WO2013020245A1 - Carbonyl derivatives of betulin - Google Patents

Carbonyl derivatives of betulin Download PDF

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Publication number
WO2013020245A1
WO2013020245A1 PCT/CN2011/001302 CN2011001302W WO2013020245A1 WO 2013020245 A1 WO2013020245 A1 WO 2013020245A1 CN 2011001302 W CN2011001302 W CN 2011001302W WO 2013020245 A1 WO2013020245 A1 WO 2013020245A1
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WIPO (PCT)
Prior art keywords
group
oxo
methyl
alkyl
compound
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PCT/CN2011/001302
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French (fr)
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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Priority to PCT/CN2011/001302 priority Critical patent/WO2013020245A1/en
Publication of WO2013020245A1 publication Critical patent/WO2013020245A1/en

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Classifications

    • 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 deriviative 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 antiretroviral 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 HIV 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.
  • Pr55Gag The HIV Gag polyprotein precursor
  • MA protein domains ⁇ matrix
  • CA capsid
  • NC nucleocapsid
  • SP1 and SP2 two spacer peptides
  • Gag mediates membrane binding. Assembly is completed by budding of the immature l 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 a (C ⁇ CeJalkylene, -C(O), -C(0)NH, -C(0)NHR 4 , -C(0)NHR 15 , -C(0)R 4 R 10 , -R NR 1 R 2 , -R NH, -R 4 NHC(0), -R 4 NHR 4 ,
  • X is (C 5 -C 14 )aryl
  • Y is independently selected from (C 2 -Cg)heterocycle or (C 2 -C 9 )heteroaryl, each one to three heteroatoms selected from S, N or O;
  • Z is (C 3 -C 7 )cycloa!kyi
  • A is selected from the group consisting of -NR 1 R 2 , -OR5,
  • R 1 and R 2 are each independently -H, (C r C 6 )alkyl, (C r 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 R 10 , -C(0)OR 5 , -R NHC(0), -C(0)R NHC(0)R 6 , -R 4 R 8 R 4 R 8 , -C(0)R 4 (R 8 ) 2 , -C(0)R 4 R 3 , -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
  • 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 (C C 6 )alkyi
  • R 6 is (CrC e )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 1 Z , and R 13 are independently selected from the group consisting of oxo, halo, (CrCe)alkoxy, -R 6 (R 9 ) q , -OR 6 (R 9 ) q , nitro, -S0 2 R 6 , (Ci-C 6 )alkyl. -C(0)R 1 °, -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 (CrC 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;
  • 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, furanyi, pyridyl, pyrazolyl, pyridazinyl, pyrrolidinyl, thiazolyl, oxazoiyl, thiophenyl, and thiomorpholinyl;
  • R and R 2 are each independently -H, (C C 6 )alkyl, (C C 6 )alkylene, -R N(R 5 ) 2l -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 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 )alkylene
  • R 5 is independently selected from -H and (CrCeJalkyl
  • R 6 is (CrC 6 )alkyl
  • 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 r 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 ⁇ 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 (CrC 6 )alkyl, oxo, halo, (C 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 -OP(0)(OH) 2 ;
  • R is selected from the group consisting of -H, (C r C 6 )alkyi, and -C(0)OR .
  • L is selected from the group consisting of a (C r C 6 )a!kylene, -C(O), -C(0)NH, ⁇ C(0)NHR 4 , -C(0)NHR 15 , -C(0)R 4 R 10 , -R 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 )heterocyc[e 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 R 2 , -OR5,
  • R 1 and R 2 are each independently -H, (C C 6 )alkyi, (C C 6 )alkylene, -R e N( 6 ) 2l -R 4 R 10 , -R 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 ,5 -R NHC(0), -C(0)R 4 NHC(0)R 6 , -R R 6 R 4 R 8 , -C(0)R 4 (R 8 ) 2 , -C(0)R 4 R s , -N(R 5 ) 2 , -C(0)N(R 5 ) 2) -C(0)R 4 N(R 5 ) 2l -C(0)C(0)N(R s ) 2 , -C(0)R (OH) 2 , -C(0)C(0)R a ,
  • R 4 is (C r C 6 )alkylene
  • R 5 is independently selected from -H and (C 1 -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 10 is -N(R 16 ) 2 ;
  • R 11 , R 12 , and R 13 are independently selected from the group consisting of oxo, halo, (CrCe)alkoxy, -R 6 (R 9 ) q , -OR 6 (R 9 ) q , nitro, -S0 2 R 6 , (C C 6 )alkyl t -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 ;
  • 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 (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 4 NHC(0), and -R 4 NHR 4 ;
  • X is (C 5 -Cu)aryl;
  • Y is independently selected from (C 2 -C 9 )heterocycle or (C 2 -Cg)heteroaryi, 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 )a!kyl, (C C 6 )aikylene, -R 4 N(R 5 ) 2 , -R 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 R 10 , -C(0)OR 5 , -R 4 NHC(0), -C(0)R 4 NHC(0)R 6 , -R 4 R 8 R R R B , -C(0)R 4 (R 8 ) 2> -C(0)R 4 R 8 , -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
  • R 3 is selected from the group consisting of -C(0)R R 7 , -C(0)R 4 R 7 R 8 ,
  • R 4 is (C C 6 )alkylene
  • R 5 is independently selected from -H and (C C 6 )a]kyl
  • R 6 is (C r 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 is independently selected from the group consisting of halo, (C r Ce)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 , (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,
  • R 14 is -OP(0)(OH) 2 ;
  • R 16 is selected from the group consisting of -H, (C-rCeJalkyl, and -C(0)OR j 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;
  • L is selected from the group consisting of a (Ci-C 6 )a!kylene, -C(O), -C(0)NH, -C ⁇ 0)NHR 4 , -C(0)NHR 15 , -C(0)R R 10 , -R 4 NR 1 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 2 are each independently -H, (C 1 -C 6 )alkyl, (C r C 6 )a!kylene, ⁇ R 4 N(R 5 ) 2 , -R R 10 , -R 4 X(R 11 ) m , -R X, -C(O), -C ⁇ 0)R 6 , -C(0)R 8 , -R 4 C(0)R 1 °, -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 4 (R 8 ) 2 , -C(0)R 4 R 8 , -N(R 5 ) 2 , -C(0)N(R s ) 2 -C(0)R N(R 5 ) 2 , -C(0)C(0)N(R 5 ) 2 , -C(0)R 4 (OH) 2 , -C
  • 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 e )alkylene
  • R 5 is independently selected from -H and (C C 6 )a!kyl
  • R 6 is (CrC e )alkyl
  • R 7 is -C(0)OR 5 ;
  • R 8 is -OR 5 ;
  • R 9 is halo; s R 0 is -N(R 6 ) 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 , -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;
  • q is an integer selected from 1 , 2, or 3,
  • L is selected from the group consisting of a (C r C 6 )aikylene, -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 NHR 4 ;
  • X is (C 5 -C 14 )aryl
  • Y is independently selected from (C 2 -Cg)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, cyclopropy!, cyclobutyl, cyclopenty!, cyclohexy!, acetidinyl, piperazinyl, furanyl, pyridyl, pyrazolyl, pyridazinyl, pyrrolidinyl, thiazolyl, oxazolyl, thiophenyl, and thiomorpholinyl;
  • R 1 and R 2 are each independently -H, (Ci-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 C(0)R 10 , -C(0)R 4 R 10 ,
  • R 3 is selected from the group consisting of -C(0)R R 7 , -C(0)R 4 R 7 R 8 ,
  • R 4 is (C r C 6 )alkylene
  • R 5 is independently selected from -H and (C r 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 10 is -N(R 16 ) 2 ;
  • R 11 is independently selected from the group consisting of halo, (CVCeJalkyl, (d- C 6 )alkoxy, -R fi (R 9 ) q , -OR 6 (R 9 ) pi and nitro;
  • R 12 is independently selected from the group consisting of -S0 2 R 6 , (C C 6 )alkyl, - C(0)R 10 , -R 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 1 -C 6 )aikoxy, -R 6 (R 9 ) q , -OR 6 (R 9 ) q , nitro, -S0 2 R 6 , (C C 6 )alkyl, -C(0)R °, -R 4 YR 6 , and - CO(0)R 5 ;
  • R 14 is -OP(0)(OH) 2 ;
  • R 5 is ;
  • R 16 is selected from the group consisting of -H, (CrCeJalkyl, and -C(0)OR 5 .
  • 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 )heteroaryi, 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 ,
  • R 1 and R 2 are each independently -H, (C 1 -C 6 )alkyl, (Ci-CeJalkylene, -R 4 N(R 5 ) 2l -R 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 1 °, -C(0)OR 5 , -R 4 NHC(0), -C(0)R 4 NHC(0)R 6 , -R R 8 R 4 R a , -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) 2l -C(0)C
  • Q is selected from the group consisting of -R 4 R 7 R B ,-R 4 R 7 R 14 , and -R C(0)R 8 ;
  • R 4 is (C r C 6 )alkylene
  • R 5 is independently selected from -H and (d-C 6 )alkyl
  • R 6 is (C C 6 )aikyl
  • R 7 is -C(0)OR 5 ;
  • R 8 is -OR 5 ;
  • R 9 is halo
  • R 0 is -N(R 16 ) 2 ;
  • R 1 ⁇ R 12 , 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 , (Ci-C e )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 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; and q is an integer selected from 1 , 2, or 3.
  • the present invention relates to a composition
  • a composition comprising a) the compound of Formulas I, II, or III 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 I, II, or III 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.
  • alkylln 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-buty!
  • Alkylene or "alkyiene” refers to divalent saturated aliphatic hydrocarbyl groups having from 1 to 0 carbon atoms and, in some embodiments, from 1 to 6 carbon atoms.
  • (C u- C v )alkylene 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 .
  • the term "dimethy!butylene 1 ould be exemplified by any of the following three structures or more:
  • (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.
  • (C2-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, f-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 alky
  • 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 -alkyl, -S0 2 -alkenyl, -S0 2 -cycloalkyl, -SO z -aryl, -S0 2 -heteroaryl, and -S0 2 -heterocyciic, and wherein R 21 and R 2 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 Z1 and R Z are alkyl
  • dialkylamino dialkylamino.
  • I 3 rnonosubstituted amino it is meant that either R or R 22 is hydrogen but not both.
  • R 21 nor R 22 are hydrogen.
  • Hydroxyamino refers to the group -NHOH.
  • alkyl refers to the group -NHO-alkyl 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, a!kyl, alkenyl, alkynyl, aryl, cycloalkyl, 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).
  • 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, cyc!obutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl, and cyclohexenyl.
  • Examples of cycloalkyl groups that include multiple bicycloalkyl ring systems are bicyclohexyl, bicyclopentyl, bicyclooctyl, and the like. Two such bicycloalkyl multiple ring structures are exemplified and named below:
  • (C u .C v )cycloalkyl refers to cycloalkyl groups having u to v carbon atoms.
  • Spiro cycloalkyl 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 cycloalkyl 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:
  • Carboxy or “carboxyl” refers interchangeably to the groups OH t
  • Halo or halogen refers to fluoro, chloro, bromo, and todo.
  • Haloalkoxy refers to substitution of a!koxy 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. trifiuoromethoxy).
  • 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), suifinyl, or sulfonyl moieties.
  • heteroaryl includes, but is not limited to, pyridyl, furanyl, thienyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, imidazolinyl, isoxazoiyi, pyrrolyl, pyrazolyl, pyridazinyl, pyrimidiny!, purinyl, phtha!azyl, naphthylpryidyl, benzofuranyl, tetrahydrobenzofuranyl, isobenzofuranyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, indolyl, isoindolyl, indolizinyl, dihydroindolyl, indazolyl, indolinyl, benzoxazolyl, quino!yl, isoquinolyl, quinolizyl, quianazolyl, quinoxalyl,
  • 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, tetrahydropyranyi, piperidinyl, piperazinyl, 3-pyrrolidinyl, 2-pyrrolidon-1-yl, morpholinyl, and pyrrolidinyl.
  • a prefix indicating the number of carbon atoms e.g., C 3 -C 10 ) 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, dihydroindo!e, 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-tetrahydr
  • 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 cycloa!kyl 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 I II, 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
  • '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
  • “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, Camilfe G.
  • Patient refers to mammals and includes humans and non-human mammals.
  • Treating" or “treatment” of a disease in a patient refers to ) 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 "arylalkyloxycarbonyi” refers to the group (aryl)-(aikyl)-0-C(0)-.
  • -C(R*) 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 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.
  • L is selected from the group consisting of a (C -CeJaikylene, -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 4 NH, -R 4 NHC(0), -R 4 NHR 4 ,
  • X is (C 5 -C 14 )aryl
  • Y is independently selected from (Cz-Cgjheterocycle 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 R 2 , -OR5,
  • R 1 and R 2 are each independently -H, (d-C 6 )alkyl, (C C 6 )alkylene, -R 4 N(R 5 ) 2 , -R R 10 , -R 4 X(R 11 ) m , -R 4 X, -C(O), -C(0)R 6 , -C(0)R B , -R 4 C(0)R 10 , -C(0)R 4 R 1 °, -C(0)OR 5 , -R 4 NHC(0), -C(0)R 4 NHC(0)R 6 , -R 4 R 6 R 4 R B , -C(0)R (R 8 ) 2 , -C(0)R 4 R B , -N(R 5 ) 2 , -C(0)N(R s ) 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
  • R 3 is selected from the group consisting of -CiOJR ⁇ 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 (C-i-C 6 )alkyl;
  • R 6 is (Ci-C B )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 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 , (d-CeJalkyl, -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-i-C 6 )alkylene, -C(O), -C(0)NH, -C(0)NHR 4 , -C(0)NHR 15 , -C(0)R 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 )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 , phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acetidinyl, piperazinyl, furanyl, pyridyl, pyrazolyl, pyridazinyl, pyrrolidinyl, thiazolyl, oxazolyl, thiophenyi, and thiomorpholinyl;
  • R 1 and R 2 are each independently -H, (Ci-C 6 )alkyl, (d-CeJaikylene, -R 4 N(R 5 ) 2 , -R R 10 , -R 4 X(R 11 ) m , -R 4 X, -C(0), -C(0)R 6 , -C(0)R 8 , -R 4 C(0)R 10 , -C(0)R 4 R 1 °
  • 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 (Ci-C 6 )alkyl
  • R 6 is (C C 6 )aikyl
  • 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, (CrC 6 )alkyi, (C C 6 )alkoxy t -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 , (Ci-C 6 )aikyl, - C(0)R 10 , -R YR 6 , -CO(0)R 5 , and oxo;
  • R 13 is independently selected from the group consisting of (CrCeialkyl, oxo, halo, (CrC 6 )alkoxy, -R 6 (R 9 ) q , nitro, -S0 2 R 6 , (C r 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, (Ci-C 6 )aikyl, and -C(0)OR 5 .
  • L is selected from the group consisting of a (C r 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 1 R 2 , -R 4 NH, -R 4 NHC(0), -R 4 NHR 4 ,
  • X is (C 5 -C 1 )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 R , -0R5, 3 ⁇ 4
  • R 1 and R 2 are each independently -H, (C Ce)aikyl, (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 C(0)R 10 , -C(0)R R 10 , -C(0)OR 5 , -R 4 NHC(0), -C(0)R NHC(0)R 6 , -R R 8 R R 8 , -C(0)R (R 8 ) 2 , -C(0)R 4 R 8 , -N(R 5 ) 2 , -C(0)N(R 5 ) -C(0)R 4 N ⁇ R 5 ) 2 , -C(0)C(0)N(R s ) 2l -C(0)R 4 (0H) 2l -C(0)C(0)R 8 , -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 , -C(0)R R 7 R and -C(0)R 4 C(0)R 8 ;
  • R 4 is (C C 6 )alkylene
  • R 5 is independently selected from -H and (C 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 2 , 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 , (d-CeJalkyl, -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;
  • q is an integer selected from 1 , 2, or 3.
  • L is selected from the group consisting of a (d-CeJalkyiene, -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), and -R 4 NHR 4 ;
  • X is (C 5 -C 14 )aryl
  • Y is independently selected from (C 2 -C9)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 , phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acetidinyl, piperazinyl, furanyl, pyridyl, pyrazoly!, pyridazinyl, pyrrolidinyl, thiazolyl, oxazolyl, thiophenyl, and thiomorpholinyl;
  • R 1 and R 2 are each independently -H, (Ci-C 6 )alkyi, (C C 6 )alkyiene, -R 4 N(R 5 ) 2 ,
  • 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 )alky!ene
  • R 5 is independently selected from -H and (C C 6 )aikyl
  • R 6 is (d-CeJalkyl
  • R 7 is ⁇ C(0)OR s ;
  • R 8 is -OR 5 ;
  • R 9 is halo
  • R D is -N(R 16 ) 2 ;
  • R 1 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 ) p , and nitro;
  • R 12 is independently selected from the group consisting of -S0 2 R 6 , (C C 6 )alkyl, - C(0)R 10 , -R YR 6 , -CO(0)R 5 , and oxo;
  • R 13 is independently selected from the group consisting of (C C6)aikyl, oxo, halo, (C C 6 )alkoxy, -R 6 (R 9 ) q , -OR 6 (R 9 ) q , nitro, -S0 2 R 6 , (C 1 -C 6 )alkyl, -C(0)R 10 , -R 4 YR 6 , and - CO(0)R 5 ;
  • R 14 is -OP(0)(OH) 2 ;
  • R B is selected from the group consisting of -H, (C C B )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 ⁇ 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 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 )cyc!oalkyl
  • R 1 and R 2 are each independently -H, (Ci-C B )alkyl p (Ci-C 6 )a[kylene, -R 4 N(R 5 ) 2 , -R 4 R 10 , -R 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 4 NHC(0), -C(0)R NHC(0)R e , -R 4 R 8 R 4 R B , -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 ) 2r -C(0)C(0)N ⁇ R 5 ) 2 , -C(O)R (0H) 2 ,
  • R 3 is selected from the group consisting of -CO ⁇ 0)R R 7 , -CO(0)R 4 R 7 R 8 ,
  • R 4 is (CrCeJalkylene
  • R s is independently selected from -H and (C -C 6 )alkyi
  • R 6 is (C r 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 , 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 ) p , nitro, -S0 2 R 6 , (d-C 6 )a!kyl, -C(0)R 10 , -R 4 YR 6 , and - CO(0)R 5 ;
  • R 4 is -OP(0)(OH) 2 ;
  • R 6 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 r C 6 )alkylene, -C(O), -C(0)NH, -
  • X is (C 5 -C 14 )aryl
  • Y is independentiy selected from (C 2 -C 9 )heterocycle or (C 2 -C9)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, cyclopentyi, cyclohexyi, acetidinyl, piperazinyl, furanyl, pyridyl, pyrazolyl, pyridazinyl, pyrrolidinyi, thiazolyl, oxazolyl, thiophenyl, and thiomorpholinyl;
  • R and R 2 are each independentl -H, (C C 6 )alkyl, (d-C 6 )a!kylene, -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 4 R 1Q , -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 (d-C 6 )alkylene
  • R 5 is independently selected from -H and (Ci-C 6 )alkyl
  • R 6 is (d-Ce)alkyl
  • R 7 is -C(0)OR 5 ;
  • R a is -OR 5 ;
  • R 9 is halo
  • R 10 is -N(R 16 ) 2 ;
  • R 1 is independently selected from the group consisting of halo, (Ci-C 6 )alkyl, (d- 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 , (d-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 (CrC 6 )alkyl, oxo, halo, (C C 6 )alkoxy, -R 6 (R 9 ) q , -OR B (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, (CrC 6 )a!kyl, and -C(0)OR 5 .
  • 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 8 )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 2 , -OR 5 ,
  • R 1 and R 2 are each independently -H, (C C 6 )alkyl, (Ci-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 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 (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 4 (OH) 2) -C(0)C(0)R 8 , -C
  • Q is selected from the group consisting of -R R 7 R 8 ,-R 4 R 7 R 14 , and -R 4 C(0)R 8 ;
  • R 4 is (C r C 6 )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 1Q is -N(R 16 ) 2 ;
  • R 1 , R 2 , and R 13 are independently selected from the group consisting of oxo, halo, (Ci-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 ;
  • 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 and R 2 are each independently H, C-i-Ce-alkyl, f-butyloxycarbonyl, Me-S0 2 -, HOOCC(CH 3 )2CH 2 C(0)-, CH 3 C(0); (R 4 ) 2 N-(CH 2 ) m -, (R 5 ) n -phenyl-Q-,
  • R 6 q -Hetaryl-(CH 2 ) P -, (R 6 ) q -Hetalk-(CH 2 )r, or (R 6 ) q -Cycloalk-(CH 2 ) p -; or R 1 and R 2 , together with the nitrogen atom to which they are attached, form a 3- to 7- membered heterocycloalky! ring optionally substituted with a methy!sulfonyl group or up to two C-rC-4-alk l roups; each R 4 is independently H or C-i-C-6-alkyl;
  • each R 5 is independently halo, C ⁇ Ce-alky!, Ci-C 6 -alkoxy, CF 3 , OCF 3 , N(CH 3 )2, or N0 2 ;
  • each R e is independently halo, C r C 6 -alky!, -COOH, -C(0)NH 2 ,
  • X is carbonyl
  • 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-cyclopropyldiyl, or 1 ,1 - cyclopentyldiyl;
  • Hetaryl is a 5-6-membered heteroaryl group
  • Hetalk is a 3-7-membered heterocycloalky! group
  • Cycloalk is a 3-6-membered cyc!oalkyl group
  • each m is independently 2 or 3;
  • each n is independently 0, , 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, dimethylaminoethyi, f-butyloxycarbonyl; e-S0 2 -, or HOOCC(CH 3 ) 2 CH 2 C(0)-;
  • R 2 is H; (R 5 )n-phenyl-Q-, (R 6 ) q -furanyl-(CH 2 )p-, (R 6 )q-pyridyl-(CH 2 )p- 1 (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 and R 2 , together with the nitrogen atom to which they are attached, form azetidinyl, piperidinyl, morpholino, thiomorpholino, piperazinyl, 4-methyl-piperazin- 1 -yi, 4-methylsulfonyl-piperazin-1-yl, 2,4-dimethyl-piperazin-l-yi, 4-methyi- diazepan-1-yl, 1-methyl-2-piperaz
  • each R 5 is independently methyl, methoxy, halo, CF 3l or OCF 3 ;
  • each R 6 is independently methyl, F, or CI
  • X is carbonyl
  • X is carbonyl and Y is methylene
  • R is H, methyl, i-butyloxycarbonyl; Me-S0 2 -, or dimethylaminoethyi;
  • 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-methylsulfonyl-piperazin-1-yl, 2,4-dimethyi-piperazin-1 -yI, 4-methyl-diazepan-1-yl, thiomorpholine- ,1 dioxide-4- yi; or pyrrolidinyl;
  • R 5 is methyl, methoxy, F, CI, CF 3 , or OCF 3 ; and q is 0 or 1
  • X is carbonyl and Y is carbonyl
  • R 1 is H, methyl, f-butyloxycarbonyl; Me-S0 2 -, or dimethylaminoethyl;
  • R 2 is H, (R 5 ) n -phenyi-(CH 2 )p- t ( 6 ) n -furany CH 2 ) q -, (R 6 )n-pyridyi-(CH 2 )c,-,
  • R 1 and R 2 together with the nitrogen atom to which they are attached, form azetidinyl, piperazinyl, 4-methyl-piperazin-l-yl, 4-methylsuifonyl-piperazin-1-yl, 2,4-dimethyl-piperazin-1 -yl, 4-methy!-diazepan-1-yl, thiomorpholine-1 ,1 dioxide-4- yl; or pyrrolidinyl;
  • R 5 is methyl, methoxy, F, CI, CF 3) or OCF 3 ;
  • q is 0 or 1 .
  • X is carbonyl and Y is carbonyl
  • R 1 is H, methyl, f-butyloxycarbonyl; Me-S0 2 -, or dimethyiaminoethyl;
  • R 2 is H, (R 5 ) n -phenyi-(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-l-yl, 4-methylsulfonyl-piperazin-1-yl, 2,4-dtmethyl-piperazin-1 -yl, 4-methyl-diazepan-1-yl, thiomorpholine- ,1 dioxide-4- yl; or pyrrolidiny!;
  • R 5 is methyl, methoxy, F, CI, CF 3 , or OCF 3 ;
  • q is 0 or 1 .
  • X is carbonyl and Y is methylene
  • R 1 is H, methyl, i-buty!oxycarbonyl; Me-S0 2 -, or dimethyiaminoethyl;
  • 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-methylsulfonyl-piperazin-1-yl, 2,4-dimethyl-piperazin-1 -yl, 4-methyl-diazepan-1-yl, thiomorpho!ine- ,1 dioxide-4- yl; or pyrrolidinyl;
  • R 5 is methyl, methoxy, F, CI, CF 3 , or OCF 3 ;
  • R 1 is H, CH3, or dimethylaminoethyl
  • X is carbonyl and Y is methylene
  • R is H, CH 3 , or dimethylaminoethyl
  • R 2 is (R )n-Phenyl-CH 2 ; thienyi-CH 2 -; furanyl-CH 2 ; pyridinyl-CH 2 -; and
  • X is carbonyl and Y is methylene
  • R 1 is H, CH 3 , or dimethylaminoethyl
  • R 2 is (R 5 ) n -phenyl-CH 2 ; thieny!-CH 2 -; furanyl-CH 2 ; pyridinyl-CH 2 -; and
  • R 3 is H0 ⁇ .
  • X is carbonyl and Y is methylene
  • R is H, CH3, or dimethylaminoethyl
  • R 2 is (R 5 ) n -phenyl-CH 2 ; thienyl-CH 2 -; furanyl-CH 2 ; pyridinyl-CH 2 -; and
  • composition comprising a) the compound of Formulas 1, II, or ill or a
  • a method of treating HIV comprising administering to a patient suffering therefrom an effective amount of the compound of Formulas I, II, III or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a compound having the structure:
  • Such compounds of the invention can exist in particular geometric or stereoisomer ⁇ 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.
  • 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 111.
  • the pharmaceutical formulation containing a compound of Formulas I, II, or III or a 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 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 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 Formulas I, I I, or II I 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, todoxii, 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 [oviride, immunocal, oltipraz, capravirine, !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 simi!ar agents;
  • Entry, attachment and fusion inhibitors such as enfuvirtide (T-20), T-1249,
  • Inteqrase 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- thiazolyl]-3,6-dioxo-8, 1 1-bis(phenylmethyl)-2, 4,7,12-tetraazatridecan-13-oic acid, 5- thiazolylmethyl 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.
  • Pgp P-gycoprotein
  • GS-9350 is a compound being developed by Gilead Sciences of Foster City
  • SPI-452 is a compound being developed by Sequoia Pharmaceuticals of
  • the combination is an oral fixed dose combination.
  • the compound of Formulas I, II, or III is formulated as a long acting parenteral injection and ritonavir is formulated as an oral composition.
  • the compound of Formulas I, l!, or III is formulated as a long acting parenteral injection and ritonavir is formulated as an injectable composition.
  • a compound of Formulas I, II, or III is used in combination with GS-9350.
  • the combination is an oral fixed dose combination
  • the compound of Formulas I, II, or Mi is formulated as a long acting parenteral injection and GS-9350 is formulated as an oral composition.
  • the compound of Formulas I, II, or III is formulated as a long acting parenteral injection and GS-9350 is formulated as an injectable composition.
  • the combination is an oral fixed dose combination.
  • the compound of Formulas I, II, or III is formuiated as a long acting parenteral injection and SPI-452 is formulated as an oral composition.
  • the compound of Formulas I, II, or III 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 I, II, or III.
  • 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;
  • Integrase inhibitors Maturation inhibitors; CXCR4 inhibitors; and CCR5 inhibitors.
  • the compound of the present invention or a pharmaceuticaily acceptable salt thereof, is chosen from the compounds set forth in Table 1

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Abstract

Disclosed are a compound characterized by the following formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising said compound or a pharmaceutically acceptable salt thereof, wherein R3, L, and A are as described in the application. Said compounds are useful for the treatment of HIV.

Description

CARBONYL DERIVATIVES OF BETULIN
FIELD OF THE INVENTION
The present invention relates to betulin deriviative 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
compounds.
BACKGROUND OF THE INVENTION
Presently, long-term suppression of viral replication with antiretroviral drugs is the only option for treating HIV-1 infection. To date, a number of approved drugs have been shown to greatly increase patient survival. However, therapeutic regimens known as highly active antiretroviral therapy (HAART) are often complex because a combination of different drugs must be administered to the patient to avoid the rapid emergence of drug-resistant HIV-1 variants. Despite the positive impact of HAART on patient survival, drug resistance can still occur.
The emergence of multidrug-resistant ( DR) HIV-1 isolates has serious clinical consequences and must be suppressed with a new drug regimen, known as salvage therapy. Current guidelines recommend that salvage therapy includes at least two, and preferably three, fully active drugs. Typically, 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. However, the options for this approach are often limited, as resistant mutations frequently confer broad cross-resistance to different drugs in the same class.
Alternative therapeutic strategies have recently become available with the development of fusion, entry, and integrase (IN) inhibitors. However, resistance to all three new drug classes has already been reported both in vitro and in vivo. Sustained successful treatment of HIV-1- infected patients with antiretroviral drugs will therefore require the continued development of new and improved drugs with new targets and mechanisms of action.
The HIV 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. Although the cleavage of the Gag polyprotein plays a central role in the progression of infectious virus particle production, to date, no antiretroviral drug has been approved for this mechanism.
In most cell types, assembly occurs at the plasma membrane, and the MA domain of
Gag mediates membrane binding. Assembly is completed by budding of the immature l 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 reduced HIV viral load by a mean of 1.3 log 0/mL in patients who achieved trough levels of >= 20 pg/mL and who did not have any of the key baseline Gag polymorphisms at Q369, V370 or T371. However, Bevirimat users with Gag polymorphisms at Q369, V370 or T371 demonstrated significantly lower load reductions than patients without Gag polymorphisms at these sites.
It would therefore be an advance in the art to discover alternative compounds that are maturation inhibitors. SUMMARY OF THE INVENTION
In accordance with one embodiment of the present invention, there is provided a compound of Formula !:
(I)
Figure imgf000003_0001
Formula I
or a pharmaceutically acceptable salt thereof, wherein:
L is selected from the group consisting of a (C^CeJalkylene, -C(O), -C(0)NH, -C(0)NHR4, -C(0)NHR15, -C(0)R4R10, -R NR1R2, -R NH, -R4NHC(0), -R4NHR4,
X is (C5-C14)aryl; Y is independently selected from (C2-Cg)heterocycle or (C2-C9)heteroaryl, each one to three heteroatoms selected from S, N or O;
Z is (C3-C7)cycloa!kyi;
A is selected from the group consisting of -NR1R2, -OR5,
Figure imgf000004_0001
Figure imgf000004_0002
R1 and R2 are each independently -H, (CrC6)alkyl, (CrC6)alkylene, -R4N(R5)2, -R R10, -R4X(R 1)m, -R"X, -C(O), -C(0)R6, -C(0)R8, -R4C(0)R10, -C(0)R R10, -C(0)OR5, -R NHC(0), -C(0)R NHC(0)R6, -R4R8R4R8, -C(0)R4(R8)2, -C(0)R4R3, -N(R5)2, -C(0)N(R5)2, -C(0)R4N(R5)2, -C(0)C(0)N(R5)2, -C(0)R4(OH)2, -C(0)C(0)R8, -C(0)R C{0)R5 and -OR8;
R3 is selected from the group consisting of -C(0)R4R7, -C(0)R4R7R8,
-C(0)R R7R14, and -C(0)R4C(0)R8;
R4 is (d-CeJalkylene;
R5 is independently selected from -H and (C C6)alkyi;
R6 is (CrCe)alkyl;
R7 is -C(0)OR5;
R8 is -OR5;
R9 is halo;
R10 is -N(R16)2;
R11, R1 Z, and R13 are independently selected from the group consisting of oxo, halo, (CrCe)alkoxy, -R6(R9)q, -OR6(R9)q, nitro, -S02R6, (Ci-C6)alkyl. -C(0)R1°, -R4YR6, and - CO(0)R5;
R14 is -OP(0)(OH)2;
Figure imgf000004_0003
Figure imgf000005_0001
Formula I
or a pharmaceutically acceptable salt thereof, wherein:
L is selected from the group consisting of a (CrC6)alkylene, -C(O), -C{0)NH,
-C(0)NHR4, -C(0)NHR15, -C(0)R4R1°, -R4NR1 R2, -R4NH, -R4NHC(0), and -R4NHR4;
X is (C5-C14)aryl;
Y is independently selected from (C2-C9)heterocycle or (C2-C8)heteroaryl, each having one to three heteroatoms selected from S, N or O;
Z is (C3-C7)cycloalkyl;
A is selected from the group consisting of -NR R2, -OR5, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acetidinyl, piperazinyl, furanyi, pyridyl, pyrazolyl, pyridazinyl, pyrrolidinyl, thiazolyl, oxazoiyl, thiophenyl, and thiomorpholinyl;
R and R2 are each independently -H, (C C6)alkyl, (C C6)alkylene, -R N(R5)2l -R4R10, -R4X(R11)m, -R4X, -C(O), -C(0)R6, -C(0)R8, -R C(0)R10, -C(0)R4R10, -C(0)OR5,
-R4NHC(0), -C(0)R NHC(0)R6, -R R8R4R8, -C(0)R4(R8)2, -C(0)R4R8, -N(R5)2, -C(0)N(R5)2, -C(0)R N(R5)2, -C(0)C(0)N{R5)2, -C(0)R4(OH)2, ~C(O)C(0)Ra, -C(0)R4C(0)R5 and -OR8;
R3 is selected from the group consisting of -C(0)R4R7, -C(0)R4R7R8,
-C(0)R4R7R14, and -C(0)R4C(0)Ra;
R4 is (C C6)alkylene;
R5 is independently selected from -H and (CrCeJalkyl;
R6 is (CrC6)alkyl;
R7 is -C(0)0R5;
R8 is -OR5;
R9 is halo;
R10 is -N(R16)2;
R11 is independently selected from the group consisting of halo, (CrC6)alkyl, (C C6)alkoxy, -R6{R9)q, -OR6(R9)q, and nitro;
R12 is independently selected from the group consisting of -S02R6, (C!-C^alkyl, - C(0)R10, -R4YR6, -CO(0)R5, and oxo; R13 is independently selected from the group consisting of (CrC6)alkyl, oxo, halo, (C C6)alkoxy, -R6(R9)q, -OR6(R9)p, nitro, -S02R6, (C C6)alkyl, -C(0)R10, -R4YR6, and - CO(0)R5;
R14 is -OP(0)(OH)2;
Figure imgf000006_0001
R is selected from the group consisting of -H, (CrC6)alkyi, and -C(0)OR .
[0002] In a further embodiment of the present invention, there is provided a compound of Formula I:
! O (I)
Figure imgf000006_0002
Formula I
or a pharmaceutically acceptable salt thereof, wherein:
L is selected from the group consisting of a (CrC6)a!kylene, -C(O), -C(0)NH, ~C(0)NHR4, -C(0)NHR15, -C(0)R4R10, -R NR1R2, -R4NH, -R4NHC(0), -R4NHR4,
X is (C5-C14)aryl;
Y is independently selected from (C2-C9)heterocyc[e or (C2-C9)heteroaryl, each having one to three heteroatoms selected from S, N or O;
Z is (C3-C7)cycioalkyl;
A is selected from the group consisting of -NR R2, -OR5,
Figure imgf000006_0003
R1 and R2 are each independently -H, (C C6)alkyi, (C C6)alkylene, -ReN( 6)2l -R4R10, -R X(R1 )m, -R"X, -C(O), -C(0)R6, -C(0)R8, -R4C(0)R10, -C(0)R4R10, -C(0)OR5,5 -R NHC(0), -C(0)R4NHC(0)R6, -R R6R4R8, -C(0)R4(R8)2, -C(0)R4Rs, -N(R5)2, -C(0)N(R5)2) -C(0)R4N(R5)2l -C(0)C(0)N(Rs)2, -C(0)R (OH)2, -C(0)C(0)Ra, -C(0)R C(0)R5 and -OR8; R3 is selected from the group consisting of -C(0)R4R7, -C(0)R4R7RB, -C(0)R4R7R14, and -C(0)R C(0)R8;
R4 is (CrC6)alkylene;
R5 is independently selected from -H and (C1-C6)alkyl;
R6 is (C C6)alkyl;
R7 is -C(0)OR5;
R8 is -OR5;
R9 is halo;
R10 is -N(R16)2;
R11, R12, and R13 are independently selected from the group consisting of oxo, halo, (CrCe)alkoxy, -R6(R9)q, -OR6(R9)q, nitro, -S02R6, (C C6)alkylt -C(0)R10, -R4YR6, and - CO(0)R5;
R14 is -OP(0)(OH)2;
Figure imgf000007_0001
R16 is selected from the group consisting of -H, (C C6)alkyl, and -C(0)OR5;
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; and
q is an integer selected from 1 , 2, or 3.
