WO2018154466A1 - Dihydroquinolizinones à utiliser en tant qu'antiviraux - Google Patents

Dihydroquinolizinones à utiliser en tant qu'antiviraux Download PDF

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WO2018154466A1
WO2018154466A1 PCT/IB2018/051080 IB2018051080W WO2018154466A1 WO 2018154466 A1 WO2018154466 A1 WO 2018154466A1 IB 2018051080 W IB2018051080 W IB 2018051080W WO 2018154466 A1 WO2018154466 A1 WO 2018154466A1
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alkyl
substituted
unsubstituted
halo
alkoxy
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PCT/IB2018/051080
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John G. Catalano
Hamilton D. Dickson
Wieslaw Mieczyslaw Kazmierski
Martin R. LEIVERS
John Gordon WEATHERHEAD
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Glaxosmithkline Intellectual Property Development Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/20—Spiro-condensed systems

Definitions

  • the present invention relates to compounds useful for treatment of HBV in animals, and more particularly for treatment of HBV in humans.
  • Hepatitis B is a viral disease transmitted parenterally by contaminated material such as blood and blood products, contaminated needles, sexually and vertically from infected or carrier mothers to their offspring. In those areas of the world where the disease is common vertical transmission at an early age results in a high proportion of infected individuals becoming chronic carriers of hepatitis B. It is estimated by the World Health Organization that more than 2 billion people have been infected worldwide, with about 4 million acute cases per year, 1 million deaths per year, and 350-400 million chronic carriers. Approximately 25% of carriers die from chronic hepatitis, cirrhosis, or liver cancer and nearly 75% of chronic carriers are Asian. Hepatitis B virus (HBV) is the second most significant carcinogen behind tobacco, causing from 60% to 80% of all primary liver cancer. HBV is 100 times more contagious than HIV.
  • HBV Hepatitis B virus
  • HBV is transmitted through percutaneous or parenteral contact with infected blood, body fluids, and by sexual intercourse. HBV is able to remain on any surface it comes into contact with for about a week, e.g. table-tops, razor blades, blood stains, without losing infectivity.
  • HBV cannot cross the skin or the mucous membrane barrier. Some break in this barrier, which can be minimal and insignificant, is required for transmission.
  • HBV is a small enveloped DNA virus belonging to the hepadnavirus family.
  • the virus replicates through an RNA intermediate form by reverse transcription, which in practice relates them to retroviruses, like HIV. Although replication takes place in the liver, the virus spreads to the blood where viral proteins and antibodies against them are found in infected people. HBV is many times more infectious than HIV due to the greater concentrations of HBV virus found in the bloodstream at any given time.
  • HBV infection results in the production of two different particles: 1 ) the HBV virus itself (or Dane particle) which includes a viral capsid assembled from the HBV core antigen protein (HBcAg) and is covered by the hepatitis B surface antigen (HBsAg) and is capable of reinfecting cells and 2) subviral particles (or SVPs) which are high density lipoprotein-like particles comprised of lipids, cholesterol, cholesterol esters and the small and medium forms of the hepatitis B surface antigen (HBsAg) which are non-infectious.
  • SVPs subviral particles
  • HBV infected cells also secrete a soluble proteolytic product of the pre-core protein called the HBV e-antigen (HBeAg).
  • HBV e-antigen HBV e-antigen
  • HDV hepatitis D virus
  • HBsAg hepatitis D virus
  • HDV infection can only occur in subjects with concomitant HBV infection. While the incidence of HDV co-infection in asymptomatic HBV carriers and chronic HBV- related liver disease is low in countries with a low incidence of HBV infection, it is a significant complication in HBV-infected subjects in countries with a high incidence of HBV infection and can increase the rate of progression of liver disease to fulminant hepatitis. As such, the clear unmet medical need in HBV infection is even more pressing in HBV/HDV co-infected subjects.
  • HBV polymerase inhibitors are effective in reducing viral production, but have little to no effect in rapidly reducing HBsAg blood levels or can slowly reduce HBsAg with long term treatment in a limited number of patients (as is the case with tenofovir disoproxil fumarate).
  • Interferon based immunotherapy can achieve a reduction of both viral production and early removal of HBsAg from the blood but only in a small percentage of treated subjects.
  • HBsAg The generally accepted role of HBsAg in the blood is to sequester anti-HBsAg antibodies and allow infectious viral particles to escape immune detection which is likely one of the reasons why HBV infection remains a chronic condition.
  • HBsAg, HBeAg and HBcAg all have immuno-inhibitory properties as discussed below and the persistence of these viral proteins in the blood of patients following the administration of any of the currently available treatments for HBV as described above is likely having a significant impact in preventing patients from achieving immunological control of their HBV infection.
  • HBsAg comprises the overwhelming majority of HBV protein in the circulation of HBV infected subjects. Additionally, while the removal (via
  • Hepatitis B viral infections in conjunction with Hepatitis D viral infections, are a continuing medical problem because, like any rapidly-replicating infectious agent, there are continuing mutations that help some sub-populations of HBV become resistant to current treatment regimens.
  • HBV Hepatitis D virus
  • HDV Hepatitis D virus
  • nucleoside and nucleotide therapies entecavir and tenofovir are successful at reducing viral load, but the rates of HBeAg seroconversion and HBsAg loss are even lower than those obtained using IFNa therapy.
  • Other similar therapies including lamivudine (3TC), telbivudine (LdT), and adefovir are also used, but for nucleoside/nucleotide therapies in general, the emergence of resistance limits therapeutic efficacy.
  • An embodiment of the present invention features a compound of Formula I:
  • R 1 and R 4 are independently selected from hydrogen; halogen; hydroxy; alkoxy; amino; cyano; unsubstituted Ci_ 6 alkyl or halo- or alkyl-substituted Ci_ 6 alkyl;
  • R 2 and R 3 are independently selected from hydrogen; hydroxy; alkoxy; halogen; cyano; NR 20 R 21 ; COR 19 ; COOR 19 ; CONR 20 R 21 ; pyrrolidinyl; unsubstituted Ci_ 6 alkyl or halo- or alkyl-substituted Ci_ 6 alkyl; Ci- 6 alkylCOOR 19 ; -BOR 19 OR 19' ; unsubstituted Ci- 6 alkoxy or halo- or alkyl-substituted Ci- 6 alkyoxy; unsubstituted C 3 . 7 cycloalkyl or halo- or alkyl-substituted C 3 .
  • R 7 and R 8 are selected from independently hydrogen; halogen; cyano; unsubstituted Ci_ 6 alkyl or halo- or alkyl-substituted Ci_ 6 alkyl; unsubstituted Ci- 6 alkoxy or halo- or alkyl-substituted Ci_6alkoxy; unsubstituted C 3 -8cycloalkyl or halo- or alkyl-substituted C 3 - 8 cycloalkyl; unsubstituted C x H 2 x-phenyl or halo- or alkyl-substituted -C x H 2 x-phenyl; and unsubstituted -0-C x H 2x -phenyl or halo- or alkyl-substituted -0-C x H 2x -phenyl, wherein x is 0, 1 , 2, 3, 4, 5 or 6; or R 7 and R 8 together form
  • R 9 is selected from hydrogen; hydroxy; halogen; cyano; unsubstituted Ci_ 6 alkyl or halo- or alkyl-substituted Ci_ 6 alkyl; unsubstituted Ci- 6 alkoxy or halo- or alkyl- substituted Ci- 6 alkoxy; unsubstituted C 3 - 8 cycloalkyl or halo- or alkyl-substituted C 3 .
  • ecycloalkyl unsubstituted or halo- or alkyl-substituted -C x H 2x -phenyl; and unsubstituted or halo- or alkyl substituted -0-C x H 2x -phenyl, wherein x is 0, 1 , 2, 3, 4, 5 or 6;
  • R 10 is selected from COOR 19 and CONR 20 R 21 6;
  • R 11 is selected from hydrogen; hydroxy; halogen; cyano; unsubstituted Ci_ 6alkyl or halo- or alkyl-substituted Ci_6alkyl; unsubstituted Ci-6alkoxy or halo- or alkyl- substituted Ci- 6 alkyoxy; unsubstituted or halo- or alkyl-substituted C 3 . 7 cycloalkyl;
  • R 12 is selected from hydrogen; unsubstituted Ci_ 6 alkyl or Ci_ 6 alkyl substituted with one or more substituents independently selected from halo, hydroxy, alkoxy, heterocycloalkyi, heteroaryl, C 3 . 8 cycloalkyl and C 2 . 6 alkenyl; Ci- 6 alkylCi- 6 alkoxy; Ci_ 6 alkylCi- 6 alkoxyCi- 6 alkoxy; Ci.
  • heteroaryl is a monocyclic heteroaryl comprising O and/or ; and Ci- 6 alkylheterocycloalkyl, wherein the heterocycloalkyi is a monocyclic heterocycloalkyi comprising O and/or N;
  • R 13 , R 13' , R 14 and R 14' are independently selected from hydrogen,; halogen; amino; aminoalkyl; cyano; Ci_ 6 alkyl; Ci- 6 alkoxy; carbonyl; carboxamide; and amide; or R 13 and R 13 ' or R 14 and R 14' together form a 3- to 8-membered cycloalkyl; or R 14 and R 14' together form a 3- to 8- membered heterocycloalkyi ring, optionally substituted with oxygen, halogen, hydroxy, amino, cyano, Ci_ 6 alkyl, C 3 - 8 cycloalkyl, C 2 - 6 alkenyl or Ci- 6 alkoxy, wherein a heteroatom in the heteroalkyl ring is O, N, NR 22 , S, SR 22 or SR 22 R 22 ';
  • R 17 , R 17 ', R 18 and R 18' are independently selected from hydrogen; halogen; amino; cyano; Ci_ 6 alkyl; Ci- 6 alkoxy; carbonyl; carboxamide; and amide; or R 17 and R 18 or R 17' and R 18' together form a 3- to 8-membered cycloalkyl ring or 3- to 8- membered heterocycloalkyi ring, optionally substituted with oxygen, halogen, hydroxy, amino, cyano, Ci- 6 alkyl, C 3 - 8 cycloalkyl, C 2 - 6 alkenyl or Ci- 6 alkoxy, wherein a heteroatom in the heteroalkyl ring is O, N, NR 22 , S, SR 22 or SR 22 R 22' ;
  • R 19 , R 19' and R 19" are independently selected from hydrogen; Ci_ 6 alkyl; C 3 . ecycloalkyl; C 2 . 6 alkenyl; phenyl; Ci- 6 alkylimidizole; Ci- 6 alkoxy; Ci- 6 alkyltriazole; Ci_
  • R 20 and R 21 are independently selected from hydrogen; Ci_ 6 alkyl; C 3 .
  • Ci_ ecycloalkyl; C 2 . 6 alkenyl; phenyl; Ci- 6 alkylimidizole; Ci- 6 alkoxy; Ci- 6 alkyltriazole; Ci_
  • R 20 and R 21 together with the nitrogen to which they are attached form unsubstituted pyrrolidinyl, unsubstituted piperidinyl, or unsubstituted morpholinyl; or R 20 and R 21 together with the nitrogen to which they are attached form carboxyl-substituted pyrrolidinyl, carboxyl-substituted piperidinyl or carboxyl-substituted morpholinyl;
  • R 22 and R 22' are independently selected from hydrogen; oxygen; Ci_ 6 alkyl; Ci- 6 haloalkyl; C 3 . 8 cycloalkyl; Ci- 6 alkylC 3 - 8 cycloalkyl; C 2 .
  • R 23 is selected from hydrogen, Ci_ 6 alkyl; C 3 - 8 cycloalkyl; C 2 - 6 alkenyl; phenyl; Ci- 6 alkylimidizole; Ci- 6 alkoxy; Ci- 6 alkyltriazole; Ci- 6 alkyltetrazole; Ci- 6 alkylthiazole; Ci- 6 alkyloxazole; Ci_ ealkyldioxazole; Ci- 6 alkyloxazolidone; -COR 19 ; -COOR 19' ; -CSOR 19 " ; and -CONR 20 R 21 ; and [0028]
  • R 23 is selected from hydrogen, Ci_ 6 alkyl; C 3 - 8 cycloalkyl; C 2 - 6 alkenyl; phenyl; Ci- 6 alkylimidizole; Ci- 6 alkoxy; Ci- 6 alkyltriazole; Ci- 6 alkyltetrazole; Ci- 6 alkylthiazole
  • One embodiment of the invention provides a compound of Formula I
  • R 1 and R 4 are independently selected from hydrogen; halogen; hydroxy; alkoxy; amino; cyano; unsubstituted Ci_ 6 alkyl or halo- or alkyl-substituted Ci_ 6 alkyl;
  • R 2 and R 3 are independently selected from hydrogen; hydroxy; alkoxy; halogen; cyano; NR 20 R 21 ; COR 19 ; COOR 19 ; CONR 20 R 21 ; pyrrolidinyl; unsubstituted Ci_ 6 alkyl or halo- or alkyl-substituted Ci_ 6 alkyl; Ci- 6 alkylCOOR 19 ; -BOR 19 OR 19' ; unsubstituted Ci- 6 alkoxy or halo- or alkyl-substituted Ci- 6 alkyoxy; unsubstituted C 3 . 7 cycloalkyl or halo- or alkyl-substituted C 3 . 7 cycloalkyl; C 3 . 7 cycloalkenyl or halo- or alkyl-substituted C 3 .
  • R 5 is selected from hydrogen and unsubstituted Ci_ 6 alkyl or halo- or alkyl- substituted Ci_ 6 alkyl;
  • R 6 and R 7 together form a 3- to 8-membere cycloalkyl ring optionally substituted with oxo, halogen, hydroxy, alkoxy, amino, cyano, OR 23 , R 15 , R 15' , R 16 and/or R 16' ; or R 6 and R 7 together form a 3- to 8- membered heterocycloalkyi ring comprising one heteroatom or two or more heteroatoms, optionally substituted with oxo, halogen, hydroxy, alkoxy, amino, cyano, R 15 , R 15' , R 16 and/or R 16' , wherein the one heteroatom in the heterocycloalkyi ring is NR 20 and the two or more heteroatoms are selected from N, NR 22 , O, S, SR 22 and SR 22 R 22' ;
  • R 8 is selected from hydrogen and unsubstituted Ci_ 6 alkyl or halo- or alkyl- substituted Ci_ 6 alkyl;
  • R 9 is selected from hydrogen, hydroxy, halogen, cyano, unsubstituted Ci_ 6 alkyl or halo- or alkyl-substituted Ci_ 6 alkyl, unsubstituted Ci- 6 alkoxy or halo- or alkyl- substituted Ci- 6 alkoxy, unsubstituted C 3 - 8 cycloalkyl or halo- or alkyl-substituted C 3 .
