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WO2013020246A1 - Dérivés méthylènes de bétuline - Google Patents

Dérivés méthylènes de bétuline Download PDF

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Publication number
WO2013020246A1
WO2013020246A1 PCT/CN2011/001303 CN2011001303W WO2013020246A1 WO 2013020246 A1 WO2013020246 A1 WO 2013020246A1 CN 2011001303 W CN2011001303 W CN 2011001303W WO 2013020246 A1 WO2013020246 A1 WO 2013020246A1
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Prior art keywords
group
alkyl
methyl
independently
compound
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English (en)
Inventor
Daxin Gao
Nianhe Han
Brian Johns
Zhimin Jin
Fangxian Ning
Jun Tang
Yongyong Wu
Heping Yang
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GlaxoSmithKline LLC
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GlaxoSmithKline LLC
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Priority to PCT/CN2011/001303 priority Critical patent/WO2013020246A1/fr
Publication of WO2013020246A1 publication Critical patent/WO2013020246A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
    • C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV

Definitions

  • the present invention relates to betulin derivative compounds, pharmaceutical compositions, and methods of use thereof for (i) inhibiting HIV replication in a subject infected with HIV, or (ii) treating a subject infected with HIV, by administering such
  • HAART highly active antiretrovira I therapy
  • salvage therapy includes at least two, and preferably three, fully active drugs.
  • first-line therapies combine three to four drugs targeting the viral enzymes RT and protease (PR).
  • One option for salvage therapy is to administer different combinations of drugs from the same mechanistic class that remain active against the resistant isolates.
  • the options for this approach are often limited, as resistant mutations frequently confer broad cross-resistance to different drugs in the same class.
  • the H!V Gag polyprotein precursor (Pr55Gag), which is composed of four protein domains - matrix (MA), capsid (CA), nucleocapsid (NC) and p6 - and two spacer peptides, SP1 and SP2, represents a new therapeutic target.
  • MA protein domains - matrix
  • CA capsid
  • NC nucleocapsid
  • SP1 and SP2 represents a new therapeutic target.
  • Gag mediates membrane binding. Assembly is completed by budding of the immature particle from the cell. Concomitant with particle release, the virally encoded PR cleaves Gag into the four mature protein domains, MA, CA, NC and p6, and the two spacer peptides, SP1 and SP2. Gag-Pol is also cleaved by PR, liberating the viral enzymes PR, RT and IN. Gag proteolytic processing induces a morphological rearrangement within the particle, known as maturation. Maturation converts the immature, donut-shaped particle to the mature virion, which contains a condensed conical core composed of a CA shell surrounding the viral RNA genome in a complex with NC and the viral enzymes RT and IN. Maturation prepares the virus for infection of a new cell and is absolutely essential for particle infectivity.
  • Bevirimat (PA-457) is a maturation inhibitor that inhibits the final step in the processing of Gag, the conversion of capsid-SP1 (p25) to capsid, which is required for the formation of infectious viral particles.
  • Bevirimat has activity against ART-resistant and wild- type HIV, and has shown synergy with antiretrovirals from all classes.
  • Bevirimat users with Gag polymorphisms at Q369, V370 or T371 demonstrated significantly lower load reductions than patients without Gag polymorphisms at these sites.
  • L is selected from the group consisting of (Ci-C e )alkylene, -C ⁇ 0), -C(0)NH, -C(0)NHR 4 , -C(0)NHR 15 , -C(0)R 4 R 10 , -R 4 NR 1 R 2 , -R 4 NH, -R 4 NHC(0), -R 4 NHR 4 ,
  • X is (C 5 -C 14 )aryl
  • Y is independently selected from (C 2 -C 9 )heterocycle or (C 2 -Cg)heteroaryl, each having one to three heteroatoms selected from S, N or O;
  • Z is (C3-C 7 )cycloalkyl
  • R and R 2 are each independently -H, (C r C 6 )a!kyl, (C C 6 )alkylene, -R 4 N(R 5 ) 2 , -R R 10 , -R X(R 11 ) mi -R 4 X, -C(O), -C(0)R e , -C(0)R 8 , -R 4 C(0 ⁇ R 10 , -C(0)R 4 R 10 , -C(0)OR 5 , -R 4 NHC(0), -C(0)R 4 NHC(0)R 6 , -R 4 R 8 R 4 R 8 , -C(0)R 4 (R 8 ) 2 , -C(0)R 4 R 8 , -N(R 5 ) 2 , -C(0)N(R 5 ) 2 , -C(0)R 4 N(R 5 ) 2l -C(0)C(0)N(R 5 ) 2 , -C(0)R (OH) 2 , -C(0)C(0)R 8
  • R 3 is selected from the group consisting of -C(0)R 4 R 7 , -C(0)R 4 R 7 R 8 ,
  • R 4 is (C C 6 )a!kylene
  • R 5 is independently selected from -H and (CrC ⁇ a!kyl
  • R 6 is (CrC 6 )alkyl
  • R 7 is -C(0)OR 5 ;
  • R 8 is -OR 5 ;
  • R 9 is halo
  • R 10 is -N(R 16 ) 2 ;
  • R 11 , R 12 , and R 13 are independently selected from the group consisting of oxo, halo, (C C 6 )alkoxy, -R 6 (R 9 ) q , -OR 6 (R 9 ) q , nitro, -S0 2 R 6 , (C C 6 )alkyl, -C(0)R 10 , -R 4 YR 6 , and - CO(0)R 5 ;
  • R 14 is -OP ⁇ 0)(OH) 2 ;
  • L is selected from the group consisting of a (C 1 -C 6 )alkylene, -C(O), -C(0)NH,
  • X is (C 5 ⁇ C 14 )aryl
  • Y is independently selected from (C 2 -C 9 )heterocycle or (Ca-Cgjheteroaryl, each having one to three heteroatoms selected from S, N or O;
  • Z is (C 3 -C 7 )cycloaIkyl
  • A is selected from the group consisting of -NR 1 R 2 , -OR 5 , phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acetidinyl, piperazinyl, furanyl, pyridyl, pyrazolyl, pyridazinyl, pyrrolidinyl, thiazolyl, oxazolyl, thiophenyl, and thiomorpholinyl;
  • R 1 and R 2 are each independentl -H, (C r C 6 )alkyl, (C C 6 )alkylene, -R 4 N(R 5 ) 2 , -R 4 R 10 , -R 4 X(R 11 ) m , -R 4 X, -C(O), -C(0)R 6 , -C(0)R 8 , -R 4 C(0)R 10 , -C(0)R 4 R 10 , -C(0)OR 5 ,
  • R 3 is selected from the group consisting of -C(0)R 4 R 7 , -C(0)R R 7 R 8 ,
  • R 4 is (C C 6 )alkylene
  • R 5 is independently selected from -H and (C r C 6 )alkyl
  • R 6 is (C C 6 )alkyl
  • R 7 is -C(0)OR 5 ;
  • R 8 is -OR 5 ;
  • R 9 is halo
  • R 0 is -N(R 16 ) 2 ;
  • R 11 is independently selected from the group consisting of halo, (CrC 6 )alkyl, (C r C 6 )alkoxy, -R 6 (R 9 ) q , -OR e ⁇ R 9 ) q , and nitro;
  • R 12 is independently selected from the group consisting of -S0 2 R 6 , (Ci-C 6 )alkyl, - C(0)R 10 , -R 4 YR 6 , -CO ⁇ 0)R 5 , and oxo;
  • R 13 is independently selected from the group consisting of (C C 6 )alkyl, oxo, halo, (C r C 6 )alkoxy, -R 6 (R 9 ) q , -OR 6 (R 9 ) q , nitro, -S0 2 R 6 , (C C 6 )alkyl, -C(0)R 1 °, -R 4 YR 6 , and - CO(0)R 5 ;
  • R 14 is -OP ⁇ 0)(OH) 2 ;
  • R 16 is selected from the group consisting of -H, (C C 6 )alkyl, and ⁇ -C(0)OR 5 .
  • L is selected from the group consisting of a (C C 6 )alkylene, -C(O), -C(0)NH,
  • X is (C 5 -C 14 )aryl
  • Y is independently selected from (C 2 -C 9 )heterocycle or (C 2 -C 8 )heteroaryl, each having one to three heteroatoms selected from S, N or O;
  • A is selected from the group consisting of -NR R , -OR5,
  • R 1 and R 2 are each independently -H, (C C 6 )alkyl, (CrC 6 )alkylene, -R 4 N(R 5 ) 2 , -R R 10 , -R 4 X(R 1 ) m , -R 4 X, -C(O), -C(0)R 6 , -C(0)R 8 , -R 4 C(0)R 10 , -C(0)R 4 R 1 °, -C(0)OR 5 , -R 4 NHC(0), -C(0)R NHC(0)R 6 , -R 4 R 8 R 4 R 8 , -C ⁇ 0)R 4 (R B ) 2l ⁇ C(0)R 4 R B , -N(R 5 ) 2l -C(0)N(R 5 ) 2 , -C(0)R 4 N(R 5 ) 2 , -C(0)C(0)N(R 5 ) 2 , -C(0)R 4 (OH) 2) -C(0)C(0)R 8
  • R 3 is selected from the group consisting of -C(0)R R 7 , -C(0)R R 7 R 8 , ⁇ C ⁇ 0)R 4 R 7 R 14 , and -C(0)R 4 C(0)R 8 ;
  • R 4 is (d-CeJalkylene
  • R 5 is independently selected from -H and (Ci-C 6 )alkyl
  • R 6 is (CrCe)alkyl
  • R 7 is -C(0)OR 5 ;
  • R 8 is -OR 5 ;
  • R 9 is hafo
  • R 10 is -N(R 16 ) 2 ;
  • R ⁇ R 2 , and R 13 are independently selected from the group consisting of oxo, halo, (d-CeJalkoxy, -R 6 ⁇ R 9 ) q . ⁇ OR 6 (R 9 ) q , nitro, -S0 2 R 6 , (C C 6 )alkyl, -C(0)R 1 °, -R 4 YR 6 , and - CO(0)R 5 ;
  • R 14 is -OP(0)(OH) 2 ;
  • R 16 is selected from the group consisting of -H, (C C 6 )alkyl, and -C(0)OR 5 ;
  • n is zero or an integer selected from 1, 2, 3, or 4;
  • n is zero or an integer selected from 1 , 2, or 3;
  • p is zero or an integer selected from 1, 2, or 3;
  • q is an integer selected from 1 , 2, or 3.
