
Figure imgf000102_0001
4-tert-Butyl-thiazole-2-carboxamidine (Compound N) was prepared in analogy to
Compound M with procedure shown in Example 10 by using l-bromo-3,3-dimethyl-butan-2-one instead of 2-bromo-l-cyclopropyl-ethanone. MS: calc'd (MH+) 184, measured (MH+) 184.
Example 12:
(R)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2-chloro-4-fluoro- phenyl)-2-(4-fluoro-thiophen-2-yl)-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester
The title compound was prepared in analogy to Example 2 with Procedure A shown in Scheme 4 by using 4-fluoro-thiophene-2-carbonitrile instead of thiazole-2-carbonitrile. The stereochemistry of Example 12 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 13:
(S)-4-[6-(2-Chloro-4-fluoro-phenyl)-5-methoxycarbonyl-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 1 with Procedure A shown in Scheme 4 by using 1 -methyl- lH-imidazole-2-carbonitrile and (5)-morpholine-3-carboxylic acid instead of thiazole-2-carbonitrile and (5)-4,4-difluoro-pyrrolidine-2-carboxylic acid.
Example 14:
(R)-6-((R)-5-Carboxy-3,3-difluoro-piperidin-l-ylmethyl)-4-(2-chloro-4-fluoro- phenyl)-2-thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester
Figure imgf000103_0001
(-)-Diastereoisomer
Scheme 6
The title compound was prepared from the diastereomeric mixture of (i?)-6-(5-carboxy- 3,3-difluoro-piperidin-l-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-l ,4-dihydro- pyrimidine-5-carboxylic acid methyl ester (Compound O) through preparative HPLC separation. [a]D 20 -26.9 (c 0.1 10, MeOH).
Preparation of (R)-6-(5-carboxy-3,3-difluoro-piperidin-l-ylmethyl)-4-(2-chloro-4- fluoro-phenyl)-2-thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester (Compound O)
Compound O was prepared in analogy to Example 2 with Procedure B shown in Scheme 5 by using 5,5-difluoro-piperidine-3-carboxylic acid (Shanghai AQ BioPharma Co. Ltd., CAS: 1255666-96-6) instead of (5)-4,4-difluoro-pyrrolidine-2-carboxylic acid.
Example 15:
(R)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2-chloro-4-fluoro- phenyl)-2-(4-methyl-oxazol-2-yl)-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester
The title compound was prepared in analogy to Example 2 with Procedure A shown in Scheme 4 by using 4-methyl-oxazole-2-carbonitrile and instead of thiazole-2-carbonitrile. The stereochemistry of Example 15 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 16:
(R)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2-chloro-4-fluoro- phenyl)-2-(4-methyl-thiazol-2-yl)-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester The title compound was prepared in analogy to Example 2 with Procedure A shown in Scheme 4 by using 4-methyl-thiazole-2-carbonitrile instead of thiazole-2-carbonitrile. The stereochemistry of Example 16 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 17:
(S)-4-[(R)-6-(2-Chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-(4-methyl-thiazol-2-yl)- 3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid
The title compound was prepared in analogy to Example 2 with Procedure A shown in Scheme 4 by using 4-methyl-thiazole-2-carbonitrile and (5)-morpholine-3-carboxylic acid instead of thiazole-2-carbonitrile and (5)-4,4-difluoro-pyrrolidine-2-carboxylic acid. The stereochemistry of Example 17 was determined by comparing its 1H NMR data and HPLC retention time with Example 2. Example 18:
(R)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2-chloro-4,5-difluoro- phenyl)-2-thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester
The title compound was prepared in analogy to Example 2 with Procedure A shown in Scheme 4 by using 2-chloro-4,5-difluoro-benzaldehyde instead of 2-chloro-4-fluoro- benzaldehyde. The stereochemistry of Example 18 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 19:
(R)-6-((5)-2-Carboxy-[3,3-2H2]-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2-chloro-4- fluoro-phenyl)-2-thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester
The title compound was prepared in analogy to Example 2 with Procedure B shown in Scheme 5 by using (i?)-[3,3-2H2]-4,4-difluoro-pyrrolidine-2-carboxylic acid hydrochloric acid salt instead of (5)-4,4-difluoro-pyrrolidine-2-carboxylic acid.
Preparation of (R)-[3,3-2H2]-4,4-difluoro-pyrrolidine-2-carboxylic acid hydrochloric acid salt (Compound R):
Figure imgf000105_0001
Figure imgf000105_0002
R
D20 (10 mL) and prewashed (with D20) silica gel (4 g) were added to a solution of (5)-di- tert-butyl 4-oxopyrrolidine-l ,2-dicarboxylate (4.0 g, 14 mmol) in dry THF (10 mL). After the reaction mixture was stirred at room temperature for 8 days, the silica gel was removed by filtration. The filtrate was extracted with ethyl acetate and the organic phase was concentrated to give (i?)-[3,3-2H2]-4-oxo-pyrrolidine-l ,2-dicarboxylic acid di-tert-butyl ester (Compound P) as a light yellow oil (4.0 g). 1H NMR (CDCl3-d, 400 MHz): δ ppm 4.55-4.70 (m, 1H), 3.82-3.92 (m, 2H), 1.49 (s, 9H), 1.48 (s, 9H).
Diethylaminosulfur trifluoride (DAST) (1.4 g, 1.2 mL, 8.7 mmol) was added to a solution of (i?)-[3,3-2H2]-4 -oxo-pyrrolidine-l ,2-dicarboxylic acid di-tert-butyl ester (1.0 g, 3.5 mmol) in anhydrous dichloromethane (15 mL) under ice cooling, and the resultant mixture was stirred 20 hrs at room temperature. Then the resulting mixture was poured onto ice and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate aqueous solution followed by brine and dried over sodium sulfate. It was filtered and concentrated in vacuo to give (i?)-[3,3-2H2]-4,4-difluoro-pyrrolidine-l ,2-dicarboxylic acid di-tert-butyl ester (Compound Q) as a yellow oil (0.94 g). 1H NMR (CDCl3-d, 400 MHz): δ ppm 4.32-4.47 (m, 1H), 3.74-3.90 (m, 2H), 1.43-1.52 (m, 18H).
To a 5 mL microwave vial was added (i?)-[3,3-2H2]-4,4-difluoro-pyrrolidine-l ,2- dicarboxylic acid di-tert-butyl ester (0.30 g) in 1 , 1 ,3,3-hexafluoroisopropanol (2 mL). The vial was capped and heated in the microwave at 135 °C for 40 mins. The light yellow reaction mixture turned red. The reaction mixture was concentrated. The residue was dissolved in methanol and treated with 10 N HC1 solution (0.10 mL) and stirred overnight. The reaction mixture was concentrated to give (i?)-[3,3-2H2]-4,4-difluoro-pyrrolidine-2-carboxylic acid hydrochloric acid salt (Compound R) as a black amorphous solid (0.40 g) which was used as is without further purification for the next step.
Example 20:
6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2- (l,4-dimethyl-lH-imidazol-2-yl)-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester
The title compound was prepared in analogy to Example 1 with Procedure A shown in Scheme 4 by using l ,4-dimethyl-lH-imidazole-2-carboxamidine instead of thiazole-2- carboxamidine.
Preparation of l,4-dimethyl-lH-imidazole-2-carboxamidine (Compound T):
Figure imgf000106_0001
S T
Compound T was prepared in analogy to Compound M with procedure shown in Example 10 by using 2-bromo-l ,4-dimethyl-lH-imidazo directly instead of 2-bromo-l-cyclopropyl- ethanone. MS: calc'd (MH+) 139, measured (MH+) 139.
Example 21:
(5)-4-[(R)-6-(2-Chloro-4,5-difluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6- dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid
The title compound was prepared in analogy to Example 2 with Procedure A shown in Scheme 4 by using 2-chloro-4,5-difluoro-benzaldehyde and (5)-morpholine-3-carboxylic acid instead of 2-chloro-4-fluoro-benzaldehyde and (5)-4,4-difluoro-pyrrolidine-2-carboxylic acid. The stereochemistry of Example 21 was determined by comparing its 1H NMR data and HPLC retention time with Example 2. Example 22:
(R)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2-chloro-4-fluoro- phenyl)-2-(3-fluoro-pyridin-2-yl)-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester
The title compound was prepared in analogy to Example 2 with Procedure A shown in Scheme 4 by using 3-fluoro-pyridine-2-carbonitrile instead of thiazole-2-carbonitrile. The stereo chemistry of Example 22 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 23:
(R)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2-chloro-4-fluoro- phenyl)-2-(4-chloro-thiophen-2-yl)-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester
The title compound was prepared in analogy to Example 2 with Procedure A shown in Scheme 4 by using 4-chloro-thiophene-2-carbonitrile instead of thiazole-2-carbonitrile. The stereochemistry of Example 23 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 24:
(R)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2-chloro-4-fluoro- phenyl)-2-(3-methyl-pyridin-2-yl)-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester The title compound was prepared in analogy to Example 2 with Procedure A shown in
Scheme 4 by using 3-methyl-pyridine-2-carbonitrile instead of thiazole-2-carbonitrile. The stereochemistry of Example 24 was determined by comparing its 1H NMR data and HPLC retention time with Example 2. Example 25:
(R)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2-chloro-4-fluoro- phenyl)-2-(4-trifluoromethyl-thiazol-2-yl)-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester
The title compound was prepared in analogy to Example 2 with Procedure A shown in Scheme 4 by using 4-trifluoromethyl-thiazole-2-carboxamidine instead of thiazole-2- carboxamidine. The stereochemistry of Example 25 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Preparation of 4-trifluoromethyl-thiazole-2-carboxamidine (Compound U):
Figure imgf000108_0001
U
4-Trifluoromethyl-thiazole-2-carboxamidine (Compound U) was prepared in analogy to Compound M with procedure shown in Example 10 by using 2-bromo-4-trifluoromethyl- thiazole (CAS: 41731-39-9) instead of 2-bromo-4-cyclopropyl-thiazole which is made from 2- bromo-l-cyclopropyl-ethanone in Example 10. MS: calc'd (MH+) 196, measured (MH+) 196.
Example 26:
6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2- thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid ethyl ester
The title compound was prepared in analogy to Example 1 with Procedure A shown in Scheme 4 by using ethyl acetoacetate instead of methyl acetoacetate.
Example 27:
(R)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2-chloro-4-fluoro- phenyl)-2-(4-methyl-thiophen-2-yl)-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester
The title compound was prepared in analogy to Example 2 with Procedure A shown in Scheme 4 by using 4-methyl-thiophene-2-carbonitrile instead of thiazole-2-carbonitrile. The stereochemistry of Example 27 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 28:
(R)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2-chloro-4-fluoro- phenyl)-2-(4-isopropyl-thiazol-2-yl)-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester
The title compound was prepared in analogy to Example 2 with Procedure A shown in Scheme 4 by using 4-isopropyl-thiazole-2-carboxamidine instead of thiazole-2-carboxamidine. The stereochemistry of Example 28 was determined by comparing its 1H NMR data and HPLC retention time with Example 2. Preparation of 4-isopropyl-thiazole-2-carboxamidine (Compound V):
Figure imgf000109_0001
V
4-Isopropyl-thiazole-2-carboxamidine (Compound V) was prepared in analogy to
Compound M with procedure shown in Example 10 by using l-bromo-3-methyl-butan-2-one instead of 2-bromo-l-cyclopropyl-ethanone. MS: calc'd (MH+) 170, measured (MH+) 170.
Example 29:
(R)-4-(4-Bromo-2-chloro-phenyl)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-l- ylmethyl)-2-thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester
The title compound was prepared in analogy to Example 2 with Procedure A shown in Scheme 4 by using 4-bromo-2-chloro-benzaldehyde instead of 4-fluoro-2-chloro-benzaldehyde. The stereochemistry of Example 29 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 30:
(R)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2-chloro-4-cyano- phenyl)-2-thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester
The title compound was prepared in analogy to Example 2 with Procedure A shown in Scheme 4 by using 4-cyano-2-chloro-benzaldehyde instead of 4-fluoro-2-chloro-benzaldehyde. The stereochemistry of Example 30 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 31:
(5)-4-[(R)-6-(2-Chloro-4-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid
The title compound was prepared in analogy to Example 1 with Procedure A shown in Scheme 4 by using ethyl acetoacetate and ( 5) - mo rp ho 1 i n e - 3 - c a rbo y 1 i c acid instead of methyl acetoacetate and (5)-4,4-difluoro-pyrrolidine-2-carboxylic acid. The stereochemistry of Example 31 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 32:
(i?)-6-((5)-2-Carboxy-4,4-difluoro-pyrrolidin- 1 -ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-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 1 with Procedure A shown in Scheme 4 by using 1 -methyl- lH-imidazole-2-carbonitrile instead of thiazole-2-carbonitrile. The stereochemistry of Example 32 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 33:
(R)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2-chloro-4-fluoro- phenyl)-2-(2,4-difluoro-phenyl)-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester The title compound was prepared in analogy to Example 1 with Procedure A shown in
Scheme 4 by using 2,4-difluoro-benzonitrile instead of thiazole-2-carbonitrile. The
stereochemistry of Example 33 was determined by comparing its 1H NMR data and HPLC retention time with Example 2. Example 34:
(R)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2-chloro-4-fluoro- phenyl)-2-thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid ethyl ester
The title compound was prepared in analogy to Example 2 with Procedure A shown in Scheme 4 by using ethyl acetoacetate instead of methyl acetoacetate. The stereochemistry of Example 34 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 35:
(5)-4-[(R)-6-(2-Chloro-4-fluoro-phenyl)-5-ethoxycarbonyl-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 2 with Procedure A shown in Scheme 4 by using ethyl acetoacetate, 1 -methyl- lH-imidazole-2-carbonitrile and (S)- morpholine-3-carboxylic acid instead of methyl acetoacetate, thiazole-2-carbonitrile and (S)-4,4- difluoro-pyrrolidine-2-carboxylic acid. The stereochemistry of Example 35 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 36:
(R)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2-chloro-4-fluoro- phenyl)-2-(l-methyl-lH-imidazol-2-yl)-l,4-dihydro-pyrimidine-5-carboxylic acid ethyl ester
The title compound was prepared in analogy to Example 2 with Procedure A shown in Scheme 4 by using ethyl acetoacetate and 1 -methyl- lH-imidazole-2-carbonitrile instead of methyl acetoacetate and thiazole-2-carbonitrile. The stereochemistry of Example 36 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 37:
(S)-4-[(R)-6-(2-Chloro-4-fluoro-phenyl)-5-ethoxycarbonyl-2-(6-methyl-pyridin-2-yl)- 3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid
The title compound was prepared in analogy to Example 2 with Procedure A shown in Scheme 4 by using ethyl acetoacetate, 6-methyl-pyridine-2-carbonitrile and (5)-morpholine-3- carboxylic acid instead of methyl acetoacetate, thiazole-2-carbonitrile and (5)-4,4-difluoro- pyrrolidine-2-carboxylic acid. The stereochemistry of Example 37 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 38:
(R)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2,4-dichloro-phenyl)-2- thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid ethyl ester
The title compound was prepared in analogy to Example 2 with Procedure A shown in
Scheme 4 by using ethyl acetoacetate and 2,4-dichloro-benzaldehyde instead of methyl acetoacetate and 2-chloro-4-fluoro-benzaldehyde. The stereochemistry of Example 38 was determined by comparing its 1H NMR data and HPLC retention time with Example 2. Example 39:
(5)-4-[(R)-6-(2,4-Dichloro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid The title compound was prepared in analogy to Example 2 with Procedure A shown in Scheme 4 by using ethyl acetoacetate, 2,4-dichloro-benzaldehyde and (5)-morpholine-3- carboxylic acid instead of methyl acetoacetate, 2-chloro-4-fluoro-benzaldehyde and (S)-4,4- difluoro-pyrrolidine-2-carboxylic acid. The stereochemistry of Example 39 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 40:
(R)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2-chloro-4-fluoro- phenyl)-2-(l-methyl-4-trifluoromethyl-lH-imidazol-2-yl)-l,4-dihydro-pyrimidine-5- carboxylic acid ethyl ester
The title compound was prepared in analogy to Example 2 with Procedure A shown in Scheme 4 by using ethyl acetoacetate and l-methyl-4-trifluoromethyl-lH-imidazole-2- carbonitrile instead of methyl acetoacetate and thiazole-2-carbonitrile. The stereochemistry of Example 40 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 41:
(S)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(3,4-difluoro-phenyl)-2- thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid ethyl ester
The title compound was prepared in analogy to Example 2 with Procedure A shown in Scheme 4 by using ethyl acetoacetate and 3,4-difluoro-benzaldehyde instead of methyl acetoacetate and 2-chloro-4-fluoro-benzaldehyde. The stereochemistry of Example 41 was determined by comparing its 1H NMR data and HPLC retention time with Example 2. Example 42:
(5)-4-[(5)-6-(3,4-Difluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid
The title compound was prepared in analogy to Example 2 with Procedure A shown in Scheme 4 by using ethyl acetoacetate, 3,4-difluoro-benzaldehyde and (5)-morpholine-3- carboxylic acid instead of methyl acetoacetate, 2-chloro-4-fluoro-benzaldehyde and (S)-4,4- difluoro-pyrrolidine-2-carboxylic acid. The stereochemistry of Example 42 was determined by comparing its 1H NMR data and HPLC retention time with Example 2. -I l l-
Example 43:
(S)-4-[(S)-5-Ethoxycarbonyl-2-thiazol-2-yl-6-(3,4,5-trifluoro-phenyl)-3,6-dihydro- pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid
The title compound was prepared in analogy to Example 2 with Procedure A shown in Scheme 4 by using ethyl acetoacetate, 3,4,5-trifluoro-benzaldehyde and (5)-morpholine-3- carboxylic acid instead of methyl acetoacetate, 2-chloro-4-fluoro-benzaldehyde and (S)-4,4- difluoro-pyrrolidine-2-carboxylic acid. The stereochemistry of Example 43 was determined by comparing its 1H NMR data and HPLC retention time with Example 2. Example 44:
(S)-4-[(R)-5-Ethoxycarbonyl-2-thiazol-2-yl-6-(2,3,4-trifluoro-phenyl)-3,6-dihydro- pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid
The title compound was prepared in analogy to Example 2 with Procedure A shown in Scheme 4 by using ethyl acetoacetate, 2,3,4-trifluoro-benzaldehyde and (5)-morpholine-3- carboxylic acid instead of methyl acetoacetate, 2-chloro-4-fluoro-benzaldehyde and (S)-4,4- difluoro-pyrrolidine-2-carboxylic acid. The stereochemistry of Example 44 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 45:
(S)-4-[(R)-6-(4-Bromo-2,3-difluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6- dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid
The title compound was prepared in analogy to Example 2 with Procedure A shown in Scheme 4 by using 4-bromo-2,3-difluoro-benzaldehyde and (5)-morpholine-3 -carboxylic acid instead of 2-chloro-4-fluoro-benzaldehyde and (5)-4,4-difluoro-pyrrolidine-2-carboxylic acid. The stereochemistry of Example 45 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 46:
(S)-4-[(S)-6-(3,4-Dichloro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid
The title compound was prepared in analogy to Example 2 with Procedure A shown in Scheme 4 by using ethyl acetoacetate, 3,4-dichloro-benzaldehyde and (5)-morpholine-3- carboxylic acid instead of methyl acetoacetate, 2-chloro-4-fluoro-benzaldehyde and (S)-4,4- difluoro-pyrrolidine-2-carboxylic acid. The stereochemistry of Example 46 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 47:
(S)-4-[(R)-6-(2-Chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6- dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid
The title compound was prepared in analogy to Example 2 with Procedure A shown in Scheme 4 by using 2-chloro-3-fluoro-benzaldehyde and (5)-morpholine-3-carboxylic acid instead of 2-chloro-4-fluoro-benzaldehyde and (5)-4,4-difluoro-pyrrolidine-2-carboxylic acid. The stereochemistry of Example 47 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 48:
((S)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(4-cyano-phenyl)-2- thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid ethyl ester
The title compound was prepared in analogy to Example 2 with Procedure A shown in Scheme 4 by using ethyl acetoacetate and 4-formyl-benzonitrile instead of methyl acetoacetate and 2-chloro-4-fluoro-benzaldehyde. The stereochemistry of Example 48 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 49:
(S)-4-[(R)-6-(4-Chloro-2-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid
The title compound was prepared in analogy to Example 2 with Procedure A shown in Scheme 4 by using ethyl acetoacetate, 4-chloro-2-fluoro-benzaldehyde and (5)-morpholine-3- carboxylic acid instead of methyl acetoacetate, 2-chloro-4-fluoro-benzaldehyde and (S)-4,4- difluoro-pyrrolidine-2-carboxylic acid. The stereochemistry of Example 49 was determined by comparing its 1H NMR data and HPLC retention time with Example 2. Example 50:
(R)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2,3-difluoro-phenyl)-2- thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid ethyl ester The title compound was prepared in analogy to Example 2 with Procedure A shown in Scheme 4 by using ethyl acetoacetate and 2,3-difluoro-benzaldehyde instead of methyl acetoacetate and 2-chloro-4-fluoro-benzaldehyde. The stereochemistry of Example 50 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 51:
(5)-4-[(R)-6-(2-Chloro-4-fluoro-phenyl)-2-thiazol-2-yl-5-(2,2,2-trifluoro- ethoxycarbonyl)-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid
The title compound was prepared in analogy to Example 2 with Procedure A shown in Scheme 4 by using 3-oxo-butyric acid 2,2,2-trifluoro-ethyl ester and (5)-morpholine-3- carboxylic acid instead of methyl acetoacetate and (5)-4,4-difluoro-pyrrolidine-2-carboxylic acid. The stereochemistry of Example 51 was determined by comparing its 1H NMR data and HPLC retention time with Example 2. Example 52:
(S)-4-[(R)-5-Ethoxycarbonyl-2-thiazol-2-yl-6-(2,3,4-trifluoro-phenyl)-3,6-dihydro- pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid
The title compound was prepared in analogy to Example 2 with Procedure A shown in Scheme 4 by using ethyl acetoacetate, 4-bromo-3-fluoro-benzaldehyde and (5)-morpholine-3- carboxylic acid instead of methyl acetoacetate, 2-chloro-4-fluoro-benzaldehyde and (S)-4,4- difluoro-pyrrolidine-2-carboxylic acid. The stereochemistry of Example 52 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 53:
(S)-4-[(5)-5-Ethoxycarbonyl-6-(3-fluoro-phenyl)-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid
The title compound was prepared in analogy to Example 2 with Procedure A shown in Scheme 4 by using ethyl acetoacetate, 3-fluoro-benzaldehyde and (5)-morpholine-3-carboxylic acid instead of methyl acetoacetate, 2-chloro-4-fluoro-benzaldehyde and (5)-4,4-difluoro- pyrrolidine-2-carboxylic acid. The stereochemistry of Example 53 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 54: (S)-4-[(S)-5-Ethoxycarbonyl-6-(4-fluoro-phenyl)-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid
The title compound was prepared in analogy to Example 2 with Procedure A shown in Scheme 4 by using ethyl acetoacetate, 4-fluoro-benzaldehyde and (5)-morpholine-3-carboxylic acid instead of methyl acetoacetate, 2-chloro-4-fluoro-benzaldehyde and (5)-4,4-difluoro- pyrrolidine-2-carboxylic acid. The stereochemistry of Example 54 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 55:
(R)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2-chloro-3,4-difluoro- phenyl)-2-thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid ethyl ester
The title compound was prepared in analogy to Example 2 with Procedure A shown in Scheme 4 by using ethyl acetoacetate and 2-chloro-3,4-difluoro-benzaldehyde instead of methyl acetoacetate and 2-chloro-4-fluoro-benzaldehyde. The stereochemistry of Example 55 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 56:
(S)-6-((5)-2-Carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(3,4-difluoro-phenyl)-2-(l- methyl-lH-imidazol-2-yl)-l,4-dihydro-pyrimidine-5-carboxylic acid ethyl ester
The title compound was prepared in analogy to Example 2 with Procedure A shown in
Scheme 4 by using ethyl acetoacetate, 3,4-difluoro-benzaldehyde and 1 -methyl- lH-imidazole-2- carbonitrile instead of methyl acetoacetate, 2-chloro-4-fluoro-benzaldehyde and thiazole-2- carbonitrile. The stereochemistry of Example 56 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 57:
(5)-4-[(S)-6-(3,4-Difluoro-phenyl)-5-ethoxycarbonyl-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 2 with Procedure A shown in Scheme 4 by using ethyl acetoacetate, 3,4-difluoro-benzaldehyde, 1 -methyl- lH-imidazole-2- carbonitrile and (5)-morpholine-3-carboxylic acid instead of methyl acetoacetate, 2-chloro-4- fluoro-benzaldehyde, thiazole-2-carbonitrile and (5)-4,4-difluoro-pyrrolidine-2-carboxylic acid. The stereochemistry of Example 57 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 58:
(S)-4-[(R)-6-(2,4-Difluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid
The title compound was prepared in analogy to Example 2 with Procedure A shown in Scheme 4 by using ethyl acetoacetate, 2,4-difluoro-benzaldehyde and (5)-morpholine-3- carboxylic acid instead of methyl acetoacetate, 2-chloro-4-fluoro-benzaldehyde and (S)-4,4- difluoro-pyrrolidine-2-carboxylic acid. The stereochemistry of Example 58 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 59:
(R)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2,4-difluoro-phenyl)-2- thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid ethyl ester
The title compound was prepared in analogy to Example 2 with Procedure A shown in Scheme 4 by using ethyl acetoacetate and 2,4-difluoro-benzaldehyde instead of methyl acetoacetate and 2-chloro-4-fluoro-benzaldehyde. The stereochemistry of Example 59 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 60:
(5)-4-[(R)-6-(2-Chloro-3,4-difluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6- dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid
The title compound was prepared in analogy to Example 2 with Procedure A shown in Scheme 4 by using ethyl acetoacetate, 2-chloro-3,4-difluoro-benzaldehyde and (5)-morpholine- 3-carboxylic acid instead of methyl acetoacetate, 2-chloro-4-fluoro-benzaldehyde and (S)-4,4- difluoro-pyrrolidine-2-carboxylic acid. The stereochemistry of Example 60 was determined by comparing its 1H NMR data and HPLC retention time with Example 2. Example 61:
(2S)-l-[[(4R)-4-(2-chloro-4-fluorophenyl)-5-methoxycarbonyl-2-(4-methylsulfanyl- 1 ,3-thiazol-2-yl)- 1 ,4-dihydropy rimidin-6-yl] methyl] -4,4-difluoropy rrolidine-2-carbox lic acid The title compound was prepared in analogy to Example 2 with Procedure B shown in Scheme 5 by using 4-methylsulfanyl-thiazole-2-carbonitrile (Compound Y) instead of thiazole- 2-carbonitrile. The stereochemistry of Example 61 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Preparation of 4-methylsulfanyl-thiazole-2-earbonitrile (Compound Y):
Figure imgf000118_0001
Y
To a stirred solution of 4-bromo-thiazole-2-carbaldehyde (5.0 g, 26 mmol) in EtOH (50 mL) was added successively diethoxymethoxy-ethane (14 mL) at room temperature. After the mixture was heated at 80 °C for 24 hours, the solvent was removed under reduced pressure. The DCM (50 mL) was added. The organic layer was separated and the aqueous layer was further extracted with DCM (50 mL x 2). The combined organic layers were washed with sat. NaHC03 (30 mL), brine (30 mL) and then dried over anhydrous Na2S04. The solvent was removed under reduced pressure to afford the crude product W (7.0 g) as an oil, which was used in the next step.
To a stirred solution of Compound W (0.50g, 1.9 mmol) and Cul (0.36 g, 1.9 mmol) in DMF (5 mL) was added MeSNa (0.53 g, 7.5 mmol) at room temperature. The reaction mixture was heated to 130 °C for 13 hours. The solvent was removed under reduced pressure. The DCM (50 mL) was added. The organic layer was separated and the aqueous layer was further extracted with DCM (50 mL x 2). The combined organic layers were washed with sat. NaHC03 (30 mL), brine (30 mL) and dried over anhydrous Na2S04. After filtration and concentration, the residue was purified by column chromatography (eluent: EA:PE = 1 :20) to afford the desired product X (250 mg) as an oil. MS: calc'd (MH+) 234, measured (MH+) 234.
The mixture of Compound X (2.0 g, 7.5 mmol) was added 1 ,4-dioxane (5mL) and HCI (IN, 5 mL) at room temperature. After the mixture was stirred for 24 hour, The DCM (50 mL) was added. The organic layer was separated and the aqueous layer was further extracted with DCM (50 mL x 2). The combined organic layers were washed with sat. NaHC03 (30 mL), brine (30 mL) and then dried over anhydrous Na2S04. The solvent was removed under reduced pressure. The residue was dissolved in DCM (50 mL) with the addition of NH2OH.HCl and pyridine at 0 °C, and then the reaction mixture was stirred overnight at room temperature. After that, more DCM (100 mL) was added. The organic layer was separated and the aqueous layer was further extracted with DCM (50 mL x 2). The combined organic layers were washed with sat. NaHC03 (100 mL), brine (100 mL) and then dried over anhydrous Na2S04. The solvent was removed under reduced pressure to afford an oil. To this oil compound was added 1 ,4-dioxane, trifluoro acetic anhydride and triethyl amine at 0 °C. After the reaction mixture was stirred overnight at room temperature, more DCM (100 mL) was added. The organic layer was separated and the aqueous layer was further extracted with DCM (50 mL x 2). The combined organic layers were washed with sat. NaHC03 (100 mL), brine (100 mL) and then dried over anhydrous Na2S04. After filtration and concentration, the residue was purified by column chromatography (eluent: EA: PE = 1 :20) to afford the desired product D (1.2 mg) as an oil. MS: calc'd (MH+) 157, measured (MH+) 157.
Example 62:
(3S)-4-[[(4R)-4-(2-chloro-4-fluorophenyl)-5-methoxycarbonyl-2-(4-methylsulfanyl- 1 ,3-thiazol-2-yl)- 1 ,4-dihydrop rimidin-6-yl] methyl] morpholine-3-carbox lic acid
The title compound was prepared in analogy to Example 2 with Procedure B shown in Scheme 5 by using 4-methylsulfanyl-thiazole-2-carbonitrile (Compound Y) and (S)-morpholine- 3-carboxylic acid instead of thiazole-2-carbonitrile and (5)-4,4-difluoro-pyrrolidine-2-carboxylic acid. The stereochemistry of Example 62 was determined by comparing its 1H NMR data and HPLC retention time with Example 2. Example 63:
(S)-4-[(R)-6-(2-Chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid
The title compound was prepared in analogy to Example 2 with Procedure B shown in Scheme 5 by using 2-chloro-3-fluorobenzaldehyde, ethyl acetoacetate and (5)-morpholine-3- carboxylic acid instead of 2-chloro-4-fluorobenzaldehyde, methyl acetoacetate and (S)-4,4- difluoro-pyrrolidine-2-carboxylic acid. The stereochemistry of Example 63 was determined by comparing its 1H NMR data and HPLC retention time with Example 2. Example 64:
(R)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2-chloro-3-fluoro- phenyl)-2-thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid ethyl ester
The title compound was prepared in analogy to Example 2 with Procedure B shown in Scheme 5 by using 2-chloro-3-fluorobenzaldehyde and ethyl acetoacetate instead of 2-chloro-4- fluorobenzaldehyde and methyl acetoacetate. The stereochemistry of Example 64 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 65:
(S)-4-[(R)-6-(2-Bromo-4-fluoro-phenyl)-5-methoxycarbonyl-2-(5-methyl-oxazol-4-yl)- 3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid
The title compound was prepared in analogy to Example 2 with Procedure A shown in Scheme 4 by using 2-bromo-4-fluorobenzaldehyde, 5-methyl-oxazole-4-carboxamidine
(Compound AB) and (5)-morpholine-3-carboxylic acid instead of 2-chloro-4- fluorobenzaldehyde, thiazole-2-carboxamidine and (5)-4,4-difluoro-pyrrolidine-2-carboxylic acid. The stereochemistry of Example 65 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Preparation of 5-methyloxazole-4-carboxamidine (Compound AB):
Figure imgf000120_0001
AA AB
A mixture of ethyl 5-methyloxazole-4-carboxylate (CAS: 32968-44-8) (2.5 g, 16 mmol) and ammonia (100 mL, 7M in MeOH) was stirred at 65 °C for 48 hours. The solvent was removed under reduced pressure to give Compound Z (1.94 g, 98%). 1H NMR (DMSO- d6, 400 MHz) δ ppm: 8.29 (s, 1H), 7.47 (s, 2H), 2.55 (s, 3H). MS: calc'd (MH+) 127, measured (MH+) 127.
To a white suspension of 5-methyloxazole-4-carboxamide Z (1.3 g, 10 mmol) in dry DMF
(10 mL) was added cyanuric chloride (3.8 g, 21 mmol) at 0 °C, the reaction was stirred at 0 °C for 2 h. The reaction was quenched with ice water (20 mL) carefully, and then basified with 2N NaOH solution to pH 10. The mixture was extracted with EtOAc (50 mL x 3), the combined organic layer was washed with water (30 mL x 2), brine (30 mL x 1), and then dried over Na2S04, then filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage, 40 g silica gel, EtOAc in PE 30%~100%) to afford colorless oil AA (0.89 g, 79%). 1H NMR (DMSO-d6, 400 MHz) δ ppm: 8.55 (s, 1H), 2.52 (s, 3H).
To a solution of 5-methyloxazole-4-carbonitrile AA (0.76 g, 7.0 mmol) in anhydrous MeOH (30 mL) was added MeONa (0.57 g, 10 mmol), after stirred at 35 °C under nitrogen for 3h, NH4C1 (0.75 g, 14 mmol) was added, refluxed for 2 h. The solvent was removed and the residue was purified by flash chromatography (Biotage, 40 g silica gel, MeOH in DCM 5%~35%) to afford brown solid AB (587 mg, 67%). 1H NMR (DMSO-d6, 400 MHz) δ ppm: 9.1 1-9.19 (m, 3H), 8.60 (s, 1H), 2.59 (s, 3H). MS: calc'd (MH+) 126, measured (MH+) 126.
Example 66:
(S)-4-[(R)-6-(2-Bromo-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid
The title compound was prepared in analogy to Example 2 with Procedure B shown in Scheme 5 by using 2-bromo-3-fluorobenzaldehyde, ethyl acetoacetate and (5)-morpholine-3- carboxylic acid instead of 2-chloro-4-fluorobenzaldehyde, methyl acetoacetate and (S)-4,4- difluoro-pyrrolidine-2-carboxylic acid. The stereochemistry of Example 66 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 67:
(R)-4-(2-Bromo-3-fluoro-phenyl)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-l- ylmethyl)-2-thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid ethyl ester
The title compound was prepared in analogy to Example 2 with Procedure B shown in Scheme 5 by using 2-bromo-3-fluorobenzaldehyde and ethyl acetoacetate instead of 2-chloro-4- fluorobenzaldehyde and methyl acetoacetate. The stereochemistry of Example 67 was
determined by comparing its 1H NMR data and HPLC retention time with Example 2. Example 68:
(S)-4-[(R)-6-(2-Chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-(5-methyl-oxazol-4-yl)- 3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid The title compound was prepared in analogy to Example 1 with Procedure A shown in Scheme 4 by using 5-methyl-oxazole-4-carboxamidine (Compound AB) and (S)-morpholine-3- carboxylic acid instead of thiazole-2-carboxamidine and (5)-4,4-difluoro-pyrrolidine-2- carboxylic acid. The stereochemistry of Example 68 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 69:
(S)-4-[(R)-6-(2-Bromo-4-fluoro-phenyl)-5-ethoxycarbonyl-2-(5-methyl-oxazol-4-yl)- 3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid
The title compound was prepared in analogy to Example 1 with Procedure A shown in
Scheme 4 by using 2-bromo-4-fluorobenzaldehyde, 5-methyl-oxazole-4-carboxamidine
(Compound AB), ethyl acetoacetate and (5)-morpholine-3-carboxylic acid instead of 2-chloro-4- fluorobenzaldehyde, thiazole-2-carboxamidine, methyl acetoacetate and (5)-4,4-difluoro- pyrrolidine-2-carboxylic acid. The stereochemistry of Example 69 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 70:
(5)-4-[(R)-6-(2,3-Difluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid
The title compound was prepared in analogy to Example 2 with Procedure A shown in
Scheme 4 by using (iS)-morpholine-3 -carboxylic acid instead of ( 5)-4,4-d i f! uo ro pyrro 1 id i n e-2- carboxylic acid, ethyl acetoacetate instead of methyl acetoacetate, and 2,3-difluoro