[0003] In a further embodiment of the present invention, there is provided a compound of Formula I:
(I)
Figure imgf000007_0002
Formula I
or a pharmaceutically acceptable salt thereof, wherein:
L is selected from the group consisting of a (CrC6)alkylene, -C(O), -C(0)NH, -C(0)NHR4, -C(0)NHR15, ~C(0)R4R10, -R4NR1R2, -R4NH, -R4NHC(0), and -R4NHR4; X is (C5-Cu)aryl;
Y is independently selected from (C2-C9)heterocycle or (C2-Cg)heteroaryi, each having one to three heteroatoms selected from S, N or O;
Z is {C3-C7)cycloalkyl;
A is selected from the group consisting of -NR1R2, -OR5, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acetidinyl, piperazinyl, furanyl, pyridyl, pyrazolyl, pyridazinyl, pyrrolidinyl, thiazolyl, oxazolyl, thiophenyl, and thiomorpholinyl;
R1 and R2 are each independently -H, (C C6)a!kyl, (C C6)aikylene, -R4N(R5)2, -R R10, -R4X(R11)m, -R4X, -C(O), -C(0)R6, -C{0)R8, -R4C(0)R10, -C(0)R R10, -C(0)OR5, -R4NHC(0), -C(0)R4NHC(0)R6, -R4R8R RB, -C(0)R4(R8)2> -C(0)R4R8, -N(R5)2l -C(0)N(R5)2, -C(0)R4N(R5)2, -C(0)C(0)N{R5)2, -C(0)R4(OH)2> -C(0)C(0)R8, -C(0)R4C(0)R5 and -OR8;
R3 is selected from the group consisting of -C(0)R R7, -C(0)R4R7R8,
-C(0)R4R7R14, and -C(0)R4C(0)R8;
R4 is (C C6)alkylene;
R5 is independently selected from -H and (C C6)a]kyl;
R6 is (CrC6)alkyl;
R7 is -C(0)OR5;
R8 is -OR5;
R9 is halo;
R10 is -N(R16)2;
R1 is independently selected from the group consisting of halo, (CrCe)alkyl, (C C6)alkoxy, -R6(R9)q, -OR6(R9)q, and nitro;
R12 is independently selected from the group consisting of -S02R6, (CrC6)alkyl, - C(0)R10, -R4YR6, -CO(0)R5, and oxo;
R13 is independently selected from the group consisting of (Ci-C6)alkyl, oxo, halo,
(C C6)aikoxy, -R6(R9)q, -OR6(R9)q, nitro, ~S02R6, (CVC^alkyl, -C(0)R10, -R4YR6, and - CO(0)R5;
R14 is -OP(0)(OH)2;
Figure imgf000008_0001
R16 is selected from the group consisting of -H, (C-rCeJalkyl, and -C(0)ORj 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; and
q is an integer selected from 1 , 2, or 3. [0004] !n a further embodiment of the present invention, there is provided a compound of Formula II:
(ID
Figure imgf000009_0001
Formula II
or a pharmaceutically acceptable salt thereof, wherein:
L is selected from the group consisting of a (Ci-C6)a!kylene, -C(O), -C(0)NH, -C{0)NHR4, -C(0)NHR15, -C(0)R R10, -R4NR1 2, -R4NH, -R4NHC(0), -R4NHR4,
X is (C5-C14)aryl;
Y is independently selected from (C2-C9)heterocycle or (C2-C9)heteroaryl, each having one to three heteroatoms selected from S, N or O;
Z is (C3-C7)cycloalkyl;
. (R11)m
A is selected from the group consisting of -NR1R2, -OR5,
Figure imgf000009_0002
R1 and R2 are each independently -H, (C1-C6)alkyl, (CrC6)a!kylene, ~R4N(R5)2, -R R10, -R4X(R11)m, -R X, -C(O), -C{0)R6, -C(0)R8, -R4C(0)R1°, -C(0)R R10, -C(0)OR5, -R NHC(0), -C(0)R4NHC(0)R6, -R4R8R4R8, -C(0)R4(R8)2, -C(0)R4R8, -N(R5)2, -C(0)N(Rs)2 -C(0)R N(R5)2, -C(0)C(0)N(R5)2, -C(0)R4(OH)2, -C(0)C(0)R3, -C(0)R C(0)Rs and -OR8;
R3 is selected from the group consisting of -C(0)R4R7, -C(0)R R7R8,
-C(0)R4R7R14, and -C(0)R4C(0)R8;
R4 is (CrCe)alkylene;
R5 is independently selected from -H and (C C6)a!kyl;
R6 is (CrCe)alkyl;
R7 is -C(0)OR5;
R8 is -OR5;
R9 is halo; s R 0 is -N(R 6)2;
R 1 , R12, and R13 are independently selected from the group consisting of oxo, halo, (C C6)alkoxy, -R6(R9)q,
Figure imgf000010_0001
-C(0)R10, -R4YR6, and - CO(0)R5;
R14 is -OP(0)(OH)2;
Figure imgf000010_0002
R16 is selected from the group consisting of -H, (CrC6)alkyl, and -C(0)OR5;
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; and
q is an integer selected from 1 , 2, or 3,
[0005] In a further embodiment of the present invention, there is provided compound of Formula II:
(II)
Figure imgf000010_0003
Formula II
or a pharmaceutically acceptable salt thereof, wherein:
L is selected from the group consisting of a (CrC6)aikylene, -C(O), -C(0)NH, -C(0)NHR4, -C(0)NHR15, -C(0)R4R1°, -R4NR1R2, -R NH, -R4NHC(0), and -R NHR4;
X is (C5-C14)aryl;
Y is independently selected from (C2-Cg)heterocycle or (C2-C9)heteroaryl, each having one to three heteroatoms selected from S, N or O;
spiro ring Z is (C3-C7)cycloalkyl;
A is selected from the group consisting of -NR1R2, -OR5, phenyl, cyclopropy!, cyclobutyl, cyclopenty!, cyclohexy!, acetidinyl, piperazinyl, furanyl, pyridyl, pyrazolyl, pyridazinyl, pyrrolidinyl, thiazolyl, oxazolyl, thiophenyl, and thiomorpholinyl; R1 and R2 are each independently -H, (Ci-C6)alkyl, (C C6)alkylene, -R4N(R5)2, -R4R10, -R4X{R11)m, -R4X, -C(O), -C(0)R6, -C(0)R8, -R C(0)R10, -C(0)R4R10, -C(0)OR5, -R NHC(0), -C(0)R4NHC(0)R6, -R4R8R4R8, -C(0)R4(R8)2l -C(0)R R8, -N(R5)2, -C(0)N(Rs)2, -C(0)R4N(Rs)2, -C(0)C(0)N(R5)2j -C(0)R4(OH)2, -C(0)C(0)R8, -C(0)R4C(0)R5 and -OR8;
R3 is selected from the group consisting of -C(0)R R7, -C(0)R4R7R8,
-C(0)R4R7R14, and -C(0)R4C(0)R8;
R4 is (CrC6)alkylene;
R5 is independently selected from -H and (CrC6)alkyl;
R6 is (d-CeJalkyl;
R7 is -C(0)OR5;
R8 is -OR5;
R9 is halo;
R10 is -N(R16)2;
R11 is independently selected from the group consisting of halo, (CVCeJalkyl, (d- C6)alkoxy, -Rfi(R9)q, -OR6(R9)pi and nitro;
R12 is independently selected from the group consisting of -S02R6, (C C6)alkyl, - C(0)R10, -R YR6, -CO(0)R5, and oxo;
R13 is independently selected from the group consisting of (Ci-C6)alkyl, oxo, halo, (C1-C6)aikoxy, -R6(R9)q, -OR6(R9)q, nitro, -S02R6, (C C6)alkyl, -C(0)R °, -R4YR6, and - CO(0)R5;
R14 is -OP(0)(OH)2;
16
R 5 is ; and
R16 is selected from the group consisting of -H, (CrCeJalkyl, and -C(0)OR5. [0006] in a further embodiment of the present invention, there is provided a compound of Formula II I:
Figure imgf000011_0001
i O Formula 111
or a pharmaceutically acceptable salt thereof, wherein:
L is selected from the group consisting of a (C-|-C6)alkylene, -C(O), -C(0)NH, -C(0)NHR4, -C(0)NHR15, -C(0)R4R10, -R4NR RZ, -R4NH, -R4NHC(0), -R4NHR4,
X is (C5-C14)aryl;
Y is independently selected from (C2-C9)heterocycle or {C2-C9)heteroaryi, each having one to three heteroatoms selected from S, N or O;
Z is (C3-C7)cycloalkyl;
A is selected from the group consisting of -NR1R2,
Figure imgf000012_0001
Figure imgf000012_0002
R1 and R2 are each independently -H, (C1-C6)alkyl, (Ci-CeJalkylene, -R4N(R5)2l -R R10, -R4X(R11)m, -R4X, -C(O), -C(0)R6, -C(0)Rs, -R4C(0)R10, -C(0)R4R1°, -C(0)OR5, -R4NHC(0), -C(0)R4NHC(0)R6, -R R8R4Ra, -C(0)R (R8)2> -C(0)R4R8, -N(R5)2, -C(0)N(R5)2, -C(0)R4N(R5)2, -C(0)C(0)N(R5)2, -C(0)R4(OH)2l -C(0)C{0)Re, -C(0)R4C(0)R5 and -OR8;
Q is selected from the group consisting of -R4R7RB,-R4R7R14, and -R C(0)R8;
R4 is (CrC6)alkylene;
R5 is independently selected from -H and (d-C6)alkyl;
R6 is (C C6)aikyl;
R7 is -C(0)OR5;
R8 is -OR5;
R9 is halo;
R 0 is -N(R16)2;
R1\ R12, and R13 are independently selected from the group consisting of oxo, halo, (d-CeJalkoxy, -R6(R9)q, -OR6(R9)q, nitro, -S02R6, (Ci-Ce)alkyl, -C(0)R1°, -R4YR6, and - CO(0)R5;
R14 is -OP(0)(OH)2;
Figure imgf000012_0003
R16 is selected from the group consisting of -H, (CrC6)alkyl, and -C(0)OR5;
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; and q is an integer selected from 1 , 2, or 3.
In a second aspect, the present invention relates to a composition comprising a) the compound of Formulas I, II, or III or a pharmaceutically acceptable salt thereof; and b) a pharmaceutically acceptable excipient.
In a third aspect, the present invention is a method of treating HIV comprising administering to a patient suffering therefrom an effective amount of the compound of Formulas I, II, or III or a pharmaceutically acceptable salt thereof.
Compounds of the present invention are useful for the treatment of patients with HIV.
DETAILED DESCRIPTION OF REPRESENTATIVE EMBODIMENTS
[0007] Throughout this application, references are made to various embodiments relating to compounds, compositions, and methods. The various embodiments described are meant to provide a variety of illustrative examples and should not be construed as descriptions of alternative species. Rather it should be noted that the descriptions of various embodiments provided herein may be of overlapping scope. The embodiments discussed herein are merely illustrative and are not meant to limit the scope of the present invention.
[0008] It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention. In this specification and in the claims that follow, reference will be made to a number of terms that shall be defined to have the following meanings.
[0009] As used herein unless otherwise specified, "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. "(Cx-Cy)alkyl" refers to alkyl groups having from x to y carbon atoms. The term "alkyllncludes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl {(CH3)2CH-), n-buty! (CH3CH2CH2CH2-), isobutyl ((CH3)2CHCH2-), sec-butyl ((CH3)(CH3CH2)CH-), f-butyf ((CH3)3C-), n-pentyl (CH3CH2CH2CH2CH2-), and neopentyl ((CH3)3CCH2-)- [0010] "Alkylene" or "alkyiene" refers to divalent saturated aliphatic hydrocarbyl groups having from 1 to 0 carbon atoms and, in some embodiments, from 1 to 6 carbon atoms. "(Cu-Cv)alkylene" refers to alkylene groups having from u to v carbon atoms. The alkylene groups include branched and straight chain hydrocarbyl groups. For example, "(C^ C6)alkylene" is meant to include methylene, ethylene, propylene, 2-methypropylene, dimethylethylene, pentylene, and so forth. As such, the term "propylene" could be
Figure imgf000013_0001
. Likewise, the term "dimethy!butylene1 ould be exemplified by any of the following three structures or more:
Figure imgf000014_0001
Figure imgf000014_0002
is meant to include such branched chain hydrocarbyl groups as cyclopropylmethylene, which could be
Figure imgf000014_0003
exemplified by the following structure:
[0011] "Alkenyl" refers to a linear or branched hydrocarbyl group having from 2 to 10 carbon atoms and in some embodiments from 2 to 6 carbon atoms or 2 to 4 carbon atoms and having at least 1 site of vinyl unsaturation (>C=C<). For example, (Cx-Cy)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.
10012] "Alkynyl" refers to a linear monovalent hydrocarbon radical or a branched monovalent hydrocarbon radical containing at least one triple bond. The term "alkynyl" is also meant to include those hydrocarbyl groups having one triple bond and one double bond.
For example, (C2-C6)alkynyl is meant to include ethynyl, propynyl, and the like.
[0013] "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, and n-pentoxy.
[0014] "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 CH3C(0)-.
[0015] "Acylamino" refers to the
groups -NR20C(O)a!kyl, -NR20C(O)cycloalkyl, -NRZ0C(O)alkenyl, -NR20C(O)alkynyl, -NR20C( OJary!, -NRz0C(O)heteroaryl, and -NR2DC(0)heterocyclic, wherein R20 is hydrogen or alkyl.
[0016] "Acyloxy" refers to the groups alky|-C(0)0-, alkenyl-C(0)0-, aikynyl-C(0)0-, aryl-C(0)0-, cycloalkyl-C(0)0-, heteroaryl-C(0)0-, and heterocyclic-C(0)0-.
[0017] "Amino" refers to the group -NR21 R22 where R21 and R22 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl,
heterocyclic, -S02-alkyl, -S02-alkenyl, -S02-cycloalkyl, -SOz-aryl, -S02-heteroaryl, and -S02-heterocyciic, and wherein R21 and R 2 are optionally joined together with the nitrogen bound thereto to form a heterocyclic group. When R21 is hydrogen and R22 is alkyl, the amino group is sometimes referred to herein as alkylamino. When RZ1 and R Z are alkyl, the amino group is sometimes referred to herein as dialkylamino. When referring to a
I 3 rnonosubstituted amino, it is meant that either R or R22 is hydrogen but not both. When referring to a disubstituted amino, it is meant that neither R21 nor R22 are hydrogen.
[0018] "Hydroxyamino" refers to the group -NHOH.
[0019] "A!koxyamino" refers to the group -NHO-alkyl wherein alkyl is defined herein.
[0020] "Aminocarbonyl" refers to the group -C(0)NR26R27 where R26 and R27 are independently selected from hydrogen, a!kyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclic, hydroxy, alkoxy, amino, and acylamino, and where R26 and R27 are optionally joined together with the nitrogen bound thereto to form a heterocyclic group.
[0021] "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). For multiple ring systems, including fused, bridged, and spiro ring systems having aromatic and non-aromatic rings that have no ring heteroatoms, 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).
[0022] "Cyano" or "nitrile" refers to the group -CN.
[0023] "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. For multiple ring systems having aromatic and non-aromatic rings that have no ring heteroatoms, the term "cycloalkyl" applies when the point of attachment is at a non-aromatic carbon atom (e.g. 5,6,7,8,-tetrahydronaphthalene-5- yl). The term "Cycloalkyl" includes cycloalkenyl groups, such as cyclohexenyl. Examples of cycloalkyl groups include, for instance, adamantyl, cyclopropyl, cyc!obutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl, and cyclohexenyl. Examples of cycloalkyl groups that include multiple bicycloalkyl ring systems are bicyclohexyl, bicyclopentyl, bicyclooctyl, and the like. Two such bicycloalkyl multiple ring structures are exemplified and named below:
Figure imgf000015_0001
bicyclohexyl, and bicyclohexyl.
[0024] "(Cu.Cv)cycloalkyl" refers to cycloalkyl groups having u to v carbon atoms.
[0025] "Spiro cycloalkyl" 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 cycloalkyl group:
Figure imgf000016_0001
[0026] "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:
Figure imgf000016_0002
[0027] "Carboxy" or "carboxyl" refers interchangeably to the groups OH t
OH
O , -C(0)0, or -C02.
[0028] "Halo" or "halogen" refers to fluoro, chloro, bromo, and todo.
[0029] "Haloalkoxy" refers to substitution of a!koxy 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. trifiuoromethoxy).
[0030] "Hydroxy" or "hydroxyl" refers to the group -OH.
[0031] "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). For multiple ring systems, including fused, bridged, and spiro ring systems having aromatic and non-aromatic rings, 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. 1 ,2,3,4-tetrahydroquinolin-6-yl and 5,6,7,8-tetrahydroquinolin-3-yl). In some embodiments, the nitrogen and/or the sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide for the N-oxide (N→0), suifinyl, or sulfonyl moieties. More specifically the term heteroaryl includes, but is not limited to, pyridyl, furanyl, thienyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, imidazolinyl, isoxazoiyi, pyrrolyl, pyrazolyl, pyridazinyl, pyrimidiny!, purinyl, phtha!azyl, naphthylpryidyl, benzofuranyl, tetrahydrobenzofuranyl, isobenzofuranyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, indolyl, isoindolyl, indolizinyl, dihydroindolyl, indazolyl, indolinyl, benzoxazolyl, quino!yl, isoquinolyl, quinolizyl, quianazolyl, quinoxalyl, tetrahydroquinolinyl, isoquinolyl,
quinazolinonyl, benzimidazolyl, benzisoxazolyl, benzothienyl, benzopyridazinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, acridinyl, phenanthrolinyl, phenazinyl, phenoxazinyl, phenothiazinyl, and phthalimidyl.
[0032] "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", "heterocycloalkyl", or "heterocyclyl" apply 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). in one embodiment, 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. More specifically the heterocyclyl includes, but is not limited to, tetrahydropyranyi, piperidinyl, piperazinyl, 3-pyrrolidinyl, 2-pyrrolidon-1-yl, morpholinyl, and pyrrolidinyl. A prefix indicating the number of carbon atoms (e.g., C3-C10) refers to the total number of carbon atoms in the portion of the heterocyclyl group exclusive of the number of heteroatoms.
[0033] Examples of heterocycle and heteroaryl groups include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, pyridone, indolizine, isoindole, indole, dihydroindo!e, 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-tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene, benzo[b]thiophene, morpholine, thiomorpholine (also referred to as thiamorpholine), piperidine, pyrrolidine, and tetrahydrofuranyl.
[0034] "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 cycloa!kyl 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:
Figure imgf000017_0001
[0035] "Compound", "compounds", "chemical entity", and "chemical entities" as used herein 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.
[0036] The term "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.
[0037] "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:
Figure imgf000018_0001
[0038] "Racemates" refers to a mixture of enantiomers. In an embodiment of the invention, the compounds of Formulas I, II, or I II, or pharmaceutically acceptable salts thereof, are enantiomerically enriched with one enantiomer wherein all of the chiral carbons referred to are in one configuration. In general, 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.
[0039] "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. In certain embodiments, solvents are volatile, non-toxic, and/or acceptable for administration to humans in trace amounts. Suitable solvates include water.
[0040] "Stereoisomer" or "stereoisomers" refer to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and
diastereomers.
[0041 ] "Tautomer" refer to alternate forms of a compound that differ in the position of a proton, such as enol-keto and imine-enamine tautomers, or the tautomeric forms of heteroaryl groups containing a ring atom attached to both a ring -NH- moiety and a ring =N- moiety such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles.
[0042] 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
!7 ref]. One skilled in the art will recognize that upon installing a nonsymmetrical R to core, the formation of atropisomers is possible. In addition, once a second chiral center is installed in a given molecule containing an atropisomer, the two chiral elements taken together can create diastereomeric and enantiomeric stereochemical species. Depending upon the substitution about the Cx axis, interconversion between the atropisomers may or may not be possible and may depend on temperature. In some instances, 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. When known, 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,
[0043] "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, Camilfe G.
Wermuth (Eds.), Handbook of Pharmaceutical Salts Properties, Selection, and Use; 2002.
[0044] "Patient" refers to mammals and includes humans and non-human mammals.
[0045] "Treating" or "treatment" of a disease in a patient refers to ) 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.
[0046] 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
pharmaceutically acceptable salt thereof (in combination).
[0047] Unless indicated otherwise, the nomenclature of 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. For example, the substituent "arylalkyloxycarbonyi" refers to the group (aryl)-(aikyl)-0-C(0)-. In a term such as "-C(R*)2", it should be understood that the two Rx groups can be the same, or they can be different if Rx is defined as having more than one possible identity. In addition, certain substituents are drawn as -RxRy, where the "-" indicates a bond adjacent to the parent molecule and Ry being the terminal portion of the functionality. Similarly, it is understood that the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluoro groups). Such impermissible substitution patterns are well known to the skilled artisan.
In accordance with one embodiment of the present invention, there is provided a compound of Formula I:
(I)
Figure imgf000020_0001
Formula I
or a pharmaceutically acceptable salt thereof, wherein:
L is selected from the group consisting of a (C -CeJaikylene, -C(O), -C(0)NH, -C(0)NHR4, -C(0)NHR15, -C(0)R4R1°, -R4NR1R2, -R4NH, -R4NHC(0), -R4NHR4,
X is (C5-C14)aryl;
Y is independently selected from (Cz-Cgjheterocycle or (C2-C9)heteroaryl, each having one to three heteroatoms selected from S, N or O;
Z is (C3-C7)cycioalkyl; A is selected from the group consisting of -NR R2, -OR5,
Figure imgf000020_0002
Figure imgf000020_0003
R1 and R2 are each independently -H, (d-C6)alkyl, (C C6)alkylene, -R4N(R5)2, -R R10, -R4X(R11)m, -R4X, -C(O), -C(0)R6, -C(0)RB, -R4C(0)R10, -C(0)R4R1°, -C(0)OR5, -R4NHC(0), -C(0)R4NHC(0)R6, -R4R6R4RB, -C(0)R (R8)2, -C(0)R4RB, -N(R5)2, -C(0)N(Rs)2, -C(0)R4N(R5)2, -C(0)C(0)N(R5)2, -C(0)R4(OH)2, -C(0)C(0)R8, -C(0)R C(0)R5 and -OR8;
R3 is selected from the group consisting of -CiOJR^R7, -C(0)R4R7R8,
-C(0)R R7R14, and -C(0)R4C(0)RB;
R4 is (C C6)a!kylene; R5 is independently selected from -H and (C-i-C6)alkyl;
R6 is (Ci-CB)alkyl;
R7 is -C(0)OR5;
R8 is -OR5;
R9 is halo;
R10 is -N(R16)2;
R1 1 , R12, and R13 are independently selected from the group consisting of oxo, halo, {C C6)alkoxy, -R6(R9)q, -OR6(R9)q, nitro, -S02R6, (d-CeJalkyl, -C(0)R10, -R4YR6, and - CO(0)R5;
R14 is -OP(0)(OH)2;
Figure imgf000021_0001
Formula I
or a pharmaceutically acceptable salt thereof, wherein:
L is selected from the group consisting of a (C-i-C6)alkylene, -C(O), -C(0)NH, -C(0)NHR4, -C(0)NHR15, -C(0)R R10, -R4NR R2, -R4NH, -R4NHC(0), and -R4NHR4;
X is (C5-C14)aryl;
Y is independently selected from (C2-C9)heterocycle or (C2-C9)heteroaryl, each having one to three heteroatoms selected from S, N or O;
Z is (C3-C7)cycloalkyl;
A is selected from the group consisting of -NR1 R2, -OR5, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acetidinyl, piperazinyl, furanyl, pyridyl, pyrazolyl, pyridazinyl, pyrrolidinyl, thiazolyl, oxazolyl, thiophenyi, and thiomorpholinyl; R1 and R2 are each independently -H, (Ci-C6)alkyl, (d-CeJaikylene, -R4N(R5)2, -R R10, -R4X(R11)m, -R4X, -C(0), -C(0)R6, -C(0)R8, -R4C(0)R10, -C(0)R4R1°, -C<0)OR5, -R4NHC(0), -C(0)R4NHC(0)R6, -R R8R4R8, -C(0)R (R8)2, -C(0)R R8, -N(R5)2, -C(0)N{R5)2, -C(0)R N(R5)2, -C(0)C(0)N(R5)2) -C(0)R4(OH)2l -C(0)C(0)R8, -C(0)R4C(0)R5 and -OR8;
R3 is selected from the group consisting of -C(0)R4R7, -C(0)R4R7R8,
-C(0)R4R7R14, and -C(0)R4C(0)R8;
R4 is (CrCe)alkylene;
R5 is independently selected from -H and (Ci-C6)alkyl;
R6 is (C C6)aikyl;
R7 is -C(0)OR5;
R8 is -OR5;
R9 is halo;
R10 is -N(R16)2;
R11 is independently selected from the group consisting of halo, (CrC6)alkyi, (C C6)alkoxyt -R6(R9)q, -OR6(R9)q, and nitro;
R12 is independently selected from the group consisting of ~S02R6, (Ci-C6)aikyl, - C(0)R10, -R YR6, -CO(0)R5, and oxo;
R13 is independently selected from the group consisting of (CrCeialkyl, oxo, halo, (CrC6)alkoxy, -R6(R9)q,
Figure imgf000022_0001
nitro, -S02R6, (CrC6)alkyl, -C(0)R10, -R4YR6, and - CO(0)R5;
R14 is -OP(0)(OH)2;
Figure imgf000022_0002
R16 is selected from the group consisting of -H, (Ci-C6)aikyl, and -C(0)OR5.
[0049] In a further embodiment of the present invention, there is provided compound of Formula I:
(0
Figure imgf000022_0003
Formula I
or a pharmaceutically acceptable salt thereof, wherein:
L is selected from the group consisting of a (CrC6)alkylene, -C(O), -C(0)NH, ~C{0)NHR4, -C(0)NHR15, -C(0)R4R10, -R4NR1R2, -R4NH, -R4NHC(0), -R4NHR4,
X is (C5-C1 )aryl;
Y is independently selected from (C2-C9)heterocycle or (C2-C9)heteroaryl, each having one to three heteroatoms selected from S, N or O;
Z is (C3-C7)cycloalkyl;
,-'"~\ (R 1)m
A is selected from the group consisting of -NR R , -0R5, ¾
Figure imgf000023_0001
R1 and R2 are each independently -H, (C Ce)aikyl, (CrC6)alkylene, -R4N(R5)2, -R4R10, -R4X(R11)m, -R4X, -C(O), -C(0)R6, -C(0)R8, -R C(0)R10, -C(0)R R10, -C(0)OR5, -R4NHC(0), -C(0)R NHC(0)R6, -R R8R R8, -C(0)R (R8)2, -C(0)R4R8, -N(R5)2, -C(0)N(R5) -C(0)R4N{R5)2, -C(0)C(0)N(Rs)2l -C(0)R4(0H)2l -C(0)C(0)R8, -C(0)R C(0)R5 and -OR8;
R3 is selected from the group consisting of -C(0)R4R7, -C{0)R4R7R8, -C(0)R R7R and -C(0)R4C(0)R8;
R4 is (C C6)alkylene;
R5 is independently selected from -H and (C C6)alkyl;
R6 is (CrCe)alkyl;
R7 is -C(0)OR5;
R8 is -OR5;
R9 is halo;
R10 is -N(R16)2;
R11, R 2, and R13 are independently selected from the group consisting of oxo, halo (C C6)alkoxy, -R6(R9)q, -OR6(R9)q, nitro, -S02R6, (d-CeJalkyl, -C(0)R10, -R4YR6, and - CO(0)R5;
R14 is -OP(0)(OH)2;
Figure imgf000023_0002
R16 is selected from the group consisting of -H, (CrC6)alkyl, and -C(0)OR5 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; and
q is an integer selected from 1 , 2, or 3.
[0050] In a further embodiment of the present invention, there is provided a compound of Formula I:
(l)
Figure imgf000024_0001
Formula I
or a pharmaceutically acceptable salt thereof, wherein:
L is selected from the group consisting of a (d-CeJalkyiene, -C(O), -C(0)NH, -C(0)NHR4, -C(0)NHR15, -C(0)R4R10, -R4NR1 R2, -R4NH, -R4NHC(0), and -R4NHR4;
X is (C5-C14)aryl;
Y is independently selected from (C2-C9)heterocycle or (C2-C9)heteroaryl, each having one to three heteroatoms selected from S, N or O;
Z is (C3-C7)cycloalkyl;
A is selected from the group consisting of -NR1 R2, -OR5, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acetidinyl, piperazinyl, furanyl, pyridyl, pyrazoly!, pyridazinyl, pyrrolidinyl, thiazolyl, oxazolyl, thiophenyl, and thiomorpholinyl;
R1 and R2 are each independently -H, (Ci-C6)alkyi, (C C6)alkyiene, -R4N(R5)2,
-R R10, -R X(R11 )m, -R4X, -C(O), -C(0)R6, -C(0)R8, -R4C(0)R10, -C(0)R R10, -C(0)OR5, -R NHC(0), -C(0)R NHC(0)R6, -R4R8R4R8, -C(0)R4(R8)2, -C(0)R4R8, -N(R5)2, -C(0)N(R5)2, -C(0)R4N(Rs)2, -C(0)C(0)N(R5)2, -C(0)R (OH)2, -C(0)C(0)R8, -C(0)R4C(0)R5 and -OR8;
R3 is selected from the group consisting of -C(0)R4R7, -C(0)R4R7R8,
-C{0)R4R7R14, and -C(0)R C(0)R8;
R4 is (C C6)alky!ene;
R5 is independently selected from -H and (C C6)aikyl;
R6 is (d-CeJalkyl;
R7 is ~C(0)ORs;
R8 is -OR5;
R9 is halo;
R D is -N(R16)2; R1 is independently selected from the group consisting of halo, (C C6)alkyl, (C C6)alkoxy, -R6(R9)q, -OR6(R9)p, and nitro;
R12 is independently selected from the group consisting of -S02R6, (C C6)alkyl, - C(0)R10, -R YR6, -CO(0)R5, and oxo;
R13 is independently selected from the group consisting of (C C6)aikyl, oxo, halo, (C C6)alkoxy, -R6(R9)q, -OR6(R9)q, nitro, -S02R6, (C1-C6)alkyl, -C(0)R10, -R4YR6, and - CO(0)R5;
R14 is -OP(0)(OH)2;
Figure imgf000025_0001
R B is selected from the group consisting of -H, (C CB)alkyl, and -C(0)OR5; 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; and
q is an integer selected from 1 , 2, or 3.
[0051] In a further embodiment of the present invention, there is provided a compound of Formula II:
(ll)
Figure imgf000025_0002
Formula II
or a pharmaceutically acceptable salt thereof, wherein:
L is selected from the group consisting of a {C C6)alkylene, -C(O), -C(0)NH, -C(0)NHR4, -C(0)NHR15, -C(0)R4R10, -R4NR R2, -R4NH, -R NHC(0), -R4NHR4,
X is (C5-C14)aryl;
Y is independently selected from (C2-C9)heterocycle or (C2-C9)heteroaryl, each having one to three heteroatoms selected from S, N or O;
Z is (C3-C7)cyc!oalkyl;
Figure imgf000026_0001
R1 and R2 are each independently -H, (Ci-CB)alkylp (Ci-C6)a[kylene, -R4N(R5)2, -R4R10, -R X(R11)m, -R4X, -C(O), -C(0)R6, -C(0)R8, -R4C{0)R10, -C(0)R4R10, -C(0)OR5, -R4NHC(0), -C(0)R NHC(0)Re, -R4R8R4RB, -C(0)R (R8)2, -C(0)R4R8, -N(R5)2, -C(0)N(R5)2, -C(0)R4N(R5)2r -C(0)C(0)N<R5)2, -C(O)R (0H)2, -C(0)C(0)R8, -C(0)R C(0)R5 and -OR8;
R3 is selected from the group consisting of -CO{0)R R7, -CO(0)R4R7R8,
-CO(0)R4R7R14, and -CO(0)R C(0)R8;
R4 is (CrCeJalkylene;
Rs is independently selected from -H and (C -C6)alkyi;
R6 is (CrC6)alkyl;
R7 is -C(0)OR5;
R8 is -OR5;
R9 is halo;
R 0 is -N(R16)2;
R11, R12, and R13 are independently selected from the group consisting of oxo, halo, (C C6)alkoxy, -R6{R9)q, -OR6(R9)p, nitro, -S02R6, (d-C6)a!kyl, -C(0)R10, -R4YR6, and - CO(0)R5;
R 4 is -OP(0)(OH)2;
Figure imgf000026_0002
R 6 is selected from the group consisting of -H, (C C6)alkyl, and -C(0)OR5;
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; and
q is an integer selected from 1 , 2, or 3.
[0052] In a further embodiment of the present invention, there is provided a compound of Formula II:
Figure imgf000027_0001
Formula II
or a pharmaceutically acceptable salt thereof, wherein:
L is selected from the group consisting of a (CrC6)alkylene, -C(O), -C(0)NH, -
C{0)NHR\ -C(0)NHR15, -C(0)R R10, -R4NR1R2, -R4NH, -R NHC{0), and -R4NHR4;
X is (C5-C14)aryl;
Y is independentiy selected from (C2-C9)heterocycle or (C2-C9)heteroaryl, each having one to three heteroatoms selected from S, N or O;
spiro ring Z is (C3-C7)cycloalkyl;
A is selected from the group consisting of -NR1R2, -OR5, phenyl, cyclopropyl, cyclobutyl, cyclopentyi, cyclohexyi, acetidinyl, piperazinyl, furanyl, pyridyl, pyrazolyl, pyridazinyl, pyrrolidinyi, thiazolyl, oxazolyl, thiophenyl, and thiomorpholinyl;
R and R2 are each independentl -H, (C C6)alkyl, (d-C6)a!kylene, -R4N(R5)2, -R4R10, -R4X(R1 )m, -R4X, -C(O), -C(0)R6, -C(0)R8, -R C(0)R10, -C(0)R4R1Q, -C(0)OR5,
-R4NHC(0), -C(0)R4NHC(0)R6, -R4R8R4R8, -C(0)R4(R8)2, -C(0)R R8, -N(R5)2l -C(0)N(R5)2, -C(0)R4N(Rs)2> -C(0)C(0)N(R5)2, -C(0)R4(OH)2, -C(0)C(0)R8, -C(0)R4C(0)R5 and -OR8;
R3 is selected from the group consisting of -C(0)R4R7, -C(0)R4R7R8,
-C(0)R4R7R14, and -C(0)R4C(0)R8;
R4 is (d-C6)alkylene;
R5 is independently selected from -H and (Ci-C6)alkyl;
R6 is (d-Ce)alkyl;
R7 is -C(0)OR5;
Ra is -OR5;
R9 is halo;
R10 is -N(R16)2;
R1 is independently selected from the group consisting of halo, (Ci-C6)alkyl, (d- C6)alkoxy, -R6(R9)q, -OR6(R9)q, and nitro;
R12 is independently selected from the group consisting of -S02R6, (d-C6)alkyl, - C(0)R10, -R4YR6, -CO(0)R5, and oxo; R13 is independently selected from the group consisting of (CrC6)alkyl, oxo, halo, (C C6)alkoxy, -R6(R9)q, -ORB(R9)q, nitro, -S02R6, (C C6)alkyl, -C(0)R10, ~R4YR6, and - CO(0)R5;
R14 is -OP(0)(OH)2;
Figure imgf000028_0001
R16 is selected from the group consisting of -H, (CrC6)a!kyl, and -C(0)OR5.
[0053] In a further embodiment of the present invention, there is provided a compound of Formula III:
(III)
Figure imgf000028_0002
Formula III
or a pharmaceutically acceptable salt thereof, wherein:
L is selected from the group consisting of a (C-|-C6)alkylene, -C(O), -C(0)NH, -C{0)NHR4, -C(0)NHR15, -C(0)R4R10, -R4NR R2, -R4NH, -R4NHC(0), -R NHR4,
X is (C5-C14)aryl;
Y is independently selected from (C2-C8)heterocycle or (C2-C9)heteroaryl, each having one to three heteroatoms selected from S, N or O;
Z is (C3-C7)cycloalkyl;
A is selected from the group consisting of -NR R2, -OR5,
Figure imgf000028_0004
R1 and R2 are each independently -H, (C C6)alkyl, (Ci-C6)alkylene, -R4N(R5)2) -R4R10, -R4X(R11)m, -R4X, -C(O), -C(0)R6, -C(0)R8, -R4C(0)R10, -C(0)R R10, -C(0)OR5, -R4NHC(0), -C(0)R NHC(0)R6, -R R8R4R8, -C(0)R (R8)2, -C(0)R4R8, -N(R5)2, -C(0)N(R5)2, -C(0)R4N(R5)2l -C(0)C(0)N(R5)2, -C(0)R4(OH)2) -C(0)C(0)R8, -C(0)R C(0)R5 and -OR8;
Q is selected from the group consisting of -R R7R8,-R4R7R14, and -R4C(0)R8;
R4 is (CrC6)alkylene;
R5 is independently selected from -H and (C C6)alkyl;
R6 is (d-CeJalkyl;
R7 is -C(0)OR5;
R8 is -OR5;
R9 is halo;
R1Q is -N(R16)2;
R1 , R 2, and R13 are independently selected from the group consisting of oxo, halo, (Ci-C6)alkoxy, -R6(R9)q> -OR6(R9)q, nitro, -S02R6, (CrC6)alkyl, -C(0)R10, -R YR6, and - CO(0)R5;
R14 is -OP(0)(OH)2;
Figure imgf000029_0001
R16 is selected from the group consisting of -H, (C C6)alkyl, and -C(0)OR5;
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; and
q is an integer selected from 1 , 2, or 3.
[0054] in a further embodiment of the present invention, there is provided a compound of Formula IV:
IV
Figure imgf000029_0002
or a pharmaceutically acceptable salt thereof, wherein:
R and R2 are each independently H, C-i-Ce-alkyl, f-butyloxycarbonyl, Me-S02-, HOOCC(CH3)2CH2C(0)-, CH3C(0); (R4)2N-(CH2)m-, (R5)n-phenyl-Q-,
(R6)q-Hetaryl-(CH2)P-, (R6)q-Hetalk-(CH2)r, or (R6)q-Cycloalk-(CH2)p-; or R1 and R2, together with the nitrogen atom to which they are attached, form a 3- to 7- membered heterocycloalky! ring optionally substituted with a methy!sulfonyl group or up to two C-rC-4-alk l roups;
Figure imgf000030_0001
each R4 is independently H or C-i-C-6-alkyl;
each R5 is independently halo, C^Ce-alky!, Ci-C6-alkoxy, CF3, OCF3, N(CH3)2, or N02;
each Re is independently halo, CrC6-alky!, -COOH, -C(0)NH2,
dimethylaminomethyl, or 1-methyi-4-piperazinylmethyl,
X is carbonyl;
Y is each independently methylene or carbonyl;
Q is -(CH2)P-, -C(O)-, -NH-C(O)-, -CH(CH3)-, -C(CH3)2-, 1 ,1-cyclopropyldiyl, or 1 ,1 - cyclopentyldiyl;
Hetaryl is a 5-6-membered heteroaryl group;
Hetalk is a 3-7-membered heterocycloalky! group;
Cycloalk is a 3-6-membered cyc!oalkyl group;
each m is independently 2 or 3;
each n is independently 0, , or 2;
each p is independently 0 or 1 ;
each q is independently 0, 1 , or 2; and
each r is independently 0, 1 , 2, 3, or 4.
