[go: up one dir, main page]

AU2008342536A1 - Novel C-21-keto lupane derivatives preparation and use thereof - Google Patents

Novel C-21-keto lupane derivatives preparation and use thereof Download PDF

Info

Publication number
AU2008342536A1
AU2008342536A1 AU2008342536A AU2008342536A AU2008342536A1 AU 2008342536 A1 AU2008342536 A1 AU 2008342536A1 AU 2008342536 A AU2008342536 A AU 2008342536A AU 2008342536 A AU2008342536 A AU 2008342536A AU 2008342536 A1 AU2008342536 A1 AU 2008342536A1
Authority
AU
Australia
Prior art keywords
alkyl
oxolup
oic acid
acetamide
acetoxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
AU2008342536A
Inventor
Laval Chan Chun Kong
Nathalie Chauret
Marc Courchesne
Liliane Halab
Christophe Moinet
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Virochem Pharma Inc
Original Assignee
Virochem Pharma Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Virochem Pharma Inc filed Critical Virochem Pharma Inc
Publication of AU2008342536A1 publication Critical patent/AU2008342536A1/en
Abandoned legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Virology (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Molecular Biology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • AIDS & HIV (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Steroid Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Description

WO 2009/082818 PCT/CA2008/002290 1 NOVEL C-21-KETO LUPANE DERIVATIVES, PREPARATION AND USE THEREOF This application is related to application Serial No. 61/018,766, filed January 3, 2008, and to application Serial No. 61/039,680, filed March 26, 2008, the entire disclosure of which is incorporated herein by reference. Infection by the Human immunodeficiency virus (HIV) can lead to the Acquired ImmunoDeficiency Syndrome (AIDS), an incurable and life threatening condition which requires life-long treatment. It is estimated that the HIV/AIDS 10 pandemic has resulted in the deaths of more than 25 million people since it was first recognized in 1981 and according to a UNAIDS report, an estimated 40 million people worldwide are infected with HIV and' about 2.5 million lost their lives to AIDS in 2005. There is presently no effective vaccine for HIV. HIV primarily infects T cells, macrophages and other important components of the immune system resulting in the gradual loss of cell-mediated immunity and as result, HIV patients become increasingly more susceptible to numerous opportunistic infections and tumors and if left untreated, death usually results within 10 years following infection. 20 The viral life cycle initiates with attachment of HIV gp120 surface protein to the CD4 receptors present of the T-cells. This event triggers a conformational change which exposes an additional binding site on gp120 and results with an interaction with the chemokine co-receptors (CCR5 and CXCR4). Another conformational change arising from co-receptor binding results in fusion of the cellular and viral membranes and release of the virion into the cell. After uncoating and release of the viral genome in the cytoplasm, viral reverse transcriptase (RT) then converts RNA into double stranded DNA which is then integrated into the host genome by the action of HIV integrase. The proviraL DNA is then transcribed and translated by host cellular system to express HIV RNA and HIV 30 proteins which are then directed to the cell membrane where they assemble and bud as immature virions. During or soon after the budding process, the viral protease cleaves specific sites in Gag and Gag-Pot releasing essential viral proteins and enzymes such as capsid, nucleocapsid, reverse transcriptase, integrase and spacer peptides SP1 and SP2. This last step is crucial for generating functional viral enzymes and also for the formation of the mature conical HIV capsid.
WO 2009/082818 PCT/CA2008/002290 2 A number of antiviral agents have been developed to interfere with various stages of viral replication. For example, viral entry can be blocked with T-20 or Maraviroc and post entry steps such as reverse transcription can be blocked with nucleoside RT inhibitors (examples: Lamivudine, Tenofovir, Zidovudine, Didanosine, Emtricitabine, Abacavir) or nonnucleoside RT inhibitors (examples: Nevirapine, Efavirenz and Delavirdine). Integration can be blocked by Raltegravir and HIV proteolytic activity can be inhibited by protease inhibitors such as Saquinavir, Indinavir, Amprenavir, Darunavir, Lopinavir, Atazanavir, and Nelfinavir. 10 Other experimental agents such as Vicriviroc (CCR5), Elvitegravir (integrase), Etravirine (RT), Apricitabine (RT), Bevirimat (maturation) are presently under investigation. The use of combinations of antiretroviral agents have been particularly effective in halting replication to undetectable levels and have led to markedly improved health and life span of HIV/AIDS patients. Nevertheless the appearance of drug resistant viruses after long term therapy is a major concern and there is still a major need for additional drugs in order to provide additional options for these patients facing these issues. Triterpenoid derivatives have been shown to possess anti-retroviral 20 properties. For example, moronic acid (D. Yu, et al. J. Med. Chem. 2006, 49, 5462 5469), oleanolic acid (H. Assefa, et al. Bioorg. Med. Chem. Lett. 1999, 9, 1889 1894), platanic acid (T. Fujioka, et al. J. Nat. Prod. 1994, 57, 243-247), betulonic acid (0. B. Flekhter, et aL. Russ. J. Bioorg. Chem. 2004, 30, 80-88) and betulinic acid (.-C. Sun, et al. Bioorg. Med. Chem. Lett. 1998, 8, 1267-1272) derivatives are shown to have anti-HIV-1 activities. Other triterpenes arising from the modification of natural product precursors such as betulin have been described, for example 21 keto derivatives shown in references (M. Urban, et al. J. Nat. Prod. 2007, 70, 526 532; M. Urban, et al. Synthesis 2006, 23, 3979-3986; J. Sarek, et al. Bioorg. Med. Chem. Lett. 2005, 15, 4196-4200; J. Sarek, et al. J. Med. Chem. 2003, 46, 5402 30 5414; M. Hajduch, J. Sarek WO 2001/090046). However, data pertaining to their anti-HIV properties are either absent or are related to uses other than for the treatment of HIV/AIDS conditions. Furthermore, the cytotoxicity of these compounds is unsuitable for the treatment of a chronic disease such as HIV/AIDS. This invention relates to 21-keto triterpenes and the discovery that these novel modified triterpenoid derivatives possess significant anti-HIV activity.
WO 2009/082818 PCT/CA2008/002290 3 The present invention relates to a compound of formula (I) and pharmaceutically acceptable salts:
CH
3 H3C O H 3 C /Y
CH
3
CH
3 X 1
CH
3
H
3 C CH3 (I) wherein
R
1 is H, a hydroxy protecting group or HO O 10 A is C 1 .3 alkyl, C 2
.
8 alkenyL, or -(CH 2
)
1
-
2 0(CH 2
)
12 Y is C=O or C-Ry 1 Ry2 Ry 1 and Ry 2 are each independently H or -CH 3 ; Xis R2 NR
R
3 0
R
2 is H, C 112 alkyl which is unsubstituted or substituted one or more times by R' 0 ,
C
2
.
1 2 alkenyl which is unsubstituted or substituted one or more times by R 1 0 , 20 or C 2
.
1 2 alkynyl which is unsubstituted or substituted one or more times by R10; WO 2009/082818 PCT/CA2008/002290 4
R
3 is H, C 1
.
1 2 alkyl which is unsubstituted or substituted one or more times by R 1 0 ,
C
2
.
12 alkenyl which is unsubstituted or substituted one or more times by R'",
C
212 alkynyl which is unsubstituted or substituted one or more times by R 1 ",
C
6
.
1 4 aryl which is unsubstituted or substituted one or more times by R", C 7 . 16 aralkyl which is unsubstituted or substituted one or more times by R", 5 12 member heteroaryl which is unsubstituted or substituted one or more times by R", 6-18 member heteroaralkyl which is unsubstituted or substituted one or more times by R", 3-12 member heterocycle which is unsubstituted or substituted one or more times by R' 2 , or 4-18 member 10 heterocycle-alkyl which is unsubstituted or substituted one or more times by R 12 ;
R
2 and R 3 can also be taken together to form 5-12 member heteroaryl which is unsubstituted or substituted one or more times by R", or a 3-12 member heterocycle which is unsubstituted or substituted one or more times by R 12 .
R
1 0 is halogen, oxo, C 1
.
6 alkoxy, -NH 2 , -NH(C.
4 alkyl), -N(C 14 alkyl) 2 , -C(O)NH 2 , C(O)NH(C 1
.
4 atkyl), -C(O)N(C 14 alkyl) 2 , -NHC(O)H, -N(C.
4 alkyL)C(O)H, -N(C 1
.
4 alkyL)C(O)C 14 alkyl, -NHC(O)C 14 alkyl, -NHC(0)OC 14 alkyl, -N(C 14 20 alkyL)C(0)OCI.
4 alkyl, -NHC(O)NH 2 , ,-N(C- 4 alkyL)C(O)NH 2 , -NHC(O)NHC 14 alkyl, -N(C 14 alkyL)C(O)NHC 14 alkyl,-N(C 14 alkyL)C(O)N(C 14 alkyL) 2 , NHC(O)N(C 14 alkyL) 2 , -C(O)H, -C(O)C 14 alkyl, C(O)OH, -C(O)0C 1
.
4 alkyl, OC(O)C 14 alkyl, -OC(O)NH(C. alkyl), -OC(O)N(C 14 alkyL) 2 , -C(NOH)C 14 aLkyl, C(NOH)H, -C(NOC 14 alkyl)C 14 alkyl, -C(NOC 14 aLkyl)H, hydroxyl, nitro, azido, cyano, -S(0) 0
.
3 H, -S(0) 0
.
3
C
14 alkyl, -S0 2
NH
2 , -SO 2
NH(C
14 alkyl), -SO 2
N(C
14 alkyl) 2 , -N(C 14 alkyL)S0 2
CI-
4 alkyl, -NHSO 2
C
1
.
4 alkyl, -P(O)(OH) 2 , -P(O)(OC 4 alkyl)OH, -P(O)(C, 4 alkyl) 2 , amidino, or guanidino; R" is halogen, C 1
.
6 alkyl, halogenated C 1
.
6 alkyl, C 2
.
6 alkenyl, C 2
-
6 alkynyl, C 1
.
6 alkoxy, 30 NH 2 , -NH(C.
4 alkyl), -N(C 1
.
4 alkyl) 2 , -C(0)NH 2 , -C(0)NH(C 14 alkyl), -C(O)N(C.
4 alkyL) 2 , -NHC(0)H, -N(C 14 alkyL)C(0)H, -N(C.
4 alkyl)C(0)C 1 . alkyt, -NHC(0)C 1 . 4 alkyL, -NHC(0)OC.
4 alkyl, -N(C.
4 alkyl)C(0)OC 1
.
4 alkyl, -NHC(0)NH 2 , ,-N(CI- 4 alkyL)C(0)NH 2 , -NHC(0)NHC 1
.
4 alkyl, -N(Cl.
4 atkyl)C(0)NHC,.
4 alkyl,-N(C 14 alkyL)C(O)N(C.
4 alkyL) 2 , -NHC(O)N(Cl.
4 aLkyL) 2 , -C(0)H, -C(0)C 14 alkyl, C(0)OH, -C(0)OCI.
4 alkyl, -OC(0)C 1
.
4 alkyL, -OC(O)NH(C 14 alkyl), -OC(0)N(C.
4 alkyL) 2 , -C(NOH)Cl.
4 alkyl, -C(NOH)H, -C(NOC 14 alkyl)C 1
.
4 alkyl, -C(NOC 1
.
4 WO 2009/082818 PCT/CA2008/002290 5 atkyl)H, hydroxyl, nitro, azido, cyano, -S(0) 0
.
3 H, -S(0) 0
.
3
C
1 4 alkyl, -S0 2
NH
2 , SO 2
NH(C
1
.
4 alkyl), -S0 2
N(C
1
.
4 alkyl) 2 , -N(C 1
.
4 alkyl)SO 2
C
1
.
4 alkyl, -NHS0 2
C
1
.
4 alkyl, -P(O)(OH) 2 , -P(O)(OC 1
.
4 akyl)OH, -P(O)(OC 1
.
4 aky) 2 , amidino, or guanidino; and R1 2 is halogen, oxo, C 1
.
6 alkyl, halogenated C 1
.
6 alkyl, C 2
.
6 alkenyl, C 2
.
6 alkynyL, C 1
.
6 alkoxy, -NH 2 , -NH(C 1
.
4 alkyl), -N(C 1
.