benzaldchydc instead of 2-chloro-4-fluoro-benzaldehyde. The stereochemistry of Example 70 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 71:
(S)-4-[(R)-6-(2-Bromo-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid
The title compound was prepared in analogy to Example 2 with Procedure B shown in Scheme 5 by using (S)-morpholine-3 -carboxylic acid instead of (5)-4,4-difluoropyrrolidine-2- carboxyl ic acid, 2-bromobenzaldehyde instead of 2-chloro-4-fiuoro-benzaldehyde. The stereochemistry of Example 70 was determined by comparing its 1H NMR data and HPLC retention time with Example 2. Example 73:
(S)-4-[(R)-6-(2-Chloro-3,4-difluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6- dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid
The title compound was prepared in analogy to Example 2 with Procedure B shown in
Scheme 5 by using ( S)-mo rpho 1 i n e- -carbo y 1 ic acid instead of ( S)-4,4-d i f! uo ro pyrro 1 id i n e-2- carboxylic acid, and 2 -ch lo ro- .4-d i fl uo robenza Id ch yde instead of 2-chloro-4-fluoro- benzaldeliyde. The stereochemistry of Example 73 was determined by comparing its Ή NMR data and HPLC retention time with Example 2.
Example 74:
(R)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2-chloro-3,4-difluoro- phenyl)-2-thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester
The title compound was prepared in analogy to Example 2 with Procedure B shown in Scheme 5 by using 2-chloro-3,4-difluorobenzaldehyde instead of 2 -ch lo ro-4-ΙΊ uo robe nzaldehyde. The stereochemistry of Example 74 was determined by comparing its Ή NMR data and HPLC retention time with Example 2.
Example 75:
(5)-4-[(R)-6-(4-Chloro-2-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6- dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid
The title compound was prepared in analogy to Example 2 with Procedure B shown in Scheme 5 by using (S)-morpho 1 ine-3-earboxy I ic acid instead of (5)-4,4-difluoropyrrolidine-2- carboxyl ic acid and 2-fluoro-4-chloro-benzaldehyde instead of 2-chloro-4-fluoro-benzaldehyde. The stereochemistry of Example 75 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 77:
(S)-4-[(S)-6-(4-Chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6- dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid
The title compound was prepared in analogy to Example 2 with Procedure B shown in Scheme 5 by using (S)-morpho 1 ine-3-carboxy 1 ic acid instead of (5)-4.4-difluoropyrrolidine-2- carboxyl ie acid and 3-fluoro-4-chioro-benzaldehyde instead of 2-chloro-4-fluoro-benzaldehyde. The stereochemistry of Example 77 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 78 and 79:
(S)-4-[(R)-6-(4-Chloro-2-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6- dihydro-pyrimidin-4-ylmethyl]-3-methyl-morpholine-3-carboxylic acid (Example 78) and (R)-4-[(R)-6-(4-Chloro-2-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl]-3-methyl-morpholine-3-carboxylic acid Example 79)
Figure imgf000124_0001
Example 79
The title compounds was prepared from the diastereomeric mixture of 4-[(i?)-6-(4-chloro- 2-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-3- methyl-morpholine-3-carboxylic acid (Compound AC) through preparative HPLC separation. The absolute stereochemistry was tentatively assigned based on SAR knowledge.
Preparation of 4-[(R)-6-(4-Chloro-2-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2- yl-3,6-dihydro-pyrimidin-4-ylmethyl]-3-methyl-morpholine-3-carboxylic acid (Compound AC)
Compound AC was prepared in analogy to Example 2 with Procedure B shown in Scheme 5 by using 3-methylmorpholine-3-carboxylic acid (Compound AD) instead of (5)-4.4- d ifluoropyrrol id ine-2-carboxyl ic acid, 2-fluoro-4-chloro-benzaldehyde instead of 2-chloro-4- fluoro-benzaldehyde.
Preparation of 3-meth lmorpholine-3-carbox lic acid (Compound AD):
Figure imgf000124_0002
To a solution of 3-metliyl-4-[(2-methylpropan-2-yl )oxycarlxinyl]mo pholine-3-carb ixylic acid (Accela ChemBio Co., Ltd., CAS: 1052680-53-1 , 50 mg, 0.20 mmo! ) in DCM (1 ml ) was added trifluoroacetic acid (1 mL) dropwi.se at room temperature. The resulting mixture was stirred at room temperature for one hour and then concentrated under the vacuum. The residue was used directly in next step without further purification.
Example 80:
(R)-6-((R)-5-Carboxy-3,3-difluoro-piperidin-l-ylmethyl)-4-(2-chloro-4-fluoro- phenyl)-2-(4-methyl-thiazol-2-yl)-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester
The title compound was prepared in analogy to Example 14 shown in Scheme 6 by using 4-methyl-thiazole-2-carboxamidine instead of thiazole-2-carboxamidine. Example 81:
(S)-4-[(R)-6-(2-Bromo-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6- dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid
The title compound was prepared in analogy to Example 2 with Procedure A shown in Scheme 4 by using 2-bromo-4-fluoro-benzaldehyde instead of 2-chloro-4-fluoro-benzaldehyde and using (5)-morpholine-3-carboxylic acid instead of(5)-4,4-difluoro-pyrrolidine-2-carboxylic acid. The stereochemistry of Example 81 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 82:
(5)-4-[(R)-6-(2-Chloro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid
The title compound was prepared in analogy to Example 2 with Procedure A shown in Scheme 4 by using 2-chloro-benzaldehyde instead of 2-chloro-4-fluoro-benzaldehyde, using ethyl acetoacetate instead of methyl acetoacetate and (5)-morpholine-3-carboxylic acid instead of (5)-4,4-difluoro-pyrrolidine-2-carboxylic acid. The stereochemistry of Example 82 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 83:
(S)-4-[(5)-6-(4-Chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid
The title compound was prepared in analogy to Example 2 with Procedure A shown in Scheme 4 by using 4-chloro-3-fluoro-benzaldehyde instead of 2-chloro-4-fluoro-benzaldehyde, using ethyl acetoacetate instead of methyl acetoacetate and using (5)-morpholine-3-carboxylic acid instead of (5)-4,4-difluoro-pyrrolidine-2-carboxylic acid. The stereochemistry of Example 83 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 84:
(R)-4-(2-Bromo-4-fluoro-phenyl)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-l- ylmethyl)-2-thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester
The title compound was prepared in analogy to Example 2 with Procedure A shown in Scheme 4 by using 2-bromo-4-fluoro-benzaldehyde instead of 2-chloro-4-fluoro-benzaldehyde. The stereochemistry of Example 84 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 85:
(R)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2,4-dichloro-phenyl)-2- thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester
The title compound was prepared in analogy to Example 2 with Procedure A shown in
Scheme 4 by using 2,4-dichloro-benzaldehyde instead of 2-chloro-4-fluoro-benzaldehyde. The stereochemistry of Example 85 was determined by comparing its 1H NMR data and HPLC retention time with Example 2. Example 86:
3-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-l,4- dihydropyrimidin-6-yl] methyl] - 1 ,3-thiazinane-4-carboxylic acid
The title compound was prepared in analogy to Example 2 with Procedure B shown in Scheme 5 by using l ,3-thiazinane-4-carboxylic acid (WuXi AppTec (Wuhan) Co., Ltd, CAS: 60175-95-3) instead of (5)-4,4-difluoro-pyrrolidine-2-carboxylic acid.
Example 87:
(35)-4-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-2-(4-cyclopropylthiazol-2-yl)-5- methoxycarbonyl-l,4-dihydropyrimidin-6-yl] methyl] morpholine-3-carboxylic acid
The title compound was prepared in analogy to Example 2 with Procedure A shown in
Scheme 4 by using 4-cyclopropyl-thiazole-2-carboxamidine (Compound M ) instead of thiazole- 2-carboxamidine and (5)-morpholine-3-carboxylic acid instead of (5)-4,4-difluoro-pyrrolidine-2- carboxylic acid. The stereochemistry of Example 87 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 88:
(3S)-4- [ [(4R)-4-(2-chloro-4-fluoro-phenyl)-2- [4-(difluoromethyl)thiazol-2-yl] -5- methoxycarbonyl-l,4-dihydropyrimidin-6-yl] methyl] morpholine-3-carboxylic acid
The title compound was prepared in analogy to Example 2 with Procedure B shown in Scheme 5 by using (35)-morpholine-3 -carboxylic acid and 4-(difluoromethyl)thiazole-2- carboxamidine (Compound AL) instead of (5)-4,4-difluoro-pyrrolidine-2-carboxylic acid and thiazole-2-carboxamidine.
Preparation of 4-(difluoromethyl)thiazole-2-carboxamidine (Compound AL):
NHBoc
Figure imgf000127_0001
AE AF AG
Figure imgf000127_0002
AK AL
Scheme 7
A solution of methyl 3-bromo-2-oxo-propanoate (10 g, 51 mmol) and thiourea (4.0 g, 552 mmol) in EtOH (200 mL) was added CuOAc (0.3 g, 2.62 mmol), then stirred at room temperature for 10 h. The mixture was concentrated to give the crude product (16 g). The crude product was basified with NaHC03 to pH=8, then extracted with EtOAc (200 mL x 3). The organic layer was washed with H20 (100 mL), brine (100 mL), and then dried over anhydrous Na2S04, and then concentrated to give the product Compound AE (8.0 g) as a yellow solid.
To a mixture of Compound AE (15g, 87 mmol) in DCM (200 mL) was added (Boc)20
(28.48 g, 130.65 mmol) and DMAP (0.37 g). The mixture was stirred at room temperature overnight. After diluted with EA (200 mL), the mixture was washed with water, aq. NaHC03 (100 mL). The organic layer was dried and then concentrated to afford light yellow oil. The residue was purified by column chromatography in silica gel (PE:EA=10: 1) to give Compound AF (20.0 g ) as light yellow oil.
To a mixture of Compound AF (18 g, 66 mmol) in THF (300 mL) was added LAH (3.0 g, 79 mmol) at -78 °C. The mixture was kept for 2 hrs. After the addition of aq. NaOH (3.0 mL 15% in water), the mixture was diluted with EA (100 mL), and then filtrated. The filtrate was concentrated to afford light yellow oil. The residue was purified by column chromatography in silica gel (PE: EA =30: 1) to give Compound AG(14.0 g) as light yellow oil.
To a mixture of Compound AG (14 g, 60.79 mmol) in DCM (200 mL) was added Dess- Martin (30.9 g, 72.95 mmol) at rt. The mixture was kept for 2 hrs. Na2 S203 was added then the mixture was washed with water, aq. NaHC03. The organic layer was dried and concentrated to afford light yellow oil. The residue was purified by column chromatography in silica gel (PE: EA =10: 1) to give Compound AH (7.0 g) as light yellow oil.
To a solution of Compound AH (7.0 g, 31 mmol) in DCM (200 mL) and EtOH (100 mL) was added DAST (7.4 g, 46.05 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was poured into water and diluted with DCM (200 mL), and then washed with water (100 mL), sat. NaHC03 (100 mL). The organic layer was dried and concentrated to afford light yellow oil. The residue was purified by column chromatography in silica gel (PE: EA =30: 1) to give the Compound AI (5.8 g) as a light yellow solid.
A solution of Compound AI (6.0 g, 24 mmol) in HC1/ EtOAc (60 mL) was stirred at room temperature overnight. After removal of solvent, aq. sat NaHC03 (100 mL) was added and the mixture was diluted with DCM (100 mL), then washed with water (50mL), brine (50mL). The organic layer was dried and concentrated to afford light yellow oil. The residue was purified by column chromatography in silica gel (PE: EA =30: 1) to give Compound AJ (3.0 g) as light yellow oil.
To a mixture of CuCN (3.6 g, 40 mmol), NaCN (1.7 g, 35 mmol) and t-BuONO (4.1 g, 40 mmol) in MeCN (100 mL) was added Compound A J (3.0 g, 20 mmol) at 0°C. The reaction mixture was stirred at room temperature overnight. After it was diluted with petroleum ether (100 mL), the mixture was washed with water, aq. NaHC03 (100 mL), and the organic layer was dried and concentrated to afford light yellow oil (1.0 g). The crude AK was used in next step directly without further purification.
To a flask charged with 60 mL MeOH was added Na (16 mg, 0.69 mmol, 0.11 eq) at rt. Then the above Compound AK (1.0 g, 6.3 mmol) was added into the resulting NaOMe solution. The reaction was stirred at rt for 24 hrs under N2. Then NH4C1 (230 mg, 4.3 mmol) was added. The reaction was stirred at 30 °C for 24 hrs. The reaction was concentrated and then 1.0 mL of isoproapnol and 10 mL of t-butylmethylether were added with stirring. The precipitate was collected and dried under vacuum to give the desired product AL (490 mg) as a white solid. Example 89:
(R)-6-((S)-2-Carboxy-4,4-difluoro-3,3-dimethyl-pyrrolidin-l-ylmethyl)-4-(2-chloro-4- fluoro-phenyl)-2-thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester
The title compound was prepared in analogy to Example 2 with Procedure B shown in Scheme 5 by using (25)-4,4-difluoro-3,3-dimethyl-pyrrolidine-2-carboxylic acid (CAS:
1408278-20-5, for synthesis, see: Hu, Shanghui; Martinez, Carlos A.; Kline, Billie; Yazbeck, Daniel; Tao, Junhua; Kucera, David J. Organic Process Research & Development, 2006, 10, 650-654) instead of (5)-4,4-difluoro-pyrrolidine-2-carboxylic acid.
Example 90:
(3R)-4-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-l,4- dihydropyrimidin-6-yl] methyl] -2,2-dimethyl-thiomorpholine-3-carboxylic acid
The title compound was prepared in analogy to Example 2 with Procedure B shown in Scheme 5 by using (3i?)-2,2-dimethylthiomorpholine-3-carboxylic acid (WuXi AppTec (Wuhan) Co., Ltd, CAS:774243-35-5) instead of (5)-4,4-difluoro-pyrrolidine-2-carboxylic acid.
Example 91:
(3S)-4-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-l,4- dihydropyrimidin-6-yl] methyl] thiomorpholine-3-carboxylic acid
The title compound was prepared in analogy to Example 14 shown in Scheme 6 by using thiomorpholine-3-carboxylic acid (PharmaBlock (Nanjing) R & D Co., Ltd. CAS:20960-92-3) instead of 5,5-difluoro-piperidine-3-carboxylic acid.
Example 92:
(5)-4-[(R)-6-(2-Chloro-4-fluoro-phenyl)-2-(l,4-dimethyl-lH-imidazol-2-yl)-5- methoxycarbonyl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid
The title compound was prepared in analogy to Example 2 with Procedure B shown in Scheme 5 by using l ,4-dimethyl-lH-imidazole-2-carbonitrile and (5)-morpholine-3-carboxylic acid instead of thiazole-2-carbonitrile and (5)-4,4-difluoro-pyrrolidine-2-carboxylic acid. The stereo chemistry of Example 92 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 93:
(S)-4-[(R)-6-(4-Bromo-2-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid
The title compound was prepared in analogy to Example 2 with Procedure B shown in Scheme 5 by using 4-bromo-2-fluoro-benzaldehyde, ethyl acetoacetate and (5)-morpholine-3- carboxylic acid instead of 2-chloro-4-fluoro-benzaldehyde, methyl acetoacetate, and (S)-4,4- difluoro-pyrrolidine-2-carboxylic acid. The stereochemistry of Example 93 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 94:
(S)-4-[(R)-6-(4-Bromo-2-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6- dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid
The title compound was prepared in analogy to Example 2 with Procedure B shown in Scheme 5 by using 4-bromo-2-fluoro-benzaldehyde and (5)-morpholine-3-carboxylic acid instead of 2-chloro-4-fluoro-benzaldehyde and (5)-4,4-difluoro-pyrrolidine-2-carboxylic acid. The stereochemistry of Example 94 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 95:
(S)-4-[(R)-6-(2-Chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-(4-trifluoromethyl- thiazol-2-yl)-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid
The title compound was prepared in analogy to Example 2 with Procedure B shown in Scheme 5 by using 4-trifluoromethyl-thiazole-2-carboxamidine (Compound U) and (S)- morpholine-3-carboxylic acid instead of thiazole-2-carboxamidine and (5)-4,4-difluoro- pyrrolidine-2-carboxylic acid. The stereochemistry of Example 95 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 96:
(S)-4-[(S)-6-(3,4-Difluoro-2-methyl-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6- dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid The title compound was prepared in analogy to Example 2 with Procedure B shown in Scheme 5 by using 3,4-difluoro-2-methyl-benzaldehyde, ethyl acetoacetate and (5)-morpholine- 3-carboxylic acid instead of 2-chloro-4-fluoro-benzaldehyde, methyl acetoacetate, and (S)-4,4- difluoro-pyrrolidine-2-carboxylic acid. The stereochemistry of Example 96 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 97:
(S)-4-[(R)-6-(2-Chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-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 2 with Procedure B shown in
Scheme 5 by using 2-chloro-3-fluoro-benzaldehyde, ethyl acetoacetate, 1-methyl-lH-imidazole- 2-carbonitrile and (5)-morpholine-3-carboxylic acid instead of 2-chloro-4-fluoro-benzaldehyde, methyl acetoacetate, thiazole-2-carbonitrile and (5)-4,4-difluoro-pyrrolidine-2-carboxylic acid. The stereochemistry of Example 97 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 98:
(S)-4-[(R)-6-(2-Chloro-4-fluoro-phenyl)-5-isopropoxycarbonyl-2-thiazol-2-yl-3,6- dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid
The title compound was prepared in analogy to Example 2 with Procedure A shown in
Scheme 4 by using 3-oxo-butyric acid isopropyl ester instead of methyl acetoacetate and (S)- morpholine-3-carboxylic acid instead of (5)-4,4-difluoro-pyrrolidine-2-carboxylic acid. The stereochemistry of Example 98 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 99:
(S)-4-[6-(2-Chloro-4-fluoro-phenyl)-5-propoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid
The title compound was prepared in analogy to Example 1 with Procedure A shown in Scheme 4 by using 3-oxo-butyric acid propyl ester instead of methyl acetoacetate and (S)- morpholine-3-carboxylic acid instead of (5)-4,4-difluoro-pyrrolidine-2-carboxylic acid.
Example 100: (S)-4-[(S)-6-(3,4-Difluoro-phenyl)-5-isopropoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid
The title compound was prepared in analogy to Example 2 with Procedure A shown in Scheme 4 by using 3,4-difluoro-benzaldehyde instead of 2-chloro-4-fluoro-benzaldehyde, 3-oxo- butyric acid isopropyl ester instead of methyl acetoacetate and (5)-morpholine-3-carboxylic acid instead of (5)-4,4-difluoro-pyrrolidine-2-carboxylic acid. The stereochemistry of Example 100 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 101:
(S)-4-[(R)-6-(2-Chloro-3-fluoro-phenyl)-5-isopropoxycarbonyl-2-thiazol-2-yl-3,6- dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid
The title compound was prepared in analogy to Example 2 with Procedure A shown in Scheme 4 by using 2-chloro-3-fluoro-benzaldehyde instead of 2-chloro-4-fluoro-benzaldehyde, 3-oxo-butyric acid isopropyl ester instead of methyl acetoacetate and (5)-morpholine-3- carboxylic acid instead of (5)-4,4-difluoro-pyrrolidine-2-carboxylic acid. The stereochemistry of Example 101 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 102:
(R)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2-chloro-4-fluoro- phenyl)-2-(5-methyl-oxazol-4-yl)-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester
The title compound was prepared in analogy to Example 2 with Procedure A shown in Scheme 4 by using 5-methyl-oxazole-4-carboxamidine (Compound AB) instead of thiazole-2- carboxamidine. The stereochemistry of Example 102 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 103:
(S)-4-[(R)-6-(2-Chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-(5-methyl-oxazol-4-yl)- 3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid
The title compound was prepared in analogy to Example 2 with Procedure A shown in
Scheme 4 by using 5-methyloxazole-4-carboxamidine (Compound AB) instead of thiazole-2- carboxamidine, 2-chloro-3-fluorobenzaldehyde instead of 2-chloro-4-fluorobenzaldehyde and (35)-morpholine-3-carboxylic acid instead of (25)-4,4-difluoropyrrolidine-2-carboxylic acid. The stereochemistry of Example 103 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 104:
(2R,3S)-4-[(R)-6-(2-Chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6- dihydro-pyrimidin-4- lmethyl]-2-methyl-morpholine-3-carbox lic acid
Figure imgf000133_0001
MI Example 104
Scheme 8
The title compounds was prepared from (2i?,3S)-4-[(i?)-6-(2-chloro-4-fluoro-phenyl)-5- methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-2-methyl-morpholine-3- carboxylic acid ethyl ester (ester Compound AN ) through saponification reaction and
preparative HPLC separation.
A mixture of (2i?,35)-4-[(i?)-6-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2- yl-3,6-dihydro-pyrimidin-4-ylmethyl]-2-methyl-morpholine-3-carboxylic acid ethyl ester
(Compound AN) (lOOmg, 0.19mmol), lithium hydroxide monohydrate (78.4 mg, 1.9mmol), water (0.5 mL) in methanol (2 mL) was stirred for 12 hours at room temperature. Then the mixture was treated with hydrochloric acid (10%) to adjust pH ~4. After filtration, the filtrate was purified by preparative HPLC separation to afford Example 104 as yellow solid. Yield: 60%.
Preparation of (2R,3S)-4-[(R)-6-(2-Chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2- thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-2-methyl-morpholine-3-carboxylic acid ethyl ester (ester Compound AN )
Compound AN was prepared in analogy to Example 2 with Procedure B shown in Scheme 5 by using (2i?,35)-2-methyl-morpholine-3-carboxylic acid ethyl ester (for its synthesis, see: WO201 1025889) instead of (25)-4,4-difluoropyrrolidine-2-carboxylic acid.
Example 105: (S)-4-[5-tert-Butoxycarbonyl-6-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid
The title compound was prepared in analogy to Example 1 with Procedure A shown in Scheme 4 by using 3-oxo-butyric acid tert-butyl ester instead of methyl acetoacetate and (35)- morpholine-3-carboxylic acid instead of (25)-4,4-difluoropyrrolidine-2-carboxylic acid.
Example 106:
(2R,3S)-4-[(R)-6-(2-Bromo-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6- dihydro-pyrimidin-4-ylmethyl]-2-methyl-morpholine-3-carboxylic acid
The title compound was prepared in analogy to Example 104 with the same procedure shown in Scheme8 by using 2-bromo-4-fluoro-benzaldehyde instead of 2-chloro-4-fluoro- benzaldehyde.
Example 107 and 108:
(R)-4-(2-Bromo-4-fluoro-phenyl)-6-((S)-2-carboxy-5,5-difluoro-piperidin-l-ylmethyl)- 2-thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid ethyl ester (Example 107) and (R)- 4-(2-Bromo-4-fluoro-phenyl)-6-((R)-2-carboxy-5,5-difluoro-piperidin-l-ylmethyl)-2-thiazol- 2-yl-l 4-dihydro-pyrimidine-5-carboxylic acid ethyl ester (Example 108)
Figure imgf000134_0001
Example 107 Example 108
The title compounds was prepared in analogy to Example 14 with Procedure C shown in Scheme 6 by using 5,5-difluoro-piperidine-2-carboxylic acid (Nanjing Pharmablock Co. Ltd. CAS : 1255663-89-8), 2-bromo-4-fluoro-benzaldehyde and ethyl acetoacetate instead of 5,5- difluoro-piperidine-3-carboxylic acid, 2-chloro-4-fluoro-benzaldehyde and methyl acetoacetate.
Example 109 and 110:
(R)-6-((S)-2-Carboxy-5,5-difluoro-piperidin-l-ylmethyl)-4-(2-chloro-3-fluoro-phenyl)- 2-thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester (Example 109) and (R)-6-((R)-2-Carboxy-5,5-difluoro-piperidin-l-ylmethyl)-4-(2-chloro-3-fluoro-phenyl)-2- thiazol-2- l-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester Example 110)
Figure imgf000135_0001
Example 109 Example 110
The title compounds was prepared in analogy to Example 14 with Procedure C shown in Scheme 6 by using 5,5-difluoro-piperidine-2-carboxylic acid (Nanjing Pharmablock Co. Ltd. CAS : 1255663-89-8) and 2-chloro-3-fluoro-benzaldehyde instead of 5,5-difluoro-piperidine-3- carboxylic acid and 2-chloro-4-fluoro-benzaldehyde.
Example 111:
(R)-6-((S)-2-Carboxy-5,5-difluoro-piperidin-l-ylmethyl)-4-(2-chloro-phenyl)-2- thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid ethyl ester
The title compound was prepared in analogy to Example 14 with Procedure C shown in Scheme 6 by using 5,5-difluoro-piperidine-2-carboxylic acid (Nanjing Pharmablock Co. Ltd. CAS : 1255663-89-8), 2-chloro-benzaldehyde and ethyl acetoacetate instead of 5,5-difluoro- piperidine-3-carboxylic acid, 2-chloro-4-fluoro-benzaldehyde and methyl acetoacetate.
Example 112:
(2R,35)-4-[(5)-6-(3,4-Difluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl]-2-methyl-morpholine-3-carboxylic acid
The title compound was prepared in analogy to Example 104 with the procedure shown in
Scheme 8 by using 3,4-difluoro-benzaldehyde and ethyl acetoacetate instead of 2-chloro-4- fluoro-benzaldehyde and methyl acetoacetate.
Example 113:
(2R,35)-4-[(S)-6-(3,4-Difluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl]-2-methyl-morpholine-3-carboxylic acid
The title compound was prepared in analogy to Example 104 with the procedure shown in Scheme 8 by using 3,4-difluoro-benzaldehyde instead of 2-chloro-4-fluoro-benzaldehyde Example 114:
(2R,3S)-4-[(R)-5-Methoxycarbonyl-2-thiazol-2-yl-6-(2,3,4-trifluoro-phenyl)-3,6- dihydro-pyrimidin-4-ylmethyl]-2-methyl-morpholine-3-carboxylic acid
The title compound was prepared in analogy to Example 104 with the procedure shown in
Scheme 8 by using 2,3,4-trifluoro-benzaldehyde instead of 2-chloro-4-fluoro-benzaldehyde.
Example 115:
(2R,35)-4-[(R)-6-(2-Chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6- dihydro-pyrimidin-4-ylmethyl]-2-methyl-morpholine-3-carboxylic acid
The title compound was prepared in analogy to Example 104 with the procedure shown in Scheme 8 by using 2-chloro-3-fluoro-benzaldehyde instead of 2-chloro-4-fluoro-benzaldehyde.
Example 116:
(2R,3S)-4-[(R)-6-(2-Bromo-4-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6- dihydro-pyrimidin-4-ylmethyl]-2-methyl-morpholine-3-carboxylic acid
The title compound was prepared in analogy to Example 104 with the procedure shown in Scheme 8 by using 2-bromo-4-fluoro-benzaldehyde and ethyl acetoacetate instead of 2-chloro-4- fluoro-benzaldehyde and methyl acetoacetate.
Example 117:
(2R,3S)-4-[(R)-6-(2-Chloro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl]-2-methyl-morpholine-3-carboxylic acid
The title compound was prepared in analogy to Example 104 with the procedure shown in Scheme 8 by using 2-chloro-benzaldehyde and ethyl acetoacetate instead of 2-chloro-4-fluoro- benzaldehyde and methyl acetoacetate.
Example 118:
(2R,35)-4-[(R)-6-(2-Chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6- dihydro-pyrimidin-4-ylmethyl]-2-methyl-morpholine-3-carboxylic acid
The title compound was prepared in analogy to Example 104 with the procedure shown in Scheme 8 by using 2-chloro-3-fluoro-benzaldehyde and ethyl acetoacetate instead of 2-chloro-4- fluoro-benzaldehyde and methyl acetoacetate. Example 119:
(2R,3S)-4-[(R)-6-(2-Bromo-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl]-2-methyl-morpholine-3-carboxylic acid
The title compound was prepared in analogy to Example 104 with the procedure shown in
Scheme 8 by using 2-bromo-benzaldehyde instead of 2-chloro-4-fluoro-benzaldehyde.
Example 120:
(2R,35)-4-[(R)-6-(2-Chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6- dihydro-pyrimidin-4-ylmethyl]-2-isopropyl-morpholine-3-carboxylic acid
The title compound was prepared in analogy to Example 104 with the procedure shown in Scheme 8 by using (2i?,35)-2-isopropyl-morpholine-3-carboxylic acid methyl ester (Compound AO) instead of (2R,3S)-2-methyl-morpholine-3-carboxylic acid ethyl ester.
Preparation of (2R,3S)-2-Isopropyl-morpholine-3-carboxylic acid methyl ester (Com ound AQ):
Figure imgf000137_0001
AO
AP AQ
Preparation of (2S,3R)-3-hydroxy-4-methyl-2-(toluene-4-sulfonylamino)-pentanoic acid methyl ester (Compound AO):
A mixture of (25',3i?)-2-amino-3-hydroxy-4-methyl-pentanoic acid methyl ester (0.50 g, 3.4 mmol) and triethylamine (0.69 g, 6.8 mmol) in dichloromethane (10 mL) was added 4- methyl-benzenesulfonyl chloride (0.7 lg, 3.7 mmol) at 0 °C. After stirring for 2 hours at room temperature, the mixture was washed with water and the organic layer was separated and then dried over sodium sulfate. After removal of solvent, the residue was used in next step without purification. MS: calc'd (MH+) 316, measured (MH+) 316.
Preparation of (2R,3S)-2-isopropyl-4-(toluene-4-sulfonyl)-morpholine-3-carboxylic acid methyl ester (Compound AP):
A mixture of (25',3i?)-3-hydroxy-4-methyl-2-(toluene-4-sulfonylamino)-pentanoic acid methyl ester (0.4 g, 1.27 mmol) and diphenylvinylsulfonium triflate (0.5g, 1.4 mmol) in dichloromethane (10 mL) was added triethylamine dropwise at 0 °C. After stirring for 12 hours, the mixture was diluted with water, and then extracted with ethyl acetate, then dried over sodium sulfate. After removal of solvent, the residue was purified by flash chromatopraphy (eluented with ethyl acetate/hexane = 1 :4) to afford the product as a white solid. MS: calc'd (MH+) 342, measured (MH+) 342.
Preparation of (2R,3S)-2-isopropyl-morpholine-3-carboxylic acid methyl
ester(Compound AQ):
A mixture of (2i?,35)-2-isopropyl-4-(toluene-4-sulfonyl)-morpholine-3-carboxylic acid methyl ester (0.20 g, 0.59 mmol) and magnesium powder (70 mg, 2.9 mmol) in anhydrous methanol (5 mL) was stirred for 3 hours at 60 °C. The solid was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue as crude product was used in next step without purification. MS: calc'd (MH+) 188, measured (MH+) 188.
Example 121:
(5)-4-(((R)-6-(2-chloro-4-fluorophenyl)-5-(methoxycarbonyl)-2-(thiazol-2-yl)-3,6- dihydropyrimidin-4-yl)methyl)-3-methylmorpholine-3-carboxylic acid
The title compound was prepared in analogy to Example 78 with the procedure by using 2- chloro-4-fluoro-benzaldehyde instead of 2-chloro,3,4-dofluoro-benzaldehyde.
Example 122:
(5)-4-(((R)-6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6- dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid
The tit le compound was prepared in analogy to Example 2 with Procedure B shown in Scheme 5 by using 2 - bro mo -4- fl uo ro -benza 1 d e h y d e instead of 2-chioro-4-fluoro-benzaidehyde, using ethyl acetoacetate instead of methyl acetoacetate and using ( 5)- mo rpholi n e-3 -ca bo y 1 i c acid instead of (5)-4,4-difluoro-pyrrolidine-2-carboxyiic acid. The stereochemistry of Example 122 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 123:
(35)-4-[[(4S)-4-(4-Bromophenyl)-5-ethoxycarbonyl-2-(l,3-thiazol-2-yl)-l,4- dihydropyrimidin-6-yl] methyl] morpholine-3-carboxylic acid
The tit le compound was prepared in analogy to Example 2 with Procedure A shown in Scheme 4 by using 4-bro mo - be nza I d e h y d e instead of 2-chioro-4-fiuoro-benzaldehyde, using ethyl acetoacetate instead of methyl acetoacetate and using (.S")-morpho!ine-3-carboxy!ie acid instead of (5)-4,4-difluoro-pyrroiidine-2-carboxyiic acid. The stereochemistry of Example 123 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 124:
(35)-4-[[(4S)-4-(3-Bromo-4-chlorophenyl)-5-ethoxycarbonyl-2-(l,3-thiazol-2-yl)-l,4- dihydropyrimidin-6-yl] methyl] morpholine-3-carboxylic acid
The tit le compound was prepared in analogy to Example 2 with Procedure A shown in Scheme 4 by using 3-bromo-4-chloro-benzaidehyde instead of 2-chloro-4-fluoro-benzaldehyde, using ethyl acetoacetate instead of methyl acetoacetate and using (5)-morpholine-3-carboxylic acid instead of (jS)-4,4-difluoro-pyrrolidine-2-carboxylic acid. The stereochemistry of Example 124 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 125:
(3S)-4-[[(45)-4-(3-Chloro-5-fluorophenyl)-5-ethoxycarbonyl-2-(l,3-thiazol-2-yl)-l,4- dihydropyrimidin-6-yl] methyl] morpholine-3-carboxylic acid
The tit le compound was prepared in analogy to Example 2 with Procedure A shown in Scheme 4 by using 3 -ch lo ro-5 - fl uo o-benza Id ehyd e instead of 2-chloro-4-fluoro-benzaldehyde, using ethyl acetoacetate instead of methyl acetoacetate and using (S)-morpholine-3-carboxyiic acid instead of (S)-4,4-difluoro-pyrrolidine-2-carboxylic acid. The stereochemistry of Example 125 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 126:
(35)-4-[[(4S)-4-(4-chlorophenyl)-5-ethoxycarbonyl-2-(l,3-thiazol-2-yl)-l,4- dihydropyrimidin-6-yl] methyl] morpholine-3-carboxylic acid
The title compound was prepared in analogy to Example 2 with Procedure A shown in Scheme 4 by using 4-chloro-benzaldehyde instead of 2-ch!oro-4-fluoro-benzaidehyde, using ethyl acetoacetate instead of methy l acetoacetate and using (S)-morpholine-3-carboxylic acid instead of (5)-4,4-difluoro-pyrrolidine-2-carboxylic acid. The stereochemistry of Example 126 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 127:
(5)-4-(((R)-6-(2-bromophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6- dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid Thc title compound was prepared in analogy to Example 2 with Procedure B shown in Scheme 5 by using 2-bromo-benzaidehyde instead of 2-ch!oro-4-fluoro-benzaldehyde, using ethyl acetoacetate instead of methyl acetoacetate and using (S)-morpho I ine-3-carboxy I ic acid instead of (iS)-4,4-difluoro-pyrrolidine-2-carboxylic acid. The stereochemistry of Example 127 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 128:
(3S)-4-[[(4R)-4-(2-bromo-3,4-difluorophenyl)-5-ethoxycarbonyl-2-(l,3-thiazol-2-yl)- l,4-dihydropyrimidin-6-yl] methyl] morpholine-3-carboxylic acid
The tit le compound was prepared in analogy to Example 2 with Procedure B shown in
Scheme 5 by using 2-bro mo-3 ,4-d i fiuoro-benza ldehyd (Compound AR) instead of 2-chioro-4- fluoro-benzaldehyde, using ethyl acetoacetate instead of methyl acetoacetate and using (S)- mo r ho 1 i n e - 3 - c a r bo y 1 i c acid instead of (5)-4,4-difluoro-pyrroiidine-2-carboxyiic acid. The stereochemistry of Example 128 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Preparation of 2-bromo-3,4-difluoro-benzaldeh d (Compound AS):
Figure imgf000140_0001
AR AS
2-Bromo-3,4-difluorobenzoic acid (3.7 g, 16 mmol, Eq: 1.00) was dissolved in anhydrous THF (20 ml) and the solution was cooled to 0 °C. BH3.THF (62.6 ml, 62.6 mmol, Eq: 4) was added dropwise. The resulting solution was allowed to warm up to room temperature and stirred overnight. The solution was cooled with an ice bath, and then 10% aqueous Na2C03 (30mL) was added slowly. The suspension was concentrated in vacuo to give a white solid. The residue was acidified with 3M aqueous HCl solution (100 mL), diluted with dichloromethane (50 mL), and the mixture was filtered through Celite. The organic layers was separated and dried over sodium sulfate, and then followed by a filtration. Resulting filtrate was concentrated in vacuum to give an off-white solid AR (2.5 g). 1H NMR (DMSO) δ 7.46-7.53 (m, 1H), 7.35-7.41 (m, 1H), 4.51 (s, 2H), 4.44-4.58 (m, 2H)
(2-Bromo-3,4-difluorophenyl)methanol (Compound AR) (2.55 g, 1 1.4 mmol, Eq: 1.00) was dissolved in dichloromethane (15ml). Dess-Martin periodinane (4.85 g, 1 1.4 mmol, Eq: 1.00) was added. The reaction mixture was stirred for 2 hrs at room temperature. The reaction mixture was filtered over a plug of celite and washed washed with DCM (30ml). Filtrate was concentrated to give a semi solid. Crude product was dissolved in EtOAc/DCM and loaded into a silica gel column (4g). Silica gel column was flushed with EtOAc to give a light yellow solid (3g). 1H NMR (DMSO) δ 10.13 (s, 1H), 7.74-7.82 (m, 1H), 7.70 (ddd, J = 9.5, 7.3, 0.8 Hz, 1H).
Example 129:
(35)-4-[[(4R)-5-ethoxycarbonyl-4-(2-iodophenyl)-2-(l,3-thiazol-2-yl)-l,4- dihydropyrimidin-6-yl] methyl] morpholine-3-carboxylic acid
The title compound was prepared in analogy to Example 2 with Procedure A shown in Scheme 4 by using 2-iodo-benzaldeliyde instead of 2-chioro-4-fluoro-benzaldehyde, using ethyl acetoacetatc instead of methyl acetoacetatc and using (5)-morpholine-3-carboxyiic acid instead of (S)-4,4-d i fi uoro-pyrro lid ine-2-carboxy 1 ic acid. The stereochemistry of Example 129 was determined by comparing its 1H NMR data and HPLC retention time with Example 2. Example 130:
(25)- 1- [ [(45)-4-(4-bromophenyl)-5-ethoxycarbonyl-2-(l ,3-thiazol-2-yl)- 1 ,4- dihydropyrimidin-6-yl] methyl] -4,4-difluoropyrrolidine-2-carboxylic acid
The tit le compound was prepared in analogy to Example 2 with Procedure A shown in Scheme 4 by using 4-bro mo-benza !dchyde instead of 2-chioro-4-fluoro-benzaldehyde, using ethyl acetoacetatc instead of methyl acetoacetatc. The stereochemistry of Example 130 was determined by comparing its 1H NMR data and HPLC retention time with Example 2.
Example 131: HBV inhibition assays
Cells and culture conditions:
HepG2.2.15 and HepDE19 are stably-transfected cell lines containing the HBV genome.
Both cell lines are derived from the hepatoblastoma cell line Hep G2 (American Type Culture Collection, ATCC® HB-8065™) by the published procedures described in references: MA Series et al. Proc. Natl. Acad. Sci. USA 1987, 84, 1005-1009 and H Guo et al. Journal of Virology 2007, 81, 12472-12484, respectively. Both cell lines were maintained in Dulbecco's modified Eagle's medium (DMEM)-F12 medium supplemented with 10% fetal bovine serum, 100 U/mL penicillin, 100 μg/mL streptomycin, and 0.5 mg/mL of G418.