[0055] In a further embodiment of the present invention, there is provided a compound of Formula IV:
IV
Figure imgf000030_0002
or a pharmaceutically acceptable salt thereof, wherein: R1 is H, methyl, dimethylaminoethyi, f-butyloxycarbonyl; e-S02-, or HOOCC(CH3)2CH2C(0)-;
R2 is H; (R5)n-phenyl-Q-, (R6)q-furanyl-(CH2)p-, (R6)q-pyridyl-(CH2)p-1 (R6)q-thienyl- (CH2)P-, 1 -methyl pyrazol-3-yl, Hetalk-(CH2)r, or C3-C6-cycloalkyl-(CH2)p-, or R and R2, together with the nitrogen atom to which they are attached, form azetidinyl, piperidinyl, morpholino, thiomorpholino, piperazinyl, 4-methyl-piperazin- 1 -yi, 4-methylsulfonyl-piperazin-1-yl, 2,4-dimethyl-piperazin-l-yi, 4-methyi- diazepan-1-yl, 1-methyl-2-piperazinon-4-yl, thiomorpholine-1 ,1 dioxide-4-yl; or pyrrolidinyl; and
each R5 is independently methyl, methoxy, halo, CF3l or OCF3;
each R6 is independently methyl, F, or CI; and
X is carbonyl.
[0056] In a further embodiment of the present invention, there is provided a compound of Formula IV:
IV
Figure imgf000031_0001
or a pharmaceutically acceptable salt thereof, wherein:
X is carbonyl and Y is methylene;
R is H, methyl, i-butyloxycarbonyl; Me-S02-, or dimethylaminoethyi;
R2 is H, (R5)n-phenyl-(CH2)p-, (R6)n-furanyl-(CH2)q-, (R6)n-pyridyl-(CH2)q-,
(R6)q-thienyl-(CH2)p-, -methyl pyrazol-3-yl, pyrrolidinyl-(CH2)r,
4-methylpiperazinyl; N-methylpiperidin-4-yl; cyclopropyl-(CH2)p-, cyclohexyl- {CH2)P-, or cyclopentyl-(CH2)p-; or
R1 and R2, 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-dimethyi-piperazin-1 -yI, 4-methyl-diazepan-1-yl, thiomorpholine- ,1 dioxide-4- yi; or pyrrolidinyl;
R5 is methyl, methoxy, F, CI, CF3, or OCF3; and q is 0 or 1
[0057] In a further embodiment of the present invention, there is provided a compound of Formula IV:
!V
Figure imgf000032_0001
or a pharmaceutically acceptable salt thereof, wherein:
X is carbonyl and Y is carbonyl;
R1 is H, methyl, f-butyloxycarbonyl; Me-S02-, or dimethylaminoethyl;
R2 is H, (R5)n-phenyi-(CH2)p-t ( 6)n-furany CH2)q-, (R6)n-pyridyi-(CH2)c,-,
{R6)q-thienyl-(CH2)p-, 1 -methyl pyrazol-3-yl, pyrroIidinyl-(CH2)r-,
4-methylpiperazinyl; N-methylpiperidin-4-yl; cyclopropyl-(CH2)p-, cyclohexyl- (CH2) -, or cyc!opentyl-(CH2)P-; or
R1 and R2, together with the nitrogen atom to which they are attached, form azetidinyl, piperazinyl, 4-methyl-piperazin-l-yl, 4-methylsuifonyl-piperazin-1-yl, 2,4-dimethyl-piperazin-1 -yl, 4-methy!-diazepan-1-yl, thiomorpholine-1 ,1 dioxide-4- yl; or pyrrolidinyl;
R5 is methyl, methoxy, F, CI, CF3) or OCF3; and
q is 0 or 1 .
[0058] In a further embodiment of the present invention, there is provided a compound of Formula IV:
IV
Figure imgf000032_0002
or a pharmaceutically acceptable salt thereof, wherein:
X is carbonyl and Y is carbonyl;
R1 is H, methyl, f-butyloxycarbonyl; Me-S02-, or dimethyiaminoethyl;
R2 is H, (R5)n-phenyi-(CH2)p-, (R6)n-furanyl-(CH2)q-, {R6)n-pyridyl-(CH2)q-,
(R6)q~thienyl-(CH2)p-, 1 -methyl pyrazol-3-yl, pyrroiidinyl-(CH2)r>
4-methyl piperazinyl; N-methylpiperidin-4-yl; cyclopropyl-(CH2)p-, cyclohexyl- (CH2)P-, or cyclopenty!-(CH2)p-; or
R1 and R2, together with the nitrogen atom to which they are attached, form azetidinyl, piperazinyl, 4-methyl-piperazin-l-yl, 4-methylsulfonyl-piperazin-1-yl, 2,4-dtmethyl-piperazin-1 -yl, 4-methyl-diazepan-1-yl, thiomorpholine- ,1 dioxide-4- yl; or pyrrolidiny!;
R5 is methyl, methoxy, F, CI, CF3, or OCF3; and
q is 0 or 1 .
[0059] In a further embodiment of the present invention, there is provided a compound of Formula IV:
IV
Figure imgf000033_0001
or a pharmaceutically acceptable salt thereof, wherein:
X is carbonyl and Y is methylene;
R1 is H, methyl, i-buty!oxycarbonyl; Me-S02-, or dimethyiaminoethyl;
R2 is H, (R5)n-phenyl-(CH2)p-, (R6)n-furanyl-(CH2)q-, (R6)n-pyridyl-(CH2)q-,
(R6)q-thienyl-{CH2)p-, 1 -methyl pyrazol-3-yl, pyrrolidinyl-(CH2)r,
4-methylpiperazinyl; N-methylpiperidin-4-yf; cyclopropyl-(CH2)p-, cyciohexyl- {CH2)P-, or cyclopentyl-(CH2)p-; or
R1 and R2, 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, thiomorpho!ine- ,1 dioxide-4- yl; or pyrrolidinyl;
R5 is methyl, methoxy, F, CI, CF3, or OCF3; and
[0060] In a further embodiment of the present invention, there is provided a compound of Formula IV:
IV
Figure imgf000034_0001
a pharmaceutically acceptable salt thereof, wherein:
R1 is H, CH3, or dimethylaminoethyl;
2 is (R5)n-phenyl-CH2; thieny!-CH2-; furany!-CH2; pyridinyl-CH2
Figure imgf000034_0002
In a further embodiment of the present invention, there is provided of Formula IV:
IV
Figure imgf000034_0003
or a pharmaceutically acceptable salt thereof, wherein:
X is carbonyl and Y is methylene
R is H, CH3, or dimethylaminoethyl;
R2 is (R )n-Phenyl-CH2; thienyi-CH2-; furanyl-CH2; pyridinyl-CH2-; and
Figure imgf000035_0001
[0062] In a further embodiment of the present invention, there is provided a compound of Formula IV:
IV
Figure imgf000035_0002
or a pharmaceutically acceptable salt thereof, wherein:
X is carbonyl and Y is methylene;
R1 is H, CH3, or dimethylaminoethyl;
R2 is (R5)n-phenyl-CH2; thieny!-CH2-; furanyl-CH2; pyridinyl-CH2-; and
R3 is H0^ .
O
[0063] in a further embodiment of the present invention, there is provided a compound of Formula IV:
IV
Figure imgf000035_0003
or a pharmaceutically acceptable salt thereof, wherein:
X is carbonyl and Y is methylene;
R is H, CH3, or dimethylaminoethyl;
R2 is (R5)n-phenyl-CH2; thienyl-CH2-; furanyl-CH2; pyridinyl-CH2-; and
Figure imgf000036_0001
[0064] In a further embodiment of the present invention, there is provided a composition comprising a) the compound of Formulas 1, II, or ill or a
pharmaceutically acceptable salt thereof; and 2) a pharmaceutically acceptable excipient.
[0065] In a further embodiment of the present invention, there is provided a method of treating HIV comprising administering to a patient suffering therefrom an effective amount of the compound of Formulas I, II, III or a pharmaceutically acceptable salt thereof.
In further embodiments, the present invention relates to a compound having the structure:
Figure imgf000036_0002
Figure imgf000036_0003
[0066] Such compounds of the invention can exist in particular geometric or stereoisomer^ 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.
[0067] 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. Alternatively, where the molecule contains a basic functional group, such as an amino group, or an acidic functional group, such as a carboxyl group, 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).
[0068] In another embodiment of the invention, there is provided a compound of
Formulas 1, II, or III, wherein the compound or salt of the compound is used in the
manufacture of a medicament for use in the treatment of a viral infection in a human.
[0069] In another embodiment of the invention, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of a compound as defined in Formulas I, II, or 111.
[0070] In one embodiment, the pharmaceutical formulation containing a compound of Formulas I, II, or III or a salt thereof is a formulation adapted for parenteral administration. In another embodiment, the formulation is a long-acting parenteral formulation. In a further embodiment, the formulation is a nano-particle formulation.
[0071] 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 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. Alternatively, 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, I I, or II I 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.
[0072] As such, the compounds of the present invention may be used in combination with one or more agents useful in the prevention or treatment of HIV.
[0073] Examples of such agents include:
[0074] Nucleotide reverse transcriptase inhibitors such as zidovudine, didanosine, lamivudine, zalcitabine, abacavir, stavudine, adefovir, adefovir dipivoxil, fozivudine, todoxii, emtricitabine, alovudine, amdoxovir, elvucitabine, and similar agents;
[0075] Non-nucleotide reverse transcriptase inhibitors (including an agent having anti-oxidation activity such as immunocal, oltipraz, etc.) such as nevirapine, delavirdine, efavirenz, [oviride, immunocal, oltipraz, capravirine, !ersivirine, GSK2248761 , TMC-278, TMC-125, etravirine, and similar agents;
[0076] Protease inhibitors such as saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, fosamprenavir, brecanavir, darunavir, atazanavir, tipranavir, palinavir, lasinavir, and simi!ar agents;
[0077] Entry, attachment and fusion inhibitors such as enfuvirtide (T-20), T-1249,
PRO-542, PRO-140, TNX-355, B S-806, B S-663068 and BMS-626529, 5-Helix and similar agents;
[0078] Inteqrase inhibitors such as raltegravir, elvitegravir, GSK1349572,
GSK1265744 and similar agents;
[0079] Maturation inhibitors such as PA-344 and PA-457, and similar agents; and
[0080] 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/US03/39644, PCT/US03/39975, PCT/US03/39619, PCT/US03/39618,
PCT/US03/39740, and PCT/US03/39732, and similar agents.
[0081 ] The scope of 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. As noted, in such combinations the compounds of the present invention and other HIV agents may be administered separately or in conjunction. In addition, one agent may be prior to, concurrent to, or subsequent to the administration of other agent(s).
[0082] 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. Examples of such pharmacological enhancers (or
pharmakinetic boosters) include, but are not limited to, ritonavir, GS-9350, and SPI-452.
[0083] Ritonavir is 10-hydroxy-2-methyl-5-(1-methyethyl)-1-1 [2-{1-methylethyl)-4- thiazolyl]-3,6-dioxo-8, 1 1-bis(phenylmethyl)-2, 4,7,12-tetraazatridecan-13-oic acid, 5- thiazolylmethyl 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.
[0084] GS-9350 is a compound being developed by Gilead Sciences of Foster City
California as a pharmacological enhancer.
[0085] SPI-452 is a compound being developed by Sequoia Pharmaceuticals of
Gaithersburg, Maryland, as a pharmacological enhancer.
[0086] In one embodiment of the present invention, a compound of Formulas I, II, or
II! is used in combination with ritonavir. In one embodiment, the combination is an oral fixed dose combination. In another embodiment, the compound of Formulas I, II, or III is formulated as a long acting parenteral injection and ritonavir is formulated as an oral composition. In one embodiment, is a kit containing the compound of Formulas I, II, or 111 formulated as a long acting parenteral injection and ritonavir formulated as an oral composition. In another embodiment, the compound of Formulas I, l!, or III is formulated as a long acting parenteral injection and ritonavir is formulated as an injectable composition. In one embodiment, is a kit containing the compound of Formulas I, II, or III formulated as a long acting parenteral injection and ritonavir formulated as an injectable composition.
[0087] In another embodiment of the present invention, a compound of Formulas I, II, or III is used in combination with GS-9350. In one embodiment, the combination is an oral fixed dose combination, in another embodiment, the compound of Formulas I, II, or Mi is formulated as a long acting parenteral injection and GS-9350 is formulated as an oral composition. In one embodiment, is a kit containing the compound of Formulas I, II, or III formulated as a long acting parenteral injection and GS-9350 formulated as an oral composition. In another embodiment, the compound of Formulas I, II, or III is formulated as a long acting parenteral injection and GS-9350 is formulated as an injectable composition. In one embodiment, is a kit containing the compound of Formulas I, II, or III formulated as a long acting parenteral injection and GS-9350 formulated as an injectable composition.
[0088] In one embodiment of the present invention, a compound of Formulas I, II, or
III is used in combination with SPi-452. In one embodiment, the combination is an oral fixed dose combination. In another embodiment, the compound of Formulas I, II, or III is formuiated as a long acting parenteral injection and SPI-452 is formulated as an oral composition. In one embodiment, is a kit containing the compound of Formulas I, II, or III formulated as a long acting parenteral injection and SPI-452 formulated as an oral composition. In another embodiment, the compound of Formulas I, II, or III is formulated as a long acting parenteral injection and SPI-452 is formulated as an injectable composition. In one embodiment, is a kit containing the compound of Formulas I, li, or III formulated as a long acting parenteral injection and SPI-452 formulated as an injectable composition.
[0089] The above other therapeutic agents, when employed in combination with the chemical entities described herein, may be used, for example, in those amounts indicated in the Physicians' Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art.
[0090] In another embodiment of the invention, there is provided 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.
[0091] In another embodiment of the invention, there is provided 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.
[0092] In another embodiment of the invention, there is provided 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.
[0093] In another embodiment of the invention, there is provided 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 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;
Integrase inhibitors; Maturation inhibitors; CXCR4 inhibitors; and CCR5 inhibitors.
[0094] In further embodiments, the compound of the present invention, or a pharmaceuticaily acceptable salt thereof, is chosen from the compounds set forth in Table 1
Table 1
Figure imgf000041_0001
2,2-dimethyl~4-oxo-4-
{[(1 R.2R.5R, 10S, 13R, 14R, 17S, 19R)-
1 ,2,14,18,18-pentamethyl-7-oxo-5-
{oxo[(thiophen-2-
5 ylmethy!)carbamoyl]methyl}-8-(propai
2- yl)pentacyclo[1 .8.0.0Λ{2, 10}.0Λ{5,9}.0 Λ{14, 19}]henicos-8-en-17- yl]oxy}bu†anoic acid
4- {[(1 R,2R,5R,10S,13R,14R,17S,19R)-
5- ({[1 -(4- chlorophenyl)cyclopropyl]carbamoyl}(o xo)methyl)-1 ,2, 14,18, 18-pentamethyl-
6
7-oxo-8-(propan-2~
yl)pentacyclo[1 1.8.0.0A{2, 10}.0A{5,9}.0 Λ{14, 9}]henicos-8-en-17-yf]oxy}-2,2- dimethyl-4-oxobutanoic acid
4- {[( 1 R.2R.5R, 10S, 13R, 14R, 17S, 19R)-
5- ({[1 -(5-chloropyridin-2- yl)cyclopropyl]carbamoy]}(oxo)methyl)- 1 ,2, 14, 18, 8-pentamethyl-7-oxo-8-
7
(propan-2- yl)peniacyclo[1 1.8.0.0A{2, 10}.0A{5,9}.0 Λ{14, 19}]henicos-8-en-17-yi]oxy}-2,2- dimethyl-4-oxobutanoic acid
( 1 R,2R,5R, 10S, 13R, 14R, 17S, 19R)-5- ({[1-(4- ch!orophenyl)cyclopropyi]carbamoyl}(o xo)methyl)-1 ,2, 4, 18, 8-pentamethyl-
8 7-oxo-8-(propan-2- yl)pentacyclo[1 1.8.0.0A{2,10}.0A{5,9}.0 Λ{14, 19}]henicos-8-en-17-yl 1 -(2- hydroxyethyl) 2,2- dimethy!butanedioate
{[(4-
{[( 1 R,2R,5R, 10S, 3R, 14R, 17S, 19R)-5- ({[1-(4- chlorophenyl)cyclopropyl]carbamoyi}(o xo)methyl)-1 ,2, 14, 18, 18-pentamethyl-
9 7-oxo-8-(propan-2- yl)pentacyclo[1 1.8.0.0A{2,10}.0A{5,9}.0 Λ{ 4, 19}]henicos-8-en-17-yl]oxy}-2,2- dimethyl-4- oxobutanoyl)oxy]methoxy}phosphonic acid
{2-K4-
{[{I R^R.SR^ OS.I SR.^R.US. e i-S- ({[1-(4- chlorophenyl)cyclopropyl]carbamoyl}(o
10 xo)methyl)-1 ,2,14,18,18-pentamethyl- 7-oxo-8-(propan-2- yl)pentacyclo[1 1.8.0.0A{2,10}.0A{5,9}.0
A{14,19}]henicos-8-en-17-yl]oxy}-2,2- dimethyl-4- oxobutanoyl)oxy]ethoxy}phosphonic acid
4- {[( 1 R,2R,5R, 10S, 3R, 14R, 17S, 19R)-
5- (2-{[(4- chlorophenyl)methyl]amino}acetyl)- 1 ,2, 14, 18, 18-pentamethyl-7-oxo-8-
11 (propan-2- yl)pentacyclo[11.8.0.0Λ{2,10}.0Λ{5,9}.0 Λ{14, 9}]henicos-8-en-17-yl]oxy}~2,2- dimethyl-4-oxobutanoic acid;
trifluoroacettc acid
4- {[( 1 R.2R.5R, 10S, 13R, 14R, 17S, 19R)-
5- (2-{bis[2-
(dime†hy]amino)e†hyl]amino}acetyl)- , 2 , 4, 18 , 18-pen tamelhy]-7-oxo-8-
12 (propan-2- yl)peniacyclo[11.8.0.0A{2,10}.0A{5,9}.0 Λ{14, 19}]henicos-8-en-17-yl]oxy}-2,2~ dimethyl-4-oxobutanoic acid;
tris(trifluoroacetic acid)
4- {[(1 R,2R, 5R, 10S, 13R, 14R, 7S, 19R)-
5- (2-{[{4-chlorophenyl)methyl][2- (dimet ylamino)ethyl]amino}acety!)- 1 ,2, 14, 8, 18-pentamethyl-7-oxo-8-
13 (propan-2- yl)pentacyclo[1 .8.0.0Λ{2,10}.0Λ{5,9}.0 Λ{14, 19}]henicos-8-en-17-yi]oxy}-2,2- dimethyl-4-oxobutanoic acid;
bisftrifluoroacetic acid)
4- {[(1 R,2R,5R,10S,13R,14R,17S,19R)-
5- (2-{bis[(4- c lorophenyl)methyl]amino}acetyl)- 1 ,2, 14, 18, 18-pentamethyl-7-oxo-8-
14 (propan-2- yl)pentacyclo[11.8.0.0Λ{2, 10}.0Λ{5,9}.0 Λ{ 4, 19}]henicos-8-en-17-yl]oxy}-2,2- dimethyl-4-oxobutanoic acid;
trifluoroacetic acid
(1 R.2R.5R.1 OS, 13R, 14R, 17S, 19R)-5- (2-{[(4-chlorophenyl)methyi3[2- (dimethylamino)ethyl]amino}acetyl)- 1 ,2,14, 18, 8-pentamethyl-7-oxo-8-
15 (propan-2-
Figure imgf000043_0001
yl)pentacyc!o[1 .8.0.0Λ{2,10}.0Λ{5,9}.0
Λ{14, 19}]henicos-8-en-17-yl 1 -ethyl 2,2-dimethylbutanedioate;
bis(trifluoroace†ic acid)
Figure imgf000044_0001
trifluoroacetic acid 4- {[( 1 R,2R,5R, 10S, 13R, 14R, 17S, 19R)-
5- [2-(N-benzyl-2- hydroxyacetamido)acetyl]-
1 ,2, 14, 18, 18-pentamethyi-7-oxo-8-
22
(propan-2- yl)pentacyclo[11.8.0.0A{2,10}.0A{5,9}.0 Λ{14, 19}]henicos-8-en-17-yi]oxy}-2,2- dimethyl-4-oxobutanoic acid
2,2-dimethyl-4-oxo-4-
{[(1 R,2R,5R, 10S, 13R, 14R, 17S, 19R)-
1 ,2, 14, 18, 8-pentamethyl-5-[2-(4- met ylpiperazin-1 -yl)acetyl]-7-oxo-8-
23
(propan-2- y[)pentacyclo[1 .8.0.0Λ{2, 10}.0Λ{5,9}.0 Λ{14, 19}]henicos-8-en-17- yl]oxy}butanoic acid
4- {[( 1 R,2R,5R, 10S, 13R, 14R, 17S, 19R)-
5- {{[(4- chlorophenyl)methyl]carbamoyl}(oxo)m ethyl)-1 ,2, 14, 18, 18-pentamethyl-7-oxo-
24
8-(propan-2- yl)pentacyclo[11.8.0.0Λ{2,10}.0Λ{5,9}.0 Λ{14, 19}]henicos-8-en-17-yi]oxy}-2,2- dimethyl-4-oxobutanoic acid
4- i[(1 R,2R,5R,10S,13R,14R,17S,19R)-
5- ({[(2- chloropheny[)methyl]carbamoyl}(oxo)m ethyl)-1 ,2, 14, 18, 18-pentamethyl-7-oxo-
25
8-(propan-2- yl)pentacyclo[1 1.8.0.0A{2,10}.0A{5,9}.0 Λ{14, 19}]henicos-8-en-17-yl]oxy}-2,2- dimethyl-4-oxobutanoic acid
4- {[(1 R,2R,5R, 10S, 13R, 14R, 17S,19R)-
5- ({[(4- fluorophenyl)methyl]carbamoyl}(oxo)m ethyl)- 1 ,2, 4, 18, 18-pentamethyl-7~oxo-
26
8-(propan-2- yl)pentacyclo[1 ,8.0.0Λ{2,10}.0Λ{5,9}.0 Λ{14, 19}]henicos-8-en-17-yl]oxy}-2,2- dimeihy!-4-oxobutanoic acid
2,2-dimethyl-4-oxo-4-
{[(1 R,2R, 5R, 10S, 13R, 14R, 17S, 19R)-
1 ,2, 14, 18, 18-pentamethyl-7-oxo-5~
{oxo[(pyridin-4-
27 yimethyl)carbamoyl]methyl}"8-(propan- 2- yl)pentacyclo[11.8.0.0Λ{2,10}.0Λ{5,9}.0 Λ{14, 19}]henicos-8-en~17- ylloxy}butanoic acid 2,2-dimethy[-4-oxo-4- {[(1 R,2R,5R,10S,13R,14R,17S,19R)- 1 ,2, 14, 18, 18-pentamethyl-7-oxo-5- {oxo[(pyridin-2-
28 ylmethyl)carbamoyl]methyl}-8-(propan- 2- yl)pentacyclo[1 1.8.0.0A{2,10}.0A{5,9}.0 Λ{14, 19}]henicos-8-en-17- yl]oxy}butanoic acid
4- {[(1 R,2R,5R, 10S, 13R, 14R, 17S, 9R)-
5- ({[(3- chlorophenyl)methyl]carbamoyl}(oxo)m 8thyl)-1 ,2, 14, 18, 18-pentamethyl-7-oxo-
29
8-(propan-2- yl)pentacyclo[1 1.8.0.0A{2,10}.0A{5,9}.0 Λ{ 4, 19}]henicos-8-en-17-yl]oxy}-2,2- dimethy[-4-oxobutanoic acid
4- {[(1 R.2R.5R, 10S, 13R, 14R, 17S, 19R)-
5- ({[(4- methoxyphenyl)methyl]carbamoy[}(oxo )methyl)-1 ,2, 14, 18, 18-pentamethyl-7-
30
oxo~8-(propan-2- yl)pentacyclo[11.8.0.0A{2,10}.0A{5,9}.0 A{14, 19}]henicos-8-en-17-yl]oxy}-2,2- dimethyl-4-oxobutanoic acid
4-{[{1 R,2R,5R,10SJ13R,14R,17S,19R)-
Oc-
{[(cyclopropylmethyl)carbamoyl](oxo)m ethy!}-1 ,2, 14, 18, 18-pentamethy!-7-oxo-
31
8-(propan-2- yl)pentacyclo[1 .8.0.0A{2,10}.0A{5,9}.0 A{14, 19}]henicos-8-en-17-yl]oxy}-2,2- dimethyl-4-oxobutanoic acid
4- {[( 1 R.2R.5R, 10S, 13R, 14R, 17S, 19R)-
5- ({[(3- methoxyphenyl)methyl]carbamoyl}(oxo )methyl)-1 ,2, 4, 18, 18-pentamethyl-7-
32
oxo-8-(propan-2- yl)pentacycio[1 1.8.0.0A{2, 10}.0A{5,9}.0 A{14, 19}]henicos-8-en-17-yl]oxy}-2,2- dimethyl-4-oxobutanoic acid
2,2-dimethyl-4-oxo-4- {[(1 R,2R,5R,10S,13R,14R,17S,19R)- 1 ,2, 14, 18, 18-pentamethyl-7-oxo-5- {oxo[(pyridin-3-yl)carbamoyl]methyl}-8-
33
(propan-2- yl)pentacyclo[1 1.8.0.0A{2, 10}.0A{5,9}.0 A{14, 19}]henicos-8-en-17- yl]oxy}butanoic acid 2,2-dimethyl-4-oxo-4-
{[(1 R.2R, 5R, 10S, 13R, 14R, 1 S, 9R)-
1 ,2, 4, 18, 18-pentamethyl-7-oxo-5-
[oxo({[2-(pyrro!idin-1-
34 yl)ethyl]carbamoyl})methyl]-8-(propan-
2- yl)pentacyc!o[11 ,8.0.0Λ{2,10}.0Λ{5,9}.0 Λ{14, 19}]henicos-8-en-17- yl]oxy}butanoic acid
2,2-dimethyl-4-oxo-4-
{[( 1 R.2R.5R, 10S, 13 , 14R, 17S, 19R)- ,2, 14, 18, 18-pentamethyl-7-oxo-5-
[oxo({[3-(pyrrol'idin-1 -
35 yl)propyl]carbamoyl})methyl]-8-
(propan-2- y[)pentacyclo[11.8.0.0Λ{2,10}.0Λ{5,9}.0 Λ{14, 19}]henicos-8-en-17- yl]oxy}butanoic acid
2,2-dimethyl-4-oxo~4-
{[(1 R,2R,5R, 10S, 13R, 14R, 17S, 19R)- ,2, 14, 18, 18-pentamethyi-7-oxo-5-
{oxo[(pyridin-3-
36 ylmethyl)carbamoyl]methyl}-8-(propan- 2- yl)pentacycto[11.8.0.0A{2,10}.0A{5,9}.0 Λ{14, 19}]henicos-8-en-17- yl]oxy}butanoic acid
2,2-dimethyl-4-oxo-4- {[(1 R,2R,5R,10S,13R,14R, 17S,19R)- 1 ,2, 14, 18, 18-pentamethyl-5-{[( 1 - methyl- 1 H-pyrazol-3-
37 yl)carbamoyl](oxo)methyl}-7-oxo-8- (propan-2- yl)pentacycio[1 1.8.0.0A{2,10}.0A{5,9}.0 Λ{14, 19}]henicos-8-en-17- yl]oxy}butanoic acid
4- {[(1 R,2R,5R,10S,13R,14R,17S,19R)-
5- ({[{4- chlorophenyl)methyl](methyl)carbamoy l}{oxo)methy!)-1 ,2,14, 18,18-
38
pentamethyl-7-oxo-8-(propan-2- yi)pentacyclo[1 1.8.0.0A{2,10}.0A{5,9}.0 Λ{14, 19}]henicos-8-en-17-yl]oxy}-2,2- dimethyl-4-oxobutanoic acid
2 , 2-d i m ethyl-4-oxo-4- {[{1 R,2R,5R,10S,13R,14R, 17S,19R)- 1 ,2, 14, 18, 18-pentamethyl-7-oxo-5- {oxo[(2-phenylpropan-2-
39
yl)carbamoyl]methyl}-8-(propan-2- y!)pentacyclo[1 1.8.0.0A{2,10}.0A{5,9}.0 Λ{ 4, 19}]henicos-8-en-17- yl]oxy}butanoic acid 4- {[( 1 R,2R,5R, 0S, 13R.14R, 17S, 19R)-
5- [{cyclohexylcarbamoyl)(oxo)methyl]- 1 ,2, 14, 18, 18-pentamethyl-7-oxo-8-
40 (propan-2- yl)pentacyclo[1 1.8.0.0Λ{2, 10}.0Λ{5,9}.0 Λ{14, 19}]henicos-8-en-17-yl]oxy}-2,2- dimethyl-4-oxobutanoic acid
4-{[(1 R.2R.5R, 10S, 13R, 14R, 17S, 19R)- 5-
{[{cyclohexy!methyl)carbamoyl](oxo)me thyl}-1 ,2,14,18,18-pentamethyl-7-oxo
41
8-(propan-2- yl)pentacyclo[11.8.0.0Λ{2, 10}.0Λ{5,9}.0 Λ{14, 19}]henicos-8-en-17-yl]oxy}-2,2- dim8thyl-4-oxobutanoic acid
4- {[(1 R,2R,5R,10S,13R,14R,17Sl19R)-
5- ({[(2,4- dichlorophenyl)methyl]carbamoyi}(oxo) methyl)- 1 ,2, 14, 18, 18-pentamethyl-7-
42
oxo-8-(propan-2- yl)pentacyclo[ .8.0.0Λ{2,10}.0Λ{5,9}.0 Λ{14, 19}]henicos-8-en- 7-yl]oxy}-2,2- dimethyl-4-oxobutanoic acid
4- {[(1 R.2R.5R, 10S, 13R, 14R, 17S, 19R)-
5- ({[2-(4-chlorophenyl)propan-2- yl]carbamoyl}(oxo)methyl)-
1 ,2, 14, 18, 18-pentamethyl-7-oxo-8-
43
(propan-2- yi)pentacyclo[ .8.0.0Λ{2, 10}.0Λ{5,9}.0 Λ{14, 9}]henicos-8-en-17-yi]oxy}-2,2- dime†hyi-4-oxobutanoic acid
4- {[( 1 R.2R.5R, 10S, 13R, 14R, 17S, 19R)-
5- ({[{4-chlorophenyl)methyl][2- (dimethyiamino)ethyl]carbamoyl}(oxo) methyl)-1 ,2,14,18,18-pentamethyl-7-
44 oxo-8~(propan-2-
"Λ, yl)pentacyclo[11.8.0.0A{2,10}.0A{5,9}.0
Λ{14, 19}]henicos-8-en-17-yl]oxy}-2,2- dimethyl-4-oxobutanoic acid;
trifluoroacetic acid
4- {[( 1 Rt2R,5R, 10S, 13R,14R, 17S, 19R)-
5- ({[(2-chloro-4- f!uorophenyi)methyl]carbamoy[}(oxo)m ethyl)-1 ,2, 14, 18, 18-pentamethyl-7-oxo-
45
8-(propan~2- yl)pentacyclo[1 1.8.0.0A{2,10}.0A{5,9}.0 A{14, 19}]henicos-8-en- 7-yl]oxy}~2,2- dimethyl-4-oxobutanoic acid 4- {[( 1 R.2R.5R, 10S, 13R, 14R, 17S, 19R)-
5- {{[(2,6- dic lorophenyl)methyl]carbamoyl}(oxo) methyl)-1 ,2, 14, 18,18-pentamethyl-7-
46
oxo-8-(propan-2- yl)pentacyclo[11.8.0.0A{2,10}.0A{5,9}.0 Λ{14, 19}]henicos-8-en-17-yl]oxy}-2,2- dimethyl-4-oxobutanoic acid
4- {[( 1 R,2R,5R, 10S, 13R, 14R, 17S, 19R)-
5- {{[(2,4- difluorop enyl)methyl]carbamoyl}(oxo) methyl)-1 ,2,14,18,18-pentame†hyl-7-
47
oxo-8-(propan-2- y[)p8ntacyclo[1 .8.0.0Λ{2, 10}.0Λ{5,9}.0 Λ{14, 9}]henicos-8-en-17-yl]oxy}-2,2- dimet yl-4-oxobutanoic acid
4- {[(1 R,2R,5R,10S,13R,14R,17S,19R)-
5- ({[(2,6- dif!uorophenyl)methyl]carbamoy!}(oxo) methyl)-1 ,2, 14, 18, 18-pentamethy!-7-
48
oxo-8-(propan-2- yl)pentacyclo[1 1.8.0.0A{2,10}.0*{5,9}.0 Λ{14, 19}]henicos-8-en-17-yl]oxy}-2,2- dimethyl-4-oxobutanoic acid
4- {[( 1 R,2R,5R, 10S, 13R, 14R, 17S, 19R)-
5- {[(furan-2- ylmethyl)carbamoyl](oxo)methyl}- 1 ,2, 14, 18, 18-pentamethyi-7-oxo-8-
49
(propan-2- yl)pentacyclo[ .8.0.0Λ{2,10}.0Λ{5,9}.0 Λ{14, 19}]henicos-8-en-17-yl]oxy}-2,2- dimethyl-4-oxobutanoic acid
4- {[( 1 R.2R.5R, 10S, 13R, 14R, 17S, 19R)-
5- {{[(1 R)-1-(4- chlorophenyl)ethyl]carbamoyl}(oxo)met hyl)-1 ,2, 14, 18, 18~pentamethyf-7-oxo-8-
50
(propan-2- yl)pentacyclo[1 1.8.0.0A{2,10}.0A{5,9}.0 Λ{1 , 19}]henicos-8-en-17-yl]oxy}-2,2- dimethyl-4-oxobutanoic acid
4- {[( 1 R,2R,5R, 10S, 13R, 14R, 17S, 19R)-
5- ({[2-(dimethy[amino)ethyl][(4- fiuorophenyl)methyl]carbamoyl}(oxo)m ethyl)-1 ,2, 4,18,18-pentamethyl-7-oxo-
51
8-(propan-2- yi)pentacyclo[11.8.0,0Λ{2,10}.0Λ{5,9}.0 Λ{14, 19}]henicos-8-en-17-yl]oxy}-2,2- dimethyl-4-oxobutanoic acid 4- {[( 1 R,2R,5R, 10S, 13R, 14R, 17S, 19R)-
5- ({[2-(2-chlorophenyl)propan-2- yl]carbamoyl}(oxo)methyl)-
1 ,2, 14, 18, 18-pentamethyi-7-oxo-8-