4 alkyl) 2 , -C(O)NH 2 , -C(O)NH(C 1
.
4 aLkyl), C(O)N(C 14 alkyl) 2 , -NHC(O)H, -N(C 1
.
4 alkyl)C(O)H, -N(C 1
.
4 alkyl)C(O)C 1
.
4 alkyl, 10 NHC(O)C 1
.
4 alkyl, -NHC(O)OC 1
.
4 alkyl, -N(C 1
.
4 alkyL)C(O)OC 1
.
4 aLkyl, NHC(O)NH 2 , ,-N(C 1
.
4 alky[)C(O)NH 2 , -NHC(O)NHC 1
.
4 alkyl, -N(C 1
.
4 alkyl)C(O)NHC 1
.
4 alkyl,-N(C 1
.
4 alkyl)C(O)N(C 1
.
4 alkyt) 2 , -NHC(O)N(C 1
.
4 alkyl) 2 , C(O)H, -C(O)C 1
.
4 alkyl, C(O)OH, -C(O)0C 1
.
4 alkyl, -OC(O)C 1
.
4 atkyl, OC(O)NH(C 1
.
4 alkyl), -OC(O)N(C 1
.
4 alkyt) 2 , -C(NOH)C 1
.
4 atkyl, -C(NOH)H, C(NOC 1
.
4 alkyl)C 1
.
4 alkyl, -C(NOC 1
.
4 alkyl)H, hydroxyl, nitro, azido, cyano, S(0) 0
.
3 H, -S(0) 0
.
3 C1.
4 alkyl, -SO 2
NH
2 , -SO 2
NH(C
1
.
4 alkyl), -SO 2
N(C
1
.
4 alkyl) 2 , N(C 1
.
4 alkyl)S0 2
C
1
.
4 alkyl, -NHS0 2
C
1
.
4 alkyl, -P(O)(OH) 2 , -P(O)(OC 1
.
4 akyl)OH, P(O)(OC 14 alkyl) 2 , amidino, or guanidino. 20 In further embodiments, the compounds of the inventions are represented by formula (1) wherein the following embodiments are present alone or in combination: Yis C=O Y is C-Ry 1 Ry 2 and Ry 1 and Ry 2 are -CH 3 Y is C-Ry 1 Ry 2 and Ry 1 and Ry 2 are H. Y is -CH 2 30 WO 2009/082818 PCT/CA2008/002290 6
R
1 is o 0 0 HOOC 0 ; HOOC O HOOC 0 o 0 HOOC O HOOCO ** 0 0 HOOC 0 ; HOOC HOOC 0 00 0 HOOC" 0;or Q ' 0 HOOC0
R
1 is succinyl, glutaryl, 3-methyigutaryl, 3'-methylsucciny, 3',3' dimethylsuccinyL, 3',3'- dimethylglutaryl, 2',2'-dimethylmalonyt, 2',3' dihydroxysuccinyl, 2', 3'-di methylsucci nyl, 2',2,3', 3'-tetramethylsucci nyl, 2' methylsuccinyl, or 2',2'- dimethylsuccinyl.
R
1 is succinyl, glutaryl, 3'-methylglutaryl, 3-methylsuccinyt, 3,3' 10 dimethylsuccinyl, 3,3'- dimethylglutaryl, 2',2'-dimethyLmalonyL, 2',3' dihydroxysuccinyl, 2',2',3',3'-tetramethylsuccinyl or 2',2'- dimethylsucciny.
R
1 is 3',3'-dimethylsuccinyl. In a further embodiment, R 1 is H, or a hydroxy protecting group. In a further embodiment, R 1 is H.
WO 2009/082818 PCT/CA2008/002290 7
R
2 is H or C 11 2 alkyl which is unsubstituted or substituted one or more times by R 1 0 .
R
2 is H or C 1
.
6 alkyl which is unsubstituted or substituted one or more times by R 1 0 .
R
2 is H, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyt, cyclopentyl, or cyclohexyl. 10 R 2 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butyl.
R
2 is methyl.
R
2 is H.
R
2 and R 3 taken together form a 5-6 member heteroaryl which is unsubstituted or substituted one or more times by R" or a 5-6 member heterocycle which is unsubstituted or substituted one or more times by R1 2 . 20 R 2 and R 3 taken together form a piperidyl, a piperazinyl, or a morpholinyl which is unsubstituted or substituted one or more times by R".
R
2 and R 3 taken together form a diazabicyclo[3.2.1]octane which is unsubstituted or substituted one or more times by R".
R
3 is C- 12 alkyl which is unsubstituted or substituted one or more times by R'4, C 6 aryl which is unsubstituted or substituted one or more times by R", C 7
.
9 aralkyl which is unsubstituted or substituted one or more times by R", 5-6 member heteroaryl which is unsubstituted or substituted one or more times by R", 7-8 30 member heteroaralkyl which is unsubstituted or substituted one or more times by R", 5-6 member heterocycle which is unsubstituted or substituted one or more times by R 1 2 , or 7-8 member heterocycle-alkyl which is unsubstituted or substituted one or more times by R 1 .
R
3 is C 1
,
6 alkyl which is unsubstituted or substituted one or more times by
R
1 0 , phenyl which is unsubstituted or substituted one or more times by R", benzyl WO 2009/082818 PCT/CA2008/002290 8 which is unsubstituted or substituted one or more times by R", 5-6 member heteroaryl which is unsubstituted or substituted one or more times by R", 7-8 member heteroaralkyl which is unsubstituted or substituted one or more times by R", 5-6 member heterocycle which is unsubstituted or substituted one or more times by R 12 , or 7-8 member heterocycle-alkyl which is unsubstituted or substituted one or more times by R 1 .
R
3 is C1.
6 alkyl which is unsubstituted or substituted one or more times by
R
1 0 , benzyl which is unsubstituted or substituted one or more times by R", 7-8 10 member heteroaralkyl which is unsubstituted or substituted one or more times by R", 5-6 member heterocycle which is unsubstituted or substituted one or more times by R", or 7-8 member heterocycle-alkyl which is unsubstituted or substituted one or more times by R'.
R
3 is C 1
.
6 alkyl which is unsubstituted or substituted one or more times by
R'
0 , benzyl which is unsubstituted or substituted one or more times by R 1 1 , 7-8 member heteroaralkyt which is unsubstituted or substituted one or more times by R", or 7-8 member heterocycle-alkyl which is unsubstituted or substituted one or more times by R 1 . 20
R
3 is C 1
.
6 alkyl which is unsubstituted or substituted one or more times by R'*, benzyl which is unsubstituted or substituted one or more times by R", or 7-8 member heterocycle-alkyl which is unsubstituted or substituted one or more times by R 1 .
R
3 is C 1
.
6 alkyl which is unsubstituted or substituted one or more times by
R
1 0 .
R
3 is 5-6 member heteroaryl which is unsubstituted or substituted one or 30 more times by R".
R
3 is 5-6 member heterocycle which is unsubstituted or substituted one or more times by R 1 .
R
3 is 7-8 member heterocycle-alkyl which is unsubstituted or substituted one or more times by R' 2
.
WO 2009/082818 PCT/CA2008/002290 9
R
3 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclohexyl(CH 2
)-
R
3 is benzyl which is unsubstituted or substituted one or more times by R".
R
3 is benzyl.
R
3 is pyridinyl(CH 2 )- which is unsubstituted or substituted one or more times by R". 10
R
3 is pyridinyL(CH 2
)-
R
3 is ethyl, iso-propyl, tert-butyl, cyclopentyl, cyclopentyl(CH 2 )-, cyclohexyl, cyclohexyl(CH 2 )-, phenyl, benzyl, pyridinyL, pyridinyL(CH 2 )-, piperidynyl, piperazinyl, thiophenyl, morpholino, oxadiazole, pyrimidinyl, pyranyl, pyrazinyl, thiazole, and pyrazole, which are unsubstituted or substituted by one or more substituents chosen from a halogen, C 1
.
4 alkyl, C 14 alkyloxy, CF 3 , COC 14 alkyl, COOH, COOC 1
.
4 alkyl, cyano, NH 2 , nitro, NH(C 1
.
6 alkyl), and N(C 1
.
6 aLkyl) 2 . 20 R 3 is piperidinyl which is unsubstituted or substituted one or more times by R 1.
R
3 is piperidinyl.
R
3 is pyrimidinyl which is unsubstituted or substituted one or more times by
R
1 1 .
R
3 is pyrimidinyl. 30 R 3 is pyridine which is unsubstituted or substituted one or more times by
R
1 1 .
R
3 is pyridine.
R
3 is pyrazole which is unsubstituted or substituted one or more times by
R
1
.
WO 2009/082818 PCT/CA2008/002290 10
R
3 is methyl pyrazole
R
3 is pyperazinyl.
R
3 is phenyl which is unsubstituted or substituted one or more times by R".
R
3 is fluorophenyt. 10 R 3 is phenyl.
R
3 is cyclohexyl(CH 2 )- which is unsubstituted or substituted one or more times by R'4.
R
3 is cyclohexyl(CH 2 )- which is unsubstituted or substituted one or more times by halogen.
R
1 0 is halogen, oxo, C 1
.
6 alkoxy, -NH 2 , -NH(C 14 alkyl), -N(C 1
.
4 alkyL) 2 , -CONH 2 , CONH(CI 4 alkyl), -CON(C 1
.
4 alkyl) 2 , -NHCOH, -N(C 1
.
4 alkyl)COH, -N(C 1 4 20 alkyl)COC 1 4 alkyl, -NHCOC 1
.
4 alkyt, -NHCOOC 14 alkyl, -NHCONHC 1 4 alkyl, N(C 1
.
4 alkyl)CONHC 14 alkyl,-N(C 1
.
4 alkyl)CON(C 1
.
4 alkyL) 2 , -NHCON(C- 4 alkyL) 2 , C(O)H, -C(O)C 1 4 alkyl, carboxy, -C(O)0CI.
4 alkyl, -C(NOH)C 1
.
4 alkyl, C(NOH)H, -C(NOC 1
.
4 alkyL)C 1
.
4 alkyl, -C(NOC 14 alkyl)H, hydroxyl, nitro, azido, cyano, -S(0) 0
-
2 H, -S(0) 0
-
2
C
1 4 alkyl, -SO 2
NH
2 , -SO 2
NH(C
1
.
4 aLkyl), -S0 2
N(C
14 alkyt) 2 , -N(C 1 4 alkyL)S0 2
C
1
.
4 alkyl, -NHS0 2
C
14 aLkyl, -P(O)(OH) 2 or P(O)(OC 4 aLkyl) 2 ;
R'
0 is halogen, oxo, C 1 .6 alkoxy,-NH 2 , -NH(C 1 4 alkyl), -N(C 1 4 alky) 2 , -CONH 2 , CONH(C 1
.
4 alkyl), -CON(C 14 alkyl) 2 , -NHCOH, -N(C 1
.
4 alkyl)COH, -N(C 1
.
4 alkyL)COC 1 4 30 alkyl, -NHCOC 14 alkyl, -NHCOOC 1
.
4 alkyl, -NHCONHC 1
.
4 alkyl, -N(C 1
.
4 alkyL)CONHC 14 alkyl, -N(C 1 4 alkyl)CON(C 14 alkyL) 2 , -NHCON(C 1 4 alkyl) 2 , -C(O)H, -C(O)C 1 4 aLkyL, carboxy, -C(O)0C 1
.
4 aLkyL,-C(NOH)C 1
.
4 aLkyl,-C(NOH)H, hydroxyL, nitro, azido, cyano, -S(0) 0
-
2 H, -S(0)- 2
CI-
4 alkyl, -SO 2
NH
2 , -SO 2
NH(C
1
.
4 alkyl), -SO 2
N(C-
4 alkyL) 2 , -N(C 14 alkyL)S0 2
C-
4 aLkyl, -NHS0 2
C
1 4 aLkyl, or -P(O)(OH) 2
.
WO 2009/082818 PCT/CA2008/002290 11 R'* is halogen, oxo, -NH 2 , -NH(C 1
.
4 alkyl), -N(C 1
.
4 alkyL) 2 , -CONH 2 , -CONH(C 1
.
4 alkyl), -CON(C 1
.
4 alkyl) 2 , -NHCOH, -N(C 1
.
4 alkyl)COH, -N(C 1
.