While HepG2.2.15 cells constitutively support HBV replication and production of virus particles, HepDE19 cells are inducible by tetracycline. Addition of ^g/mL tetracycline in culture medium suppresses HBV replication in HepDE19 cells, whereas switching to tetracycline-free medium resumes this process.
Anti-HBV activity in vitro:
HepG2.2.15 cells were seeded into 96-well plates (3 x 104 cells in 100 μΐ media per well) and incubated overnight at 37 °C. The test compounds were serially half-log diluted in DMSO, then diluted 100 times in culture media. 100 μΐ, diluted compounds were added into the plates to reach 0.5% final concentration of DMSO in every well. Five days after compound treatment, culture supernatant was collected for further analysis.
For quantitative PCR detection of extracellular HBV DNA, 100 μΐ^ culture supernatant was collected and processed in MagNA Pure 96 Nucleic Acid Purification System (Roche
Applied Science) for viral DNA extraction. The extracted samples were subjected to HBV DNA quantification by qPCR. The effective compound concentration at which HBV replication is inhibited by 50% (EC50) was determined.
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 assays as described herein and found to have EC50 <0.10 μΜ in HepG2.2.15 assay. Particular compounds of formula I were found to have EC50 <0.02 μΜ in HepG2.2.15 assay (See Table 3).
Cytotoxicity and selectivity index:
In a cell culture model, apparent antiviral activity of a compound can be the result of host cell death after exposure to the compound. To determine whether the anti-HBV effect of a test compound is due to cytotoxicity, HepDE19 cells were seeded into 96-well plates (5 x 103 cells per well) and treated with compounds as described above for EC50 determination. Five days after treatment, cell viability was measured by addition of 20 μΐ^ of CCK-8 reagent. Two hours after incubation at 37°C, the absorbance at wavelengths of 450 nm and 630 nm (OD450 and OD63o) was recorded by a plate reader. The concentration results in the death of 50% of the host cells (CC50) of each compound was determined (See Table 6).
The relative effectiveness of the compound in inhibiting viral replication compared to inducing cell death is defined as the selectivity index (CC50 value/ECso value). It is desirable to have a high selectivity index giving maximum antiviral activity with minimal cell toxicity. Based on CC50 and EC50 data, selectivity indexes were determined as shown in Table 7.
Based on CC50 and EC50 data, selectivity indexes were determined as shown in Table 7. Example 132: mouse SDPK description: The single dose PK in male ICR mouse was performed to assess their pharmacokinetic properties. Two groups of animals were dosed via either bolus intravenous (IV) or oral gavage (PO) of the respective compound. The animals for oral administration were fasted overnight prior to dosing and food was resumed 4 hours postdose. Blood samples (approximately 400 μί) were collected via cardiac puncture after euthanasia by carbon dioxide inhalation at 2 mins, 5 mins, 15 mins, 30 mins, 1 h, 2 firs, 4 firs, 6 firs, 8 firs, and 24 firs postdose for IV group, and at 5 mins, 15 mins, 30 mins, 1 h, 2 firs, 4 firs, 6 firs, 8 firs, and 24 firs postdose for PO group. Blood samples were placed into tubes containing sodium heparin and centrifuged at 8000 rpm for 6 minutes at 4°C to separate plasma from the samples.
Following centrifugation, the resulting plasma was transferred to clean tubes for
bioanalysis on LC/MS/MS. The pharmacokinetic parameters were calculated using non- compartmental module of WinNonlin® Professional 5.2.
Results of SDPK are given in Table 4. Example 1 3: description of metabolic stability study: Human Microsomes were pre incubated with test compound for 10 min at 37°C in 100 mM phosphate buffer, pH 7.4. The reactions were initiated by adding ADPH or NADPH regenerating system to give a final incubation volume of 400 iiL. For NADPH system, the final incubations contained 1 μ,Μ test compound, 0.5 mg/mL liver microsomal protein, 1 mM NADPH in 100 mM phosphate buffer, pH 7.4. For the ADPH regenerating system, the final incubations contained 1 ιιΜ test compound, 0.5 mg/mL liver microsomal protein, 3 mM glucose 6-phosphate, 1 mM NADP, 3 mM MgCL and 0.05 mg/mL glucose 6-phosphate dehydrogenase in 100 mM phosphate buffer, pH 7.4. After incubat ion times of 0, 3, 6, 9. 1 5 and 30 minutes at 37°C, 50 μΐ. samples was removed and transferred to 150 μΐ, methanol solution which was maintained at 4 °C containing 2μ tolbutamide ( internal standard) to terminating the reac t io n . Fo I lo vv i n g precipitation and centrifugation. the amount of compound remaining in the samples were determined by LC- MS 'MS. Controls of no NADPH o NADPH regenerating system at zero and 30min were also prepared and analyzed.
Results of metabolic stability study in human microsome are given in Table 5.
Example 134: LYSA description: Samples are prepared in duplicate from 10 mM DMSO stock solutions. After evaporation of DMSO with a centrifugal vacuum evaporator, the residue is solved in 0.05 M phosphate buffer (pH 6.5), stirred for one hour and shaked for two hours. After one night, the solutions is filtered using a microtiter filter plate and the filtrate and its 1/10 dilution are then analyzed by direct UV measurement or by HPLC-UV. In addition a four-point calibration curve is prepared from the 10 mM stock solutions and used for the solubility determination of the compounds. The results are in μg/mL. In case the percentage of sample measured in solution after evaporation divided by the calculated maximum of sample amount is bigger than 80% the solubility is reported as bigger than this value.
Results of Lysa are given in Table 6.
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
Micro crystalline cellulose 155 mg
Corn starch 25 mg
Talc 25 mg
Hydro xypropylmethylcellulose 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
1. Compounds of formula (I)
Figure imgf000145_0001
wherein
R1 is Ci_6alkyl or trifluoromethyl-CxH2x-, wherein x is 1-6;
One of R2 and R3 is phenyl, which is once or twice or three times substituted by Ci_6alkyl, cyano or halogen; and the other one is hydrogen or deuterium;
R4 is phenyl, thiazolyl, oxazolyl, imidazolyl, thienyl or pyridinyl, which is unsubstituted or substituted by Ci_6alkyl, Ci_6alkylsulfanyl, halogen or cycloalkyl, where said Ci_6alkyl can be further o tionally substituted with halogen;
Figure imgf000145_0002
, which is unsubstituted or substituted by groups selected from C^aUcyl, deuterium and halogen;
or pharmaceutically acceptable salts, or enantiomers, or diastereomers thereof.
2. A compound according to claim 1 , wherein
R1 is methyl, ethyl, propyl, isopropyl, tert-butyl or trifluoromethylmethyl; One of R2 and R3 is phenyl, which is once or twice or three times substituted by fluoro, chloro, bromo, iodo, methyl or cyano; and the other one is hydrogen or deuterium;
R4 is phenyl, thiazolyl, oxazolyl, imidazolyl, thienyl or pyridinyl, which is unsubstituted or substituted by methyl, isopropyl, tert-butyl, bifluoromethyl, trifluoromethyl, cyclopropyl, meth lsulfanyl, fluoro or chloro;
Figure imgf000146_0001
, which is unsubstituted or substituted by groups selected from methyl, isopropyl, deuterium and fluoro;
or pharmaceutically acceptable salts, or enantiomers, or diastereomers thereof.
3. A compound according to claim 1 , wherein
R1 is Ci_6alkyl or trifluoromethyl-CxH2x-, wherein x is 1-6;
One of R2 and R3 is phenyl, which is once or twice or three times substituted by Ci_6alkyl, cyano or halogen; and the other one is hydrogen or deuterium;
R4 is phenyl, thiazolyl, oxazolyl, imidazolyl, thienyl or pyridinyl, which is unsubstituted or substituted by Ci_6alkyl, Ci_6alkylsulfanyl, halogen or cycloalkyl, where said Ci_6alkyl can be further optionally substituted with halogen;
Figure imgf000146_0002
A is T or which is unsubstituted or substituted by groups selected from Ci-ealkyl, deuterium and halogen;
or pharmaceutically acceptable salts, or enantiomers, or diastereomers thereof.
4. A compound according to any one of claims 1 to 3, wherein
R1 is methyl, ethyl, propyl, isopropyl or trif uoromethylmethyl; One of R2 and R3 is phenyl, which is once or twice or three times substituted by fluoro, chloro, bromo, iodo, methyl or cyano; and the other one is hydrogen or deuterium;
R4 is phenyl, thiazolyl, oxazolyl, imidazolyl, thienyl or pyridinyl, which is unsubstituted or substituted b methyl, isopropyl, trifluoromethyl, cyclopropyl, methylsulfanyl, fluoro or chloro;
Figure imgf000147_0001
, which is unsubstituted or substituted by groups selected from methyl, isopropyl, deuterium and fluoro; or pharmaceutically acceptable salts, or enantiomers, or diastereomers thereof.
5. A compound according to claim 1 or 3 or pharmaceutically acceptable salts, or
enantiomers, or diastereomers thereof, wherein
R1 is Ci_6alkyl or trifluoromethyl-CxH2x-, wherein x is 1-6;
One of R2 and R3 is phenyl, which is once or twice or three times substituted by halogi and the other one is hydrogen or deuterium;
Figure imgf000147_0002
R4 is , which is unsubstituted or substituted by Ci_6alkyl, Ci_6alkylsulfanyl or cycloalkyl, where said Ci_6alkyl can be further optionally substituted with halogen;
A is
Figure imgf000147_0003
or which is unsubstituted or substituted by groups selected from Ci_6alkyl, deuterium and halogen.
6. A compound according to any one of claims 1 to 5 or pharmaceutically acceptable salts, enantiomers, or diastereomers thereof, wherein
R1 is methyl, ethyl, propyl, isopropyl or trifiuoromethylmethyl;
One of R2 and R3 is phenyl, which is once or twice or three times substituted by fluoro, chloro, bromo or iodo; and the other one is hydrogen or deuterium;
Figure imgf000148_0001
R4 is , which is unsubstituted or substituted by methyl, isopropyl, trifiuoromethyl, cyclopropyl or methylsulfanyl;
A is
Figure imgf000148_0002
or which is unsubstituted or substituted by groups selected from methyl, isopropyl, deuterium and fluoro.
7. A compound according to any one of claims 1 to 6 or pharmaceutically acceptable salts, enantiomers, or diastereomers thereof, wherein
R1 is Ci_6alkyl;
One of R2 and R3 is phenyl, which is once or twice or three times substituted by halogen; and the other one is hydrogen;
Figure imgf000148_0003
A is , which is unsubstituted or substituted by Ci_6alkyl.
8. A compound according to any one of claims 1 to 7 or pharmaceutically acceptable salts, enantiomers, or diastereomers thereof, wherein
R1 is methyl or ethyl;
One of R2 and R3 is phenyl, which is once or twice or three times substituted by fluoro, chloro or bromo; and the other one is hydrogen;
Figure imgf000148_0004
Figure imgf000149_0001
, which is unsubstituted or substituted by methyl.
9. A compound according to any one of claims 1 to 8 or pharmaceutically acceptable salts, enantiomers, or diastereomers thereof, wherein
R1 is methyl or ethyl;
One of R2 and R3 is
Figure imgf000149_0002
and the other one is hydrogen, wherein
A1 is hydrogen or fluoro;
A2 is hydrogen or fluoro;
A3 is fluoro, chloro or bromo; provided that at least one of A1 and A2 is hydrogen;
Figure imgf000149_0003
, wherein A4 is hydrogen or methyl.
10. A compound according to claim 1 or 3 or pharmaceutically acceptable salts, or
enantiomers, or diastereomers thereof, wherein
R1 is Ci_6alkyl;
Figure imgf000149_0004
One of R2 and R3 is , and the other one is hydrogen; , which is unsubstituted or substituted by Ci_6alkyl;
Figure imgf000150_0001
A is b , which is substituted by halogen.
1 1. A compound according to claim 1 or 3 or pharmaceutically acceptable salts, or
enantiomers, or diastereomers thereof, wherein
R1 is Ci_6alkyl;
One of R2 and R3 is phenyl, which is substituted by halogen; and the other one is hydrogen;
Figure imgf000150_0002
, which is substituted by Ci_6alkyl;
Figure imgf000150_0003
, which is unsubstituted or substituted by halogen.
12. A compound according to any one of claims 1 , 2, 3, 4 or 1 1 or pharmaceutically acceptable salts, or enantiomers, or diastereomers thereof, wherein
R1 is methyl or ethyl;
One of R2 and R3 is phenyl, which is substituted by fluoro or chloro; and the other one is hydrogen;
Figure imgf000150_0004
a
Figure imgf000151_0001
, which is unsubstituted or substituted by fluoro.
13. A compound according to claim 1 or 3 or pharmaceutically acceptable salts, or
enantiomers, or diastereomers thereof, wherein
R1 is Ci_6alkyl;
One of R2 and R3 is henyl, which is substituted by halogen; and the other one is hydrogen;
Figure imgf000151_0002
, which is unsubstituted or substituted by halogen. 14. A compound according to any one of claims 1, 2, 3, 4 or 13 or pharmaceutically acceptable salts, or enantiomers, or diastereomers thereof, wherein
R1 is methyl or ethyl;
One of R2 and R3 is phenyl, which is substituted by fluoro, chloro or bromo; and the other one is hydrogen;
Figure imgf000151_0003
Figure imgf000151_0004
, which is unsubstituted or substituted by fluoro. -ISO- IS. A compound according to claim 1 of formula (lb)
Figure imgf000152_0001
wherein
R1 is Ci_6alkyl;
One of R2 and R3 is phenyl, which is twice or thrice substituted by cyano or halogen; and the other one is hydrogen or deuterium;
R4 is phenyl, thiazolyl, oxazolyl, imidazolyl, thienyl or pyridinyl; which is unsubstituted or once or twice substituted by Ci_6alkyl, halogen, cycloalkyl or trifluoromethyl;
R5 is hydrogen;
R6 is hydrogen;
A
Figure imgf000152_0002
; which is unsubstituted or twice or four times substituted by deuterium or halogen;
or pharmaceutically acceptable salts, or enantiomers, or diastereomers thereof. 16. A compound according to claim 15, wherein
R1 is methyl or ethyl;
One of R2 and R3 is phenyl, which is twice or thrice substituted by cyano, fluoro, chloro or bromo; and the other one is hydrogen or deuterium;
R4 is phenyl, thiazolyl, oxazolyl, imidazolyl, thienyl or pyridinyl; which is unsubstituted or once or twice substituted by methyl, isopropyl, tert-butyl, fluoro, chloro, cyclopropyl or trifluoromethyl;
R5 is hydrogen;
R6 is hydrogen; A is
Figure imgf000153_0001
, , " or ; which is unsubstituted or twice or four times substituted by deuterium or fluoro;
or pharmaceutically acceptable salts, or enantiomers, or diastereomers thereof.
17. A compound according to claim 15, wherein
R1 is Ci_6alkyl;
One of R2 and R3 is phenyl, which is twice or thrice substituted by cyano or halogen; and the other one is hydrogen or deuterium;
R4 is thiazolyl or imidazolyl; which is unsubstituted or once or twice substituted by Ci_ 6alkyl, halogen, cycloalkyl or trifluoromethyl;
R5 is hydrogen;
R6 is hydrogen;
A is
Figure imgf000153_0002
or which is unsubstituted or twice or four times substituted by deuterium or halogen.
18. A compound according to claim 15 or 17, wherein
R1 is methyl or ethyl;
One of R2 and R3 is phenyl, which is twice or thrice substituted by cyano, fluoro, chloro or bromo; and the other one is hydrogen or deuterium;
R4 is thiazolyl or imidazolyl; which is unsubstituted or once or twice substituted by methyl, isopropyl, tert-butyl, cyclopropyl or trifluoromethyl;
R5 is hydrogen;
R6 is hydrogen; A is
Figure imgf000154_0001
, , " or which is unsubstituted or twice or four times substituted by deuterium or fluoro.
19. A compound according to claim 15, wherein
R1 is Ci_6alkyl;
One of R2 and R3 is phenyl, which is twice substituted by halogen; and the other one is hydrogen;
R4 is phenyl, oxazolyl, thienyl or pyridinyl; which is unsubstituted or once or twice substituted by Ci_6alkyl, halogen, cycloalkyl or trifluoromethyl;
R5 is hydrogen;
R6 is hydrogen;
A is
Figure imgf000154_0002
; which is unsubstituted or twice substituted by halogi
20. A compound according to claim 15 or 19, wherein
R1 is methyl;
One of R2 and R3 is phenyl, which is twice substituted by fluoro or chloro; and the other one is hydrogen;
R4 is phenyl, oxazolyl, thienyl or pyridinyl; which is once or twice substituted by methyl, fluoro or chloro;
R5 is hydrogen;
R6 is hydrogen;
Figure imgf000154_0003
; which is unsubstituted or twice substituted by fluoro
A compound according to any one of claims 1 to 20, selected from 6-((5)-2-carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-tM yl-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
(i?)-6-((5)-2-carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2-chloro-4-fluoro-phen^
2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
(5)-6-((5)-2-carboxy-4,4-difluoro-pyrrolidin- 1 -ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-[4-2H]-2- thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
(i?)-6-((5)-2-carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-(3,5- difluoro-pyridin-2-yl)-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
(5)-4-[(i?)-6-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl] -morpho line-3 -carboxylic acid;
(5)-4-[(i?)-6-(2-chloro-4-fluoro-phenyl)-2-(3,5-difluoro-pyridin-2-yl)-5-methoxycarbonyl-3,6- dihydro-pyrimidin-4-ylmethyl] -morpho line-3 -carboxylic acid;
(i?)-6-(2-carboxy-5,5-difluoro-piperidin-l-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2- yl-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
(i?)-6-((5)-2-carboxy-4,4-difluoro-pyrrolidin- 1 -ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-(4- methyl-pyridin-2-yl)-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
(5)-4-[(i?)-6-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-(4-methyl-pyridin-2-yl)-3,6- dihydro-pyrimidin-4-ylmethyl] -morpho line-3 -carboxylic acid;
(i?)-6-((5)-2-carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-(4- cyclopropyl-thiazol-2-yl)-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
(i?)-2-(4-tert-butyl-thiazol-2-yl)-6-((5)-2-carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2- chloro-4-fluoro-phenyl)-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
(i?)-6-((5)-2-carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-(4- fluoro-thiophen-2-yl)-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
(5)-4-[6-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-(l -methyl- lH-imidazol-2-yl)-3, 6- dihydro-pyrimidin-4-ylmethyl] -morpho line-3 -carboxylic acid;
(i?)-6-((i?)-5-carboxy-3,3-difluoro-piperidin-l-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol- 2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
(i?)-6-((5)-2-carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-(4- methyl-oxazol-2-yl)-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
(i?)-6-((5)-2-carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-(4- methyl-thiazol-2-yl)-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester; (5)-4-[(i?)-6-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-(4-methyl-thiazol-2-yl)-3^ dihydro-pyrimidin-4-ylmethyl] -morpho line-3 -carboxylic acid;
(i?)-6-((5)-2-carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2-chloro-4,5-difluoro-p
thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
(i -6-((S)-2-carboxy-[3,3-2H2]-4,4-difluoro^
phenyl)-2-thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
6-((5)-2-carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-(l,4- dimethyl- lH-imidazol-2-yl)-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
(5)-4-[(i?)-6-(2-chloro-4,5-difluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl] -morpho line-3 -carboxylic acid;
(i?)-6-((5)-2-carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-(3- fluoro-pyridin-2-yl)-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
(i?)-6-((5)-2-carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-(4- chloro-thiophen-2-yl)-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
(i?)-6-((5)-2-carboxy-4,4-difluoro-pyrrolidin- 1 -ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-(3- methyl-pyridin-2-yl)-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
(i?)-6-((5)-2-carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-(4- trifluoromethyl-thiazol-2-yl)-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
6-((5)-2-carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2- yl-l,4-dihydro-pyrimidine-5-carboxylic acid ethyl ester;
(i?)-6-((5)-2-carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-(4- methyl-thiophen-2-yl)-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
(i?)-6-((5)-2-carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-(4- isopropyl-thiazol-2-yl)-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester
(i?)-4-(4-bromo-2-chloro-phenyl)-6-((5)-2-carboxy-4,4-difluoro-pyrrolidin- 1 -ylmethyl)-2- thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
(i?)-6-((5)-2-carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2-chloro-4-cyano-phenyl)-2-thiazol- 2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
(5)-4-[(i?)-6-(2-chloro-4-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin- 4-ylmethyl] -morpho line-3 -carboxylic acid;
(i?)-6-((5)-2-Carboxy-4,4-difluoro-pyrrolidin- 1 -ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-( 1 - methyl- lH-imidazol-2-yl)-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester; (i?)-6-((5)-2-carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2-chloro-4-fluoro-ph^ difluoro-phenyl)-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
(i?)-6-((5)-2-Carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2-chloro-4-fluoro-phenyi^ thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid ethyl ester;
(5)-4-[(i?)-6-(2-Chloro-4-fluoro-phenyl)-5-ethoxycarbonyl-2-(l -methyl- lH-imidazol-2-yl)-3, 6- dihydro-pyrimidin-4-ylmethyl] -morpho line-3 -carboxylic acid;
(i?)-6-((5)-2-Carboxy-4,4-difluoro-pyrrolidin- 1 -ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-( 1 - methyl- lH-imidazol-2-yl)-l,4-dihydro-pyrimidine-5-carboxylic acid ethyl ester;
(5)-4-[(i?)-6-(2-Chloro-4-fluoro-phenyl)-5-ethoxycarbonyl-2-(6-methyl-pyridin-2-yl)-3,6- dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;
(i?)-6-((5)-2-Carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2,4-dichloro-phenyl)-2-thiazol-2- yl-l,4-dihydro-pyrimidine-5-carboxylic acid ethyl ester;
(5)-4-[(i?)-6-(2,4-Dichloro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4- ylmethyl] -morpho line-3 -carboxylic acid;
(i?)-6-((5)-2-Carboxy-4,4-difluoro-pyrrolidin- 1 -ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-( 1 - methyl-4-trifluoromethyl-lH-imidazol-2-yl)-l,4-dihydro-pyrimidine-5-carboxylic acid ethyl ester;
(S)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(3,4-difluoro-phenyl)-2-thiazol-2-yl- l,4-dihydro-pyrimidine-5-carboxylic acid ethyl ester;
(S)-4-[(S)-6-(3,4-Difluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4- ylmethyl] -morpho line-3 -carboxylic acid;
(S)-4-[(S)-5-Ethoxycarbonyl-2-thiazol-2-yl-6-(3,4,5-trifluoro-phenyl)-3,6-dihydro-pyrimidin-4- ylmethyl] -morpho line-3 -carboxylic acid;
(S)-4-[(R)-5-Ethoxycarbonyl-2-thiazol-2-yl-6-(2,3,4-trifluoro-phenyl)-3,6-dihydro-pyrimidin-4- ylmethyl]-morpholine-3-carboxylic acid;
(S)-4-[(R)-6-(4-Bromo-2,3-difluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl] -morpho line-3 -carboxylic acid;
(S)-4-[(S)-6-(3,4-Dichloro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4- ylmethyl] -morpho line-3 -carboxylic acid;
(S)-4-[(R)-6-(2-Chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl] -morpho line-3 -carboxylic acid;
(S)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin- 1 -ylmethyl)-4-(4-cyano-phenyl)-2-thiazol-2-yl- 1 ,4- dihydro-pyrimidine-5-carboxylic acid ethyl ester; (S)-4-[(R)-6-(4-Chloro-2-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl] -morpho line-3 -carboxylic acid;
(R)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidm^
yl-l,4-dihydro-pyrimidine-5-carboxylic acid ethyl ester;
(S)-4-[(R)-6-(2-Chloro-4-fluoro-phenyl)-2-th^
dihydro-pyrimidin-4-ylmethyl] -morpho line-3 -carboxylic acid;
(S)-4-[(S)-6-(4-Bromo-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin- 4-ylmethyl] -morpho line-3 -carboxylic acid;
(S)-4-[(S)-5-Ethoxycarbonyl-6-(3-fluoro-phenyl)-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4- ylmethyl]-morpholine-3-carboxylic acid;
(S)-4-[(S)-5-Ethoxycarbonyl-6-(4-fluoro-phenyl)-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4- ylmethyl] -morpho line-3 -carboxylic acid;
(R)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin- 1 -ylmethyl)-4-(2-chloro-3 ,4-difluoro-phenyl)-2- thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid ethyl ester;
(S)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(3,4-difluoro-phenyl)-2-(l -methyl- lH-imidazol-2-yl)-l,4-dihydro-pyrimidine-5-carboxylic acid ethyl ester;
(S)-4-[(S)-6-(3,4-Difluoro-phenyl)-5-ethoxycarbonyl-2-(l-methyl-lH-imidazol-2-yl)-3,6- dihydro-pyrimidin-4-ylmethyl] -morpho line-3 -carboxylic acid;
(S)-4-[(R)-6-(2,4-Difluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4- ylmethyl]-morpholine-3-carboxylic acid;
(R)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2,4-difluoro-phenyl)-2-thiazol-2- yl-l,4-dihydro-pyrimidine-5-carboxylic acid ethyl ester;
(S)-4-[(R)-6-(2-Chloro-3,4-difluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl] -morpho line-3 -carboxylic acid;
(3S)-4-[[(4R)-4-(2-chloro-4-fluorophenyl)-5-methoxycarbonyl-2-(4-methylsulfanyl-l,3-thiazol- 2-yl)- 1 ,4-dihydropyrimidin-6-yl]methyl]morpholine-3-carboxylic acid;
(2S)-l-[[(4R)-4-(2-chloro-4-fluorophenyl)-5-methoxycarbonyl-2-(4-methylsulfanyl-l,3-thiazol- 2-yl)- 1 ,4-dihydropyrimidin-6-yl]methyl]-4,4-difluoropyrrolidine-2-carboxylic acid;
(S)-4-[(R)-6-(2-Chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl] -morpho line-3 -carboxylic acid;
(R)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2-chloro-3-fluoro-phenyl)-2- thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid ethyl ester; (S)-4-[(R)-6-(2-Bromo-4-fluoro-phenyl)-5-methoxycarbonyl-2-(5-methyl-oxazol-4-yl)-3,6- dihydro-pyrimidin-4-ylmethyl] -morpho line-3 -carboxylic acid;
(S)-4-[(R)-6-(2-Bromo-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl] -morpho line-3 -carboxylic acid;
(R)-4-(2-Bromo-3-fluoro-phenyl)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin- 1 -ylmethyl)-2- thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid ethyl ester;
(S)-4-[(R)-6-(2-Chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-(5-methyl-oxazol-4-yl)-3,6- dihydro-pyrimidin-4-ylmethyl] -morpho line-3 -carboxylic acid;
(S)-4-[(R)-6-(2-Bromo-4-fluoro-phenyl)-5-ethoxycarbonyl-2-(5-methyl-oxazol-4-yl)-3,6- dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;
(5)-4-[(R)-6-(2,3-Difluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4- ylmethyl] -morpho line-3 -carboxylic acid;
(S)-4-[(R)-6-(2-Bromo-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4- ylmethyl] -morpho line-3 -carboxylic acid;
(R)-4-(2-Bromo-phenyl)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin- 1 -ylmethyl)-2-thiazol-2-yl- l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
(S)-4-[(R)-6-(2-Chloro-3,4-difluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl] -morpho line-3 -carboxylic acid;
(R)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin- 1 -ylmethyl)-4-(2-chloro-3 ,4-difluoro-phenyl)-2- thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
(S)-4-[(R)-6-(4-Chloro-2-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl] -morpho line-3 -carboxylic acid;
(R)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(4-chloro-2-fluoro-phenyl)-2- thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
(S)-4-[(S)-6-(4-Chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl] -morpho line-3 -carboxylic acid;
(S)-4-[(R)-6-(2-Chloro-3,4-difluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl] -3 -methyl-morpho line-3 -carboxylic acid;
(R)-4-[(R)-6-(2-Chloro-3,4-difluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl] -3 -methyl-morpho line-3 -carboxylic acid;
(R)-6-((R)-5-Carboxy-3,3-difluoro-piperidin-l-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-(4- methyl-thiazol-2-yl)-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester; (S)-4-[(R)-6-(2-Bromo-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl] -morpho line-3 -carboxylic acid;
(S)-4-[(R)-6-(2-Chloro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4- ylmethyl] -morpho line-3 -carboxylic acid;
(S)-4-[(S)-6-(4-Chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidm^ 4-ylmethyl] -morpho line-3 -carboxylic acid;
(R)-4-(2-Bromo-4-fluoro-phenyl)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-2- thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
(R)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2,4-dichloro-phenyl)-2-thiazol-2- yl-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
3 - [ [(4R)-4-(2-chloro-4-fluoro-phenyl)-5 -methoxycarbonyl-2-thiazo 1-2-yl- 1 ,4-dihydropyrimidin- 6-yl]methyl]- 1 ,3-thiazinane-4-carboxylic acid;
(3S)-4-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-2-(4-cyclopropylthiazol-2-yl)-5-methoxycarbonyl-
1 ,4-dihydropyrimidin-6-yl]methyl]morpholine-3-carboxylic acid;
(3S)-4-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-2-[4-(difluoromethyl)thiazol-2-yl]-5- methoxycarbonyl- 1 ,4-dihydropyrimidin-6-yl]methyl]morpholine-3-carboxylic acid;
(R)-6-((S)-2-Carboxy-4,4-difluoro-3,3-dimethyl-pyrrolidin-l-ylmethyl)-4-(2-chloro-4-fluoro- phenyl)-2-thiazo 1-2-yl- l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
(3R)-4-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazo 1-2-yl- 1,4- dihydropyrimidin-6-yl]methyl]-2,2-dimethyl-thiomorpholine-3-carboxylic acid;
(3S)-4-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-l,4- dihydropyrimidin-6-yl]methyl]thiomorpholine-3-carboxylic acid;
(S)-4-[(S)-6-(2-Chloro-4-fluoro-phenyl)-2-(l,4-dimethyl-lH-imidazol-2-yl)-5-methoxycarbonyl- 3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;
(S)-4-[(R)-6-(4-Bromo-2-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl] -morpho line-3 -carboxylic acid;
(S)-4-[(R)-6-(4-Bromo-2-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl] -morpho line-3 -carboxylic acid;
(S)-4-[(R)-6-(2-Chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-(4-trifluoromethyl-thiazo 1-2-yl)- 3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid;
(S)-4-[(S)-6-(3,4-Difluoro-2-methyl-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl] -morpho line-3 -carboxylic acid; (S)-4-[(R)-6-(2-Chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-(l -methyl- lH-imidazol-2-yl)-3, 6- dihydro-pyrimidin-4-ylmethyl] -morpho line-3 -carboxylic acid;
(S)-4-[(R)-6-(2-Chloro-4-fluoro-phenyl)-5-isopropoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl] -morpho line-3 -carboxylic acid;
(S)-4-[6-(2-Chloro-4-fluoro-phenyl)-5-propoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4- ylmethyl] -morpho line-3 -carboxylic acid;
(S)-4-[(S)-6-(3,4-Difluoro-phenyl)-5-isopropoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin- 4-ylmethyl] -morpho line-3 -carboxylic acid;
(S)-4-[(R)-6-(2-Chloro-3-fluoro-phenyl)-5-isopropoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl] -morpho line-3 -carboxylic acid;
(R)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-l-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-(5- methyl-oxazol-4-yl)-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
(S)-4-[(R)-6-(2-Chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-(5-methyl-oxazol-4-yl)-3,6- dihydro-pyrimidin-4-ylmethyl] -morpho line-3 -carboxylic acid;
(2R,3S)-4-[(R)-6-(2-Chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl] -2-methyl-morpho line-3 -carboxylic acid;
(S)-4-[5-tert-Butoxycarbonyl-6-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl] -morpho line-3 -carboxylic acid;
(2R,3S)-4-[(R)-6-(2-Bromo-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl] -2-methyl-morpho line-3 -carboxylic acid;
(R)-4-(2-Bromo-4-fluoro-phenyl)-6-((S)-2-carboxy-5,5-difluoro-piperidin-l-ylmethyl)-2-thiazol- 2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid ethyl ester;
(R)-4-(2-Bromo-4-fluoro-phenyl)-6-((R)-2-carboxy-5,5-difluoro-piperidin-l-ylmethyl)-2- thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid ethyl ester;
(R)-6-((S)-2-Carboxy-5,5-difluoro-piperidin-l-ylmethyl)-4-(2-chloro-3-fluoro-phenyl)-2-thiazol- 2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
(R)-6-((R)-2-Carboxy-5,5-difluoro-piperidin-l-ylmethyl)-4-(2-chloro-3-fluoro-phenyl)-2- thiazol-2-yl-l,4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
(R)-6-((S)-2-Carboxy-5,5-difluoro-piperidin-l-ylmethyl)-4-(2-chloro-phenyl)-2-thiazol-2-yl-l,4- dihydro-pyrimidine-5-carboxylic acid ethyl ester;
(2R,3S)-4-[(S)-6-(3,4-Difluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin- 4-ylmethyl] -2-methyl-morpho line-3 -carboxylic acid; (2R,3S)-4-[(S)-6-(3,4-Difluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl] -2-methyl-morpho line-3 -carboxylic acid;
(2R,3S)-4-[(R)-5-Methoxycarbonyl-2-thiazol-2-yl-6-(2,3,4-trifluoro-phenyl)-3,6-dihydro- pyrimidin-4-ylmethyl] -2-methyl-morpho line-3 -carboxylic acid;
(2R,3S)-4-[(R)-6-(2-Chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl] -2-methyl-morpho line-3 -carboxylic acid;
(2R,3S)-4-[(R)-6-(2-Bromo-4-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl] -2-methyl-morpho line-3 -carboxylic acid;
(2R,3S)-4-[(R)-6-(2-Chloro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4- ylmethyl] -2-methyl-morpho line-3 -carboxylic acid;
(2R,3S)-4-[(R)-6-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl] -2-methyl-morpho line-3 -carboxylic acid;
(2R,3S)-4-[(R)-6-(2-Bromo-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4- ylmethyl] -2-methyl-morpho line-3 -carboxylic acid;
(2R,3S)-4-[(R)-6-(2-Chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro- pyrimidin-4-ylmethyl] -2-isopropyl-morpho line-3 -carboxylic acid;
(S)-4-(((R)-6-(2-chloro-4-fluorophenyl)-5-(methoxycarbonyl)-2-(thiazol-2-yl)-3,6- dihydropyrimidin-4-yl)methyl)-3 -methylmorpho line-3 -carboxylic acid;
(S)-4-(((R)-6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6- dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid;
(3S)-4-[[(4S)-4-(4-bromophenyl)-5-ethoxycarbonyl-2-(l,3-thiazol-2-yl)-l,4-dihydropyrimidin-6- yl]methyl]morpholine-3-carboxylic acid;
(3S)-4-[[(4S)-4-(3-bromo-4-chlorophenyl)-5-ethoxycarbonyl-2-(l,3-thiazol-2-yl)-l,4- dihydropyrimidin-6-yl]methyl]morpholine-3-carboxylic acid;
(3S)-4-[[(4S)-4-(3-chloro-5-fluorophenyl)-5-ethoxycarbonyl-2-(l,3-thiazol-2-yl)-l,4- dihydropyrimidin-6-yl]methyl]morpholine-3-carboxylic acid;
(3S)-4-[[(4S)-4-(4-chlorophenyl)-5-ethoxycarbonyl-2-(l,3-thiazol-2-yl)-l,4-dihydropyrimidin-6- yl]methyl]morpholine-3-carboxylic acid;
(S)-4-(((R)-6-(2-bromophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4- yl)methyl)morpholine-3-carboxylic acid;
(3S)-4-[[(4R)-4-(2-bromo-3,4-difluorophenyl)-5-ethoxycarbonyl-2-(l,3-thiazol-2-yl)-l,4- dihydropyrimidin-6-yl]methyl]morpholine-3-carboxylic acid; (3S)-4-[[(4R)-5-ethoxycarbonyl-4-(2-iodoph
yl]methyl]morpholine-3-carboxylic acid; and
(2S)-l-[[(4S)-4-(4-bromophenyl)-5-ethoxycarbonyl-2-(l,3-thiazol-2-yl)-l,4-di ydropyrimidm yl]methyl]-4,4-difluoropyrrolidine-2-carboxylic acid.
A process for the preparation of a compound according to any one of claims 1 to 21 comprising the reaction of
a compound of formula (XZ)
Figure imgf000163_0001
(b) a compound of formula (YZ)
Figure imgf000163_0002
under chiral separation condition;
wherein R1 to R4 and A are defined as in any one of claims 1 to 20.
23. A compound according to any one of claims 1 to 21 for use as therapeutically active substance.
24. A pharmaceutical composition comprising a compound in accordance with any one of claims 1 to 21 and a therapeutically inert carrier.
25. The use of a compound according to any one of claims 1 to 21 for the treatment or prophylaxis of hepatitis B virus infection. 26. The use of a compound according to any one of claims 1 to 21 for the preparation of a medicament for the treatment or prophylaxis of hepatitis B virus infection.
27. A compound according to any one of claims 1 to 21 for the treatment or prophylaxis of hepatitis B virus infection.
28. A compound according to any one of claims 1 to 21 as inhibitors of hepatitis B virus.
29. A compound according to any one of claims 1 to 21, when manufactured according to a process of claim 18.
30. 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 21. 31. The invention as hereinbefore described.
PCT/EP2013/068429 2012-09-10 2013-09-06 6-amino acid heteroaryldihydropyrimidines for the treatment and prophylaxis of hepatitis b virus infection Ceased WO2014037480A1 (en)