52
(propan-2- yl)pentacyc!o[11.8.0.0Λ{2,10}.0Λ{5,9}.0 Λ{14, 19}] enicos-8-en- 7-yl]oxy}-2,2- dimethyl-4-oxobutanoic acid
4- {[{1 RJ2R,5R,10S,13R,14R,17Sl19R)-
5- ({[1-(2- chlorophenyl)ethyl]carbamoyl}(oxo)met hyl)-1 ,2,14,18,18-pentamethyl-7-oxo-8-
53
(propan-2- yl)pentacyclo[1 .8.0.0Λ{2, 10}.0Λ{5,9}.0 Λ{14, 19}]henicos-8-en-17-yl]oxy}-2,2~ dimethyl-4-oxobutanoic acid
4- {[(1 R,2R,5R,10S,13R,14R,17S,19R)-
5- ({[(2-chioro-6- fluorophenyi)methyl]carbamoyl}(oxo)m ethyl)-1 ,2,14,18,18-pentamet yl-7-oxo~
54
8-{propan-2- yl)pentacyclo[1 1 ,8.0.0Λ{2,10}.0Λ{5,9}.0 Λ{ 4, 19}]henicos-8-en-17- l]oxy}-2,2- dimethyl-4-oxobutanoic acid
4- {[(1 R,2R,5R, 10S, 13R, 14R, 17S, 19R)-
5- ({[(1 S)-1-(4- ch!orophenyl)ethyl]carbamoyl}(oxo)met hyl)-1 ,2, 14, 18, 18-pentamethyl-7-oxo-8-
55
(propan-2- yl)pentacyclo[1 1.8.0.0A{2,10}.0A{5,9}.0 Λ{14, 19}]henicos-8-en-17-yl]oxy}-2,2- dim6thy]-4-oxobutanoic acid
2,2-dim6thyi-4-oxo-4- {[(1 R,2R,5R,10S,13R,14R,17S,19R)- 1 ,2, 14, 18, 18-pentamethyl-5- {[methyl({[4-
56 {trifiuoromethyl)phenyl]methyl})carbam oyl](oxo)methyl}-7-oxo-8-(propan-2- yl)pentacyclo[11.8.0.0Λ{2,10}.0Λ{5,9}.0 Λ{14, 9}]henicos-8-en- 7- yl]oxy}butanoic acid
2,2-dimethyl-4-oxo-4-
{[(1 R.2R.5R, 10S, 3R, 14R, 17S, 9R)-
1 ,2,14,18,18-pentamethyl-7-oxo-5-
[oxo({[4-
57 {trifluoromethyl)phenyl]methyi}carbamo yi)methy!]-8-(propan-2- yl)p8ntacyclo[11.8.0.0Λ{2, 10}.0Λ{5,9}.0 Λ{14, 19}]henicos-8-en-17- yl]oxy}butanoic acid 4- {[(1 R,2R,5R, 10S, 13R, 14R, 17S, 9R)-
5- ({[(2,4-difluorophenyl)methyl][2- (dime†hylamino)ethyl]carbamoyl}(oxo) methyl)-1 ,2, 14, 18,18-pentamethyl-7-
58
oxo-8-(propan-2- yl)p8ntacyclo[ 1.8.0.0Λ{2, 10}.0Λ{5,9}.0 Λ{14, 19}]henicos-8-en-17-yi]oxy}-2,2- dimethyl-4-oxobutanoic acid
4- {[( 1 R^R^R, 10S, 13R,14R, 17S, 19R)-
5- ({[1-(4- chlorophenyl)cyclopenty]]carbamoyl}(o xo)methyl)-1 ,2, 14, 18, 18-pentamethyl-
59
7-oxo-8-(propan-2- yl)pentacyc!o[1 .8.0.0A{2,10}.0A{5,9}.0 Λ{ 4, 9}]henicos-8-en-17-yl]oxy}-2,2- dimethyl-4-oxobutanoic acid
4- {[( 1 R.2R.5R, 0S, 13R, 14R, 17S, 19R)-
5- ({[(4-chlorophenyl)methyi][2- (dimethy!amino)ethy!]carbamoyl}(oxo) methyl)-1 ,2, 14, 18, 18-pentamethyi-7-
60 oxo-8-(propan-2- yl)pentacyclo[11.8.0.0Λ{2,10}.0Λ{5,9}.0 Λ{14, 19}]henicos-8-en-17-yl]oxy}-2,2- dimethyl-4-oxobutanoic acid hydrochloride
2,2-dimethyl-4-oxo-4- {[(1 ^2^5^103,13^ 14^178,19^- 1 ,2, 14, 18, 18-pentamethyl-7-oxo-5- [oxo({[(S)-
61 phenyi(carboxy)methyl]carbamoyl})met hyl]-8-(propan-2- yl)pentacyclo[11.8.0.0Λ{2,10}.0Λ{5,9}.0 Λ{ 4, 19}]henicos-8-en- 7- yl]oxy}butanoic acid
2,2-dimethyl-4-oxo-4- {[(1 R,2R,5R,10S,13R,14R,17S,19R)- 1 ,2, 4, 8, 18-pentamethy!-7-oxo-5- [oxo({[(1 R)-1-
62 phenylethy!]carbamoyl})methyl]-8- (propan-2- yl)pentacyclo[1 1.8.0.0A{2,10}.0A{5,9}.0 Λ{14, 19}]henicos-8-en-17- y!]oxy}butanoic acid
4- {[(1 R,2R,5R,10S,13R.14R, 17S,19R)-
5- ({[(1 S)-1-(4- chlorophenyl)propyl]carbamoyl}(oxo)m ethyl)-1 ,2,14,18,18-pentamethyl-7-oxo-
63
8-(propan-2- yl)pentacydo[1 1.8.0.0A{2,10}.0A{5,9}.0 Λ{14, 19}]henicos-8-en-17~yl]oxy}-2,2- dimethyi-4-oxobutanoic acid 2,2-dimethyi-4-oxo-4- {[(1 R,2R,5R, 10S,13R, 14R,17S,19R)- 1 ,2, 14, 18, 18-pentamethyl-5-({[1 -(4- m6thylphenyl)cyclopropyl]carbamoyl}(o
64
xo)methyl)-7-oxo-8-(propan-2- yl)pentacyclo[1 1.8.0.0A{2,10}.0A{5,9}.0 Λ{14, 19}]henicos-8-en-17- yl]oxy}butanoic acid
4- {[(1 R,2R,5R,10S,13R,14R,17S,19R)-
5- ({[(1 )-1-(4- chlorophenyf)propyl]carbamoyl}(oxo)m ethyl)-1 ,2, 14, 18, 18~pentamethyl-7-oxo-
65
8-(propan-2- yl)pentacyclo[ 1.8.0.0A{2,10}.0A{5,9}.0 Λ{14, 19}]henicos-8-en-17-yl]oxy}-2,2- dimethyl-4-oxobu†anoic acid
( 1 R,2R,5R, 10S, 13R, 14R, 17S, 19R)-5- ({[(1 R)-1-(4- chlorophenyl)ethyl]carbamoyl}(oxo)met hyi)-1 ,2, 14, 18, 18-pentamethyl-7-oxo-8-
66
(propan-2- yl)pentacyclo[11.8.0.0A{2,10}.0A{5,9}.0 Λ{14, 19}]henicos-8-en~17-yl 1 -ethyl 2,2-dimethy!butanedioate
4- {[(1 R,2R,5R, 10S, 13R, 14R, 17S, 19R)-
5- ({[1-(3,4- dich[orophenyl)cyclopropyi]carbamoyl}( oxo)methy!)-1 ,2, 14, 18, 18-pentamethyl-
67
7-oxo-8-(propan-2- yl)pentacyclo[11.8.0.0Λ{2, 10}.0Λ{5,9}.0 Λ{14, 19}]henicos-8-en-17-yl]oxy}-2,2- dimethyl-4-oxobutanoic acid
2,2-dim8thyl-4-oxo-4-
{[(1 R,2R, 5R, 10S, 13R, 14R, 17S, 19R)-
1 ,2, 14, 18, 18-pentamethy!-5-({[{1 R)-1 -
(4-
68 methylphenyl)ethylJcarbamoyl}(oxo)me thyl)-7-oxo-8-(propan-2- yl)pentacyclo[11.8.0.0Λ{2,10}.0Λ{5,9}.0 Λ{14, 19}]henicos-8-en-17- yl]oxy}butanoic acid
4- {[(1 R.2R.5R, 10S, 13R, 14R, 17S, 19R)-
5- {{[(1 R)-1-(3,4- dichlorophenyl)ethyljcarbamoyl}(oxo)m ethyl)-1 ,2, 14, 18, 18-pentamethyl-7-oxo-
69
8-(propan-2- yl)pentacyclo[11.8.0.0Λ{2, 10}.0Λ{5,9}.0 Λ{14, 19}]henicos-8-en-17-yl]oxy}-2,2- dimethyl-4-oxobutanoic acid 4- {[(1 R,2R,5R, 10S, 13R, 14R, 17S, 19R)-
5- ({[1-(4- ch!orophenyl)cyclopropyl]carbamoyl}{o xo)methyl)-1 ,2,14,18,18-pentamethyl-
70
7-oxo-8-(propan-2- yl)pentacyclo[ 1.8.0.0A{2,10}.0A{5,9}.0 Λ{14, 19}]henicos-8-en-17-yl]oxy}-3,3- dimethyl-4-oxobutanoic acid
4- {[(1 R,2R, 5R, 10S, 13R, 14R, 17S, 19R)-
5- ({[1-{4-chloro-2- methoxypheny!)cyclopropyi]carbamoyl} (oxo)methyl)-1 ,2,14,18,18-
71
pentamethy!-7-oxo-8-(propan-2- y[)pentacyclo[ 1.8.0.0Λ{2, 10}.0Λ{5,9}.0 Λ{14, 19}]henicos~8-en-17-yl]oxy}-2,2- dim8thyl-4-oxobutanoic acid
4- {[(1 R,2R,5R,10S,13R,14R,17S,19R)-
5- {{[(1 R)-1-(4- chlorophenyI)ethyl]carbamoy]}(oxo)met hyl)-1 ,2, 14, 18, 18-pentamethy!-7-oxc~8-
72
(propan-2- yl)pentacyclo[11.8.0.ΟΛ{2,10}.0Λ{5,9}.0 Λ{14, 19}]henicos-8~en-17-yl]oxy}-3,3- dimethyl-4-oxobutanoic acid
4- {[(1 R,2R,5R,10S,13R,14R,17S,19R)-
5- ({[1 -(4-chloro-3- methoxypheny[)cyciopropyl]carbamoyl} {oxo)methy[)-1 ,2,14,18,18-
73
pentamethyl-7-oxo-8-(propan-2- yl)pentacyclo[1 1.8.0.0A{2,10}.0A{5,9}.0 Λ{14, 19}]henicos-8-en-17-yl]oxy}-2,2- dimethyl-4-oxobutanoic acid
4- {[(1 R,2R,5R,10S,13R,14R,17Sl19R)-
5- ({[1-(3,4- dichloropheny[)cyclopropyl]carbamoyl}( oxo)m8thyl)-1 ,2, 14, 18, 18-pentamethyl-
74
7-oxo-8-(propan-2- yl)pentacyclo[1 1.8.0.0A{2,10}.0A{5,9}.0 Λ{14, 19}]henicos-8-en-17-yl]oxy}-3,3- dimethy!-4-oxobutanoic acid
(1 R,2RJ5R,10S,13R,14R,17S,19R)-5- {{[1-(4- chlorophenyl)cyclopropyl]carbamoyl}(o xo)methyl)-1 ,2,14,18,18-pentamet yl-
75 7-oxo-8-(propan-2- yl)pentacyclo[1 1.8.0.0A{2,10}.0A{5,9}.0 Λ{1 , 19}]henicos-8-en-17-y[ 1 -[2-(2- hydroxyethoxy)et yl] 2,2- dimethy!butanedioate 1†
Figure imgf000054_0001
Figure imgf000055_0001
dimethyl-5-oxopentanoic acid
2,2-dimethyl-4-oxo-4-
{[(1 R,2R,5R, 10S, 13R, 14R, 17S, 19R)-
1 ,2, 14, 18, 18-pentamethyl-7-oxo-5-
[oxo({[(1S)-1-{pyridin-2-
87 y!)ethyl]carbamoy!})methyl]-8-(propan-
2- yl)pentacycio[1 1.8.0.0Λ{2, 10}.0Λ{5,9}.0 Λ{ 4, 19}]henicos-8-en-17- yl]oxy}butanoic acid; trifluoroacetic acid
2 , 2-d i m et h y l-4-oxo-4- {[(1 R,2R,5R,10S,13R,14R,17S,19R)- 1 ,2, 14, 18, 18-pentamethyl-7-oxo-5- [oxo({[1 -(pyridazin-3-
88 yl)cyclopropyl]carbamoyl})methy!]-8- (propan-2- yl)pentacyclo[11.8.0.0A{2,10}.0A{5,9}.0 A{14, 19}]henicos-8-en-17- yl]oxy}butanoic acid
2,2-dimethyi-4-oxo-4-
{[( 1 R,2R,5R, 10S, 13R, 14R, 17S, 19R)-
1 ,2,14,18,18-pentamethyl-7-oxo-5-
[oxo({[(1 R)-1-(pyridin-2-
89 yi)ethyl]carbamoyl})methyl]-8-(propan-
2~
yl)pentacyclo[1 1.8.0.0Λ{2, 10}.0Λ{5, 9}.0 Λ{14, 19}] enicos-8-en-17- yl]oxy}butanoic acid; trifiuoroacetic acid
2 , 2-d i methyl-4-oxo-4- {[<1 R,2R,5R,10S, 13R,14R,17S,19R)- 1 ,2, 14, 8, 18-pentamethyl-7-oxo-5- [oxo({[(1 R)-1-(pyrimidin-2-
90 yl)ethyl]carbamoyl})methyi]-8-(propan- 2- yl)pentacycio[ 1.8.0.0Λ{2,10}.0Λ{5,9}.0 Λ{14, 19}]henicos-8-en-17- yl]oxy}butanoic acid; trifluoroacetic acid
2,2-dimethyl-4-oxo-4-
{[(1 R,2R,5R,10S,13R,14R,17S,19R)-
1 ,2, 14, 18, 18-pentamethyl-7-oxo-5-
[oxo({[(1 S)-1-(pyrimidin-2-
91 y[)ethyl]carbamoyl})methyl]-8-(propan-
2- yl)pentacyclo[1 1.8.0.0A{2,10}.0A{5,9}.0 A{14, 19}]henicos-8-en-17- yl]oxy}butanoic acid; trifluoroacetic acid
Figure imgf000057_0001
4- {[( 1 R,2R,5R, 10S, 13R, 14R, 17S, 19R)-
5- {[(5-chloropyridin-2- yl)carbamoyl](oxo)methyl}- ,2, 14, 18, 18-pentamethyl-7-oxo-8-
98 (propan-2- yl)pentacyc!o[1 1.8.0.0A{2,10}.0A{5,9}.0 Λ{14, 19}]henicos-8-en-17-yl]oxy}-2,2- dimethyl-4-oxobutanoic acid;
trifluoroacetic acid
4- {[(1 R,2R,5R, 10S, 13R, 14R, 17S, 19R)-
5- ({[(1 S)-1-(3- chlorophenyl)ethyl]carbamoyl}(oxo)met hyl)-1 ,2, 14, 18, 18-p6ntamethyl-7-oxo-8-
99
(propan-2- yI)pentacyclo[11.8.0.0A{2,10}.0A{5,9}.0 Λ{14, 19}]henicos-8-en-17-yl]oxy}-2,2- dimethyi-4-oxobutanoic acid
4- {[(1 R,2R,5R,10S,13R,14R,17S,19R)-
5- ({[1-(5-chIoropyrirnidir 2- yl)cyclopropyl]carbamoyl}(oxo)methyl)- 1 ,2, 14, 18, 18-pentamethyl-7-oxo-8-
100 (propan-2- yl)pen†acyclo[1 1.8.0.0Λ{2, 10}.0Λ{5, 9}.0 Λ{14, 19}]henicos-8-en-17-y!]oxy}-2,2- dimethyl-4-oxobutanoic acid;
trifluoroacetic acid
4- {[(1 R,2R,5R,10S,13R,14R,17S,19R)-
5- ({[1-(3- chlorophenyl)cyclopropyl]carbamoyl}(o xo)methyl)-1 ,2, 14, 8, 18-pentamethyl-
101
7-oxo-8-(propan-2- yl)pentacyclo[1 1.8.0.0A{2,10}.0A{5,9}.0 Λ{14, 19}]henicos-8-en-17-yl]oxy}-2,2- dimethyl-4-oxobutanoic acid
2, 2-d i methy]-4-oxo-4-
{[( 1 R.2R.5R, 10S, 13R, 14R, 17S, 19R)-
1 ,2, 4, 18, 18-pentamethyi-5-{[(4- methylphenyl)carbamoyl](oxo)methyl}-
102
7-oxo-8-(propan-2-
Figure imgf000058_0001
yl)pentacycIo[11 ,8.0.0Λ{2,10}.0Λ{5,9}.0
Λ{14, 9}]henicos-8-en-17- y|]oxy}butanoic acid
4- {[(1 R,2R,5R,10S,13R,14R,17S,19R)-
5- ({[(1R)-1-(2- chlorophenyl)ethyl]carbamoyl}(oxo)met hyl)-1 ,2, 14, 18, 18-pentamethyl-7-oxo-8-
103
(propan-2- yl)pentacyclo[11.8.0.0Λ{2, 10}.0Λ{5,9}.0 Λ{14, 9}]henicos-8-en-17-yl]oxy}-2,2- dimethy!-4-oxobutanoic acid 4- {[(1 R,2R, 5R, 10S, 13R, 14R, 17S, 19R)-
5- ({[(1 S)-1-{2- ch!orophenyi)ethy!]carbamoyl}(oxo)met hyl)-1 ,2, 14, 18, 18-pentamethyl-7-oxo-8-
104
{propan-2- yl)pentacyclo[11.8.0.0Λ{2,10}.0Λ{5,9}.0 A{14,19}]henicos-8-en-17-yl]oxy}-2,2- dimethyl-4-oxobutanoic acid
(1 R,2R,5R,10S,13R,14R,17S,19R)-5- ({[(1 R)-1-(4- chlorophenyl)ethyl]carbamoyl}(oxo)met hyi)-1 ,2, 14, 18, 18~pentamethyl-7-oxo-8-
105 (propan-2- yl)pentacycio[11.8.0.0A{2,10}.0A{5,9}.0 Λ{14, 19}]henicos-8-en-17-yl 1 -{[2- (dimethylamino)acetyl]oxy}methyl 2,2- dimethylbutanedioate
{3-[(4-
{[(1 R.2R.5R, 10S, 13R, 14R, 17S, 19R)-5- ({[1-(4- chlorophenyl)cyclopropyl]carbamoyl}(o xo)methyl)-1 ,2, 14, 18, 18-pentamethyl-
106 7-oxo-8-(propan-2- yl)pentacyclo[1 1.8.0.0A{2,10}.0A{5,9}.0 Λ{14, 19}]henicos-8-en-17-yl]oxy}-2,2- dimethy!-4- oxobutanoyl)oxy]propoxy}phosphonic acid
1 -tert-butyl
(1 R,2R,5R,10S,13R,14R,17S,19R)-5- {{[1-(4- chlorophenyl)cyclopropyl]carbamoyl}(o
107 xo)methyf)- ,2, 14, 18, 18-pentamethyl- 7-oxo-8-(propan-2- yl)pentacyclo[11.8.0.0Λ{2, 0}.0Λ{5,9}.0 A{14,19}]henicos-8-er>17-yl 2,2- dimethylbutanedioate
2,2-dimethyl-4-oxo-4- {[(1 R,2R,5R,10S,13R,14R,17S,19R)- 1 ,2, 14, 18, 18-pentamethyl-7-oxo-8- 08 (propan-2-yl)-5-{2-[{pyridin-3- ylmethyl)amino]acetyl}pentacyclo[1 1.8, 0.0Λ{2, 10}.0Λ{5,9}.0Λ{14, 19}]henicos-8- en-1 ~yl]oxy}butanoic acid
2, 2-di methy)-4-oxo-4-
{[( 1 R.2R.5R, 10S, 13R, 14R, 17S, 19R)-
1 ,2, 14, 18, 18-pentamethyl-7-oxo-8-
(propan-2-yl)-5-[2-({[3- 09
(trifiuoromethyl)phenyl]methyl}amino)a cetyl]pentacyclo[1 1.8.0.0A{2,10}.0A{5,9
}.0A{14, 19}]henicos-8-en-17- yl]oxy}butanoic acid; trifiuoroacetic acid 4- {[( 1 R,2R,5R, 10S, 3R,14R, 17S, 19R)-
5- {2-[(cyclop ropyl methyl )a m ino]acetyl}- 1 ,2, 14, 18, 18-pentamethyi-7-oxo-8- (propan-2- yl)pentacyclo[1 1.8.0.0A{2,10}.0A{5,9}.0 Λ{ 4, 9}]henicos-8-en-17-yl]oxy}-2,2- dimethyl-4-oxobutanoic acid
2,2-dimethyl-4-oxo-4- {[(I R^R.S .IOS.ISR. R.I TS.igR)- 1 ,2, 14, 18, 18-pentamethyl-5-(2-{[(4- nitrophenyl)methyl]amino}acetyl)-7- ii f Τ 5 Τ»·- i's.*0 oxo-8-(propan-2- yl)pentacyclo[1 1.8.0.0Λ{2, 10}.0Λ{5,9}.0 A{14,19}]henicos-8-en-17- yl]oxy}butanoic acid; trifluoroacetic acid
4- {[(1 R.2R.5R, 10S, 13R, 14R, 17S, 19R)-
5- (2-{[(4- methoxyphenyl)methyl]amino}acetyl)- 1 ,2, 14, 18, 18-pentamethyl-7-oxo-8- (propan-2- yl)pentacyclo[1 .8.0.0A{2,10}.0A{5,9}.0 A{14,19}]henicos-8-en-17-yl]oxy}-2,2- dimethyl-4-oxobutanoic acid
4- {[(1 R,2R,5R, 10S, 13R, 14R, 17S, 19R)-
5- (2-{[(4- fluorophenyl)methy[]amino}acetyl)- 1 ,2, 14, 18, 18-pentamethyl-7-oxo-8- (propan-2- y!)pentacyclo[1 1.8.0.0A{2,10}.0A{5,9}.0 Λ{14, 9}]henicos-8-en-17-yl]oxy}-2,2~ dimethyl-4-oxobutanoic acid;
trifluoroacetic acid
2 , 2-d i m et h y l-4-oxo-4- {[(1 R,2R, 5R, 10S, 13R, 14R, 17S, 19R)- 1 ,2,14, 8,18-pentamethyl-7-oxo-8- (propan-2-yl)-5-{2-[(pyridin-4- ylmethyl)amino]acetyl}pentacyclo[11.8. 0.0Λ{2, 10}.0Λ{5,9}.0Λ{14, 19}]henicos-8- en-17-yl]oxy}butanoic acid;
bis(trifluoroacetic acid)
4- {[(1 R.2R.5R, 10S, 13R, 14R, 17S, 19R)-
5- [2-(cyclopentylamino)acety]]-
1 ,2, 4, 18, 18-pentamethyl-7-oxo-8- (propan-2- yl)pentacyclo[11.8.0.0A{2,10}.0A{5,9}.0 A{14, 19}]henicos-8-en-17-yl]oxy}-2,2- dimethyl-4-oxobutanoic acid;
trifluoroacetic acid 5-{[(1 R.2R.5R, 10S, 13R, 4R, 17S, 19R)- 5-[2-(cyclopentylamino)acety!]- 1 ,2, 14, 18, 18-pentamethyl-7-oxo-8- (propan-2-
1 16
yl)pentacyclo[1 1.8.0.0A{2,10}.0A{5,9}.0 Λ{14, 19}]henicos-8-en-17-yl]oxy}-3,3- dimethyl-5-oxopentanoic acid;
trifluoroacetic acid
2,2-dimet yl-4-oxo-4- {[(1 R,2R,5R,10S,13R,14R,17S, 19R)- 1 ,2, 14, 8 8-pentamethy!-7-oxo-8- (propan-2-yl)-5-{2-[(thiophen-2-
1 17
ylmethyl)amino]acetyl}pentacyclo[11.8. 0.0A{2,10}.0A{5,9}.0A{14,19}]henicos-8- en-17-yl]oxy}butanoic acid;
trifluoroacetic acid
4- {[(1 R,2RI5R,10S,13R,14R,17S,19R)-
5- (2-aminoacetyl)-1.2,14,18,18- pentamethyi-7-oxo-8-(propan-2-
1 18 yl)pentacyclo[ 1.8.0.0Λ{2,10}.0Λ{5,9}.0
Λ{14, 19}]henicos-8-en- 7-yl]oxy}-2,2- dimethyl-4-oxobutanoic acid;
trifluoroacetic acid
2,2-dimethyl-4-oxo-4- {[{1 R.2R.5R, 10S, 13R, 14R, 17S, 19R)- 1 ,2, 14, 18, 18-pentamethyl-7-oxo-8- (propan-2-yl)-5-{2-[(thiophen-3-
119
ylmethyl)amino]acetyl}pentacyclo[1 1.8. 0.0Λ{2, 10}.0Λ{5,9}.0Λ{14, 19}]henicos-8- en-17-yl]oxy}butanoic acid;
trifluoroacetic acid
3 , 3 -d i m et hy l-5-oxo-5-
{[(1 R,2R,5R, 10S, 13R, 14R, 17S, 19R)-
1 ,2, 14, 18, 18-pentamethyl-7-oxo-8-
(propan-2-yl)-5-[2-({[3-
120 (trifluoromethyl)phenyl]methyl}amino)a cetyl]pentacyclo[1 1.8.0.0Λ{2, 10}.0Λ{5,9
}.0Λ{14, 19}]henicos-8-en-17- yl]oxy}pentanoic acid; trifluoroacetic acid
3,3-dimethyl-5-oxo-5- {[(1 R,2R,5R,10S, 13R,14R,17S,19R)- 1 ,2, 14, 18, 18-pentamethyl-7-oxo-8- (propan-2-yl)-5-{2-[(thiophen-2-
121
ylmethy[)amino]acetyl}pentacyclo[1 1.8. 0.0Λ{2, 10}.0Λ{5,9}.0Λ{14, 19}]henicos-8- en-17-yl]oxy}pentanoic acid;
trifluoroacetic acid 2,2-dimethy!-4-oxo-4- {[( 1 R.2R.5R, 10S, 13R, 14R, 17S, 19R)- 1 ,2, 4, 18, 18-pentamethyl-7-oxo-8- (propan-2-yl)-5-{2-[(pyridin-2-
122
ylmethy!)amino]acety[}pen†acyclo[11.8. 0.0Λ{2, 10}.0Λ{5,9}.0Λ{14, 19}]henicos-8- en-17-yl]oxy}butanoic acid;
bis(trifluoroacetic acid)
3,3-dimethyl-5-oxo-5- {[(1 R,2R,5R,10S,13R,14R,17S,19R)- 1 ,2, 14, 18, 18-pentamethyl-5-{2- [methyl({[3-
(trifluoromethyi)phenyl]methyl})amino]a
123
cetyi}-7-oxo-8-{propan-2- yl)p8ntacyc[o[11.8.0.0Λ{2,10}.0Λ{5,9}.0 A{14,19}]henicos-8-en-17- yi]oxy}pentanoic acid; trifluoroacetic acid
2,2-dimethyl-4-oxo-4- {[(1 R.2R.5R, 10S, 13R, 14R, 17S, 19R)- 1 ,2, 4,18,18-pentamethyl-7-oxo-8- (propan-2-yl)-5-(2-{[3-(pyrrolidin-1-
124
yf)propyl]amino}acetyl)pentacyclo[1 1.8. 0.0Λ{2, 10}.0Λ{5,9}.0Λ{ 4, 19}]henicos-8- en-17-yl]oxy}butanoic acid;
bis(trifluoroacetic acid)
4- {[(1 R.2R.5R, 10S, 13R, 14R, 7S, 19R)-
5- {2-[(furan-2- ylmethyl)(methy[)amino]acetyl}- 1 ,2, 14, 8, 18-pentamethyl-7-oxo-8-
125 (propan-2- yl)pentacyclo[1 .8.0.0Λ{2,10}.0Λ{5,9}.0 Λ{14, 19}]henicos-8-en-17-yl]oxy}-2,2- dimethyl-4-oxobutanoic acid;
trifluoroacetic acid
2,2-dimethyl-4-oxo-4- {[(1 R,2R,5R,10S,13R,14R,17S,19R)- 1 ,2, 14, 18, 18-pentamethy[-7-oxo-5-[2-
126 (phenylformamido)acetyf]-8-(propari-2- yl)pentacyclo[ .8.0.0Λ{2,10}.0Λ{5,9}.0 Λ{14, 19}]henicos-8-en-17- yl]oxy}butanoic acid
4- {[(1 R.2R.5R, 10S, 13R, 14R, 17S, 19R)-
5- (2-{[(4- fluorophenyl)methyl](methyf)amino}ace tyl)-1 ,2, 14, 18, 18-pentamethy[~7-oxo-8-
127 (propan-2- y!)pentacyclo[ 1.8.0.0Λ{2,10}.0Λ{5,9}.0 Λ{14, 19}]henicos-8-en-17-yl]oxy}-2,2~ dimethyl-4-oxobutanoic acid;
trifluoroacetic acid 4- {[( 1 R.2R.5R, 10S, 13R.14R, 17S, 19R)-
5- (2-{[(4- chlorophenyl)methyl](methy[)amino}ac etyl)-1 ,2, 14, 18, 18-pentamethyl-7-oxo-
128 8-(propan-2- yl)pentacyclo[1 1.8.0.0A{2,10}.0A{5,9}.0 Λ{14, 9}]henicos-8-en-17-yl]oxy}-2,2- dimeihyl-4-oxobutanoic acid;
trifluoroacetic acid
4- {[(1 R,2R,5R,10S,13R,14R,17S,19R)-
5- (2-{[(4- chlorophenyl)carbamoyl]amino}acetyl)~ 1 ,2, 14, 18, 18-pentamethyl-7-oxo-8-
129
(propan-2- y!)pentacyclo[11.8.0.0A{2,10}.0A{5,9}.0 Λ{14, 19}]henicos-8-en-17-yl]oxy}-2,2- dimethyi-4-oxobutanoic acid
2 , 2-di methyl-4-oxo-4-
{[( 1 R,2R,5R, 10S, 13R, 14R, 17S, 19R)-
1 ,2, 4, 18, 18-pentamethyl-5-{2-
[methyl({[4-
130 (trifluoromethyl)phenyl]methyl})amino]a cetyl}-7-oxo-8-(propan-2- yi)pentacyclo[11.8.0.0Λ{2,10}.0Λ{5,9}.0 Λ{14,19}]henicos-8-en-17- ylloxy}butanoic acid; trifluoroacetic acid
4- {[(1 R.2R.5R, 10S, 13R, 14R, 17S, 19R)-
5- (2-{[(3- chlorophenyl)methyl]amino}acetyl)- 1 ,2, 14, 18, 18-pentamethyl-7-oxo-8-
131 (propan-2- yl)pentacyclo[1 1.8.0.0Λ{2, 0}.0Λ{5,9}.0 Λ{14, 19}]henicos-8-en-17-yl]oxy}-2,2- dimethyl-4-oxobutanoic acid;
trifluoroacetic acid
4- {[(1 R.2R.5R, 10S, 13R, 14R, 17S, 19R)-
5- (2-{[(2,4- difluoropheny!)methyl]amino}acetyl)- 1 ,2, 4, 18, 18-pentamethyl-7-oxo-8-
132 (propan-2- yl)pentacyclo[11.8.0.0Λ{2, 10}.0Λ{5,9}.0 Λ{14, 19}]henicos-8-en-17-yl]oxy}-2,2- dimethyl-4-oxobutanoic acid;
trifluoroacetic acid
4~{[(1 R.2R.5R, 10S, 3R, 4R, 17S, 19R)- 5-(2-{[(2,4- difluorophenyl)methyl](methyl)amino}a cetyl)-1 ,2, 14, 18, 18-pentamethyl-7-oxo-
133 8-(propan-2- yl)pentacyclo[1 1.8.0.0A{2,10}.0A{5,9}.0 A{14, 19}]henicos-8-en-17-yl]oxy}-2,2- dimethyl-4-oxobutanoic acid;
trifluoroacetic acid 4- {[(1 R,2R,5R,10S,13R,14R,17S,19R)-
5- (2~{[(2- chlorophenyl)methyl]amino}acetyl)~ 1 ,2, 14, 18, 18-pentamethyl-7-oxo-8~
134 (propan-2- yl)pentacyclo[1 1.8.0.0A{2,10}.0A{5,9}.0 Λ{14, 19}]henicos-8-en-17-yl]oxy}-2,2- dimethyl-4-oxobutanoic acid;
trifluoroacetic acid
4- {[( 1 R.2R.5R, 0S, 13R, 14R, 17S, 19R)-
5- (2-{[(2- chlorophenyl)methyl](methy[)amino}ac eiyl)-1 ,2, 14, 18, 18-pentamethyi-7-oxo-
135 8-(propan-2- yl)pentacyclo[1 ,8.0.0A{2,10}.0A{5,9}.0 Λ{14, 19}]henicos-8-en-17-yl]oxy}-2,2- dimethyl-4-oxobutanoic acid;
trifluoroacetic acid
4- {[( 1 R.2R.5R, 0S, 3R, 4R, 17S, 19R)-
5- (2-{[(2-chlorophenyl)rnethyl][2~ (dimethylamino)ethy!]amino}acetyl)- 1 ,2, 14, 18, 18-pentamethyl-7-oxo-8-
136 (propan-2- y!)pentacycio[1 1.8.0.0Λ{2,10}.0Λ{5,9}.0 Λ{14, 19}]henicos-8-en-17-yl]oxy}-2,2- dimethyl-4-oxobutanoic acid;
bis(trifluoroacetic acid)
2,2-dimethyl-4-oxo-4-
{[(1 R,2R, 5R, 10S, 13R, 14R, 17S, 19R)-
1 ,2, 14, 18, 18-pentamethyl-5-[2-( N- methyi-1 -phenylformamtdo)acetyl]-7-
137
oxo-8-(propan-2- yl)pentacyc!o[1 1.8.0.0A{2,10}.0A{5,9}.0 A{ 4,19}]henicos-8-en-17- yl]oxy}butanoic acid
4- {[( 1 R.2R.5R, 10S, 13R.14R, 17S, 19R)-
5- (2-{[(3- chlorophenyl)methyl](methyl)amino}ac etyl)-1 ,2, 14, 8, 18-pentamethyl~7-oxo-
138 8-(propan-2- yl)pentacyclo[1 1.8.0.0A{2, 10}.0A{5,9}.0 A{14, 19}]henicos-8-en-17-y!]oxy}-2,2- dimet yl-4-oxobutanoic acid;
trifluoroacetic acid
4- {[(1 R,2R,5R,10S,13Rl14R,17S,19R)-
5- (2-{[(2,4-dif!uorophenyl)methyl][2- (dimethyiamino)ethyl]amino}acetyl)- ,2, 14, 18, 18-pentamethyl-7-oxo-8-
139 {propan-2- yl)pentacyclo[11.8.0.0A{2,10}.0A{5,9}.0 A{14, 19}]henicos-8-en-17-yl]oxy}-2,2- dimethyl-4-oxobutano!C acid;
bis(trifluoroacetic acid) 2,2-dimethyl-4-oxo-4- {[(1 R,2R,5R,10S,13R,14R,17S,19R)- 1 ,2, 14, 18, 18-pentamethyl-7-oxo-8- (propan-2-yl)-5-[2-{{[3-
140
{trifluoromethoxy)phenyl]rriethyl}amino) acetyl]pentacyclo[1 1.8.0.0A{2,10}.0ft{5, 9}.0Λ{14, 19}]henicos-8-en- 7- yl]oxy}bu†anoic acid; trifluoroacetic acid
2,2-dimethyl-4-oxo-4-
{[(1 R.2 .5R, 10S, 13R, 14R, 17S, 19R)-
1 ,2, 14, 18, 18-pentamethyi-5-{2-
[methy]({[3-
141 (trifluoromethoxy)p enyl]methyl})amino
]a cety l}-7-oxo-8-( pro pa n -2- yl)pentacyclo[1 1.8.0.0Λ{2, 10}.0Λ{5,9}.0 Λ{14, 19}]henicos-8-en-17- yl]oxy}butanoic acid; trifluoroacetic acid
4- {[(1 R,2R,5R,10S,13R,14R,17S,19R)-
5- (2-{[2-(dimethyiamino)ethyI]{{[3- (tnfluoromethoxy)phenyl]methyl})amino }acetyl)-1 ,2, 14, 18, 18-pentamethyl-7-
142 oxo-8-(propan-2- y))pentacyclo[1 1.8.0.0A{2,10}.0A{5,9}.0 Λ{14, 19}]henicos-8-en-17-yl]oxy}-2,2- dimethyl-4-oxobutanoic acid;
bis(trifluoroacetic acid)
4- {[(1 R,2R,5R, 10S, 13R, 14R, 1 S, 19R)-
5- (2-{[2-(dimethylamino)ethyl](furan-2- ylmethy!)amino}acetyl)-1 ,2, 14, 18, 18- pentamethyl-7-oxo-8-(propan-2-
143
yl)pentacyc!o[1 1.8.0.0A{2,10}.0A{5,9}.0 Λ{14, 19}]henicos-8-en-17-yl]oxy}-2,2- dimethyi-4-oxobutanoic acid;
bis(trifluoroacetic acid)
2,2-dimethyl-4-oxo-4- {[(1 R,2R,5R,10S,13R,14R, 17S, 19R)- 1 ,2, 14, 18, 18-pentamethyl-7-oxo-8-
144 (propan-2~yl)-5-[2-({[4- (trifluoromethyi)phenyl]methyl}amino)a cetyl]pentacyc!o[1 1.8.0.0A{2,10}.0A{5,9 }.0Λ{14, 19}]henicos-8-en-17- yl]oxy}butanoic acid; trifluoroacetic acid
4- {[( 1 R,2R,5R, 10S, 13R.14R, 17S, 19R)-
5- [2-({[4-c loro-3-
(trifluoromethyl)phenyl]carbamoyl}amin o)acetyl]-1 ,2,14, 18, 18-pentamethyl-7-
145
oxo-8-(propan-2- y!)pentacyclo[1 1.8.0.0A{2,10}.0 {5,9}.0 Λ{14, 19}]henicos-8-en-17-yl]oxy}-2,2- dimethyl-4-oxobutanoic acid 4- {[{1 R,2R,5RI10Sl13R,14R,17S,19R)-
5- (2-{N-[(2-fluorophenyl)methyl]-2- hyd roxya ceta m ido}a cetyl )-
1 ,2, 4, 8,18-pentamethyl-7-oxo-8-
146
(propan-2- yjJpentacyclotH .S.O.O^.I OJ.O^S^J.O Λ{14, 19}]henicos-8-en-17-yl]oxy}-2,2- dimethyl-4-oxobutanoic acid
4- {[(1 R,2R,5R, 10S, 13R, 14R, 17S, 19R)-
5- (2-{[(3-chlorophenyl)methy]][2- (dimethylamino)ethyl]amino}acetyl)- ,2, 14, 18, 18-pentamethyl-7-oxo-8-
147 (propan-2- yl)pentacyclo[11.8.0.0Λ{2, 10}.0Λ{5,9}.0 Λ{14, 19}]henicos-8-en-17-y[]oxy}-2,2- dimethyl-4-oxobutanoic acid dihydrochloride
4- {[(1 R,2R,5R,10S,13R,14R,17S,19R)-
5- (2-{N-[(3-fluorophenyl)methyl]-2- hydroxyacetamido}acetyl)-
1 ,2, 4, 18, 18-pentamethyl-7-oxo-8-
148
(propan-2- yl)pentacyclo[1 1.8.0.0A{2,10}.0A{5,9}.0 Λ{ 4, 19}]henicos-8-en-17-yl]oxy}-2,2- dim8thyl-4-oxobutanoic acid
4- {[( 1 R,2R,5R, 10S, 13R, 14R, 7S, 19R)-
5- (2-{N-[{3-chlorophenyl)methyl]-2- hyd roxyacetam ido}acetyl )- 1 ,2, 4, 8,18-pentamethyl-7-oxo-8-
149
(propan-2- yl)pentacyc!o[11 ,8.0.0Λ{2,10}.0Λ{5,9}.0 Λ{14, 19}]henicos-8-en-17-yl]oxy}-2,2- dimethyl-4-oxobutanoic acid
4- {[(1 R,2R,5R,10S,13R,14R,17S,19R)-
5- {2-[benzyl(carbamoyl)amino]acety!}- 1 ,2,14,18,18-pentamethyl-7-oxo-8-
150 (propan-2- y[)pentacyclo[ 1.8.0.0Λ{2,10}.0Λ{5,9}.0 Λ{14, 19}]henicos-8-en-17-yl]oxy}-2,2- dimethyl-4-oxobutanotc acid
4- {[( 1 R,2R,5R, 0S, 13R, 14R, 17S, 19R)-
5- (2-{N-[(4-chlorophenyl)methyl]-2- hydroxyacetamido}acetyl)-
1 ,2, 14, 18, 18-pentamethyi-7-oxo-8-
151
(propan-2- yl)pentacyclo[1 1.8.0.0A{2,10}.0A{5,9}.0 Λ{14, 19}]h8nicos-8-en-17-yl]oxy}-2,2- dimethyl-4-oxobutanoic acid 4- {[(1 R,2R,5R,10S,13R,14R,17S,19R)-
5- [2-(N- benzylcarbamoy[formamido)acetyl3- 1 ,2,14,18,18-pentamethyl-7-oxo-8-
152
(propan-2- yl)pentacyclo[11.8.0.0Λ{2,10}.0Λ{5,9}.0 Λ{14, 19}]henicos-8-en-17-yl]oxy}-2,2- dimethyl-4-oxobutanoic acid
4- {[( 1 R,2R,5R, 10S, 13R, 14R, 17S, 19R)-
5- [2-(N- benzylcarboxyformarnido)acety(]- 1 ,2, 4, 18, 18-pentamethyl-7-oxo-8~
153
(propan-2- yl)pentacyclo[1 1.8.0.0A{2,10}.0A{5,9}.0 Λ{14, 19}]henicos-8-en-17-yl]oxy}-2,2- dimethyl-4-oxobutanoic acid
4- {[(1 R,2R,5R,10S,13R,14R, 17Sl19R)-
5- (2-{N-[(1 R)-1-(4-chlorophenyl)ethy!]- 2-hydroxyacetamido}acetyl)-
1 , 2 , 14, 18 , 18-p enta m ethy I-7-OXO-8 - 54
(propan-2- yl)pentacyclo[11.8.0.0Λ{2,10}.0Λ{5,9}.0 Λ{14, 19}]henicos-8-en-17-yl]oxy}-2,2- dimethyl-4-oxobutanoic acid
4- {[(1 R,2R,5R,10S,13R,14R,17S,19R)-
5- {2~[(2R)-N-[(4-chlorophenyl)methyl]- 2,3-dihydroxypropanamido]acetyl}-
1 ,2, 14, 8, 18-pentamethyl-7-oxo-8-
155
(propan-2- yl)pentacyclo[1 1.8.0.0A{2,10}.0A{5,9}.0 Λ{14, 19}]henicos-8-en-17-yi]oxy}-2,2- dimethyl-4-oxobutanoic acid
4- {[( 1 R.2R.5R, 10S, 13R, 14R, 17S, 19R)-
5- (2-{N-[(1 R)-1-(4-chiorophenyl)ethyl]- 2-(dimethylamino)acetamido}acetyl)-
1 ,2, 14, 18, 18-pentamethyl-7-oxo-8-
156 (propan-2- yl)pentacycio[1 1.8.0.0A{2,10}.0A{5,9}.0 Λ{14, 19}]henicos-8-en-17-yl]oxy}-2,2- dimethyl-4-oxobutanoic acid;
trifluoroacetic acid
4- {[{1 R,2R,5R,10SJ13R,14R,17S,19R)-
5- (2-{[(2,6- dichlorophenyl)methyl]amino}acetyl)- 1 ,2,14, 18, 18-pentamethyl-7-oxo-8-
157 (propan-2- yl)pentacyclo[11.8.0.0Λ{2,10}.0Λ{5,9}.0 Λ{14, 9}]henicos-8-en-17-yl]oxy}-2,2- dimethy!-4-oxobutanoic acid;
trifluoroacetic acid
Figure imgf000068_0001
trifluoroacetic acid 4- {[(1R,2R,5R,10S,13R,14R,17S,19R)-
5- (2-{[(2,6- dichlorophenyl)methyl](methyl)amino}a cetyl)-1 ,2, 4, 18, 18-pentamethy!-7-oxo- 8-{propan-2- yi)pentacyclo[11.8.0.0A{2,10}.0A{5,9}.0 A{14,19}]henicos-8-en-17-yl]oxy}-2,2~ dimethyl-4-oxobutanoic acid;
trifluoroacetic acid
4- {[( 1 R,2R, 5R, 10S, 13R, 14R, 17S, 19R)-
5- {2-{benzyl[2-
(dimethyiatnino)ethyi]amino}acetyl)- 1 ,2, 14, 18, 8-pentamethyl-7-oxo-8- (propan-2- yl)pentacyclo[1 .8.0.0Λ{2,10}.0Λ{5,9}.0 Λ{ 4, 19}]henicos-8-en-17-yl]oxy}-2,2- dimethyl-4-oxobutanoic acid dihydrochloride
4- {[{1 R,2R,5R, 10S, 13R, 14R, 17S, 19R)-