4 alkyl)COC 1
.
4 alkyl, NHCOC 1
.
4 alkyl, -NHCOOC 1
.
4 alkyl, -NHCONHC 1
.
4 alkyl, -C(O)H, -C(O)C 1
.
4 alkyl, carboxy, -C(O)0C 1
.
4 alkyl, hydroxyl, C 1 .4 alkoxy, nitro, nitroso, azido, or cyano.
R
1 0 is halogen, oxo, -NH 2 , -NH(C 1
.
4 alkyl), -N(C 1
.
4 alkyl) 2 , -CONH 2 , -CONH(C 1 .4 alkyl), -CON(C 1
.
4 alkyl) 2 , -NHCOH, -N(C 1
.
4 alkyl)COH, -N(C 1
.
4 alkyl)COC 1
.
4 alkyl, NHCOC 1
.
4 alkyl, -NHCOOC 1
.
4 alkyl, -NHCONHC 1
.
4 alkyl, -C(O)H, -C(O)C 1 4 alkyl, carboxy, -C(O)OC- 4 alkyl, hydroxyL, C 14 alkoxy, nitro, azido, or cyano. 10
R
1 0 is halogen, oxo, -NH 2 , -NH(C 1
.
4 alkyl), -N(C 1
.
4 alkyL) 2 , -CONH 2 , -CONH(C 1
.
4 alkyl), -CON(C 1 4 alkyl) 2 , -NHCOH, -N(C 14 alkyl)COH, -N(C 1
.
4 alkyl)COC 1
.
4 alkyl, NHCOC 14 alkyL, -NHCOOC 14 alkyl, -NHCONHC.
4 alkyl, -C(O)H, -C(O)C 1 4 alkyl, carboxy, -C(O)0C 1
.
4 alkyl, hydroxyl, or C 1
.
4 alkoxy.
R
1 0 is halogen, oxo, -NH 2 , -NH(C 1
.
4 alkyl), -N(C 1
.
4 alkyl) 2 , -CONH 2 , -CONH(C 1
.
4 alkyl), -CON(C 1
.
4 alkyl) 2 , -N(C 1
.
4 alkyl)COC 14 alkyl, -NHCOC 1
.
4 alkyl, carboxy, C(O)0C 1
.
4 alkyl, hydroxyl, C 1
.
4 alkoxy, or cyano. 20 R" is halogen, C 1
.
6 alkyl, halogenated C 1
.
6 alkyl, C 2
.
6 alkenyl, C 2
-
6 alkynyl, C 1
.
6 alkoxy, NH 2 , -NH(C 1 4 alkyl), -N(Cl.
4 alkyl) 2 , -CONH 2 , -CONH(C 1
.
4 alkyl), -CON(C 14 alkyl) 2 , -NHCOH, -N(C 1
.
4 alkyl)COH, -N(C 1 4 alkyl)COC 1
.
4 alkyl, -NHCOC 1 4 alkyl,
-NHCOOC
14 alkyl, -NHCONHC 1
.
4 alkyl, -N(C 14 alkyl)CONHC 14 alkyl, -N(C 1 4 alkyl)CON(C 14 alkyL) 2 , -NHCON(C 1
.
4 alkyl) 2 , -C(O)H, -C(O)C 1 4 alkyl, carboxy, C(O)0C 1 4 alkyl, -C(NOH)C 1 4 alkyl, -C(NOH)H, -C(NOC 14 alkyl)C 1 4 alkyl, C(NOC 1
.
4 alkyL)H, hydroxyl, nitro, azido, cyano, -S(0) 0
-
2 H, -S(0) 0
-
2
C
1 4 alkyl, SO 2
NH
2 , -SO 2
NH(CI.
4 alkyl), -SO 2
N(C-
4 alkyl) 2 , -N(C 14 alkyl)SO 2
C
14 alkyl, NHSO 2
C
14 alkyl, -P(O)(OH) 2 or P(O)(OC 1
.
4 akyl) 2 ; and 30 R" is halogen, C 1
.
6 alkyl, halogenated C 1
.
6 alkyl, C 2
.
6 alkenyl, C 2
-
6 alkynyl, C 1
.
6 alkoxy,-NH 2 , -NH(C 1
.
4 alkyl), -N(C 1
.
4 alkyl) 2 , -CONH 2 , -CONH(C.
4 alkyl), -CON(C 1 4 alkyl) 2 , -NHCOH, -N(C 1
.
4 alkyl)COH, -N(C 1
.
4 alkyl)COC 1
.
4 ,alkyl, -NHCOC 1
.
4 alkyl, NHCOOC 14 alkyl, -NHCONHC 14 alkyl, -N(C 14 alkyl)CONHC.
4 alkyl, -N(C 1
.
4 alkyl)CON(Cl.
4 alkyl) 2 , -NHCON(C.
4 alkyL) 2 , -C(O)H, -C(O)C 1
.
4 alkyl, carboxy, C(O)0C 1
.
4 alkyl, -C(NOH)C 1
.
4 alkyl, -C(NOH)H, hydroxyl, nitro, azido, cyano, -S(0) 0
.
WO 2009/082818 PCT/CA2008/002290 12 2 H, -S(0) 0
.
2
C-
4 alkyl, -SO 2
NH
2 , -SO 2
NH(C
1
.
4 alkyl), -S0 2
N(C
14 alkyl) 2 , -N(C.
4 alkyl)S0 2
C
14a lkyl, -NHS0 2
C
14 alkyl, or -P(O)(OH) 2 .
R
1 is halogen, C 1
.
6 alkyl, halogenated C 1
.
6 alkyl, C 2
.
6 alkenyl, C 2
.
6 alkynyl,-NH 2 , NH(C 1 4 alkyl), -N(C 1
.
4 alkyl) 2 , -CONH 2 , -CONH(CI.
4 alkyl), -CON(Ca.
4 alkyl) 2 , -NHCOH, N(C 1
.
4 alkyl)COH, -N(C 1 4 alkyl)COCI- 4 alkyl, -NHCOC 14 alkyl, -NHCOOCI.
4 alkyl, NHCONHC 1
.
4 alkyl, -C(O)H, -C(O)C 1
.
4 alkyl, carboxy, -C(0)O C 1
.
4 alkyl, hydroxyl, C 1
.
6 alkoxy, nitro, nitroso, azido, or cyano. 10 R" is halogen, C 1
.
6 alkyl, halogenated C 1
.
6 alkyl, C 2
.
6 alkenyl, C 2
-
6 alkynyl,-NH 2 , NH(C 1
.
4a lkyl), -N(Cl 4 a lkyl) 2 , -CONH 2 , -CONH(C.
4 akyl), -CON(C.
4 alkyl) 2 , -NHCOH, N(C 1
.
4 alkyl)COH, -N(CI.
4 alkyl)COC 1
.
4 alkyl, -NHCOC,.
4 alkyl, -NHCOOC 1
.
4 alkyl, NHCONHC 1
.
4 alkyl, -C(Q)H, -C(O)C 1
.
4 alkyl, carboxy, -C(0)O C 1
.
4 alkyl, hydroxyl, C 1
.
6 alkoxy, nitro, azido, or cyano. R' is halogen, C 1
.
6 alkyl, halogenated C 1
.
6 alkyl, C 2
.
6 alkenyt, C 2
-
6 alkynyl, -NH 2 , -NH(Cl.
4 alkyl), -N(C 1
.
4 alkyL) 2 , -CONH 2 , -CONH(C 1
.
4 alkyl), -CON(C.
4 alkyl) 2 , -NHCOH,
-N(C
1
.
4 alkyl)COH, -N(C 1
.
4 alkyl)COC 1
.
4 alkyl, -NHCOC 1
.
4 alkyl, -NHCOOC.
4 alkyl, NHCONHC.4 alkyl, -C(O)H, -C(O)C 1 4 alkyl, carboxy, -C(O)OC 1
.
4 aLkyl, hydroxyl, or C 1
.
6 20 alkoxy.
R
1 is halogen, C 1
.
6 alkyl, halogenated C 1
.
6 alkyl, C 2
.
6 alkenyl, C 2
-
6 alkynyl, -NH 2 , -NH(Cl.
4 alkyl), -N(C 1
.
4 alkyL) 2 , -CONH 2 , -CONH(C 1
.
4 alkyl), -CON(C 1
.
4 alkyt) 2 , -N(C 1
.
4 alkyl)COC,.
4 alkyl, -NHCOC 1
.
4 alkyl, carboxy, -C(O)0C.
4 alkyl, hydroxyl, or C 1
.
6 alkoxy.
R
12 is halogen, oxo, C 1
.
6 alkyl, halogenated C 1
.
6 alkyl, C 2
-
6 alkenyl, C 2
.
6 alkynyt, C 1
.
6 alkoxy,-NH 2 , -NH(C.
4 alkyl), -N(C 1 4 alkyt) 2 , -CONH 2 , -CONH(C 1
.
4 alkyl), CON(C 1
.
4 alkyl) 2 , -NHCOH, -N(C 1
.
4 alkyl)COH, -N(C 1
.
4 alkyl)COC.
4 alkyl, 30 NHCOC 14 alkyl, -NHCOOC.
4 alkyl, -NHCONHC.
4 alkyl, -N(C 1
.
4 alkyL)CONHC 1
.
4 alkyL, -N(C 1
.
4 alkyl)CON(Cl.
4 alkyl) 2 , -NHCON(C 1
.
4 alkyt) 2 , -C(O)H, -C(O)C 1
.
4 alkyt, carboxy, -C(0)OC.
4 alkyl, -C(NOH)C 1
.
4 aLkyl, -C(NOH)H, -C(NOC.
4 alkyl)C 1
.
4 alkyL, -C(NOC 1
.
4 alkyl)H, hydroxyl, nitro, azido, cyano, -S(0) 0
-
2 H, S(0) 0
-
2
C-
4 alkyl, -S0 2
NH
2 , -SO 2
NH(C
1
.
4 alkyl), -50 2
N(C-
4 aLkyl) 2 , -N(C 1
.
4 alkyt)SO 2
C.
4 alkyl, -NHSO 2
C
1
.
4 alkyl, -P(O)(OH) 2 or P(O)(OC 1
.
4 alkyl) 2
.
WO 2009/082818 PCT/CA2008/002290 13
R
1 2 is halogen, oxo, C 1
.
6 alkyl, halogenated C 1
.
6 alkyl, C 2
-
6 alkenyl, C 2
-
6 alkynyl,,
C
1
.
6 alkoxy,-NH 2 , -NH(CI- 4 alkyl), -N(C.
4 alkyl) 2 , -CONH 2 , -CONH(C 1
.
4 alkyl), -CON(Cl.
4 alkyl) 2 , -NHCOH, -N(C 1
.
4 alkyl)COH, -N(C 1
.
4 alkyl)COC.
4 ,alkyl, -NHCOC 1
.
4 alkyl, NHCOOCj.
4 alkyl, -NHCONHC 1
.
4 alkyl, -N(C 1
.
4 alkyl)CONHC.
4 alkyl, -N(Cl.
4 alkyl)CON(C 1 4 alkyl) 2 , -NHCON(Cl.
4 alkyl) 2 , -C(O)H, -C(O)CI- 4 alkyl, carboxy, C()OC 1 .4 alkyl,-C(NOH)C 1
-
4 alkyl, -C(NOH)H, hydroxyl, nitro, azido, cyano, -S(0) 0
.
2 H, -S(0) 0
.
2 Cl.
4 alkyl, -SO 2
NH
2 , -SO 2
NH(C
1
.
4 alkyl), -SO 2
N(C
1 4 alkyL) 2 , -N(C 1
.
4 alkyl)S0 2
C
1
-
4 alkyl, -NHSO 2
C
1
.
4 alkyl, or -P(O)(OH) 2 . 10 R"is halogen, oxo, C 1
.
6 alkyl, halogenated C 1
.
6 alkyl, C 2
.
6 alkenyl, C 2
.
6 alkynyl, NH 2 , -NH(C 1
.
4 alkyl), -N(C 1
.
4 alkyl) 2 , -CONH 2 , -CONH(C.
4 alkyl), -CON(Cl.
4 alkyl) 2 , NHCOH, -N(C 1
.
4 alkyl)COH, -N(C 1
.
4 alkyl)COCI.
4 alkyl, -NHCOC 1
.