  • L is selected from the group consisting of a (C-
  • X is (C 5 -C 14 )aryl
  • Y is independently selected from (C 2 -C 9 )heterocycle or (C 2 -C 9 )heteroaryl, each having one to three heteroatoms selected from S, N or O;
  • Z is (C 3 -C 7 )cycIoalkyl
  • A is selected from the group consisting of -NR 1 R 2 , -OR 5 , phenyl, cyclopropyl, cyclobutyl, cyciopentyl, cyclohexyl, acetidinyl, piperazinyl, furanyl, pyridy!, pyrazolyl, pyridazinyl, pyrrolidinyl, thiazolyl, oxazolyl, thiophenyl, and thiomorpholinyl;
  • R and R 2 are each independently -H, ⁇ C r C 6 )alkyI, (C 1 -C 6 )alkylene, -R 4 N(R 5 ) 2 , -R R 10 , -R 4 X(R 1 ) m , ⁇ R X, -C(O), -C(0)R 6 , ⁇ C(0)R 8 , -R 4 C(0)R 10 , -C(0)R 4 R 10 , -C(0)OR 5 , -R 4 NHC(0), -C(0)R NHC(0)R 6 , -R 4 R 8 R 4 R 8 , -C(0)R 4 (R 6 ) 2 , -C(0)R 4 R 8 , -N(R 5 ) 2 , -C(0)N(R 5 ) 2 -C(0)R N(R 5 ) 2 , -C(0)C(0)N(R 5 ) 2 , -C(0)R 4 (OH) 2 , -C(0)C(0)R
  • R 3 is selected from the group consisting of -C(0)R 4 R 7 , -C(0)R 4 R 7 R 8 ,
  • R 4 is (d-CeJalkylene
  • R 5 is independently selected from -H and (Ci-C 6 )alkyl
  • R 6 is (C C 6 )alkyI
  • R 7 is -C(0)0R 5 ;
  • R 8 is -OR 5 ;
  • R 9 is halo
  • R 10 is -N(R 16 ) 2 ;
  • R 11 is independently selected from the group consisting of halo, (C C 6 )alkyl, (Ci- C 6 )alkoxy, -R 6 (R 9 ) q , -OR 6 (R 9 ) q , and nitro;
  • R 12 is independently selected from the group consisting of -S0 2 R 6 , (CrC 6 )alkyl, - C(0)R 10 , -R 4 YR 6 , -CO(0)R 5 , and oxo;
  • R 13 is independently selected from the group consisting of (Ci-C 6 )alkyl, oxo, halo, (C C 6 )alkoxy, -R 6 (R 9 ) q , -OR 6 (R 9 ) q , nitro, -S0 2 R 6 , (d-CeJalkyl, -C(0)R 1 °, -R 4 YR 6 , and - CO(0)R 5 ;
  • R 14 is -OP(0)(OH) 2 ;
  • R 6 is selected from the group consisting of -H, (C r C 6 )alkyl, and -C(0)OR 5 ;
  • n is zero or an integer selected from 1 , 2, 3, or 4;
  • q is an integer selected from 1 , 2, or 3.
  • X is (C 5 -C 14 )aryi
  • Y is independently selected from ⁇ C 2 -C 9 )heterocycle or (C 2 -C 8 )heteroaryl, each having one to three heteroatoms selected from S, N or O;
  • Z is (C 3 -C7)cycloalkyl;
  • A is selected from the group consisting of -NR R , -OR ,
  • R 1 and R 2 are each independently -H, (C C 6 )alkyl, (C C 6 )alkylene, -R 4 N ⁇ R 5 ) 2 , -R 4 R 10 , -R X(R 11 ) m , -R 4 X, ⁇ C ⁇ 0), -C(0)R 6 , -C(0)R 8 , -R C(0)R 10 , -C(0)R 4 R 10 , -C(0)OR 5 , -R NHC(0), -C(0)R 4 NHC(0)R 6 , -R 4 R 8 R 4 R 8 , -C(0)R (R 8 ) 2 , -C(0)R 4 R 8 , -N(R 5 ) 2 , -C(0)N(R 5 ) 2 , -C(0)R 4 N(R 5 ) 2 , -C(0)C(0)N(R 5 ) 2 , -C(0)R 4 (OH) 2 , -C(0)C(0)R 8 ,
  • R 3 is selected from the group consisting of -C(0)R 4 R 7 , -C(0)R R 7 R 8 ,
  • R 4 is (CrCe)alkylene
  • R 5 independently selected from -H and (CrC 6 )alkyl
  • R 9 s halo;
  • R 10 is -N(R 16 ) 2 ;
  • R 11 , R 2 , and R 13 are independently selected from the group consisting of oxo, (C C 6 )alkoxy, -R 6 (R 9 ) q , -OR 6 (R 9 ) q , nitro, -S0 2 R 6 , (C r C 6 )alkyl, -C(0)R 10 , -R YR 6 , and CO(0)R 5 ;
  • R 14 is -OP(0)(OH) 2 ;
  • R 16 is selected from the group consisting of -H, (C C 6 )alkyl, and -C(0)OR 5 ; m is zero or an integer selected from 1 , 2, 3, or 4;
  • n is zero or an integer selected from 1 , 2, or 3;
  • p is zero or an integer selected from 1 , 2, or 3;
  • q is an integer selected from 1 , 2, or 3.
  • X is (C 5 -C 14 )aryl
  • Y is independently selected from (C 2 -C 9 )heterocycle or (C2-C 9 )heteroaryl, each having one to three heteroatoms selected from S, N or O;
  • spiro ring Z is (C 3 -Cr)cycloalkyl
  • 5 A is selected from the group consisting of -NR 1 R 2 , -OR 5 , phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acetidinyl, piperazinyl, furanyl, pyridyl, pyrazolyl, pyridazinyl, pyrrolidinyl, thiazolyl, oxazolyl, thiophenyl, and thiomorpholinyl;
  • R 1 and R 2 are each independently -H, (C C 6 )alkyl, ⁇ C C B )alky[ene, -R 4 N(R 5 ) 2 , -R 4 R 10 , -R 4 X(R 1 ) m , -R 4 X, -C(O), ⁇ C(0)R 6 , -C(0)R 8 , -R C(0)R 10 , -C ⁇ 0)R R 10 , -C(0)OR 5 , -R NHC(0), -C(0)R 4 NHC(0)R 6 , -R 4 R 8 R 4 R 8 , -C(0)R (R 8 ) 2l -C(0)R R 8 , -N(R 5 ) 2 , -C(0)N(R 5 ) 2 , -C(0)R N(R s ) 2l -C(0)C(0)N(R 5 ) 2 , -C(0)R 4 (OH) 2 , -C(0)C(0)R 8
  • R 3 is selected from the group consisting of -C(0)R 4 R 7 , -C(0)R R 7 R 8 ,
  • R 4 is (C r C 6 )alkylene
  • R 5 is independently selected from -H and (CrC 6 )alkyl
  • R 6 is ⁇ C C 6 )alkyl
  • R 7 is -C(0)OR s ;
  • R 8 is -OR 5 ;
  • R 9 is halo
  • R 10 is -N ⁇ R 16 ) 2 ;
  • R 11 is independently selected from the group consisting of halo, (CrC 6 )alkyl, (C C 6 )alkoxy, -R 6 (R 9 ) q , -OR 6 (R 9 ) q , and nitro;
  • R 12 is independently selected from the group consisting of -S0 2 R 6 , (C CeJalkyl, - C(0)R 10 , -R 4 YR 6 , -CO(0)R 5 , and oxo;
  • R 13 is independently selected from the group consisting of (C-i-C 6 )a!kyl, oxo, halo, (C C B )alkoxy, -R 6 (R 9 ) q , -OR 6 (R 9 ) q , nitro, -S0 2 R 6 , (C C 6 )alkyl, -C(0)R 10 , -R 4 YR 6 , and - CO(0)R 5 ;
  • R 14 is -OP(0)(OH) 2 ;
  • R 16 is selected from the group consisting of -H, (C C 6 )alkyl, and -C(0)OR 5 .
  • Y is independently selected from (C 2 -C 9 )heterocycle or (C 2 -C 9 )heteroaryl, each having one to three heteroatoms selected from S, N or O;
  • Z is (C 3 -C 7 )cycloalkyl
  • A is selected from the group consisting of -NR R , -OR ,
  • R 1 and R 2 are each independently -H, (C r C e )alkyl, ⁇ CrC 6 )aikylene, -R 4 N(R 5 ) 2 , -R 4 R 10 , -R 4 X(R 11 ) m , -R 4 X, -C(O), -C(0)R 6 , -C(0)R s , -R 4 C(0)R 10 , -C ⁇ 0)R 4 R 10 , -C ⁇ 0)OR 5 , -R 4 NHC(0), -C(0)R 4 NHC(0)R 6 , -R 4 R 8 R 4 R 8 , -C(0)R (R 8 ) 2 , -C ⁇ 0)R R 8 , -N(R 5 ) 2 , -C(0)N(R 5 ) z , -C(0)R N(R 5 ) z , -C(0)C(0)N(R 5 ) 2> -C(0)R 4 (
  • Q is selected from the group consisting of -R R 7 R 8 ,-R R 7 R 14 , and -R 4 C(0)R a ;
  • R 4 is (CrCe)alkylene
  • R s is independently selected from -H and (C r C 6 )alkyl
  • R 6 is (CrCe)alkyl
  • R 7 is -C(0)OR 5 ;
  • R 8 is -OR 5 ;
  • R 9 is halo
  • R 10 is -N(R 16 ) 2 ;
  • R 11 , R 12 , and R 3 are independently selected from the group consisting of oxo, halo, (C r C 6 )alkoxy, -R 6 (R 9 ) q , -OR 6 (R 9 ) p , nitro, -S0 2 R 6 , (C C 6 )alkyl, -C(0)R 10 , -R 4 YR 6 , and - CO(0)R 5 ;
  • R 14 is -0P(0)(OH) 2 ;
  • R 16 is selected from the group consisting of -H, ⁇ C-
  • n is zero or an integer selected from 1 , 2, 3, or 4;
  • n is zero or an integer selected from 1 , 2, or 3;
  • p is zero or an integer selected from 1 , 2, or 3;
  • the present invention relates to a composition
  • a composition comprising a) the compound of Formulas l-IV or a pharmaceutically acceptable salt thereof; and b) a pharmaceutically acceptable excipient.