5- (2-{[2-(dimethylamino)ethyl][(2- fluorophenyi)methy!]amino}acetyl)- 1 ,2, 4, 18, 18~pentamethyl-7-oxo-8- (propan-2-
Figure imgf000069_0001
yl)pentacyclo[11.8.0.0A{2,10}.0A{5,9}.0
Λ{14, 19}]henicos-8-en-17-yl]oxy}-2,2- dimethyl-4-oxobutanoic acid dihydrochloride
4- {[(1 R,2R,5R,10S,13R,14R,17S,19R)-
5- (2-{[2-(dimethylamino)ethyl][(3- f[uorophenyl)meihyl]amino}acetyt)- ,2, 14, 18, 8-pentamethyl-7-oxo-8- (propan-2- yl)pentacyclo[11.8.0.0A{2,10}.0A{5,9}.0 Λ{14, 19}]henicos-8-en-17-yl]oxy}-2,2- dimethyl-4-oxobutanoic acid
dihydrochloride
4- {[( 1 R.2R.5R, 10S, 13R, 14R, 17S, 19R)-
5- {2-[({5-[(dimethylamino)methyl]furan- 2-yl}methyl)amino]ac6tyl}-1 ,2,14, 18,18- pentamethyl-7-oxo-8-(propan-2- yl)pentacycio[1 1.8.0.0Λ{2, 10}.0Λ{5,9}.0 Λ{14, 19}]henicos-8-en-17-yl]oxy}-2,2- dimethyl-4-oxobutanoic acid;
bis(trifluoroacetic acid)
2,2-dimethyl-4-oxo-4-
{[(1 R,2R,5R,10S,13R,14Rt17S,19R)-
1 ,2, 14, 18, 18-pentamethyl-5-{2-[({5-[{4- methylpiperazin-1-yl)methyl]thiophen-
2-yl}methy[)amino]acetyl}-7-oxo-8-
(propan-2- yl)pentacyclo[1 1.8.0.0A{2,10}.0A{5,9}.0 A{14, 9}]henicos-8-en-17- yl]oxy}butanoic acid; tris(trifluoroacetic acid) 4- {[(1 R,2R,5R,10S,13R,14R,17S,19R)-
5- {2-[(3S)-N-benzyl-3,4- dihydroxybutanamido]acetyl}-
1 ,2, 14, 18, 18-pentamethyl-7-oxo-8~
170
(propan-2- yl)pentacyclo[11.8.0.0A{2,10}.0A{5,9}.0 Λ{14, 19}]henicos-8-en-17-yl]oxy}-2,2- dimethyI-4-oxobutanoic acid
4- {[(1 R,2R,5R, 10S, 13R, 14R, 17S, 19R)-
5- {2-[3-carboxy-N-(furan-2-y[methyl)- 3,3-dimethylpropanamido]acetyl}-
1 ,2, 14, 18, 18-pentamethyl-7-oxo-8-
171
(pro an-2- yl)pentacyclo[1 1.8.0.0Λ{2,10}.0Λ{5,9}.0 Λ{14, 19}]henicos-8-en-17-yl]oxy}-2,2- dimethyl-4-oxobutanoic acid
4- {[( 1 R.2R.5R, 10S, 13R, 14R, 17S, 19R)-
5- (2-{[(tert-butoxy)carbonyl](pyridin-3- ylmethyl)amino}ace†yl)-1 ,2,14,18,18- pentamethyl-7-oxo-8-(propan-2-
172
yl)pentacyclo[11.8.0.0Λ{2,10}.0Λ{5,9}.0 Λ{ 4, 9}]henicos-8-en-17-yijoxy}-2,2- dimethyl-4-oxobutanoic acid;
trifluoroacetic acid
4- {[(1 R,2R,5R, 10S, 13R, 14R, 17S, 19R)-
5- (2-acetamidoacetyl)-1 ,2,14,18,18- pentamethyl-7-oxo-8-(propan-2-
173
yl)pentacycfo[1 .8.0.0A{2,10}.0A{5,9}.0 Λ{14, 19}jhenicos-8-en-17-yl]oxy}-2,2- dimethy[-4-oxobutanoic acid
4- {[( 1 R,2R,5R, 10S, 13R, 14R, 17S, 19R)-
5- {2-[(2R)-N-benzy[-2,3- d i hyd roxypro pa na m ido]ace†yl}- 1 ,2, 14, 18, 18-pentamethyl-7-oxo-8-
174
(propan-2- yl)pentacyclo[1 1.8.0.0A{2,10}.0A{5,9}.0 Λ{14, 19}]henicos-8-en-17-yl]oxy}-2,2- dimethyl-4-oxobutanoic acid
4- {[{1 R,2R,5R,10S,13R,14R,17S,19R)-
5- {2-[(2S)-N-[(4-chioropheny[)methy[]- 2,3-dihydroxypropanamido]aceiyl}-
1 ,2, 14, 18, 18-pentamethyl-7-oxo-8-
175
(propan-2- yl)pentacyclo[1 .8.0.0Λ{2, 10}.0Λ{5,9}.0 Λ{14, 19}jhenicos-8-en-17-yl]oxy}-2,2- dimethyi-4-oxobutanoic acid 4- {[(1 R,2R,5R,10S,13R,14R,17S,19R)-
5- {2-[(2S)-N-benzyl-2,3- dihydroxypropanarnido]acetyl}- 1 ,2,14,18,18-pentamethyl-7-oxo-8-
176
(propan-2- yl)pentacyc[o[11.8.0.0Λ{2,10}.0Λ{5,9}.0 Λ{14, 19}]henicos-8-en-17-yl]oxy}-2,2- dimethyl-4-oxobutanoic acid
4- {[(1 R,2R,5R,10S,13R,14R,17S,19R)-
5- {2-[(2S)-N-[(1 R)-1-(4- chlorophenyl)ethyl]~2,3- dihydroxypropanamidojacetyl}-
177 ,2, 14, 18, 18-pentamethy!-7-oxo-8- (propan-2- yl)pentacyclo[11.8.0.0Λ{2, 0}.0Λ{5,9}.0 Λ{14, 19}]henicos-8-en-17-yl]oxy}-2,2- dimethyl-4-oxobutanoic acid
4- {[( 1 R,2R,5R, 10S, 13R, 14R, 17S, 19R)-
5- (2-{[(1 R)-1-(4- ch!orophenyl)ethyl]amino}acetyl)- 1 ,2, 14, 18, 18-pentamethyl-7-oxo-8-
178 (propan-2- yl)pentacyclo[11.8.0.0Λ{2, 10}.0Λ{5,9}.0 Λ{14, 19}]henicos-8-en-17-yl]oxy}-2,2- dimethyl-4-oxobutanoic acid;
trifluoroacetic acid
4- {[(1 R,2R, 5R, 10S, 13R, 14R, 17S, 19R)-
5- (2-
{[(dimethylcarbamoy!)methyl][(1 R)-1- phenylethyl]arnino}acetyl)-
1 ,2, 14, 18, 18-pentamethyl-7-oxo-8-
179
(propan-2- yl)pentacyclo[11.8.0.0Λ{2,10}.0Λ{5,9}.0 Λ{14, 19}]henicos-8-en-17-yl]oxy}-2,2- dimethyt-4-oxobutanoic acid;
trifluoroacetic acid
4- {[(1 R,2R, 5R, 10S, 13R, 14R, 17S, 19R)-
5- {2-[(2R)-N-[(1 R)-1-(4- chlorophenyl)ethyl]-2,3- dihydroxypropanamidojacetyl}-
180 1 ,2, 14, 18, 18-pentamethyl-7-oxo-8- (propan-2- yl)pentacyclo[1 1.8.0.0Λ{2, 10}.0Λ{5,9}.0 Λ{14,19}]henicos-8-en-17-yl]oxy}-2,2- dimethyl-4-oxobutanoic acid
4- {[{1 R,2R,5R, 10S, 13R, 14R, 17S, 19R)-
5- (2-{N-[(1 S)-1 -(4-ch!orophenyl)ethy - 2-(dimethylamino)acetamido}acetyl)-
1 ,2, 14, 18, 18-pentamethyl-7-oxo-8-
181
(propan-2-
-or yl)pentacydo[11.8.0.0Λ{2, 10}.0Λ{5,9}.0
Λ{14, 19}]henicos-8-en-17-yl]oxy}-2,2- dimethyl-4-oxobutanoic acid 4- {[( 1 R.2R.5R, 10S, 13R, 14R, 17S, 19R)-
5- {2-[N-benzyl-2-
(dimethylamino)acetarnido]acetyl}- 1 ,2, 14, 18, 18-pentamethyl-7-oxo-8-
182 (propan-2- yl)pentacyc[o[11.8.0.0 {2,10}.0A{5,9}.0 Λ{14, 19}jhenicos-8-ei 17-yl]oxy}-2,2- dimethyl-4-oxobutanoic acid;
trifluoroacetic acid
4- {[(1 R,2R,5R, 10S, 13R, 14R, 7S, 9R)-
5- {2-[(carbamoylmethyl)[(1 R)-1 - phenylethyl]amino]acetyl}-
1 ,2, 14, 18, 18-pentamethyl-7-oxo-8-
183 (propan-2- yl)pentacyclo[11.8.0.0A{2,10}.0A{5,9}.0 Λ{14, 9}]henicos~8-en-17-yl]oxy}-2,2- dimethyl-4-oxobutanoic acid;
trifluoroacetic acid
4- {[( 1 R,2R,5R, 0S, 13R, 14R, 17S, 19R)-
5- (2-{N-[(4-chlorophenyl)methyl]-2- (dimethy!amino)acetamido}acetyi)- 1 ,2, 14, 18, 18-pentamethy[-7-oxo-8-
184 (propan-2- yl)pentacyclo[11 ,8.0.0Λ{2,10}.0Λ{5,9}.0 Λ{14, 19}]henicos-8-en-1 -yl]oxy}-2,2- dimethyl-4-oxobutanoic acid;
trifluoroacetic acid
4- {[(1 R,2R,5R,10S,13R,14R,17S,19R)-
5- {2-[2-(dimethylamino)-N-[(1 R)-1- phenylethyl]acetamido]acetyl}- 1 ,2, 4, 8,18-pentamethyl-7-oxo-8-
185 (propan-2- yi)pentacyclo[11.8.0.0Λ{2,10}.0Λ{5,9}.0 Λ{ 4, 19}]henicos-8-en-17-yl]oxy}-2,2- dimethyl-4-oxobutanoic acid;
trifluoroacetic acid
4- {[( 1 R.2R.5R, 10S, 3R,14R, 17S, 19R)-
5- (2-{[(1 R)-1 -(4-chlorophenyl)ethyl][2- (dimethylamino)ethyl]amino}acetyl)-
1 ,2, 14, 18, 18-pentamethyl-7-oxo-8-
186 (propan-2- yl)pentacyc!o[ ,8.0.0Λ{2,10}.0Λ{5,9}.0 Λ{ 4, 19}]henicos-8-en-17-yl]oxy}-2,2- dimethyl-4-oxobutanoic acid;
bis(trifluoroacetic acid)
4- {[(1 R,2R,5R, 10S, 13R, 14R, 17S, 19R)-
5- (2-{[(1 R)-1-(4- chlorophenyl)ethyl][(dimethylcarbamoyl )methyl]amino}acetyl)- ,2,14, 18,18-
187 pentamethyl-7-oxo-8-(propan-2- yl)pentacyclo[ 1.8.0.0Λ{2,10}.0Λ{5,9}.0 Λ{14, 19}] enicos-8-en-17-yl]oxy}-2,2- dimethy[-4-oxobutanoic acid;
trifluoroacetic acid 4- {[(1 R.2R.5R, 10S, 13R, 14R, 17S, 19 )-
5- (2-{[( 1 S)-1 -(4-chloropheny])ethyl][2- (dimethylamino)ethyl]amino}acetyl)-
1 ,2, 14, 8, 18-pentamethyl-7-oxo-8-
188 (propan-2- yl)pentacyclo[1 .8.0.0Λ{2, 10}.0Λ{5,9}.0 Λ{14, 19}]henicos-8-en-17-yl]oxy}-2,2- dimethyl-4-oxobutanoic acid;
bis(trifluoroacetic acid)
4- {[(1 R,2R,5R,10S,13R,14R, 17S,19R)-
5- (2-{[(1 S)-1 -(4- chlorophenyl)ethyl][(dimethylcarbamoyl )methyl]amino}acetyl)-1 ,2,14, 8, 8-
189 pentamethyl-7-oxo-8-(propan-2- yl)pentacyclo[1 1.8.0.0A{2, 10}.0A{5,9}.0 Λ{14, 19}]henicos-8-en-17-yl]oxy}-2,2~ dimethyl-4-oxobutanoic acid;
trifluoroacetic acid
4- {[( 1 R,2R,5R, 10S, 13R, 14R, 17S, 19R
5- [carboxy(oxo)methyl]- ,2, 14,18,18- pentamethyl-7-oxo-8-(propan-2-
1 90
yl)pentacyclo[ 1 .8.0.0Λ{2, 10}.0Λ{5,9}.0 Λ{ 4, 9}]henicos-8-en-17-yl]oxy}-2,2- dimethyl-4-oxobutanoic acid
2, 2-d imethyl-4-oxo-4-
{[( 1 R.2R.5R, 10S, 13R, 14R, 17S, 19R)-
1 ,2, 14, 18, 18-pentamethyl-7-oxo-5-[2- oxo-2-(piperazin-1 -yl)acetyl]-8-(propan-
191
2- yl)pentacyclo[1 1 .8.0.0Λ{2,10}.0Λ{5,9}.0 Λ{14, 19}]h8nicos-8-en-17- yl]oxy}butanoic acid; trifluoroacetic acid
4- {[( 1 R.2R.5R, 10S, 13R, 14R, 17S, 19R)-
5- [2-(1 , 1 -dioxo-1 $lA{6},4-thiomorpholin- 4-yl)-2-oxoacetyl]-1 ,2, 14,18, 8-
192 pentamethyl-7-oxo-8-(propan-2- yl)pentacyclo[1 1 .8.0.0Λ{2, 10}.0Λ{5,9}.0 Λ{14, 9}]henicos-8-en- 7-yl]oxy}-2,2- dimethyl-4-oxobutanoic acid
[0095] The compounds of Table 1 were synthesized according to the Synthetic
Methods, General Schemes, and the .Examples described below.
[0096] In certain embodiments, the compound(s) of the present invention, or a pharmaceutically acceptable salt thereof, is chosen from the compounds set forth in Table 1 .
Synthetic Methods [0097] The methods of synthesis for the provided chemical entities employ readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions {i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given; other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
[0098] Additionally, 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. uts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999, and references cited therein.
[0099] Furthermore, 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.
[00100] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, 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
Science Publishers, 1989), Organic Reactions, Volumes 1 -40 (John Wiley and Sons, 1991 ), March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989).
[00101 ] Unless specified to the contrary, the reactions described herein take place at atmospheric pressure, generally within a temperature range from -78 °C to 200 °C. Further, except as employed in the Examples or as otherwise specified, 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 110 °C over a period of about 1 to about 24 hours; reactions left to run overnight average a period of about 16 hours.
[00102] The terms "solvent," "organic solvent," and "inert solvent" each mean a solvent inert under the conditions of the reaction being described in conjunction therewith, including, for example, benzene, toluene, acetonitrile, tetrahydrofuranyl ("THF"),
dimethylformamide {"DMF"), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, N-methylpyrrolidone ("NMP"), pyridine and the like.
[00103] 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.
Specific illustrations of 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.
[00104] When desired, 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, followed 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. Alternatively, a specific enantiomer may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.
EXAMPLES
[00105] The following examples serve to more fully describe the manner of making and using the above-described invention. It is understood that these examples in no way serve to limit the true scope of the invention, but rather are presented for illustrative purposes. In the examples below and the synthetic schemes above, the following abbreviations have the following meanings. If an abbreviation is not defined, it has its generally accepted meaning. aq. = aqueous
pL = microliters micromolar
nuclear magnetic resonance
tert-butoxycarbonyl
broad
benzyloxycarbonyl
doublet
chemical shift
degrees celcius
dichloromethane
doublet of doublets
Dulbeco's Modified Eagle's Medium
Ν,Ν-dimethylformamide
dimethylsu!foxide
ethyl acetate
gram
hours
hepatitus C virus
high performance liquid chromatography hertz
International Units
inhibitory concentration at 50% inhibition coupling constant (given in Hz unless otherwise indicated)
multiplet
molar
parent mass spectrum peak plus H+ milligram
minutes
milliliter
millimolar
millimole
mass spectrum
nanomolar
parts per million
sufficient amount
singlet room temperature
saturated
triplet
trifluoroacetic acid
Equipment Description
1 H NMR spectra were recorded on a Bruker Avance-ll l 400 spectrometer. Chemical shifts are expressed in parts per million (ppm, δ units). Coupling constants are in units of hertz (Hz). Splitting patterns describe apparent multiplicities and are designated as s (sing!et), d (doublet), t (triplet), q (quartet), quint (quintet), m (multiplet), br (broad).
The analytical low-resolution mass spectra (MS) were recorded on Agilent 1200 HPLC/61 10 or Agilent 1200 HPLC/6130 using a SunFire C18, 4.6 x 50 mm, 3.5 Mm using a gradient elution method.
Solvent A: 0.01 % trifluoroacetic acid (TFA) in water;
Solvent B: 0.01 % TFA in acetonitrile;
Constant A for 1 .2 min followed by 5%-95% or 20%-95% B over 4 min.
Schemes and Experimental procedures
The following schemes and procedures illustrate how compounds of the present invention can be prepared. The specific solvents and reaction conditions referred to are also illustrative and are not intended to be limiting. Compounds not described are either commercially available or are readily prepared by one skilled in the art using available starting materials. The Examples disclosed herein are for illustrative purposes only and are not intended to limit the scope of the invention. All examples exhibited LHIV IC50 values between 1 μ and 1 nM using the assay disclosed herein.
Synthesis of the intermediat compounds:
Figure imgf000077_0001
Figure imgf000078_0001
Step A: Intermediate 2
To a solution of the intermediate 1 (20 g, 45.2 mmol), 4-dimethylaminopyridine
(DMAP, 1.66 g, 13.6 mmol), and Et3N (63 mL, 136 mmol) in CHZCI2 (DCM, 100 mL) at room temperature was added acetic anhydride (Ac20, 17.1 mL, 1 13 mmol). After it was heated at reflux overnight, and cooled down to room temperature, the reaction was quenched with water (50 mL). The organic phase was then washed with water (50 mL χ 2) and dried over sodium sulfate. After removing most of the organic solvent under reduced pressure, anhydrous ethanol (50 mL) was added and the resulting precipitates were collected by filtration as a white solid (intermediate 2, 20 g, 84 %). 1H NMR (400 MHz, CDCI3) δ ppm 4.69 (1 H, m), 4.59 (1 H, m), 4.51 -4.43 (1 H, m), 4.25 (1 H, d, J = 1 1.2 Hz), 3.85 (1 H, d, J = 10.8 Hz), 2.49-2.40 (1 H, m), 2.07 (3H, s), 2.04 (3H, s), 1 .98-0.77 (42H, m). LC/ S: m/z calculated 526.4, found 527.7 (M + 1 )+.
Step B: Intermediate 3
HBr in acetic acid (40 mL, 33 %) was added to a suspension of the intermediate 2 (20 g, 38 mmol) in toluene (40 mL), Ac20 (40 mL), and acetic acid (AcOH, 40 mL) previously heated at 105 °C. The reaction mixture was stirred and heated at this temperature for .5 h. After cooling down, sodium acetate (24 g) was added and the resulting reaction mixture was evaporated to dryness. The pale brownish residue was taken up in DCM (200 mL) and the organic phase was washed with water (100 mL χ 3), dried over sodium sulfate, and evaporated to dryness under reduced pressure to provide a residue, which was
recrystallized from ethanol (EtOH, 95 %) and DCM to afford the intermediate 3 (13.8 g, 69 %) as a white solid. 1 H NMR (400 MHz, CDCI3) δ ppm 4.50-4.46 (1 H, m), 4.02 (1 H, d, J = 10.8 Hz), 3.98 (1 H, d, J = 10.8 Hz), 3.18-3.10 (1 H, m), 2.43-2.40 (1 H, m), 2.26-2.22 (2H, m), 2.04 (3H, s), 2.05 (3H, s), 2.00-1 .95 (1 H, m), 1 .90-1.85 (1 H, m), 1 .77-0.83 (39 H, m). LC/MS: m/z calculated 526.4, found 549.2 (M+Na)+.
Step C: Intermediate 4
A mixture of the intermediate 3 (7 g, 13.29 mmol), sodium acetate (NaOAc, 6.21 g, 76 mmol) and sodium dichromate dihydrate (4.75 g, 15.95 mmol) in anhydrous toluene (90 mL), AcOH (1 19 mL), and Ac20 (29 mL) was stirred at 60 °C overnight. After cooling down, the reaction mixture was partitioned between water (150 mL) and ethyl acetate
(EtOAc, 250 mL). The organic phase was washed successively with water (100 mL), saturated solution of sodium carbonate (100 mL * 2) and brine (100 mL χ 2), dried over sodium sulfate, and concentrated under reduced pressure to afford a sticky oil. The sticky oil was triturated with MeOH (250 mL) and the precipitates were collected to give the
intermediate 4 (6 g, 1 1.1 mmol, 83 % yield) as a white solid. ΊΗ NMR (400 MHz, CDCI3) δ ppm 4.52-4.46 (1 H, m), 4.33 (1 H, d, J = 10.8 Hz), 4.06 (1 H, d, J = 1 1.2 Hz), 3.21 -3.16 (1 H, m), 2.86 (1 H, dd, J = 12.8, 3.2 Hz), 2.42-2.36 (1 H, m), 2.05 (3H, s), 2.00 (3H, s), 1.94-0.84 (40H, m). LC/MS: m/z calculated 540.4, found 563.3 (M + Na)+.
Step D: Intermediate 5
A mixture of the intermediate 4 (7 g, 12.94 mmol) and potassium hydroxide (KOH,
0.872 g, 15.5 mmol) in EtOH (200 mL) and toluene (200 mL) was stirred vigorously at room temperature for 1 h. The reaction mixture was neutralized with aqueous HCI (1 /V) to pH 7 and evaporated to dryness. The obtained residue was taken up in water and a small amount of acetone. The precipitates were collected and then washed with water and dried in vacuo to obtain the intermediate 5 (6.0 g, 93 %) as a white solid. LC/MS: m/z calculated 498.4, found 499.3 (M + 1 )+. Step E: Intermediate 6
To a solution of the intermediate 5 (5.1 g, 10.23 mmol) in DCM (300 mL) at room temperature were added pyridinium chlorochromate (PCC, 6.61 g, 30.7 mmol), and silica gel (6.6 g). The reaction mixture was stirred at room temperature for 1 h. After the reaction was quenched with water, the organic phase was washed with saturated sodium bicarbonate solution (100 mL), dried over sodium sulfate, and evaporated under reduced pressure to provide a crude product, which was purified by column chromatography on silica gel (EtOAc: PE = 1 :10 to 1 :5) to provide the intermediate 6 (4.2 g, 83 % ) as a white solid. LC/MS: m/z calculated 496.4, found 497.2 (M + 1 )+.
Step F: Intermediate 7
To a solution of 1 , 3-dithiane (5,7 g, 47.4 mmol) in anhydrous tetrahydrofuran (THF, 60 mL) under an atmosphere of nitrogen at -40 °C was slowly added a solution of n-BuLi (27 mL, 67.5 mmol). After the reaction mixture was stirred at -20 °C for another 2 h, a solution of the intermediate 6 (4.2 g, 8.46 mmol) in anhydrous THF (40 mL) was slowiy added under an atmosphere of nitrogen at -70 °C. The reaction was then stirred at -78 °C for 1 h before it was quenched with a saturated solution of NaHC03. Extraction was conducted with EtOAc and the organic phase was washed with water (50 mL), saturated brine (50 mL), dried over sodium sulfate, and evaporated under reduced pressure to provide a crude product, which was purified by column chromatography on silica gel (PE:EtOAc = 8:1 to 4:1 ) to afford the intermediate 7 (3.0 g, 5.22 mmol, 61.7 %). LC/MS: m/z calculated 574.4, found 575.0 (M + 1 )+.
Step G: Intermediate 8
To a solution of the intermediate 7 (3.5 g, 6.09 mmol), Et3N (2.55 mL, 18.26 mmol), and DMAP (0.149 g, .218 mmol) in DCM (40 mL) was added Ac20 (3.45 mL, 36.5 mmol) at room temperature. After stirring at 50 °C for 2 h, the reaction mixture was quenched with water. The organic phase was washed with water (100 mL), dried over sodium sulfate, and evaporated under reduced pressure to provide the intermediate 8 (3.41 g, 85 %). LC/MS: m/z calculated 658.4, found 659.1 (M + 1 )+.
Step H: Intermediate 9
To a solution of the intermediate 8 (4.5 g, 6.83 mmol) in acetonitrile (160 mL) and water (40 mL) was added /V-bromosuccinimide (NBS, 7.29 g, 41.0 mmol) at room
temperature. After stirring at room temperature for 10 min, the reaction was quenched with water. The organic layer was washed with saturated sodium sulfite solution (200 mL), dried over sodium sulfate, and evaporated under reduced pressure to afford the intermediate 9 (3.2g, 82 %). LC/MS: m/z calculated 568.4, found 569.3 (M + 1 )+.
Step I: Intermediate 10 To an ice-cooled solution of the intermediate 9 (3.2 g, 5.63 mmol) in i-butanol (300 mL), THF (60 ml_), and 2-methyl-2-butene (2 mL) was added slowly a solution of NaCI02 (7.19 g, 67.5 mmol) and NaH2P04 (6.75 g, 56.3 mmol) in water (60 mL) over 15 min. After stirring at 0 °C for 10 min, the reaction mixture was warmed to room temperature and stirred for another 30 min, followed by the difution with EtOAc. The organic phase was washed with water (100 mL), dried over sodium sulfate, filtered, and concentrated to dryness. The obtained residue was purified by column chromatography on silica gel (DC : eOH = 50:1 to 10:1 ) to afford the intermediate 10 (2.8 g, 81 %) as a white solid. LC/MS: m/z calculated 584.4, found 585.3 (M + 1 )+.
The following examples are for illustrative purposes only and not intended to limit the scope of the invention. For the scheme following Example 1, R1NHR2 represents an azetidinyl group; and R3 is HOOCC(CH3)2CH2C(0)0-.
Example 1 : 4-frf3aR,5aR,5bR,7a ,9S,11aR.11bR.13aS)-3a-ri - Azetidinyl(oxo)acetvn-5a,5b,8,8,11a-pentamet yl-1-(1-methylethvn-2-oxo- 3,3a,4,5,5aT5b,6JJa,8,9.10,11,11a,11b,12.13,13a-octadecahvdro-2H- cvclopentafa1chrvsen-9-vnoxy!-2,2-dimethvi-4-oxobutanoic acid
Figure imgf000081_0001
19-1
Figure imgf000082_0001
Figure imgf000082_0002
Step A: Intermediate 11
To a solution of the intermediate 10 (680 mg, 1.163 mmol) in DCM (5 mL) were added oxalyl chloride (3 mL, 35.5 mmol) and a few drops of DMF. The reaction mixture was stirred at room temperature for 3 h and evaporated under reduced pressure to afford the intermediate 11 as a light yellow solid.
Step B: Intermediate 12-1
To a solution of the intermediate 11 (430 mg, 0.713 mmol), DMAP (100 mg, 0.819 mmol) and Et3N (2 mL, 14.35 mmol) in DCM (10 mL) was added azetidine (200 mg,
3.5 mmol) at room temperature. After stirring at room temperature for 4 h, the reaction was diluted with DCM (50 mL). The organic phase was washed with water (50 mL), aqueous hydrochloric acid (2 N, 50 mL), then dried over sodium sulfate, and evaporated under reduced pressure to provide a crude product, which was purified by column chromatography on silica gel (PE:EtOAc =5:1 to 1 :1 ) to afford the intermediate 12-1 (300 mg, 67.5 %) as a white solid. LC/MS: m/z calculated 623.4, found 624.3 (M + 1 )+.
Step C: Intermediate 13-1 A mixture of the intermediate 12-1 (350 mg, 0.561 mmol) and KOH (19 mg, 0.353 mmol) in EtOH (6 mL) and toluene (6 mL) was stirred vigorously at room temperature for 15 min. The reaction mixture was neutralized with aqueous HCI (1 N) to pH 7. After the addition of water, the reaction was extracted with EtOAc. The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the intermediate 13-1 (320 mg, 97 %) as a light yellow solid. LC/ S: m/z calculated 581.4, found 582.3 (M + 1 )+.
Step D: Intermediate 14-1
To a solution of the intermediate 13-1 (430 mg, 0.74 mmol) in dimethylsulfoxide (DMSO, 8 mL) was added 2-iodoxybenzoic acid (IBX, 1.1 g, 3.93 mmol) at room
temperature. After stirring at room temperature overnight, the reaction was quenched with water and extracted with EtOAc. The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide a residue, which was purified by column chromatography on silica gel (PE:EA = 5:1 to 3:1 ) to afford the intermediate 14-1 (300 mg, 70 %) as a white solid. LC/MS: m/z calculated 579.4, found 580.3 (M + 1 )+.
Step E: Intermediate 18-1
A solution of the intermediate 14-1 (300 mg, 0.52 mmol) in 1 ,4-dioxane (15 mL) and concentrated HCI (5 mL) was stirred at room temperature overnight. The reaction was quenched with water (30 mL) and extracted with EtOAc (60 mL). The organic phase was washed with water, dried over sodium sulfate, and evaporated under reduced pressure to provide a residue, which was purified by column chromatography on silica gel (PE: EtOAc = 5: 1 to 3:1 ) to afford the intermediate 18-1 (70 mg, 25 %) as a white solid. LC/MS: m/z calculated 537.4, found 538.3 (M + 1 )+.
Step F: Compound 19-1
To a solution of the intermediate 8-1 (70 mg, 0.13 mmol) in pyridine (3 mL) were added 3,3-dimethyidihydro-2, 5-furandione (159 mg, 1.302 mmol) and DMAP (334 mg, 2.6 mmol). After heating at 90 "C overnight, the reaction mixture was extracted with DCM. The organic phase was washed with HCI (2 N, 25 mL), water (50 mL x 2), dried over sodium sulfate, and evaporated under reduced pressure to provide a residue, which was purified by column chromatography on silica gel (PE:EtOAc = 3:1 to 2:1 ) to afford the compound 19-1 (30 mg, 34.6 %) as a white solid product. 1H NMR (400 MHz, CDCI3) δ ppm 4.54-4.42 (2H, m), 4.28-4.35 ( H, m), 4.05-4. 5 (2H, m), 3.17-3.25 (1H, m), 2.75-2.62 (4H, m), 2.60-2.52 (2H, m), 2.35(1 H, quint, J = 8.0 Hz), 2.17 (1 H, d, J = 19.2 Hz), 2.10-2.00 (1 H, m), 1.96-1.82 (1 H, m), 1.78-0.78 (42H, m). LC/MS: m/z calculated 665.9, found 664.4 (M - 1 )-.
Example 2: 2,2-Dimethyl-4-oxo-4-qf3aR,5aR,5bR,7aR,9S.11aR,11 bR.13aS)- 5a,5b,8,8,11a-pentamethyl-1-f1-methylethvn-3a-r[4-fmethylsulfonvn-1- piperazinyl1(oxo)acetvn-2-oxo-3.3aA5,5a,5b,6,7Ja,8,9T10,11,11a,11 b,12,13,13a- octadecahvdro-2H-cvclopentara1chrysen-9-yl)oxy)butanoic acid
Figure imgf000084_0001
Figure imgf000084_0002
Intermediate 12-2
To a mixture of the intermediate 10 (600 mg, 1.026 mmoi), diisopropylethylamine (DIPEA, 2 g, 15.47 mmol), and 2-(1 /- -7-azabenzotriazol-1 -yi)-1 ,1 ,3,3-tetramethyl uronium hexafluorophosphate methanaminium (HATU, 1.4 g, 3.68 mmol) in DMF (8 mL) was added 1 -(methyisulfonyl)piperazine (700 mg, 4.26 mmo!) at room temperature. After stirring at room temperature for 4 h, the reaction mixture was quenched with water (100 mL), and extracted with EtOAc (200 mL). The organic phase was dried over sodium sulfate, and evaporated under reduced pressure to provide a residue, which was purified by column chromatography on silica gel (DCM:MeOH = 100: 1 to 30:1 ) to afford the intermediate 12-2 (650 mg, 87 %) as a white solid. LC/MS: m/z calculated 730.4, found 731.3 ( + 1 )+.