  • ecycloalkyl unsubstituted -C x H 2 x-phenyl or halo- or alkyl-substituted -C x H 2x -phenyl an unsubstituted -0-C x H 2x -phenyl or halo- or alkyl-substituted -0-C x H 2 x-phenyl, wherein x is 0, 1 , 2, 3, 4, 5 or 6;
  • R 10 is selected from COOR 19 and CONR 20 R 21 ;
  • R 11 is selected from hydrogen, hydroxy, halogen, cyano, unsubstituted Ci_ 6 alkyl or halo- or alkyl-substituted Ci_ 6 alkyl, unsubstituted Ci- 6 alkoxy or halo- or alkyl- substituted Ci- 6 alkyoxy; unsubstituted C 3 - 7 cycloalkyl or halo- or alkyl substituted C 3 .
  • ycycloalkyl unsubstituted -C x H 2x -phenyl or halo- or alkyl-substituted -C x H 2x -phenyl; and unsubstituted -0-C x H 2x -phenyl or halo- or alkyl-substituted -0-C x H 2x -phenyl, wherein x is 0, 1 , 2, 3, 4, 5 or 6;
  • R 12 is hydrogen; unsubstituted Ci_ 6 alkyl or Ci_ 6 alkyl substituted with one or more substituents independently selected from halo, hydroxy, alkoxy, heterocycloalkyi, heteroaryl, C 3 . 8 cycloalkyl and C 2 . 6 alkenyl; Ci- 6 alkylCi- 6 alkoxy; Ci- 6 alkylCi- 6 alkoxyCi- 6 alkoxy; Ci- 8 alkylamino; Ci- 8 alkylaminocarbonylCi- 6 alkyl; Ci- 6 alkylaminosulfonylCi- 6 alkyl; Ci_
  • R 15 , R 15' , R 16 and R 16' are independently hydrogen, halogen, amino, cyano, Ci- 6 alkyl, or Ci- 6 alkoxy, wherein any or R 15 , R 15' , R 16 or R
  • R 19 , R 19' and R 19" are independently hydrogen, Ci_ 6 alkyl, C 3 - 8 cycloalkyl, C 2 . 6 alkenyl, phenyl, Ci- 6 alkylimidizole, Ci- 6 alkoxy, Ci- 6 alkyltriazole, Ci- 6 alkyltetrazole, Ci_
  • R 20 and R 21 are independently hydrogen, Ci_6alkyl, C 3 -8cycloalkyl, C 2 .
  • R 22 and R 22' are independently selected from hydrogen, oxygen, Ci_ 6 alkyl, Ci- 6 haloalkyl, C 3 - 8 cycloalkyl, Ci- 6 alkylC 3 - 8 cycloalkyl, C 2 .
  • R 23 is hydrogen, Ci_ 6 alkyl, C 3 . 8 cycloalkyl, C 2 . 6 alkenyl, phenyl, Ci_
  • 6alkyloxazole Ci. 6 alkyldioxazole; Ci. 6 alkyloxazolidone; aryl, heteroaryl or benzyl, or a pharmaceutically acceptable salt thereof.
  • One embodiment of the invention provides a compound of Formula I
  • R 1 , and R 4 are independently selected from hydrogen; halogen; hydroxy; alkoxy; amino; cyano; unsubstituted Ci_ 6 alkyl or halo- or alkyl-substituted Ci_ 6 alkyl;
  • R 2 and R 3 are independently selected from hydrogen; hydroxy; alkoxy; halogen; cyano; NR 20 R 21 ; COR 19 ; COOR 19 ; CONR 20 R 21 ; pyrrolidinyl; unsubstituted Ci_ 6 alkyl or halo- or alkyl-substituted Ci_ 6 alkyl; Ci- 6 alkylCOOR 19 '; -BOR 19 OR 19' ; unsubstituted Ci- 6 alkoxy or halo- or alkyl-substituted Ci- 6 alkyoxy; C 3 - 7 cycloalkyl or halo- or alkyl-substituted C 3 - 7 cycloalkyl; unsubstituted C 3 .
  • R 5 and R 6 are independently selected from hydrogen; halogen; cyano; unsubstituted Ci_ 6 alkyl or halo-or alkyl-substituted Ci_ 6 alkyl; unsubstituted Ci- 6 alkoxy or halo- or alkyl-substituted Ci_6alkoxy; unsubstituted C 3 -ecycloalkyl or halo- or alkyl-substituted C 3 .
  • ecycloalkyl unsubstituted -C x H 2x -phenyl or halo- or alkyl-substituted -C x H 2x -phenyl; and unsubstituted -0-C x H 2x -phenyl or halo- or alkyl-substituted -0-C x H 2x -phenyl, wherein x is 0, 1 , 2, 3, 4, 5 or 6; or R 5 and R 6 together form a 3- to 8-membered cycloalkyi ring optionally substituted with oxo, halogen, hydroxy, alkoxy, amino, cyano, OR 23 , R 13 , R 13' , R 14 and/or R 14' , or R 5 and R 6 together form a 3- to 8- membered heterocycloalkyi ring, optionally substituted with oxo, halogen, hydroxy, alkoxy, amino, cyano, R 13 ,
  • R 7 and R 8 together form a 3- to 8-membered cycloalkyi ring optionally substituted with oxo, halogen, hydroxy, alkoxy, amino, cyano, OR 23 , R 17 , R 17' , R 18 and/or R 18' , or R 7 and R 8 together form a 3- to 8- membered
  • heterocycloalkyi ring optionally substituted with oxo, halogen, hydroxy, alkoxy, amino, cyano, R 17 , R 18 ', R 17 and/or R 18' , wherein a heteroatom in the heterocycloalkyi ring is O, N, NR 22 , S, SR 22 or SR 22 R 22' ;
  • R 9 is selected from hydrogen; hydroxy; halogen; cyano; unsubstituted Ci_ 6 alkyl or halo-or alkyl-substituted Ci_ 6 alkyl; unsubstituted Ci- 6 alkoxy or halo- or alkyl- substituted Ci-6alkoxy; unsubstituted C3-ecycloalkyl or halo- or alkyl-substituted C3- ecycloalkyl; unsubstituted -C x H 2 x-phenyl or halo- or alkyl-substituted -C x H 2 x-phenyl; and unsubstituted -0-C x H 2x -phenyl or halo- or alkyl-substituted -0-C x H 2x -phenyl, wherein x is 0, 1 , 2, 3, 4, 5 or 6;
  • R 10 is selected from COOR 19 and CONR 20 R 21 ;
  • R 11 is selected from hydrogen; hydroxy; halogen; cyano; unsubstituted Ci_ 6 alkyl or halo- or alkyl-substituted Ci_ 6 alkyl; unsubstituted Ci- 6 alkoxy or halo- or alkyl- substituted Ci- 6 alkyoxy; unsubstituted or halo- or alkyl-substituted C 3 -7cycloalkyl;
  • R 12 is selected from hydrogen; unsubstituted Ci_ 6 alkyl or Ci_ 6 alkyl substituted with one or more substituents independently selected from halo, hydroxy, alkoxy, C 3 - ecycloalkyl and C 2 .
  • R 13 , R 13' , R 14 and R 14' are independently selected from hydrogen; halogen; amino; aminoalkyl; cyano; Ci_ 6 alkyl; Ci- 6 alkoxy; carbonyl; carboxamide; and amide; or R 13 and R 14 or R 13 ' and R 14' together form a 3- to 8-membered cycloalkyl ring or 3- to 8- membered heterocycloalkyi ring, optionally substituted with oxygen, halogen, hydroxy, amino, cyano, Ci_ 6 alkyl, C 3 - 8 cycloalkyl, C 2 - 6 alkenyl or Ci- 6 alkoxy, wherein a heteroatom in the heteroalkyl ring is O, N, NR 22 , S, SR 22 or SR 22 R 22' ;
  • R 17 , R 17 ', R 18 and R 18' are independently selected from hydrogen; halogen; amino; cyano; Ci_ 6 alkyl; and Ci- 6 alkoxy; or R 17 and R 18 or R 17' and R 18' together form a 3- to 8-membered cycloalkyl ring or 3- to 8- membered heterocycloalkyi ring, optionally substituted with oxygen, halogen, hydroxy, amino, cyano, Ci_ 6 alkyl, C 3 - 8 cycloalkyl, C 2 . 6 alkenyl or Ci- 6 alkoxy, wherein a heteroatom in the heteroalkyl ring is O, N, NR 22 , S, SR 22 or SR 22 R 22' ;
  • R 19 , R 19' and R 19" are independently selected from hydrogen; Ci-ealkyl; C 3 . ecycloalkyl; C 2 - 6 alkenyl; phenyl; Ci- 6 alkylimidizole; Ci- 6 alkoxy; Ci- 6 alkyltriazole; Ci_
  • R 20 and R 21 are independently selected from hydrogen; Ci_ 6 alkyl; C 3 . ecycloalkyl; C 2 -6alkenyl; phenyl; Ci-6alkylimidizole; Ci-6alkoxy; Ci-6alkyltriazole; Ci- 6 alkyltetrazole; Ci- 6 alkylthiazole; Ci- 6 alkyloxazole; Ci- 6 alkyldioxazole; and Ci_
  • R 20 and R 21 together with the nitrogen to which they are attached form unsubstituted pyrrolidinyl, unsubstituted piperidinyl, or unsubstituted morpholinyl; or form carboxyl-substituted pyrrolidinyl, carboxyl-substituted piperidinyl or carboxyl-substituted morpholinyl; and
  • R 22 and R 22' are independently selected from hydrogen; oxygen; Ci_ 6 alkyl; Ci- 6 haloalkyl, C 3 - 8 cycloalkyl; Ci- 6 alkylC 3 - 8 cycloalkyl; C 2 - 6 alkenyl; phenyl; Ci- 6 alkylimidizole; Ci- 6 alkoxy; Ci- 6 alkyltriazole; Ci- 6 alkyltetrazole; Ci- 6 alkylthiazole; Ci- 6 alkyloxazole; Ci_ ealkyldioxazole; Ci- 6 alkyloxazolidone; -COR 19 ; -COOR 19' ; -CSOR 19 " ; and -CONR 20 R 21 ; and
  • R 23 is selected from hydrogen; Ci_ 6 alkyl; C 3 . 8 cycloalkyl; C 2 - 6 alkenyl; phenyl; Ci- 6 alkylimidizole; Ci- 6 alkoxy; Ci- 6 alkyltriazole; Ci- 6 alkyltetrazole; Ci- 6 alkylthiazole; Ci_
  • Another embodiment provides a compound of Formula IA or Formula IB:
  • C* is a carbon atom stereocenter which has a configuration which is (R) or (S);
  • R 1 , R 2 , R 3 and R 4 are independently selected from hydrogen; hydroxy; alkoxy; halogen; cyano; NR 20 R 21 COR 19 ; COOR 19 ; CONR 20 R 21 ; pyrrolidinyl; unsubstituted Ci- 6 alkyl or halo- or alkyl substituted Ci_ 6 alkyl; Ci- 6 alkylCOOR 19 ; -BOR 19 OR 19' ; unsubstituted Ci- 6 alkoxy or halo-or alkyl-substituted Ci- 6 alkyoxy; unsubstituted C 3 - 7 cycloalkyl or halo-or alkyl-substituted C 3 - 7 cycloalkyl; unsubstituted C 3 - 7 cycloalkenyl or halo- or alkyl-substituted C 3 - 7 cycloalkenyl; unsubstituted or halo- or cyano
  • R 5 and R 6 are independently selected from halogen; cyano;
  • R 7 and R 8 are independently hydrogen; halogen; cyano; unsubstituted Ci_ 6alkyl or halo- or alkyl-substituted Ci_ 6 alkyl; unsubstituted Ci- 6 alkoxy or halo- or alkyl- substituted Ci-6alkoxy; unsubstituted C3-ecycloalkyl or halo- or alkyl-substituted C3- ecycloalkyl; unsubstituted or halo- or alkyl-substituted-C x H 2 x-phenyl; unsubstituted or halo- or alkyl-substituted -0-C x H 2x -phenyl, wherein x is 0, 1 , 2, 3, 4, 5 or 6; or R 7 and R 8 together form a 3- to 8-membered cycloalkyi ring optionally substituted with oxo, halogen, hydroxy, al
  • R 5 and R 8 are independently selected from hydrogen, unsubstituted Ci_ 6 alkyl, and halo- or alkyl-substituted Ci_ 6 alkyl;
  • R 6 and R 7 together form a 3- to 8-membered cycloalkyi ring optionally substituted with oxo, halogen, hydroxy, alkoxy, amino, cyano, OR 23 , R 15 , R 15' , R 16 and/or R 16' ; or R 6 and R 7 together form a 3- to 8- membered heterocycloalkyi ring comprising one heteroatom or two or more heteroatoms, optionally substituted with oxo, halogen, hydroxy, alkoxy, amino, cyano, R 15 , R 15' , R 16 and/or R 16' , wherein the one heteroatom in the heterocycloalkyi ring is NR 20 and the two or more heteroatoms are selected from N, NR 22 , O, S, SR 22 and SR 22 R 22' ; or
  • R 5 and R 6 are independently selected from hydrogen; halogen; cyano; unsubstituted Ci_ 6 alkyl or halo- or alkyl-substituted Ci_ 6 alkyl; unsubstituted Ci- 6 alkoxy or halo- or alkyl-substituted Ci- 6 alkoxy; unsubstituted C 3 - 8 cycloalkyl or halo- or alkyl- substituted C 3 - 8 cycloalkyl; unsubstituted or halo- or alkyl-substituted -C x H 2x -phenyl;
  • R 5 and R 6 together form a 3- to 8-membered cycloalkyi ring optionally substituted with oxo, halogen, hydroxy, alkoxy, amino, cyano, OR 23 , R 17 , R 17' , R 18 and/or R 18' , or R 5 and R 6 together form a 3- to 8- membered heterocycloalkyi ring, optionally substituted with oxo, halogen, hydroxy, alkoxy, amino, cyano, R 13 , R 13 ', R 14 and/or R 14' , wherein a heteroatom in the heterocycloalkyi ring is selected from O, N, NR 22 , S, SR 22 or SR 22 R 22' ; and
  • R 7 and R 8 are independently selected from halogen; cyano; unsubstituted Ci- 6 alkyl or halo- or alkyl-substituted Ci_ 6 alkyl; unsubstituted Ci- 6 alkoxy or halo- or alkyl- substituted Ci-6alkoxy; unsubstituted C3-ecycloalkyl or halo- or alkyl-substituted C3- ecycloalkyl; unsubstituted or halo- or alkyl-substituted -C x H 2x -phenyl; unsubstituted or halo- or alkyl-substituted -0-C x H 2x -phenyl, wherein x is 0, 1 , 2, 3, 4, 5 or 6; aryl; and heteroaryl; or R 7 and R 8 together form a 3- to 8-membered cycloalkyi ring optionally substituted with ox
  • R 9 is selected from hydrogen; hydroxy; halogen; cyano; unsubstituted Ci_ 6 alkyl or halo- or alkyl-substituted Ci_ 6 alkyl; unsubstituted Ci- 6 alkoxy or halo- or alkyl- substituted Ci- 6 alkoxy; unsubstituted C 3 - 8 cycloalkyl or halo- or alkyl-substituted C 3 .