Priority Applications (16)

Application Number Priority Date Filing Date Title
CN201380046738.5A CN104603125A (en) 2012-09-10 2013-09-06 6-amino acid heteroaryl dihydropyrimidines for the treatment and prevention of hepatitis B virus infection
SG11201500377UA SG11201500377UA (en) 2012-09-10 2013-09-06 6-amino acid heteroaryldihydropyrimidines for the treatment and prophylaxis of hepatitis b virus infection
ES13763201.4T ES2617906T3 (en) 2012-09-10 2013-09-06 6-Amino acid heteroaryl dihydropyrimidines for the treatment and prophylaxis of hepatitis B virus infection
MX2015002954A MX2015002954A (en) 2012-09-10 2013-09-06 6-amino acid heteroaryldihydropyrimidines for the treatment and prophylaxis of hepatitis b virus infection.
MA37942A MA37942B1 (en) 2012-09-10 2013-09-06 6-amino acid heteroaryldihydropyrimidines for the treatment and prophylaxis of hepatitis b virus infection
HK15110886.9A HK1210152A1 (en) 2012-09-10 2013-09-06 6-amino acid heteroaryldihydropyrimidines for the treatment and prophylaxis of hepatitis b virus infection
BR112015004113A BR112015004113A2 (en) 2012-09-10 2013-09-06 6-Amino Acid Heteroaryl Dihydropyrimidines for the Treatment and Prophylaxis of Hepatitis B Virus Infection
JP2015530405A JP6113285B2 (en) 2012-09-10 2013-09-06 6-amino acid heteroaryl dihydropyrimidines for the treatment and prevention of hepatitis B virus infection
EP13763201.4A EP2892893B2 (en) 2012-09-10 2013-09-06 6-amino acid heteroaryldihydropyrimidines for the treatment and prophylaxis of hepatitis b virus infection
CA2881322A CA2881322A1 (en) 2012-09-10 2013-09-06 6-amino acid heteroaryldihydropyrimidines for the treatment and prophylaxis of hepatitis b virus infection
EA201590384A EA201590384A1 (en) 2012-09-10 2013-09-06 6-AMINO ACID-HETEROARYDYHYDROPYRIMIDINES FOR THE TREATMENT AND PREVENTION OF INFECTION OF THE HEPATITIS B VIRUS
AU2013311705A AU2013311705A1 (en) 2012-09-10 2013-09-06 6-amino acid heteroaryldihydropyrimidines for the treatment and prophylaxis of Hepatitis B virus infection
KR1020157005893A KR20150054795A (en) 2012-09-10 2013-09-06 6-amino acid heteroaryldihydropyrimidines for the treatment and prophylaxis of hepatitis b virus infection
IL236691A IL236691A0 (en) 2012-09-10 2015-01-13 6-amino acid heteroaryldihydropyrimidines for the treatment and prophylaxis of hepatitis b virus infection
ZA2015/00580A ZA201500580B (en) 2012-09-10 2015-01-26 6-amino acid heteroaryldihydropyrimidines for the treatment and prophylaxis of hepatitis b virus infection
CR20150085A CR20150085A (en) 2012-09-10 2015-02-19 NEW 6-AMINO ACID-HETEROARILDIHYDROPIRMIDINDAS FOR THE TREATMENT AND PROFILAXIS OF HEPATITIS B VIRUS INFECTION