Compound 19-2
Compound 19-2 was prepared as a white solid from the intermediate 12-2 with a procedure similar to that used in Example 1 , where R NHR2 is methylsulfonylpiperazine. 1H N R (400 MHz, CDCI3) 0" ppm 4.54-4.46 (1 H, m), 3.82-3.73 (1 H, m), 3.68-3.53 (2H, m), 3.50-3.42 (1 H, m), 3.36-3.18 (5H, m), 2.82(3H, s), 2.78-2.50 (5H, m), 2.20 (1 H, d, J = 18.4 Hz), 2.10-2.06 ( H, m), 1.90-0.82 (43H, m). LC/MS: m/z calculated 772.4, found 773.3 (M + 1 )+.
Example 3: 2,2-dimethy|-4-oxo-4-»Y3aR,5aR.5bR.7aR,9S,11 aR,11 pR, 13aS - 5a<5b.8.8 1a-pentamethyl-1-(1-methylethyl)-3a-rf4-methyl-1-piperazinyl)(oxo)acetvn-2- oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11 , 11 a,11 b, 12, 13,13a-octadecahvdro-2H- cyclopentara1chrvsen-9-yl)oxy)butanoic acid
Figure imgf000085_0001
A similar procedure used to prepare the compound of Example 2 was followed to prepare the title compound as a light yellow solid. In this case, R NHR2 is
1 -methyipiperazine. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.38-4.32 (1 H, m), 3.52-3.17 (6H, m), 2.60-2.20 (9H, m), 2.19 (3H, s), 1.98-0.79 (44H, m). LC/MS: m/z calculated 709.0, found 707.5 (M - 1 )-.
Example 4: 4-fFf3aR,5aR,5bR,7aR.9S,11aR,11bR,13aS)-3a-rr(4- Fluorophenv[)amino1(oxo)acetvn-5a,5b.8,8.11a-pentamethyl-1-fi-rnethylethy[)-2-oxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a.11b,12.13,13a-octadecahvdro-2H- cvclopentaralchrvsen-9-ynoxy>-2,2-dimethyl-4-oxobutanoic acid
Figure imgf000085_0002
Step A: Intermediate 15
To a solution of the intermediate 10 (500 mg, 0.855 mmol) in EtOH (2 mL) and toluene (2 mL) at room temperature was added KOH (192 mg, 3.42 mmol). After stirring at room temperature for 30 min, the reaction mixture was diluted with DCM (100 mL). The organic phase was washed with aqueous NH4CI (50 mL χ 2) and brine (50 mL), dried over sodium sulfate and evaporated to dryness under reduced pressure to afford the intermediate 15 (400 mg, 86 %). LC/MS: m/z calculated 542.4, found 543.1 (M + 1 )+.
Step B: Intermediate 16
To a solution of the intermediate 15 (290 mg, 0.534 mmol) in DMSO (6 mL) at room temperature was added IBX (1496 mg, 5.34 mmol). After stirring at 50 °C for 3 h, the reaction mixture was cooled down to room temperature and diluted with DCM (100 mL). The organic phase was washed with water (50 mL χ 4), dried over sodium sulfate and evaporated to dryness under reduced pressure to afford the intermediate 16 (234 mg, 81 %) as a yellow solid. LC/MS: m/z calculated 540.4, found 541 .1 (M + 1 )+.
Step C: Intermediate 17
To a solution of the intermediate 16 (350 mg, 0.664 mmo!) in DCM (8 mL) under an atmosphere of nitrogen at 0 °C was added slowly oxalyl chloride (1 .4 mL, 15.99 mmol) over 5 min. After stirring at room temperature for 1 h, the reaction mixture was evaporated to dryness to afford the intermediate 17 as a light yellow solid.
Step D: Intermediate 14-4
A mixture of 4-fluoroaniline (221 mg, 1 .992 mmol) and Et3N (0.463 mL, 3.32 mmol) in DCM (7 mL) was added the intermediate 17 (371 mg, 0.664 mmol) at room temperature. After stirring at room temperature for 1 h, the reaction mixture was diluted with DCM (50 mL). The organic phase was washed with water (50 mL), brine (25 mL), dried over sodium sulfate, and evaporated to dryness under reduced pressure to provide a residue, which was purified by column chromatography on silica gel (PE: EtOAc = 5: 1 to 1 : 1 ) to afford the intermediate 14-4 (150 mg, 36 %) as a white solid. LC/MS: m/z calculated 634.4, found 635.3 (M + 1 )+.
Compound 19-4
The compound 19-4 was prepared as a yellow solid from the intermediate 14-4 with a similar procedure used in Example 1. H NMR (400 MHz, CDCI3) δ ppm 8.72 (1 H, s), 7.61 - 7.57 (2H, m), 7.08-7.03 (2H, m), 4.52-4.48 (1 H, m), 3.28-3.20 (1 H, m), 2.78-2.53 (5H, m), 2.25 (1 H, d, J = 18.8 Hz), 2.08-1 .87 (2H, m), 1.18-0.81 (42H, m). LC/MS: m/z calculated 719.4, found 720.3 (M + 1 )+.
Example 5: 2,2-dimethyl-4-oxo-4-rff3aR,5aR,5bR,7aR,9S,11aR,11 bR.13aS)- 5a,5b,8,8,11 a-pentamethyl-1 -(1-methylethyl)-2-oxo-3a-foxo (2- thienylmethyl amino1acetyl>-3.3a.4.5.5a,5b.6,7,7a,8.9.10.11 ,11a.11 b,12.13.13a- octadecahvdro-2H-cvclopentara1chrvsen-9-yl)oxylbutanoic acid
Figure imgf000087_0001
intermediate 14-5
To a solution of the intermediate 16 (220 mg, 0.407 mmol), HATU (309 mg, 0.814 mmol), and DIPEA (0.36 mL, 2.1 mmol) in DMF (10 mL) was added (2-thienylmethyl)amine (46 mg, 0.407 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight and diluted with DCM. The organic phase was washed with water (50 mL), dried over sodium sulfate and evaporated to dryness in vacuo to provide a residue, which was purified by column chromatography on silica gel ( PE:EtOAc = 20:1 to 4:1 ) to afford the intermediate 14-5 (60 mg, 23 %) as a yellow solid. LC/MS: m/z calculated 636.4, found 637.3 (M + 1 )+.
Compound 19-5
The compound 19-5 was prepared as a yellowish solid from the intermediate 14-5 with a similar procedure used in Example 1. 1H NMR {400 MHz, CDCI3): <5 ppm 7.25 (1 H, dd, J = 4.8 Hz, 1.6 Hz), 7.19 (1 H, t, J = 5.6 Hz), 7.00-6.94 (2H, m), 4.66 (1 H, dd, J = 15.2 Hz, 6.0 Hz), 4.57 (1 H, dd, J - 15.2 Hz, 6.0 Hz), 4.54-4.47 (1 H, m), 3.25-3.20 (1 H, m), 2.76-2.52 (5H, m), 2.21 (1 H, d, J = 18.8 Hz), 2.08-1.86 (2H, m), 1.78-0.81 (42H, m). LC/MS: m/z calculated 722.4, found 723.3 (M + 1 )+. Example 6: 4-g3aR.5aR,5bR,7aR,9S,i1aR.11bR,13aS)-3a-(2-f1-(4- chlorophenvncvclopropylamino)-2-oxoacetyl)-1-isopropyl-5a.5b,8,8,11a-pentamethyl- 2-oxo-3,3a,4,5,5a.5b.6.7,7a,8,9,10,1l11a,11b,12,13,13a-octadecahvdro-2H- cvclopentara1chrvsen-9-yloxy)-2,2-dimethyl-4-oxobutanoic acid
Figure imgf000088_0001
Figure imgf000088_0002
Figure imgf000088_0003
Figure imgf000088_0004
To a solution of the intermediate 16 (10 g, 1 S.5 mmoi), 1 -(4-chlorophenyl) cyclopropanamine hydrochloride (4.15 g, 20.34 mmol), and HATU (14.06 g, 37 mmol) in DMF (35 mL) was added DIPEA (12.92 mL, 74 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. After the pH of the reaction mixture was adjusted to 3-4 with 2 N HCI, the resulting precipitates were collected and washed with water (600 mL). The obtained solid was dissolved in DC , and the solution was dried over sodium sulfate. DCM was removed by rotary evaporation under reduced pressure to provide a crude product, which was taken up in PE/EtOAc/DCM (10/1/1 ) to afford the intermediate 14-6 (1 1 g, 15.16 mmol, 82 %) as a solid. LC/MS: m/z calculated 689.4, found 690.3 (M+1 )+. Step B: Intermediate 18-6-1
To a solution of the intermediate 14-6 (1 1 g, 15.93 mmol) in 1 ,4-dioxane (300 mL) was added cone. HCI (100 mL, 15.93 mmol) at room temperature. The reaction mixture was stirred at 45 °C overnight, and concentrated under reduced pressure to dryness. The residue was dissolved in DCM (300 mL). The organic phase was washed with saturated NaHC03l brine, water, dried over Na2S0 , and purified by column chromatography on silica gel (EtOAc:PE = 1 : 10) to afford the intermediate 18-6-1 (9.7 g, 13.8 mmol, 87 %) as a white solid. LC/MS: m/z calculated 647.4, found 648.3 (M + 1 ) +.
Step C: Intermediate 18-6-2
To a solution of 4-ferf-butoxy-3, 3-dimethyl-4-oxobutanoic acid (9.08 g, 44.9 mmol), DMAP (9.14 g, 74.8 mmol) in DCM (25 mL) were added 1 -ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDCI, 14.34 g, 74.8 mmol) and the intermediate 18-6-1 (9.7 g, 14.96 mmol) at room temperature. After stirring at room temperature for 1 h, the pH of the reaction mixture was adjusted to 3-4 by 2 N HCI. The precipitates were collected, washed with water, and then dissolved in DCM (300 mL). The organic phase was washed with saturated aqueous NaHC03 (300 mL x 8), 2 N HCI (300 mL), water and brine, and dried over Na2S04. Removal of the solvent under reduced pressure provided a crude product, which was further dissolved in DCM (80 mL). Trituration with hexane (120 mL) led to a suspension. The precipitates were collected, washed with hexane, dried in vacuo to afford the intermediate 18-6-2 (10 g, 12.01 mmol, 80.3 %) as a off-white solid. HNMR (400 MHz, CDCL3) δ ppm 7.36 (1 H, s), 7.27 (2H, d, J = 8.4 Hz), 7.20 (2H, d, J = 8.4 Hz ), 4.52 (1 H, dd, J = 1 1 .2, 5.2 Hz), 3.22-3.15 (1 H, m), 2.725 (1 H, d, J = 13.2 Hz), 2.59 (1 H, d, J = 22 Hz), 2.46 (1 H, t, J = 8, 7.6 Hz), 2.19 (1 H, d, J = 18.8 Hz), 1 .90 (2H, s), 1 .77-0.79 (57H, m). LC/MS: m/z calculated 831 .5, found 832.3 (M+1 )+. Step D: Compound 19-6
To a solution of the intermediate 18-6-2 (10 g, 12.01 mmol) in DCM ( 00 mL) was added TFA (30 mL, 389 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water (30 mL), and extracted with DCM (20 mL x 3). The organic phase was washed with saturated aqueous NaHC03 (15 mL x 2), water (20 mL), brine (20 mL), and dried over sodium sulfate. Removal of the solvent under reduced pressure afforded a crude product as a light yellow solid, which was purified by column chromatography on silica gel (Hex:EtOAc = 5: 1 to 4: 1 ) to afford the compound 19-6 (8.2 g, 10.56 mmol, 88 %) as a white solid. This material was combined with additional batches made in a similar manner such that 41.5 g of 4-({(3aR,5aR,5bR,7aR,9S, 1 1 aR, 1 bR, 13aS)- 3a-(2-((1 -(4-Chlorophenyl)cyclopropyl)amino)-2-oxoacetyl)-l HSopropyl-5a,5b,8,8, 1 1 a- pentamethyl-2-oxo-3,3a,4)5,5a,5b)6J7,7a,8,9,10)11 l1 1 a,11 b,12,13, 13a-octadecahydro-2H- cyclopenta[ajchrysen-9-yl)oxy)-2,2-dimethyi-4-oxobutanoic acid was dissolved into dichloromethane ( 200 mL) and n-hexane (300 mL) was added. The solution was slowly concentrated at r.t to remove the half of the dichloromethane resulting in a white solid appearing. The suspension was filtered, washed with hexane to afford the title compound (34 g, 43.8 mmol, 82 % yield) as a white solid. H NMR (400MHz ,CHLOROFORM-d) =
10.42 (br. s„ 1 H), 7.39 (s, 1 H), 7.25 (d, J = 8.8 Hz, 2 H), 7. 8 (d, J = 8.5 Hz, 2 H), 4.50 (dd
J = 5.0, 1 1.0 Hz, 1 H), 3.16 (m, 1 H), 2.76 - 2.63 (m, 2 H), 2.63 - 2.52 (m, 2 H), 2.43 (dd, J = 7.5, 8.3 Hz, 1 H), 2.18 (d, J = 18.8 Hz, 1 H), 1.96 - 1 .81 (m, 2 H), 1 .79 - 1.47 (m, 6 H), 1 .46 - 0.74 (m, 13 H), 1.31 (s, 3 H), 1 .30 (s, 3 H), 1 .22 (d, J = 6.8 Hz, 3 H), 1.21 (d, J = 6.8 Hz, 3 H), 0.93 (s, 3 H), 0.91 (s, 3 H), 0.88 (s, 3 H), 0.84 (s, 3 H), 0.81 (s, 3 H); LC/MS: m/z calculated 775.4, found 776.2 (M + 1 )+.
The intermediate IV used above was prepared according to the following procedure.
Figure imgf000090_0001
Figure imgf000090_0002
IV
Step A: Intermediate II A solution of 3,3-dimethyl-dihydrofuran-2,5-dione I (25 g, 195 mmol) in anhydrous EtOH ( 150 mL) was stirred at 50 °C overnight. After cooling down to room temperature, the solvent was removed under reduced pressure with a rotary evaporator and the residue was triturated with hexane at -50 °C to afford the intermediate II (25 g, 33 mmol, 67.9 %) as a white solid. 1 H NMR (400 MHz, CDCI3) 5 ppm 4.13-4.18 (2H, q, J = 7.2 Hz), 2.62 (2H, s),
1.28 (6H, s), 1.32-1 .25 (3H, t, J = 7.6 Hz). LC/MS: m/z calculated 174.1 , found 1 3.1 (M-1 )-.
Step B: Intermediate HI
To a mixture of the intermediate II (20 g, 109 mmol), magnesium sulfate (52.5 g, 436 mmol), and tert-butanol (60 mL) in DC (480 mL) was added sulfuric acid (8.72 mL, 164 mmol). After stirring at room temperature overnight, the reaction mixture was poured into saturated sodium bicarbonate solution (300 mL) and water (300 mL). DCM was added to extract the desired product, and the organic phase was washed with brine, dried, and concentrated to afford the intermediate III (19 g, 83 mmol, 80 %) as a colorless oil. 1H NMR (400 MHz, CDCI3) δ ppm 4.02-4.08 (2H, q, J = 7.2 Hz), 2.46 (2H, s), 1.07 (9H, s), 1.14-1 .20 (9H, m). LC/MS: m/z calculated 230.2, found 253.1 (M+Na)+.
Step C: Intermediate IV
To a solution of the intermediate III (10 g, 41 .3 mmol) in EtOH (200 mL) was added potassium hydroxide (12.86 g, 206 mmol) in water (100 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The pH of the reaction mixture was adjusted to 3-4 by 1 N HCI. The resulting solution was extracted with ether (300 mL), and the ether phase was dried and concentrated to afford a crude product, which was re- crystallized from hexane at -10°C to afford the intermediate IV (4 g, 19.78 mmol, 47.9 %) as a white solid. 1H NMR (400 MHz, CDCI3) 5 ppm 2.58 (2H, s), 1 .43 (9H, s), 1 .25 (6H, s). LC/MS: m/z calculated 202.1 , found 201 .1 (M-1 )-. Example 7: 4-((3aR,5aR,5bR,7aR.9S, 1 1 aR,11 bR, 13aS)-3a-(2-( 1 -f 5-chloropyridin-
2-yl)cvclopropyiamino 2-oxoacetvn-1-isopropyl-5a,5b,8,8,1 a-pentamethyl-2-oxo- 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-oxobutano)c acid
Figure imgf000091_0001
Figure imgf000092_0001
Step A: Intermediate 17-2 To a solution of the intermediate 16 (5 g, 9.25 mmol) in 1 ,4-dioxane (100 mL) was added HCI (1 N, 50 mL, 50 mmol) at room temperature. The reaction mixture was further stirred at 40 °C overnight. The reaction mixture was concentrated and the residue was taken up in water (200 mL). The precipitates were collected by filtration, washed with water (400 mL), and dissolved in DCM. The DCM solution was washed with brine, dried over Na2S04, and evaporated under reduced pressure with a rotary evaporator to afford a yellow solid. This solid was re-crystallized from EtOAc and petroleum ether, and then re-crystallized from DCM and petroleum ether to provide the intermediate 17-2 (4.2 g, 7.16 mmol, 77 %) as a white solid. LC/MS: m/z calculated 498.3, found 499.2 (M+1 )+.
Step B: Intermediate 18-7 To a solution of the intermediate 17-2 (3 g, 5.41 mmol), HATU (4.12 g, 10.83 mmol), and 1-(5-chloropyndin-2-yl)cyclopropanamine (1.22 g, 6.5 mmol) in DMF (3.5 mL) was added DIPEA (3.78 mL, 21.66 mmol) at 0 °C. The reaction mixture was further stirred at 25 °C for 1 h. After adding saturated aqueous ammonium chloride, the reaction was extracted with DCM (15 mL x 3). The combined organic layer was washed with iced brine (10 mL), dried over Na2S04, filtered, and concentrated under reduced pressure to afford the intermediate 18-7 (2.97 g, 3.79 mmol, 70 %) as a solid. LC/MS: m/z calculated 649.3, found 649.3 (M+1 )+.
Compound: 19-7 The compound 19-7 was prepared as a white solid from the intermediate 18-7 with a similar procedure used in Example 6. H NMR (400 MHz, CDCI3) δ ppm 8.40 (1 H, d, J = 2.4 Hz), 7.56 (1 H, s), 7.55 (1 H, dd, J = 2.4 Hz, 8.4 Hz), 7.1 1 (1 H, d, J = 8.4 Hz), 4.50 ( H, dd, J = 4.8 Hz, 1 1.2 Hz), 3.23-3.13 (1 H, m), 2.78-2.54 (5H, m), 2.21 (1 H, d, J = 18.8 Hz), 2.03- 1 .85 (2H, m) 1 .77-0.75 (46H, m). LC/MS: m/z calculated 776.4, found 777.3 (M+1 )+.
Example 8: 4-(3aR.5aR.5bR,7aR,9S.1 1aR.11 bR.13aS)-3a-f2-f1-f4- chlorophenvncvclopropylamino)'2-oxoacetyl)-1-isopropyl-5a15b,8,8,11a-pentamethyl- 2-oxo-3.3a,4,5,5a,5b,6,7,7a,8,9,10, 1 ,11a,11 b.12.13.13a-octadecahvdro-2H- cyclopentaralchrysen-9-yl 1 -(2-hydroxyethvO 2,2-dimethylsuccinate
Figure imgf000093_0001
To a solution of the compound 19-6 (1 g, 1 .29 mmol), DMAP (0.79 g, 6.44 mmol) in DCM (50 mL) were added EDC! (1 .23 g, 6.44 mmol) and ethane-1 ,2-diol (0.4 g, 6.44 mmol) at room temperature. After stirring at room temperature overnight, the reaction mixture was diluted with water (200 mL), and extracted with DCM (100 mL x 3). The organic phase was washed with saturated brine (200 mL), dried over sodium sulfate, and evaporated to dryness under reduced pressure to provide a crude product, which was purified by column
chromatography on silica gel (EtOAcPE = 1 :10 to 1 :3) to afford the compound 19-8 (700 mg, 65.9 %) as a white solid. 1 H NMR (400 MHz, CDCI3) δ ppm 7.34 (1 H, S), 7.25-7.23 (2H, m), 7.18-7.16 (2H, m), 4.51 -4.47 (2H, m), 4.30-4.17 (2H, m), 3.81 -3.77 (2H, m), 3.18-3.12 (1 H, m), 2.71 -2.54 (4H, m), 2.45-2.41 (1 H, t, J = 8 Hz), 2.19-2.14 (1 H, d, J = 9.4Hz), 1 .87-1 .86 (2H, m), 1 .74-0.76 (46H, m). LC/MS: m/z calculated 819.4, found 820.4(M + 1 )+. Example 9: ^iSaR.SaR.S R.TaR.QS.HaR.l l bR.I SaS^-aa^-fl-f^
chlorophenyl)cvctopropyiamino)-2-oxoacetv0-1 -isopropyl-5a,5b,8.8,11 a-pentamethyl- 2-oxo-3,3a,4,5,5a.5b,6,7Ja,8,9.10.11 ,11a,11 b,12.13.13a-octadecahvdro-2H- cyclopentafalchrysen-9-yl 1 -phosphonooxymethyl 2,2-dimethylsuccinate
Figure imgf000094_0001
19-9
Step A: Intermediate 19-6-1 To a solution of the compound 19-6 (500 mg, 0.644 mmol) in anhydrous D F (4 mL) were added di-ierf-butyl chloromethyl phosphate (333 mg, 1 .29 mmol) and K2C03 (267 mg, 1 .93 mmol) at room temperature. The reaction was then warmed to 50 °C and stirred for 4 h. DCM (15 mL) was added to the reaction mixture, and the organic phase was washed with water (1 0 mL x 3), dried over Na2S04l and concentrated. The residue was purified by column chromatography on silica gel (EtOAc:PE = 1 :4) to afford the intermediate 19-6-1
(330 mg, 0.33 mmol, 51.2 %) as a white solid. 1 H NMR (400 MHz, CDCi3) δ ppm 7.34 (1 H, s), 7.26 (2H, d, J - 8.4 Hz), 7.19 (2H, d, J = 8.4 Hz), 5.62 (2H, d, J = 12.8 Hz), 4.49 (1 H, q, J = 5.2 Hz), 3.20-3.13 (1 H, m), 2.73-2.56 (4H, m), 2.44 (1 H, t, J = 7.8 Hz), 2.21 -2.10 (1 H, m), 1.89-0.76 (66H, m).
Step B: Compound 19-9
The intermediate 19-6-1 (330 mg, 0.33 mmol) was dissolved in DCM FA (3:2, 10 mL). After stirring at room temperature for 30 min, the reaction was diluted with DCM (50 mL), and the organic phase was washed with water (50 mL x 4) and concentrated to afford a residue, which was taken up in MeCN (3 mL). The precipitates were collected and re- crystallized from MeCN to provide the compound 19-9 (80 mg, 0.089 mmol, 27 %) as a light yellow solid. 1H NMR (400 MHz, CDCI3) 5 ppm 7.45 (1 H, s), 7.25 (2H, d, J = 8.4 Hz), 7.19 (2H, d, J = 8.4 Hz), 5.67-5.51 (2H, m), 4.51-4.42 (1 H, m), 3.22-3.1 1 (1 H, m), 2.73-2.56 (4H, m), 2.45 (1 H, t, J = 7.8 Hz), 2.20-2.16 <1 H, m), 1.89-0.82 (48H, m). LC/MS: m/z calculated 885.4, found 884.2 (M - 1 )-.
Example 10: 4-(3aR.5aR,5bR,7aR,9S,11aR.11bR,13aS)-3a-(2-(1-(4- chlorophenyl)cyclopropylamino)-2-oxoacetyl)-1 -isopropyl-5a,5bT8,8, 1 a-pentamethyl-
2-oxo-3,3a.4,5,5a,5b.6.7.7a,8,9,10, 1 ,11a,11b,12.13.13a-octadecahvdro-2H- cyclopentaralchrvsen-9-yl 1 -(2-(phosphonooxy)ethvi) 2,2-dimethylsuccinate
Figure imgf000095_0001
19-6 19-6-2
Figure imgf000095_0002
Step A: Intermediate 19-6-2
To a stirring mixture of the compound 19-6 (200 mg, 0.26 mmol) and K2C03 (107 mg, 0.773 mmol) in DMF (5 mL) under a nitrogen atmosphere at room temperature was added 2- bromoethanol (48.3 mg, 0.386 mmol) in one portion. The reaction mixture was stirred at 70 °C overnight. After cooling down to room temperature, the reaction mixture was quenched with water. The aqueous phase was extracted with EtOAc. And the organic phase was dried over Na2S04, filtered, and concentrated. The crude product was purified by column chromatography on silica gel (PE: EtOAc = 30-0%) to afford the intermediate 19-6-2 (150 mg, 67.4 %) as a white foam. LC/MS: m/z calculated 819.5, found 820.3 (M + 1 )+.
Step B: Intermediate 19-6-3 To a solution of the intermediate 19-6-2 (83 mg, 0.1 mmol) in DC (2,5 mL) at room temperature were added DMAP (4.86 mg, 0.04 mmol), 1-H-tetrazole (20.9 mg, 0.3 mmol), and then di-feri-butyl N, /V-diisopropylphosphoramidite (83 mg, 0.3 mmol). The reaction mixture was stirred at room temperature for 2 h. At 0 °C, H202 (30% aq., 0.2 mL) was added and the reaction mixture was stirred for another 30 min. The reaction was quenched with water (100 mL) and extracted with EtOAc (100 mL). The organic phase was separated, washed with brine, dried over Na2S04, and concentrated to provide the intermediate 19-6-3 (70 mg, 65.1 %), which was used in next step without further purification. LC/MS: m/z calculated 101 1 .5, found 1012.3 (M + 1 )+.
Step C: Compound 19-10 The intermediate 19-6-3 (360 mg, 0.355 mmol) was dissolved in DCM/TFA (1 :1 , 2 mL) and the reaction mixture was stirred for 30 min at room temperature. After the removal of the solvents, the residue was washed with water (3 x 30 mL), HCI (1 Λ/, 30 mL), and then water (3 x 30 mL). Further concentration under reduced pressure afforded a crude product, which was re-crystallized from MeCN/Et20 to provide the compound 19-10 (300 mg, 93 %) as a pale-yellow solid. HNMR (400 MHz, CD3OD) δ ppm 7.37 (1 H, s), 7.26-7.16 (4H, m),
4.45 (1 H, m), 4.24 (4H, m), 2.41 (1 H, m), 2.71 -2.56 (4H, m), 2.17 (1 H, m), 1 .88 (2H, m), 1 .72 -0.80 (49H, m). LC/MS: m/z calculated 899.4, found 898.2 (M - 1 )-.
The preparation of the intermediate 16 was described in Example 4. Another method as indicated below was also used to make the same intermediate.
Figure imgf000097_0001
Step A: Intermediate 20
To a mixture of the intermediate 6 (300 mg, 0.604 mmol) and MeN02 (7.5 mL, 139 mmol) was added Et3N (0.6 mL, 4.30 mmol) at room temperature. After stirring overnight, the reaction mixture was quenched with water (1.0 mL), and partitioned between EtOAc (50 mL) and water (25 mL), The organic phase was washed with brine (50 mL), dried over sodium sulfate and evaporated to dryness in vacuo. The obtained residue was purified by column chromatography on silica gel (Hex:EtOAc = 4:1 ) to afford the intermediate 20 (335 mg, 99 %) as a white solid.
Step B: Intermediate 20-1 To a solution of the intermediate 20 (20 g, 35.9 mmol) in DCM (500 mL) was added
1 , 1 , 1 -trisacetoxy-1 , 1 -dihydro-1 ,2-benziodoxo!-3-(1 H)-one (DMP, 22.81 g, 53.8 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h, followed by the filtration with a MgS04 pad and washed with DCM (100 mL). DCM was removed by rotary evaporation and the residue was taken up in EtOAc (1.5 L). This mixture was stirred overnight, and the insoluble material was removed by filtration. The organic phase was washed with water (500 mL χ 4), dried over sodium sulfate, evaporated under reduced pressure to provide the intermediate 20-1 (14 g, 23.47 mmol, 65.4 %) as a yellow solid.
LC/MS: m/z calculated 555.3, found 556.3 (M + 1 )+.
Step C: Intermediate 16 To a solution of the intermediate 20-1 (15 g, 27 mmol) and sodium nitrite (7.45 g, 108 mmol) in DMSO (150 mL) was added acetic acid (30.9 mL, 540 mmol) at 0 °C. The reaction mixture was further stirred at room temperature overnight. After the starting material was consumed, the pH of the reaction mixture was adjusted to 4-5 with 2 N HCI (c.a. 1200 mL). The precipitates were collected by filtration, washed with water (400 mL). The obtained yellow solid was dissolved in DCM. The resulting solution was washed with saturated brine, dried over sodium sulfate and evaporated under reduced pressure to provide a crude product. The crude product was re-crystallized from EtOAc and PE (1 :8, 300 mL) and then re-crystallized again from DCM and PE (1 :10, 200 mL) to afford the intermediate 16 (8.5 g, 15,26 mmol, 56.5 %) as a white solid. LC/MS: m/z calculated 540.3, found 541.3 (M + 1 )+.
Example 11 : 4-ffl3aR,5aR,5bR,7aR,9S,11aR.11bR,13aS)-3a-((r(4-
Ch ioropheny[)methyl1amino acetvH-5a,5b,8,8,11 a-pentamethyl-1 -(1 -methylethvO-2- oxo-3.3a,4.5,5a.5b.6.7Ja,8,9,10,11.11a,11b.12.13,13a-octadecahvdro-2H- cvclopentafa1chrvsen-9-vnoxy>-2,2-d?methyl-4-oxobutanoic acid
Figure imgf000098_0001
Figure imgf000099_0001
Step A: Intermediate 21
To a solution of NiCI2-6H20 (0.929 g, 7.17 mmol) in MeOH (125 mL) was added portionwise sodium borohydride (0.271 g, 7.17mmol) at 0 °C. After stirring for 30 min, the intermediate 20 (2 g, 3.59 mmol) was added, followed by the addition of another portion of sodium borohydride (2.44 g, 64.53 mmol). The reaction mixture was stirred at 0 "C for another 30 min, and filtration was performed to remove the insoluble material. The filtrate was concentrated to dryness in vacuo. The obtained residue was dissolved in EtOAc (100 mL), and the organic phase was washed with water (40 mL), brine (40 mL), dried over sodium sulfate, and evaporated to dryness In vacuo to provide the intermediate 21 (1.79 g, 95 %) as an off-white solid. LC/MS: m/z calculated 527.3, found 528.2 (M + 1 )+.
Step B: Intermediates 22-1 and 23-1 To a suspension of the intermediate 21 (450 mg, 0.853 mmol) and 4- chlorobenzaldehyde (120 mg, 0.853 mmol) in MeOH (30 mL) was added ZnCI2 (69.7 mg, 0.083 mmol) at room temperature. After stirring at room temperature for 2 h, sodium cyanoborohydride (107 mg, 0.25 mmol) was added, and the resulting mixture was stirred for another 2 h to provide the intermediate 22-1.
To the reaction mixture obtained above were added Boc20 (0.297 mL, 1 .279 mmol) and Et3N (0.238 mL, 1.705 mmol). After stirring at room temperature overnight, the insoluble material was removed by filtration, and the filtrate was concentrated to dryness under reduced pressure. The obtained residue was dissolved in EtOAc (50 mL), and the rganic phase was washed with water (25 mL), brine (25 m), dried over magnesium sulfate, and evaporated to dryness in vacuo to provide a residue, which was purified by Prep-TLC to afford the intermediate 23-1 (164 mg, 25.6 %) as a white solid.
Step C: Intermediate 24-1
To a solution of the intermediate 23-1 (130 mg, 0.1 3 mmol) in DC (5 mL) were added PCC (372 mg, 1 .728 mmol) and silica gel (120 mg) at room temperature. After stirring at room temperature for 8 h, the insoluble material was removed by filtration and the filtrate was concentrated to dryness under reduced pressure. The obtained residue was purified by column chromatography on silica gel (Hex:EtOAc = 1 :6) to provide the intermediate 24-1 (92 mg, 71 %) as a white solid. LC/MS: m/z calculated 785.4, found 686.0 (M - Boc+1 )+.
Step D: Intermediate 25-1
To a solution of the intermediate 24-1 (28 mg, 0.037mmol) in 1 , 4-dioxane (2.5 mL) was added cone. HCI (1.0 mL, 32.9 mmol). After stirring at room temperature overnight, the reaction mixture was diluted with EtOAc (50 mL), neutralized with saturated sodium bicarbonate solution, and partitioned between EtOAc (50mL) and saturated sodium bicarbonate (25 mL). The organic phase was washed with saturated sodium bicarbonate (25 mL), brine (25 mL), dried over sodium sulfate and evaporated to dryness in vacuo to provide the intermediate 25-1 (22.3 mg, 98 %) as a colorless oil. LC/MS: m/z calculated 607.3, found 608.1 (M + 1 )+.
Step E: Intermediate 26-1
To a solution of the intermediate 25-1 (79 mg, 0.13 mmol) and Boc20 (28.3 mg,
0.13 mmol) in DCM (5 mL) was added Et3N (18 pL, 0.13 mmol). After stirring at room temperature for 1 h, the reaction mixture was quenched with water (1.0 mL), and partitioned between EtOAc (25 mL) and water (10 mL). The organic phase was washed with saturated sodium bicarbonate ( 10 mL), brine (10 mL), dried over sodium sulfate and evaporated to dryness in vacuo to provide a residue, which was purified by column chromatography on silica gel (Hex:EtOAc = 5: 1 ) to afford the intermediate 26-1 (57 mg, 62 %) as a white foam.
Step F: Intermediate 27-1 To a solution of the intermediate 26-1 (26 mg, 0.037 mmol) in anhydrous pyridine (2 mL) were added D AP (22.42 mg, 0.184 mmol) and 3,3-dimethy[dihydro-2,5-furandione (47 mg, 0.367 mmol). After stirring at 80 °C overnight, the reaction mixture was diluted with EtOAc (30 mL). The organic phase was washed with aqueous HCI (2 N, 10 mL), brine (20 mL), dried over sodium sulfate and evaporated to dryness in vacuo to provide a residue, which was purified by column chromatography on silica gel (Hex:EtOAc = 4:1 ) to afford the intermediate 27-1 (15 mg, 48.9 %) as a white foam. LC/MS: m/z calculated 835.4, found 858.4 (M + Na)+.
Step G: Compound 28-1
To a solution of the intermediate 27-1 (27 mg, 0.032 mmol) in DCM (1.0 mL) was added TFA (0.5 mL, 6.49 mmol) dropwise. After stirring at room temperature for 1 h, the reaction mixture was neutralized by aqueous sodium bicarbonate (25 mL). The reaction mixture was partitioned between EtOAc (50 mL) and aqueous sodium bicarbonate (25 mL) and the organic phase was washed with brine (25 mL), dried over sodium sulfate and evaporated to dryness in vacuo to afford a residue, which was purified by Prep-HPLC to provide the title compound 28-1 (9 mg, 29.5 %). LC/MS: m/z calculated 735.3, found 736.3 (M + 1 )+.
Example 12: 4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-fbis(2- (dimethv[amino)ethyl)amino)acetyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-
3,3a,4.5,5a.5b,6,7.7a,8.9.10.11.11 a.1 ΐ b, 12.13.13a-octadecahvdro-2H- cvclopentaralchrvsen-9-yloxy¾-2,2-dimethyl-4-oxobutanoic acid
Figure imgf000101_0001
28-2
Figure imgf000102_0001
Step A: Intermediate 22-2
To a solution of the intermediate 21 (3 g, 5.68 mmoi), which was made from the intermediate 6, and Boc20 (1.861 g, 8.53 mmol) in DCM (25 ml_) was stirred at room temperature for 30 min. The reaction mixture was concentrated first and diluted with EtOAc and water. The organic phase was washed with brine, dried with Na2S04 and evaporated to afford the intermediate 22-2 (4 g, 4.46 mmol, 78 % yield) which was used in next step reaction without further purification. Step B: intermediate 23-2
To a solution of the intermediate 22-2 (4 g, 6.37 mmol) in DCM (100 mL) stirred at 45 °C were added PCC (4.12 g, 9.1 1 mmol) and siiica gel (5 g). The reaction mixture was stirred at 45 °C overnight. To the reaction mixture were added water and EtOAc. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to provide a crude
l O l product, which was purified by column chromatography on silica gel (PE: EtOAc = 7:1 ) to afford the intermediate 23-2 (2.4 g, 3.53 mmol, 55.4 % yield) as a light yellow solid.
Step C: Intermediate 24-2
A solution of the intermediate 23-2 (1.5 g, 2.397 mmol) in 1 ,4-dioxane (30 mL) and cone. HCI (20 mL) was stirred at 35 °C overnight. To the reaction mixture was added water (30 mL) and the crude product was extracted with EtOAc. The organic phase was washed with water, dried over sodium sulfate, and evaporated in vacuo to provide the intermediate 24-2 (1 g, 2.05 mmol, 85 % yield) as a yellow solid. LC/MS: m/z calculated 483.4, found 484.2 (M + 1 )+. Step D: Intermediate 25-2
To a solution of the intermediate 24-2 (900 mg, 1.861 mmol) in DCM (10 mL) and TEA (0.5 mL) was added Boc20 (0.648 mL, 2.79 mmol). The reaction mixture was stirred at room temperature for 0.5 h. Then the reaction mixture was evaporated to dryness and the residue was purified by column chromatography on silica gel (PEtEtOAc = 3:1 ) to afford the intermediate 25-2 (170 mg, 0.272 mmol, 14.6 % yield) as a yellow solid.