  • the present invention is a method of treating HIV comprising administering to a patient suffering therefrom an effective amount of the compound of Formulas l-IV or a pharmaceutically acceptable salt thereof.
  • Compounds of the present invention are useful for the treatment of patients with HIV,
  • alkyl refers to to a monovalent saturated aliphatic hydrocarbyl group having from 1 to 14 carbon atoms and, in some embodiments, from 1 to 6 carbon atoms.
  • (C x- C y )alkyl refers to alkyl groups having from x to y 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 (CH 3 CH 2 CH 2 -), isopropyl ((CH 3 ) 2 CH-), n-butyl (CH 3 CH 2 CH 2 CH 2 -), isobutyl ((CH 3 ) 2 CHCH 2 -), sec-butyl ((CH 3 )(CH 3 CH 2 )CH-), i-butyl ((CH 3 ) 3 C-), n-pentyl (CH 3 CH 2 CH 2 CH 2 CH 2 -), and neopentyl ((CH 3 ) 3 CCH 2 -).
  • Alkylene or “alkylene” refers to divalent saturated aliphatic hydrocarbyl groups having from 1 to 10 carbon atoms and, in some embodiments, from 1 to 6 carbon atoms.
  • (Cu.CvJalkylene” refers to alkylene groups having from u to v carbon atoms.
  • the alkylene groups include branched and straight chain hydrocarbyl groups.
  • (C ⁇ . C 6 )alkylene is meant to include methylene, ethylene, propylene, 2-methypropylene, dimethylethylene, pentylene, and so forth.
  • the term “propylene” could be
  • (C 1- C 6 )alkylene is meant to include such branched chain hydrocarbyl groups as cyclopropylmethylene, which could be
  • (C x -C y )alkenyl refers to alkenyl groups having from x to y carbon atoms and is meant to include for example, ethenyl, propenyl, isopropylene, 1 ,3-butadienyl, and the like.
  • Alkynyl refers to a linear monovalent hydrocarbon radical or a branched monovalent hydrocarbon radical containing at least one triple bond.
  • alkynyl is also meant to include those hydrocarbyl groups having one triple bond and one double bond.
  • (C 2 -C 6 )alkynyl is meant to include ethynyl, propynyl, and the like.
  • 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, i-butoxy, sec-butoxy, and n-pentoxy.
  • Acyl refers to the groups H-C(O)-, alkyl-C(O)-, alkenyl-C(O)-, alkynyl-C(O)-, cycloalkyl-C(O)-, aryl-C(O)-, heteroaryl-C(O)-, and heterocyclic-C(O)-.
  • Acyl includes the "acetyl” group CH 3 C(0)-.
  • R 20 is hydrogen or alkyl.
  • Acyloxy refers to the groups alkyl-C(0)0-, alkenyl-C(0)0-, alkynyl-C(0)0-, aryl-C(0)0-, cyc!oalkyl-C(0)0-, heteroaryl-C(0)0-, and heterocyclic-C(0)0-,
  • Amino refers to the group -NR 21 R 22 where R 21 and R 22 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl,
  • heterocyclic -S0 2 -a!kyl, -S0 2 -alkenyl, -S0 2 -cycloalkyl, -S0 2 -aryl, -S0 2 -heteroaryl, and -S0 2 -heterocyciic, and wherein R 21 and R 22 are optionally joined together with the nitrogen bound thereto to form a heterocyclic group.
  • R 21 is hydrogen and R 22 is alkyl
  • the amino group is sometimes referred to herein as alkylamino.
  • R 21 and R 22 are alkyl, the amino group is sometimes referred to herein as dialkylamino.
  • a monosubstituted amino it is meant that either R 21 or R 22 is hydrogen but not both.
  • disubstituted amino it is meant that neither R 2 nor R 22 are hydrogen.
  • Hydroxyamino refers to the group -NHOH.
  • 'A!koxyamino refers to the group -NHO-alkyI wherein alkyl is defined herein.
  • 'Aminocarbonyl refers to the group -C(0)NR 26 R 27 where R 26 and R 27 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyi, heteroaryl, heterocyclic, hydroxy, alkoxy, amino, and acylamino, and where R 26 and R 27 are optionally joined together with the nitrogen bound thereto to form a heterocyclic group.
  • 'Aryl refers to an aromatic group of from 6 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).
  • 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).
  • Cycloalkyi 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.
  • cycloalkyi applies when the point of attachment is at a non-aromatic carbon atom (e.g. 5,6,7,8,-tetrahydronaphthalene-5- yl).
  • Cycloalkyi includes cycloalkenyl groups, such as cyclohexenyl.
  • cycloalkyi groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl, and cyclohexenyl.
  • Examples of cycloalkyi groups that include multiple bicycloalkyl ring systems are bicyclohexyl, bicyclopentyl, bicyclooctyl, and the like. Two such bic cloalkyl multiple ring structures are exemplified and named below:
  • '(C u- C v )cycloalkyl refers to cycloalkyi groups having u to v carbon atoms.
  • 'Spiro cycloalkyi refers to a 3 to 10 member cyclic substituent formed by replacement of two hydrogen atoms at a common carbon atom in a cyclic ring structure or in an alkylene group having 2 to 9 carbon atoms, as exemplified by the following structure wherein the group shown here attached to bonds marked with wavy lines is substituted with a spiro cycloalkyi group:
  • "Fused cycloalkyl” 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 structure wherein the cycloalkyl group shown here contains bonds marked with wavy lines which are bonded to carbon atoms that are substituted with a fused cycloalkyl group:
  • Halo or "halogen” refers to fluoro, chloro, bromo, and iodo.
  • Haloalkoxy refers to substitution of alkoxy groups with 1 to 5 (e.g. when the alkoxy group has at least 2 carbon atoms) or in some embodiments 1 to 3 halo groups (e.g. trifluoromethoxy).
  • Heteroaryl refers to an aromatic group of from 1 to 14 carbon atoms and 1 to 6 heteroatoms selected from oxygen, nitrogen, and sulfur 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 moteties.
  • heteroaryl includes, but is not limited to, pyridyl, furanyl, thienyl, thiazolyf, isothiazolyl, triazolyl, imidazolyl, imidazolinyl, isoxazolyl, pyrrolyl, pyrazolyl, pyridazinyl, pyrimidinyl, purinyl, phthalazyl, naphthylpryidyl, benzofuranyl, tetrahydrobenzofuranyl, isobenzofuranyl, benzothiazolyl, benzoisothiazolyl, benzotriazol l, indolyl, isoindolyl, indolizinyl, dihydroindolyl, indazolyl, indolinyl, benzoxazolyl, quinolyl, isoquinolyl, quinolizyl, quianazolyl, quinoxalyl, tetrahydr
  • quinazolinonyl benzimidazolyl, benzisoxazolyl, benzothienyl, benzopyridazinyl, pteridinyl, carbazoly!, carbolinyl, phenanthridinyl, acridinyl, phenanthro!inyl, phenazinyl, phenoxazinyl, phenothiazinyl, and phthalimidyl.
  • Heterocyclic or “heterocycle” or “heterocycloalkyl” or “heterocyciyl” 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-y[, 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, suifonyl 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, piperidine, piperazine, indoline, phthalimide, 1 ,2,3,4-tetra
  • 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 structure wherein the cycloalkyl group shown here contains bonds marked with wavy lines which are bonded to carbon atoms that are substituted with a fused heterocyclic group:
  • 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.
  • Oxazolidinone refers to a 5-membered heterocyclic ring containing one nitrogen and one oxygen as heteroatoms and also contains two carbons and is substituted at one of the two carbons by a carbonyl group 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:
  • Racemates refers to a mixture of enantiomers.
  • the compounds of Formulas I, II, or III, 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
  • the term 'atropisomer' refers to a stereoisomer resulting from an axis of asymmetry. This can result from restricted rotation about a single bond where the rotational barrier is high enough to allow differentiation of the isomeric species up to and including complete isolation of stable non-interconverting diastereomer or enantiomeric species [Eliel ref].
  • a nonsymmetrical R x to core
  • the formation of atropisomers is possible.
  • the two chiral elements taken together can create diastereomeric and enantiomeric stereochemical species.
  • interconversion between the atropisomers may or may not be possible and may depend on temperature.
  • the atropisomers may interconvert rapidly at room temperature and not resolve under ambient conditions.
  • Other situations may allow for resolution and isolation but interconversion can occur over a period of seconds to hours or even days or months such that optical purity is degraded measurably over time.
  • Yet other species may be completely restricted from interconversion under ambient and/or elevated temperatures such that resolution and isolation is possible and yields stable species.
  • the resolved atropisomers were named using the helical nomenclature. For this designation, only the two ligands of highest priority in front and behind the axis are considered. When the turn priority from the front ligand 1 to the rear ligand 1 is clockwise, the configuration is P, if counterclockwise it is M.
  • “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.
  • 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.
  • the present invention includes compounds as well as their pharmaceutically acceptable salts. Accordingly, the word “or” in the context of "a compound or a
  • pharmaceutically acceptable salt thereof is understood to refer to either a compound or a pharmaceutically acceptable salt thereof (alternative), or a compound and a
  • 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)-.
  • -C(R X ) 2 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*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.
  • L is selected from the group consisting of a (C r C 6 )alkylene, -C ⁇ 0), -C(0)NH, -C(0)NHR 4 , -C ⁇ 0)NHR 15 , -C(0)R 4 R 10 , -R 4 NR 1 R 2 , -R 4 NH, -R 4 NHC(0), -R NHR 4 ,
  • X is (C 5 -C»)aryl
  • Y is independently selected from (C 2 -C 9 )heterocycle or (C2-C 9 )heteroaryl, each having one to three heteroatoms selected from S, N or O;
  • Z is (C 3 -C 7 )cycloalkyl
  • A is selected from the group consisting of -NR R , -OR5,
  • R 1 and R a are each independently -H, ⁇ Ci-C e )alkyl, (C r C 6 )alkylene, -R 4 N(R 5 ) 2 , -R 4 R 10 , -R 4 X(R 11 ) m , -R 4 X, -C(O), -C(0)R 6 , -C(0)R 8 , -R 4 C(0)R 10 , -C(0)R 4 R 10 , -C(0)OR 5 ,
  • R 3 is selected from the group consisting of -C(0)R 4 R 7 , -C(0)R 4 R 7 R 8 ,
  • R 4 is (CrCe)alkylene
  • R 5 is independently selected from -H and (C C 6 )alkyl
  • R 6 is (d-CeJalkyl
  • R 7 is -C(0)OR 5 ;
  • R 8 is -OR 5 ;
  • R 9 is halo
  • R 0 is -N(R 6 ) 2 ;
  • R 11 , R 1Z , and R 13 are independently selected from the group consisting of oxo, halo, (C C 6 )alkoxy, -R 6 (R 9 ) q , nitro, -S0 2 R 6 , (C Ce)alkyl, -C(0)R 10 , -R 4 YR 6 , and - CO(0)R 5 ;
  • R 14 is -OP(0)(OH) 2 ;
  • R 16 is selected from the group consisting of -H, (CrC 6 )alkyl, and -C(0)OR 5 .