4 alkyl, -NHCOOCI.
4 alkyl, -NHCONHC,.
4 alkyl, -C(O)H, -C(O)C 1
.
4 alkyl, carboxy, -C(0)OC 1
.
4 alkyl, hydroxyl, C 1
.
6 alkoxy, nitro, nitroso, azido, or cyano.
R
1 2 is halogen, oxo, C 1
.
6 alkyL, halogenated C 1
.
6 alkyl, C 2
.
6 alkenyl, C 2
.
6 alkynyl, NH 2 , -NH(C 1
.
4 alkyl), -N(C 1
.
4 alkyl) 2 , -CONH 2 , -CONH(Cl.
4 alkyl), -CON(C.
4 alkyl) 2 , NHCOH, -N(C 1
.
4 alkyl)COH, -N(C 1
.
4 alkyl)COC 1
.
4 alkyl, -NHCOC.
4 alkyl, -NHCOOC.
4 alkyl, -NHCONHC.
4 alkyl, -C(O)H, -C(O)C 1
.
4 alkyl, carboxy, -C(0)OC.
4 alkyl, 20 hydroxyl, C 1
.
6 alkoxy, nitro, azido, or cyano.
R
1 2 is halogen, oxo, C 1
.
6 alkyl, halogenated C 1
.
6 alkyl, C 2
.
6 alkenyl, C 2
.
6 alkynyl, NH 2 , -NH(C 1
.
4 alkyl), -N(C 1
.
4 alkyl) 2 , -CONH 2 , -CONH(C.
4 alkyl), -CON(C 1
.
4 alkyl) 2 , NHCOH, -N(C 1
.
4 alkyl)COH, -N(C 1
.
4 alkyl)COC.
4 alkyL, -NHCOC.
4 alkyl, -NHCOOC 1
.
4 alkyl, -NHCONHC 1
.
4 alkyl, -C(O)H, -C(O)C 1
.
4 alkyl, carboxy, -C(0)OC.
4 alkyl, hydroxyl, or C 1
.
6 alkoxy. R1 2 is halogen, oxo, C 1
.
6 alkyl, halogenated C 1
.
6 alkyl, -NH 2 , -NH(C 1
.
4 alkyl), N(C.
4 alkyl) 2 , -CONH 2 , -CONH(C.
4 aLkyl), -CON(C.
4 alkyl) 2 , -N(C 14 alkyl)COC.
4 alkyl, 30 NHCOC.
4 alkyl, carboxy, -C(O)0CI- 4 alkyl, hydroxyl, or C 1
.
6 alkoxy. It will be appreciated by those skilled in the art that the compounds in accordance with the present invention can exists as stereoisomers (for example, optical (+ and -), geometrical (cis and trans) and conformational isomers (axial and equatorial). All such stereoisomers are included in the scope of the present invention.
WO 2009/082818 PCT/CA2008/002290 14 It will be appreciated by those skilled in the art that the compounds in accordance with the present invention can contain a chiral center. The compounds of formula (1) may thus exist in the form of two different optical isomers (i.e. (+) or (-) enantiomers). All such enantiomers and mixtures thereof including racemic mixtures are included within the scope of the invention. The single optical isomers or enantiomers can be obtained by method well known in the art, such as chiral HPLC, enzymatic resolution and chiral auxiliary. 10 In one embodiment, the compounds of the present invention are provided in the form of a single enantiomer at least 95%, at least 97% and at least 99% free of the corresponding enantiomer. In a further embodiment the compound of the present invention are in the form of the (+) enantiomer at least 95% free of the corresponding (-) enantiomer. In a further embodiment the compound of the present invention are in the form of the (+) enantiomer at least 97% free of the corresponding (-) enantiomer. 20 In a further embodiment the compound of the present invention are in the form of the (+) enantiomer at least 99% free of the corresponding (-) enantiomer. In a further embodiment, the compounds of the present invention are in the form of the (-) enantiomer at least 95% free of the corresponding (+) enantiomer. In a further embodiment the compound of the present invention are in the form of the (-) enantiomer at least 97% free of the corresponding (+) enantiomer. In a further embodiment the compound of the present invention are in the 30 form of the (-) enantiomer at least 99% free of the corresponding (+) enantiomer. There is also provided pharmaceutically acceptable salts of the compounds of the present invention. By the term pharmaceutically acceptable salts of compounds are meant those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acids include hydrochloric, hydrobromic, sulphuric, nitric, perchloric, fumaric, maLeic, phosphoric, glycollic, WO 2009/082818 PCT/CA2008/002290 15 lactic, saLicylic, succinic, toleune-p-sulphonic, tartaric, acetic, trifluoroacetic, citric, methanesulphonic, formic, benzoic, malonic, naphthalene-2-sulphonic and benzenesulphonic acids. Other acids such as oxalic, while not themselves pharmaceutically acceptable, may be useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts. Salts derived from amino acids are also included (e.g. L-arginine, L-Lysine). 10 Salts derived from appropriate bases include alkali metals (e.g. sodium, lithium, potassium), alkaline earth metals (e.g. calcium, magnesium), ammonium,
NR
4 + (where R is C 1
.
4 alkyl) salts, choline, meglumine and tromethamine. A reference hereinafter to a compound according to the invention includes that compound and its pharmaceutically acceptable salts. In one embodiment of the invention, the pharmaceutically acceptable salt is a sodium salt. 20 In one embodiment of the invention, the pharmaceutically acceptable salt is a lithium salt. In one embodiment of the invention, the pharmaceutically acceptable salt is a potassium salt. In one embodiment of the invention, the pharmaceutically acceptable salt is a tromethamine salt. In one embodiment of the invention, the pharmaceutically acceptable salt 30 is an L-arginine salt. In one embodiment of the invention, the pharmaceutically acceptable salt is meglumine salt. It will be appreciated by those skilled in the art that the compounds in accordance with the present invention can exist in different polymorphic forms. As WO 2009/082818 PCT/CA2008/002290 16 known in the art, polymorphism is the ability of a compound to crystallize as more than one distinct crystalline or "polymorphic" species. A polymorph is a solid crystalline phase of a compound with at least two different arrangements or polymorphic forms of that compound molecule in the solid state. Polymorphic forms of any given compound are defined by the same chemical formula or composition and are as distinct in chemical structure as crystalline structures of two different chemical compounds. It will further be appreciated by those skilled in the art that the compounds 10 in accordance with the present invention can exist in different solvate forms, for example hydrates. Solvates of the compounds of the invention may also form when solvent molecules are incorporated into the crystalline lattice structure of the compound molecule during the crystallization process. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In 20 addition, the materials, methods, and examples are illustrative only and not intended to be limiting. The' term "alkyl" represents a linear, branched or cyclic hydrocarbon moiety. The terms "alkenyl" and "alkynyl" represent a linear, branched or cyclic hydrocarbon moiety which has one or more double bonds or triple bonds in the chain, respectively. Examples of alkyl, alkenyl, and alkynyl groups include but are not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, neohexyl, allyl, vinyl, acetylenyl, ethylenyl, propenyl, isopropenyl, butenyl, isobutenyl, butadienyl, 30 pentenyl, pentadienyl, hexenyl, hexadienyl, hexatrienyl, heptenyl, heptadienyl, heptatrienyl, octenyl, octadienyl, octatrienyl, octatetraenyl, propynyl, butynyl, pentynyl, hexynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexenyl, cyclohexdienyt and cyclohexyl. Where indicated the "alkyl," "alkenyl," and "alkynyl" can be optionally substituted such as in the case of haloalkyls in which one or more hydrogen atom is replaced by a halogen, e.g., an alkylhalide. Examples of haloalkyls include but are not limited to trifluoromethyl, difluoromethyl, WO 2009/082818 PCT/CA2008/002290 17 fluoromethyl, trichloromethyl, dichloromethyl, chloromethyl, trifluoroethyl, difluoroethyl, fluoroethyl, trichloroethyl, dichloroethyl, chloroethyl, chlorofluoromethyl, chlorodifluoromethyl, dichlorofluoroethyl. Aside from halogens, where indicated, the alkyl, alkenyl or alkynyl groups can also be optionally substituted by, for example, oxo, -NRdRe, -CONRdRe, =NO-Re, -NRdCORe, carboxy, -C(=NRd)NReRf, azido, cyano, C 1
.
6 alkyloxy, C 2
.
6 alkenyloxy, C 2
-
6 alkynyloxy, -N(Rd)C(=NRe)-NRRg, hydroxyl, nitro, nitroso, -N(Rh)CONRiRj, -S(0)o.
2 Ra, -C(O)R., C(O)0Ra , -SO 2 NRaRb, -NRaSO 2 Rb, -NRaSO 2 NRbRc, -CRaN=ORb, -OCONReRf and/or NRaCOORb, wherein Ra-Rj are each independently H, C 1
.
4 alkyl, C 2
.
4 alkenyt or C 2
-
4 10 alkynyl. The terms "cycloalkyl" and "cycloalkenyt" represent a cyclic hydrocarbon alkyl or alkenyl, respectively, and are meant to include monocyclic (e.g., cyclohexyl), spiro (e.g., spiro [2.3]hexanyl), fused (e.g., bicyclo[4.4.0]decanyl), and bridged (e.g., bicyclo[2.2.1]heptanyl) hydrocarbon moieties. Where indicated, the "cycloalkyl", and "cycloalkenyl" groups can also be optionally substituted as defined in "alkyl" and "alkenyl" definition, 20 The terms "alkoxy," "alkenyloxy," and "alkynyloxy" represent an alkyl, alkenyl or alkynyl moiety, respectively, which is covalently bonded to the adjacent atom through an oxygen atom. Like the alkyl, alkenyl and alkynyl groups, where indicated the alkoxy, alkenyloxy and alkynyloxy groups can also be optionally substituted. Examples include but are not limited to methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy, hexyloxy, isohexyloxy, trifluoromethoxy and neohexyloxy. The alkoxy, alkenyloxy, and alkynyloxy groups can be optionally substituted by, for example, halogens, oxo, -NRdRe, -CONRdRe, -NRdCORe, carboxy, C(=NRd)NReRf, azido, cyano, -N(Rd)C(=NR)NRfRg, hydroxyl, nitro, nitroso, C 1 6 alkyl, 30 C 2
-
6 alkenyl, C 2
.
6 alkynyl, -N(Rh)CONRiRj, S(0)o- 2 Ra, C(O)Ra, C(O)ORa, =NO-Re, SO 2 NRaRb, -NRaSO 2 Rb, -NRaSO 2 NRbRc, -CRaN=ORb, -OCONReRf and/or -NRaCOORb, wherein Ra-Rj are each independently H, C 1 .4 alkyl, C 2 .4 alkenyl or C 2 .4 alkynyl. The term "aryl" represents a carbocyclic moiety containing at least one benzenoid-type ring (i.e., may be monocyclic or polycyclic), and which where indicated may be optionally substituted with one or more substituents. Examples WO 2009/082818 PCT/CA2008/002290 18 include but are not limited to phenyl, tolyl, dimethylphenyl, aminophenyl, anilinyl, naphthyl, anthryl, phenanthryl or biphenyls. The aryl groups can be optionally substituted by, for example, halogens, -NRdRe, -CONRdRe, -NRdCORe, carboxy, C(=NRd)NReRf, azido, cyano, -N(Rd)C(=NRe)NRRg, hydroxyl, nitro, nitroso, N(Rh)CONRiRj, C 1
.
6 alkyl, C 2
.
6 alkenyl, C 2
.
6 alkynyl, C 1
.
6 alkyloxy, C 2
.
6 alkenyloxy, C 2 -6 alkynyloxy, -S(0)o- 2 Ra, optionally substituted 5-12 member heteroaryl, optionally substituted 6-18 member heteroaralkyl, optionally substituted 3-12 member heterocycle, optionally substituted 4-18 member heterocycle-alkyl, -C(O)Ra, C(O)ORa, -SO 2 NRaRb, -NRaSO 2 Rb, -NRaS0 2 NRbRc, -CRaN=ORb, -OCONReRf and/or 10 NRaCOORb, wherein Ra-Rj are each independently H, C 1
.
4 alkyl, C 2
.
4 alkenyl or C 2
.