Step E: Intermediate 26-2
To a solution of the intermediate 25-2 in pyridine (1 mL) were added DMAP (150 mg, 1.171 mmol) and 3, 3-dimethyldihydro-2,5-furandione (480 mg, 3.93 mmol). The reaction mixture was stirred at 80 °C for 1.5 h. After cooling down to room temperature, the reaction mixture was extracted with DCM (50 mL x 3). The organic phase was separated, washed with water, brine, and dried with Na2S04. Removal of the solvent provided a crude product, which was purified by column chromatography on silica gel (PE: EtOAc = 3:1 ) to afford the intermediate 26-2 (240 mg, 0.337 mmol, 70.3 % yield) as a white solid.
Step F: Intermediate 27-2 A solution of the intermediate 26-2 (240 mg, 0.337 mmol) in DCM (3 mL) and TFA
(0.5 mL) was stirred at room temperature for 0.5 h. The reaction mixture was evaporated to dryness under reduced pressure to provide the intermediate 27-2 (100 mg, 0.155 mmol, 46.1 % yield) as a yellow oil.
Step G: Compound 28-2 A solution of the intermediate 27-2 (120 mg, 0.196 mmol) and 2-{dimethylamino) acetaidehyde (280 mg, 2.27 mmol) in MeOH (25 mL) was stirred at room temperature for 2 h. Then sodium cyanoborohydride (61 .6 mg, 0.981 mmol) was added, and the resulting mixture was stirred at room temperature for another 3 h. The reaction mixture was evaporated to dryness and the residue was purified by Pre-HPLC to provide the compound 28-2 (53 mg, 0.046 mmol, 23.63 %) as a white solid. 1 HN R (400 MHz, CDCI3) δ ppm 4.52-4.48 (1 H,m), 3.72-3.60 (1 H, m), 3.27.3.24 (4H, m), 3.03-2.99 (4H, m), 2.96 (12H, s), 2.68-2.48 (4H, m), 2.48 (1 H, d, J = 19.2 Hz), 2.20 (1 H, d, J = 19.2 Hz), 2.10-0.89 (55H, m). LC/MS: m/z calculated 753.6, found 754.3 (M + 1 )+. Example 13: 4-(i3aR,5aR,5bR,7aR,9S.11aR,11 bR,13aS)-3a-(2-ff4- chiorobenzyl)(2-(dimethv[amino)ethyl¾amino)acetyl)-1-isopropyl-5a,5b,8,8,1 a- pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9.10,11 ,11 a,11 b,12,13,13a-octadecahvdro- 2H-cyclopentaralchrvsen-9-yloxy)-2,2-dimethyl-4-oxobutanoic acid
Figure imgf000104_0001
28-3
Step A: Intermediate 26-3
To a solution of 2-(dimethylamino)acetaldehyde (5.75 g, 46.5 mmol) in MeOH (56.2 mL) were added the intermediate 25-1 (7 g, 10.86 mmol) and TEA (10 mL), The reaction mixture was stirred at 40 °C for 2 h. After cooling down to room temperature, sodium cyanoborohydride (3.41 g, 54.3 mmol) was added and the resulting mixture was stirred overnight. The reaction mixture was filtered and the filtered cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was taken up in DCM (200 mL), washed with saturated NaHC03 solution (200 mL x 2), water (200 mL x 2), brine (200 mL), dried over Na2SO,i, filtered, and evaporated under reduced pressure to afford a crude product as a light yellow foam, which was purified by column chromatography on a silica gel (DCM:MeOH = 50:1 to 15:1 ) to provide the intermediate 26-3 (3 g, 40.7%) as a white solid. LC/MS: m/z calculated 678.5, found 679.3 (M+1 )+.
Step B: Compound 28-3
To a solution of the intermediate 26-3 (13 g, 19.13 mmol) and 3,3-dimethyl- dihydrofuran-2,5-dione (12.26 g, 96 mmol) in pyridine (10 mL) was added DMAP (7.01 g, 57.4 mmol). The reaction mixture was stirred at 80 °C for 1.5 h. After cooling down, the solvent was removed by evaporation. The residue was dissolved in DCM (300 mL), and the solution was washed with ammonium chloride solution (120 mL x 2), water (120 mL x 2), brine (120 mL), dried over Na2S04, filtered, and evaporated under reduced pressure to afford a crude product, which was purified by column chromatography on silica gel
( EtOAc:PE = 1 :1 to DCM:MeOH = 10:1 ) to provide the compound 28-3 (7.2 g, 8.92 mmol, 46.6 %) as a white solid. 1HNMR (400 MHz, CD3OD) o~ ppm 7.37 (4H, s), 4.47-4.43 (1 H, m), 3.93 (1 H, d, J = 13.2Hz), 3.56 (1 H, d, J = 13.2Hz), 3.22-3.12 (2H, m), 2.96-2.91 (8H, m), 2.64-2,47 (3H, m), 2.36-2.32 (1 H, m),2.10-1.93 (2H, m), 1.83-0.87 (48H, m). LC/MS: m/z calculated 806.5, found 807.3 (M + 1 )+.
Example 14: 4-((3aR,5aR.5bR.7aR,9S.11aR.11bR.13aS)-3a-(2-(bis(4- chlorobenzyl)amino)acetvn-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo- 3,3a ,4,5,5a,5b.6,7,7a,8,9.10,11,11a,11 b,12.13,13a-octadecahvdro-2H- cvclopentaralchrvsen-9-yloxy)-2,2-dimethyl-4-oxobutanoic acid
Figure imgf000105_0001
Figure imgf000106_0001
Compound 28-4
To a solution of compound 28-1 (250 mg, 0.339 mmol) and 4-chlorobenzaldehyde (143 mg, 1.018 mmol) in 1 ,2-dichloroethane (DCE, 3 ml_), MeOH (5 ml_) was added zinc chloride (27.8 mg, 0.204 mmol). The reaction mixture was stirred at room temperature for 1 h, followed by the addition of sodium cyanoborohydride (32 mg, 0.509 mmol). The reaction was diluted with water, and extracted with EtOAc. The organic phase was washed with water and concentrated to provide a crude product, which was purified by Pre-HPLC to afford the compound 28-4 as a white solid. 1HNMR (400 MHz, CDCi3) δ ppm 7.33-7.26 (8H, m), 4.50- 4.46 ( H, m), 3.87 (2H, d, J = 13.6 Hz), 3.57 (2H, d, J = 13.6 Hz), 3.27 (2H, s), 3.15-3.09 (1 H, m), 2.68 (1 H, d, J = 15.6 Hz), 2.57(1 H, d, J = 15.6 Hz), 2.48-2.45 (1 H, m), 2.12 (1 H, d, J = 19.2 Hz), 2.09-0.80 (47H, m). LC/MS: m/z calculated 859.4, found 860.3 (M+1 )+.
Example 15: 4-f3aR,5aR,5bRJaR,9S,11aR.11bR,13aS¾-3a-f2-((4-chlorobenzv[)f2-
(dimethylamino)ethyl)amino)acetyli-1 -isopropyl-5a,5b.8.8.11 a-pentamethyl-2-oxo- 3.3a,4,5.5a,5b,6,7T7a,8,9,10,11,11a,11b,12,13,13a-octadecahvdro-2H- cyciopentaralchrysen-9-νί 1 -ethyl 2,2-dimethylsuccinate
Figure imgf000106_0002
28-3 Z3-5
Compound 28-5 To the solution of the compound 28-3 (0.35 g, 0.433 mmol) in EtOH (10 mL) was added oxalyl chloride (5 mL, 57.1 mmol) at 0 °C. The reaction mixture was stirred at room temperature overnight. After that, the reaction was quenched with water, extracted with EtOAc. The combined organic phase was concentrated to provide a crude product, which was purified by Pre-HPLC to afford the compound 28-5 as a white solid. HN R (400 MHz, CD3OD) ό" pm 7.39 (4H, s), 4.47-4.43 (1 H, m), 4.14-4.12 (2H, m) 3.93 (1 H, d, J = 13.2 Hz), 3.56 (1 H, d, J = 13.2Hz), 3.22-3.12 (2H, m), 2.96-2.91 (8H, m), 2.64-2.47 (3H, m), 2.36-2.32 (1 H, m), 2.12 ( H, d, J = 19.2 Hz) 1 .83-0.87 (5 H, m). LC/MS: m/z calculated 834.5, found 835.4 (M+1 )+. Example 16: 4-fr(3aR,5aR.5bR,7aR,9S,11 aR,11 b ,13aS)-3a-m2-
Furanylmethyljaminolacetyl Sa.Sb^S^.l l a-pentamethyl-l -fl-methylethyll^-oxo- 3,3a A5,5a,5b,6,7,7a,8,9,10, 11 , 11 a, 11 b.12.13.13a-octadecahvdro-2H- cvclopentaralchrvsen-9-vnoxy}-2,2-diniethyl-4-oxobutanoic acid
Figure imgf000107_0001
2S-6
Intermediate 24-6
To a solution of the intermediate 23-6 (1.46 g, 1 .24 mmol) in DMSO ( 0 mL), which was prepared according to the description in previous examples, was added IBX (2 g, 7.14 mmol). After stirring at 60 °C for 2 h, the reaction mixture was diluted with EtOAc (50 mL). The organic phase was washed with water (30 mL), brine (30 mL), dried over sodium sulfate and evaporated to dryness in vacuo to provide a residue, which was purified by column chromatography on silica gel (PE:EtOAc = 100:0 to 85: 15) to afford the intermediate 24-6 (180 mg, 20.6 %) as a white solid. LC/MS: m/z calculated 727.3, found 728.3 (M + 1 )+. Compound 28-6
Compound 28-6 was prepared as a white sofid from the intermediate 24-6 by a similar procedure used in previous examples. 1HNMR (400 MHz, CD3OD) δ ppm 7.54 (1 H, d, J = 1.2 Hz), 6.52 (1 H, d, J = 3.2 Hz), 6.41 (1 H, dd, J = 3.2, 2.0 Hz ), 4.39 (1 H, dd, J= 10.8, 5.6 Hz), 4.21 (2H, s), 3.99 (1 H, d, J = 18.0 Hz), 3.89 (1 H, d, J = 18.0 Hz), 3.27-3.19 (1 H, m), 2.54 (1 H, d, J = 16.0 Hz), 2.46 (1 H, d, J = 16.0 Hz), 2.49-2.39 (2H, m), 2.34 (1 H, d, J = 19.2 Hz), 2.13 (1 H, d, J = 19.2 Hz), 1.99-1.81 (2H, m), 1.73-1.18 (13H, m), 1.17 (3H, s), 1.16 (3H, s), 1.13 (3H, s), 1.1 1 (3H, s), 1 .04-0.92 (3H, m), 0.96 (3H, s), 0.90 (3H, s), 0.85 (3H, s), 0.77 (6H, s). LC/MS: m/z calculated 691.3, found 692.1 (M + 1 )+.
Example 17: (3aR.5aR.5bR.7aR.9S.11aR.11 bR,13aS)-3a-f2-(tert- butoxycarbonyl((5-((4-methylpiperazin-1-yl)methyl)furan-2-yl)methyl)arnino)acetyli-1- isopropyl-Sa.Sb^S.Ha-pentamethyl^-oxo-
3,3a A5,5a,5b,6,7,7a,8.9.10.11.11 a.11 b,12,13,13a-octadecahydro-2H- cvc!opentaralchrysen-9-yl acetate
Figure imgf000108_0001
Intermediate 24-7
To a solution of the intermediate 23-7 (800 mg, 1.08 mmol) in DMSO (10 mL), which was prepared according to the description in previous examples, was added IBX (1.82 g, 6.50 mmol). After the reaction mixture was stirred at 60 *C for 2 h, the reaction mixture was diluted with EtOAc (50 mL). The organic phase was washed with water (30 mL), brine (30 mL), dried over sodium sulfate, and evaporated to dryness. The residue was purified by column chromatography with Biotage (PE:EtOAc = 100:0 to 85:15) to afford the intermediate 24-7 (240 mg, 28.6 %) as a white solid. LC/ S: m/z calculated 733.5, found 756.3 (M + 23)+. Intermediate 25-7
To a solution of the intermediate 24-7 (120 mg, 0.163 mmol) and 1-methylpiperazine (24.56 mg, 0.245mmol) in DCE (5 mL) and MeOH (5 mL) was added zinc chloride (13.37 mg, 0.098 mmol). The reaction mixture was stirred at room temperature for 4 h, followed by the addition of sodium cyanoborohydride (30.8 mg, 0.490 mmol). The reaction mixture was further stirred at room temperature for 2 h, and then was diluted with water (20 mL). It was extracted with DCM (20 ml x 3) and the combined organic phase was washed with brine (10 ml), dried over sodium sulfate, filtered and evaporated in vacuo to afford the intermediate 25- 7 (120 mg, 83 %) as a white solid, which was used in next step without further purification. LC/MS: m/z calculated 817.6, found 818.4 (M + 1 )+. Compound 28-7
Compound 28-7 was prepared as a white solid from the intermediate 25-7 with a similar procedure used in previous examples. HNMR (400 MHz, CD3OD) o" ppm 6.60 (1 H, d, J = 3.2 Hz), 6.44 (1 H, d, J = 3.2 Hz) , 4.50 (1 H, dd, J= 10.8, 5.6 Hz), 4.31 (2H, q), 4.10 (2H, q), 3.75 (2H, s), 2.92 (3H,s), 2.63-0.89 (63H, m). LC/MS: m/z calculated 803.5, found 804.4 (M + 1 )+.
Example 18: 4-g3aR,5aR.5bR.7aR.9S,11aR,11bR,13aS¾-3a-(2-((5- carbamoylfuran-2-y[)methv]amino)acetyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2- oxo-3.3a A5.5a.5b.6.7.7a.8.9.10,11 ,11 a,11 b,12.13.13a-octadecahvdro-2H- cvclopentaralchrvsen-9-y[oxy)-2,2-dimethyl-4-oxobutanoic acid
Figure imgf000109_0001
i 08
Figure imgf000110_0001
intermediate 25-8 To a so!ution of the intermediate 24-8 (20 mg, 0.027 mmol), which was prepared according to the description in previous examples, HATU (30.4 mg, 0.08 mmol), and DIPEA (0.028 mL, 0.16 mmo!) in DMF (1 mL) was added ammonium chloride (4.28 mg, 0.08 mmol) at room temperture. After it was stirred at room temperture overnight, the reaction mixture was diluted with EtOAc. The organic phase was washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide the intermediate 25-8 ( 5 mg, 75%) as a white solid. LC/MS: m/z calculated 748.5, found 771.3 (M + 23)+.
Compound 28-8
Compound 28-8 was prepared as a white solid from the intermediate 25-8 with a similar procedure used in previous examples. HNMR (400 MHz, CD3OD) δ ppm 7.00 (1 H, d, J = 4.0 Hz), 6.37 (1 H, d, J = 3.6 Hz) , 4.40 (1 H, dd, J- 10.8, 5.6 Hz), 3.81 (2H, q), 3.24-3.23 (3H, m), 2.54-2.29 (6H, m), 2.10-0.79 (48H, m) . LC/MS: m/z calculated 734.4, found 733.3 (M - 1 )-.
Example 19: 4-ii3aR,5aR,5bRJaR.9S,11aR,11bR,13aS)-3a-f2-fN- benzylacetamido)acetyli-1-isopropyl-5a,5b,8,8,11a-pentamethvt-2-oxo- 3,3a,4,5,53,5b,6,7,73,8,9, 10,11 ,11 a,11 b, 12,13,13a-octadecahvdro-2H- cvclopentara1chrvsen-9-yloxy)-2,2-dimethyl-4-oxobutanoic acid
Figure imgf000110_0002
28-9
Figure imgf000111_0001
Compound 28-9
To a solution of the intermediate 27-9 (40 mg, 0.057 mmol), which was prepared according to the description in previous examples, and TEA (0.016 mL, 0.1 14 mmol) in DCM (5 mL) were added acetic anhydride (6.98 mg, 0.068 mmol) and DMAP (4.18 mg, 0.034 mmol). The reaction mixture was stirred at room temperature for 1 h. Removal of the solvent provided a residue, which was purified by prep-HPLC to afford the compound 28-9 (12 mg, 28.4%) as a white solid. 1HNMR (400 MHz, CD3OD) δ ppm 7.40-7.05 (6H, m), 4.65-4.58 (2H, m) , 4.36 (1 H, dd, J= 10.8, 5.6 Hz), 4.01-3.90 (2H, m), 3.20 (1 H, m), 2.54-2.29 (6H, m), 2.08-0.71 (47H, m) LC/MS: m/z calculated 743.5, found 744.3 (M + 1 )+.
Example 20: 4-((3aR,5aR,5b ,7aRt9S.11aR.11bR,13aS -3a-(2-(2-acetamido-N- benzylacetamido)acetyl)-i-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10, 11 , 11 a, 11 b,12,13,13a-octadecahvdro-2H- cvclopentaralchrysen-9-yloxy)-2,2-dimethyl-4-oxobutanoic acid
Figure imgf000111_0002
Compound 28-10
A solution of 2-acetamidoacetic acid (20.34 mg, 0.174 mmol), HATU (33.0 mg, 0.087 mmol), and DIPEA (0.030 mL, 0. 74 mmol) in DMF (2 mL) was stirred at 20 °C for 1 h. Then the intermediate 27-10 (75 mg, 0.058 mmol), which was prepared according to the no description in previous examples, was added to the above reaction mixture. After stirring overnight, the reaction mixture was diluted with EtOAc. The organic phase was separated, washed with 2 N HCI and saturated brine, dried over sodium sulfate and evaporated to dryness in vacuo. The obtained residue was purified by Prep-HPLC to provide the compound 28-10 (30 mg, 64 %) as a white solid. HNMR (400 MHz, CD3OD) δ ppm 7.42- 7.32 (4H, m), 7.22 (1 H, d, J = 6.8 Hz ), 4.64-4.49 (2H, m) , 4.47 (1 H, dd, J= 10.8, 5.6 Hz), 4.24-4.14 (2H, m), 4.09-3.94 (1 H, m), 3.26 (2H, m) 2.68-2.48 (5H, m), 2.08-0.71 (50H, m) LC/MS: m/z calculated 800.5, found 801.4 (M + 1 )+.
Example 21 : 4-ff3aR,5aR,5bR,7a ,9S,11aR,11bR.13aS)-3a-(2-(benzv (S)-3,4- dihvdroxybutvnamino)acetyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo- 3,33,4,5,53,5b,6,7,73,8,9,10, 11 , 11 a, 11 b,12.13.13a-octadecahydro-2H- cvclopentafalchrvsen-9-yloxy)-2,2-dimethyl-4-oxobutanoic acid
Figure imgf000112_0001
Compound 28-11
The intermediate 27-11 (100 mg, 0.12 mmol), which was prepared according to the description in previous examples, was dissolved in acetic acid (3 mL) and water (1 mL). The reaction mixture was stirred at 55 °C for 3 h, and the solvent was removed under reduced pressure to provide a residue. The obtained residue was purified by Pre-HPLC to afford the compound 28-11 (30 mg, 27.5 %) as a white soiid. 1HNMR (400 MHz, CD3OD) δ ppm 7.56 l l I (5H, m), 4.47 (1 H, dd, J = 10.8, 5.6 Hz), 4.40 (1 H, m), 4.20 (1 H, m), 3.50 (4H, m), 3.32 (1 H, m), 2.70-2.17 (6H, m), 2.08-0.80 (52H, m) LC/ S: m/z calculated 789.5, found 790.4 (M + 1 )+.
Example 22: 4-( i 3aR,5aR,5bR,7aR,9S,11 aR,11 bR, 13aS)-3a-(2-( N-benzyl-2- hydroxyacetamido)acetyl)-1 -isopropyl-5a,5b,8,8,11 a-pentamethyl-2-oxo- 3,3a,4,5T5a,5b,6,7,7a,8.9,10.11 , 11 a, 11 b,12.13,13a-octadecahydro-2H- cyctopentafalchrvsen-9-yloxy)-2,2-dimethyl-4-oxobutanoic acid
Figure imgf000113_0001
28-12 Compound 28-12
To a solution of the intermediate 27-12 (150 mg, 0.187 mmol) prepared as in previous examples in MeOH (3 mL), THF (2 mL), and water (1 mL) was added NaOH (37.4 mg, 0.935 mmol). The reaction mixture was stirred at room temperature for 3 h. The solvent was removed under reduced pressure and the obtained residue was extracted with EtOAc (20 mL). The organic layer was washed with water (2 x 30 mL), brine (30 mL), and dried over sodium sulfate. The organic phase was evaporated to dryness in vacuo to provide a crude product, which was purified via Pre-HPLC to afford the compound 28-12 (60 mg, 42.2 %) as a white solid. 1HNMR (400 MHz, CD3OD) δ ppm 7,34 (5H, m), 4.54-4.42 (3H, m), 4.15-3.98 (2H, m), 3.26 (1 H, m), 2.68-2.49 (4H, m), 2.10-0.80 (50H, m). LC/MS: m/z calculated 759.5, found 760.3 (M + 1 )+.
I l 2 Examp!e 23: 4-ff3aR,5aR.5bR.7aR,9S,11aR,11bR.13aS)-1-isopstickyl- 5a,5b,8,8,11a-pentamethyl-3a-f2-(4-methylpiperazin-1-yl)acetyl¾-2-oxO"
3, 3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahvdro-2H- cvclopentaFa1chrvsen-9-yloxy¾-2,2-dimethyl-4-oxobutanoic acid
Figure imgf000114_0001
Step A: Intermediate 29
A suspension of the intermediate 8 (863 mg, 1.31 mmol) and KOH (367 mg, 6.55 mmol) in toluene (20 mL) and EtOH (20 mL) was stirred vigorously at room temperature for 1 h. After neutralizing with aqueous HCI (1 /V), the reaction mixture was evaporated to dryness.
The obtained residue was dissolved in DCM (200 mL) and this solution was washed with water (200 mL), saturated sodium bicarbonate solution (100 mL χ 2), dried over sodium sulfate and evaporated to dryness in vacuo to provide a residue, which was purified by column chromatography on silica gel (EtOAcPE = 1 :30 to 1 :15) to afford the intermediate 29
(464 mg, 57.4 %) as a white solid. LC/MS: m/z calculated 616.3, found 617.0 (M + 1 )+.
Step B: Intermediate 30
To a solution of NBS (803 mg, 4.51 mmol) in acetonitrile (20 mL) and water (5 mL) was added the intermediate 29 (464 mg, 0.752 mmol) at room temperature. After stirring at room temperature for 0.5 h, the reaction was quenched with aqueous sodium sulfite, and concentrated. The obtained residue was dissolved into ether (30 mL), and the organic phase was washed with brine (15 mL), dried over sodium sulfate and evaporated to dryness to afford the intermediate 30 (541 mg, 96 %) as a white solid. LC/MS: m/z calculated 526.3, found 527.1 (M + 1 )+.
Step C: Intermediate 31
A suspension of the intermediate 30 (450 mg, 0.598 mmol), 1-methylpiperazine (0.133 mL, 1.196 mmol), and zinc chloride (48.9 mg, 0.359 mmol) in MeOH (20 mL) was heated at 70 °C for 0.5 h. After cooling down to room temperature, sodium cyanoborohydride (225 mg, 3.59 mmol) was added in one portion. The reaction mixture was stirred at room temperature for another 17 h before it was diluted with EtOAc (50 mL). The organic phase was washed with saturated aqueous sodium bicarbonate solution (30 mL), dried over sodium sulfate and evaporated to dryness in vacuo to provide a residue, which was purified by Prep-HPLC to afford the intermediate 31 (291 mg, 80 %) as a white solid. LC/MS: m/z calculated 610.3, found 61 1.4 (M + 1 )+.
Step D: Intermediate 32
A solution of the intermediate 31 (50 mg, 0.082 mmol), and IBX (68.8 mg, 0.246 mmol) in DMSO (5 mL) was stirred at 60 °C for 4 h. After that, the reaction mixture was diluted with EtOAc (30 mL), and the organic phase was washed with saturated sodium bicarbonate (15 mL), water (15 mL), brine (15 mL), dried over sodium sulfate and
evaporated to dryness in vacuo to provide the intermediate 32 (42 mg, 84 %) as a white foam. LC/MS: m/z calculated 608.3, found 609.3 (M + 1 )+.
Step E: Intermediate 33
A solution of the intermediate 32 (42 mg, 0.069 mmol) in 1 ,4-dioxane (4 mL) and cone. HCI (2 mL, 65.8 mmol) was stirred at room temperature overnight. After that, the reaction mixture was evaporated to dryness. The obtained residue was dissolved in EtOAc (30 mL), and the organic phase was washed with saturated sodium bicarbonate (15 mL), brine (15 mL), dried over sodium sulfate and evaporated to dryness in vacuo to provide the intermediate 33 (42 mg, 97 %) as a white foam. LC/MS: m/z calculated 566.3, found 567.4 (M + 1 )+.
Step F: Compound 28-13
A solution of the intermediate 33 (80 mg, 0.141 mmol), 3,3-dimethyl-dihydrofuran- 2,5-dione (362 mg, 2.82 mmol) and DMAP (86 mg, 0.706 mmol) in pyridine (0.8 mL) was stirred under an atmosphere of nitrogen at 100 °C for 3 h. After cooling down to room temperature, the reaction mixture was diluted with EtOAc (30 mL). The organic phase was washed with brine, dried over sodium sulfate and evaporated to dryness. The obtained residue was purified by Prep-HPLC to provide the compound 28-13 (50 mg, 38 %) as a white foam. 1HNMR (400 MHz, CD3OD) <5 ppm 4.50 (1 H, dd, J= 10.8, 5.6 Hz), 3.62-3.40 (2H, m), 3.38-3.20 (4H, m), 2.99-2.81 (6H, m), 2.68-2.53 (4H, m), 2.40 (1 H, d, J = 19.2 Hz), 2.15 (1 H, d, J = 19.2 Hz), 2.10-1.93 (2H, m), 1.83-0.87 (44H, m). LC/MS: m/z calculated 694.3, found 695.4 ( + 1 )+.
Example 24: 4-f ( (3aR,5aR,5bR.7aR.9S,1 aR, 11 bR,13aS -3a-(2-f ( 1-f5- Chloropyrimidin-2-yl)cvclopropynamino)-2-oxoacetyl)-1-isopropyl-5a,5b,8,8,11a- pentamethyl^-oxo-S^a^.S.Sa.Sb.ejJa.S^.IO.m ia.Hb.^.lS.ISa-octadecahvdro- 2H-cvclopentafalchrysen-9-vnoxy)-2,2-dimethyl-4-oxobutanoic acid
Figure imgf000116_0001
Step A: Intermediate 34
To a solution of 16 (5 g, 9.25 mmol) in 1 ,4-dioxane (100 mL) stirred in air at room temp was added HCI (50 mi, 1646 mmol). The reaction mixture was stirred at 40 °C overnight and monitored by LCMS. The reaction mixture was concentrated to give the residue, which was disoived into water (200mL). The anqueous layer was filtered, washed with water (400 mL) to obtain the yellow solid, which was dissolved into dichloromethane, washed with saturated NaCI solution, dried over sodium sulphate and evaporated in vacuo, recrystallized from ethyl acetate to petroleum ether to give the 2- ((3aR,5aR,5bR,7aR,9S, 1 1 aR, 1 1 bR, 13aS)-9-hydroxy-1 -isopropyi-5a,5b,8,8, 1 1 a- pentamethyl-2-oxo-3,3a ,4,5,5a,5b,6,7,7a,8,9, 10, 1 1 , 1 1 a, 11 b, 12, 13, 13a-octadecahydro-2H- cyc!openta[a]chrysen-3a-yl)-2-oxoacetic acid (4.1 g, 7.40 mmol, 80 % yield) as a white solid. LC/MS: m/z calculated 498.3, found 499.2 (M+1 )+.
Step B: Intermediate 35
To 2-((3aR, 5aR,5bR,7aR,9S, 11 aR, 1 1 bR, 13aS)-9-hydroxy-1 -isopropyl- Sa.Sb.S^. l l a-pentamethyl^-oxo-S.Sa^.S.Sa.Sb.ejJa.S.g.l O.1 1 ,1 18,1 1 ^12, 13,133- octadecahydro-2H-cyclopenta[a]chrysen-3a-yl)-2-oxoacetic acid (9.8 g, 9.65 mmol), 1-(5- chloropyrimidin-2-yl)cyclopropanamine, hydrobromide (6.42 g, 23.58 mmol) and DIPEA (20.59 mL, 118 mmol) in Ν,Ν-dimethylformamide (DMF) (80 mL) was added HATU (29.9 g, 79 mmol), The reaction mixture was stirred at rt for overnight. The reaction mixture was added to ethyl acetate (25 mL), washed with 1 M HCI (25 mL* 2) and brine(25 ml), dried over sodium sulfate and evaporated in vacuo to give the crude product N-(1-(5- chloropyrimidin-2-yl)cyciopropyl)-2-((3aR, 5aR,5bR,7aR,9S, 1 1 aR, 1 bR, 13aS)-9-hydroxy-1 - isopropyl-5a,5b,8,8, 1 a-pentamethyl-2-oxo-
3,3a,4,5,5a,5b,6,7,7a,8,9,10,1 1 ,1 1 a, 11 b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysen-3a-yl)-2-oxoacetamide (7.5g, 1 1.28 mmol, 57.4 % yield) as a yellow solid. LC/MS: m/z calculated 649.4, found 650.3 (M + 1 )+.
Step C: Intermediate 36
To a solution of 4-tert-butoxy-3,3-dimethyl-4-oxobutanoic acid (7.00 g, 34.6 mmol), DMAP (7.04 g, 57.7 mmol) in dichloromethane (DCM) (100 mL) stirred at rt was added EDC (11.05 g, 57.7 mmol). The reaction mixture was stirred at rt for 2h after which N-(1 -(5- chloropyrimtdin-2-yl)cyclopropyl)-2-((3aR,5aR,5bR,7aR,9S, 11 aR, 1 1 bR, 13aS)-9-hydroxy-1 - isopropyl-5a,5b,8,8, 1a-pentamethyl-2-oxo-
S.SaAS.Sa.Sb.e a.B.g O. H .H a.l l b.^^ S.ISa-octadecahydro^H- cyciopenta[a]chrysen-3a-yi)-2-oxoacetamide (7.5 g, 1 1.53 mmol) was added to the reaction. The reaction mixture was stirred at rt for 2 h. The reaction mixture was diluted with dichloromethane (25 mL), washed with 1 M HCI (25 mL* 2), dried over sodium sulfate and evaporated in vacuo to give the crude product, which was purified by silica gel column (PE/EtOAc 0-30%) to give 1-tert-butyl 4-((3aR,5aR,5bR,7aR,9S,1 1 aR, 1 bR,13aS)-3a-(2-((1- (5-ch[oropyrimidin-2-y[)cyclopropyl)amino)-2-oxoacetyl)-1-isopropyl-5a,5b,8,8,1 1 a- pentamethyl-2-oxo-3,3a,4,5,5a, 5b,6,7,7a18,9, 10, 11 , 1 1 a, 11 b, 12, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (8g, 9.59 mmol, 83 % yield) as a yellow solid. H NM (400MHz .CHLOROFOR -d) = 8.50 (s, 2 H), 7.47 (s, 1 H), 4.51 (dd, J = 5.3, 1 1.3 Hz, 1 H), 3.19 (m, 1 H), 2.75 (m, 2 H), 2.73 (J = 18.8 Hz, 1 H), 2,20 (d, J = 18,6 Hz, 1 H), 2.05 (m, 1 H), 1.90 (m, 1 H), 1.44 (s, 9 H), 1.82-0.80 (m 21 H), 1.24 (s, 3 H), 1.23 (s, 3 H), 1.22 (d, J = 6.8 Hz, 3 H), 1.18 (d, J = 6.8 Hz, 3 H), 1.04 (s, 3 H), 0.96 (s, 3 H), 0.91 (s, 3 H), 0.86 (s, 3 H), 0.84 (s, 3 H); LC/MS: m/z calculated 833.5, found 834.2 (M+1 )+.
Step D: Compound 19-11
To a solution of 1-tert-butyl 4-((3aR,5aR,5bR,7aR,9S,1 aR,1 1 bR,13aS)-3a-(2-((1-(5- chloropyrimidin-2-yl)cyclopropyl)amino)-2-oxoacetyl)-1 -isopropyl-5a,5b,8,8,1 1a-pentamethyl- 2-oxo-3l3a,4,5,5a,5b,6,7,7a,8,9,10,1 1 ,1 1a,1 1 b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (36) {48 g, 57.5 mmol, resulting from several batches made in a similar manner to the above methods) in dichloromethane (DCM) (300 mL) stirred at rt°C was added TFA (150 mL). The reaction mixture was stirred at rt for 2h. Then it was washed with water (50 ml three times) and brine, dried (Na2S04), filtered and evaporated in vacuo to provide a crude product. The crude product was washed with hexane give 4-(((3aR,5aR,5bRl7aR,9S,1 1aR,1 1 bR,13aS)-3a-{2-((1-(5-Chloropyrimidin-2- yl)cycfopropyl)amino)-2-oxoacetyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,1 1 ,11a,1 1 b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid (41 g, 52.1 mmol, 91 % yield) as a pale-yellow solid. 1H NMR (400MHz , CHLOROFORM-d) = 8.49 (s, 2 H), 7.48 (s, 1 H), 4.50 (dd, J = 5.1 , 11.1 Hz, 1 H), 3.19 (m, 1 H), 2.82 - 2.68 (m, 3 H), 2.66 (d, J = 15.6 Hz, 1 H), 2.57 (d, J = 15.6 Hz, 1 H), 2.19 (d, J = 18.7 Hz, 1 H), 2.03 (m, 1 H), 1.98 - 1.91 (m, 1 H), 1.83 - 0.72 (m, 19 H), 1.29 (s, 3 H), 1.28 (s, 3 H), 1.22 (d, J = 6.8 Hz, 3 H), 1.17 (d, J = 6.8 Hz, 3 H), 1.03 (s, 3 H), 0.96 (s, 3 H), 0.90 (s, 3 H), 0.84 (s, 3 H), 0.82 (s, 3 H); LC/MS: m/z calculated 777.4, found 778.3 (M + 1 )+.
Intermediate XII used above was prepared according to the methods below.
Figure imgf000119_0001
Step A: intermediate VI
A solution of benzyl (2,5-dioxopyrrolidin-1-yl) carbonate (83 g, 334 mmol) in tetrahydrofuran (THF) (500 ml) was added to a solution of 1-aminocyclopropanecarboxylic acid (25 g, 247 mmol) in water (500 ml). At ice temperature, a solution of sodium bicarbonate (91 g, 1088 mmol) in water (500 ml) was poured into the mixture. After the addition, the reaction was allowed to warm to room temperature and was stirred for 16 h. The solvent was removedunder reduced pressure. The residue was suspended in200 mL of methylene chloride and extracted with water (500 mL). The water solution was acidified with acetic acid and the precipitate was filtered yielding 1-
(((benzyloxy)carbonyl)amino)cyclopropanecarboxyiic acid (53 g, 171 mmol, 69.2 % yield) as a white solid. Used crude in next reaction. LC/MS: m/z calculated 235.1 , found 258.0 ( +Na)+.
Step B: Intermediate VII To a solution of 1-(((benzyloxy)carbonyl)amino)cyclopropanecarboxylic acid (28 g,
1 19 mmol) in Ν,Ν-dimethylformamide (DMF) (120 ml) was added HATU (45.3 g, 1 19 mmol) and TEA (16.59 ml, 1 19 mmol). The mixture was allowed to stir at 20 °C for 20 min, then ammonium hydrogencarbonate (28.2 g, 357 mmol) was added in one portion. The reaction was heated at 60 °C for 12h. The mixture was cooled to room temperature, diluted with water and extracted with EtOAc ( 2 x 100 mL). The combined extracts were washed with satd NaHC03, water, brine and dried with gS04. The mixture was filtered and the solvent removed to give benzyl (l-carbamoylcyclopropyl)carbamate (21.4 g, 75 mmol, 63.0 % yield) as a white solid which was used crude in next reaction. LC/ S: m/z calculated 234.1 , found 235.1 (M+1 )+.
Step C; Intermediate Vlll
To a OoC solution of benzyl (l-carbamoylcyclopropyl)carbamate (40.7g, 174 mmol) in N,N- Dimethylformamide (DMF) (200 ml) was added 2,4,6-tn'chforo-1 ,3,5-triazine (19.22 g, 104 mmol) in one portion. The reaction was stirred at 20 °C for 1 h. The reaction was quenched with water and extracted with EtOAc (3x 100 mL). The combined extracts were washed with water (3 x 50 mL), brine and dried with MgS04. The mixture was filtered and concentrated to give benzyl (l-cyanocyclopropyl)carbamate (37g, 158 mmol, 91 % yield) as a pale-yellow solid. This material was used without further purification.
Step D: Intermediate IX
Benzyl (l -cyanocyc!opropyl)carbamate ( 8.5 g, 86 mmol) was dissolved in ethanol (250 mL) , dry HCI gas was bubbled through the reaction mixture for 1 h and then stirred at rt, for 15 h. Et20 was then added and the separated solids were collected by suction and rinsed with Et20 to give ethyl 1-(((benzyloxy)carbonyl)amino)cyclopropanecarbimidate
hydrochloride (21 g, 59.1 mmol, 69.1 % yield) as white solid. This was used without further purification. LC/MS: m/z calculated 262.1 , found 263.1 (M+1 )+.