  • ecycloalkyl unsubstituted or halo- or alkyl-substituted -C x H 2x -phenyl; and unsubstituted or halo- or alkyl-substituted-0-C x H 2) ⁇ phenyl, wherein x is 0, 1 , 2, 3, 4, 5 or 6;
  • R 10 is selected from COOR 19 and CONR 20 R 21 ;
  • R 11 is selected from hydrogen; hydroxy; halogen; cyano; unsubstituted Ci_ 6 alkyl or halo- or alkyl-substituted Ci_ 6 alkyl; unsubstituted Ci- 6 alkoxy or halo- or alkyl- substituted Ci- 6 alkyoxy; unsubstituted or halo- or alkyl-substituted C 3 - 7 cycloalkyl;
  • R 12 is selected from hydrogen; unsubstituted Ci_ 6 alkyl or Ci_ 6 alkyl substituted with one or more substituents independently selected from halo, hydroxy, alkoxy, heterocycloalkyi, heteroaryl, C 3 - 8 cycloalkyl and C 2 - 6 alkenyl; Ci- 6 alkylCi- 6 alkoxy; Ci_ 6 alkylCi- 6 alkoxyCi- 6 alkoxy; Ci.
  • heteroaryl is an O-containing or N-containing monocyclic heteroaryl
  • R 13 , R 13' , R 14 and R 14' are independently selected from hydrogen; halogen; amino; aminoalkyl; cyano; Ci_6alkyl; Ci-6alkoxy; carbonyl; carboxamide; and amide; or R 13 and R 13 ' or R 14 and R 14' together form a 3- to 8-membered cycloalkyi ring or 3- to 8- membered heterocycloalkyi ring, optionally substituted with oxygen, halogen, hydroxy, amino, cyano, Ci_6alkyl, C 3 -ecycloalkyl, C 2 -6alkenyl or Ci_6alkoxy, wherein a heteroatom in the heterocycloalkyi ring is selected from O, N, NR 22 , S, SR 22 or SR 22 R 22' ; [0074] R 15 , R 15' , R 16 and R 16' are independently hydrogen, halogen, amino, cyano, Ci- 6 alkyl, or Ci-
  • R 17 , R 17 ', R 18 and R 18' are independently selected from hydrogen; halogen; amino; cyano; Ci_ 6 alkyl; and Ci- 6 alkoxy; or R 17 and R 18 or R 17' and R 18' together form a 3- to 8-membered cycloalkyl ring or 3- to 8- membered heterocycloalkyi ring, optionally substituted with oxygen, halogen, hydroxy, amino, cyano, Ci_ 6 alkyl, C 3 - 8 cycloalkyl, C 2 .
  • 6alkenyl or Ci_6alkoxy wherein a heteroatom in the heterocycloalkyi ring is selected from O, N, NR 22 , S, SR 22 or SR 22 R 22' ;
  • R 19 , R 19' and R 19" are independently selected from hydrogen; Ci- 6 alkyl; C 3 . ecycloalkyl; C 2 - 6 alkenyl; phenyl; Ci- 6 alkylimidizole; Ci- 6 alkoxy; Ci- 6 alkyltriazole; Ci_
  • R 20 and R 21 are independently selected from hydrogen; Ci_ 6 alkyl; C 3 .
  • Ci_ ecycloalkyl; C 2 . 6 alkenyl; phenyl; Ci- 6 alkylimidizole; Ci- 6 alkoxy; Ci- 6 alkyltriazole; Ci_
  • R 20 and R 21 together with the nitrogen to which they are attached form unsubstituted pyrrolidinyl, unsubstituted piperidinyl, or unsubstituted morpholinyl; or form carboxyl-substituted pyrrolidinyl, carboxyl-substituted piperidinyl or carboxyl-substituted morpholinyl; and
  • R 22 and R 22' are independently selected from hydrogen; oxygen; Ci_ 6 alkyl; Ci- 6 haloalkyl; C 3 . 8 cycloalkyl; Ci- 6 alkylC 3 - 8 cycloalkyl; C 2 .
  • R 23 is selected from hydrogen; Ci_ 6 alkyl; C 3 . 8 cycloalkyl; C 2 . 6 alkenyl; phenyl; Ci- 6 alkylimidizole; Ci- 6 alkoxy; Ci- 6 alkyltriazole; Ci. 6 alkyltetrazole; Ci. 6 alkylthiazole; Ci_
  • a particular embodiment provides a compound selected from the group consisting of: 9'-(Benzyloxy)-10'-bromo-2'-oxo-2',7'-dihydrospiro[cyclobutane-1 ,6'-pyrido[2,1 - a]isoquinoline]-3'-carboxylic acid;
  • a particular embodiment provides a compound from Table 1 B, or a pharmaceutically acceptable salt thereof.
  • the present invention is directed to treatment the treatment of a hepatitis B infection or hepatitis B/hepatitis D co-infection in a human subject. Therefore, in certain embodiments, the present invention provides a method for the treatment of a hepatitis B infection or hepatitis B/hepatitis D co-infection, the method comprising administering to a subject in need of such treatment a compound of Formula I, IA or IB or a compound selected from Table 1A and Table 1 B as described herein.
  • the present invention provides a method for the treatment of a hepatitis B infection or hepatitis B/hepatitis D co-infection, the method comprising administering to a subject in need of such treatment a first pharmaceutically acceptable agent comprising a compound of Formula I, Formula IA or Formula IB or a compound selected from Table 1A and Table 1 B as described as described herein, in combination with a second pharmaceutically acceptable agent that stimulates immune function and a third pharmaceutically acceptable agent comprising an antiviral compound.
  • the administration of a compound of Formula I, IA or IB or a compound selected from Table 1 A and Table 1 B as described as described herein inhibits the release of hepatitis B surface antigen (HBsAg), HB core antigen protein (HBcAg), and/or hepatitis B pre-core protein known as the HBV e-antigen antigen (HBeAg) from infected hepatocytes.
  • HBsAg hepatitis B surface antigen
  • HBcAg HB core antigen protein
  • HBV eAg hepatitis B pre-core protein known as the HBV e-antigen antigen
  • Embodiments of the present invention features compounds that inhibit levels of HBe and/or HBs antigens in a subject infected with hepatitis B virus, and therefore are useful for treating human hepatitis B virus infections, and disease and symptoms associated with such virus infections.
  • Table 1 A and Table 1 B show a listing of compounds and structures, with ELISA data showing EC 5 o value ranges measured against the HBs antigen in a Hep AD 38 cell line (uM), for compounds from Table 1 A described herein.
  • alkyl refers to a monovalent saturated aliphatic hydrocarbyl group having from 1 to 14 carbon atoms and, in some embodiments, from 1 to 6 carbon atoms
  • alkyl includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH 3 -), ethyl (CH 3 CH 2 -), n-propyl
  • CH3CH2CH2- isopropyl ((CH 3 ) 2 CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH 3 ) 2 CHCH 2 -), sec-butyl ((CH 3 )(CH 3 CH 2 )CH-), /-butyl ((CH 3 ) 3 C-), ⁇ -pentyl (CH 3 CH2CH 2 CH 2 CH2-), and neopentyl ((CH 3 ) 3 CCH 2 -).
  • AlkyI groups may also be substituted, for example, with one or more alkyl, cycloalkyl, heterocycloalkyl, alkoxy, carboxy, amido, keto, amino, cyano, aryl, heteroaryl, halo or haloalkyl substituents.
  • Alkoxy refers to the group -O-alkyl wherein alkyl is defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, f-butoxy, sec-butoxy, n-pentoxy, morpholinylpropoxy, piperidinylethoxy.
  • Amino refers to the group -NR a R b where R a and R b are independently selected from hydrogen, alkyl, alkenyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, heterocyclic, and wherein R a and R b are optionally joined together with the nitrogen bound thereto to form a heterocyclic group.
  • R a is hydrogen and R b is alkyl
  • the amino group is sometimes referred to herein as alkylamino.
  • R a and R b are alkyl
  • dialkylamino When referring to a monosubstituted amino, it is meant that either R a or R b is hydrogen but not both.
  • a disubstituted amino it is meant that neither R a nor R b are hydrogen.
  • Aryl refers to an aromatic group of from 5 to 14 carbon atoms and no ring heteroatoms and having a single ring (e.g. , phenyl) or multiple condensed (fused) rings (e.g. , naphthyl or anthryl).
  • a single ring e.g. , phenyl
  • multiple condensed (fused) rings e.g. , naphthyl or anthryl.
  • the term “Aryl” or “Ar” applies when the point of attachment is at an aromatic carbon atom (e.g. , 5,6,7,8 tetrahydronaphthalene-2-yl is an aryl group as its point of attachment is at the 2- position of the aromatic phenyl ring).
  • Cycloalkyl refers to a saturated or partially saturated cyclic group of from 3 to 14 carbon atoms and no ring heteroatoms and having a single ring or multiple rings including fused, bridged, and spiro ring systems.
  • cycloalkyl applies when the point of attachment is at a non-aromatic carbon atom (e.g. 5,6,7,8,- tetrahydronaphthalene-5-yl).
  • Cycloalkyl includes cycloalkenyl groups, such as cyclohexenyl.
  • cycloalkyl groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl, and cyclohexenyl.
  • cycloalkyl groups that include multiple bicycloalkyl ring systems are bicyclohexyl, bicyclopentyl, bicyclooctyl, and the like.
  • Cycloalkyl groups may also be substituted, for example, with one or more alkyl, cycloalkyl, heterocycloalkyl, alkoxy, carboxy, amido, keto, amino, cyano, aryl, heteroaryl, halo or haloalkyl substituents.
  • Halo or "halogen” refers to fluoro, chloro, bromo, and iodo.
  • Haloalkyl refers to substitution of alkyl groups with 1 to 9 (e.g. when the alkyl group has 3 carbon atoms, such as a t-butyl group fully-substituted with halogen) or in some embodiments 1 to 3 halo groups (e.g. trifluoromethyl).
  • Heteroaryl refers to an aromatic group of from 1 to 14 carbon atoms and 1 to 6 heteroatoms selected from oxygen, nitrogen, sulfur, phosphorus, silicon and boron, and includes single ring (e.g. imidazolyl) and multiple ring systems (e.g. benzimidazol-2-yl and benzimidazol-6-yl).
  • single ring e.g. imidazolyl
  • multiple ring systems e.g. benzimidazol-2-yl and benzimidazol-6-yl
  • the term “heteroaryl” applies if there is at least one ring heteroatom and the point of attachment is at an atom of an aromatic ring (e.g.
  • the nitrogen and/or the sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide for the N-oxide (N ⁇ 0), sulfinyl, or sulfonyl moieties.
  • heteroaryl includes, but is not limited to, pyridyl, furanyl, thienyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, imidazolinyl, isoxazolyl, pyrrolyl, pyrazolyl, pyridazinyl, pyrimidinyl, purinyl, phthalazyl, naphthyl, naphthylpryidyl, oxazolyl, quinolyl, benzofuranyl,
  • quinazolinonyl benzimidazolyl, benzisoxazolyl, benzothienyl, benzopyridazinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, acridinyl, phenanthrolinyl, phenazinyl, phenoxazinyl, phenothiazinyl, and phthalimidyl.
  • Heterocyclic or “heterocycle” or “heterocycloalkyl” or “heterocyclyl” refers to a saturated or partially saturated cyclic group having from 1 to 14 carbon atoms and from 1 to 6 heteroatoms selected from nitrogen, sulfur, phosphorus or oxygen and includes single ring and multiple ring systems including fused, bridged, and spiro ring systems. For multiple ring systems having aromatic and/or non-aromatic rings, the terms “heterocyclic",
  • heterocycle when there is at least one ring heteroatom and the point of attachment is at an atom of a non-aromatic ring (e.g. 1 ,2,3,4- tetrahydroquinoline-3-yl, 5,6,7,8-tetrahydroquinoline-6-yl, and decahydroquinolin-6-yl).
  • the nitrogen, phosphorus and/or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N-oxide, phosphinane oxide, sulfinyl, sulfonyl moieties.
  • heterocyclyl includes, but is not limited to, tetrahydropyranyl, piperidinyl, piperazinyl, 3-pyrrolidinyl, 2-pyrrolidon-1 -yl, morpholinyl, and pyrrolidinyl.
  • a prefix indicating the number of carbon atoms e.g., C 3 -Ci 0 ) refers to the total number of carbon atoms in the portion of the heterocyclyl group exclusive of the number of heteroatoms.
  • heterocycle and heteroaryl groups include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, pyridone, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, naphthalene, oxazole, oxopyrrolidine, piperidine, piperazine
  • cyclopentathiazole thiazolidine, thiophene, benzo[b]thiophene, morpholine, thiomorpholine (also referred to as thiamorpholine), piperidine, pyrrolidine, and tetrahydrofuranyl.
  • fused heterocyclic refers to a 3 to 10 member cyclic substituent formed by the replacement of two hydrogen atoms at different carbon atoms in a cycloalkyl ring structure, as exemplified by the following cyclopentathiazole structure:
  • fused aryl and fused heteroaryl refers to a 5 to 6 member aryl structure or heteroaryl structure fused with a 5- to 6- member aryl, heteroaryl or cycloalkyl ring at different carbon atoms in the aryl structure or the heteroaryl structure, which may be substituted at one of the carbons in the fused aryl or fused heteroaryl and connected to the core molecule at another of the carbons, as exemplified by the following cyclopentylthiazole, quinoline or naphthalene structures:
  • Compound refers to a compound encompassed by the generic formulae disclosed herein, any subgenus of those generic formulae, and any forms of the compounds within the generic and subgeneric formulae, including the racemates, stereoisomers, and tautomers of the compound or compounds.