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
CNPCT/CN2012/081190 2012-09-10
CNPCT/CN2012/081190 2012-09-10
CNPCT/CN2013/080301 2013-07-29
CNPCT/CN2013/080301 2013-07-29
CNPCT/CN2013/081196 2013-08-09
CNPCT/CN2013/081196 2013-08-09
CNPCT/CN2013/081287 2013-08-12
CNPCT/CN2013/081287 2013-08-12

Publications (1)

Publication Number Publication Date
WO2014037480A1 true WO2014037480A1 (en) 2014-03-13

Family

ID=49212746

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2013/068429 Ceased WO2014037480A1 (en) 2012-09-10 2013-09-06 6-amino acid heteroaryldihydropyrimidines for the treatment and prophylaxis of hepatitis b virus infection

Country Status (24)

Country Link
US (1) US9447086B2 (en)
EP (1) EP2892893B2 (en)
JP (1) JP6113285B2 (en)
KR (1) KR20150054795A (en)
CN (1) CN104603125A (en)
AR (1) AR092503A1 (en)
AU (1) AU2013311705A1 (en)
BR (1) BR112015004113A2 (en)
CA (1) CA2881322A1 (en)
CL (1) CL2015000482A1 (en)
CO (1) CO7170160A2 (en)
CR (1) CR20150085A (en)
EA (1) EA201590384A1 (en)
ES (1) ES2617906T3 (en)
HK (1) HK1210152A1 (en)
IL (1) IL236691A0 (en)
MA (1) MA37942B1 (en)
MX (1) MX2015002954A (en)
PE (1) PE20150776A1 (en)
PH (1) PH12015500347A1 (en)
SG (1) SG11201500377UA (en)
TW (1) TW201416360A (en)
WO (1) WO2014037480A1 (en)
ZA (1) ZA201500580B (en)

Cited By (157)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104211696A (en) * 2014-08-20 2014-12-17 河北科技大学 Preparation method of TMC-435 (Simeprevir) important intermediate
CN104327006A (en) * 2014-10-19 2015-02-04 湖南华腾制药有限公司 Preparation method of 5-ehtyl-4-formamidooxazole
US8993771B2 (en) 2013-03-12 2015-03-31 Novira Therapeutics, Inc. Hepatitis B antiviral agents
CN104650068A (en) * 2013-11-19 2015-05-27 广东东阳光药业有限公司 Dihydropyrimidine compound and application thereof to drugs
CN104672223A (en) * 2013-11-27 2015-06-03 广东东阳光药业有限公司 Preparation method of dihydropyrimidine derivative and intermediate of dihydropyrimidine derivative
US9061008B2 (en) 2011-12-21 2015-06-23 Novira Therapeutics, Inc. Hepatitis B antiviral agents
CN104945395A (en) * 2014-03-28 2015-09-30 广东东阳光药业有限公司 Dihydropyrimidine compound and application thereof in medicaments
US9169212B2 (en) 2014-01-16 2015-10-27 Novira Therapeutics, Inc. Azepane derivatives and methods of treating hepatitis B infections
US9181288B2 (en) 2014-01-16 2015-11-10 Novira Therapeutics, Inc. Azepane derivatives and methods of treating hepatitis B infections
WO2016012470A1 (en) * 2014-07-25 2016-01-28 F. Hoffmann-La Roche Ag New amorphous and crystalline forms of (3s)-4-[[(4r)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1, 4-dihydropyrimidin-6-yl]methyl]morpholine-3-carboxylic acid
WO2016016196A1 (en) * 2014-07-31 2016-02-04 F. Hoffmann-La Roche Ag Novel chiral resolution of 4-aryl-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylic acid esters
WO2016102438A1 (en) * 2014-12-23 2016-06-30 F. Hoffmann-La Roche Ag Process for the preparation of 4-phenyl-5-alkoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidine analogues
US9400280B2 (en) 2014-03-27 2016-07-26 Novira Therapeutics, Inc. Piperidine derivatives and methods of treating hepatitis B infections
WO2016120186A1 (en) 2015-01-27 2016-08-04 F. Hoffmann-La Roche Ag Recombinant hbv cccdna, the method to generate thereof and the use thereof
WO2016124126A1 (en) * 2015-02-07 2016-08-11 Sunshine Lake Pharma Co., Ltd. Complexes and salts of dihydropyrimidine derivatives and their application in pharmaceuticals
WO2016141092A1 (en) 2015-03-04 2016-09-09 Gilead Sciences, Inc. Toll-like receptor modulating 4,6-diamino-pyrido[3,2-d]pyrimidine compounds
WO2016146598A1 (en) 2015-03-16 2016-09-22 F. Hoffmann-La Roche Ag Combined treatment with a tlr7 agonist and an hbv capsid assembly inhibitor
WO2016202721A1 (en) 2015-06-16 2016-12-22 F. Hoffmann-La Roche Ag Salts of (s)-4-[(r)-6-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6- dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid, salt former and methods for preparing and using the same
WO2017035408A1 (en) 2015-08-26 2017-03-02 Achillion Pharmaceuticals, Inc. Compounds for treatment of immune and inflammatory disorders
WO2017035230A1 (en) 2015-08-26 2017-03-02 Gilead Sciences, Inc. Deuterated toll-like receptor modulators
US9598446B2 (en) 2014-02-25 2017-03-21 Achillion Pharmaceuticals, Inc. Amino compounds for treatment of complement mediated disorders
WO2017048954A1 (en) 2015-09-15 2017-03-23 Assembly Biosciences, Inc. Hepatitis b core protein modulators
WO2017064156A1 (en) 2015-10-16 2017-04-20 F. Hoffmann-La Roche Ag Novel 6-fused and 2-heteroaryldihydropyrimidines for the treatment and prophylaxis of hepatitis b virus infection
WO2017076791A1 (en) * 2015-11-03 2017-05-11 F. Hoffmann-La Roche Ag Combination therapy of an hbv capsid assembly inhibitor and an interferon
WO2017108630A1 (en) * 2015-12-21 2017-06-29 F. Hoffmann-La Roche Ag Combination therapy of an hbsag inhibitor and an hbv capsid assembly inhibitor
WO2017205115A1 (en) 2016-05-27 2017-11-30 Gilead Sciences, Inc. Compounds for the treatment of hepatitis b virus infection
WO2017205078A1 (en) 2016-05-27 2017-11-30 Gilead Sciences, Inc. Methods for treating hepatitis b virus infections using ns5a, ns5b or ns3 inhibitors
US9884831B2 (en) 2015-03-19 2018-02-06 Novira Therapeutics, Inc. Azocane and azonane derivatives and methods of treating hepatitis B infections
US9884818B2 (en) 2013-05-17 2018-02-06 Janssen Sciences Ireland Uc Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US9895349B2 (en) 2013-04-03 2018-02-20 Janssen Sciences Ireland Us N-phenyl-carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
EP3139954A4 (en) * 2014-05-09 2018-02-28 Indiana University Research and Technology Corporation Methods and compositions for treating hepatitis b virus infections
WO2018039531A1 (en) 2016-08-26 2018-03-01 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof
WO2018036941A1 (en) 2016-08-24 2018-03-01 F. Hoffmann-La Roche Ag Combination therapy of an hbv capsid assembly inhibitor and a nucleos(t)ide analogue
WO2018045150A1 (en) 2016-09-02 2018-03-08 Gilead Sciences, Inc. 4,6-diamino-pyrido[3,2-d]pyrimidine derivaties as toll like receptor modulators
WO2018045144A1 (en) 2016-09-02 2018-03-08 Gilead Sciences, Inc. Toll like receptor modulator compounds
WO2018050571A1 (en) 2016-09-13 2018-03-22 F. Hoffmann-La Roche Ag Combined treatment with a tlr7 agonist and an hbv capsid assembly inhibitor
WO2018053157A1 (en) 2016-09-15 2018-03-22 Assembly Biosciences, Inc. Hepatitis b core protein modulators
US10000516B2 (en) 2015-08-26 2018-06-19 Achillion Pharmaceuticals, Inc. Phosphonate compounds for treatment of medical disorders
US10011612B2 (en) 2015-08-26 2018-07-03 Achillion Pharmaceuticals, Inc. Aryl, heteroaryl, and heterocyclic compounds for treatment of medical disorders
WO2018144390A1 (en) 2017-01-31 2018-08-09 Gilead Sciences, Inc. Crystalline forms of tenofovir alafenamide
WO2018144605A1 (en) 2017-02-02 2018-08-09 Gilead Sciences, Inc. Compounds for the treatment of hepatitis b virus infection
WO2018160889A1 (en) 2017-03-01 2018-09-07 Achillion Pharmaceuticals, Inc. Aryl, heteroary, and heterocyclic pharmaceutical compounds for treatment of medical disorders
WO2018160878A1 (en) 2017-03-02 2018-09-07 Assembly Biosciences, Inc. Cyclic sulfamide compounds and methods of using same
US10071961B2 (en) 2013-10-23 2018-09-11 Janssen Sciences Ireland Uc Carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10077239B2 (en) 2015-09-29 2018-09-18 Novira Therapeutics, Inc. Crystalline forms of a hepatitis B antiviral agent
US10092584B2 (en) 2015-08-26 2018-10-09 Achillion Pharmaceuticals, Inc. Compounds for the treatment of medical disorders
WO2018195321A1 (en) 2017-04-20 2018-10-25 Gilead Sciences, Inc. Pd-1/pd-l1 inhibitors
US10125094B2 (en) 2013-02-28 2018-11-13 Janssen Sciences Ireland Uc Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B
US10138225B2 (en) 2015-08-26 2018-11-27 Achillion Pharmaceuticals, Inc. Amide compounds for treatment of medical disorders
US10213420B2 (en) 2014-02-05 2019-02-26 Novira Therapeutics, Inc. Combination therapy for treatment of HBV infections
WO2019040102A1 (en) 2017-08-22 2019-02-28 Gilead Sciences, Inc. Therapeutic heterocyclic compounds
US10385097B2 (en) 2015-08-26 2019-08-20 Achillion Pharmaceuticals, Inc. Ether compounds for treatment of medical disorders
WO2019160882A1 (en) 2018-02-13 2019-08-22 Gilead Sciences, Inc. Pd-1/pd-l1 inhibitors
US10392349B2 (en) 2014-01-16 2019-08-27 Novira Therapeutics, Inc. Azepane derivatives and methods of treating hepatitis B infections
WO2019165374A1 (en) 2018-02-26 2019-08-29 Gilead Sciences, Inc. Substituted pyrrolizine compounds as hbv replication inhibitors
WO2019195181A1 (en) 2018-04-05 2019-10-10 Gilead Sciences, Inc. Antibodies and fragments thereof that bind hepatitis b virus protein x
WO2019193542A1 (en) 2018-04-06 2019-10-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 2'3'-cyclic dinucleotides
WO2019193543A1 (en) 2018-04-06 2019-10-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 3'3'-cyclic dinucleotides
WO2019193533A1 (en) 2018-04-06 2019-10-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 2'2'-cyclic dinucleotides
US10441589B2 (en) 2016-04-15 2019-10-15 Novira Therapeutics, Inc. Combinations and methods comprising a capsid assembly inhibitor
WO2019200247A1 (en) 2018-04-12 2019-10-17 Precision Biosciences, Inc. Optimized engineered meganucleases having specificity for a recognition sequence in the hepatitis b virus genome
US10450270B2 (en) 2013-07-25 2019-10-22 Janssen Sciences Ireland Uc Glyoxamide substituted pyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
WO2019204609A1 (en) 2018-04-19 2019-10-24 Gilead Sciences, Inc. Pd-1/pd-l1 inhibitors
WO2019211799A1 (en) 2018-05-03 2019-11-07 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 2'3'-cyclic dinucleotide analogue comprising a cyclopentanyl modified nucleotide
US10501489B2 (en) 2012-09-10 2019-12-10 Reata Pharmaceuticals, Inc. C17-alkanediyl and alkenediyl derivatives of oleanolic acid and methods of use thereof
EP3590943A1 (en) 2015-07-02 2020-01-08 Janssen Sciences Ireland Unlimited Company Cyclized sulfamoylarylamide derivatives and the use thereof as medicaments for the treatment of hepatitis b
WO2020010223A1 (en) 2018-07-06 2020-01-09 Gilead Sciences, Inc. Therapeutic heterocyclic compounds
WO2020010200A1 (en) 2018-07-06 2020-01-09 Gilead Sciences, Inc. Therapeutic heterocyclic compounds
WO2020014643A1 (en) 2018-07-13 2020-01-16 Gilead Sciences, Inc. Pd-1/pd-l1 inhibitors
WO2020028097A1 (en) 2018-08-01 2020-02-06 Gilead Sciences, Inc. Solid forms of (r)-11-(methoxymethyl)-12-(3-methoxypropoxy)-3,3-dimethyl-8-0x0-2,3,8,13b-tetrahydro-1h-pyrido[2,1-a]pyrrolo[1,2-c] phthalazine-7-c arboxylic acid
EP3607950A2 (en) 2014-03-13 2020-02-12 Indiana University Research & Technology Corporation Hepatitis b core protein allosteric modulators
WO2020086533A1 (en) 2018-10-22 2020-04-30 Assembly Biosciences, Inc. 5-membered heteroaryl carboxamide compounds for treatment of hbv
WO2020086556A1 (en) 2018-10-24 2020-04-30 Gilead Sciences, Inc. Pd-1/pd-l1 inhibitors
WO2020087107A1 (en) 2018-10-31 2020-05-07 The University Of Sydney Compositions and methods for treating viral infections
WO2020092528A1 (en) 2018-10-31 2020-05-07 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds having hpk1 inhibitory activity
WO2020092621A1 (en) 2018-10-31 2020-05-07 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds as hpk1 inhibitors
US10662175B2 (en) 2015-08-26 2020-05-26 Achillion Pharmaceuticals, Inc. Aryl, heteroaryl, and heterocyclic compounds for treatment of immune and inflammatory disorders
US10660876B2 (en) 2015-08-26 2020-05-26 Achillion Pharmaceuticals, Inc. Amino compounds for treatment of medical disorders
US10662416B2 (en) 2016-10-14 2020-05-26 Precision Biosciences, Inc. Engineered meganucleases specific for recognition sequences in the hepatitis B virus genome
US10676429B2 (en) 2012-08-28 2020-06-09 Janssen Sciences Ireland Uc Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B
WO2020125730A1 (en) * 2018-12-20 2020-06-25 Janssen Pharmaceutica Nv Heteroaryldihydropyrimidine derivatives and methods of treating hepatitis b infections
US10696669B2 (en) 2016-11-18 2020-06-30 Sichuan Kelun-Biotech Biopharmaceuticals Co., Ltd. Dihydropyrimidine compound and preparation method and use thereof
WO2020178769A1 (en) 2019-03-07 2020-09-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 2'3'-cyclic dinucleotides and prodrugs thereof
WO2020178770A1 (en) 2019-03-07 2020-09-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 3'3'-cyclic dinucleotides and prodrugs thereof
WO2020178768A1 (en) 2019-03-07 2020-09-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 3'3'-cyclic dinucleotide analogue comprising a cyclopentanyl modified nucleotide as sting modulator
WO2020210379A1 (en) 2019-04-10 2020-10-15 Hangzhou Zhengxiang Pharmaceuticals Co., Ltd. Phosphatidylinositol 3-kinase inhibitors
WO2020214663A1 (en) 2019-04-17 2020-10-22 Gilead Sciences, Inc. Solid forms of a toll-like receptor modulator
WO2020214652A1 (en) 2019-04-17 2020-10-22 Gilead Sciences, Inc. Solid forms of a toll-like receptor modulator
WO2020237025A1 (en) 2019-05-23 2020-11-26 Gilead Sciences, Inc. Substituted exo-methylene-oxindoles which are hpk1/map4k1 inhibitors
WO2020242999A1 (en) 2019-05-24 2020-12-03 Assembly Biosciences, Inc. Pharmaceutical compositions for the treatment of hbv
WO2020247504A1 (en) 2019-06-06 2020-12-10 Aligos Therapeutics, Inc. Heterocyclic compounds
WO2020255038A1 (en) 2019-06-18 2020-12-24 Janssen Sciences Ireland Unlimited Company Combination of hepatitis b virus (hbv) vaccines and pyridopyrimidine derivatives
WO2020263830A1 (en) 2019-06-25 2020-12-30 Gilead Sciences, Inc. Flt3l-fc fusion proteins and methods of use
WO2021011891A1 (en) 2019-07-18 2021-01-21 Gilead Sciences, Inc. Long-acting formulations of tenofovir alafenamide
US10906887B2 (en) 2015-08-26 2021-02-02 Achillion Pharmaceuticals, Inc. Amino compounds for treatment of immune and inflammatory disorders
WO2021018239A1 (en) * 2019-07-31 2021-02-04 Janssen Sciences Ireland Unlimited Company Dihydropyrimidine derivatives and uses thereof in the treatment of hbv infection or of hbv-induced diseases
WO2021018238A1 (en) * 2019-07-31 2021-02-04 Janssen Sciences Ireland Unlimited Company Dihydropyrimidine derivatives and uses thereof in the treatment of hbv infection or of hbv-induced diseases
US10919884B2 (en) 2015-08-26 2021-02-16 Achillion Pharmaceuticals, Inc. Amide compounds for treatment of immune and inflammatory disorders
US10927116B2 (en) 2016-02-19 2021-02-23 Hoffmann-La Roche Inc. Process for the preparation of 4-phenyl-5-alkoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-carboxylic acid
WO2021034804A1 (en) 2019-08-19 2021-02-25 Gilead Sciences, Inc. Pharmaceutical formulations of tenofovir alafenamide
US10966966B2 (en) 2019-08-12 2021-04-06 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US10966999B2 (en) 2017-12-20 2021-04-06 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 3′3′ cyclic dinucleotides with phosphonate bond activating the sting adaptor protein
WO2021067181A1 (en) 2019-09-30 2021-04-08 Gilead Sciences, Inc. Hbv vaccines and methods treating hbv
US10973801B2 (en) 2018-03-14 2021-04-13 Janssen Sciences Ireland Unlimited Company Capsid assembly modulator dosing regimen
US11001600B2 (en) 2015-08-26 2021-05-11 Achillion Pharmaceuticals, Inc. Disubstituted compounds for treatment of medical disorders
WO2021113765A1 (en) 2019-12-06 2021-06-10 Precision Biosciences, Inc. Optimized engineered meganucleases having specificity for a recognition sequence in the hepatitis b virus genome
US11053235B2 (en) 2018-08-09 2021-07-06 Janssen Sciences Ireland Unlimited Company Substituted 1,4-dihydropyrimidines for the treatment of HBV infection or HBV-induced diseases
US11053253B2 (en) 2017-03-01 2021-07-06 Achillion Pharmaceuticals, Inc. Macrocyclic compounds for treatment of medical disorders
US11078193B2 (en) 2014-02-06 2021-08-03 Janssen Sciences Ireland Uc Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US11096931B2 (en) 2019-02-22 2021-08-24 Janssen Sciences Ireland Unlimited Company Amide derivatives useful in the treatment of HBV infection or HBV-induced diseases
USRE48731E1 (en) 2012-06-07 2021-09-14 Deciphera Pharmaceuticals, Llc Dihydronaphthyridines and related compounds useful as kinase inhibitors for the treatment of proliferative diseases
WO2021188959A1 (en) 2020-03-20 2021-09-23 Gilead Sciences, Inc. Prodrugs of 4'-c-substituted-2-halo-2'-deoxyadenosine nucleosides and methods of making and using the same
WO2021216656A1 (en) 2020-04-22 2021-10-28 Assembly Biosciences, Inc. 5-membered heteroaryl carboxamide compounds for treatment of hbv
WO2021216661A1 (en) 2020-04-22 2021-10-28 Assembly Biosciences, Inc. Pyrazole carboxamide compounds for treatment of hbv
WO2021216642A1 (en) 2020-04-22 2021-10-28 Assembly Biosciences, Inc. Pyrazole carboxamide compounds for treatment of hbv
WO2021216660A1 (en) 2020-04-22 2021-10-28 Assembly Biosciences, Inc. 5-membered heteroaryl carboxamide compounds for treatment of hbv
US11166954B2 (en) 2016-11-18 2021-11-09 Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. Dihydropyrimidine compound and preparation method and use thereof
US11185535B2 (en) 2019-12-30 2021-11-30 Deciphera Pharmaceuticals, Llc Amorphous kinase inhibitor formulations and methods of use thereof
US11203610B2 (en) 2017-12-20 2021-12-21 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 2′3′ cyclic dinucleotides with phosphonate bond activating the sting adaptor protein
WO2022031894A1 (en) 2020-08-07 2022-02-10 Gilead Sciences, Inc. Prodrugs of phosphonamide nucleotide analogues and their pharmaceutical use
US11266635B2 (en) 2019-08-12 2022-03-08 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
WO2022087149A2 (en) 2020-10-22 2022-04-28 Gilead Sciences, Inc. Interleukin-2-fc fusion proteins and methods of use
US11395818B2 (en) 2019-12-30 2022-07-26 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea
US11447489B2 (en) 2017-12-28 2022-09-20 Hoffmann-La Roche Inc. Dihydropyrimidinylthiazole for the treatment and prophylaxis of hepatitis B virus infection
US11447465B2 (en) 2017-03-01 2022-09-20 Achillion Pharmaceuticals, Inc. Pharmaceutical compounds for treatment of medical disorders
US11491148B2 (en) 2019-05-06 2022-11-08 Janssen Sciences Ireland Unlimited Company Amide derivatives useful in the treatment of HBV infection or HBV-induced diseases
WO2022241134A1 (en) 2021-05-13 2022-11-17 Gilead Sciences, Inc. COMBINATION OF A TLR8 MODULATING COMPOUND AND ANTI-HBV siRNA THERAPEUTICS
WO2022271659A1 (en) 2021-06-23 2022-12-29 Gilead Sciences, Inc. Diacylglyercol kinase modulating compounds
WO2022271684A1 (en) 2021-06-23 2022-12-29 Gilead Sciences, Inc. Diacylglyercol kinase modulating compounds
WO2022271677A1 (en) 2021-06-23 2022-12-29 Gilead Sciences, Inc. Diacylglyercol kinase modulating compounds
WO2022271650A1 (en) 2021-06-23 2022-12-29 Gilead Sciences, Inc. Diacylglyercol kinase modulating compounds
WO2023069545A1 (en) 2021-10-20 2023-04-27 Assembly Biosciences, Inc. 5-membered heteroaryl carboxamide compounds for treatment of hbv
WO2023069544A1 (en) 2021-10-20 2023-04-27 Assembly Biosciences, Inc. 5-membered heteroaryl carboxamide compounds for treatment of hbv
WO2023069547A1 (en) 2021-10-20 2023-04-27 Assembly Biosciences, Inc. 5-membered heteroaryl carboxamide compounds for treatment of hbv
US11639350B2 (en) 2017-06-27 2023-05-02 Janssen Pharmaceutica Nv Heteroaryldihydropyrimidine derivatives and methods of treating hepatitis B infections
WO2023164186A1 (en) 2022-02-25 2023-08-31 Assembly Biosciences, Inc. Benzothia(dia)zepine compounds for treatment of hbv and hdv
WO2023164181A1 (en) 2022-02-25 2023-08-31 Assembly Biosciences, Inc. Benzothia(dia)zepine compounds for treatment of hbv and hdv
WO2023164179A1 (en) 2022-02-25 2023-08-31 Assembly Biosciences, Inc. Benzothia(dia)zepine compounds for treatment of hbv and hdv
WO2023164183A1 (en) 2022-02-25 2023-08-31 Assembly Biosciences, Inc. Benzothia(dia)zepine compounds for treatment of hbv and hdv
US11779572B1 (en) 2022-09-02 2023-10-10 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US11807627B2 (en) 2018-09-25 2023-11-07 Achillon Pharmaceuticals, Inc. Morphic forms of complement factor D inhibitors
US11814363B2 (en) 2018-09-06 2023-11-14 Achillion Pharmaceuticals, Inc. Morphic forms of danicopan
US11814391B2 (en) 2018-09-06 2023-11-14 Achillion Pharmaceuticals, Inc. Macrocyclic compounds for the treatment of medical disorders
US11873302B2 (en) 2019-03-25 2024-01-16 Hoffmann-La Roche Inc. Solid forms of a compound of HBV core protein allosteric modifier
US11986463B2 (en) 2018-01-31 2024-05-21 Deciphera Pharmaceuticals, Llc Combination therapy for the treatment of gastrointestinal stromal tumor
US12076319B2 (en) 2017-08-02 2024-09-03 Achillion Pharmaceuticals, Inc. Therapeutic regimens for treatment of paroxysmal nocturnal hemoglobinuria
US12102620B2 (en) 2018-01-31 2024-10-01 Deciphera Pharmaceuticals, Llc Combination therapy for the treatment of mastocytosis
WO2025043094A1 (en) 2023-08-23 2025-02-27 Assembly Biosciences, Inc. Benzothia(dia)zepine compounds for treatment of hbv and hdv
US12239645B2 (en) 2018-12-17 2025-03-04 Achillion Pharmaceuticals, Inc. Targeted dosing for the treatment of complement mediated disorders
WO2025240243A1 (en) 2024-05-13 2025-11-20 Gilead Sciences, Inc. Combination therapies with bulevirtide and an inhibitory nucleic acid targeting hepatitis b virus
WO2025240246A1 (en) 2024-05-13 2025-11-20 Gilead Sciences, Inc. Combination therapies with ribavirin
WO2025240242A1 (en) 2024-05-13 2025-11-20 Gilead Sciences, Inc. Combination therapies with ribavirin
WO2025240244A1 (en) 2024-05-13 2025-11-20 Gilead Sciences, Inc. Combination therapies comprising bulevirtide and lonafarnib for use in the treatment of hepatitis d virus infection
US12479856B2 (en) 2019-03-22 2025-11-25 Achillion Pharmaceuticals, Inc. Pharmaceutical compounds for the treatment of complement mediated disorders
US12509456B2 (en) 2019-03-11 2025-12-30 Deciphera Pharmaceuticals, Llc Solid state forms of ripretinib
WO2026038156A1 (en) 2024-08-15 2026-02-19 Assembly Biosciences, Inc. Novel crystalline forms
US12616683B2 (en) 2024-04-10 2026-05-05 Deciphera Pharmaceuticals, Llc Combination therapy for the treatment of gastrointestinal stromal tumors