  • L is selected from the group consisting of a (C C 6 )alkylene, -C(O), -C(0)NH, -C(0)NHR 4 , -C(0)NHR 15 , -C(0)R 4 R 1 °, -R 4 NR 1 R 2 , -R NH, -R 4 NHC(0), and -R 4 NHR 4 ;
  • Y is independently selected from (C 2 -C 9 )heterocycle or (C2-C 9 )heteroaryl, each having one to three heteroatoms selected from S, N or O;
  • Z is (C 3 -C 7 )cycloalkyl
  • A is selected from the group consisting of -NR 1 R 2 , -OR 5 , phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acetidinyl, piperazinyl, furanyl, pyridyl, pyrazolyl, pyridazinyl, pyrrolidinyl, thiazolyl, oxazolyl, thiophenyl, and thiomorpholinyl;
  • R 1 and R 2 are each independently -H, (C C 6 )alkyl, (C C 6 )alkylene, -R 4 N(R 5 ) 2 , -R 4 R 10 , -R 4 X(R 1 ) m , -R 4 X, -C(O), -C(0)R 6 , -C ⁇ 0)R e , -R C(0)R 10 , -C(0)R 4 R 10 , -C(0)OR 5 , -R 4 NHC(0), -C(0)R 4 NHC(0)R 6 , -R R e R R R 8 , -C(0)R 4 (R 8 ) 2l -C(0)R 4 R 8 , -N(R 5 ) 2 , -C ⁇ 0)N(R 5 ) 2 -C(0)R N(R 5 ) 2 , -C(0)C(0)N(R 5 ) 2 , -C(0)R (0H) 2 , -C(0)C(0)R
  • R 4 is ⁇ C C 6 )alkylene
  • R 5 is independently selected from -H and (C 1 -C 6 )a!kyl
  • R 6 is (CrCe)alkyl
  • R 7 is -C(0)OR 6 ;
  • R 8 is -OR 5 ;
  • R 9 is halo
  • R 10 is -N(R 16 ) 2 ;
  • R 11 is independently selected from the group consisting of halo, (C C 6 )alkyl, (C
  • R 12 is independently selected from the group consisting of -S0 2 R 6 , (CrC e )alkyl, - C(0)R 10 , -R 4 YR 6 , -CO(0)R 5 , and oxo;
  • R 13 is independently selected from the group consisting of (d-CeJalkyl, oxo, halo, (CrC 6 )alkoxy, -R 6 (R 9 ) q , -OR 6 (R ) q , nitro, -S0 2 R 6 , ⁇ C C 6 )alkyl, -C(0)R 10 , -R 4 YR 6 , and - CO(0)R 5 ;
  • R 14 is -OP(0)(OH) 2 ;
  • R 16 is selected from the group consisting of -H, (C C 6 )alkyl, and -C(0)OR 5
  • L is selected from the group consisting of a (CrC 6 )alkylene, -C(O), -C(0)NH, -C(0)NHR 4 , -C(0)NHR 15 , -C(0)R 4 R 10 , ⁇ R 4 NR 1 R 2 , -R 4 NH, -R NHC(0), -R NHR 4 ,
  • X is (C 5 -C 14 )aryl
  • Y is independently selected from (C2-Cg)heterocycle or (C2-C 8 )heteroaryl, each having one to three heteroatoms selected from S, N or O;
  • Z is ⁇ C 3 -C 7 )cycloa[kyl
  • R 1 and R 2 are each independently -H, (Ci-Cejalkyl, (C C 6 )afkylene, -R 4 N(R 5 ) 2 , -R R 10 , -R 4 X(R ) m , -R X, -C(O), -C(0)R 6 , -C(0)R & , -R C(0)R 10 , -C(0)R 4 R 10 , -C(0)OR 5 , -R 4 NHC(0), -C(0)R NHC(0)R 6 , -R 4 R 8 R 4 R 8 , -C(0)R (R 8 ) 2 , -C(0)R 4 R 8 , -N ⁇ R 5 ) 2 , -C(0)N(R 5 ) 2 , -C(0)R 4 N(R 5 ) 2 , -C(0)C(0)N(R 5 ) 2 , -C(0)R 4 (OH) 2 , -C(0)C(0)R 8
  • R 3 is selected from the group consisting of -C(0)R 4 R 7 , -C(0)R 4 R 7 R 8 , -C(0)R 4 R 7 R 14 , and -C ⁇ 0)R 4 C(0)R 8 ;
  • R 4 is (d-CeJalkylene
  • R 5 is independently selected from -H and (C C 6 )alkyl
  • R 6 is (C C 6 )alkyl
  • R 7 is -C(0)OR 5 ;
  • R B is -OR 5 ;
  • R 9 is halo
  • R 10 is -N(R 16 ) 2 ;
  • R 11 , R 2 , and R 13 are independently selected from the group consisting of oxo, halo, (CrCe)alkoxy, -R 6 (R 9 ) q , -OR 6 (R 9 ) p , nitro, -S0 2 R 6 , (C C 6 )alkyl, -C(0)R 10 , -R 4 YR 6 , and - CO(0)R 5 ;
  • R 14 is -OP(0)(OH) 2 ;
  • R 16 is selected from the group consisting of -H, (C r C 6 )alkyl, and -C(0)OR 5 ;
  • n is zero or an integer selected from 1 , 2, 3, or 4;
  • n is zero or an integer selected from 1 , 2, or 3;
  • p is zero or an integer selected from 1 , 2, or 3;
  • L is selected from the group consisting of a (C C 6 )alkylene, -C(O), -C(0)NH, -C(0)NHR 4 , -C(0)NHR 15 , -C(0)R 4 R 10 , -R 4 NR R 2 , -R 4 NH, -R 4 NHC(0), and -R 4 NHR 4 ;
  • X is (C 5 -C 14 )ary!
  • Y is independently selected from (C 2 -C 9 )heterocycle or (C 2 -C9)heteroaryl, each having one to three heteroatoms selected from S, N or O;
  • Z is ⁇ C 3 -C 7 )cycloalkyl
  • A is selected from the group consisting of -NR R 2 , -OR 5 , phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acetidinyl, piperazinyl, furanyl, py dyl, pyrazolyl, pyridaztnyl, pyrrolidinyl, thiazolyl, oxazolyl, thiopheny!, and thiomorpholinyl;
  • R 1 and R 2 are each independently -H, (d-CeJalkyl, (C r C 6 )alkylene, -R 4 N ⁇ R 5 ) 2 ,
  • R 3 is selected from the group consisting of -C(0)R 4 R 7 , -C(0)R R 7 R 8 ,
  • R 4 is (CrC f alky!ene
  • R 5 is independently selected from -H and (CrC B )alkyl
  • R B is (C C 6 )alkyl
  • R 7 is -C(0)OR 5 ;
  • R 8 is -OR 5 ;
  • R 9 is halo
  • R 10 is -N(R 16 ) 2 ;
  • R 11 is independently selected from the group consisting of halo, (C C 6 )alkyl, (C C 6 )alkoxy, -R 6 (R 9 ) q , -OR 6 (R 9 ) q , and nitro;
  • R 12 is independently selected from the group consisting of -S0 2 R 6 , (C C 6 )alkyl, -
  • R 13 is independently selected from the group consisting of (Ci-C 6 )alkyl, oxo, halo, (Ci-Ce)alkoxy, -R 6 (R 9 ) q , -OR 6 (R 9 ) q , nitro, -S0 2 R 6 , (C-C e )alkyl, -C(0)R 10 , -R 4 YR 6 , and - CO(0)R 5 ;
  • R 14 is -OP(0)(OH) 2 ;
  • R 16 is selected from the group consisting of -H, (C r C 6 )alkyl, and -C(0)OR 5 ; m is zero or an integer selected from 1 , 2, 3, or 4;
  • n is zero or an integer selected from 1 , 2, or 3;
  • p is zero or an integer selected from 1 , 2, or 3;
  • q is an integer selected from 1 , 2, or 3.
  • L is selected from the group consisting of a ⁇ CrCeJalkylene, -C(O), -C(0)NH, -C(0)NHR ⁇ -C(0)NHR 15 , -C(0)R 4 R 10 , -R 4 NR 1 R 2 , -R 4 NH, -R 4 NHC(0), -R 4 NHR 4 ,
  • X is (C 5 -C 14 )aryl
  • Y is independently selected from (C 2 -C 8 )heterocycle or (C 2 -C 8 )heteroaryl, each having one to three heteroatoms selected from S, N or O;
  • A is selected from the group consisting of -NR 1 R 2 ,
  • R and R 2 are each independently -H, ⁇ Ci-C B )alkyl, (CrC 6 )alkylene r -R 4 N(R 5 ) 2 , -R 4 R 10 , -R 4 X(R 11 ) m , -R 4 X, -C(O), -C(0)R 6 , -C(0)R 8 , -R C ⁇ 0)R 10 , -C(0)R 4 R 10 , -C(0)OR 5 , -R 4 NHC(0), -C(0)R NHC(0)R 6 , -R R 8 R 4 R 8 , -C(0)R 4 (R 8 ) 2 , -C(0)R 4 R 8 , ⁇ N(R ) 2 , -C(0)N(R 5 ) 2 , -C(0)R 4 N(R 5 ) 2 , -C(0)C(0)N(R 5 ) 2 , -C(0)R 4 (0H) 2 , -C(0)
  • R 3 is selected from the group consisting of -CO(0)R 4 R 7 , ⁇ CO(0)R 4 R 7 R 8 ,
  • R 4 is (d-Ce)alkylene
  • R 5 is independently selected from -H and (d-CgJalkyl
  • R 6 is (d-C 6 )alkyl
  • R 7 is -C(0)OR 5 ;
  • R 8 is -OR 5 ;
  • R 9 is halo
  • R 10 is -N(R 16 ) 2 ;
  • R 1 , R 2 , and R 13 are independently selected from the group consisting of oxo, halo, (Ci-C e )alkoxy, -R 6 (R 9 ) q , -OR 6 (R 9 ) q , nitro, -S0 2 R 6 , (C C 6 )alkyl, -C(0)R 10 , -R YR 6 , and - CO(0)R 5 ;
  • R 4 is -0P(0)(0H) 2 ;
  • R 1S is selected from the group consisting of -H, (C C 6 )alkyl, and -C(0)OR 5 ;
  • n is zero or an integer selected from 1, 2, or 3;
  • p is zero or an integer selected from 1 , 2, or 3;
  • q is an integer selected from 1, 2, or 3.