  • heteroatom means nitrogen, oxygen, or sulfur and includes any oxidized form of nitrogen, such as N(O) ⁇ N + — O " ⁇ and sulfur such as S(O) and S(O) 2 , and the quaternized form of any basic nitrogen.
  • Oxazole and oxazolyl refers to a 5-membered heterocyclic ring containing one nitrogen and one oxygen as heteroatoms and also contains three carbons and may be substituted at one of the three carbons and may be connected to another molecule at another of the three carbons, as exemplified by any of the following structures, wherein the oxazolidinone groups shown here are bonded to a parent molecule, which is indicated by a wavy line in the bond to the parent molecule:
  • Oxopyrrolidine and “oxopyrrolidinyl” refers to a 5-membered heterocyclic ring containing nitrogen and 4 carbons that is substituted at one of the carbons in the heterocyclic ring by a carbonyl and may be connected to another substituent at another carbon in the heterocyclic ring, as exem by the structure below:
  • Pyridine and pyridinyl refers to a 6-membered heteroaryl ring containing one nitrogen and 5 carbons that may also be substituted at one or more of the carbons in the heteroaryl ring, and may be connected to another substituent at another carbon in the heteroaryl ring, as exemplified by the structures below:
  • Thiazole and thiazolyl refers to a 5-membered heteroaryl containing one sulfur and one nitrogen in the heteroaryl ring and 3 carbons in the heteroaryl ring that may also be substituted at one or more of the carbons in the heteroaryl ring, and may be connected to another substituent at another carbon in the heteroaryl ring, as exemplified by the structures belo
  • Pyrimidine and pyrimidinyl refers to a 6-membered heteroaryl ring containing two nitrogens in the heteroaryl ring and 4 carbons in the heteroaryl ring that may be substituted at one or more of the carbons in the heteroaryl ring, and may be connected to another substituent at another carbon in the heteroaryl ring, as exemplified by the structures below:
  • Racemates refers to a mixture of enantiomers.
  • the compounds of Formulas I, or pharmaceutically acceptable salts thereof are enantiomerically enriched with one enantiomer wherein all of the chiral carbons referred to are in one configuration.
  • reference to an enantiomerically enriched compound or salt is meant to indicate that the specified enantiomer will comprise more than 50% by weight of the total weight of all enantiomers of the compound or salt.
  • Solvate or “solvates” of a compound refer to those compounds, as defined above, which are bound to a stoichiometric or non-stoichiometric amount of a solvent.
  • Solvates of a compound includes solvates of all forms of the compound.
  • solvents are volatile, non-toxic, and/or acceptable for administration to humans in trace amounts. Suitable solvates include water.
  • Stereoisomer or “stereoisomers” refer to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and
  • “Pharmaceutically acceptable salt” refers to pharmaceutically acceptable salts derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, and tetraalkylammonium, and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, and oxalate. Suitable salts include those described in P. Heinrich Stahl, Camille G. Wermuth (Eds.), Handbook of Pharmaceutical Salts Properties, Selection, and Use; 2002.
  • Patient refers to mammals and includes humans and non-human mammals.
  • Treating or “treatment” of a disease in a patient refers to 1) preventing the disease from occurring in a patient that is predisposed or does not yet display symptoms of the disease; 2) inhibiting the disease or arresting its development; or 3) ameliorating or causing regression of the disease.
  • dashed line represents an optional double bond at that position.
  • dashed circles appear within ring structures denoted by solid lines or solid circles, then the dashed circles represent one to three optional double bonds arranged according to their proper valence taking into account whether the ring has any optional substitutions around the ring as will be known by one of skill in the art.
  • the dashed line in the structure below could either indicate a double bond at that position or a single bond at that position:
  • ring A below could be a cyclohexyl ring without any double bonds or it could also be a phenyl ring having three double bonds arranged in any position that still depicts the proper valence for a phenyl ring.
  • any of X 1 -X 5 could be selected from: C, CH, or CH 2 , N, or NH, and the dashed circle means that ring B could be a cyclohexyl or phenyl ring or a N-containing heterocycle with no double bonds or a N- containing heteroaryl ring with one to three double bonds arranged in any position that still depicts the proper valen
  • substituents that are not explicitly defined herein are arrived at by naming the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment.
  • substituent "arylalkyloxycarbonyl” refers to the group (aryl)-(alkyl)-0-C(0)-.
  • -CCR' it should be understood that the two R x groups can be the same, or they can be different if R x is defined as having more than one possible identity.
  • certain substituents are drawn as -R x R y , where the "-" indicates a bond adjacent to the parent molecule and R y being the terminal portion of the functionality.
  • impermissible substitution patterns e.g., methyl substituted with 5 fluoro groups. Such impermissible substitution patterns are well known to the skilled artisan.
  • substitution with isotopes such as deuterium, i.e. 2 H may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • C* is a carbon atom stereocenter which has a configuration which is (R) or (S);
  • R 1 , R 2 , R 3 and R 4 are independently selected from hydrogen; hydroxy; alkoxy; halogen; cyano; NR 20 R 21 COR 19 ; COOR 19 ; CONR 20 R 21 ; pyrrolidinyl; unsubstituted Ci- 6 alkyl or halo- or alkyl substituted Ci_ 6 alkyl; Ci- 6 alkylCOOR 19 ; -BOR 19 OR 19' ; unsubstituted Ci- 6 alkoxy or halo-or alkyl-substituted Ci- 6 alkyoxy; unsubstituted C 3 - 7 cycloalkyl or halo-or alkyl-substituted C 3 - 7 cycloalkyl; unsubstituted C 3 - 7 cycloalkenyl or halo- or alkyl-substituted C 3 - 7 cycloalkenyl; unsubstituted or halo- or cyano
  • R 5 and R 6 are independently selected from halogen; cyano;
  • R 7 and R 8 are independently hydrogen; halogen; cyano; unsubstituted Ci_ 6 alkyl or halo- or alkyl-substituted Ci_ 6 alkyl; unsubstituted Ci- 6 alkoxy or halo- or alkyl- substituted Ci- 6 alkoxy; unsubstituted C 3 - 8 cycloalkyl or halo- or alkyl-substituted C 3 .
  • ecycloalkyl unsubstituted or halo- or alkyl-substituted-C x H 2 x-phenyl; unsubstituted or halo- or alkyl-substituted -0-C x H 2x -phenyl, wherein x is 0, 1 , 2, 3, 4, 5 or 6; or R 7 and R 8 together form a 3- to 8-membered cycloalkyi ring optionally substituted with oxo, halogen, hydroxy, alkoxy, amino, cyano, OR 23 , R 17 , R 17' , R 18 and/or R 18' , or R 7 and R 8 together form a 3- to 8- membered heterocycloalkyi ring, optionally substituted with oxo, halogen, hydroxy, alkoxy, amino, cyano, R 17 , R 17' , R 18 and/or R 18' , wherein a heteroatom in the heterocycloalkyi
  • R 5 and R 8 are independently selected from hydrogen, unsubstituted Ci-6alkyl, and halo- or alkyl-substituted Ci_6alkyl;
  • R 6 and R 7 together form a 3- to 8-membered cycloalkyi ring optionally substituted with oxo, halogen, hydroxy, alkoxy, amino, cyano, OR 23 , R 15 , R 15' , R 16 and/or R 16' ; or R 6 and R 7 together form a 3- to 8- membered heterocycloalkyi ring comprising one heteroatom or two or more heteroatoms, optionally substituted with oxo, halogen, hydroxy, alkoxy, amino, cyano, R 15 , R 15' , R 16 and/or R 16' , wherein the one heteroatom in the heterocycloalkyi ring is NR 20 and the two or more heteroatoms are selected from N, NR 22 , O, S, SR 22 and SR 22 R 22' ; or
  • R 5 and R 6 are independently selected from hydrogen; halogen; cyano; unsubstituted Ci_ 6 alkyl or halo- or alkyl-substituted Ci_ 6 alkyl; unsubstituted Ci- 6 alkoxy or halo- or alkyl-substituted Ci- 6 alkoxy; unsubstituted C 3 - 8 cycloalkyl or halo- or alkyl- substituted C 3 - 8 cycloalkyl; unsubstituted or halo- or alkyl-substituted -C x H 2x -phenyl;
  • R 5 and R 6 together form a 3- to 8-membered cycloalkyi ring optionally substituted with oxo, halogen, hydroxy, alkoxy, amino, cyano, OR 23 , R 17 , R 17' , R 18 and/or R 18' , or R 5 and R 6 together form a 3- to 8- membered heterocycloalkyi ring, optionally substituted with oxo, halogen, hydroxy, alkoxy, amino, cyano, R 13 , R 13 ', R 14 and/or R 14' , wherein a heteroatom in the heterocycloalkyi ring is selected from O, N, NR 22 , S, SR 22 or SR 22 R 22' ; and
  • R 7 and R 8 are independently selected from halogen; cyano; unsubstituted Ci- 6 alkyl or halo- or alkyl-substituted Ci_ 6 alkyl; unsubstituted Ci- 6 alkoxy or halo- or alkyl- substituted Ci- 6 alkoxy; unsubstituted C 3 - 8 cycloalkyl or halo- or alkyl-substituted C 3 .
  • ecycloalkyl unsubstituted or halo- or alkyl-substituted -C x H 2 x-phenyl; unsubstituted or halo- or alkyl-substituted -0-C x H 2 x-phenyl, wherein x is 0, 1 , 2, 3, 4, 5 or 6; aryl; and heteroaryl; or R 7 and R 8 together form a 3- to 8-membered cycloalkyi ring optionally substituted with oxo, halogen, hydroxy, alkoxy, amino, cyano, OR 23 , R 17 , R 17' , R 18 and/or R 18' , or R 7 and R 8 together form a 3- to 8- membered heterocycloalkyi ring, optionally substituted with oxo, halogen, hydroxy, alkoxy, amino, cyano, R 17 , R 18 ', R 17 and/or R 18' , wherein a
  • R 9 is selected from hydrogen; hydroxy; halogen; cyano; unsubstituted Ci_ 6 alkyl or halo- or alkyl-substituted Ci_ 6 alkyl; unsubstituted Ci- 6 alkoxy or halo- or alkyl- substituted Ci- 6 alkoxy; unsubstituted C 3 . 8 cycloalkyl or halo- or alkyl-substituted C 3 .
  • ecycloalkyl unsubstituted or halo- or alkyl-substituted -C x H 2 x-phenyl; and unsubstituted or halo- or alkyl-substituted-0-C x H 2x -phenyl, wherein x is 0, 1 , 2, 3, 4, 5 or 6;
  • R 10 is selected from COOR 19 and CONR 20 R 21 ;
  • R 11 is selected from hydrogen; hydroxy; halogen; cyano; unsubstituted Ci_ 6 alkyl or halo- or alkyl-substituted Ci_ 6 alkyl; unsubstituted Ci- 6 alkoxy or halo- or alkyl- substituted Ci- 6 alkyoxy; unsubstituted or halo- or alkyl-substituted C 3 .
  • R 12 is selected from hydrogen; unsubstituted Ci_ 6 alkyl or Ci- 6 alkyl substituted with one or more substituents independently selected from halo, hydroxy, alkoxy, heterocycloalkyi, heteroaryl, C 3 -8cycloalkyl and C 2 -6alkenyl; Ci-6alkylCi-6alkoxy; Ci-6alkylCi- 6 alkoxyCi- 6 alkoxy; Ci.
  • Ci-6alkynylCi- 6 hydroxy Ci-6alkylCi- 6 alkoxyamino; Ci-6alkylCi-6alkoxyaminoCi- 6 alkyl; Ci_ 6 alkylCi- 6alkoxyaminodiCi- 6 alkyl; Ci- 6 alkylcarboxy; Ci-6alkylaminocarbonylCi- 6 alkoxy; Ci_
  • heteroaryl is an O-containing or N-containing monocyclic heteroaryl
  • R 13 , R 13' , R 14 and R 14' are independently selected from hydrogen; halogen; amino; aminoalkyl; cyano; Ci_ 6 alkyl; Ci- 6 alkoxy; carbonyl; carboxamide; and amide; or R 13 and R 13 ' or R 14 and R 14' together form a 3- to 8-membered cycloalkyl ring or 3- to 8- membered heterocycloalkyi ring, optionally substituted with oxygen, halogen, hydroxy, amino, cyano, Ci_ 6 alkyl, C 3 -8cycloalkyl, C 2 -6alkenyl or Ci- 6 alkoxy, wherein a heteroatom in the heterocycloalkyi ring is selected from O, N, NR 22 , S, SR 22 or SR 22 R 22' ;
  • R 15 , R 15' , R 16 and R 16' are independently hydrogen, halogen, amino, cyano, Ci- 6 alkyl, or Ci. 6 alkoxy, wherein any or R 15 , R 15' , R 16 or R 16' , together with R 5 or R 8 , form a 3- to 8-membered cycloalkyl ring or a 3-8 membered heterocycloalkyi ring, optionally substituted with oxygen, halogen, hydroxy, amino, cyano, Ci_ 6 alkyl, C 3 -8cycloalkyl, C 2 .
  • R 17 , R 17 ', R 18 and R 18' are independently selected from hydrogen; halogen; amino; cyano; Ci_ 6 alkyl; and Ci- 6 alkoxy; or R 17 and R 18 or R 17' and R 18' together form a 3- to 8-membered cycloalkyl ring or 3- to 8- membered heterocycloalkyi ring, optionally substituted with oxygen, halogen, hydroxy, amino, cyano, Ci_ 6 alkyl, C 3 . 8 cycloalkyl, C 2 .