4 alkynyl. The terms "aryloxy," represent an aryl moiety substituted with an oxygen, wherein the point of attachement to the molecule it substitutes is on the oxygen. Where indicated the aryloxy group can also be optionally substituted by one or more substituents, for example, halogens, -NRdRe, -CONRdRe, -NRdCORe, carboxy, C(=NRd)NReRf, azido, cyano, -N(Rd)C(=NRe)NRfRg, hydroxyl, nitro, -N(Rh)CONRiRj, CI 6 alkyl, C 2
-
6 alkenyl, C 2
.
6 alkynyl, C 1
.
6 alkyloxy, C 2
.
6 alkenyloxy, C 2
-
6 alkynyloxy, S(0)o. 2 Ra, optionally substituted 5-12 member heteroaryl, optionally substituted 6-18 20 member heteroaralkyl, optionally substituted 3-12 member heterocycle, optionally substituted 4-18 member heterocycle-alkyl, C(O)Ra, C(O)ORa, SO 2 NRaRb, NRaSO 2 Rb, NRaSO 2 NRbRc, CRaN=ORb, -OCONReRf or NRaCOORb, wherein Ra-Rj are each independently H, C 1
.
4 alkyl, C 2
.
4 alkenyl, or C 2
.
4 alkynyl. The term "aralkyl" represents an aryl group attached to the adjacent atom by an alkyl, alkenyl or alkynyl. Like the aryl groups, where indicated the aralkyl groups can also be optionally substituted. Examples include but are not limited to benzyl, benzhydryl, trityl, phenethyl, 3-phenylpropyl, 2-phenylpropyl, 4 phenylbutyl and naphthylmethyl. Where indicated, the aralkyl groups can be 30 optionally substituted by, for example, halogens, -NRARe, -CONRdRe, -NRdCORe, carboxy, -C(=NRd)NReRf, azido, cyano, -N(Rd)C(=NRe)NRRg, hydroxyl, nitro, nitroso, -N(Rh)CONRiRj, C 1
.
6 alkyl, C 2
.
6 alkenyl, C 2
.
6 alkynyl, C 1
.
6 alkyloxy, C 2
.
6 alkenyloxy, C 2
-
6 alkynyloxy, -S(0)o- 2 Ra, optionally substituted 5-12 member heteroaryl, optionally substituted 6-18 member heteroaralkyl, optionally substituted 3-12 member heterocycle, optionally substituted 4-18 member heterocycle-alkyl, -C(O)Ra, C(O)ORa, -SO 2 NRaRb, -NRaSO 2 Rb, -NRaSO 2 NRbRc, -CRaN=ORb, -OCONR.Rf and/or - WO 2009/082818 PCT/CA2008/002290 19 NRaCOORb, wherein Ra-Rj are each independently H, C 1
.
4 alkyl, C 2
.
4 alkenyl or C 2
.
4 alkynyl. The term "heterocycle" represents an optionally substituted, non aromatic, saturated or partially saturated wherein said cyclic moiety is interrupted by at least one heteroatom selected from oxygen (0), sulfur (S) or nitrogen (N). It is understood that in a 3-12 member heterocycle moiety, the 3-12 member represents the total of the ring atoms present in the heterocycle moiety. Heterocycles may be monocyclic or polycyclic rings. Examples include but are not 10 limited to azetidinyl, dioxolanyl, morpholinyl, morpholino, oxetanyl, piperazinyl, piperidyl, piperidino, cyclopentapyrazolyl, cyclopentaoxazinyl, cyclopentafuranyl, tetrahydrofuranyl, tetrahydrothiofuranyl, tetrahydrothiofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl dioxyde, thiazolinyl, oxazolinyl, pyranyl, thiopyranyl, aziridinyl, azepinyl, dioxazepinyl, diazepinyl, oxyranyl, oxazinyl, pyrrolidinyl, thiopyranyl, thiolane, pyrazolidinyt, dioxanyl, and imidazolidinyl. Where indicated, the heterocyclic groups can be optionally substituted by, for example, halogens, oxo, -NRdRe, -CONRdRe, =NO-Re, NRjCORe, carboxy, -C(=NRd)NReRf, azido, cyano, -N(Rd)C(=NRe)NRRg, hydroxyl, nitro, nitroso, -N(Rh)CONRiRj, C 1
.
6 aLkyL, C 2
.
6 alkenyl, C 2
.
6 alkynyl, C 7
.
12 aralkyl, C 6
.
1 2 20 aryl, C 1
.
6 alkyloxy, C 2
.
6 alkenyloxy, C 2
-
6 alkynyloxy, -S(0)o- 2 Ra, C 6
.
1 0 aryl, C 6
.
1 o arytoxy,
C
7
.
1 0 arylalkyL, C 6 .1o aryl-C 1
.
1 o alkyloxy, -C(0)Ra, -C(0)ORa, -SO 2 NRaRb, -NRaSO 2 Rb, NRaSO 2 NRbRc, -CRaN=ORb, -OCONRRf and/or -NRaCOORb, wherein Ra-Rj are each independently H, C 1
.
4 alkyL, C 2
.
4 alkenyl or C 2
.
4 alkynyL. The term "heterocycle-alkyl" represents an optionally substituted heterocycle group attached to the adjacent atom by an aLkyl, alkenyl or alkynyl group. It is understood that in a 5-18 member heterocyce-akyl moiety, the 5-18 member represents the total of the ring atoms present in the heterocycle moiety and the carbon atoms present in the aLkyL, aLkenyl or aLkynyl group. For example, 30 the following groups are encompassed by a 7 member heterocycle-alkyl (* represents the attachment point): N N CH 3 S 0 * * * * WO 2009/082818 PCT/CA2008/002290 20 Where indicated the heterocycle-alkyl groups can be optionally substituted by, for example, halogens, oxo, -NRdRe, -CONRdRe, -NRdCORe, carboxy, C(=NRd)NReRf, azido, cyano, -N(Rd)C(=NRe)NRfRg, hydroxyl, nitro, nitroso, N(Rh)CONRiRj, C 1
-
6 alkyl, C 2
.
6 alkenyl, C 2
.
6 alkynyl, C 1
.
6 alkyloxy, C 2
.
6 alkenyloxy, C 2
.
6 alkynyloxy, -S(0)o- 2 Ra, C 61 o aryl, C 610 aryloxy, C 7
.
1 0 arylalkyl, C 610 aryl-C 1 o alkyloxy, C(O)Ra, -C(O)ORa, =NO-Re, -SO 2 NRaRb, -NRaSO 2 Rb, -NRaSO 2 NRbRc, -CRaN=ORb, OCONRRf and/or -NRaCOORb, wherein Ra-Rj are each independently H, C 1
.
4a lkyl, C 2 4 alkenyl or C 2
.
4 alkynyl. 10 The term "heteroaryl" represents an optionally substituted aromatic cyclic moiety wherein said cyclic moiety is interrupted by at least one heteroatom selected from oxygen (0), sulfur (S) or nitrogen (N). It is understood that in a 5-12 member heteroaryl moiety, the 5-12 member represents the total of the ring atoms present in the heteroaryl moiety. Heteroaryls may be monocyclic or polycyclic rings. Examples include but are not limited to dithiadiazinyl, furanyl, isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, dioxazole, oxatriazole, oxazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyridyl, pyrazolyl, pyrrolyl, thiatriazolyl, tetrazolyl, thiadiazolyl, triazolyl, thiazolyl, thienyl, tetrazinyl, thiadiazinyl, triazinyl, 20 thiazinyl, furoisoxazolyl, imidazothiazolyl, thienoisothiazolyl, thienothiazolyl, imidazopyrazolyl, pyrrolopyrrolyl, thienothienyl, thiadiazolopyrimidinyl, thiazolothiazinyl, thiazolopyrimidinyl, thiazolopyridinyl, oxazolopyrimidinyl, oxazolopyridyl, benzoxazolyl, benzisothiazolyl, benzothiazolyl, imidazopyrazinyl, purinyl, pyrazolopyrimidinyl, imidazopyridinyl, benzimidazolyl, indazolyl, benzoxathiolyl, benzodioxolyl, benzodithiolyl, indolizinyl, indolinyl, isoindolinyl, furopyrimidinyl, furopyridyl, benzofuranyl, isobenzofuranyl, thienopyrimidinyl, thienopyridyl, benzothienyl, benzoxazinyl, benzothiazinyl, quinazolinyl, naphthyridinyl, quinolinyl, isoquinolinyl, benzopyranyl, pyridopyridazinyl and pyridopyrimidinyl. Where indicated the heteroaryl groups can be optionally 30 substituted by, for example, halogens, -NRdRe, -CONRdRe, -NRdCORe, carboxy, C(=NRd)NR.Rf, azido, cyano, -N(Rd)C(=NRe)NRRg, hydroxyl, nitro, nitroso, N(Rh)CONRRj, C 1
.
6 alkyl, C 2
.
6 alkenyl, C 2
.
6 alkynyl, C 1
.
6 alkyloxy, C 2
.
6 alkenyloxy, C 2
-
6 alkynyloxy, -S(0)o- 2 Ra, C 6
.
1 0 aryl, C 61 o aryloxy, C 7
.
1 0 arylalkyl, C 6
.
1 0 aryl-Co 1 0 alkyloxy, C(0)Ra, -C(0)ORa, -SO 2 NRaRb, -NRaSO 2 Rb, -NRaSO 2 NRbRc, -CRaN=ORb, -OCONReRf and/or -NRaCOORb, wherein Ra-Rj are each independently H, C 1
.
4 alkyl, C 2
.
4 alkenyl or C 2
.
4 alkynyl.
WO 2009/082818 PCT/CA2008/002290 21 The term "heteroaralkyt" represents an optionally substituted heteroaryl group attached to the adjacent atom by an alkyl, alkenyl or alkynyl group. Where indicated the heteroaralkyl groups can be optionally substituted by, for example, halogens,-NRRe, -CONRdRe, -NRdCORe, carboxy, -C(=NRd)NR.Rf, azido, cyano, N(Rd)C(=NRe)NRRg, hydroxyl, nitro, nitroso, -N(Rh)CONRiRj, C 1
.
6 alkyl, C 2
-
6 alkenyl,
C
2
.
6 alkynyl, C 1
.
6 alkyloxy, C 2
.
6 alkenyLoxy, C 2
.
6 alkynyloxy, -S(0)o.
2 Ra, C 6
.
1 0 aryl, C 6
.
1 0 aryloxy, C 7
.
10 arylalkyl, C 6
.
1 0 aryl-C 1
.
1 0 alkyloxy, -C(0)Ra, -C(0)ORa, -SO 2 NRaRb, NRaSO 2 Rb, -NRaSO 2 NRbRc, -CRaN=ORb, -OCONReRf and/or -NRaCOORb, wherein Ra-Rj 10 are each independently H, C 1
.
4 alkyL, C 2
.
4 alkenyl or C 2
.
4 alkynyl. It is understood that in a 6-18 member heteroaralkyl moiety, the 6-18 member represents the total of the ring atoms present in the heteroaryl moiety and the carbon atoms present in the alkyl, alkenyl or alkynyl group. For example, the following groups are encompassed by a 7 member heteroaralkyl (* represents the attachment point): N N CH 3 / /0 * * * * "Halogen atom" is specifically a fluorine atom, chlorine atom, bromine atom or iodine atom. 20 The term "oxo" represents =0. A dash ("-") that is not between two letters or symbols is used to indicate a point of attachement for a substitutent. For example, -CONRdRe is attached through the carbon of the amide. A bond represented by a combination of a solid and dashed line, ie. may be either a single or double bond. The term "guanidino" represents -N(Rd)C(=NRe)NRRg wherein Rd, Re, Rf 30 and Rg are each independently selected from H, C 1
.
1 0 alkyl, C 2
-
1 0 alkenyl, C 2
-
1 0 alkynyl, C 6
.
1 2 aryl, and C 7
.
1 2 aralkyl, or Rf and R, are taken together with the WO 2009/082818 PCT/CA2008/002290 22 nitrogen to which they are attached to form an optionally substituted 4 to 10 member heterocycle or an optionally substituted 5-12 member heteroaryl. The term "amidino" represents -C(=NRd)NReRf wherein Rd, Re and Rf are each independently selected from H, C 1
.
1 0 alkyl, C 2
-
1 0 alkenyl, C 2
-
1 0 alkynyl, C 6
.