Families Citing this family (60)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2524356T3 (en) 2010-07-22 2014-12-05 Gilead Sciences, Inc. Methods and compounds to treat infections caused by Paramyxoviridae virus
US20130267517A1 (en) 2012-03-31 2013-10-10 Hoffmann-La Roche Inc. Novel 4-methyl-dihydropyrimidines for the treatment and prophylaxis of hepatitis b virus infection
CN104926808B (en) * 2012-08-24 2018-09-14 广东东阳光药业有限公司 Dihydropyrimidines and its application in drug
BR112015028873A2 (en) * 2013-05-17 2017-07-25 Hoffmann La Roche 6-linked heteroaryl dihydropyrimidines for the treatment and prophylaxis of hepatitis B virus infection
TWI687432B (en) 2014-10-29 2020-03-11 美商基利科學股份有限公司 Methods for treating filoviridae virus infections
US10442788B2 (en) 2015-04-01 2019-10-15 Enanta Pharmaceuticals, Inc. Hepatitis B antiviral agents
US20160303095A1 (en) * 2015-04-14 2016-10-20 Gilead Sciences, Inc. Methods of treating hepatitis b virus
WO2016183266A1 (en) 2015-05-13 2016-11-17 Enanta Pharmaceuticals, Inc. Ehpatitis b antiviral agents
US10179131B2 (en) 2015-07-13 2019-01-15 Enanta Pharmaceuticals, Inc. Hepatitis B antiviral agents
US10301255B2 (en) 2015-07-22 2019-05-28 Enanta Pharmaceuticals, Inc. Hepatitis B antiviral agents
DK3785717T3 (en) 2015-09-16 2022-03-21 Gilead Sciences Inc PROCEDURES FOR THE TREATMENT OF CORONAVIRIDAE INFECTIONS
WO2017136403A1 (en) 2016-02-02 2017-08-10 Enanta Pharmaceuticals, Inc. Hepatitis b antiviral agents
KR102398439B1 (en) 2016-03-07 2022-05-16 이난타 파마슈티칼스, 인코포레이티드 Hepatitis B antiviral drugs
CN107200733A (en) * 2016-03-18 2017-09-26 广东东阳光药业有限公司 The crystal formation of dihydropyrimidine derivatives and its application in medicine
CA3028228A1 (en) 2016-06-10 2017-12-14 Enanta Pharmaceuticals, Inc. Hepatitis b antiviral agents
US10682368B2 (en) * 2017-03-14 2020-06-16 Gilead Sciences, Inc. Methods of treating feline coronavirus infections
CA3059777C (en) 2017-05-01 2023-02-21 Gilead Sciences, Inc. Crystalline forms of (s)-2-ethylbutyl 2-(((s)-(((2r,3s,4r,5r)-5-(4-aminopyrrolo[2,1-f] [1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy) phosphoryl)amino)propanoate
WO2019014247A1 (en) 2017-07-11 2019-01-17 Gilead Sciences, Inc. Compositions comprising an rna polymerase inhibitor and cyclodextrin for treating viral infections
SG11202001685TA (en) 2017-08-28 2020-03-30 Enanta Pharm Inc Hepatitis b antiviral agents
WO2019113175A1 (en) 2017-12-06 2019-06-13 Enanta Pharmaceuticals, Inc. Hepatitis b antiviral agents
WO2019113173A1 (en) 2017-12-06 2019-06-13 Enanta Pharmaceuticals, Inc. Hepatitis b antiviral agents
US11058678B2 (en) 2018-01-22 2021-07-13 Enanta Pharmaceuticals, Inc. Substituted heterocycles as antiviral agents
WO2019191166A1 (en) 2018-03-29 2019-10-03 Enanta Pharmaceuticals, Inc. Hepatitis b antiviral agents
CN108218809B (en) * 2018-04-14 2021-03-26 宁夏法安德药业有限公司 Synthetic method of medicine intermediate 2-aminothiazole-4-ethyl formate
JP2022500466A (en) 2018-09-21 2022-01-04 エナンタ ファーマシューティカルズ インコーポレイテッド Functionalized heterocycle as an antiviral agent
IL283190B2 (en) 2018-11-21 2025-08-01 Enanta Pharm Inc Heterocyclics that function as antibiotic agents
TW202104210A (en) 2019-04-17 2021-02-01 美商基利科學股份有限公司 Hiv protease inhibitors
WO2020247444A1 (en) 2019-06-03 2020-12-10 Enanta Pharmaceuticals, Inc, Hepatitis b antiviral agents
WO2020247561A1 (en) 2019-06-04 2020-12-10 Enanta Pharmaceuticals, Inc, Hepatitis b antiviral agents
WO2020247575A1 (en) 2019-06-04 2020-12-10 Enanta Pharmaceuticals, Inc. Hepatitis b antiviral agents
US11738019B2 (en) 2019-07-11 2023-08-29 Enanta Pharmaceuticals, Inc. Substituted heterocycles as antiviral agents
US11236108B2 (en) 2019-09-17 2022-02-01 Enanta Pharmaceuticals, Inc. Functionalized heterocycles as antiviral agents
KR102264881B1 (en) 2019-11-08 2021-06-14 중앙대학교 산학협력단 Actuator for mobile terminal camera with dual msm elements and camera module for mobile terminal with same
IL294032A (en) 2019-12-24 2022-08-01 Carna Biosciences Inc Diacylglycerol kinase modulating compounds
JP2023512656A (en) 2020-01-27 2023-03-28 ギリアード サイエンシーズ， インコーポレイテッド Methods for treating SARS CoV-2 infection
KR20220153619A (en) 2020-03-12 2022-11-18 길리애드 사이언시즈, 인코포레이티드 Method for producing 1'-cyano nucleoside
WO2021188414A1 (en) 2020-03-16 2021-09-23 Enanta Pharmaceuticals, Inc. Functionalized heterocyclic compounds as antiviral agents
CA3172483A1 (en) 2020-04-06 2021-10-14 Scott Ellis Inhalation formulations of 1'-cyano substituted carbanucleoside analogs
TW202203941A (en) 2020-05-29 2022-02-01 美商基利科學股份有限公司 Remdesivir treatment methods
PE20230618A1 (en) 2020-06-24 2023-04-14 Gilead Sciences Inc 1'-CYANO NUCLEOSIDE ANALOGS AND USES THEREOF
IL300412A (en) 2020-08-24 2023-04-01 Gilead Sciences Inc Phospholipid compounds and uses thereof
IL300453A (en) 2020-08-27 2023-04-01 Gilead Sciences Inc Compounds and methods for treatment of viral infections
WO2022052923A1 (en) * 2020-09-08 2022-03-17 和博医药有限公司 Dihydropyrimidine compound and application thereof
TW202344257A (en) 2020-10-16 2023-11-16 美商基利科學股份有限公司 Phospholipid compounds and uses thereof
EP4289842A4 (en) * 2021-02-05 2025-01-08 Hepagene Therapeutics (HK) Limited PHENYLDIHYDROPYRIMIDINE COMPOUND AND ITS USE
WO2022251318A1 (en) 2021-05-26 2022-12-01 Gilead Sciences, Inc. Phospholipid formulations of 1'-cyano substituted carba-nucleoside analogs
AU2022328698B2 (en) 2021-08-18 2025-02-20 Gilead Sciences, Inc. Phospholipid compounds and methods of making and using the same
KR20240154647A (en) 2022-03-02 2024-10-25 길리애드 사이언시즈, 인코포레이티드 Compounds and methods for treating viral infections
KR20240154646A (en) 2022-03-02 2024-10-25 길리애드 사이언시즈, 인코포레이티드 Compounds and methods for treating viral infections
JP2025508941A (en) 2022-03-03 2025-04-10 ギリアード サイエンシーズ， インコーポレイテッド Antiviral compounds and methods for making and using same
KR20240155326A (en) 2022-03-03 2024-10-28 길리애드 사이언시즈, 인코포레이티드 Antiviral compounds and methods for their preparation and use
US20240009220A1 (en) 2022-06-06 2024-01-11 Gilead Sciences, Inc. Methods for treatment of viral infections
WO2024006376A1 (en) 2022-06-29 2024-01-04 Gilead Sciences, Inc. Solid forms of a nucleoside analogue and uses thereof
EP4547665A1 (en) 2022-06-30 2025-05-07 Gilead Sciences, Inc. Solid forms of a nucleoside analogue and uses thereof
US12357577B1 (en) 2024-02-02 2025-07-15 Gilead Sciences, Inc. Pharmaceutical formulations and uses thereof
WO2024173458A1 (en) 2023-02-16 2024-08-22 Gilead Sciences, Inc. Phospholipid compounds and methods of making and using the same
AU2024330988A1 (en) 2023-08-31 2026-02-19 Gilead Sciences, Inc. Antiviral compounds and methods of making and using the same
US20250090537A1 (en) 2023-08-31 2025-03-20 Gilead Sciences, Inc. Antiviral compounds and methods of making and using the same
WO2025054278A1 (en) 2023-09-06 2025-03-13 Gilead Sciences, Inc. Solid forms of a nucleoside analogue and uses thereof
US20250109157A1 (en) 2023-09-28 2025-04-03 Gilead Sciences, Inc. Compounds and methods for treatment of viral infections

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999001438A1 (en) * 1997-07-02 1999-01-14 Astra Aktiebolag (Publ) New compounds
WO2000001005A1 (en) 1998-06-30 2000-01-06 Sony Corporation Method for forming monocrystalline silicon layer, method for manufacturing semiconductor device, and semiconductor device
WO2000058302A1 (en) 1999-03-25 2000-10-05 Bayer Aktiengesellschaft Dihydropyrimidines and their use in the treatment of hepatitis b
WO2001068640A1 (en) * 2000-03-16 2001-09-20 Bayer Aktiengesellschaft Medicaments against viral diseases
WO2011025889A1 (en) 2009-08-28 2011-03-03 Takeda Pharmaceutical Company Limited HEXAHYDROOXAZINOPTERINE COMPOUNDS FOR USE AS mTOR INHIBITORS
WO2013019967A1 (en) * 2011-08-02 2013-02-07 Scripps Research Institute, A Not-For-Profit Public Benefit Corporation Of California Modulators of virus assembly as antiviral agents

Family Cites Families (41)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3234684A1 (en) 1982-09-18 1984-03-22 Bayer Ag, 5090 Leverkusen NEW DIHYDROPYRIMIDINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE IN MEDICINAL PRODUCTS
GB8906168D0 (en) 1989-03-17 1989-05-04 Pfizer Ltd Therapeutic agents
GB9727523D0 (en) 1997-12-31 1998-02-25 Pharmacia & Upjohn Spa Alpha-aminoamide derivatives useful as analgesic agents
DE19817264A1 (en) 1998-04-18 1999-10-21 Bayer Ag New dihydropyrimidine derivatives and their corresponding mesomers useful as antiviral agents
DE19817265A1 (en) 1998-04-18 1999-10-21 Bayer Ag Treating hepatitis B using new or known dihydropyrimidine derivative antiviral agents
DE19817262A1 (en) 1998-04-18 1999-10-21 Bayer Ag New dihydropyrimidine derivatives and their corresponding mesomers useful in treatment of hepatitis
AU3009801A (en) 1999-12-22 2001-07-03 Bayer Aktiengesellschaft Combinations of medicaments for treating viral diseases
DE10012549A1 (en) 2000-03-15 2001-09-20 Bayer Ag New heterocyclic-substituted dihydropyrimidine derivatives useful for treatment of viral infections, especially hepatitis B infections
DE10012824A1 (en) 2000-03-16 2001-09-20 Bayer Ag New 6-hydroxyhydrocarbyl or 6-thiohydrocarbyl-dihydropyrimidine-5-carboxylic acid derivatives, useful for the treatment of viral infections, especially hepatitis B infections
DE10013126A1 (en) * 2000-03-17 2001-09-20 Bayer Ag New 6-aminoalkyl-dihydropyrimidine-5-carboxylate ester derivatives, useful as antiviral agents having strong activity against hepatitis B virus and low cytotoxicity
DE10013125A1 (en) 2000-03-17 2001-09-20 Bayer Ag New 4-dihalophenyl-dihydropyrimidine-5-carboxylate ester derivatives, useful as antiviral agents having strong activity against hepatitis B virus and low cytotoxicity
EP1646615B1 (en) 2003-06-06 2009-08-26 Vertex Pharmaceuticals Incorporated Pyrimidine derivatives as modulators of atp-binding cassette transporters
US7157461B2 (en) 2003-07-23 2007-01-02 Bristol-Myers Squibb Co. Substituted dihydropyrimidine inhibitors of calcium channel function
EP1756092A4 (en) 2004-06-17 2009-12-02 Smithkline Beecham Corp Novel inhibitors of rho-kinases
WO2006033995A2 (en) 2004-09-16 2006-03-30 Valeant Research And Development Thiazolidin-4-ones having anti-hepatitis b activity
WO2007014023A1 (en) 2005-07-21 2007-02-01 Valeant Research & Development Thiazolidinones, oxazolidinones, and pyrrolidinones for hbv
WO2007051062A2 (en) 2005-10-28 2007-05-03 Chemocentryx, Inc. Substituted dihydropyridines and methods of use
KR101130380B1 (en) 2006-06-13 2012-04-23 상하이 인스티튜트 오브 마테리아 메디카 차이니즈 아카데미 오브 싸이언시즈 Heterocyclic non-nucleoside compounds, their preparation, pharmaceutical composition and their use as antiviral agents
CN101104604B (en) 2006-07-10 2011-03-02 北京摩力克科技有限公司 Optically pure dihydropyrimidine compounds and use for the same in preparing medicament for curing and preventing virosis
CN101104617B (en) 2006-07-10 2010-06-23 北京摩力克科技有限公司 Dihydropyrimidine compounds and their use in the preparation of medicines for treating and preventing viral diseases
CN101225084A (en) 2007-01-16 2008-07-23 北京摩力克科技有限公司 Dihydropyrimidine compounds and their use in the preparation of medicines for treating and preventing viral diseases
CN101328170B (en) 2007-06-18 2011-09-14 张中能 Fluorophenyl-substituted thiazole dihydropyrimidine
WO2008154820A1 (en) * 2007-06-18 2008-12-24 Zhang, Zhongneng Carbethoxy-substituted thiazolyl dihydropyrimidines
AU2008265397C1 (en) 2007-06-18 2013-08-29 Sunshine Lake Pharma Co., Ltd. Bromo-phenyl substituted thiazolyl dihydropyrimidines
WO2008154819A1 (en) 2007-06-18 2008-12-24 Zhang, Zhongneng Carbethoxy-substituted thiazolyl dihydropyrimidines
CN101918389A (en) 2007-11-02 2010-12-15 梅特希尔基因公司 Histone deacetylase inhibitor
WO2010069147A1 (en) * 2008-12-17 2010-06-24 张中能 Dihydropyrimidine derivatives, compositions thereof and their use
CN101575314B (en) 2009-06-25 2011-05-11 中国人民解放军军事医学科学院毒物药物研究所 Dihydropyridine compounds and application thereof on preparing drugs for curing and/or preventing virus diseases
CN101575318B (en) * 2009-06-25 2012-02-08 中国人民解放军军事医学科学院毒物药物研究所 Dihydropyrimidine compounds and their use in the preparation of medicines for treating and/or preventing viral diseases
US20120263646A1 (en) 2009-10-15 2012-10-18 Guerbet Imaging agents and their use for the diagnostic in vivo of neurodegenerative diseases, notably alzheimer's disease and derivative diseases
EP2800742B1 (en) * 2012-01-06 2016-04-06 Janssen Sciences Ireland UC 4,4-disubstituted-1,4-dihydropyrimidines and the use thereof as medicaments for the treatment of hepatitis b
ES2575398T3 (en) * 2012-03-31 2016-06-28 F. Hoffmann-La Roche Ag Novel 4-Methyl-dihydropyrimidines for the treatment and prophylaxis of hepatitis B virus infection
CN103570626A (en) * 2012-08-06 2014-02-12 上海壹志医药科技有限公司 Salt of dihydropyrimidine derivative
CN104926808B (en) * 2012-08-24 2018-09-14 广东东阳光药业有限公司 Dihydropyrimidines and its application in drug
CN103664897B (en) * 2012-09-01 2018-04-03 广东东阳光药业有限公司 Dihydropyrimidines and its application in medicine
CN103664925B (en) * 2012-09-07 2018-01-23 广东东阳光药业有限公司 The Dihydropyrimidines of heteroaryl substitution and its application in medicine
CN103664899B (en) * 2012-09-11 2017-06-16 广东东阳光药业有限公司 The Dihydropyrimidines of heteroaryl substitution and its application in medicine
CN103724339B (en) * 2012-09-27 2015-10-14 广东东阳光药业有限公司 Crystal forms of dihydropyrimidine derivatives
HK1215030A1 (en) * 2012-11-09 2016-08-12 Indiana University Research And Technology Corporation Alternative uses for hbv assembly effectors
SG11201507698QA (en) * 2013-03-20 2015-10-29 Univ Indiana Res & Tech Corp Fluorescent-hap: a diagnostic stain for hbv cores in cells
BR112015028873A2 (en) * 2013-05-17 2017-07-25 Hoffmann La Roche 6-linked heteroaryl dihydropyrimidines for the treatment and prophylaxis of hepatitis B virus infection

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999001438A1 (en) * 1997-07-02 1999-01-14 Astra Aktiebolag (Publ) New compounds
WO2000001005A1 (en) 1998-06-30 2000-01-06 Sony Corporation Method for forming monocrystalline silicon layer, method for manufacturing semiconductor device, and semiconductor device
WO2000058302A1 (en) 1999-03-25 2000-10-05 Bayer Aktiengesellschaft Dihydropyrimidines and their use in the treatment of hepatitis b
WO2001068640A1 (en) * 2000-03-16 2001-09-20 Bayer Aktiengesellschaft Medicaments against viral diseases
WO2011025889A1 (en) 2009-08-28 2011-03-03 Takeda Pharmaceutical Company Limited HEXAHYDROOXAZINOPTERINE COMPOUNDS FOR USE AS mTOR INHIBITORS
WO2013019967A1 (en) * 2011-08-02 2013-02-07 Scripps Research Institute, A Not-For-Profit Public Benefit Corporation Of California Modulators of virus assembly as antiviral agents

Non-Patent Citations (15)