  • R 19 , R 19' and R 19" are independently selected from hydrogen; Ci_ 6 alkyl; C 3 . ecycloalkyl; C 2 -6alkenyl; phenyl; Ci-6alkylimidizole; Ci-6alkoxy; Ci-6alkyltriazole; Ci- 6 alkyltetrazole; Ci- 6 alkylthiazole; Ci- 6 alkyloxazole; Ci- 6 alkyldioxazole; and Ci_
  • R 20 and R 21 are independently selected from hydrogen; Ci_ 6 alkyl; C 3 . ecycloalkyl; C 2 - 6 alkenyl; phenyl; Ci- 6 alkylimidizole; Ci- 6 alkoxy; Ci- 6 alkyltriazole; Ci_
  • R 20 and R 21 together with the nitrogen to which they are attached form unsubstituted pyrrolidinyl, unsubstituted piperidinyl, or unsubstituted morpholinyl; or form carboxyl-substituted pyrrolidinyl, carboxyl-substituted piperidinyl or carboxyl-substituted morpholinyl; and
  • R 22 and R 22' are independently selected from hydrogen; oxygen; Ci_ 6 alkyl; Ci- 6 haloalkyl; C 3 - 8 cycloalkyl; Ci- 6 alkylC 3 - 8 cycloalkyl; C 2 - 6 alkenyl; phenyl; Ci- 6 alkylimidizole; Ci- 6 alkoxy; Ci- 6 alkyltriazole; Ci- 6 alkyltetrazole; Ci- 6 alkylthiazole; Ci- 6 alkyloxazole; Ci_ ealkyldioxazole; Ci- 6 alkyloxazolidone; -COR 19 ; -COOR 19' ; -CSOR 19 " ; and -CONR 20 R 21 ; and
  • R 23 is selected from hydrogen; Ci_ 6 alkyl; C 3 - 8 cycloalkyl; C 2 - 6 alkenyl; phenyl; Ci- 6 alkylimidizole; Ci- 6 alkoxy; Ci- 6 alkyltriazole; Ci- 6 alkyltetrazole; Ci- 6 alkylthiazole; Ci_ 6alkyloxazole; Ci-6alkyldioxazole; Ci-6alkyloxazolidone; aryl; heteroaryl; and benzyl, or a pharmaceutically acceptable salt thereof.
  • One particular embodiment provides a compound according of Formula I, Formula IA or Formula IB as described herein, wherein:
  • R 1 is selected from hydrogen, hydroxy, halogen, cyano, amino, pyrrolidinyl, unsubstituted Ci_ 6 alkyl or halo-substituted Ci_ 6 alkyl, unsubstituted Ci- 6 alkoxy or halo- substituted Ci- 6 alkyoxy; C 3 . 7 cycloalkyl or halo-substituted C 3 .
  • R 2 and R 3 are independently OR 12 ;
  • R 4 is selected from hydrogen, hydroxy, halogen, cyano, amino, pyrrolidinyl, unsubstituted Ci_ 6 alkyl or halo-substituted Ci_ 6 alkyl, unsubstituted Ci- 6 alkoxy or halo- substituted Ci- 6 alkyoxy; C 3 . 7 cycloalkyl or halo-substituted C 3 .
  • R 6 and R 7 together form a 3- to 8-membered cycloalkyi ring or 3- to 8- membered heterocycloalkyi ring comprising one heteroatom or two or more heteroatoms, optionally substituted with R 15 , R 15' , R 16 and/or R 16' , wherein the one heteroatom in the heteroalkyl ring is NR 20 and the two or more heteroatoms are selected from N, NR 22 , O, S, SR 22 and SR 22 R 22' ; R 11 is hydrogen; R 12 is as described herein; and R 15 and R 16 or R 15' and R 16' together form a 3- to 8- membered cycloalkyi ring or heterocycloalkyi ring optionally substituted with oxygen, halogen, hydroxy, amino, cyano, Ci_ 6 alkyl, C 3 - 8 cycloalkyl, C 2 - 6 alkenyl or Ci- 6 alkoxy, wherein the heteroatom in the heteroalkyl ring is
  • Another embodiment provides a compound of Formula I, Formula IA or Formula IB as described herein, wherein R 10 is COOR 19 or CONR 20 R 21 ; or a
  • Another particular embodiment provides a compound of Formula I, Formula IA or Formula IB as described herein, wherein R 10 is COOR 19 ; R 12 is unsubstituted Ci_ 6 alkyl; and R 19 is hydrogen, or a pharmaceutically acceptable salt thereof.
  • Another particular embodiment provides a compound of Formula I, Formula IA or Formula IB as described herein wherein R 4 is hydrogen; R 10 is COOR 19 ; R 12 is -CH 3 ; and R 19 is hydrogen, or a pharmaceutically acceptable salt thereof.
  • Another particular embodiment provides a compound of Formula I, Formula IA or Formula IB as described herein, wherein R 2 and R 3 are independently OR 12 ; R 5 and R 6 together form a 3- to 8-membered cycloalkyi ring or 3- to 8- membered heterocycloalkyi ring, optionally substituted with R 13 and R 14 , wherein the heteroatom in the heteroalkyl ring is O, N, NR 22 , S, SR 22 or SR 22 R 22 '; R 10 is COOR 19 ; R 11 is hydrogen; R 12 is unsubstituted Ci- 6alkyl; R 13 and R 14 or R 13' and R 14' together form a 3- to 8-membered cycloalkyi ring or 3- to 8- membered heterocycloalkyi ring, optionally substituted with oxygen, halogen, hydroxy, amino, cyano, Ci_ 6 alkyl, C 3 - 8 cycloalkyl, C 2 - 6 alkeny
  • Still another particular embodiment provides a compound of Formula I, Formula IA or Formula IB as described herein, wherein R 2 and R 3 are independently OR 12 ; R 7 and R 8 together form a 3- to 8-membered ring, optionally substituted with R 17 and R 18 ; R 10 is COOR 19 ; R 11 is hydrogen; R 12 is unsubstituted Ci_ 6 alkyl; R 17 and R 18 or R 17' and R 18' together form a 3- to 8-membered cycloalkyi ring or 3- to 8- membered heterocycloalkyi ring, optionally substituted with oxygen, halogen, hydroxy, amino, cyano, Ci_6alkyl, C 3 .
  • ecycloalkyl C 2 - 6 alkenyl or Ci. 6 alkoxy, wherein the heteroatom in the heteroalkyl ring is O, N, NR 22 , S, SR 22 or SR 22 R 22' ; and R 19 is hydrogen, or a pharmaceutically acceptable salt thereof.
  • Another particular embodiment provides a compound of Formula I, Formula IA or Formula IB as described herein, wherein R 2 and R 3 are independently OR 12 ; and R 5 and R 6 together form a 3- to 8- membered cycloalkyl ring or 3- to 8- membered
  • heterocycloalkyl ring optionally substituted with R 13 , R 14 , R 13' and/or R 14' , wherein the heteroatom in the heteroalkyl ring is O, N, NR 22 , S, SR 22 or SR 22 R 22' , or a pharmaceutically acceptable salt thereof.
  • Another particular embodiment provides a compound of Formula I, Formula IA or Formula IB as described herein wherein R 2 and R 3 are independently OR 12 ; and R 7 and R 8 together form a 3- to 8-membered cycloalkyl ring or 3- to 8- membered
  • heterocycloalkyl ring optionally substituted with R 17 , R 18 , R 17' and/or R 18' , wherein the heteroatom in the heteroalkyl ring is O, N, NR 22 , S, SR 22 or SR 22 R 22' , or a pharmaceutically acceptable salt thereof.
  • R is H or alkyl
  • compounds of Formula I, Formula IA or Formula IB are selected from:
  • R is hydrogen or alkyi and R' is H, alkyl, ester, carbamate, urea, or sulfonyl urea.
  • R 1 , R 2 , R 3 , R 4 , R 9 , R 10 and R 11 are as described, and R' and R are independently selected from hydrogen, halo, alkyl, aryl, carbocycle, heterocycle, heteroaryl, alkylene optionally substituted with
  • R and R' are independently H, alkyl, acyl, ester, carbamoyl, sulfonyl urea, or urea, and wherein Z is substituted C, O, N or S.
  • R 4 , R 5 , R 6 , R 9 , R 10 and R 11 are as described, and R 1 is halogen, R 2 and R 3 are independently selected from:
  • Compounds described herein can exist in particular geometric or stereoisomeric forms.
  • the invention contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)- isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, as falling within the scope of the invention.
  • Additional asymmetric carbon atoms can be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.
  • Optically active (R)- and (S)-isomers and d and I isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If, for instance, a particular enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis, or by derivatization with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
  • diastereomeric salts can be formed with an appropriate optically active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means known in the art, and subsequent recovery of the pure
  • enantiomers In addition, separation of enantiomers and diastereomers is frequently accomplished using chromatography employing chiral, stationary phases, optionally in combination with chemical derivatization (e.g., formation of carbamates from amines).
  • chemical derivatization e.g., formation of carbamates from amines.
  • a pharmaceutical composition comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of a compound of Formula I, Formula IA or Formula IB, or a compound selected from Table 1 A and Table 1 B, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical formulation containing a compound of Formula I, Formula IA or Formula IB or a compound selected from Table 1 A and Table 1 B or a pharmaceutically acceptable salt thereof is a formulation adapted for parenteral administration.
  • the formulation is a long-acting parenteral formulation.
  • the formulation is a nano-particle formulation.
  • the pharmaceutical formulation containing a compound of Formula I, Formula IA or Formula IB, or a compound selected from Table 1 A and Table 1 B, or a pharmaceutically acceptable salt thereof is a formulation adapted for oral, rectal, topical or intravenous formulation, wherein the pharmaceutical formulation optionally comprises any one or more of a pharmaceutically acceptable carrier, adjuvant or vehicle.
  • the compound of Formula I, Formula IA or Formula IB or a compound selected from Table 1A and Table 1 B or a pharmaceutically acceptable salt thereof is formulated for oral administration, and can be administered as a conventional preparation, for example, as any dosage form of a solid agent such as tablets, powders, granules, capsules and the like; an aqueous agent; an oily suspension; or a liquid agent such as syrup and elixir.
  • the compound of Formula I, Formula IA or Formula IB or a compound selected from Table 1 A and Table 1 B or a pharmaceutically acceptable salt thereof is formulated for parenteral administration, and can be administered as an aqueous or oily suspension injectable, or a nasal drop.
  • a preparation of a compound of Formula I, Formula IA or Formula IB or a compound selected from Table 1A and Table 1 B or a pharmaceutically acceptable salt thereof may be prepared by combining (e.g. mixing) a therapeutically effective amount of a compound of Formula I, Formula IA or Formula IB or a compound selected from Table 1 A and Table 1 B or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier or diluent.
  • compositions adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.
  • the compound of Formula I, Formula IA or Formula IB or a compound selected from Table 1A and Table 1 B can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • Powders are prepared by comminuting the compound of Formula I, Formula IA or Formula IB or a compound selected from Table 1 A and Table 1 B to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing and coloring agent can also be present.
  • Capsules are made by preparing a powder mixture, as described above, and filling formed gelatin sheaths.
  • Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture before the filling operation.
  • a disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.
  • suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture.
  • Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant and pressing into tablets.
  • a powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or an absorption agent such as bentonite, kaolin or dicalcium phosphate.
  • the powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen.
  • the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules.
  • the granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil.
  • the lubricated mixture is then compressed into tablets.
  • the compounds of the present invention can also be combined with a free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps.
  • a clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages.
  • Oral fluids such as solutions, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound.
  • Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle.
  • Suspensions can be formulated by dispersing the compound in a non-toxic vehicle.
  • Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives, flavor additive such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, and the like can also be added.
  • dosage unit formulations for oral administration can be microencapsulated.
  • the formulations of compounds of Formula I, Formula IA or Formula IB can also be prepared to prolong or sustain the release of the compound, as for example by coating or embedding particulate material in polymers, wax or the like.
  • the compounds of Formula I, Formula IA or Formula IB or compounds selected from Table 1A and Table 1 B, or salts, solvates or hydrates thereof, can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • the compounds of Formula I, Formula IA or Formula IB or compounds selected from Table 1 A and Table 1 B, or salts, solvates or hydrates thereof, may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the compounds may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinylpyrrolidone, pyrancopolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamide-phenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues.
  • the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • compositions adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time.
  • the compounds of Formula I, Formula IA or Formula IB or compounds selected from Table 1 A and Table 1 B may be delivered from a patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318 (1986).
  • compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
  • the active ingredient When formulated in an ointment, the active ingredient may be employed with either a paraffinic or a water-miscible ointment base.
  • the active ingredient may be formulated in a cream with an oil-in-water cream base or a water-in-oil base.
  • compositions adapted for rectal administration may be presented as suppositories or as enemas.
  • compositions adapted for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • Suitable formulations wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops, include aqueous or oil solutions of the active ingredient.
  • Fine particle dusts or mists which may be generated by means of various types of metered, dose pressurized aerosols, nebulizers or insufflators.
  • compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
  • formulations described herein may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.
  • a therapeutically effective amount of a compound of Formula I, Formula IA or Formula IB or a compound selected from Table 1A and Table 1 B will depend upon a number of factors including, for example, the age and weight of the human or other animal, the precise condition requiring treatment and its severity, the nature of the formulation, and the route of administration, and will ultimately be at the discretion of the attendant physician or veterinarian.
  • An effective amount of a salt or hydrate thereof may be determined as a proportion of the effective amount of the compound of Formula I, Formula IA or Formula IB or the compound selected from Table 1 A and Table 1 B, or salts, solvates or hydrates thereof, per se.
  • Embodiments of the present invention provide administration of a compound of Formula I, Formula IA or Formula IB or a compound selected from Table 1 A and Table 1 B to a healthy or virus-infected patient, either as a single agent or in combination with (a) another agent that is effective in treating or preventing hepatitis B virus of hepatitis D virus, (b) another agent that improves immune response and robustness, or (c) another agent that reduces inflammation and/or pain.
  • a method of treating a hepatitis B virus and/or hepatitis D virus by administering a therapeutically effective amount of a compound of Formula I, Formula IA or Formula IB or a compound selected from Table 1 A and Table 1 B, or a pharmaceutically acceptable salt, solvate or hydrate thereof, to a mammal.
  • the mammal is a human.
  • a method of reducing HBe and/or HBs antigens in a mammal by administering to said mammal a therapeutically effective amount of a compound of Formula I, Formula IA or Formula IB or a compound selected from Table 1A and Table 1 B or a pharmaceutically acceptable salt, solvate or hydrate thereof.
  • the mammal is a human.
  • the compounds of the present invention may be used in combination with one or more antiviral therapeutic agents or anti-inflammatory agents useful in the prevention or treatment of viral diseases or associated pathophysiology.
  • the compounds of the present invention and their salts, solvates, or other pharmaceutically acceptable derivatives thereof may be employed alone or in combination with other antiviral or anti-inflammatory therapeutic agents.
  • the compounds of the present invention and any other pharmaceutically active agent(s) may be administered together or separately and, when administered separately, administration may occur simultaneously or sequentially, in any order.