1 2 aryl, and C 7
.
1 2 aralkyl, or Re and Rf are taken together with the nitrogen to which they are attached to form an optionally substituted 4 to 10 member heterocycle or an optionally substituted 5-12 member heteroaryl. 10 The term "hydroxyl protecting group" is well known in the field of organic chemistry. Such protecting groups may be found in "Protective Groups in Organic Synthesis" second edition, Wiley-interscience publication, by T.W. Greene and P.G.M. Wuts. Examples of hydroxy protecting groups include but are not limited to benzyl, acetyl, benzoyl, pivaloyl and isopropyloxycarbonyl. When there is a sulfur atom present, the sulfur atom can be at different oxidation levels, i.e., S, SO, or S0 2 . All such oxidation levels are within the scope of the present invention. 20 The term "independently" means that a substituent can be the same or a different definition for each item. In still another aspect, there is provided a method for prevention or treatment of HIV infections in a subject in need of such treatment comprising administering to the subject a therapeutically effective amount of a compound of formula (1) or a composition of the invention. In stilL another aspect, there is provided a method for delaying the onset of AIDS or treating AIDS in a subject in need of such treatment comprising 30 administering to the subject a therapeutically effective amount of a compound of formula (I) or a composition of the invention. In stilL another aspect, there is provided a method for blocking cellular entry of HIV in a subject or for the prevention or treatment of HIV infections in a subject in need of such treatment comprising administering to the subject a WO 2009/082818 PCT/CA2008/002290 23 pharmaceutical combination comprising at least one compound of formula (1) and at least one further therapeutic agent. In still another aspect, there is provided a method for delaying the onset of AIDS or treating AIDS in a subject in need of such treatment comprising administering to the subject a pharmaceutical combination comprising at least one compound of formula (1) and at least one further therapeutic agent. In another embodiment, the pharmaceutical combination of this invention 10 may contain at least one further therapeutic agent which is an antiviral agent. In one embodiment, the pharmaceutical combination of this invention may contain at least one further antiviral agent which is chosen from nucleoside and nucleotide analog reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, attachment and fusion inhibitors, integrase inhibitors, and maturation inhibitors. In one embodiment, the pharmaceutical combinations of this invention may contain at least one other antiviral agent which is a nucleoside and nucleotide 20 analog reverse transcriptase inhibitors chosen from 3TC (lamivudine, Epivir@), AZT (zidovudine, Retrovir@), Emtricitabine (Coviracil®, formerly FTC), d4T (2',3' dideoxy-2',3'-didehydro-thymidine, stavudine and Zerit®), tenofovir (Viread®), 2',3'-dideoxyinosine (ddl, didanosine, Videx®), 2',3'-dideoxycytidine (ddC, zalcitabine, Hivido), Combivir® (AZT/3TC or zidovudine/lamivudine combination), Trivizir® (AZT/3TC/abacavir or zidovudine/lamivudine/abacavir combination), abacavir (1592U89, Ziagen®), Epzicom@ (abacavir and lamivudine), Truvada® (Tenofovir and emtricitabine), SPD-754 (apricitabine), Elvucitabine (ACH-126,443, (Beta-L-Fd4C), Alovudine (MIV-310), DAPD (amdoxovir), Racivir, phosphazid, stampidine, CMX-157, PPI-801/802 (formerly MIV-410), MIV-210, fozivudine tidoxil, 30 KP-1461, Fosalvudine (HDP 99.0003), 9-[(2-hydroxymethyl)-1,3-dioxolan-4 yl]guanine, and 2-amino-9-[(2-hydroxymethyl)-1,3-dioxolan-4-yl]adenine. In another embodiment, the pharmaceutical combination of this invention may contain at least one other antiviral agent which is a non-nucleoside reverse transcriptase inhibitor chosen from Nevirapine (Viramune@, NVP, BI-RG-587), delavirdine (Rescriptor@, DLV), efavirenz (DMP 266, Sustiva®), (+)-Calanolide A, WO 2009/082818 PCT/CA2008/002290 24 Capravirine (AG1549, formerly S-1153), DPC083, MIV-150, TMC120, Intelence (etravirine@, TMC125), TMC-278 or BHAP (delavirdine), calanolides, GW695634, RDEA806, RDEA427, RDEA640, UK-453061, BILR355, VRX 840773 and L-697,661 (2 Pyridinone 3benzoxazoMeNH derivative). In another embodiment, the pharmaceutical combination of this invention may contain at least one other antiviral agent which is a protease inhibitor chosen from nelfinavir (Viracept®, NFV), amprenavir (141W94, Agenerase®), indinavir (MK-639, IDV, Crixivan@), saquinavir (Invirase@, Fortovase®, SQV), ritonavir 10 (Norvir@, RTV), lopinavir (ABT-378, Kaletra®), Atazanavir (Reyataz@, BMS232632), mozenavir (DMP-450), fosamprenavir (GW433908), R0033-4649, Tipranavir (Aptivus®, PNU-140690), Darunavir (Prezista®, TMC114), SPI-256, Brecanavir (GW640385), P-1946, MK-8122 (formerly PPL-100) and VX-385. In another embodiment, the pharmaceutical combination of this invention may contain at least one other antiviral agent which is an attachment and fusion inhibitor chosen from T-20 (enfuvirtide, Fuzeon®), T-1249, TRI-999, TRI-1144, Schering C (SCH-C), Vicriviroc (Schering D, SCH-D), FP21399, PRO-140, PRO 542, PRO 452, TNX-355, Aplaviroc (GW873140, AK602), TBR-220 (formerly TAK-220), 20 TBR-652 (formerly TAK-652), PF-232798, Maraviroc (Selzentry@, UK-427,857) or soluble CD4, CD4 fragments, CD4-hybrid molecules, BMS-806, BMS-488043, AMD3100, AMDO70, AMD887, INCB9471, INCB15050, KRH-2731, KRH-3140, SJ-3366, SP-01A, sifuvirtide, and KRH-3955. In another embodiment, the pharmaceutical combination of this invention may contain at least one other antiviral agent which is an integrase inhibitor chosen from S-1360, L-870,810, elvitegravir (GS9137, JKT 303), GS9137, L-870,812, raltegravir (Isentress®, MK-0518), MK-2048, GSK1349572, and C-2507. 30 In another embodiment, the pharmaceutical combination of this invention may contain at least one other antiviral agent which is a maturation inhibitor chosen from Vivecon (MPC-9055) and Bevirimat (PA-457). In another embodiment, the pharmaceutical combination of this invention may contain at least one other antiviral agent which is a zinc finger inhibitor and is azodicarbonamide (ADA).
WO 2009/082818 PCT/CA2008/002290 25 In another embodiment, the pharmaceutical combination of this invention may contain at least one other antiviral agent which is an antisense drug and is HGTV43. In another embodiment, the pharmaceutical combination of this invention may contain at least one other antiviral agent which is an immunomodulator, immune stimulator or cytokine chosen from interLeukin-2 (IL-2, AldesLeukin, Proleukin), granulocyte macrophage colony stimulating factor (GM-CSF), 10 erythropoietin, Multikine, Ampligen, thymomodulin, thymopentin, foscarnet, HE2000, Reticulose, Murabutide, Resveratrol, HRG214, HIV-1 Immunogen (Remune), WF1O and EP HIV-1090. In another embodiment, the pharmaceutical combination of this invention may contain at least one other antiviral agent chosen from 2',3'-dideoxyadenosine, 3'-deoxythymidine, 2',3'-dideoxy-2',3'-didehydrocytidine and ribavirin; acyclic nucleosides such as acyclovir and ganciclovir; interferons such as alpha-, beta-and gamma-interferon; glucuronation inhibitors such as probenecid; and TIBO drugs, HEPT, Pictovir@ (VGX-410) and TSAO derivatives. 20 In another embodiment, the pharmaceutical combination of this invention may contain an inhibitor of the cytochrome P450. In another embodiment, the pharmaceutical combination of this invention may contain an inhibitor of the cytochrome P450 chosen from' atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, amprenavir, erythromycin, fluconazole, fosamprenavir, grapefruit juice, fluvoxamine, fluoxetine, macrolide antibiotics, sertraline sulfaphenazole, Troleandomycin, cyclosporine, 30 clomethiazole, atazanavir, mibefradil, vitamin E, bergamottin, dihydroxybergamottin, and pharmaceutically acceptable salts thereof. In another embodiment, the pharmaceutical combination of this invention may contain an inhibitor of the cytochrome P450 which is ritonavir or a pharmaceutically acceptable salt thereof.
WO 2009/082818 PCT/CA2008/002290 26 The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier thereof comprises a further aspect of the invention. The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations. 10 The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations. In a further embodiment, the compound of formula (1) and at least one further therapeutic agent are administered sequentially. In a further embodiment, the compound of formula (1) and at least one further therapeutic agent are administered simultaneously. 20 Thus, a further embodiment of the invention is a kit for use in administering a combinations, the kit comprising: a first containment means for storing a compound according to formula I in the form of a pharmaceutical formulation further comprising a pharmaceutically acceptable carrier; and a second containment means for storing at least one further therapeutic agent in the form of a pharmaceutical formulation further comprising a pharmaceutically acceptable carrier. In one embodiment, the present invention further provides a pharmaceutical composition comprising at least one compound having the formula 30 (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable hydrate thereof, or a pharmaceutically acceptable solvate thereof, and at least one pharmaceutically acceptable carrier or excipient. The terms "host'' or "patient" or "subject" means a human, male or female, for example, a child, an adolescent, or an adult.