  • L is selected from the group consisting of a (CrC 6 )alkyIene, -C(O), -C ⁇ 0)NH, -C(0)NHR 4 , -C(0)NHR 15 , -C(0)R 4 R 10 , -R 4 NR 1 R 2 , -R NH, -R 4 NHC(0), and -R NHR 4 ;
  • Y is independently selected from (C 2 -C 9 )heterocycle or (C 2 -C 9 )heteroaryl, each having one to three heteroatoms selected from S, N or O;
  • spiro ring Z is (C 3 -C 7 )cycloalkyl
  • A is selected from the group consisting of -NR 1 R 2 , -OR 5 , phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acetidinyl, piperazinyi, furanyl, pyridyl, pyrazolyl, pyridazinyl, pyrrolidinyl, thiazolyl, oxazolyl, thiophenyl, and thiomorpholinyl;
  • R 1 and R 2 are each independently -H, (C r C 6 )alkyl, (CrC 6 )alkylene, -R 4 N(R 5 ) 2 , -R R 10 , -R 4 X(R 11 ) m , -R X, -0(0), -C(0)R 6 , -C(0)R 8 , -R 4 C(0)R 10 , -C(0)R R 10 , -C(0)OR 5 , -R 4 NHC(0), -C(0)R 4 NHC(0)R 6 , -R 4 R 8 R R 8 , -C(0)R 4 ⁇ R 8 ) 2 , -C(0)R 4 R 8 , -N(R 5 ) 2 , -C(0)N(R 5 ) 2 -C(0)R 4 N(R 5 ) 2> -C(0)C(0)N(R 5 ) 2 , ⁇ C(0)R 4 (OH) 2 , -C(0)C(0)R 8 ,
  • R 3 is selected from the group consisting of -C(0)R 4 R 7 , -C(0)R 4 R 7 R 8 ,
  • R 4 is (CrCe)alkylene
  • R 5 is independently selected from -H and (C-i-Ce)alkyl
  • R 6 is (C C 6 )alkyl
  • R 7 is -C(0)OR 5 ;
  • R 8 is -OR 5 ;
  • R 9 is halo
  • R 0 is -N(R 6 ) 2 ;
  • R 11 is independently selected from the group consisting of halo, (C C 6 )alkyl, (C C 6 )alkoxy, -R 6 (R 9 ) q , -OR 6 (R 9 ) q , and nitro;
  • R 2 is independently selected from the group consisting of ⁇ S0 2 R 6 , (C r C 6 )alkyl, - C(0)R 1 °, -R 4 YR 6 , -CO(0)R 5 , and oxo;
  • R 13 is independently selected from the group consisting of (C r C 6 )alkyl, oxo, halo, (C C e )alkoxy, -R 6 (R ) q , -OR 6 (R 9 ) q , nitro, ⁇ S0 2 R 6 , (d-CeJalkyl, -C ⁇ 0)R 10 , -R YR 6 , and - CO ⁇ 0)R 5 ;
  • R 14 is -OP ⁇ 0)(OH) 2 ;
  • R 16 is selected from the group consisting of -H, (CrC 6 )alkyl, and -C(0)OR 5 .
  • L is selected from the group consisting of a (C C6)alkylene, -C(O), -C(0)NH, -C(0)NHR 4 , -C(0)NHR 15 , -C(0)R 4 R 10 , -R 4 NR 1 R 2 , -R 4 NH, -R 4 NHC(0), -R 4 NHR 4 ,
  • X is (C 5 -C 14 )aryl
  • Y is independently selected from (C 2 -C 9 )heterocycle or (C 2 -C 9 )heteroaryl, each having one to three heteroatoms selected from S, N or O;
  • Z is (C 3 -C 7 )cycloalkyl
  • A is selected from the group consisting of -NR 1 R 2 , -OR 5
  • R 1 and R z are each independently -H, (C C B )alkyl, (C r C 6 )alkylene, -R N(R 5 ) 2 , -R 4 R 10 , -R 4 X(R 1 ) m , -R 4 X, -C(O), -C(0)R 6 , -C(0)R 8 , -R C(0)R 10 , -C(0)R 4 R 10 , -C(0)OR 6 , -R 4 NHC(0), -C(0)R NHC(0)R 6 , -R 4 R 8 R 4 R 6 , -C(0)R 4 (R 8 ) 2 , -C(0)R 4 R B , -N ⁇ R 5 ) 2 , -C(0)N(R 5 ) 2l -C(0)R 4 N(R 5 ) 2 , -C(0)C(0)N(R 5 ) 2 , -C(0)R 4 (OH) 2 , -C(0)C(0)R
  • Q is selected from the group consisting of -R 4 R 7 R 8 ,-R 4 R 7 R 14 , and -R 4 C(0)R 8 ;
  • R 4 is (C C 6 )a!kylene
  • R 5 is independently selected from -H and (CrC 6 )alkyl
  • R 6 is (CrC e )alkyl
  • R 7 is -C(0)OR s ;
  • R 8 is -OR 5 ;
  • R 9 is haio
  • R 10 is -N(R 16 ) 2 ;
  • R 1 , R 12 , and R 13 are independently selected from the group consisting of oxo, halo, (C C 6 )alkoxy, -R 6 (R 9 ) q , -OR 6 (R 9 ) q , nitro, -S0 2 R 6 , (C C B )alkyf J -C(0)R 10 , -R 4 YR 6 , and - CO(0)R 5 ;
  • R 14 is -OP(0)(OH) 2 ;
  • R 16 is selected from the group consisting of -H, (CrC e )alkyl, and -C(0)OR 5 ;
  • n is zero or an integer selected from 1 , 2, 3, or 4;
  • n is zero or an integer selected from 1 , 2, or 3;
  • p is zero or an integer selected from 1 , 2, or 3;
  • q is an integer selected from 1 , 2, or 3.
  • R 1 and R 2 are each independently H, Ci-C6-alkyl, i-buty!oxycarbonyl, Me-S0 2 -,
  • each R 4 is independently H or d-Ce-alkyl
  • each R 5 is independently halo, Ci-C 6 -alkyl, d-Cs-alkoxy, CF 3 , OCF 3 , N(CH 3 ) 2l or N0 2 ; each R 6 is independently halo, CrC 6 -alkyl, -COOH, -C(0)NH 2 , dimethyiaminomethyl, or 1 -methyl-4-piperazinylmethyl,
  • Y is each independently methylene or carbonyl
  • Q is -(CH 2 )p-, -C(O)-, -NH-C(O)-, -CH(CH 3 )-, -C(CH 3 ) 2 -, 1 ,1-cyc!opropyldiyl, or 1 ,1- cyclopentyldiyl;
  • Hetaryl is a 5-6-membered heteroaryl group
  • Hetalk is a 3-7-membered heterocycloalkyi group
  • Cycloalk is a 3-6-membered cycloalkyl group
  • each m is independently 2 or 3;
  • each n is independently 0, 1 , or 2;
  • each p is independently 0 or 1 ;
  • each q is independently 0, 1 , or 2;
  • each r is independently 0, 1 , 2, 3, or 4.
  • R 1 is H, methyl, dimethylaminoethyl, i-butyloxycarbonyl; Me ⁇ S0 2 -, or
  • R 2 is H; (R 5 ) n -pheny!-Q-, (R 6 ) q -furanyl-(CH 2 ) p -, (R 6 ) q -pyridyl-(CH 2 ) p -, (R 6 ) q -thienyl-(CH 2 ) p -, 1 -methyl pyrazol-3-yl, Hetalk-(CH 2 ) r , or C 3 -C 6 -cycloalkyl-(CH 2 ) p -, or R 1 and R 2 , together with the nitrogen atom to which they are attached, form azetidinyl, piperidinyi, morphoiino, thiomorphoiino, piperazinyl, 4-methyl-piperazin-l-yl, 4- methylsulfonyl-piperazin-1 -yl, 2,4-dimethyl-piperazin-1 -yl, 4-methyl-dia
  • each R 6 is independently methyl, F, or CI. in a further embodiment of the present invention, there is provided a compound of Formula IV:
  • Y is methylene
  • R 1 is H, methyl, f-butyloxycarbonyl; Me-S0 2 -, or dimethylaminoethyl;
  • R 2 is H, (R 5 )n-Phenyl-(CH 2 ) P -, (R 6 ) n -furanyl-(CH 2 ) q -, (R 6 ) n -pyridyl-(CH 2 ) q -,
  • R 6 q -thienyl-(CH 2 )p-, 1 -methyl pyrazol-3-yl, pyrrolidinyl-(CH 2 ) r -, 4-methyipiperazinyl; N-methylpiperidin-4-yl; cyclopropyl-(CH 2 ) p -, cyclohexy[-(CH 2 ) P -, or cyclopentyl-(CH a ) p -; or R 1 and R 2 , together with the nitrogen atom to which they are attached, form azetidinyl, piperazinyl, 4-methyl-piperazin-1-yl, 4-methylsulfonyl-piperazin-1-yl, 2,4-dimethyl- piperazin-1 -yl, 4-methyl-diazepan-1-yl, thiomorpholine-1 ,1 dioxide-4-yl; or pyrrolidinyl; R 5 is methyl, methoxy
  • q 0 or 1.