  • the amounts of the compounds of the present invention and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • the administration in combination of a compound of the present invention and salts, solvates, or other pharmaceutically acceptable derivatives thereof with other treatment agents may be in combination by administration concomitantly in: (1) a unitary pharmaceutical composition including both compounds; or (2) separate pharmaceutical compositions each including one of the compounds.
  • the combination may be administered separately in a sequential manner wherein one treatment agent is administered first and the other second or vice versa. Such sequential administration may be close in time or remote in time.
  • the amounts of the compound(s) of Formula I, Formula IA or Formula IB or compounds selected from Table 1 A and Table 1 B or salts thereof, and the other pharmaceutically active agent(s), and the relative timings of administration, will be selected in order to achieve the desired combined therapeutic effect.
  • embodiments provide a method as described comprising administering an additional agent selected from an antiviral agent, an antibiotic, an analgesic, a non-steroidal anti-inflammatory (NSAID) agent, an antifungal agent, an antiparasitic agent, an anti-nausea agent, an anti-diarrheal agent, or an immunosuppressant agent.
  • the antiviral agent is an anti-hepatitis B agent or an anti- hepatitis C agent.
  • the additional agent is administered as part of a single dosage form of said pharmaceutical formulation, or as a separate dosage form.
  • the present invention is directed to compounds, compositions and pharmaceutical compositions that have utility as novel treatments and/or preventative therapies for virus infections. While not wanting to be bound by any particular theory, it is thought that the present compounds are able to inhibit the levels of HBe and HBs antigens in a subject infected with hepatitis B virus or suffering from a chronic hepatitis B viral infection. By reducing the levels of HBe and HBs antigens in a subject infected with hepatitis B virus, compounds described herein are effective at treating hepatitis B infections, and secondary disorders such as liver cirrhosis, liver failure and liver cancer which are often associated with hepatitis B virus infections.
  • a method of treating or preventing a hepatitis B virus infection in a subject suffering from the HBV infection comprising administering to the subject an inhibitor of HBe and/or HBs antigens, wherein the inhibitor is a compound of Formula I, Formula IA or Formula IB.
  • a method of treating a hepatitis B virus infection and/or a hepatitis D virus infection in a subject suffering from the virus infection comprising administering to the subject a compound from Table 1 A or a compound from Table 1 B .
  • a method for treating a viral infection in a subject mediated at least in part by a virus in the hepatitis B family and or the hepatitis D family comprising administering to the subject a composition comprising a compound of any of Formula I, Formula IA or Formula IB, or a compound selected from Table 1 A and Table 1 B, or a pharmaceutically acceptable salt thereof.
  • another embodiment of the present invention provides a method of inhibiting progression of a viral infection in a subject at risk for infection with a hepatitis B virus and/or a hepatitis D virus, comprising administering to the subject a therapeutically effective amount of the compound of Formula I, Formula IA or Formula IB, or a compound selected from Table 1A and Table 1 B, or a pharmaceutically acceptable salt thereof.
  • another embodiment of the present invention provides a method of preventing a viral infection in a subject at risk for infection from a hepatitis B virus and/or a hepatitis D virus comprising administering to the subject a therapeutically effective amount of the compound of Formula I or Formula IA, or a compound selected from Table 1 A and Table 1 B, or a pharmaceutically acceptable salt thereof.
  • another embodiment of the present invention provides a method of treating a virus infection in a subject suffering from said virus infection, comprising administering to the subject a therapeutically effective amount of the compound of Formula I, Formula IA or Formula IB, or a compound selected from Table 1 A and Table 1 B, or a pharmaceutically acceptable salt thereof.
  • Compounds, methods and pharmaceutical compositions for treating viral infections, by administering a compound of Formula I, Formula IA or Formula IB or a compound selected from Table 1A and Table 1 B in a therapeutically effective amount are disclosed.
  • Methods for preparing compounds of Formula I, Formula IA or Formula IB or compounds selected from Table 1A and Table 1 B and methods of using the compounds and pharmaceutical compositions thereof are also disclosed.
  • the treatment and prophylaxis of viral infections such as those caused by hepatitis B and/or hepatitis D are disclosed.
  • the compounds described herein are useful for treating infections in a subject wherein the infection is caused by a multi-drug resistant strain of the hepatitis B virus and/or a hepatitis D virus.
  • the compound of the present invention is chosen from the compounds set forth in Table 1A and Table 1 B.
  • C* is a carbon atom stereocenter which has a configuration which is (R) or
  • R 1 , R 2 , R 3 and R 4 are independently selected from hydrogen, hydroxy, halogen, cyano, amino, pyrrolidinyl, unsubstituted Ci_ 6 alkyl or halo-substituted Ci_ 6 alkyl, unsubstituted Ci- 6 alkoxy or halo-substituted Ci- 6 alkyoxy; C 3 - 7 cycloalkyl or halo-substituted C 3 - 7 cycloalkyl; N-containing monocyclic heterocycloalkyi, pyrrolidinyl, -C x H 2x -phenyl, -O- C x H 2x -phenyl or -(Ci-6alkyl)N- C x H 2x -phenyl wherein x is 0, 1 , 2, 3, 4, 5 or 6; or -OR 12 ; and wherein
  • R 5 and R 6 are independently halogen, cyano, unsubstituted Ci_ 6 alkyl or halo-substituted Ci_ 6 alkyl, unsubstituted Ci- 6 alkoxy or halo-substituted Ci- 6 alkoxy, unsubstituted C 3 - 8 cycloalkyl or halo-substituted C 3 - 8 cycloalkyl, -C x H 2 x-phenyl or -0-C x H 2x - phenyl wherein x is 0, 1 , 2, 3, 4, 5 or 6; aryl; heteroaryl; or R 5 and R 6 together form a 3- to 8-membered cycloalkyi ring or 3- to 8- membered heterocycloalkyi ring, optionally substituted with R 13 , R 13' , R 14 and/or R 14' , wherein the heteroatom in the heterocycloalkyi ring is
  • R 7 and R 8 are independently hydrogen, halogen, cyano, unsubstituted Ci_ 6 alkyl or halo-substituted Ci_ 6 alkyl, unsubstituted Ci- 6 alkoxy or halo-substituted Ci- 6 alkoxy, unsubstituted C 3 . 8 cycloalkyl or halo-substituted C 3 .
  • R 5 is selected from hydrogen, unsubstituted Ci_ 6 alkyl, and halo- or alkyl-substituted Ci_ 6 alkyl;
  • R 6 and R 7 together form a 3- to 8-membered cycloalkyi ring or 3- to 8- membered heterocycloalkyi ring comprising one heteroatom or two or more heteroatoms, optionally substituted with R 15 , R 15' , R 16 and/or R 16' , wherein the one heteroatom in the heteroalkyl ring is NR 20 and the two or more heteroatoms are selected from N, NR 22 , O, S, SR 22 and SR 22 R 22' ; and
  • R 8 is selected from hydrogen, unsubstituted Ci_ 6 alkyl, and halo- or alkyl- substituted Ci- 6 alkyl; or
  • R 5 and R 6 are independently hydrogen, halogen, cyano,
  • Ci_ 6 alkyl or halo-substituted Ci_ 6 alkyl unsubstituted Ci- 6 alkoxy or halo- substituted Ci- 6 alkoxy, unsubstituted C 3 . 8 cycloalkyl or halo-substituted C 3 . 8 cycloalkyl, - C x H 2x -phenyl or -0-C x H 2x -phenyl wherein x is 0, 1 , 2, 3, 4, 5 or 6; aryl; heteroaryl; or R 5 and R 6 together form a 3- to 8-membered cycloalkyi ring or 3- to 8- membered
  • heterocycloalkyi ring optionally substituted with R 13 , R 13 ', R 14 and/or R 14' , wherein the heteroatom in the heterocycloalkyi ring is selected from O, N, NR 22 , S, SR 22 or SR 22 R 22' ; and
  • R 7 and R 8 are independently halogen, cyano, unsubstituted Ci_ 6 alkyl or halo- substituted Ci- 6 alkyl, unsubstituted Ci- 6 alkoxy or halo-substituted Ci- 6 alkoxy, unsubstituted C 3 - 8 cycloalkyl or halo-substituted C 3 - 8 cycloalkyl, -C x H 2 x-phenyl or -0-C x H 2x -phenyl wherein x is 0, 1 , 2, 3, 4, 5 or 6; aryl; heteroaryl; or R 7 and R 8 together form a 3- to 8- membered cycloalkyi ring or a 3- to 8- membered heterocycloalkyi ring, optionally substituted with R 17 , R 18 ', R 17 and/or R 18' , wherein the heteroatom in the heterocycloalkyi ring is selected from O, N
  • R 9 is hydrogen, hydroxy, halogen, cyano, unsubstituted Ci_ 6 alkyl or halo- substituted Ci- 6 alkyl, unsubstituted Ci- 6 alkoxy or halo-substituted Ci- 6 alkoxy, unsubstituted C 3 - 8 cycloalkyl or halo-substituted C 3 - 8 cycloalkyl, -C x H 2 x-phenyl or -0-C x H 2x -phenyl wherein x is 0, 1 , 2, 3, 4, 5 or 6;
  • R 10 is hydrogen; hydroxy; halogen; cyano; COOR 19 , CONR 20 R 21 , unsubstituted Ci_ 6 alkyl or halo-substituted Ci_ 6 alkyl; unsubstituted Ci- 6 alkoxy or halo- substituted Ci- 6 alkyoxy; C 3 . 7 cycloalkyl; -C x H 2 x-phenyl or -0-C x H 2x -phenyl wherein x is 0, 1 , 2, 3, 4, 5 or 6;
  • R 11 is hydrogen, hydroxy, halogen, cyano, unsubstituted Ci_ 6 alkyl or halo- substituted Ci- 6 alkyl, unsubstituted Ci- 6 alkoxy or halo-substituted Ci- 6 alkyoxy; C 3 . 7 cycloalkyl; -C x H 2x -phenyl or -0-C x H 2x -phenyl wherein x is 0, 1 , 2, 3, 4, 5 or 6;
  • R 12 is hydrogen; unsubstituted Ci_ 6 alkyl or Ci_ 6 alkyl substituted with one or more substituents independently selected from halo, hydroxy, alkoxy, C 3 . 8 cycloalkyl and C 2 . 6alkenyl; Ci- 6 alkylCi- 6 alkoxy; Ci- 6 alkylCi- 6 alkoxyCi- 6 alkoxy; Ci- 8 alkylamino; Ci_
  • R 13 , R 13' , R 14 and R 14' are independently hydrogen, halogen, amino, aminoalkyl, cyano, Ci_ 6 alkyl, Ci- 6 alkoxy, carbonyl, carboxamide, amide; or R 13 and R 13 ' or R 14 and R 14' together form a 3- to 8-membered cycloalkyi ring or 3- to 8- membered heterocycloalkyi ring, optionally substituted with oxygen, halogen, hydroxy, amino, cyano, Ci- 6 alkyl, C 3 - 8 cycloalkyl, C 2 - 6 alkenyl or Ci- 6 alkoxy, wherein the heteroatom in the
  • heterocycloalkyi ring is selected from O, N, NR 22 , S, SR 22 or SR 22 R 22' ;
  • R 15 , R 15' , R 16 and R 16' are independently hydrogen, halogen, amino, cyano, Ci- 6 alkyl, or Ci- 6 alkoxy, wherein any of R 15 , R 15' , R 16 or R 16' , together with R 5 or R 8 , form a 3- to 8-membered cycloalkyi ring or a 3-8 membered heterocycloalkyi ring, optionally substituted with oxygen, halogen, hydroxy, amino, cyano, Ci_ 6 alkyl, C 3 - 8 cycloalkyl, C 2 .
  • R 17 , R 17 ', R 18 and R 18' are independently hydrogen, halogen, amino, cyano, Ci- 6 alkyl, or Ci- 6 alkoxy; or R 17 and R 18 or R 17' and R 18' together form a 3- to 8-membered cycloalkyi or 3- to 8- membered heterocycloalkyi ring, optionally substituted with oxygen, halogen, hydroxy, amino, cyano, Ci_ 6 alkyl, C 3 - 8 cycloalkyl, C 2 - 6 alkenyl or Ci- 6 alkoxy, wherein the heteroatom in the heterocycloalkyi ring is selected from O, N, NR 22 , S, SR 22 or SR 22 R 22' ;
  • R 19 , R 19' and R 19 " are independently hydrogen, Ci_ 6 alkyl, C 3 - 8 cycloalkyl, C 2 . 6 alkenyl, phenyl, Ci- 6 alkylimidizole, Ci- 6 alkoxy, Ci- 6 alkyltriazole, Ci- 6 alkyltetrazole, Ci_
  • R 20 and R 21 are independently hydrogen, Ci_ 6 alkyl, C 3 - 8 cycloalkyl, C 2 . 6 alkenyl, phenyl, Ci- 6 alkylimidizole, Ci- 6 alkoxy, Ci- 6 alkyltriazole,Ci- 6 alkyltetrazole, Ci_
  • R 22 and R 22' are independently selected from hydrogen, oxygen, Ci_ 6 alkyl, C 3 -ecycloalkyl, C 2 -6alkenyl, phenyl, Ci-6alkylimidizole, Ci_6alkoxy, Ci-6alkyltriazole,Ci- 6 alkyltetrazole, Ci- 6 alkylthiazole, Ci- 6 alkyloxazole, Ci- 6 alkyldioxazole; Ci- 6 alkyloxazolidone, - COR 19 , -COOR 19' , -CSOR 19 " , -CONR 20 R 21 , or a pharmaceutically acceptable salt thereof.
  • One particular embodiment provides a compound according of Formula I, Formula IA or Formula IB as described herein, wherein:
  • R 1 is selected from hydrogen, hydroxy, halogen, cyano, amino, pyrrolidinyl, unsubstituted Ci_ 6 alkyl or halo-substituted Ci_ 6 alkyl, unsubstituted Ci- 6 alkoxy or halo- substituted Ci- 6 alkyoxy; C 3 . 7 cycloalkyl or halo-substituted C 3 .