Step E: Intermediate X
Ethyl 1 -(((benzyloxy)carbonyl)amino)cyclopropanecarbimidate hydrochloride (21 g, 70.3 mmol) was dissolved in NH3 saturated EtOH and the solution thus obtained was stirred at rt for 14 h. Excess solvent was removed In vacuo to give benzyl (1- carbamimidoylcyclopropyl)carbamate hydrochloride (18g, 55.4 mmol, 79 % yield) as a white powder which was used without further purification. LC/MS: m/z calculated 233.1 , found 234.1 (M+1 )+. Step F: Intermediate XI
To a solution of benzyl ( -carbamimidoylcyclopropyl)carbamate hydrochloride (32.7 g, 121 mmol) and 2-chioromalonaldehyde (24.47 g, 2 8 mmol) in Acetic Acid (30 mL) stirred at 20°C was added solid sodium acetate (29.8 g, 364 mmol) in one charge . The reaction mixture was stirred at 100 °C for overnight. The solvent was removed by evaporation. The residue was diluted with EtOAc. The orgainic phase was washed with water and brine, dried (Na2S04), concentrated to give benzyl (1-(5-chloropyrimidin-2-yl)cyclopropy!)carbamate (21.5 g, 67.0 mmol, 55.3 % yield) as a brown oil. 1H NMR (400MHz ,DMSO-d6) = 8.81 (s, 2 H), 8.14 (s, 1 H), 7.45 - 7.28 (m, 5 H), 5.04 (s, 2 H); LC/MS: m/z calculated 303.1 , found 304.0 ( +1 )\
Step G: Intermediate XII Benzyl (1-(5-chloropyrimidin-2-yl)cyclopropyl)carbamate (26g, 86 mmol) was dissolved in HBr in AcOH (33%, 10 mi). The reaction was stirred at rt for 30 min., evaporated and the residue was washed with Et20 to give 1 -(5-chloropyrimidin-2-yl)cyclopropanamine hydrobromide (20 g, 73.5 mmol, 86 % yield) as a brown solid. 1H N R (400MHz ,DMSO-d6) = 9.00 (s, 2 H), 8.93 (br. s., 3 H), 1.64 - 1 .46 (m, 4 H); LC/MS: m/z calculated 169.0, found 170.0 (M+1 )+.
The following compounds listed in Table 1 were prepared using methods similar to those listed above. In each case, X and Y are each carbonyl.
Figure imgf000121_0001
Table 1
Figure imgf000121_0002
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
The compounds in Table 2 were prepared in a manner similar to the indicated procedures above. In each case, X is carbonyl and Y Is CH2.
Figure imgf000128_0002
Table 2
Figure imgf000128_0003
Figure imgf000129_0001
I28
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
I3l
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Administration and Formulation
[00106] In another embodiment, there is provided 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.
[00107] The compounds of the present invention can be supplied in the form of a pharmaceutically acceptable salt. The terms "pharmaceutically acceptable salt" refer to salts prepared from pharmaceutically acceptable inorganic and organic acids and bases.
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 pharmaceutically acceptable salt thereof (in combination).
[00108] As used herein, the term "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. The skilled artisan will appreciate that pharmaceutically acceptable salts of compounds according to Formulas I, II, or III 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.
[00109] 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, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, phosphoric, phosphonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, sulfuric, salicylic, cyclohexylaminosulfonic, algenic, β-hydroxybutyric, galactaric and galacturonic acids. Preferred pharmaceuticaily acceptable salts include the salts of hydrochloric acid and trifluoroacetic acid.
[001 10] Illustrative pharmaceutically acceptable inorganic base salts of the compounds of the present invention include 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, Na2C03, K2C03, NaH, and potassium-t- butoxide.
[001 11] Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, including in part, trimethylamine, diethylamine, N, N'-dibenzylethyienediamine, 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, isopropy!amine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
[00112] All of the above salts can be prepared by those skilled in the art by conventional means from the corresponding compound of the present invention. For example, 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. Generally, 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, isopropanol, 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
Publishing Company, Easton, Pa., 1985, p.1418, the disclosure of which is hereby incorporated by reference only with regards to the lists of suitable salts. [00113] The compounds of the invention may exist in both unsoivated 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.
Pharmaceutically acceptable solvates include hydrates and other solvates wherein the solvent of crystallization may be isotopically substituted, e.g. D20, d6-acetone, d6-DMSO.
[00114] 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.
[00115] Included within the scope of the claimed compounds present invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds of formula (I), including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof. Also included are acid addition or base salts wherein the counterion is optically active, for example, D-lactate or L-lysine, or racemic, for example, DL-tartrate or DL-arginine.
[00116] Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation.
[00117] Conventional techniques for the preparation/isolation of individual
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).
[00118] Alternatively, 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-phenylethylamine. 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.
[00119] Chiral compounds of the invention (and chiral precursors thereof) 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 e!uate affords the enriched mixture.
! 37 [00120] Mixtures of stereoisomers may be separated by conventiona! techniques known to those skilled in the art. [see, for example, "Stereochemistry of Organic
Compounds" by E L Eliel (Wiley, New York, 1994).]
[00121] 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.
[00122] Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2H and 3H, carbon, such as C, 13C and 14C, chlorine, such as 36CI, fluorine, such as 18F, iodine, such as 123l and 2SI, nitrogen, such as 13N and 15N, oxygen, such as lsO, 170 and 180, phosphorus, such as 32P, and sulphur, such as 35S.
[00123] Certain 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. 3H, and carbon-14, i. e. 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
[00124] Substitution with heavier isotopes such as deuterium, i.e. 2H, 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.
[00125] 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
isotopically-labelled reagents in place of the non-labelled reagent previously employed.
[00126] The compounds of the present invention may be administered as prodrugs. Thus, certain derivatives of compounds of formula (!) which may have little or no
pharmacologicai 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'.
[00127] Administration of the chemical entities described herein can be via any of the accepted modes of administration for agents that serve similar utilities including, but not limited to, orally, subiinguaily, subcutaneousiy, intravenously, intranasally, topically, transdermally, intraperitoneal^, intramuscularly, intrapulmonarilly, vaginally, recta!ly, or intraoculariy. In some embodiments, oral or parenteral administration is used.
[00128] Pharmaceutical 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. In certain embodiments, the
compositions are provided in unit dosage forms suitable for single administration of a precise dose.
[00129] 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). If desired, 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, cyc!odextrine derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate, and the like).
Generally, depending on the intended mode of administration, 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.
[00130] In certain embodiments, 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, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or the like. In another solid dosage form, a powder, marume, solution or suspension (e.g., in propylene carbonate, vegetable oils or triglycerides) is encapsulated in a gelatin capsule.
[00131] Liquid pharmaceutically administrab!e compositions can, for example, be prepared by dissolving, dispersing, etc. at least one chemical entity and optional
pharmaceutical adjuvants in a carrier (e.g., water, saline, aqueous dextrose, glycerol, glycols, ethanol or the like) to form a solution or suspension. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, as emulsions, or in solid forms suitable for dissolution or suspension in liquid prior to injection. The percentage of chemical entities contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the activity of the chemical entities and the needs of the subject. However, percentages of active ingredient of 0.01 % to 10% in solution are employable, and will be higher if the composition is a solid which will be subsequently diluted to the above
percentages. In certain embodiments, the composition will comprise from about 0.2 to 2% of the active agent in solution. [00132] Pharmaceutical 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. In such a case, the particles of the pharmaceutical composition have diameters of less than 50 microns, in certain embodiments, less than 10 microns.
[00133] In general, the chemical entities provided will be administered in a
therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. 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.
[00134] 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- 00 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.
[00135] In general, 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. In certain embodiments, 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.
[00136] The choice of formulation depends on various factors such as the mode of drug administration and bioavailability of the drug substance. For delivery via inhalation the chemical entity can be formulated as liquid solution, suspensions, aerosol propellants or dry powder and loaded into a suitable dispenser for administration. There are several types of pharmaceutical inhalation devices-nebulizer inhalers, metered dose inhalers (MDI) and dry powder inhalers (DPI). 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. 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. In order to achieve a free flowing powder, the therapeutic agent is formulated with an excipient such as !actose. A measured amount of the therapeutic agent is stored in a capsule form and is dispensed with each actuation.
[00137] Recently, pharmaceutical 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. For example, 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
macromolecules. 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.
[00138] The 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. Such 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.
[00139] 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 petroleum, 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.
[00140] Compressed gases may be used to disperse a chemical entity described herein in aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc. Other suitable pharmaceutical excipients and their formulations are described in
Remington's Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 18th ed., 1990).
[00141] The amount of the chemical entity in a composition can vary within the full range employed by those skilled in the art. Typically, 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. In certain embodiments, 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.
!4l [00142] The following examples serve to more fully describe the manner of making and using the above-described invention. It is understood that these examples in no way serve to limit the true scope of the invention, but rather are presented for illustrative purposes.
BIOLOGICAL EXAMPLES
EXAMPLE 194
ANTI-HIV ACTIVITY
Biological Assay
[00143] The antiviral activity of test compounds was determined in a two cell co- culture HIV lifecycle assay, in this assay Jurkat T-lymphocytes that are chronically infected with HIV-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.
[00144] Prior to the beginning the assay, a frozen stock vial of infected Jurkat, J4HxB2, cells are rapidly thawed in a 37 °C waterbath and slowly diluted to 15 mL with ceil 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% C02, and expanded to 30 mL on day 4 and to 60 mL on day 7 by the addition of cell medium.
[00145] On the day the assay were started, HOS cells were rapidly thawed, slowly diluted to 15 mL in cell culture medium, centrifuged at 400 rpm for 5 min and resuspended in 10 mL cell medium. 2x107 HOS cells were diluted to 1 112 mL in chilled (4 °C) cell medium and placed on a stir plate. 6.7x107 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. In the 96-wel! assay format 0.2 mL J4HxB2/HOS cell suspension was added to 2 pL of test compound in the assay plate. For the 384-well assay format, 0.05 mL cell suspension was added to 0.5 μΐ 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% C02 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. For data analysis, high and low signal controls corresponding to wells containing DMSO or an HIV-1 inhibitor (efavirenz, brecanavir or similar antiviral), were used to normalize the data which was then fit to a nonlinear regression model using a suitable data analysis package to determine IC50 values.
[00146] MT4 Assay
[00147] 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, tyrosyi-based human immunodeficiency virus (HIV) type 1 protease inhibitor brecanavir (GW640385) in combination with other antiretrovirals and against a panel of protease inhibitor-resistant HIV (Hazen et al., "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 panel of protease inhibitor-resistant HIV", Antimicrob. Agents Chemother. 2007, 51: 3147-3154; and 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).
[0001] Luciferase activity was measured 96 hours later by adding a cell titer glo
(Promega, Madison, Wis.). Percent inhibition of cell protection data was plotted relative to no compound control. Under the same condition, cytotoxicity of the compounds was determined using cell titer Glo™ (Promega, Madison, Wis). IC50s were determined from a 10 point dose response curve using 3-4-foid serial dilution for each compound, which spans a concentration range > 000 fold.
[0002] These values are plotted against the molar compound concentrations using the standard four parameter logistic equation: y = ((Vmax * xAn) / (KAn + χΛη)) + Y2
where:
Y2 = minimum y n = slope factor
Vmax= maximum y x = compound concentration [M]
Formulation Examples [0003] The following are representative pharmaceutical formulations containing a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
Example 195
Tablet formulation
[0004] The following ingredients are mixed intimately and pressed into single scored tablets.
Ingredient Quantity per tablet (mg)
compound 400
cornstarch 50
croscarmellose sodium 25
lactose 120
magnesium stearate 5 Example 196
Capsule formulation
[0005] The following ingredients are mixed intimately and loaded into a hard-shel! gelatin capsule. Ingredient Quantity per capsule (mg)
compound 200
Lactose, spray-dried 148
magnesium stearate 2 Example 197
Suspension formulation
[0006] The following ingredients are mixed to form a suspension for oral administration.
Ingredient Amount
compound 1.0 g
fumaric acid 0.5 g
sodium chloride 2.0 g
methyl paraben 0.15 g
propyl paraben 0.05 g
granulated sugar 25.0 g
sorbitol (70% solution) 13.00 g
Veegum K (Vanderbilt Co.) 1.0 g flavoring 0.035 mL
colorings 0.5 mg
Distilled water q.s. (quantity sufficient) to 100 mL
Example 198
Injectable formulation
[0007] The following ingredients are mixed to form an injectable formulation.
Ingredient Amount
compound 0.2 mg-20 mg sodium acetate buffer solution, 0.4 M 2.0 mL HCI (1 N) or NaOH (1 N) q.s. to suitable pH
water (distilfed, sterile) q.s. to 20 mL
Example 199
Suppository Formulation
[0008] 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:
Ingredient Amount
compound 500 mg
Witepsol® H-15 balance
[0009] Although the invention has been shown and described above with reference to some embodiments, those skilled in the art will readiiy appreciate that the specific experiments detailed are only illustrative of the invention. It should be understood that various modifications can be made without departing from the spirit of the invention.
For example, for claim construction purposes, it is not intended that the claims set forth hereinafter be construed in any way narrower than the literal language thereof, and it is thus not intended that exemplary embodiments from the specification be read into the claims. Accordingly, it is to be understood that the present invention has been described by way of iilustration and not limitations on the scope of the claims. Accordingly, the invention is limited only by the following claims. All publications, issued patents, patent applications, books and journal articles, cited in this application are each herein incorporated by reference in their entirety.

Claims

WHAT IS CLAIMED IS:
1. A compound comprising the structure of Formula (l):
(I)
Figure imgf000147_0001
Formufa I
or a pharmaceutically acceptable salt thereof, wherein:
L is selected from the group consisting of a (CrC6)alkylene, -C(O), -C(0)NH, -C(0)NHR4, -C(0)NHR1S, -C(0)R4R10, -R NR R2, -R NH, -R NHC(0), -R4NHR4,
X is (C5-C14)aryl;
Y is independently selected from (C2-C8)heterocycle or (C2-C9)heteroaryl, each having one to three heteroatoms selected from S, N or O;
Z is (C3-C7)cycloalkyl;
(R )i m x
A is selected from the group consisting of -NR R , -OR5,
Figure imgf000147_0002
R and R2 are each independently -H, (OrC6)alkyl, (C C6)aikylene, -R4N(R5)2, -R4R Q, -R4X(R )mt -R4X, -C(O), -C(0)R6, -C(0)R8, -R4C(0)R10, -C(0)R R1°, -C(0)OR5, -R4NHC(0), -C(0)R4NHC(0)R6, -R R8R4RB, -C(0)R (R8)2, -C(0)R4Ra, -N(R5)2, -C(0)N(R5)2) -C(0)R4N(R5)2, -C(0)C(0)N(R5)2, -C(0)R4(OH)2l -C(0)C(0)R8, -C(0)R C(0)R5 and -ORe;
R3 is selected from the group consisting of -C(0)R4R7, -C(0)R R7R8,
-C(0)R4R7R14, and -C(0)R4C(0)R8;
R4 is (CrC6)alkylene;
R5 is independently selected from -H and {Ci-C6)alkyl;
R6 is (C C6)alkyl;
R7 is -C(0)OR5;
R8 is -OR5;
R9 is halo;
!46 R10 is -N(R16)2;
R11, R12, and R 3 are independently selected from the group consisting of oxo, halo, (CrCe)alkoxy, -R6(R9)P, -OR6(R9)q, nitro, -S02R6, (C C6)alkyl, -C(0)R10, -R YR6, and - CO(0)R5;
R14 is -OP(0){OH)2;
Figure imgf000148_0001
R 6 is selected from the group consisting of -H, (Ci-C6)alkyl, and -C(0)OR5;
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; and
q is an integer selected from 1 , 2, or 3.
2. A compound comprising the structure of Formula (I):
0)
Figure imgf000148_0002
Formula I
or a pharmaceutically acceptable salt thereof, wherein:
L is selected from the group consisting of a (CrC6)alkylene, -C(O), -C(0)NH, ~C(0)NHR4, -C(0)NHR15, -C(0)R4R10, -R NR1RZ, -R4NH, -R4NHC(0), and -R4NHR4;
X is (C5-C14)aryl;
Y is independently selected from (C2-C8)heterocycle or (C2-Cg)heteroaryl, each having one to three heteroatoms selected from S, N or O;
Z is (C3-C7)cycloalkyl;
A is selected from the group consisting of -NR1R2, -OR5, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acetidinyl, piperazinyl, furanyl, pyridyi, pyrazoiyi, pyridazinyl, pyrroiidinyi, thiazolyl, oxazolyl, thiophenyl, and thiomorpholinyl; R and R2 are each independently -H, (C1-CB)alkyl, (C1-C6)alkylene, -R4N(R5)2, -R4R10, -R4X(R1 )m, -R X, -C(0), -C(0)R6, -C(0)R8, -R4C(0)R10, -C(0)R4R1°, -C(0)OR5, -R4NHC(0), -C(0)R4NHC(0)R6, -R4R8R4R8, -C(0)R4(Re)2r -C(0)R4R8, -N(RS)2, -C(0)N(R5)2, -C{0)R4N(R5)2, -C(0)C(0)N(R5)2, -C(0)R (OH)2, -C(0)C(0)R8, -C(0)R4C(0)R5 and -OR8;
R3 is selected from the group consisting of -C(0)R R7, -C(0)R4R7R8,
-C(0)R4R7R14, and -C(0)R4C(0)R8;
R4 is (CrC6)alkylene;
R5 is independently selected from -H and (CrC6)alkyl;
R6 is (d-C6)alkyl;
R7 is -C(0)OR5;
R8 is -OR5;
R9 is halo;
R 0 is -N(R16)2;
R11 is independently selected from the group consisting of halo, (CrC6)alkyl, (C-r C6)alkoxy, -R6(R9)q, -OR6(R9)q, and nitro;
R 2 is independently selected from the group consisting of -S02R6, (CrC6)alky!, - C(0)R10, -R YR6, -CO(0)R5, and oxo;
R 3 is independently selected from the group consisting of (C C6)aikyl, oxo, halo, (CrCe)alkoxy, -R6(R9)q, -OR6(R9)q, nitro, -S02R6, (C C6)alkyl, -C(0)R1°, -R4YR6, and - CO(0)R5;
R 4 is -OP(0)(OH)2;
Figure imgf000149_0001
R16 is selected from the group consisting of -H, (C C6)alkyl, and -C(0)ORs;
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; and
q is an integer selected from 1 , 2, or 3.
3. A compound comprising the structure of Formula (II):
Figure imgf000150_0001
Formula II
or a pharmaceutically acceptable salt thereof, wherein:
L is selected from the group consisting of a (C C6)alkylene, -C(O),
-C(0)NH, -C(0)NHR4, -C(0)NHR15, -C(0)R4R10, -R4NR1R2, -R NH, -R NHC(0),
-R4NHR4,
X is (C3-C14)aryl;
Y is independently selected from (C2-C9)heterocycle or (C2-C9)heteroaryl, each having one to three heteroatoms selected from S, N or O;
Z is (C3-C7)cycloalkyl;
A is selected from the group consisting of -NR R , -OR
Figure imgf000150_0002
Figure imgf000150_0003
R1 and Rz are each independently -H, (C C6)alkyl, (d-CeJalkylene, -R4N(R5)2, -R4R10, -R4X(R1 )mt -R4X, -C(O), -C(0)R6, -C(0)R8, -R4C(0)R10, -C(0)R4R10, -C(0)OR5, -R4NHC(0), -C(0)R4NHC(0)R6, -R4RaR4R8, -C(0)R4(R6)2l -C(0)R4R8, -N(R5)2, -C(0)N(Rs)2l -C(0)R4N(R5)2, -C(0)C(0)N(R )2, -C(0)R (OH)2, -C(0)C(0)R8, -C(0)R4C(0)R5 and -OR8;
R3 is selected from the group consisting of -C(0)R4R7, -C(0)R4R7R8,
C(0)R R7R14, and -CO(0)R4C(0)R8;
R4 is (CrCe)alkylene;
R5 is independently selected from -H and (C_VCe)alkyl;
R6 is (Ci-Ce)alkyl;
R7 is -C(0)OR5;
R8 is -OR5;
R9 is halo;
R10 is -N(R16)2; R1 1 , R12, and R 3 are independently selected from the group consisting of oxo, halo, (C C6)alkoxy, -R6(R9)q, -OR6(R9)q, nitro, -S02R6, (C C6)alkyl, -C(0)R10, -R4YR6, and - CO(0)R5;
R14 is -OP(0)(OH)2;
Figure imgf000151_0001
R16 is selected from the group consisting of -H, (C CeJalkyl, and -C(0)OR5;
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; and
q is an integer selected from 1 , 2, or 3.
A compound comprising the structure of Formula (II):
Figure imgf000151_0002
Formula II
or a pharmaceutically acceptable salt thereof, wherein:
L is selected from the group consisting of a (C C6)alkylene, -C(O),
-C(0)NH, -C(0)NHR4, -C(0)NHR15, -C(0)R R10, -R NR1 R2, -R4NH, -R4NHC(0), and
-R4NHR4;
X is (Cs-Cu)aryl;
Y is independently selected from (C2-C9)heterocycle or {C2-Cg)heteroaryi, each having one to three heteroatoms selected from S, N or O;
spiro ring Z is (C3-C7)cycloalkyl;
A is selected from the group consisting of -NR1R2, -OR5, phenyl, cyclopropyl, cyclobutyl, cydopentyl, cyclohexyl, acetidinyl, piperazinyl, furanyi, pyridyl, pyrazolyl, pyridazinyl, pyrrolidinyl, thiazolyl, oxazolyl, thiophenyi, and thiomorphoiinyl;
R1 and R2 are each independently -H, (CrC6)alkyl, (CrC6)alkylene, -R4N(R5)2, -R4R10, -R X(R11 )m, -R4X, -C(O), -C(0)R6, -C(0)Ra, -R4C(0)R10, -C(0)R R10, -C(0)OR5, -R NHC(0), -C(0)R4NHC(0)R6, -R4R8R4R8, -C(0)R4(R8)2, -C(0)R4R8, -N(R5)2, -C(0)N(R5)2, -C(0)R N(R5)2, -C(0)C(0)N(R5)2, -C(0)R (OH)2, -C(0)C(0)R8, -C(0)R C(0)R5 and -OR8;
R3 is selected from the group consisting of -C(0)R4R7, -C(0)R4R7R8,
-C(0)R4R7R14, and -C(0)R C(0)R8;
R4 is (CrC6)alkylene;
R5 is independently selected from -H and (CrC6)a!kyl;
R6 is (d-CeJalkyl;
R7 is -C(0)OR5;
R8 is -OR5;
R9 is halo;
R10 is -N{R16)2;
R1 1 is independently selected from the group consisting of halo, (C -C6)alkyl, (C C6)alkoxy, -RB(R )q, -OR6(R9)q, and nitro;
R 2 is independently selected from the group consisting of -S02R6, (Ci-C6)alkyi, - C(0)R10, -R4YR6, -CO(0)R5, and oxo;
R13 is independently selected from the group consisting of (CrC6)alkyl, oxo, halo, (C C6)alkoxy, -R6(R9)q, -OR6(R9)q, nitro, -S02R6, (C1-C6)alkyl, -C(0)R10, -R YR6, and - CO(0)R5;
R14 is -0P(0)(0H)2;
Figure imgf000152_0001
selected from the group consisting of -H, (C C6)alkyl, and -C(0)OR5
5. A compound comprising the structure of Formula (III):
(""I)
Figure imgf000152_0002
Formula III
or a pharmaceutically acceptable salt thereof, wherein: L is selected from the group consisting of a (C C6)alkylene, -C(O), -C(0)NH, -C(0)NHR4, -C(0)NHR15, -C(0)R4R10, -R4NR R2, -R4NH, -R NHC(0)r -R NHR4,
X is (C5-C14)aryi;
Y is independently selected from (C2-C9)heterocycle or (C2-C9)heteroaryl, each having one to three heteroatoms selected from S, N or O;
Z is (C3-C7)cycloalkyl;
A is selected from the group consisting of -NR1R2, -OR5
Figure imgf000153_0001
Figure imgf000153_0002
R1 and R2 are each independently -H, (d-CeJalkyl, (C C6)alky!ene, ~R4N(RS)2, -R4R10, -R4X(R11)m, -R4X, -C(O), -C(0)R6, -C(0)R8, -R4C(0)R10, -C(0)R4R10, -C(0)OR5, -R4NHC(0), -C(0)R4NHC(0)R6, -R4R8R4R8, -C(0)R4(Re)2l -C(0)R4R8, -N(R5)2j -C(0)N(R5)2, -C(0)R4N(R5)2, -C(0)C(0)N(R5)2> -C(0)R4(OH)2, -C(0)C(0)R8, -C(0)R4C(0)R5 and -OR8;
Q is selected from the group consisting of -R4R7R8,-R R7R14, and -R C(0)R8;
R4 is (C C6)alkylene;
R5 is independently selected from -H and (Ci-C6)alkyl;
R6 is (CrC6)alkyl;
R7 is -C(0)OR5;
R8 is -OR5;
R9 is halo;
R10 is -N(R16)2;
R11, R12, and R13 are independently selected from the group consisting of oxo, haio, (C C6)alkoxy, -R6(R9)q, -OR6{R9)q> nitro, -S02R6, (C C6)alkyl, -C(0)R10, -R4YR6, and - CO(0)R5;
R 4 is ~OP(0)(OH)2;
Figure imgf000153_0003
R16 is selected from the group consisting of -H, {C C6)alkyl, and -C(0)OR5 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; and
q is an integer selected from 1 , 2, or 3. A compound comprising the structure of Formula (I):
Figure imgf000154_0001
Formula I
or a pharmaceutically acceptable salt thereof, wherein:
L is selected from the group consisting of a (C-|-C6)alkylene, -C(O),
-C(0)NH, -C(0)NHR4, -C(0)NHR15, -C(0)R4R10, -R4NR1R2, -R NH, -R4NHC(0), and
-R4NHR4;
X is (C5-C14)aryl;
Y is independently selected from (C2-C9)heterocycle or (C2-C9)heteroaryl, each having one to three heteroatoms selected from S, N or O;
Z is (C3-C7)cycloalkyl;
A is selected from the group consisting of -NR1R2, -OR5, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, acetidinyl, piperazinyl, furanyf, pyridyl, pyrazolyl, pyridazinyl, pyrrolidinyl, thiazo!yl, oxazolyl, thiophenyl, and thiomorpholinyl;
R1 and R2 are each independently -H, (CrC6)alkyl, (C C6)alkyiene, -R4N(R5)2, -R4R10, -R4X(R11)m, -R X, -C(O), -C(0)R6, -C(0)R8, -R4C(0)R10, -C(0)R4R10, -C(0)OR5, -R4NHC(0), -C(0)R4NHC(0)R6, -R R8R R8, -C(0)R (RB)2, -C(0)R4RB, -N(R5)2l -C(0)N(R5)2, -C(0)R4N(R5)2, -C(0)C(0)N(R5)2, -C(0)R4(OH)2, -C(0)C(0)R8, -C(0)R4C(0)R5 and -OR8;
R3 is selected from the group consisting of -CO(0)R R7, -CO(0)R4R7R8,
-CO(0)R4R7R14, and -CO(0)R4C(0)RB;
R4 is (C C6)alkylene;
R5 is independently selected from -H and (d-C6)alkyl;
R6 is (d-CeJalkyl;
R7 is -C(0)0R5;
Re is -OR5;
R9 is halo;
R10 is -N(R16)2;
R11 is independently selected from the group consisting of halo, (CrC6)alkyl, (C C6)alkoxy, -R6(R9)q, -ORB(R )q, and nitro; R12 is independently selected from the group consisting of -S02R6, (CrC^alkyl, - C(0)R10, -R YR6, -CO(0)R5, and oxo;
R13 is independently selected from the group consisting of (CrC6)alkyl, oxo, halo, (d-CeJalkoxy, -R6(R9)q, -OR6(R9)q, nitro, -S02Re, (d-CeJalkyl, -C(0)R °, -R4YR6, and - CO(0)R5;
R14 is -OP(0)(OH)2;
Figure imgf000155_0001
R 6 is selected from the group consisting of -H, (C C6)alkyl, and -C(0)OR5; 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; and
q is an integer selected from 1 , 2, or 3.
7. A compound characterized b the following formula:
Figure imgf000155_0002
or a pharmaceutically acceptable salt thereof, wherein:
R1 and R2 are each independently H, Ci-C6-alkyl, f-butyloxycarbonyl, e-S02-, HOOCC(CH3)2CH2C(0)-, CH3C{0); (R4)2N-(CH2)m-, (R5)n-phenyl-Q-,
(R6)q-Hetaryl-(CH2)p-, (R6)q-Hetalk-(C-H2)r-, or (R6)q-Cycioalk-(CH2)p-; 0r R and R2, together with the nitrogen atom to which they are attached, form a 3- to 7- membered heterocycloalkyl ring optionally substituted with a methylsu!fonyl group or up to two Ci-C4-alk l rou s;
Figure imgf000155_0003
each R4 is independently H or CrCe-alkyl;
each R5 is independently halo, CrCe-alkyl, CrC6-alkoxy, CF3, OCF3, N(CH3)2, or N02; each R6 is independently halo, C C6-alkyl, -COOH, -C(0)NH2, dimethylaminomethyl, or 1-methyl-4-piperazinylmethyl,
X is carbonyl and Y is methylene;
Q is -(CH2)p-, -C(O)-, -NH-C(O)-, -CH(CH3)-, -C(CH3)2-, 1 ,1 -cyclopropyldiyl, or 1 ,1-cycjopentyldiyl;
Hetaryl is a 5-6-membered heteroaryl group;
Hetalk is a 3-7-membered heterocydoalkyi group;
Cyc!oalk 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; and
each r is independently 0, 1 , 2, 3, or 4.
8. The compound of Claim 7 or a pharmaceutically acceptable salt thereof, wherein:
R1 is H, methyl, dimethylaminoethyl, f-butyloxycarbony!; Me-S02-, or
HOOCC(CH3)2CH2C(0)-;
R2 is H; (R5)n-phenyl-Q-, (R6)q-furanyl-{CH2)p-, (R6)q-pyridyl-(CH2)p-,
(R6)q-thienyl-(CH2)p-, 1 -methyl pyrazol-3-yl, Hetalk-(CH2)r, or C3-C6-cycloalkyl- (CH2)p-, or
R1 and R2, together with the nitrogen atom to which they are attached, form azetidinyl, piperidinyl, morpholino, thiomorpholino, piperazinyl, 4-methyl- piperazin-1-yl, 4-methylsulfonyl-piperazin-1-y[, 2,4-dimethy!-piperaztn-1-yl, 4- methyl-diazepan-1 -yl, 1 -methyl-2-piperazinon-4-yl, thiomorpholine-1 ,1 dioxide- 4-yl; or pyrrolidinyl; and
each R5 is independently methyl, methoxy, halo, CF3, or OCF3; and
each R6 is independently methyl, F, or CI.
9. The compound of Claim 7 or a pharmaceutically acceptable salt thereof, wherein:
X is carbonyl and Y is methylene;
R1 is H, methyl, f-butyloxycarbonyl; e-S02~, or dimethylaminoethy!; R2 is H, (R5)n-Phenyl-(CH2)P-, (R6)n-furany!-(CH2)q-, (R6)n-pyridyl-(CH2)q-, (R6)q-thieny[-(CH2)p-, 1 -methyl pyrazol-3-yl, pyrrolidinyi-(CH2)r-,
4-methylpiperaziny!; N-methylpiperidin-4-yl; cyclopropyl-(CH2)p-, cyclohexyl- (CH2)P-, or cycIopentyl-(CH2)p-; or
R1 and R2, 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;
R5 is methyl, methoxy, F, CI, CF3, or OCF3; and
q is 0 or 1.
10. The compound of Claim 7 a pharmaceutically acceptable salt thereof, wherein X is carbonyl and Y is carbonyl;
R is H, methyl, f-butyloxycarbonyl; Me-S02-, or dimethylaminoethyl;
R2 is H, (R5)n-phenyl-(CH2)p-, (R6)n-furanyl-<CH2)q-, {R6)n-pyridyi-(CH2)q-, (R6)q-thienyl-(CH2)p-, -methyl pyrazol-3-yl, pyrrolidinyl-(CH2)r-,
4-methylpiperazinyl; N-methylpiperidin-4-yl; cyclopropyl-(CH2)p-, cyclohexyl- (CH2)P-, or cyclopentyI-(CH2)p~; or
R1 and R2, together with the nitrogen atom to which they are attached, form azetidinyl, piperazinyl, 4-methyl-piperazin-1-y], 4-methylsulfonyl-piperazin-1-yl, 2,4-dimethyI-piperazin-1-yl, 4-methyl-diazepan-1 -yl, thiomorpholine-1 ,1 dioxide- 4-yl; or pyrrolidinyl;
R5 is methyl, methoxy, F, CI, CF3, or OCF3; and
q is 0 or 1 .
1 1. The compound of Claim 7 or a pharmaceutically acceptable salt thereof, wherein
X is carbonyl and Y is carbonyl;
R1 is H, methyl, f-butyloxycarbonyl; Me-S02-, or dimethylaminoethyl;
R2 is H, (R5)n-phenyl-(CH2)p-, (R6)n-furanyl-{CH2)q-, {R6)n-pyridyl-(CH2)q-, (R6)q-thienyl-(CH2)P-, -methyl pyrazol-3-yl, pyrrol id inyl-(CH2)r,
4-methylpiperazinyl; N-methy!pipehdin-4-yl; cyciopropyl-(CH2)p-, cyclohexyl- (CH2)P-, or cyclopentyl-(CH2)p-; or R and R2, together with the nitrogen atom to which they are attached, form azetidinyl, piperazinyi, 4-methy!-piperazin-1-yl, 4-methylsu!fonyl-piperazin-1-yl, 2,4-dimethyl-piperazin-l-yl, 4-methyl-diazepan-1-yl, thiomorpholine-1 ,1 dioxide- 4-yl; or pyrrolidinyl;
R5 is methyl, methoxy, F, CI, CF3, or OCF3; and
q is 0 or 1.
12. The compound of Claim 7 or a pharmaceutically acceptable salt thereof, wherein
X is carbonyl and Y is methylene;
R1 is H, methyl, f-butyloxycarbonyl; Me-S02~, or dimethylaminoethyl;
R2 is H, (R5)n-phenyl-(CH2)p-, (R6)n-furanyl-(CH2)q-, (R6)n-pyridyl-(CH2)q-, (R6)q-thienyl-(CH2)p-, 1 -methyl pyrazol-3-yl, pyrroiidinyl-(CH2)r,
4-methylpiperazinyl; N-methylpiperidin-4-y!; cyclopropyl-(CH2)p-, cyclohexyl- (CH2)p-, or cyclopentyl-(CH2)P-; or
R1 and R2, together with the nitrogen atom to which they are attached, form azetidinyl, piperazinyi, 4-methyl-piperazin-1~yl, 4-methylsulfonyl-piperazin-1-yl, 2,4-dimethyl-piperazin-1-yl, 4-methyl-diazepan-1-yl, thiomorphoiine-1 ,1 dioxide- 4-yi; or pyrrolidinyl;
R5 is methyl, methoxy, F, CI, CF3, or OCF3; and
q is 0 or 1.
13. The compound of Claim 7 or a pharmaceutically acceptable salt thereof, wherein
R is H, CH3, or dimethylaminoethyl;
2 is (R5)n-phenyl-CH2; thienyl-CH2-; furanyl-CH2; pyridinyl-CH2-; and
Figure imgf000158_0001
14. The compound of Claim 7 or a pharmaceutically acceptable salt thereof, wherein
R is H, CH3, or dimethylaminoethyl;
R2 is (R5)n-phenyl-CH2; thienyl-CH2-; furanyl-CH2; pyridinyl-CH2-; and
Figure imgf000159_0001
15. The compound of Claim 7 or a pharmaceutically acceptable salt thereof, wherein
R1 is H, CH3, or dimethyiaminoethyl;
2 is (R5)n-phenyl-CH2; thieny!-CH2-; furanyl-CH2; pyridinyl-CH2-; and
Figure imgf000159_0002
16. The compound of Claim 7 or a pharmaceutically acceptable salt thereof, wherein
R1 is H, CH3, or dimethyiaminoethyl;
2 is (R5)n-phenyl-CH2; thienyl-CH2-; furanyl-CH2; pyridinyl-CH2-; and
Figure imgf000159_0003
17. A compound or a pharmaceutically acceptable salt thereof having the structure:
Figure imgf000159_0004
18. A compound or a pharmaceutically acceptable salt thereof having the structure:
Figure imgf000160_0001
19. A composition comprising a) a compound of any of Claims 1-18 or a pharmaceutically acceptable salt thereof; and 2) a pharmaceuticaily acceptable excipient.
20. A method of treating HIV comprising administering to a patient suffering therefrom an effective amount of the compound of any of Claims 1 -18, or a pharmaceuticaily acceptable salt thereof.
PCT/CN2011/001302 2011-08-08 2011-08-08 Carbonyl derivatives of betulin WO2013020245A1 (en)

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JP2015501845A (en) * 2011-12-16 2015-01-19 グラクソスミスクライン エルエルシー Derivatives of betulin
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US9795619B2 (en) 2012-12-14 2017-10-24 Glaxosmithkline Llc Pharmaceutical compositions
US9637516B2 (en) 2012-12-31 2017-05-02 Hetero Research Foundation Betulinic acid proline derivatives as HIV inhibitors
US9868758B2 (en) 2014-06-30 2018-01-16 Hetero Labs Limited Betulinic proline imidazole derivatives as HIV inhibitors
US10092523B2 (en) 2014-09-26 2018-10-09 Glaxosmithkline Intellectual Property (No. 2) Limited Long acting pharmaceutical compositions
WO2016178092A2 (en) 2015-02-09 2016-11-10 Hetero Research Foundation C-3 novel triterpenone with c-28 reverse amide derivatives as hiv inhibitors
US10533035B2 (en) 2015-02-09 2020-01-14 Hetero Labs Ltd. C-3 novel triterpenone with C-17 reverse amide derivatives as HIV inhibitors
US11034718B2 (en) 2015-02-09 2021-06-15 Hetero Labs Limited C-3 novel triterpenone with C-17 reverse amide derivatives as HIV inhibitors
US10370405B2 (en) 2015-03-16 2019-08-06 Hetero Labs Limited C-3 novel triterpenone with C-28 amide derivatives as HIV inhibitors
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CN115504947A (en) * 2022-08-23 2022-12-23 山东和源制药有限公司 Preparation method of furanone acid
CN115504947B (en) * 2022-08-23 2024-04-26 山东和源制药有限公司 Preparation method of furanone acid

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