  • Y is carbonyl
  • R 1 is H, methyl, i-butyloxycarbonyl; Me-S0 2 -, or dimethylaminoethyl;
  • R 2 is H, (R 5 ) n -phenyl- ⁇ CH 2 ) p -, (R 6 ) n -furanyl-(CH 2 ) q -, (R 6 ) n -pyridyl-(CH 2 ) p -,
  • R 5 is methyl, methoxy, F, CI, CF 3 , or OCF 3 ;
  • q 0 or 1.
  • Y is carbonyl
  • R 1 is H, methyl, i-butyloxycarbonyl; Me-S0 2 -, or dimethylaminoethyl;
  • R 2 is H, (R 5 )n-phenyl-(CH 2 ) p ⁇ , (R 6 ) n -furanyl-(CH 2 ) q -, (R 6 ) n -pyridyl-(CH 2 ) q -,
  • R 5 is methyl, methoxy, F, CI, CF 3 , or OCF 3 ;
  • q 0 or 1.
  • Y is methylene
  • R 1 is H, methyl, i-butyloxycarbonyl; e-S0 2 -, or dimethylaminoethyl;
  • R 2 is H, (R 5 ) n -phenyl-(CH 2 ) p -, (R 6 ) n -furanyl-(CH 2 ) q -, (R 6 ) n -pyridyl-(CH 2 ) q -,
  • R 1 and R 2 together with the nitrogen atom to which they are attached, form azetidinyl, piperazinyl, 4-methyl-piperazin-1-yl, 4-methylsuifony! ⁇ piperazin-1-yl, 2,4-dimethyl- piperazin-1-yl, 4-methyl-diazepan-1-yl, thiomorpholine-1 ,1 dioxide-4-yl; or pyrrolidinyl; R 5 is methyl, methoxy
  • R 1 is H, CH 3 , or dimethylaminoethyl
  • R 1 is H, CH 3 , or dimethylaminoethyl
  • R 2 is (R 5 ) n -phenyl-CH 2 ; thienyl-CH 2 -; furanyl-CH 2 ; pyridinyl-CH 2 -; and
  • Y is methylene
  • R 1 is H, CH 3 , or dimethylaminoethyl
  • z is (R 5 ) n -phenyl-CH z ; thienyl-CH 2 -; furanyl-CH 2 ; pyridinyl-CH 2 -; and
  • Y is methylene
  • R 1 is H, CH 3 , or dimethylaminoethyl
  • composition comprising a) the compound of Formulas l-IV or a pharmaceutically acceptable salt thereof; and 2) a pharmaceutically acceptable excipient.
  • a method of treating HIV comprising administering to a patient suffering therefrom an effective amount of the compound of Formulas I, II, III, or IV, or a pharmaceutically acceptable salt thereof.
  • Such compounds of the invention 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 diastereomerical!y 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. Ail 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.
  • 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).
  • a pharmaceutical composition comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of a compound as defined in Formulas I, II, or III.
  • the pharmaceutical formulation containing a compound of Formulas 1-iV or a salt thereof is a formulation adapted for parenteral administration, !n another embodiment, the formulation is a iong-acting parenteral formulation. In a further embodiment, the formulation is a nano-particle formulation.
  • 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 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 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 Formulas I-IV 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.
  • the compounds of the present invention may be used in combination with one or more agents useful in the prevention or treatment of HIV.
  • Nucleotide reverse transcriptase inhibitors such as zidovudine, didanosine, lamivudine, zalcitabine, abacavir, stavudine, adefovir, adefovir dipivoxil, fozivudine, todoxil, emtricitabine, alovudine, amdoxovir, elvucitabine, and similar agents;
  • Non-nucleotide reverse transcriptase inhibitors including an agent having anti-oxidation activity such as immunocal, oltipraz, etc.
  • an agent having anti-oxidation activity such as immunocal, oltipraz, etc.
  • nevirapine delavirdine, efavirenz, loviride
  • immunocal immunocal
  • oltipraz immunocal
  • capravirine immunocal
  • !ersivirine GSK2248761 , TMC-278, TMC-125, etravirine, and similar agents
  • Protease inhibitors such as saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, fosamprenavir, brecanavir, darunavir, atazanavir, tipranavir, palinavir, lasinavir, and similar agents;
  • Entry, attachment and fusion inhibitors such as enfuvirtide (T-20), T-1249,
  • Integrase inhibitors such as raltegravir, elvitegravir, GSK1349572,
  • Maturation inhibitors such as PA-344 and PA-457, and similar agents.
  • CXCR4 and/or CCR5 inhibitors such as vicriviroc (Sch-C), Sch-D, TAK779, maraviroc (UK 427,857), TAK449, as well as those disclosed in WO 02/74769,
  • PCT/US03/39740 and PCT/US03/39732, and similar agents.
  • combinations of compounds of this invention with HIV agents is not limited to those mentioned above, but includes in principle any combination with any pharmaceutical composition useful for the treatment of HIV.
  • the compounds of the present invention and other HIV agents may be administered separately or in conjunction.
  • one agent may be prior to, concurrent to, or subsequent to the administration of other agent(s).
  • the present invention may be used in combination with one or more agents useful as pharmacological enhancers as well as with or without additional compounds for the prevention or treatment of HIV.
  • agents useful as pharmacological enhancers as well as with or without additional compounds for the prevention or treatment of HIV.
  • examples of such pharmacological enhancers or
  • pharmakinetic boosters include, but are not limited to, ritonavir, GS-9350, and SPI-452.
  • Ritonavir is 10-hydroxy-2-methyl-5-(1-methyethyl)-1-1 [2- ⁇ 1-methylethyl)-4- thiazolyiJ-S.e-dioxo-S.H -bisiphenylmethy ⁇ .T. ⁇ -tetraazatridecan-IS-oic acid, 5- thiazo!ylmethyl ester, [5S-(5S*,8R*,10R*,11 R*)] and is available from Abbott Laboratories of Abbott park, Illinois, as Norvir.
  • Ritonavir is an HIV protease inhibitor indicated with other antiretroviral agents for the treatment of HIV infection.
  • Ritonavir also inhibits P450 mediated drug metabolism as well as the P-gycoprotein (Pgp) cell transport system, thereby resulting in increased concentrations of active compound within the organism,
  • GS-9350 is a compound being developed by Gilead Sciences of Foster City
  • SPI-452 is a compound being developed by Sequoia Pharmaceuticals of
  • a compound of Formulas 1-IV is used in combination with ritonavir.
  • the combination is an oral fixed dose combination.
  • the compound of Formulas l-IV is formulated as a long acting parenteral injection and ritonavir is formulated as an oral composition.
  • the compound of Formulas l-IV is formulated as a long acting parenteral injection and ritonavir is formulated as an injectable composition.
  • a compound of Formulas l-IV is used in combination with GS-9350.
  • the combination is an oral fixed dose combination.
  • the compound of Formulas l-IV is formulated as a long acting parenteral injection and GS-9350 is formulated as an oral composition.
  • the compound of Formulas l-IV is formulated as a long acting parenteral injection and GS-9350 is formulated as an injectable composition.
  • a compound of Formulas !-IV is used in combination with SPI-452.
  • the combination is an oral fixed dose combination.
  • the compound of Formulas l-IV is formulated as a long acting parenteral injection and SPI-452 is formulated as an oral composition
  • the compound of Formulas l-IV is formulated as a long acting parenteral injection and SPI- 452 is formulated as an injectable composition.
  • a method for treating a viral infection in a mammal mediated at least in part by a virus in the retrovirus family of viruses which method comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a compound of Formulas l-IV.
  • a method for treating a viral infection in a mammal mediated at least in part by a virus in the retrovirus family of viruses which method comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a compound of Formulas I, II, or III, wherein said virus is an HIV virus.
  • a method for treating a viral infection in a mammal mediated at least in part by a virus in the retrovirus family of viruses which method comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a compound of Formulas I, II, or III, further comprising administration of a therapeutically effective amount of one or more agents active against an HIV virus.
  • a method for treating a viral infection in a mammal mediated at least in part by a virus in the retrovirus family of viruses comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a compound of Formulas I, II, or III, further comprising administration of a therapeutically effective amount of one or more agents active against the HIV virus, wherein said agent active against HIV virus is selected from Nucleotide reverse transcriptase inhibitors; Non-nucleotide reverse transcriptase inhibitors; Protease inhibitors; Entry, attachment and fusion inhibitors;
  • the compound of the present invention is chosen from the compounds set forth in Table 1.
  • Table 1 the compounds set forth in Table 1.
  • oxobutanoic acid 4- ⁇ [(1 R.2R.5S, 10S, 13R, 1 R, 17S, 19R)-5-[2- (N-benzyl-2-hydroxyacetamido)acetyl]- 1 ,2,14,18,18-pentamet yl-8-(propan-2- yl)pentacyclo[11.8.0.0 ⁇ ⁇ 2, 10 ⁇ .0 ⁇ ⁇ 5, 9 ⁇ .0 ⁇ ⁇ 14, 19 ⁇ ]henicos-8-en-17-yl]oxy ⁇ -2,2-dimethyl-4- oxobutanoic acid
  • the compound(s) of the present invention is chosen from the compounds set forth in Table 1.
  • the methods of this invention may employ protecting groups which prevent certain functional groups from undergoing undesired reactions.
  • Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999, and references cited therein.
  • the provided chemical entities may contain one or more chiral centers and such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this specification, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents and the like.
  • the starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof.
  • many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Ernka-Chemce or Sigma (St. Louis, Missouri, USA).
  • Others may be prepared by procedures, or obvious modifications thereof, described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplemental (Elsevier
  • reaction times and conditions are intended to be approximate, e.g., taking place at about atmospheric pressure within a temperature range of about -78 °C to about 1 10 °C over a period of about 1 to about 24 hours; reactions left to run overnight average a period of about 16 hours.
  • solvent each mean a solvent inert under the conditions of the reaction being described in conjunction therewith, including, for example, benzene, toluene, acetonitrile, tetrahydrofurany! (“THF”),
  • DMF dimethylformamide
  • chloroform chloroform
  • methylene chloride or dichioromethane
  • diethyl ether diethyl ether
  • methanol methanol
  • NMP N-methylpyrrolidone
  • Isolation and purification of the chemical entities and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography or thick-layer chromatography, or a combination of these procedures.
  • suitable separation and isolation procedures can be had by reference to the examples herein below. However, other equivalent separation or isolation procedures can also be used.