  • R 2 and R 3 are independently OR 12 ;
  • R 4 is selected from hydrogen, hydroxy, halogen, cyano, amino, pyrrolidinyl, unsubstituted Ci_ 6 alkyl or halo-substituted Ci_ 6 alkyl, unsubstituted Ci- 6 alkoxy or halo- substituted Ci- 6 alkyoxy; C 3 - 7 cycloalkyl or halo-substituted C 3 - 7 cycloalkyl; N-containing monocyclic heterocycloalkyl, pyrrolidinyl, -C x H 2x -phenyl, -0-C x H2x-phenyl, or -(Ci_ 6 alkyl)N- C x H 2 x-phenyl wherein x is 0, 1 , 2, 3, 4, 5 or 6; or -OR 12 ;
  • R 6 and R 7 together form a 3- to 8-membered cycloalkyl ring or 3- to 8- membered heterocycloalkyl ring, optionally substituted with R 15 , R 15 ', R 16 and/or R 16' , wherein the heteroatom in the heteroalkyl ring is O, N, NR 22 , S, SR 22 or SR 22 R 22' ; R 9 is hydrogen; R 11 is hydrogen; R 12 is as described herein; and R 15 and R 16 or R 15' and R 16' together form a 3- to 8-membered cycloalkyl ring or heterocycloalkyl ring optionally substituted with oxygen, halogen, hydroxy, amino, cyano, Ci_ 6 alkyl, C 3 - 8 cycloalkyl, C 2 . 6 alkenyl or Ci- 6 alkoxy, wherein the heteroatom in the heteroalkyl ring is O, N, NR 22 , S, SR 22 or SR 22
  • Suitable synthetic routes are depicted below in the following general reaction schemes.
  • the skilled artisan will appreciate that if a substituent described herein is not compatible with the synthetic methods described herein, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions.
  • the protecting group may be removed at a suitable point in the reaction sequence to provide a desired intermediate or target compound.
  • Suitable protecting groups and the methods for protecting and de-protecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which may be found in T. Greene and P. Wuts, Protecting Groups in Chemical Synthesis (3rd ed.), John Wiley & Sons, NY (1999).
  • a substituent may be specifically selected to be reactive under the reaction conditions used. Under these circumstances, the reaction conditions convert the selected substituent into another substituent that is either useful as an intermediate compound or is a desired substituent in a target compound.
  • DIPEA or DIEA
  • ⁇ , ⁇ -diisopropylethylamine or Hiinig's base
  • T3P 1 -Propanephosphonic anhydride solution 2,4,6-Tripropyl-1 ,3,5,2,4,6- trioxatriphosphorinane-2,4,6-trioxide
  • Flash chromatography was run over Merck Silica gel 60 (230 - 400 mesh), or using a Teledyne Isco Combiflash Companion with normal phase, disposable Redi-Sep flash columns.
  • Mass spectra were run on an open access LC-MS system using electrospray ionization.
  • the analytical low-resolution mass spectra (MS) were recorded on Waters SQD instrument with UPLC analysis was conducted on a Phenomenex Kinetex 1 .7um, 2.1 x 50mm XB-C18 column at 40CSQ using a gradient elution method.
  • Solvent A 0.2% formic acid (FA) in water
  • Solvent B 0.15% FA in acetonitrile
  • 1 % - 99% Solvent B gradient over 1 .1 minutes and holding steady at 99% solvent B for another 0.4 minutes, at 1 ml/min flow rate.
  • MS analytical low-resolution mass spectra
  • Solvent A 0.1 % formic acid (FA) in water
  • Solvent B 0.1 % FA in acetonitrile
  • compound 1 can be prepared by reacting 4-bromo-1 ,2-dimethoxybenzene 9 with a ketone, as shown, using a palladium/xantphos Buchwald-Hartwig chemistry in sodium t-butoxide and THF. Reductive amination of 1 by reaction of compound 1 with sodium cyanoborohydride in ammonium acetate follows, to yield amine 2. Amine 2 is then reacted with formic acid in reflux conditions to yield amide 3. The dihydroisoquinoline compound 4 is obtained by a cyclization/condensation reaction using phosphoryl chloride in acetonitrile.
  • R 15 , R 15' ' R 16 and R 16' are as described herein.
  • compound 10 can be prepared by reacting 4-bromo-1 ,2- dimethoxybenzene 9 with a ketone, as shown, using a palladium/xantphos Buchwald- Hartwig chemistry in sodium t-butoxide and THF. Reductive amination of 10 by reaction of compound 10 with sodium cyanoborohydride in ammonium acetate follows, to yield amine 11. Amine 11 is then reacted with formic acid in reflux conditions to yield amide 12. The dihydroisoquinoline compound 13 is obtained by a cyclization/condensation reaction using phosphoryl chloride in acetonitrile.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 amd R 8 are as described herein.
  • Step 1 Benzyl 3-(benzyloxy)-4-bromobenzoate
  • Step 5 romobenzyl)cvclobutane-1 -carboxylic acid
  • Step 6 bromobenzyl)cvclobutan-1 -amine
  • Step 8 '-(Benzyloxy)-7'-bromo-4'H-spiro[cvclobutane-1 ,3'-isoquinoline
  • Step 9 Ethyl 9'-(benzyloxy)-10'-bromo-2'-oxo-1 '.2'.7'.1 1 b 1 - tetrahydrospirofcyclobutane-1 ,6'-pyrido[2,1 -alisoquinolinel-3'-carboxylate
  • Step 10 Ethyl 9'-(benzyloxy)-10'-bromo ⁇ '-oxo ⁇ 'J 1 - dihydrospirofcyclobutane-1 ,6'-pyrido[2,1 -alisoquinolinel-3'-carboxylate
  • Step 1 1 9'-(Benzyloxy)-10'-bromo-2'-oxo-2',7'-dihvdrospiro[cvclobutane- 1 ,6'-pyrido[2,1 -alisoquinolinel-3'-carboxylic acid
  • Step 1 Ethyl 10'-bromo-9'-hvdroxy-2'-oxo-2',7'-dihvdrospiro[cvclobutane- 1 ,6'-pyrido[2,1 -alisoquinolinel-3'-carboxylate
  • Step 2 Ethyl 10'-bromo-9'-(cvclopropylmethoxy)-2'-oxo-2'.7'- dihydrospirofcyclobutane-1 ,6'-pyrido[2,1 -alisoquinolinel-3'-carboxylate
  • Step 3 Ethyl 10'-acetyl-9'-(cvclopropylmethoxy)-2'-oxo-2'.7'- dihvdrospiro[cvclobuta -1 ,6'-pyrido[2,1 -alisoquinolinel-3'-carboxylate
  • Step 4 Ethyl 9'-(cvclopropylmethoxy)-10'-(2-methyl-1 .3-dithiolan-2-yl)-2'- oxo-2', 7'-dihvdrospiro[cyclobutane-1 ,6'-pyrido[2,1 -alisoquinolinel-3'-carboxylate
  • Step 5 Ethyl 9'-(cvclopropylmethoxy)-1 Q'-(1 .1 -difluoroethyl)-2'-oxo-2'.7'- dihydrospirofcyclobuta '-pyrido[2,1 -alisoquinolinel-3'-carboxylate
  • Step 6 9'-(Cvclopropylmethoxy)-10'-(1 .1 -difluoroethyl)-2'-oxo-2'.7'- dihydrospirofcyclobuta '-pyrido[2,1 -alisoquinolinel-3'-carboxylic acid
  • Step 1 Ethyl 9'-(cvclopropylmethoxyV2'-oxo-10'-vinyl-2'.7'- dihvdrospiro[cvclobutane-1 ,6'-pyrido[2,1 -alisoquinolinel-3'-carboxylate
  • Step 2 Ethyl 9'-(cvclopropylmethoxy)-10'-ethyl-2'-oxo-2'.7'- dihydrospirofcyclobutane-1 ,6'-pyrido[2,1 -alisoquinolinel-3'-carboxylate
  • Step 3 9'-(Cvclopropylmethoxy)-10'-ethyl-2'-oxo-2'.7'- dihvdrospiro[cvclobutane-1 ,6'-pyrido[2,1-alisoquinolinel-3'-carboxylic acid
  • Step 1 Ethyl 9'-(cvclopropylmethoxy)-2'-oxo-10'-vinyl-2'.7'- dihydrospirofcyclobutane-1 ,6'-pyrido[2,1 -alisoquinolinel-3'-carboxylate
  • Step 2 Ethyl 9'-(cvclopropylmethoxy)-10'-formyl-2'-oxo-2'.7'- dihydrospirofcyclo
  • Step 3 Ethyl 9'-(cvclopropylmethoxy)-10'-(difluoromethyl)-2'-oxo-2'.7'- dihydrospirofcyclobutane-1 ,6'-pyrido[2,1 -alisoquinolinel-3'-carboxylate
  • Step 4 9'-(Cvclopropylmethoxy)-10'-(difluoromethyl)-2'-oxo-2'.7'- dihydrospirofcyclobutane-1 ,6'-pyrido[2,1-alisoquinolinel-3'-carboxylic acid
  • Step 1 Ethyl 9'-(cvclopropylmethoxy)-10'-(hvdroxymethyl)-2'-oxo-2',7'- dihydrospiro [cyclobuta '-pyrido[2,1 -alisoquinolinel-3'-carboxylate
  • Step 2 Ethyl 9'-(cvclopropylmethoxyV10'-(fluoromethyr)-2'-oxo-2'.7'- dihydrospiro [cyclobuta -1 ,6'-pyrido[2,1 -alisoquinolinel-3'-carboxylate
  • Step 3 9'-(Cvclopropylmethoxy)-10'-(fluoromethyl)-2'-oxo-2'.7'- dihydrospirofcyclobutane-1 ,6'-pyrido[2,1 -alisoquinolinel-3'-carboxylic acid
  • Step 1 Ethyl 9'-(cvclopropylmethoxyV2'-oxo-10'-(trifluoromethvn-2'.7'- dihydrospirofcyclobutane-1 ,6'-pyrido[2,1 -alisoquinolinel-3'-carboxylate
  • Step 2 9'-(Cvclopropylmethoxy)-2'-oxo-10'-(trifluoromethyl)-2'.7'- dihydrospirofcyclobutane-1 ,6'-pyrido[2,1 -alisoquinolinel-3'-carboxylic acid
  • n-Butyllithium (2.5 M in hexanes) (0.581 mL, 1 .45 mmol) was added dropwise to a -78 °C solution of diisopropylamine (0.207 mL, 1 .45 mmol) in tetrahydrofuran (THF) (5 mL). The mixture was allowed to warm to room temperature and stirred for 15 minutes. The mixture was cooled to -78 °C before methyl tetrahydro-2H-pyran-4- carboxylate (0.185 mL, 1 .38 mmol) was added dropwise. The mixture was warmed to 0 °C and stirred for 15 minutes. A white precipitate formed.
  • THF tetrahydrofuran
  • Step 2 4-(4-Methoxy-3-(3-methoxypropoxy)benzyl)tetrahvdro-2H-pyran-4- carboxylic acid
  • Step 3 4-(4-Methoxy-3-(3-methoxypropoxy)benzyl)tetrahvdro-2H-pyran-4- amine
  • Step 4 N-(4-(4-Methoxy-3-(3-methoxypropoxy)benzyl)tetrahvdro-2H-pyran- 4-yl)formamide
  • Step 5 7-Methoxy-6-(3-methoxypropoxy)-2',3',5',6'-tetrahydro-4H-
  • Step 6 Ethyl 10'-methoxy-9'-(3-methoxypropoxy)-2'-oxo-2.2'.3.5.6.7'- hexahvdrospiro[pyran-4,6'-pyrido[2,1 -alisoquinolinel-3'-carboxylate
  • Step 7 10'-Methoxy-9'-(3-methoxypropoxy)-2'-oxo-2.2'.3.5.6.7'- hexahvdrospiro[pyran-4,6'-pyrido[2,1 -alisoquinolinel-3'-carboxylic acid
  • Step 1 Methyl 1 -(4-chloro-3-methoxybenzyl)cvclohexanecarboxylate
  • n-Butyllithium (2.5 M in hexanes) (6.06 mL, 15.2 mmol) was added dropwise to a -78 °C solution of diisopropylamine (2.16 mL, 15.2 mmol) in tetrahydrofuran (THF) (40 mL). The mixture was allowed to warm to room temperature and stirred for 15 minutes. The mixture was cooled to -78 °C before methyl cyclohexanecarboxylate (2.06 mL, 14.4 mmol) was added dropwise. The mixture was warmed to 0 °C and stirred for 15 minutes.
  • THF tetrahydrofuran
  • Step 2 -(4-Chloro-3-methoxybenzyl)cvclohexanecarboxylic acid
  • Step 3 1 -(4-Chloro-3-methoxybenzyl)cvclohexanamine
  • Diphenyl phosphorazidate (3.84 ml_, 17.82 mmol) was added dropwise to a 0 °C stirring mixture of 1 -(4-chloro-3-methoxybenzyl)cyclohexane-1 -carboxylic acid (2.29 g, 8.10 mmol) and triethylamine (2.483 ml_, 17.82 mmol) in toluene (40 ml_). The mixture was allowed to warm to room temperature and stirred for 15 minutes before being heated at 80 °C for 1 hour.
  • the mixture was allowed to cool to room temperature before a mixture 5N hydrogen chloride (40 ml_, 200 mmol) and 1 ,4-dioxane (40 ml_) was added.
  • the mixture was heated at 80 °C with vigorous stirring for 1 hour.
  • the mixture was allowed to cool to room temperature and was extracted with ethyl ether.
  • the ethyl ether layer was back-extracted 2 times with 1 N hydrochloric acid.
  • the combined acidic aqueous layers were basified with 1 M sodium hydroxide and extracted 3 times with ethyl acetate.
  • Step 4 N-(1 -(4-chloro-3-methoxybenzyl)cvclohexyl)formamide
  • Step 5 7'-Chloro-6'-methoxy-4'H-spiro[cvclohexane-1 ,3'-isoquinolinel
  • Step 6 Ethyl 10'-chloro-9'-methoxy-2'-oxo-2',7'-dihvdrospiro[cyclohexane- 1 ,6'-pyrido[2,1 -alisoquinolinel-3'-carboxylate
  • Step 7 10'-Chloro-9'-hvdroxy-2'-oxo-2',7'-dihvdrospiro[cvclohexane-1 ,6'- pyrido[2,1 -alisoquinolinel-3'-carboxylic acid
  • the mixture was poured into ice, diluted with 1 M hydrochloric acid, and extracted 3 times with ethyl acetate. The combined organic layers were concentrated. The residue was dissolved in methanol (5 mL), basified with 1 M sodium hydroxide (10 ml_), and heated at 70 C for 3 hours. The mixture was allowed to cool to room temperature, acidified with 1 N hydrochloric acid, and extracted 3 times with ethyl acetate.
  • Step 8 10'-Chloro-9'-(cvclopropylmethoxy)-2'-oxo-2'.7'- dihydrospirofcyclohexa -1 ,6'-pyrido[2,1 -alisoquinolinel-3'-carboxylic acid
  • the mixture was allowed to cool to room temperature, acidified with 1 N hydrochloric acid, and a precipitate collected by filtration.