WO 2009/082818 PCT/CA2008/002290 27 It will be appreciated that the amount of a compound of the invention required for use in treatment will vary not only with the particular compound selected but also with the route of administration, the nature of the condition for which treatment is required and the age and condition of the patient and will be ultimately at the discretion of the attendant physician. In general however a suitable dose will be in the range of from about 0.1 to about 750 mg/kg of body weight per day, for example, in the range of 0.5 to 60 mg/kg/day, or, for example, in the range of 1 to 20 mg/kg/day. 10 The desired dose may conveniently be presented in a single dose or as divided dose administered at appropriate intervals, for example as two, three, four or more doses per day. The compound is conveniently administered in unit dosage form; for example containing 10 to 1500 mg, conveniently 20 to 1000 mg, most conveniently 50 to 700 mg of active ingredient per unit dosage form. Ideally the active ingredient should be administered to achieve peak plasma concentrations of the active compound of from about 1 to about 75pM, about 2 to 20 50 pM, about 3 to about 30 pM. This may be achieved, for example, by the intravenous injection of a 0.1 to 5% solution of the active ingredient, optionally in saline, or orally administered as a bolus containing about 1 to about 500 mg of the active ingredient. Desirable blood levels may be maintained by a continuous infusion to provide about 0.01 to about 5.0 mg/kg/hour or by intermittent infusions containing about 0.4 to about 15 mg/kg of the active ingredient. When a compound of the present invention or a pharmaceutically acceptable salt thereof is used in combination with a second therapeutic agent active against the same virus, the dose of each compound may be either the same 30 as or differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art. While it is possible that, for use in therapy, a compound of the invention may be administered as the raw chemical, it is preferable to present the active ingredient as a pharmaceutical composition. The invention thus further provides a pharmaceutical composition comprising a compound of the present invention or a WO 2009/082818 PCT/CA2008/002290 28 pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers therefore and, optionally, other therapeutic and/or prophylactic ingredients. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Pharmaceutical compositions include those suitable for oral, rectal, nasal, topical (including buccal and sub-lingual), transdermal, vaginal or parenteral (including intramuscular, sub-cutaneous and intravenous) administration or in a 10 form suitable for administration by inhalation or insufflation. The formulations may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the active compound with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation. Pharmaceutical compositions suitable for oral administration may conveniently be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or 20 granules; as a solution, a suspension, or as an emulsion. The active ingredient may also be presented as a bolus, electuary or paste. Tablets and capsules for oral administration may contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, or wetting agents. The tablets may be coated according to methods well known in the art. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), or preservatives. 30 The compounds according to the invention may also be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as WO 2009/082818 PCT/CA2008/002290 29 suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use. For topical administration to the epidermis, the compounds according to the invention may be formulated as ointments, creams or lotions, or as a transdermal patch. Such transdermal patches may contain penetration enhancers such as linalool, carvacrol, thymol, citral, menthol and t-anethole. Ointments and 10 creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. Compositions suitable for topical administration in the mouth include lozenges comprising active ingredient in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active 20 ingredient in a suitable liquid carrier. Pharmaceutical compositions suitable for rectal administration wherein the carrier is a solid are for example presented as unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art, and the suppositories may be conveniently formed by admixture of the active compound with the softened or melted carrier(s) followed by chilling and shaping in moulds. Compositions suitable for vaginal administration may be presented as 30 pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate. For intra-nasal administration the compounds of the invention may be used as a liquid spray or dispersible powder or in the form of drops. Drops may be formulated with an aqueous or non-aqueous base also comprising one more WO 2009/082818 PCT/CA2008/002290 30 dispersing agents, solubilizing agents or suspending agents. Liquid sprays are conveniently delivered from pressurized packs. For administration by inhalation the compounds according to the invention are conveniently delivered from an insufflator, nebulizer or a pressurized pack or other convenient means of delivering an aerosol spray. Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be 10 determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, the compounds according to the invention may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch. The powder composition may be presented in unit dosage form in, for example, capsules or cartridges or e.g. gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator. 20 When desired the above described formulations adapted to give sustained release of the active ingredient may be employed. Compounds according to the present invention include: 91 3f-O-(3',3'-Dimethysucciny)-21 -oxolup-18-en-28-oic acid N benzylamide; 9-2 3A-(3',3'-Dimethysucciny)-21 -oxolup-18-en-28-oic acid N methylamide; 9-3 3P-O-(3',3'-Dimethylsuccinyl)-21 -oxolup-18-en-28-oic acid N isopropylamide; 9-4 3-O-(3',3'-Dimethylsucciny)-21 -oxolup-18-en-28-oic acid N cyclohexylamide; 9-5 3P-O-(3',3'-Dimethylsuccinyl)-21 -oxolup-18-en-28-oic acid N cyclohexyl methylamide; 9-6 3f-O-(3',3'-Dimethysucciny)-21-oxolup-18-en-28-oic acid N piperidinyl acetamide; WO 2009/082818 PCT/CA2008/002290 31 3/3-0-(3',3'-Dimethylsuccinyl)-21 -oxolup-1 8-en-28-oic acid N morpholyl acetamide; 9-8 3-O-(3',3'-Dimethylsucciny)-21 -oxotup-18-en-28-oic acid N-(4 acetyl piperazinyl) acetamide; 3fO-(3',3'-Dimethylsucciny)-21-oxolup-18-en-28-oic acid N-(4 methyl piperazinyl) acetamide; 9-10 33-O-(3',3'-Dimethylsucciny)-21-oxotup-18-en-28-oic acid N benzamide; 9-11 3P-O-(3',3'-Dimethylsucciny)-21-oxolup-18-en-28-oic acid N methyl-N-benzytamide; 9-12 3O-(3',3'-Dimethylsucciny)-21-oxolup-18-en-28-oic acid N-2 chloro-benzytamide; 9-13 3#-O-(3',3'-Dimethylsuccinyt)-21-oxolup-18-en-28-oic acid N-3 chloro-benzylamide; 9-14 3fO-(3',3'-Dimethylsucciny)-21-oxolup-18-en-28-oic acid N-4 chloro-benzylamide; 9-15 3#-O-(3',3'-Dimethylsucciny)-21-oxolup-18-en-28-oic acid N-4 methoxy-benzylamide; 9-16 3/&O-(3',3'-Dimethylsuccinyl)-21-oxotup-18-en-28-oic acid N pyridin-2-ylmethylamide; 9-17 3--(3',3'-Dimethylsucciny)-21-oxotup-18-en-28-oic acid N pyridin-3-ylmethylamide; 9-18 3P-O-(3',3'-Dimethysucciny)-21-oxolup-18-en-28-oic acid N pyridin-4-ytmethylamide; 9-19 3P-O-(3',3'-Dimethylsucciny)-21-oxolup-18-en-28-oic acid N-[2-(4 methoxy- phenyL)-ethy]a-acetamide; 9-20 3/O-(3 ',3'-DimethyLsucciny)-21-oxoup-1 8-en-28-oic acid N-(2 acetyami no- ethyl)-carbaiac acid tert-butyL ester; 9-21 3/-O-(3',3'-DimethysuccinyL)-21-oxoup-1 8-en-28-oic acid N-(2 amino-ethyl)-acetamide; 9-22 3-O-(3',3'-DimethyLsuccinyL)-21-oxotup-1 8-en-28-oic acid N-(2 acetyLamiano-ethyL)-acetamide; 9-23 3P-O-(3',3'-DimethyLsuccinyL)-21-oxoup-1 8-en-28-oic acid N-[2-(3 isopropy-ureido)-ethy]-acetamide; WO 2009/082818 PCT/CA2008/002290 32 9-24 3-O-(3',3'-Dimethylsuccinyl)-21 -oxolup-1 8-en-28-oic acid N-(2 acetylamino-ethyl)-carbamic acid methyl ester; 9-25 3fO-(3',3'-Dimethylsuccinyl)-21 -oxolup-18-en-28-oic acid
N
pyridin-2-yl-acetamide; 9-26 3O-(3',3'-Dimethylsuccinyl)-21 -oxotup-18-en-28-oic acid
N
pyridin-3-yl-acetamide; 9-27 3/O-(3',3'-Dimethylsuccinyt)-21-oxotup-18-en-28-oic acid N-1 acetyl-piperazine-4-carboxylic acid tert-butyl ester; 9-28 3-O-(3',3'-Dimethylsuccinyt)-21-oxotup-18-en-28-oic acid
N
piperazinyL-acetamide; 9-29 3f-O-(3',3'-Dimethylsucciny)-21-oxotup-18-en-28-oic acid N-1-(4 hydroxy-piperidin-1 -y)-acetamide; 9-30 3-O-(3',3'-Dimethylsuccinyt)-21 -oxotup-1 8-en-28-oic acid N-1 acetylamino-piperidine-4-carboxylic acid tert-butyl ester; 9-31 3AO-(3',3'-Dimethylsuccinyl)-21 -oxotup-1 8-en-28-oic acid N-(4 aminopi peridi ne)-acetamide; 9-32 3AO-(3',3'-Dimethylsuccinyl)-21 -oxolup-1 8-en-28-oic acid N-(4 amino-N-1 -acetyl-pi peridine)-acetamide; 9-33 30-(3',3'-Dimethylsuccinyl)-21 -oxoLup-1 8-en-28-oic acid N-(1 phenyl-ethyl)-acetamide; 9-34 3--(3',3'-Dimethylsuccinyl)-21 -oxoLup-1 8-en-28-oic acid N-(1 methyl-I -phenyt-ethyl)-acetamide; 9-35 3fO-(3',3'-DimethylsuccinyL)-21-oxoLup-18-en-28-oic acid N-(tert butyl)-acetamide; 9-36 3-O-(3',3'-DimethylsuccinyL)-21-oxotup-18-en-28-oic acid N-(8 amino-3,8-diaza-bicyclo[3.2. 1 ]octane-3-benzamide)-acetamide; 9-37 3,O-(3',3'-Dimethylsuccinyt)-21 -oxoLup-1 8-en-28-oic acid N-4 piperazi-2-one acetamide; 9-38 3/O-(3',3'-Dimethylsuccinyl)-21-oxoLup-18-en-28-oic acid
N
pyrimidin-2-y-acetamide; 9-39 3-O-(3',3'-DimethylsuccinyL)-21-oxoLup-18-en-28-oic acid N-(4-N' isopropylureido-1 -piperazine)-acetamide; 9-40 3/-O-(3',3'-Dimethylsuccinyt)-21 -oxotup-1 8-en-28-oic acid N-1 acetyl-piperazine-4-carboxylic acid methyL ester; WO 2009/082818 PCT/CA2008/002290 33 9-41 3/-O-(3',3'-Dimethylsucciny)-21 -oxolup-1 8-en-28-oic acid N-(4 amino carboxylic acid tert-butyl-ester-1-piperidine)-acetamide; 9-42 3-O-(3',3'-Dimethylsuccinyl)-21 -oxolup-1 8-en-28-oic acid N-(4 amino-1 -piperidi ne)-acetamide; 9-43 3f0-(3',3'-Dimethylsuccinyl)-21 -oxolup-1 8-en-28-oic acid N-(4 acetylami no-1- pi peri dine) -acetamide; 9-44 3-O-(3',3'-Dimethylsuccinyl)-2.-oxolup-18-en-28-oic acid N-[(4 amino-N'-isopropylureido)-1-piperidine]-acetamide; 9-45 3-O-(3',3'-Dimethylsuccinyt)-21-oxolup-18-en-28-oic acid N-(4 amino carboxylic acid methyl ester-1-piperidine)-acetamide; 9-46 3P-O-(3',3'-Dimethysuccinyl)-21-oxolup-18-en-28-oic acid N-4-(1 methyl-piperazi-2-one)-acetamide; 9-47 3P-O-(3',3'-Dimethylsuccinyl)-21-oxolup-18-en-28-oic acid N-2 methyl-phen-1-yl acetamide; 9-48 3/-O-(3',3'-DimethylsuccinyL)-21-oxolup-18-en-28-oic acid N-3 methyl-phen-1 -yl acetamide; 9-49 3P-O-(3',3'-Dimethysuccinyl)-21-oxoLup-18-en-28-oic acid N-4 methyl-phen-1 -yl acetamide; 3/?-O-(3',3'-Dimethylsuccinyl)-21-oxoLup-18-en-28-oic acid N-8 9-50 acetylami no-3,8-diaza-bicyclo[3.2. 1 ]octane-3-carboxylic acid tert butyl ester; 9-51 3,60-(3',3'-Dimethylsucciny)-21 -oxolup-18-en-28-oic acid