  • the (R)- and (S)-isomers may be resolved by methods known to those skilled in the art, for example by formation of diastereoisomeric salts or complexes which may be separated, for example, by crystallization; via formation of diastereoisomeric derivatives which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic oxidation or reduction, fo!lowed by separation of the modified and unmodified enantiomers; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support, such as silica with a bound chiral ligand or in the presence of a chiral solvent.
  • a specific enantiomer may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to
  • Solvent A 0.01% trifiuoroacetic acid (TFA) in water;
  • Solvent B 0.01 % TFA in acetonitri!e
  • Step B Intermediate 5 To a solution of the intermediate 4 (3 g, 6.19 mmol) in DCM (75 mL) at room temperature were added PCC (4 g, 18.57 mmol) and silica gel (3.0 g). After stirring at room temperature for 2 h, the reaction was quenched with water (100 mL). The organic phase was separated, washed with saturated sodium bicarbonate (50 mL), dried over sodium sulfate and concentrated in vacuo to provide a residue, which was purified by column
  • Example 2 4-ff3aS.5aR,5bR,7aR.9S,11aR,11bR,13aS)-3a-(2-(4- fluorobenzylamino)acetvn-1-isopstickyl-5a,5b,8,8,11a-pentamethyl- 3,3a.4,5,5a,5b.6,7,7a,8,9,10,11,11a.11 b,12.13.13a-octadecahvdro-2H- cvclopentara1chrvsen-9-yloxy)-2,2-dimethyl-4-oxobutanoic acid
  • Example 3 4-ii3aS,5a ,5bR,7aR,9S.11aR.11bR.13aS)-3a-f2-(Furan-2- ylmethylamino)acetyl)-1-isopstickyl-5a,5b,8 1 8.11a-pentamethyl- 3,3a ,4,5,5a,5b.6,7.7a.8,9.10, 1 , 11 a,11 b, 12,13.13a-octadecahvdro-2H- cvclopentaralchrysen-9-yloxy)-2,2-dimethyl-4-oxobutanoic acid
  • Example 4 4-((3aS,5aR.5bR,7aR,9S,11aR.11 bR,13aS)-3a-f2- (cyclopentylamino)acetyl)-1-isopstickyl-5a,5b T 8 1 8,11a-pentamethyl- 3,3a,4,5,5a,5b,6.7,7a.8.9.10.11.11 a, 11 b.12.13.13a-octadecahvdro-2H- cvclopentaraIchrvsen-9-yloxy)-2,2-dimethyl-4-oxobutanoic acid
  • Example 5 4-((3aS,5aR,5bR.7aR.9S,11aR,11bR.13aS)-1-lsopstickv!- 5a,5b, 8,8,11 a-pentamethyl-3a-(2-(4-methylpiperazin-1-v0acetv0- 3,3a,4,5,5a.5b,6.7,7a.8.9,10,11,11a.11b.12,13,13a-octadecahvdro-2H- cvclopentara1chrvsen-9-yloxy)-2,2-dimethyl-4-oxobutanoic acid
  • Step B Intermediate 18 To a mixture of the intermediate 17 (300 mg, 0.66 mmol) in DCM (10 mL) were added DMAP (7.25 mg, 0.059 mmol), acetic anhydride (0.182 mL, 1.781 mmol) and Et 3 N (0.494 mL, 3.56 mmol). After stirring at room temperature for 1 h, the reaction mixture was diluted with iced water (20 mL), and extracted with DCM (100 mL). The organic phase was washed with water (40 mL x 3), brine (40 mL), dried over sodium sulfate, and evaporated in vacuo to provide a pale yellow solid. The solid was taken up in MeOH (5 mL), and the precipitates were collected and rinsed with cold MeOH (5 mL) to afford the intermediate 18 (250 mg, 85 %) as a white solid.
  • DMAP 7.25 mg, 0.059 mmol
  • acetic anhydride 0.182 mL, 1.781 mmol
  • Example 79 4-ff3aS.5aR.5bR.7aR,9S.11aR.11bR,13aS)-1-lsopstickyl- 5a,5b,8,8,11a-pentamethyl-3a-f2-f4-methylpiperazin-1-yl)-2-oxoacetyl)- 3,3a A5,5a,5b,6,7,7a,8.9.10,11.11 a.11 b. 2.13.13a-octadecahvdro-2H- cvclopentaralchrvsen-9-yloxy)-2.2-dimethyl-4-oxobutanoic acid
  • Example 80 4-f(3aS.5aR.5bR.7aR.9S.11aR.11bR.13aS)-1-lsopstickyl- 5a,5b,8,8,11a-pentamethyl-3a-(2-oxo-2-(2-phenylpropan-2-ylamino)acetyl)- 3,3aA5,5a,5b,6,7,7a,8,9,10,11,11a, 1 b,12,13,13a-octadecahvdro-2H- cvclopentara1chrysen-9-yloxyi-2,2-dimethyl-4-oxobutanoic acid
  • Example 81 4-((3aS 1 5aR,5bR,7aR,9S,11aR,11bR,13aS3 ⁇ 4-3a-(2-(f4-)
  • a pharmaceutical composition comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the compounds of the present invention can be supplied in the form of a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salt refer to salts prepared from pharmaceutically acceptable inorganic and organic acids and bases.
  • a compound or a pharmaceutically acceptable salt thereof is understood to refer to either a compound or a pharmaceutically acceptable salt thereof (alternative), or a compound and a pharmaceutically acceptable salt thereof (in combination).
  • pharmaceutically acceptable refers to those compounds, materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication.
  • pharmaceutically acceptable salts of compounds according to Formulas I-IV may be prepared. These pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively.
  • Illustrative pharmaceutically acceptable acid salts of the compounds of the present invention can be prepared from the following acids, including, without limitation formic, acetic, propionic, benzoic, succinic, glycolic, gluconic, lactic, maleic, malic, tartaric, citric, nitic, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, hydrochloric, hydrobromic, hydroiodic, isocitric, trifluoroacetic, pamoic, propionic, anthranilic, mesylic, oxalacetic, oleic, stearic, salicylic, p-hydroxybenzoic, nicotinic, pheny!acetic, mandeiic, embonic (pamoic), methanesulfonic, phosphoric, phosphonic, ethanesulfonic, benzenesulfonic, pantothenic, to
  • metallic ions More preferred metallic ions include, but are not limited to, appropriate alkali metal salts, alkaline earth metal salts and other physiological acceptable metal ions.
  • Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like and in their usual valences.
  • Exemplary base salts include aluminum, calcium, lithium, magnesium, potassium, sodium and zinc.
  • Other exemplary base salts include the ammonium, calcium, magnesium, potassium, and sodium salts.
  • Still other exemplary base salts include, for example, hydroxides, carbonates, hydrides, and alkoxides including NaOH, KOH, Na 2 C0 3 , K2CO3, NaH, and potassium-t- butoxide.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, including in part, trimethylamine, diethylamine, N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine; substituted amines including naturally occurring substituted amines; cyclic amines; quaternary ammonium cations; and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lys
  • salts can be prepared by those skilled in the art by conventional means from the corresponding compound of the present invention.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropano!, or acetonitrile are preferred.
  • the salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
  • the degree of ionisation in the salt may vary from completely ionised to almost non-ionised. Lists of suitable salts are found in Remington's Pharmaceutical Sciences. 17th ed., Mack
  • the compounds of the invention may exist in both unso!vated and solvated forms.
  • the term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
  • the term 'hydrate' is employed when said solvent is water.
  • solvates include hydrates and other solvates wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 0, d 6 -acetone, d 6 -DMSO.
  • Compounds of Formula (I) containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where a compound of Formula (I) contains an alkenyl or alkenylene group or a cycloalkyl group, geometric cis/trans (or Z E) isomers are possible. Where the compound contains, for example, a keto or oxime group or an aromatic moiety, tautomeric isomerism ('tautomerism') can occur. It follows that a single compound may exhibit more than one type of isomerism.
  • Cisltrans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation.
  • enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).
  • HPLC high pressure liquid chromatography
  • the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of formula (I) contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-pheny!ethylamine.
  • a suitable optically active compound for example, an alcohol, or, in the case where the compound of formula (I) contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-pheny!ethylamine.
  • the resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.
  • Chiral compounds of the invention may be obtained in enantiomericaily-enriched form using chromatography, typically HPLC, on a resin with an asymmetric stationary phase and with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine, typically 0.1 % diethylamine. Concentration of the eluate affords the enriched mixture.
  • the present invention includes all pharmaceutically acceptable isotopically- labelled compounds of formula (I) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 CI, fluorine, such as 18 F, iodine, such as 23 l and 125 l, nitrogen, such as 3 N and 5 N, oxygen, such as 15 0, 17 0 and s O, phosphorus, such as 32 P, and sulphur, such as 35 S.
  • isotopically-labelled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e. 3 H, and carbon-14, i.e. 4 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • Substitution with heavier 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.
  • Isotopically-labelled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate
  • the compounds of the present invention may be administered as prodrugs.
  • pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of formula (I) having the desired activity, for example, by hydrolytic cleavage.
  • Such derivatives are referred to as 'prodrugs'.
  • compositions or formulations include solid, semi-solid, liquid and aerosol dosage forms, such as, e.g., tablets, capsules, powders, liquids, suspensions, suppositories, aerosols or the like.
  • the chemical entities can also be administered in sustained or controlled release dosage forms, including depot injections, osmotic pumps, pills, transdermal (including electrotransport) patches, and the like, for prolonged and/or timed, pulsed administration at a predetermined rate.
  • sustained or controlled release dosage forms including depot injections, osmotic pumps, pills, transdermal (including electrotransport) patches, and the like, for prolonged and/or timed, pulsed administration at a predetermined rate.
  • compositions are provided in unit dosage forms suitable for single administration of a precise dose.
  • the chemical entities described herein can be administered either alone or more typically in combination with a conventional pharmaceutical carrier, excipient or the like (e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium crosscarmellose, glucose, gelatin, sucrose, magnesium carbonate, and the like).
  • a conventional pharmaceutical carrier e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium crosscarmellose, glucose, gelatin, sucrose, magnesium carbonate, and the like.
  • the pharmaceutical composition can also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents and the like (e.g., sodium acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate, and the like).
  • the pharmaceutical composition will contain about 0.005% to 95%; in certain embodiments, about 0.5% to 50% by weight of a chemical entity.
  • Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania.
  • the compositions will take the form of a pill or tablet and thus the composition will contain, along with the active ingredient, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, polyvinylpyrrolidone, gelatin, cellulose, cellulose derivatives or the like.
  • a powder, marume, solution or suspension e.g., in propylene carbonate, vegetable oils or triglycerides
  • a gelatin capsule e.g., in propylene carbonate, vegetable oils or triglycerides
  • Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc. at least one chemical entity and optional
  • compositions will comprise from about 0.2 to 2% of the active agent in solution.
  • compositions of the chemical entities described herein may also be administered to the respiratory tract as an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose.
  • the particles of the pharmaceutical composition have diameters of less than 50 microns, in certain embodiments, less than 10 microns.
  • the actual amount of the chemical entity i.e., the active ingredient, will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the chemical entity used, the route and form of administration, and other factors.
  • the drug can be administered more than once a day, such as once or twice a day.
  • Therapeutically effective amounts of the chemical entities described herein may range from approximately 0.01 to 200 mg per kilogram body weight of the recipient per day; such as about 0.01-100 mg/kg/day, for example, from about 0.1 to 50 mg/kg/day. Thus, for administration to a 70 kg person, the dosage range may be about 7-3500 mg per day.
  • the chemical entities will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic ⁇ e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration.
  • oral administration with a convenient daily dosage regimen that can be adjusted according to the degree of affliction may be used.
  • compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions.
  • Another manner for administering the provided chemical entities is inhalation.
  • the choice of formulation depends on various factors such as the mode of drug administration and bioavailability of the drug substance.
  • the chemical entity can be formulated as liquid solution, suspensions, aerosol propellants or dry powder and loaded into a suitable dispenser for administration.
  • suitable dispenser for administration There are several types of pharmaceutical inhalation devices-nebulizer inhalers, metered dose inhalers (MDI) and dry powder inhalers (DPI).
  • MDIs metered dose inhalers
  • DPI dry powder inhalers
  • Nebulizer devices produce a stream of high velocity air that causes the therapeutic agents (which are formulated in a liquid form) to spray as a mist that is carried into the patient's respiratory tract.
  • MDIs typically are formulation packaged with a compressed gas.
  • the device Upon actuation, the device discharges a measured amount of therapeutic agent by compressed gas, thus affording a reliable method of administering a set amount of agent.
  • DPI dispenses therapeutic agents in the form of a free flowing powder that can be dispersed in the patient's inspiratory air-stream during breathing by the device.
  • the therapeutic agent In order to achieve a free flowing powder, the therapeutic agent is formulated with an excipient such as lactose.
  • a measured amount of the therapeutic agent is stored in a capsule form and is dispensed with each actuation.
  • compositions have been developed for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area i.e., decreasing particle size.
  • U.S. Patent No. 4, 107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1 ,000 nm in which the active material is supported on a cross-linked matrix of
  • U.S. Patent No. 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability.
  • compositions are comprised of, in general, at least one chemical entity described herein in combination with at least one pharmaceutically acceptable excipient.
  • Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the at least one chemical entity described herein.
  • excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
  • Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like.
  • Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petrofeum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.
  • Liquid carriers, for injectable solutions include water, saline, aqueous dextrose, and glycols.
  • Compressed gases may be used to disperse a chemical entity described herein in aerosoi form.
  • Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.
  • Other suitable pharmaceutical excipients and their formulations are described in
  • the amount of the chemical entity in a composition can vary within the full range employed by those skilled in the art.
  • the composition will contain, on a weight percent (wt%) basis, from about 0.01-99.99 wt% of at least one chemical entity described herein based on the total composition, with the balance being one or more suitable pharmaceutical excipients.
  • the at least one chemical entity described herein is present at a level of about 1-80 wt%. Representative pharmaceutical compositions containing at least one chemical entity described herein are described below.
  • test compounds were determined in a two cell co- culture HIV lifecycle assay.
  • Jurkat T-lymphocytes that are chronically infected with H!V-1 HxB2 were co-cultured with indicator HOS cells that harbor a modified HIV LTR- luciferase reporter.
  • Virus produced by the infected Jurkat cells can infect the HOS cells leading to LTR-directed expression of the luciferase reporter.
  • Compounds that interfere with virus production in the Jurkat cells, maturation of the virus, entry or post-entry steps in the HIV lifecycle decrease the luciferase signal.
  • J4HxB2 cells are rapidly thawed in a 37 " C waterbath and slowly diluted to 15 mL with cell medium (RPMI 1640 medium containing 10% fetal bovine serum and gentamycin) with gentle swirling. The cells are then placed into culture at 37 ° C, 5% C0 2 , and expanded to 30 mL on day 4 and to 60 mL on day 7 by the addition of cell medium.
  • cell medium RPMI 1640 medium containing 10% fetal bovine serum and gentamycin
  • HOS cells were rapidly thawed, slowly diluted to 15 mL in cell culture medium, centrifuged at 1400 rpm for 5 min and resuspended in 10 mL cell medium.
  • 2x10 7 HOS cells were diluted to 1 1 12 mL in chilled (4 ° C) cell medium and placed on a stir plate.
  • 6.7x10 7 J4HxB2 cells in culture were pelleted by centrifugation at 1400 rpm for 5 min and resuspended into the chilled HOS cell suspension.
  • the HOS and J4HxB2 cells were mixed on the stir plate for at least 5 min prior to plating into 96- or 384- well plates.
  • a Multidrop (or similar instrument) was used to dispense the cells into assay plates containing test compounds.
  • 0.2 mL J4HxB2/HOS cell suspension was added to 2 pL of test compound in the assay plate.
  • 0.05 mL cell suspension was added to 0.5 pL of test compound in the assay plate.
  • Compounds were tested as 10- or 11 -point serial dilutions. After addition of cells to compound plates, plates were allowed to sit at room temperature for 30 min to 1 h then moved to humidified 5% C0 2 37 ° C incubator for 5 days. At the end of five days, plates were removed from the incubator and equilibrated to room temperature for 30 min to 1 h.
  • Promega Steady-Glo reagent was prepared according to the manufacturer's directions and added to plates using Multidrop (or similar instrument). 0.02 mL of Steady-Glo was added to the wells of 384-well plate. For the 96-well plate, 0.1 mL of medium was removed from each well and 0.06 mL of Steady-Glo was added. Luminescence was then detected using an Envision or Topcount Microplate Reader or similar instrument.
  • Antiviral HIV activity and cytotoxicity values for compounds of the invention from Table 1 were measured in parallel in the HTLV-1 transformed cell line MT-4 based on the method previously described (Hazen et al., 2007, In vitro antiviral activity of the novel, tyrosyl-based human immunodeficiency virus (HIV) type 1 protease inhibitor brecanavir (GW640385) in combination with other antiretrovirals and against a pane!
  • HIV human immunodeficiency virus
  • HIV protease inhibitor-resistant HIV
  • HIV tyrosyl-based human immunodeficiency virus
  • brecanavir tyrosyl-based human immunodeficiency virus type 1 protease inhibitor brecanavir
  • Pauwels et al. "Sensitive and rapid assay on MT-4 cells for the detection of antiviral compounds against the AIDS virus
  • J. of Virological Methods 1987 ' , 16: 171-185 J. of Virological Methods 1987 ' , 16: 171-185
  • IC 50 s were determined from a 10 point dose response curve using 3-4-fold serial dilution for each compound, which spans a concentration range > 000 fold.
  • the following ingredients are mixed to form an injectable formulation.
  • a suppository of total weight 2.5 g is prepared by mixing the compound with
  • Witepsol® H-15 triglycerides of saturated vegetable fatty acid; Riches-Nelson, Inc., New York, and has the following composition:

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Abstract

La présente invention concerne un composé caractérisé par la formule I suivante ou un sel pharmaceutiquement acceptable de celui-ci, où R, L et A sont tels que décrits présentement. Des composés de la présente invention sont utiles pour le traitement du VIH.
PCT/CN2011/001303 2011-08-08 2011-08-08 Dérivés méthylènes de bétuline Ceased WO2013020246A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013090664A1 (fr) 2011-12-16 2013-06-20 Glaxosmithkline Llc Dérivés de bétuline
US9795619B2 (en) 2012-12-14 2017-10-24 Glaxosmithkline Llc Pharmaceutical compositions
US10092523B2 (en) 2014-09-26 2018-10-09 Glaxosmithkline Intellectual Property (No. 2) Limited Long acting pharmaceutical compositions

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006105356A2 (fr) * 2005-03-29 2006-10-05 Regents Of The University Of Minnesota Procedes de production d'esters 3 bioactif d'aldehyde betulinique et d'acide betulinique
US20090275583A1 (en) * 2006-10-13 2009-11-05 Myriad Genetics, Incorporated Antiviral compounds and use thereof
WO2011100308A1 (fr) * 2010-02-11 2011-08-18 Glaxosmithkline Llc Dérivés de bétuline

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006105356A2 (fr) * 2005-03-29 2006-10-05 Regents Of The University Of Minnesota Procedes de production d'esters 3 bioactif d'aldehyde betulinique et d'acide betulinique
US20090275583A1 (en) * 2006-10-13 2009-11-05 Myriad Genetics, Incorporated Antiviral compounds and use thereof
WO2011100308A1 (fr) * 2010-02-11 2011-08-18 Glaxosmithkline Llc Dérivés de bétuline

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013090664A1 (fr) 2011-12-16 2013-06-20 Glaxosmithkline Llc Dérivés de bétuline
JP2015501845A (ja) * 2011-12-16 2015-01-19 グラクソスミスクライン エルエルシー ベツリンの誘導体
US9102685B2 (en) 2011-12-16 2015-08-11 Glaxosmithkline Llc Derivatives of betulin
JP2018065867A (ja) * 2011-12-16 2018-04-26 グラクソスミスクライン エルエルシー ベツリンの誘導体
US10064873B2 (en) 2011-12-16 2018-09-04 Glaxosmithkline Llc Compounds and compositions for treating HIV with derivatives of Betulin
US9795619B2 (en) 2012-12-14 2017-10-24 Glaxosmithkline Llc Pharmaceutical compositions
US10092523B2 (en) 2014-09-26 2018-10-09 Glaxosmithkline Intellectual Property (No. 2) Limited Long acting pharmaceutical compositions

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