  • the product was slurried in acetonitrile, sonicated, and the precipitate collected by filtration.
  • the sample was air dried.
  • the crude product was purified by medium pressure reverse phase chromatography (C18 / acetonitrile / water / 0.1 % formic acid / 10% to 100% gradient).
  • Step 1 Ethyl 9'-(cvclopropylmethoxy)-10'-methyl-2'-oxo-2'.7'- dihydrospirofcyclobutane-1 ,6'-pyrido[2,1 -alisoquinolinel-3'-carboxylate
  • Step 2 9'-(CvclopropylmethoxyV10'-methyl-2'-oxo-2'.7'- dihydrospirofcyclobutane-1 ,6'-pyrido[2,1 -alisoquinolinel-3'-carboxylic acid
  • Step 1 Ethyl 9'-(benzyloxy)-10'-methyl ⁇ '-oxo ⁇ 'J 1 - dihvdrospiro[cvclobutan '-pyrido[2,1 -alisoquinolinel-3'-carboxylate
  • Step 2 Ethyl 9'-hvdroxy-10'-methyl-2'-oxo-2',7'-dihvdrospiro[cyclobutane- 1 ,6'-pyrido[2,1 -alisoquinolinel-3'-carboxylate
  • Step 3 Ethyl 10'-methyl-2'-oxo-9'-(((trifluoromethyl)sulfonyl)oxy)-2'.7'- dihydrospirofcyclobutane-1 ,6'-pyrido[2,1 -alisoquinolinel-3'-carboxylate
  • Step 4 Ethyl 10'-methyl ⁇ '-oxo-g'-foyrrolidin-l -yl)-2'.7'- dihydrospirofcyclobuta -1 ,6'-pyrido[2,1 -alisoquinolinel-3'-carboxylate
  • Step 5 10'-Methyl-2'-oxo-9'-(pyrrolidin-1 -yl)-2',7'-dihvdrospiro[cyclobutane-
  • Step 1 Ethyl 10'-methyl-9'-(oxetan-3-ylmethoxy)-2'-oxo-2'.7'- dihvdrospiro[cvclobutane-1 ,6'-pyrido[2,1 -alisoquinolinel-3'-carboxylate
  • Step 2 10'-Methyl-9'-(oxetan-3-ylmethoxy)-2'-oxo-2'.7'- dihvdrospiro[cvclobuta -1 ,6'-pyrido[2,1 -alisoquinolinel-3'-carboxylic acid
  • Step 1 Ethyl 9'-(cvclopentylmethoxy)-10'-methyl-2'-oxo-2'.7'- dihydrospirofcyclobutane-1 ,6'-pyrido[2,1 -alisoquinolinel-3'-carboxylate
  • Step 2 9'-(Cvclopentylmethoxy)-10'-methyl-2'-oxo-2'.7'- dihydrospirofcyclobutane-1 ,6'-pyrido[2,1 -alisoquinolinel-3'-carboxylic acid
  • Stepl Ethyl 10'-methoxy-9'-f 1 -methyl-1 H-pyrazol ⁇ -vD ⁇ '-oxo ⁇ 'J'- dihydrospiro
  • Step 2 10'-Methoxy-9'-(1 -methyl-1 H-pyrazol-4-yl)-2'-oxo-2'.7'-dihvdrospiro
  • Stepl Ethyl 9'-(furan-3-yl)-10'-methoxy ⁇ '-oxo ⁇ 'J 1 - dihvdrospiro[cvclobutane-1 ,6'-pyrido[2,1-alisoquinolinel-3'-carboxylate
  • Step 2 9'-(Furan-3-yl)-10'-methoxy-2'-oxo-2',7'-dihvdrospiro[cyclobutane- 1 ,6'-pyrido[2,1 -alisoquinolinel-3'-carboxylic acid
  • Step 1 10'-Chloro-9'-methoxy-2'-oxo-2',7'-dihvdrospiro[cyclohexane-1 ,6'- pyrido[2,1 -alisoquinolinel-3'-carboxylic acid
  • Step 1 (Tetrahydro-2/-/-pyran-4-yl)methyl 4-methylbenzenesulfonate
  • Step 2 Ethyl 9'-(benzyloxy)-2'-oxo-10'-vinyl-2',7'-dihvdrospiro[cyclobutane- 1 ,6'-pyrido[2,1 -alisoquinolinel-3'-carboxylate
  • Step 3 Ethyl 9'-(benzyloxy)-10'-formyl-2'-oxo-2',7'-dihvdrospiro[cyclobutane- 1 ,6'-pyrido[2,1 -alisoquinolinel-3'-carboxylate
  • Step 4 Ethyl 9'-(benzyloxy)-10'-toifluoromethyl ⁇ '-oxo ⁇ 'J 1 - dihvdrospiro[cvclobutan -1 ,6'-pyrido[2,1-alisoquinolinel-3'-carboxylate
  • Step 5 Ethyl 1 O'-toifluoromethviyg'-hvdroxy ⁇ '-oxo ⁇ 'J 1 - dihydrospirofcyclobutan -1 ,6'-pyrido[2,1-alisoquinolinel-3'-carboxylate
  • Step 6 Ethyl 10'-(difluoromethyl)-2'-oxo-9'-((tetrahvdro-2H-pyran-4- yl)methoxy)-2',7'-dihvdrospiro[cyclobutane-1 ,6'-pyrido[2,1-alisoquinolinel-3'-carboxylate
  • Step 7 10'-(Difluoromethyl)-2'-oxo-9'-((tetrahydro-2H-pyran-4-yl)methoxy)- 2',7'-dihvdrospiro[cyclobutane- '-pyrido[2,1 -alisoquinolinel-3'-carboxylic acid
  • Example 17 [00432] 10'-(DifluoromethylV2'-oxo-9'-((tetrahvdrofuran-3-vnmethoxyV2'.7'-)
  • Step 3 Ethyl 10'-formyl-2'-oxo-9'-((tetrahvdrofuran-3-yl)methoxyV2'.7'- dihydrospirofcyclobuta -1 ,6'-pyrido[2,1 -alisoquinolinel-3'-carboxylate
  • Step 4 Ethyl 10'-(difluoromethyl)-2'-oxo-9'-((tetrahydrofuran-3-yl)methoxy)- 2',7'-dihvdrospiro[cyclobutane-1 ,6'-pyrido[2,1 -alisoquinolinel-3'-carboxylate
  • Step 5 10'-(DifluoromethylV2'-oxo-9'-((tetrahvdrofuran-3-yl)methoxyV2'.7'- dihvdrospiro[cvclobuta -1 ,6'-pyrido[2,1 -alisoquinolinel-3'-carboxylic acid
  • Step 1 3-Hvdroxy-3-methylbutyl 4-methylbenzenesulfonate
  • Step 3 Ethyl 10'-(difluoromethyl)-9'-(3-hvdroxy-3-methylbutoxy)-2'-oxo-2'.7'- dihydrospirofcyclobutane-1 ,6'-pyrido[2,1 -alisoquinolinel-3'-carboxylate
  • Step 3 10'-(Difluoromethvn-9'-(3-hvdroxy-3-methylbutoxyV2'-oxo-2'.7'- dihydrospirofcyclobutan -1 ,6'-pyrido[2,1 -alisoquinolinel-3'-carboxylic acid
  • Step 1 Oxetan-3-ylmethyl 4-methylbenzenesulfonate
  • Step 2 Ethyl 10'-formyl-9'-hvdroxy-2'-oxo-2',7'-dihvdrospiro[cyclobutane-
  • Step 3 Ethyl 10'-formyl-9'-(oxetan-3-ylmethoxy)-2'-oxo-2'.7'- dihvdrospiro[cvclobuta -1 ,6'-pyrido[2,1 -alisoquinolinel-3'-carboxylate
  • Step 4 Ethyl 10'-(difluoromethyl)-9'-(oxetan-3-ylmethoxy)-2'-oxo-2'.7'- dihydrospirofcyclobuta -1 ,6'-pyrido[2,1 -alisoquinolinel-3'-carboxylate
  • Step 5 10'-(Difluoromethyl)-9'-(oxetan-3-ylmethoxy)-2'-oxo-2'.7'- dihvdrospiro[cvclobuta -1 ,6'-pyrido[2,1 -alisoquinolinel-3'-carboxylic acid
  • Step 1 3-Methoxy-3-methylbutyl 4-methylbenzenesulfonate
  • Step 2 Ethyl 10'-formyl-9'-(3-methoxy-3-methylbutoxy)-2'-oxo-2'.7'- dihvdrospiro[cvclobutane-1 ,6'-pyrido[2,1 -alisoquinolinel-3'-carboxylate
  • Step 3 Ethyl 10'-(difluoromethyl)-9'-(3-methoxy-3-methylbutoxy)-2'-oxo-2'.7'- dihydrospirofcyclobuta -1 ,6'-pyrido[2,1 -alisoquinolinel-3'-carboxylate
  • Step 4 10'-(DifluoromethylV9'-(3-methoxy-3-methylbutoxyV2'-oxo-2'.7'- dihvdrospiro[cvclobuta -1 ,6'-pyrido[2,1 -alisoquinolinel-3'-carboxylic acid
  • Step 1 (3-Methyloxetan-3-yl)methyl 4-methylbenzenesulfonate
  • Step 2 Ethyl 10'-formyl-9'-((3-methyloxetan-3-yl)methoxy)-2'-oxo-2'.7'- dihvdrospiro[cvclobuta -1 ,6'-pyrido[2,1 -alisoquinolinel-3'-carboxylate
  • Step 3 Ethyl 10'-(difluoromethyl)-9'-((3-methyloxetan-3-yl)methoxy)-2'-oxo- 2',7'-dihvdrospiro[cyclobutane-1 ,6'-pyrido[2,1 -alisoquinolinel-3'-carboxylate
  • Step 4 10'-(Difluoromethvn-9'-((3-methyloxetan-3-vnmethoxyV2'-oxo-2'.7'- dihydrospirofcyclobutane-1 ,6'-pyrido[2,1 -alisoquinolinel-3'-carboxylic acid
  • Step 1 4-Methoxy-3-(3-methoxypropoxy)benzaldehvde
  • Step 3 -(Bromomethyl)-1 -methoxy-2-(3-methoxypropoxy)benzene

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Abstract

L'invention concerne des composés chimiques, en particulier des inhibiteurs du virus de l'hépatite B et/ou du virus de l'hépatite D, plus spécifiquement des composés qui inhibent l'antigène HBe et l'antigène HBs chez un sujet, pour le traitement d'infections virales, ainsi que des méthodes de préparation et d'utilisation desdits composés. Formule (I) :
PCT/IB2018/051080 2017-02-21 2018-02-21 Dihydroquinolizinones à utiliser en tant qu'antiviraux WO2018154466A1 (fr)

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WO2020063870A1 (fr) 2018-09-30 2020-04-02 Sunshine Lake Pharma Co., Ltd. Composés tétracycliques fusionnés et leurs utilisations en médecine
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CN111217811A (zh) * 2018-11-26 2020-06-02 广东东阳光药业有限公司 稠合三环类化合物及其在药物中的应用
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CN111943946A (zh) * 2020-08-19 2020-11-17 中国医学科学院医药生物技术研究所 含有氮杂环片段的二氢喹嗪酮羧酸类化合物及其应用
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US10966970B2 (en) * 2017-06-01 2021-04-06 Sunshine Lake Pharma Co., Ltd. Fused tricyclic compounds and uses thereof in medicine
WO2021143885A1 (fr) * 2020-01-19 2021-07-22 东莞市东阳光新药研发有限公司 Composé tétracyclique fusionné et son application dans un médicament
US11198693B2 (en) 2018-11-21 2021-12-14 Enanta Pharmaceuticals, Inc. Functionalized heterocycles as antiviral agents
US11236108B2 (en) 2019-09-17 2022-02-01 Enanta Pharmaceuticals, Inc. Functionalized heterocycles as antiviral agents
US11236111B2 (en) 2019-06-03 2022-02-01 Enanta Pharmaceuticals, Inc. Hepatitis B antiviral agents
EP3909951A4 (fr) * 2019-01-08 2022-03-30 Suzhou Ark Biopharmaceutical Co., Ltd Composé de dihydroisoquinoléine
US11472808B2 (en) 2019-06-04 2022-10-18 Enanta Pharmaceuticals, Inc. Substituted pyrrolo[1,2-c]pyrimidines as hepatitis B antiviral agents
US11738019B2 (en) 2019-07-11 2023-08-29 Enanta Pharmaceuticals, Inc. Substituted heterocycles as antiviral agents
US11760755B2 (en) 2019-06-04 2023-09-19 Enanta Pharmaceuticals, Inc. Hepatitis B antiviral agents
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CN110964023A (zh) * 2018-09-30 2020-04-07 广东东阳光药业有限公司 稠合四环类化合物及其在药物中的应用
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WO2020063870A1 (fr) 2018-09-30 2020-04-02 Sunshine Lake Pharma Co., Ltd. Composés tétracycliques fusionnés et leurs utilisations en médecine
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US11891393B2 (en) 2018-11-21 2024-02-06 Enanta Pharmaceuticals, Inc. Functionalized heterocycles as antiviral agents
CN111217811B (zh) * 2018-11-26 2024-01-16 广东东阳光药业股份有限公司 稠合三环类化合物及其在药物中的应用
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CN109678724A (zh) * 2018-12-18 2019-04-26 常州大学 一种2-甲基-1-取代苯基-2-丙胺类化合物的新合成方法
EP3909951A4 (fr) * 2019-01-08 2022-03-30 Suzhou Ark Biopharmaceutical Co., Ltd Composé de dihydroisoquinoléine
US11236111B2 (en) 2019-06-03 2022-02-01 Enanta Pharmaceuticals, Inc. Hepatitis B antiviral agents
US11472808B2 (en) 2019-06-04 2022-10-18 Enanta Pharmaceuticals, Inc. Substituted pyrrolo[1,2-c]pyrimidines as hepatitis B antiviral agents
US11760755B2 (en) 2019-06-04 2023-09-19 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
WO2021143885A1 (fr) * 2020-01-19 2021-07-22 东莞市东阳光新药研发有限公司 Composé tétracyclique fusionné et son application dans un médicament
US11802125B2 (en) 2020-03-16 2023-10-31 Enanta Pharmaceuticals, Inc. Functionalized heterocyclic compounds as antiviral agents
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