* Cited by examiner, † Cited by third party
Title
ANSEL, H. ET AL.: "Pharmaceutical Dosage Forms and Drug Delivery Systems", 1995, pages: 196,1456 - 1457
ANSEL, HOWARD C. ET AL.: "Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems", 2004, LIPPINCOTT, WILLIAMS & WILKINS
BASTIN R.J. ET AL., ORGANIC PROCESS RESEARCH & DEVELOPMENT, vol. 4, 2000, pages 427 - 435
BREZILLON N. ET AL., PLOS ONE, 2011, pages E25096
DERES K. ET AL., SCIENCE, 2003, pages 893
DERES KARL ET AL: "Inhibition of hepatitis B virus replication by drug-induced depletion of nucleocapsids", SCIENCE, AMERICAN ASSOCIATION FOR THE ADVANCEMENT OF SCIENCE, US, vol. 299, no. 5608, 7 February 2003 (2003-02-07), pages 893 - 896, XP009100473, ISSN: 1095-9203, DOI: 10.1126/SCIENCE.1077215 *
FELD J. ET AL., ANTIVIRAL RESEARCH, 2007, pages 168 - 177
GENNARO, ALFONSO R. ET AL.: "Remington: The Science and Practice of Pharmacy", 2000, LIPPINCOTT, WILLIAMS & WILKINS
GOLUBEV, A. ET AL., TETRAHEDRON LETT., vol. 45, 2004, pages 1445 - 1447
H GUO ET AL., JOURNAL OF VIROLOGY, vol. 81, 2007, pages 12472 - 12484
HU, SHANGHUI; MARTINEZ, CARLOS A.; KLINE, BILLIE; YAZBECK, DANIEL; TAO, JUNHUA; KUCERA, DAVID J., ORGANIC PROCESS RESEARCH & DEVELOPMENT, vol. 10, 2006, pages 650 - 654
MA SELLES ET AL., PROC. NATL. ACAD. SCI. USA, vol. 84, 1987, pages 1005 - 1009
ROWE, RAYMOND C.: "Handbook of Pharmaceutical Excipients", 2005, PHARMACEUTICAL PRESS
STOLTING, J. ET AL., PCT INT. APPL., 2000
ZLOTNICK A. ET AL., J. VIROL., 2002, pages 4848 - 4854

Cited By (319)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10196376B2 (en) 2011-12-21 2019-02-05 Novira Therapeutics, Inc. Hepatitis B antiviral agents
US9676747B2 (en) 2011-12-21 2017-06-13 Novira Therapeutics, Inc. Hepatitis B antiviral agents
US9066932B2 (en) 2011-12-21 2015-06-30 Novira Therapeutics, Inc. Hepatitis B antiviral agents
US9751857B2 (en) 2011-12-21 2017-09-05 Novira Therapeutics, Inc. Hepatitis B antiviral agents
US9061008B2 (en) 2011-12-21 2015-06-23 Novira Therapeutics, Inc. Hepatitis B antiviral agents
USRE48731E1 (en) 2012-06-07 2021-09-14 Deciphera Pharmaceuticals, Llc Dihydronaphthyridines and related compounds useful as kinase inhibitors for the treatment of proliferative diseases
US10676429B2 (en) 2012-08-28 2020-06-09 Janssen Sciences Ireland Uc Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B
US10995064B2 (en) 2012-08-28 2021-05-04 Janssen Sciences Ireland Uc Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B
US10501489B2 (en) 2012-09-10 2019-12-10 Reata Pharmaceuticals, Inc. C17-alkanediyl and alkenediyl derivatives of oleanolic acid and methods of use thereof
US10125094B2 (en) 2013-02-28 2018-11-13 Janssen Sciences Ireland Uc Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B
US10941113B2 (en) 2013-02-28 2021-03-09 Janssen Sciences Ireland Uc Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B
US9579313B2 (en) 2013-03-12 2017-02-28 Novira Therapeutics, Inc. Hepatitis B antiviral agents
US8993771B2 (en) 2013-03-12 2015-03-31 Novira Therapeutics, Inc. Hepatitis B antiviral agents
US9205079B2 (en) 2013-03-12 2015-12-08 Novira Therapeutics, Inc. Hepatitis B antiviral agents
US9895349B2 (en) 2013-04-03 2018-02-20 Janssen Sciences Ireland Us N-phenyl-carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10398677B2 (en) 2013-04-03 2019-09-03 Janssen Sciences Ireland Uc N-phenyl-carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10457638B2 (en) 2013-05-17 2019-10-29 Janssen Sciences Ireland Uc Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US9884818B2 (en) 2013-05-17 2018-02-06 Janssen Sciences Ireland Uc Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10450270B2 (en) 2013-07-25 2019-10-22 Janssen Sciences Ireland Uc Glyoxamide substituted pyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10377709B2 (en) 2013-10-23 2019-08-13 Janssen Sciences Ireland Uc Carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
US10071961B2 (en) 2013-10-23 2018-09-11 Janssen Sciences Ireland Uc Carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
JP2016537358A (en) * 2013-11-19 2016-12-01 サンシャイン・レイク・ファーマ・カンパニー・リミテッドＳｕｎｓｈｉｎｅ Ｌａｋｅ Ｐｈａｒｍａ Ｃｏ．，Ｌｔｄ． Dihydropyrimidine compounds and their application in medicine
CN104650068A (en) * 2013-11-19 2015-05-27 广东东阳光药业有限公司 Dihydropyrimidine compound and application thereof to drugs
US20160206616A1 (en) * 2013-11-19 2016-07-21 Sunshine Lake Pharma Co., Ltd. Dihydropyrimidine compounds and their application in pharmaceuticals
WO2015074546A1 (en) * 2013-11-19 2015-05-28 Sunshine Lake Pharma Co., Ltd. Dihydropyrimidine compounds and their application in pharmaceuticals
AU2014352404B2 (en) * 2013-11-19 2018-07-19 Sunshine Lake Pharma Co., Ltd. Dihydropyrimidine compounds and their application in pharmaceuticals
CN104650068B (en) * 2013-11-19 2018-08-10 广东东阳光药业有限公司 Dihydropyrimidines and its application in drug
RU2678990C1 (en) * 2013-11-19 2019-02-05 Саншайн Лейк Фарма Ко., Лтд. Dihydropyrimidine compounds and their application in pharmaceuticals
US9498479B2 (en) * 2013-11-19 2016-11-22 Sunshine Lake Pharma Co., Ltd. Dihydropyrimidine compounds and their application in pharmaceuticals
CN104672222B (en) * 2013-11-27 2018-03-13 广东东阳光药业有限公司 The Preparation Method And Their Intermediate of dihydropyrimidine derivatives
CN104672223A (en) * 2013-11-27 2015-06-03 广东东阳光药业有限公司 Preparation method of dihydropyrimidine derivative and intermediate of dihydropyrimidine derivative
CN104672225A (en) * 2013-11-27 2015-06-03 广东东阳光药业有限公司 Method for preparing dihydropyrimidine derivative and intermediate of dihydropyrimidine
CN104672224A (en) * 2013-11-27 2015-06-03 广东东阳光药业有限公司 Preparation method of dihydropyrimidine derivative and intermediate of dihydropyrimidine derivative
CN104672222A (en) * 2013-11-27 2015-06-03 广东东阳光药业有限公司 Preparation method of dihydropyrimidine derivative and intermediate of dihydropyrimidine derivative
CN104672223B (en) * 2013-11-27 2018-03-13 广东东阳光药业有限公司 The Preparation Method And Their Intermediate of dihydropyrimidine derivatives
CN104672225B (en) * 2013-11-27 2019-02-12 广东东阳光药业有限公司 Preparation method of dihydropyrimidine derivatives and intermediates thereof
US9169212B2 (en) 2014-01-16 2015-10-27 Novira Therapeutics, Inc. Azepane derivatives and methods of treating hepatitis B infections
US9505722B2 (en) 2014-01-16 2016-11-29 Novira Therapeutics, Inc. Azepane derivatives and methods of treating hepatitis B infections
US10392349B2 (en) 2014-01-16 2019-08-27 Novira Therapeutics, Inc. Azepane derivatives and methods of treating hepatitis B infections
US9873671B2 (en) 2014-01-16 2018-01-23 Novira Therapeutics, Inc. Azepane derivatives and methods of treating hepatitis B infections
US9181288B2 (en) 2014-01-16 2015-11-10 Novira Therapeutics, Inc. Azepane derivatives and methods of treating hepatitis B infections
US9339510B2 (en) 2014-01-16 2016-05-17 Novira Therapeutics, Inc. Azepane derivatives and methods of treating hepatitis B infections
US10213420B2 (en) 2014-02-05 2019-02-26 Novira Therapeutics, Inc. Combination therapy for treatment of HBV infections
US10632112B2 (en) 2014-02-05 2020-04-28 Novira Therapeutics, Inc. Combination therapy for treatment of HBV infections
US11078193B2 (en) 2014-02-06 2021-08-03 Janssen Sciences Ireland Uc Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
EP4129407A1 (en) 2014-02-25 2023-02-08 Achillion Pharmaceuticals, Inc. Aryl, heteroaryl, and heterocyclic compounds for treatment of complement mediated disorders
US9598446B2 (en) 2014-02-25 2017-03-21 Achillion Pharmaceuticals, Inc. Amino compounds for treatment of complement mediated disorders
US9732103B2 (en) 2014-02-25 2017-08-15 Achillion Pharmaceuticals, Inc. Carbamate, ester, and ketone compounds for treatment of complement mediated disorders
US9695205B2 (en) 2014-02-25 2017-07-04 Achillion Pharmaceuticals, Inc. Amide compounds for treatment of complement mediated disorders
US9758537B2 (en) 2014-02-25 2017-09-12 Achillion Pharmaceuticals Compounds for treatment of complement mediated disorders
US9796741B2 (en) 2014-02-25 2017-10-24 Achillion Pharmaceuticals, Inc. Aryl, heteroaryl, and heterocyclic compounds for treatment of complement mediated disorders
US9828396B2 (en) 2014-02-25 2017-11-28 Achillion Pharmaceuticals, Inc. Alkyne compounds for treatment of complement mediated disorders
US12065459B2 (en) 2014-02-25 2024-08-20 Achillion Pharmaceuticals, Inc. Aryl, heteroaryl, and heterocyclic compounds for treatment of complement mediated disorders
US10370394B2 (en) 2014-02-25 2019-08-06 Achillion Pharmaceuticals, Inc. Carbamate, ester, and ketone compounds for treatment of complement mediated disorders
US10301336B2 (en) 2014-02-25 2019-05-28 Achillion Pharmaceuticals, Inc. Phosphonate compounds for treatment of complement mediated disorders
US9663543B2 (en) 2014-02-25 2017-05-30 Achillion Pharmaceuticals, Inc. Phosphonate compounds for treatment of complement mediated disorders
US10253053B2 (en) 2014-02-25 2019-04-09 Achillion Pharmaceuticals, Inc. Aryl, heteroaryl, and heterocyclic compounds for treatment of complement mediated disorders
US9643986B2 (en) 2014-02-25 2017-05-09 Achillion Pharmaceuticals, Inc. Factor D inhibitors useful for treating inflammatory disorders
US10428095B2 (en) 2014-02-25 2019-10-01 Achillion Pharmaceuticals, Inc. Compounds for treatment of complement mediated disorders
US10428094B2 (en) 2014-02-25 2019-10-01 Achillion Pharmaceuticals, Inc. Amide compounds for treatment of complement mediated disorders
US9732104B2 (en) 2014-02-25 2017-08-15 Achillion Pharmaceuticals, Inc. Ether compounds for treatment of complement mediated disorders
US10464956B2 (en) 2014-02-25 2019-11-05 Achillion Pharmaceuticals, Inc. Aryl, heteroaryl, and heterocyclic compounds for treatment of complement mediated disorders
US10689409B2 (en) 2014-02-25 2020-06-23 Achillion Pharmaceuticals, Inc. Amino compounds for treatment of complement mediated disorders
US10189869B2 (en) 2014-02-25 2019-01-29 Achillion Pharmaceuticals, Inc. Amino compounds for treatment of complement mediated disorders
US10550140B2 (en) 2014-02-25 2020-02-04 Achillion Pharmaceuticals, Inc. Ether compounds for treatment of complement mediated disorders
US10005802B2 (en) 2014-02-25 2018-06-26 Achillion Pharmaceuticals, Inc. Amide compounds for treatment of complement mediated disorders
EP3623367A1 (en) 2014-02-25 2020-03-18 Achillion Pharmaceuticals, Inc. Aryl, heteroaryl, and heterocyclic compounds for treatment of complement mediated disorders
US10106563B2 (en) 2014-02-25 2018-10-23 Achillion Pharmaecuticals, Inc. Ether compounds for treatment of complement mediated disorders
US10100072B2 (en) 2014-02-25 2018-10-16 Achillion Pharmaceuticals, Inc. Phosphonate compounds for treatment of complement mediated disorders
US10087203B2 (en) 2014-02-25 2018-10-02 Achillion Pharmaceuticals, Inc. Compounds for treatment of complement mediated disorders
US10081645B2 (en) 2014-02-25 2018-09-25 Achillion Pharmaceuticals, Inc. Aryl, heteroaryl, and heterocyclic compounds for treatment of complement mediated disorders
EP3607950A2 (en) 2014-03-13 2020-02-12 Indiana University Research & Technology Corporation Hepatitis b core protein allosteric modulators
EP3974426A1 (en) 2014-03-13 2022-03-30 Indiana University Research and Technology Corporation Hepatitis b core protein allosteric modulators
US9400280B2 (en) 2014-03-27 2016-07-26 Novira Therapeutics, Inc. Piperidine derivatives and methods of treating hepatitis B infections
JP2017512789A (en) * 2014-03-28 2017-05-25 サンシャイン・レイク・ファーマ・カンパニー・リミテッドＳｕｎｓｈｉｎｅ Ｌａｋｅ Ｐｈａｒｍａ Ｃｏ．，Ｌｔｄ． Dihydropyrimidine compounds and their application in medicine
WO2015144093A1 (en) * 2014-03-28 2015-10-01 Sunshine Lake Pharma Co., Ltd. Dihydropyrimidine compounds and their application in pharmaceuticals
RU2682672C2 (en) * 2014-03-28 2019-03-20 Саншайн Лейк Фарма Ко., Лтд. Dihydropyrimidin compounds and their application in pharmaceuticals
CN104945395A (en) * 2014-03-28 2015-09-30 广东东阳光药业有限公司 Dihydropyrimidine compound and application thereof in medicaments
EP3139954A4 (en) * 2014-05-09 2018-02-28 Indiana University Research and Technology Corporation Methods and compositions for treating hepatitis b virus infections
WO2016012470A1 (en) * 2014-07-25 2016-01-28 F. Hoffmann-La Roche Ag New amorphous and crystalline forms of (3s)-4-[[(4r)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1, 4-dihydropyrimidin-6-yl]methyl]morpholine-3-carboxylic acid
WO2016016196A1 (en) * 2014-07-31 2016-02-04 F. Hoffmann-La Roche Ag Novel chiral resolution of 4-aryl-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylic acid esters
CN104211696A (en) * 2014-08-20 2014-12-17 河北科技大学 Preparation method of TMC-435 (Simeprevir) important intermediate
CN104327006A (en) * 2014-10-19 2015-02-04 湖南华腾制药有限公司 Preparation method of 5-ehtyl-4-formamidooxazole
WO2016102438A1 (en) * 2014-12-23 2016-06-30 F. Hoffmann-La Roche Ag Process for the preparation of 4-phenyl-5-alkoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidine analogues
WO2016120186A1 (en) 2015-01-27 2016-08-04 F. Hoffmann-La Roche Ag Recombinant hbv cccdna, the method to generate thereof and the use thereof
CN105859708A (en) * 2015-02-07 2016-08-17 广东东阳光药业有限公司 Salts of dihydropyrimidine derivative and application thereof in medicines
WO2016124126A1 (en) * 2015-02-07 2016-08-11 Sunshine Lake Pharma Co., Ltd. Complexes and salts of dihydropyrimidine derivatives and their application in pharmaceuticals
CN105859709A (en) * 2015-02-07 2016-08-17 广东东阳光药业有限公司 Composite of dihydropyrimidine derivative and application thereof in medicines
US10098889B2 (en) * 2015-02-07 2018-10-16 Sunshine Lake Pharma Co., Ltd. Complexes and salts of dihydropyrimidine derivatives and their application in pharmaceuticals
EP3321265A1 (en) 2015-03-04 2018-05-16 Gilead Sciences, Inc. 4,6-diamino-pyrido[3,2-d]pyrimidine compounds and their utilisation as modulators of toll-like receptors
EP3722297A1 (en) 2015-03-04 2020-10-14 Gilead Sciences, Inc. Toll-like receptor modulating 4,6-diamino-pyrido[3,2-d]pyrimidine compounds
WO2016141092A1 (en) 2015-03-04 2016-09-09 Gilead Sciences, Inc. Toll-like receptor modulating 4,6-diamino-pyrido[3,2-d]pyrimidine compounds
JP2021100967A (en) * 2015-03-16 2021-07-08 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ Combined treatment with tlr7 agonist and hbv capsid assembly inhibitor
EP3845227A1 (en) * 2015-03-16 2021-07-07 F. Hoffmann-La Roche AG Combined treatment with a tlr7 agonist and an hbv capsid assembly inhibitor
JP2020100637A (en) * 2015-03-16 2020-07-02 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ Combination treatment with TLR7 agonist and HBV capsid assembly inhibitor
EP3695837A1 (en) * 2015-03-16 2020-08-19 F. Hoffmann-La Roche AG Combined treatment with a tlr7 agonist and an hbv capsid assembly inhibitor
WO2016146598A1 (en) 2015-03-16 2016-09-22 F. Hoffmann-La Roche Ag Combined treatment with a tlr7 agonist and an hbv capsid assembly inhibitor
AU2019202966B2 (en) * 2015-03-16 2021-04-15 F. Hoffmann-La Roche Ag Combined treatment with a TLR7 agonist and an HBV capsid assembly inhibitor
CN107427514B (en) * 2015-03-16 2021-07-13 豪夫迈·罗氏有限公司 Combination therapy with TLR7 agonists and HBV capsid assembly inhibitors
US11771699B2 (en) 2015-03-16 2023-10-03 Hoffmann-La Roche Inc. Combined treatment with a TLR7 agonist and an HBV capsid assembly inhibitor
AU2016232353B2 (en) * 2015-03-16 2019-05-16 F. Hoffmann-La Roche Ag Combined treatment with a TLR7 agonist and an HBV capsid assembly inhibitor
CN107427514A (en) * 2015-03-16 2017-12-01 豪夫迈·罗氏有限公司 Use TLR7 activators and the combined therapy of HBV capsids assembling inhibitor
JP7195360B2 (en) 2015-03-16 2022-12-23 エフ．ホフマン－ラ ロシュ アーゲー Combination treatment with TLR7 agonists and HBV capsid assembly inhibitors
JP2018508552A (en) * 2015-03-16 2018-03-29 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ Combined treatment with TLR7 agonist and HBV capsid assembly inhibitor
US9884831B2 (en) 2015-03-19 2018-02-06 Novira Therapeutics, Inc. Azocane and azonane derivatives and methods of treating hepatitis B infections
US10537580B2 (en) 2015-03-19 2020-01-21 Novira Therapeutics, Inc. Azocane and azonane derivatives and methods of treating hepatitis B infections
WO2016202721A1 (en) 2015-06-16 2016-12-22 F. Hoffmann-La Roche Ag Salts of (s)-4-[(r)-6-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6- dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic acid, salt former and methods for preparing and using the same
EP3590943A1 (en) 2015-07-02 2020-01-08 Janssen Sciences Ireland Unlimited Company Cyclized sulfamoylarylamide derivatives and the use thereof as medicaments for the treatment of hepatitis b
US10875876B2 (en) 2015-07-02 2020-12-29 Janssen Sciences Ireland Uc Cyclized sulfamoylarylamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
WO2017035230A1 (en) 2015-08-26 2017-03-02 Gilead Sciences, Inc. Deuterated toll-like receptor modulators
US11926617B2 (en) 2015-08-26 2024-03-12 Achillion Pharmaceuticals, Inc. Aryl, heteroaryl, and heterocyclic compounds for treatment of immune and inflammatory disorders
US10662175B2 (en) 2015-08-26 2020-05-26 Achillion Pharmaceuticals, Inc. Aryl, heteroaryl, and heterocyclic compounds for treatment of immune and inflammatory disorders
US10906887B2 (en) 2015-08-26 2021-02-02 Achillion Pharmaceuticals, Inc. Amino compounds for treatment of immune and inflammatory disorders
US11649223B2 (en) 2015-08-26 2023-05-16 Achillion Pharmaceuticals, Inc. Amino compounds for treatment of immune and inflammatory disorders
US11649229B2 (en) 2015-08-26 2023-05-16 Achillion Pharmaceuticals, Inc. Amide compounds for treatment of immune and inflammatory disorders
US10660876B2 (en) 2015-08-26 2020-05-26 Achillion Pharmaceuticals, Inc. Amino compounds for treatment of medical disorders
US10919884B2 (en) 2015-08-26 2021-02-16 Achillion Pharmaceuticals, Inc. Amide compounds for treatment of immune and inflammatory disorders
US10822352B2 (en) 2015-08-26 2020-11-03 Achillion Pharmaceuticals, Inc. Aryl, heteroaryl, and heterocyclic compounds for treatment of medical disorders
US12139497B2 (en) 2015-08-26 2024-11-12 Achillion Pharmaceuticals, Inc. Aryl, heteroaryl, and heterocyclic compounds for treatment of medical disorders
US10807952B2 (en) 2015-08-26 2020-10-20 Achillion Pharmaceuticals, Inc. Compounds for treatment of immune inflammatory disorders
EP4053117A1 (en) 2015-08-26 2022-09-07 Achillion Pharmaceuticals, Inc. Aryl, heteroaryl, and heterocyclic compounds for treatment of medical disorders
WO2017035408A1 (en) 2015-08-26 2017-03-02 Achillion Pharmaceuticals, Inc. Compounds for treatment of immune and inflammatory disorders
US10138225B2 (en) 2015-08-26 2018-11-27 Achillion Pharmaceuticals, Inc. Amide compounds for treatment of medical disorders
US11407738B2 (en) 2015-08-26 2022-08-09 Achillion Pharmaceuticals, Inc. Aryl, heteroaryl, and heterocyclic compounds for treatment of immune and inflammatory disorders
US10011612B2 (en) 2015-08-26 2018-07-03 Achillion Pharmaceuticals, Inc. Aryl, heteroaryl, and heterocyclic compounds for treatment of medical disorders
US10385097B2 (en) 2015-08-26 2019-08-20 Achillion Pharmaceuticals, Inc. Ether compounds for treatment of medical disorders
US12338230B2 (en) 2015-08-26 2025-06-24 Achillion Pharmaceuticals, Inc. Aryl, heteroaryl, and heterocyclic compounds for treatment of immune and inflammatory disorders
US10000516B2 (en) 2015-08-26 2018-06-19 Achillion Pharmaceuticals, Inc. Phosphonate compounds for treatment of medical disorders
US11001600B2 (en) 2015-08-26 2021-05-11 Achillion Pharmaceuticals, Inc. Disubstituted compounds for treatment of medical disorders
US10092584B2 (en) 2015-08-26 2018-10-09 Achillion Pharmaceuticals, Inc. Compounds for the treatment of medical disorders
US10287301B2 (en) 2015-08-26 2019-05-14 Achillion Pharmaceuticals, Inc. Aryl, heteroaryl, and heterocyclic compounds for treatment of medical disorders
EP3782626A1 (en) 2015-09-15 2021-02-24 Assembly Biosciences, Inc. Hepatitis b core protein modulators
WO2017048954A1 (en) 2015-09-15 2017-03-23 Assembly Biosciences, Inc. Hepatitis b core protein modulators
WO2017048962A1 (en) 2015-09-15 2017-03-23 Assembly Biosciences, Inc. Hepatitis b core protein modulators
US10077239B2 (en) 2015-09-29 2018-09-18 Novira Therapeutics, Inc. Crystalline forms of a hepatitis B antiviral agent
WO2017064156A1 (en) 2015-10-16 2017-04-20 F. Hoffmann-La Roche Ag Novel 6-fused and 2-heteroaryldihydropyrimidines for the treatment and prophylaxis of hepatitis b virus infection
US10596173B2 (en) 2015-11-03 2020-03-24 Hoffmann-La Roche Inc. Combination therapy of an HBV capsid assembly inhibitor and an interferon
KR102181168B1 (en) * 2015-11-03 2020-11-23 에프. 호프만-라 로슈 아게 Combination treatment of HBV capsid assembly inhibitor and interferon
KR20180058828A (en) * 2015-11-03 2018-06-01 에프. 호프만-라 로슈 아게 Combination therapy of HBV capsid assembly inhibitor and interferon
WO2017076791A1 (en) * 2015-11-03 2017-05-11 F. Hoffmann-La Roche Ag Combination therapy of an hbv capsid assembly inhibitor and an interferon
WO2017108630A1 (en) * 2015-12-21 2017-06-29 F. Hoffmann-La Roche Ag Combination therapy of an hbsag inhibitor and an hbv capsid assembly inhibitor
US10927116B2 (en) 2016-02-19 2021-02-23 Hoffmann-La Roche Inc. Process for the preparation of 4-phenyl-5-alkoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-carboxylic acid
US11129834B2 (en) 2016-04-15 2021-09-28 Novira Therapeutics, Inc. Combinations and methods comprising a capsid assembly inhibitor
US10441589B2 (en) 2016-04-15 2019-10-15 Novira Therapeutics, Inc. Combinations and methods comprising a capsid assembly inhibitor
WO2017205115A1 (en) 2016-05-27 2017-11-30 Gilead Sciences, Inc. Compounds for the treatment of hepatitis b virus infection
WO2017205078A1 (en) 2016-05-27 2017-11-30 Gilead Sciences, Inc. Methods for treating hepatitis b virus infections using ns5a, ns5b or ns3 inhibitors
WO2018036941A1 (en) 2016-08-24 2018-03-01 F. Hoffmann-La Roche Ag Combination therapy of an hbv capsid assembly inhibitor and a nucleos(t)ide analogue
US20190275052A1 (en) * 2016-08-24 2019-09-12 Hoffmann-La Roche Inc. Combination therapy of an hbv capsid assembly inhibitor and a nucleos(t)ide analogue
WO2018039531A1 (en) 2016-08-26 2018-03-01 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof
EP3922634A1 (en) 2016-08-26 2021-12-15 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof
WO2018045144A1 (en) 2016-09-02 2018-03-08 Gilead Sciences, Inc. Toll like receptor modulator compounds
WO2018045150A1 (en) 2016-09-02 2018-03-08 Gilead Sciences, Inc. 4,6-diamino-pyrido[3,2-d]pyrimidine derivaties as toll like receptor modulators
US11337982B2 (en) 2016-09-13 2022-05-24 Hoffmann-La Roche, Inc. Combined treatment with a TLR7 agonist and an HBV capsid assembly inhibitor
WO2018050571A1 (en) 2016-09-13 2018-03-22 F. Hoffmann-La Roche Ag Combined treatment with a tlr7 agonist and an hbv capsid assembly inhibitor
WO2018053157A1 (en) 2016-09-15 2018-03-22 Assembly Biosciences, Inc. Hepatitis b core protein modulators
US11274285B2 (en) 2016-10-14 2022-03-15 Precision Biosciences, Inc. Engineered meganucleases specific for recognition sequences in the Hepatitis B virus genome
US10662416B2 (en) 2016-10-14 2020-05-26 Precision Biosciences, Inc. Engineered meganucleases specific for recognition sequences in the hepatitis B virus genome
US10696669B2 (en) 2016-11-18 2020-06-30 Sichuan Kelun-Biotech Biopharmaceuticals Co., Ltd. Dihydropyrimidine compound and preparation method and use thereof
US11166954B2 (en) 2016-11-18 2021-11-09 Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. Dihydropyrimidine compound and preparation method and use thereof
EP4424374A2 (en) 2017-01-31 2024-09-04 Gilead Sciences, Inc. Crystalline forms of tenofovir alafenamide
WO2018144390A1 (en) 2017-01-31 2018-08-09 Gilead Sciences, Inc. Crystalline forms of tenofovir alafenamide
WO2018144605A1 (en) 2017-02-02 2018-08-09 Gilead Sciences, Inc. Compounds for the treatment of hepatitis b virus infection
US10442804B2 (en) 2017-02-02 2019-10-15 Gilead Sciences, Inc. Compounds for the treatment of hepatitis B virus infection
WO2018160889A1 (en) 2017-03-01 2018-09-07 Achillion Pharmaceuticals, Inc. Aryl, heteroary, and heterocyclic pharmaceutical compounds for treatment of medical disorders
US11053253B2 (en) 2017-03-01 2021-07-06 Achillion Pharmaceuticals, Inc. Macrocyclic compounds for treatment of medical disorders
US11718626B2 (en) 2017-03-01 2023-08-08 Achillion Pharmaceuticals, Inc. Macrocyclic compounds for treatment of medical disorders
US11708351B2 (en) 2017-03-01 2023-07-25 Achillion Pharmaceuticals, Inc. Aryl, heteroaryl, and heterocyclic pharmaceutical compounds for treatment of medical disorders
US12006307B2 (en) 2017-03-01 2024-06-11 Achillion Pharmaceuticals, Inc. Pharmaceutical compounds for treatment of medical disorders
US11447465B2 (en) 2017-03-01 2022-09-20 Achillion Pharmaceuticals, Inc. Pharmaceutical compounds for treatment of medical disorders
US12162860B2 (en) 2017-03-01 2024-12-10 Achillion Pharmaceuticals, Inc. Aryl, heteroaryl, and heterocyclic pharmaceutical compounds for treatment of medical disorders
US11084800B2 (en) 2017-03-01 2021-08-10 Achillion Pharmaceuticals, Inc. Aryl, heteroaryl, and heterocyclic pharmaceutical compounds for treatment of medical disorders
US12297205B2 (en) 2017-03-01 2025-05-13 Achillion Pharmaceuticals, Inc. Macrocyclic compounds for treatment of medical disorders
WO2018160878A1 (en) 2017-03-02 2018-09-07 Assembly Biosciences, Inc. Cyclic sulfamide compounds and methods of using same
WO2018195321A1 (en) 2017-04-20 2018-10-25 Gilead Sciences, Inc. Pd-1/pd-l1 inhibitors
US12590062B2 (en) 2017-04-20 2026-03-31 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
EP4026835A2 (en) 2017-04-20 2022-07-13 Gilead Sciences, Inc. Pd-1/pd-l1 inhibitors
US11639350B2 (en) 2017-06-27 2023-05-02 Janssen Pharmaceutica Nv Heteroaryldihydropyrimidine derivatives and methods of treating hepatitis B infections
US12076319B2 (en) 2017-08-02 2024-09-03 Achillion Pharmaceuticals, Inc. Therapeutic regimens for treatment of paroxysmal nocturnal hemoglobinuria
WO2019040102A1 (en) 2017-08-22 2019-02-28 Gilead Sciences, Inc. Therapeutic heterocyclic compounds
US10966999B2 (en) 2017-12-20 2021-04-06 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 3′3′ cyclic dinucleotides with phosphonate bond activating the sting adaptor protein
US11203610B2 (en) 2017-12-20 2021-12-21 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 2′3′ cyclic dinucleotides with phosphonate bond activating the sting adaptor protein
US11447489B2 (en) 2017-12-28 2022-09-20 Hoffmann-La Roche Inc. Dihydropyrimidinylthiazole for the treatment and prophylaxis of hepatitis B virus infection
US11986463B2 (en) 2018-01-31 2024-05-21 Deciphera Pharmaceuticals, Llc Combination therapy for the treatment of gastrointestinal stromal tumor
US12102620B2 (en) 2018-01-31 2024-10-01 Deciphera Pharmaceuticals, Llc Combination therapy for the treatment of mastocytosis
EP4227302A1 (en) 2018-02-13 2023-08-16 Gilead Sciences, Inc. Pd-1/pd-l1 inhibitors
WO2019160882A1 (en) 2018-02-13 2019-08-22 Gilead Sciences, Inc. Pd-1/pd-l1 inhibitors
WO2019165374A1 (en) 2018-02-26 2019-08-29 Gilead Sciences, Inc. Substituted pyrrolizine compounds as hbv replication inhibitors
US10973801B2 (en) 2018-03-14 2021-04-13 Janssen Sciences Ireland Unlimited Company Capsid assembly modulator dosing regimen
WO2019195181A1 (en) 2018-04-05 2019-10-10 Gilead Sciences, Inc. Antibodies and fragments thereof that bind hepatitis b virus protein x
WO2019193533A1 (en) 2018-04-06 2019-10-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 2'2'-cyclic dinucleotides
US11149052B2 (en) 2018-04-06 2021-10-19 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 2′3′-cyclic dinucleotides
WO2019193542A1 (en) 2018-04-06 2019-10-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 2'3'-cyclic dinucleotides
US11292812B2 (en) 2018-04-06 2022-04-05 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 3′3′-cyclic dinucleotides
WO2019193543A1 (en) 2018-04-06 2019-10-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 3'3'-cyclic dinucleotides
US11788077B2 (en) 2018-04-12 2023-10-17 Precision Biosciences, Inc. Polynucleotides encoding optimized engineered meganucleases having specificity for a recognition sequence in the Hepatitis B virus genome
US11142750B2 (en) 2018-04-12 2021-10-12 Precision Biosciences, Inc. Optimized engineered meganucleases having specificity for a recognition sequence in the Hepatitis B virus genome
WO2019200247A1 (en) 2018-04-12 2019-10-17 Precision Biosciences, Inc. Optimized engineered meganucleases having specificity for a recognition sequence in the hepatitis b virus genome
EP4600247A2 (en) 2018-04-19 2025-08-13 Gilead Sciences, Inc. Pd-1/pd-l1 inhibitors
WO2019204609A1 (en) 2018-04-19 2019-10-24 Gilead Sciences, Inc. Pd-1/pd-l1 inhibitors
WO2019211799A1 (en) 2018-05-03 2019-11-07 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 2'3'-cyclic dinucleotide analogue comprising a cyclopentanyl modified nucleotide
WO2020010223A1 (en) 2018-07-06 2020-01-09 Gilead Sciences, Inc. Therapeutic heterocyclic compounds
US11098027B2 (en) 2018-07-06 2021-08-24 Gilead Sciences, Inc. Therapeutic heterocyclic compounds
WO2020010200A1 (en) 2018-07-06 2020-01-09 Gilead Sciences, Inc. Therapeutic heterocyclic compounds
US11186579B2 (en) 2018-07-06 2021-11-30 Gilead Sciences, Inc. Therapeutic heterocyclic compounds
WO2020014643A1 (en) 2018-07-13 2020-01-16 Gilead Sciences, Inc. Pd-1/pd-l1 inhibitors
EP4234030A2 (en) 2018-07-13 2023-08-30 Gilead Sciences, Inc. Pd-1/pd-l1 inhibitors
WO2020028097A1 (en) 2018-08-01 2020-02-06 Gilead Sciences, Inc. Solid forms of (r)-11-(methoxymethyl)-12-(3-methoxypropoxy)-3,3-dimethyl-8-0x0-2,3,8,13b-tetrahydro-1h-pyrido[2,1-a]pyrrolo[1,2-c] phthalazine-7-c arboxylic acid
US11053235B2 (en) 2018-08-09 2021-07-06 Janssen Sciences Ireland Unlimited Company Substituted 1,4-dihydropyrimidines for the treatment of HBV infection or HBV-induced diseases
US11814363B2 (en) 2018-09-06 2023-11-14 Achillion Pharmaceuticals, Inc. Morphic forms of danicopan
US11814391B2 (en) 2018-09-06 2023-11-14 Achillion Pharmaceuticals, Inc. Macrocyclic compounds for the treatment of medical disorders
US11807627B2 (en) 2018-09-25 2023-11-07 Achillon Pharmaceuticals, Inc. Morphic forms of complement factor D inhibitors
US11560370B1 (en) 2018-10-22 2023-01-24 Assembly Biosciences, Inc. 5-membered heteroaryl carboxamide compounds for treatment of HBV
US12030869B2 (en) 2018-10-22 2024-07-09 Assembly Biosciences, Inc. 5-membered heteroaryl carboxamide compounds for treatment of HBV
WO2020086533A1 (en) 2018-10-22 2020-04-30 Assembly Biosciences, Inc. 5-membered heteroaryl carboxamide compounds for treatment of hbv
WO2020086556A1 (en) 2018-10-24 2020-04-30 Gilead Sciences, Inc. Pd-1/pd-l1 inhibitors
EP4371987A1 (en) 2018-10-31 2024-05-22 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds as hpk1 inhibitors
WO2020087107A1 (en) 2018-10-31 2020-05-07 The University Of Sydney Compositions and methods for treating viral infections
WO2020092528A1 (en) 2018-10-31 2020-05-07 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds having hpk1 inhibitory activity
WO2020092621A1 (en) 2018-10-31 2020-05-07 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds as hpk1 inhibitors
EP4671244A1 (en) 2018-10-31 2025-12-31 Gilead Sciences, Inc. SUBSTITUTED 6-AZABENZIMIDAZOLE COMPOUNDS AS HPK1 HIBITORS
US12239645B2 (en) 2018-12-17 2025-03-04 Achillion Pharmaceuticals, Inc. Targeted dosing for the treatment of complement mediated disorders
WO2020125730A1 (en) * 2018-12-20 2020-06-25 Janssen Pharmaceutica Nv Heteroaryldihydropyrimidine derivatives and methods of treating hepatitis b infections
US11096931B2 (en) 2019-02-22 2021-08-24 Janssen Sciences Ireland Unlimited Company Amide derivatives useful in the treatment of HBV infection or HBV-induced diseases
US11766447B2 (en) 2019-03-07 2023-09-26 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 3′3′-cyclic dinucleotide analogue comprising a cyclopentanyl modified nucleotide as sting modulator
US12318403B2 (en) 2019-03-07 2025-06-03 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 2′3′-cyclic dinucleotides and prodrugs thereof
WO2020178768A1 (en) 2019-03-07 2020-09-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 3'3'-cyclic dinucleotide analogue comprising a cyclopentanyl modified nucleotide as sting modulator
WO2020178770A1 (en) 2019-03-07 2020-09-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 3'3'-cyclic dinucleotides and prodrugs thereof
WO2020178769A1 (en) 2019-03-07 2020-09-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 2'3'-cyclic dinucleotides and prodrugs thereof
US12509456B2 (en) 2019-03-11 2025-12-30 Deciphera Pharmaceuticals, Llc Solid state forms of ripretinib
US12479856B2 (en) 2019-03-22 2025-11-25 Achillion Pharmaceuticals, Inc. Pharmaceutical compounds for the treatment of complement mediated disorders
US11873302B2 (en) 2019-03-25 2024-01-16 Hoffmann-La Roche Inc. Solid forms of a compound of HBV core protein allosteric modifier
WO2020210379A1 (en) 2019-04-10 2020-10-15 Hangzhou Zhengxiang Pharmaceuticals Co., Ltd. Phosphatidylinositol 3-kinase inhibitors
US11542262B2 (en) 2019-04-10 2023-01-03 Nanjing Zhengxiang Pharmaceuticals Co., Ltd. Phosphatidylinositol 3-kinase inhibitors
WO2020214663A1 (en) 2019-04-17 2020-10-22 Gilead Sciences, Inc. Solid forms of a toll-like receptor modulator
EP4458416A2 (en) 2019-04-17 2024-11-06 Gilead Sciences, Inc. Solid forms of a toll-like receptor modulator
WO2020214652A1 (en) 2019-04-17 2020-10-22 Gilead Sciences, Inc. Solid forms of a toll-like receptor modulator
US11491148B2 (en) 2019-05-06 2022-11-08 Janssen Sciences Ireland Unlimited Company Amide derivatives useful in the treatment of HBV infection or HBV-induced diseases
WO2020237025A1 (en) 2019-05-23 2020-11-26 Gilead Sciences, Inc. Substituted exo-methylene-oxindoles which are hpk1/map4k1 inhibitors
WO2020242999A1 (en) 2019-05-24 2020-12-03 Assembly Biosciences, Inc. Pharmaceutical compositions for the treatment of hbv
US11464783B2 (en) 2019-06-06 2022-10-11 Aligos Therapeutics, Inc. Heterocyclic compounds
WO2020247504A1 (en) 2019-06-06 2020-12-10 Aligos Therapeutics, Inc. Heterocyclic compounds
EP3980406A4 (en) * 2019-06-06 2023-06-28 Aligos Therapeutics, Inc. Heterocyclic compounds
WO2020255038A1 (en) 2019-06-18 2020-12-24 Janssen Sciences Ireland Unlimited Company Combination of hepatitis b virus (hbv) vaccines and pyridopyrimidine derivatives
WO2020263830A1 (en) 2019-06-25 2020-12-30 Gilead Sciences, Inc. Flt3l-fc fusion proteins and methods of use
WO2021011891A1 (en) 2019-07-18 2021-01-21 Gilead Sciences, Inc. Long-acting formulations of tenofovir alafenamide
WO2021018238A1 (en) * 2019-07-31 2021-02-04 Janssen Sciences Ireland Unlimited Company Dihydropyrimidine derivatives and uses thereof in the treatment of hbv infection or of hbv-induced diseases
WO2021018239A1 (en) * 2019-07-31 2021-02-04 Janssen Sciences Ireland Unlimited Company Dihydropyrimidine derivatives and uses thereof in the treatment of hbv infection or of hbv-induced diseases
US12023327B2 (en) 2019-08-12 2024-07-02 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US12318373B2 (en) 2019-08-12 2025-06-03 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US10966966B2 (en) 2019-08-12 2021-04-06 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US12295944B2 (en) 2019-08-12 2025-05-13 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US11266635B2 (en) 2019-08-12 2022-03-08 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US11344536B1 (en) 2019-08-12 2022-05-31 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US11426390B2 (en) 2019-08-12 2022-08-30 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US12059411B2 (en) 2019-08-12 2024-08-13 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US12059410B2 (en) 2019-08-12 2024-08-13 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US11433056B1 (en) 2019-08-12 2022-09-06 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US12023325B2 (en) 2019-08-12 2024-07-02 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US12023326B2 (en) 2019-08-12 2024-07-02 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US11529336B2 (en) 2019-08-12 2022-12-20 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US11813251B2 (en) 2019-08-12 2023-11-14 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US11576904B2 (en) 2019-08-12 2023-02-14 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US11534432B2 (en) 2019-08-12 2022-12-27 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US11969414B2 (en) 2019-08-12 2024-04-30 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
WO2021034804A1 (en) 2019-08-19 2021-02-25 Gilead Sciences, Inc. Pharmaceutical formulations of tenofovir alafenamide
EP4458975A2 (en) 2019-09-30 2024-11-06 Gilead Sciences, Inc. Hbv vaccines and methods treating hbv
WO2021067181A1 (en) 2019-09-30 2021-04-08 Gilead Sciences, Inc. Hbv vaccines and methods treating hbv
WO2021113765A1 (en) 2019-12-06 2021-06-10 Precision Biosciences, Inc. Optimized engineered meganucleases having specificity for a recognition sequence in the hepatitis b virus genome
US12410418B2 (en) 2019-12-06 2025-09-09 Precision Biosciences, Inc. Optimized engineered meganucleases having specificity for a recognition sequence in the Hepatitis B virus genome
EP4567109A2 (en) 2019-12-06 2025-06-11 Precision Biosciences, Inc. Optimized engineered meganucleases having specificity for a recognition sequence in the hepatitis b virus genome
US12318374B2 (en) 2019-12-30 2025-06-03 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoropheyl)-3-phenylurea
US11918564B1 (en) 2019-12-30 2024-03-05 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoropheyl)-3-phenylurea
US11844788B1 (en) 2019-12-30 2023-12-19 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoropheyl)-3-phenylurea
US11969415B1 (en) 2019-12-30 2024-04-30 Deciphera Pharmaceuticals, Llc (methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoropheyl)-3-phenylurea
US11911370B1 (en) 2019-12-30 2024-02-27 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoropheyl)-3-phenylurea
US11850241B1 (en) 2019-12-30 2023-12-26 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoropheyl)-3-phenylurea
US11576903B2 (en) 2019-12-30 2023-02-14 Deciphera Pharmaceuticals, Llc Amorphous kinase inhibitor formulations and methods of use thereof
US11801237B2 (en) 2019-12-30 2023-10-31 Deciphera Pharmaceuticals, Llc Amorphous kinase inhibitor formulations and methods of use thereof
US12023328B2 (en) 2019-12-30 2024-07-02 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoropheyl)-3-phenylurea
US11896585B2 (en) 2019-12-30 2024-02-13 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea
US11793795B2 (en) 2019-12-30 2023-10-24 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea
US11612591B2 (en) 2019-12-30 2023-03-28 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea
US11850240B1 (en) 2019-12-30 2023-12-26 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoropheyl)-3-phenylurea
US12226406B2 (en) 2019-12-30 2025-02-18 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoropheyl)-3-phenylurea
US11903933B2 (en) 2019-12-30 2024-02-20 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoropheyl)-3-phenylurea
US12064422B2 (en) 2019-12-30 2024-08-20 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoropheyl)-3-phenylurea
US11395818B2 (en) 2019-12-30 2022-07-26 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea
US12213968B2 (en) 2019-12-30 2025-02-04 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoropheyl)-3-phenylurea
US12213967B2 (en) 2019-12-30 2025-02-04 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoropheyl)-3-phenylurea
US11185535B2 (en) 2019-12-30 2021-11-30 Deciphera Pharmaceuticals, Llc Amorphous kinase inhibitor formulations and methods of use thereof
WO2021188959A1 (en) 2020-03-20 2021-09-23 Gilead Sciences, Inc. Prodrugs of 4'-c-substituted-2-halo-2'-deoxyadenosine nucleosides and methods of making and using the same
WO2021216660A1 (en) 2020-04-22 2021-10-28 Assembly Biosciences, Inc. 5-membered heteroaryl carboxamide compounds for treatment of hbv
WO2021216642A1 (en) 2020-04-22 2021-10-28 Assembly Biosciences, Inc. Pyrazole carboxamide compounds for treatment of hbv
WO2021216656A1 (en) 2020-04-22 2021-10-28 Assembly Biosciences, Inc. 5-membered heteroaryl carboxamide compounds for treatment of hbv
WO2021216661A1 (en) 2020-04-22 2021-10-28 Assembly Biosciences, Inc. Pyrazole carboxamide compounds for treatment of hbv
EP4667477A2 (en) 2020-08-07 2025-12-24 Gilead Sciences, Inc. Prodrugs of phosphonamide nucleotide analogues and their pharmaceutical use
WO2022031894A1 (en) 2020-08-07 2022-02-10 Gilead Sciences, Inc. Prodrugs of phosphonamide nucleotide analogues and their pharmaceutical use
EP4667499A2 (en) 2020-10-22 2025-12-24 Gilead Sciences, Inc. Interleukin-2-fc fusion proteins and methods of use
WO2022087149A2 (en) 2020-10-22 2022-04-28 Gilead Sciences, Inc. Interleukin-2-fc fusion proteins and methods of use
WO2022241134A1 (en) 2021-05-13 2022-11-17 Gilead Sciences, Inc. COMBINATION OF A TLR8 MODULATING COMPOUND AND ANTI-HBV siRNA THERAPEUTICS
WO2022271677A1 (en) 2021-06-23 2022-12-29 Gilead Sciences, Inc. Diacylglyercol kinase modulating compounds
WO2022271684A1 (en) 2021-06-23 2022-12-29 Gilead Sciences, Inc. Diacylglyercol kinase modulating compounds
WO2022271650A1 (en) 2021-06-23 2022-12-29 Gilead Sciences, Inc. Diacylglyercol kinase modulating compounds
WO2022271659A1 (en) 2021-06-23 2022-12-29 Gilead Sciences, Inc. Diacylglyercol kinase modulating compounds
WO2023069545A1 (en) 2021-10-20 2023-04-27 Assembly Biosciences, Inc. 5-membered heteroaryl carboxamide compounds for treatment of hbv
WO2023069544A1 (en) 2021-10-20 2023-04-27 Assembly Biosciences, Inc. 5-membered heteroaryl carboxamide compounds for treatment of hbv
WO2023069547A1 (en) 2021-10-20 2023-04-27 Assembly Biosciences, Inc. 5-membered heteroaryl carboxamide compounds for treatment of hbv
WO2023164179A1 (en) 2022-02-25 2023-08-31 Assembly Biosciences, Inc. Benzothia(dia)zepine compounds for treatment of hbv and hdv
WO2023164181A1 (en) 2022-02-25 2023-08-31 Assembly Biosciences, Inc. Benzothia(dia)zepine compounds for treatment of hbv and hdv
WO2023164186A1 (en) 2022-02-25 2023-08-31 Assembly Biosciences, Inc. Benzothia(dia)zepine compounds for treatment of hbv and hdv
WO2023164183A1 (en) 2022-02-25 2023-08-31 Assembly Biosciences, Inc. Benzothia(dia)zepine compounds for treatment of hbv and hdv
US11779572B1 (en) 2022-09-02 2023-10-10 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
WO2025043094A1 (en) 2023-08-23 2025-02-27 Assembly Biosciences, Inc. Benzothia(dia)zepine compounds for treatment of hbv and hdv
US12616683B2 (en) 2024-04-10 2026-05-05 Deciphera Pharmaceuticals, Llc Combination therapy for the treatment of gastrointestinal stromal tumors
WO2025240244A1 (en) 2024-05-13 2025-11-20 Gilead Sciences, Inc. Combination therapies comprising bulevirtide and lonafarnib for use in the treatment of hepatitis d virus infection
WO2025240242A1 (en) 2024-05-13 2025-11-20 Gilead Sciences, Inc. Combination therapies with ribavirin
WO2025240246A1 (en) 2024-05-13 2025-11-20 Gilead Sciences, Inc. Combination therapies with ribavirin
WO2025240243A1 (en) 2024-05-13 2025-11-20 Gilead Sciences, Inc. Combination therapies with bulevirtide and an inhibitory nucleic acid targeting hepatitis b virus
WO2026038156A1 (en) 2024-08-15 2026-02-19 Assembly Biosciences, Inc. Novel crystalline forms

Also Published As

Publication number Publication date
ES2617906T3 (en) 2017-06-20
HK1210152A1 (en) 2016-04-15
US20150031687A1 (en) 2015-01-29
CN104603125A (en) 2015-05-06
EP2892893B1 (en) 2016-12-21
MX2015002954A (en) 2015-06-05
CO7170160A2 (en) 2015-01-28
CR20150085A (en) 2015-04-06
CA2881322A1 (en) 2014-03-13
AR092503A1 (en) 2015-04-22
US9447086B2 (en) 2016-09-20
EA201590384A1 (en) 2015-10-30
TW201416360A (en) 2014-05-01
CL2015000482A1 (en) 2015-07-10
BR112015004113A2 (en) 2017-07-04
EP2892893A1 (en) 2015-07-15
MA37942B1 (en) 2020-01-31
JP6113285B2 (en) 2017-04-12
PE20150776A1 (en) 2015-05-21
ZA201500580B (en) 2017-09-27
US20160237078A9 (en) 2016-08-18
SG11201500377UA (en) 2015-02-27
AU2013311705A1 (en) 2015-02-05
PH12015500347A1 (en) 2015-04-20
IL236691A0 (en) 2015-02-26
MA37942A2 (en) 2016-12-30
KR20150054795A (en) 2015-05-20
MA37942A3 (en) 2018-05-31
EP2892893B2 (en) 2019-10-16
JP2015527382A (en) 2015-09-17

Similar Documents

Publication Publication Date Title
EP2892893B1 (en) 6-amino acid heteroaryldihydropyrimidines for the treatment and prophylaxis of hepatitis b virus infection
EP3114128B1 (en) Novel 6-fused heteroaryldihydropyrimidines for the treatment and prophylaxis of hepatitis b virus infection
EP2831060B1 (en) Novel 4-methyl-dihydropyrimidines for the treatment and prophylaxis of hepatitis b virus infection
WO2018011163A1 (en) 6,7-dihydro-4h-pyrazolo[1,5-a]pyrazine and 6,7-dihydro-4h-triazolo[1,5-a]pyrazine compounds for the treatment of infectious diseases
WO2017064156A1 (en) Novel 6-fused and 2-heteroaryldihydropyrimidines for the treatment and prophylaxis of hepatitis b virus infection
CN113272309A (en) Tricyclic inhibitors of hepatitis B virus
HK40002665A (en) Novel 6-fused heteroaryldihydropyrimidines for the treatment and prophylaxis of hepatitis b virus infection
HK1230189A1 (en) Novel 6-fused heteroaryldihydropyrimidines for the treatment and prophylaxis of hepatitis b virus infection
HK1230189B (en) Novel 6-fused heteroaryldihydropyrimidines for the treatment and prophylaxis of hepatitis b virus infection

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 13763201

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 236691

Country of ref document: IL

WWE Wipo information: entry into national phase

Ref document number: 15012151

Country of ref document: CO

ENP Entry into the national phase

Ref document number: 2013311705

Country of ref document: AU

Date of ref document: 20130906

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2881322

Country of ref document: CA

REEP Request for entry into the european phase

Ref document number: 2013763201

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2013763201

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: CR2015-000085

Country of ref document: CR

WWE Wipo information: entry into national phase

Ref document number: 2015000482

Country of ref document: CL

WWE Wipo information: entry into national phase

Ref document number: 000297-2015

Country of ref document: PE

ENP Entry into the national phase

Ref document number: 2015530405

Country of ref document: JP

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 20157005893

Country of ref document: KR

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: MX/A/2015/002954

Country of ref document: MX

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: IDP00201501404

Country of ref document: ID

WWE Wipo information: entry into national phase

Ref document number: 201590384

Country of ref document: EA

WWE Wipo information: entry into national phase

Ref document number: 37942

Country of ref document: MA

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112015004113

Country of ref document: BR

WWE Wipo information: entry into national phase

Ref document number: DZP2015000189

Country of ref document: DZ

ENP Entry into the national phase

Ref document number: 112015004113

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20150225