N
pyrimidin-5-yl-acetamide; 9-52 3/O-(3',3'-DimethylsuccinyL)-21 -oxoLup-18-en-28-oic acid
N
pyridin-4-yl-acetamide; 9-53 3fO-(3',3'-Dimethylsuccinyt)-21 -oxolup-18-en-28-oic acid N-3 amino-1 -methyl-1 H-pyrazole-acetamide; 9-54 3PO-(3',3'-Dimethysuccinyl)-21 -oxolup-i 8-en-28-oic acid N-5 amino-1 -methyl-1 H-pyrazole acetamide; 9-55 3fO-(3',3'-DimethylsuccinyL)-21 -oxolup-1 8-en-28-oic acid N-4 methyl-pyrimidin-5-yl-acetamide; 9-56 3/O-(3',3'-Dimethylsuccinyl)-21 -oxoLup-1 8-en-28-oic acid N-4 methyl-pyrimidin-2-yL-acetamide; 9-57 3/O-(3',3'-DimethylsuccinyL)-21 -oxolup-1 8-en-28-oic acid N-4 amino-1-methyL-1H-pyrazole acetamide; WO 2009/082818 PCT/CA2008/002290 34 9-58 3-O-(3',3'-Dimethylsucciny)-21-oxolup-18-en-28-oic acid N-4,6 dimethyl-pyrimidin-2-yl-acetamide; 9-59 3P-O-(3',3'-Dimethylsucciny)-21-oxolup-18-en-28-oic acid
N
pyrazin-2-y-acetamide; 9-60 3/3-0-(3',3'-Dimethylsucciny)-21-oxolup-18-en-28-oic acid
N
quinoLin-3-yi-acetamide; 3/3-(3',3'-Dimethylsucciny)-21-oxolup-18-en-28-oic acid N-(2 9-61 pyrrolidin-1 -yl-ethyl)-acetamide; 9-62 3P-O-(3',3'-Dimethylsuccinyl)-21-oxotup-18-en-28-oic acid N-(5 methyl- [1, 3,4]oxadiazol-2-yl)-acetamide; 963 3/90-(3',3'-Dimethylsucciny)-21 -oxolup-1 8-en-28-oic acid
N
isoqui noli n-4-yt-acetamide; 9-64 3,&O-(3',3'-Dimethylsuccinyl)-21 -oxolup-1 8-en-28-oic acid
N
pyrimidin-4-yl-acetamide; 9-65 3l-O-(3',3'-Dimethylsucciny)-21 -oxolup-1 8-en-28-oic acid N-2 trifluoromethyl-phen-1-yL acetamide; 9-66 3/O-(3',3'-Dimethylsuccinyt)-21-oxotup-18-en-28-oic acid N-(1 methyl-1H-tetrazol-5-y)-acetamide; 9-67 3p-0-(3',3'-Dimethylsucciny)-21-oxolup-18-en-28-oic acid N-(4 amino carboxylic acid ethyl ester-1-piperidine)-acetamide; 9-68 3#l0-(3',3'-DimethylsuccinyL)-21 -oxoLup-1 8-en-28-oic acid N-(4 amino carboxylic acid isopropyl ester-1 -piperidine)-acetamide; 9-69 3 O-(3',3'-Dimethylsuccinyl)-21 -oxolup-1 8-en-28-oic acid
N
cyclopropylmethyl acetamide; 9-70 3/-O-(3',3'-DimethylsuccinyL)-21-oxoLup-18-en-28-oic acid
N
azetidine-1 acetamide; 9-71 3-O-(3',3'-Dimethylsucciny)-21-oxoLup-18-en-28-oic acid N-(2,2,2 trifluoro-ethyl)-acetamide; 9-72 3/J-O-(3',3'-Dimethylsuccinyl)-21-oxolup-18-en-28-oic acid N-4 trifluoro-pyrimidin-2-y-acetamide; 9-73 3/O-(3',3'-DimethylsuccinyL)-21-oxotup-18-en-28-oic acid N-(1 cyclopropyl-1 -methyl-ethyl)-acetamide; 9-74 3-O-(3',3'-Dimethylsuccinyl)-21-oxolup-18-en-28-oic acid N-(4 dimethylamino-piperidin- 1 -yl)-acetamide; WO 2009/082818 PCT/CA2008/002290 35 9-75 3P-O-(3',3'-Dimethylsucciny)-21-oxolup-18-en-28-oic acid N-(2,2,2 trifluoro-1 -methyl-ethyl)-acetamide; 9-76 3P0-(3',3'-Dimethylsucciny)-21-oxolup-18-en-28-oic acid N-(5 methyl-[1,3,4]thiadiazol-2-yl)-acetamide; 9-77 3f0-(3',3'-Dimethylsucciny)-21-oxolup-18-en-28-oic acid N-(2,2,2 trifluoro-1,1-dimethyl-ethyl)-acetamide; 9-78 3f-O-(3',3'-Dimethylsuccinyt)-21-oxotup-18-en-28-oic acid N-tert butyl-N-methyl-acetamide; 3/3-O-(3',3'-Dimethylsucciny)-21-oxolup-18-en-28-oic acid N-(R)-2 9-79 acetylaminomethyl-pyrrolidine-1-carboxylic acid tert-butyt ester; 3p-0-(3',3'-Dimethylsucciny)-21-oxotup-18-en-28-oic acid N-(S)-2 9-80 acetylaminomethyl-pyrrolidine-1 -carboxylic acid tert-butyt ester; 9-81 3P-O-(3',3'-Dimethylsucciny)-21-oxotup-18-en-28-oic acid N-((R)-1 pyrrolidin-2-ytmethyl)-acetamide; 9-82 3,03--(3',3'-Dimethylsucciny)-21-oxotup-18-en-28-oic acid N-((S)-1 pyrrolidin-2-ytmethyl)-acetamide; 3P-O-(3',3'-Dimethylsucciny)-21-oxotup-18-en-28-oic acid N-((R)-1 9-83 methyl-pyrrolidin-2-ylmethyl)-acetamide; 3/-O-(3',3'-Dimethylsucciny)-21-oxotup-18-en-28-oic acid N-((S)-1 9-84 methyt-pyrrotidin-2-ytmethyl)-acetamide; 9-85 3/?0-(3',3'-Dimethylsucciny)-21-oxotup-18-en-28-oic acid N-(4,4 difluoro-cyclohexyl) acetamide; 9-86 3/30-(3',3'-Dimethytsuccinyt)-21-oxotup-18-en-28-oic acid N-2 chloro-phen-1 -yL acetamide; 9-87 3,O-(3',3'-Dimethytsuccinyt)-21-oxotup-18-en-28-oic acid N-2 isopropyt-phen-1-yL acetamide; 9-88 3,eO-(3',3'-Dimethylsucciny)-21-oxotup-18-en-28-oic acid N-4 ftuoro-phen-1-yL acetamide; 9-89 3/-O-(3',3'-Dimethylsuccinyt)-21-oxolup-18-en-28-oic acid
N
quinazolin-2-yl acetamide; 9-90 3-O-(3',3'-Dimethylsucciny)-21-oxotup-18-en-28-oic acid N-(1 methyL-1H-tetrazol-3-yl)-acetamide; 9-91 3-O-(3',3'-Dimethysucciny)-21-oxotup-18-en-28-oic acid N-(5 methyt-isoxazol-3-yl)-acetamide; WO 2009/082818 PCT/CA2008/002290 36 9-92 3-O-(3',3'-Dimethylsuccinyl)-21-oxolup-18-en-28-oic acid N-(1,3 dihydro-isoindol-2-yl)-acetamide; 9-93 3-O-(3',3'-Dimethylsucciny)-21-oxolup-18-en-28-oic acid N-(4,4 difluoro-cyclohexylmethyl)-acetamide; 9-94 3f-O(3',3'-Dimethylsucciny)-21-oxolup-18-en-28-oic acid N-4,4 difluoro-piperidine acetamide; 36O-(3',3'-Dimethylsucciny)-21-oxotup-18-en-28-oic acid N-8 9-95 acetylamino-3,8-diaza-bicyclo[3.2.1 ]octane-3-acetamide. and pharmaceutically acceptable salts thereof. Analytical HPLC is carried out under standard conditions using a Phenomenex Gemini C18 column, 250 x 4.6 mm, 3 ptm, I1A for the methods A, B, C, D and E. Elution is performed using a linear gradient over 40 minutes with a flow rate of 1 mL/min. as described in the following table (Solvent A is 0.01% TFA in
H
2 0; solvent B is 0.01% TFA in CH 3 CN): Methods A B C D E Solvent B 50 to 90% 60 to 100% 30 to 70% 20 to 60% 40 to 80% Analytical HPLC is carried out under standard conditions using a Waters 10 Symmetry C18 column, 50 x 4.6 mm, 3.5 pm, for the method F and a Varian Pursuit C18 column, 50 x 4.6 mm, 3.5 pim, for the methods G and H. Elution is performed using a linear gradient over 20 minutes with a flow rate of 1 mL/min. as described in the following table (Solvent A is 0.01% TFA in H 2 0; solvent B is 0.01% TFA in
CH
3 CN): Methods F G H Solvent B 50 to 95% 40 to 85% 50 to 95% Analytical LC/MS is carried out under standard conditions using a Symmetry Shield RP18 column, 2.1 X 50 mm, 3.5 pM for methods a and b. Elution is performed using a linear gradient over 20 minutes with a flow rate of 0.5 mL/min. as described in the following table (Solvent A is 0.01% TFA in H 2 0; solvent B is 20 0.01% TFA in CH 3 CN): Methods a b Solvent B 5 to 85% 40 to 95% WO 2009/082818 PCT/CA2008/002290 37 The following abbreviations may be used as follows: br broad DCE 1,2-dichloroethane DCM dichloromethane DMAP 4-Dimethylaminopyridine DMF Dimethylformamide Eq. equivalent HCL hydrochloric acid 10 NaOH Sodium hydroxide ND not determined PCC Pyridinium chlorochromate Sept. Septuplet TFA Trifluoroacetic acid THF Tetrahydrofuran H H H Pyridine, Ac2O H HBr/AcOH OH DMAP 0 0 Toluene, AcOH, Ac 2 0 HO 0 H0 H H 2 H /Na 2 Cr 2 Oy.2H 2 0 H 0C 0 H -Toluene, NaOAc, AcOH, Ac 2 O 0 H ~0 0 - 0 H H 4C0 0 0 KOH H RuO 2
.H
2 0, Nal0 4 H 0 0 Toluene, EtOH AcOEt, H 2 0, TFA 0 - - OH 0 OH H- H O H 5 0 H 6 Scheme 1 20 Lup-20(29)-ene-3p,28-divl diacetate 2 WO 2009/082818 PCT/CA2008/002290 38 To a mixture of Betulin 1 (100 g, 0.225 mol) in 120 mL of anhydrous pyridine is added DMAP (2.68 g, 0.022 moL) and 48 mL (0.495 mol) of acetic anhydride. The reaction mixture is stirred at room temperature for 5 hours and diluted with iced water. The mixture is then extracted with DCM (3 x 200 mL) and the combined organic layers are washed back with aqueous HCL 1N (3 x 200 mL), brine and dried over sodium sulfate. The pale yellow solid is taken up with methanol (400 mL), filtered off and rinsed with methanol (2 x 400 mL) to give the title compound 2 (102.35 g, 86.3%) as a colorless solid. 10 Lup-18-ene-3fl,28-diyl diacetate 3 A solution of 90 mL of HBr in acetic acid (33%) is added to a mixture of 2 (45.03 g, 85.48 mmol) in 90 mL of toluene, 90 mL of acetic anhydride and 90 mL of acetic acid previously heated at 90*C. The reaction mixture is stirred and heated at this temperature for 4 hours. After cooling, 46 g of sodium acetate is added and the mixture is evaporated to dryness. The pale brownish residue is re-evaporated from methanol (50 mL) and the residue is triturated with methanol, filtered off and washed with methanol to obtain 42.35 g of a pale brownish solid. After recrystallization in ethyl acetate (0.5 L) and cooling on ice for 0.5 hour, the title compound 3 (25.78 g, 60.4%) is isolated as a colorless solid. 20 21 -Oxo-lup- 1 8-ene-3, 28-diyl diaceate 4 A mixture of 3 (22 g, 41.76 mmol), sodium acetate (19.5 g, 238 mmol) and sodium dichromate dihydrate (14.9 g, 50.1 mmol) in 280 mL of anhydrous toluene, 350 mL of acetic acid and 76 mL of acetic anhydride is stirred overnight at 60 C. After cooling, water (500 mL) and ethyl acetate (350 mL) are added and the layers are separated. The organic layer is washed successively with water (500 mL), a saturated solution of sodium carbonate (3 x 250 mL), water (500 mL) and brine (3 x 200 mL), dried over sodium sulfate and concentrated in vacuo. The gummy yellow solid is triturated with methanol and filtered off to yield the title compound 4 30 (21.41 g, 94.8%) as a colorless solid. 28-Hydroxy-21-oxolup-18-en-3p-yl acetate 5 A solution of compound 4 (12.07 g, 22.3 mmol) and potassium hydroxide (1.49 g, 26.76 mmol) in a mixture 1:1 of toluene and ethanol (0.72 L) is stirred vigorously at room temperature for 1 hour. The reaction mixture is neutralized with aqueous HC[ 1 N (27 mL) and evaporated to dryness. The solid is taken up with water and a WO 2009/082818 PCT/CA2008/002290 39 minimum of acetone then filtered off. The precipitate is washed with water and dried to yield the title compound 5 (10.24 g, 92%) as a colorless solid. 3#-Acetoxy-21-oxolup-18-en-28-oic acid 6 (see W02003/045971) A suspension of compound 5 (10.24 g, 20.5 mmol) in ethyl acetate (720 mL) is added to a mixture of ruthenium oxide (IV) hydrate (272 mg, 2.05 mmol) and sodium periodate (26.3 g, 123 mmoL) in water (650 mL) and TFA (11 mL). The biphasic mixture is stirred vigorously overnight at room temperature. Ethanol (100 mL) is added and the separated organic layer is filtered through a short column of 10 silica gel. Water (400 mL) is added and the organic layer is dried over sodium sulfate, and concentrated in vacuo. The yellow solid is taken up with diethyl ether, filtered off and washed with diethyl ether to give the title compound 6 (4.96 g, 47.2%) as a colorless solid. 0 0 H H H 1) (COC1) 2 , DCM 0 OH 2) R 2
NHR
3 , Base, DCM 0 N H - ' a 0 H 6 H 7 H O/ - H NaOH or KOH O A O O Solvent N Pyridine, DMAP 0 0 N, H -R R 2 'H -R R 2 HO HO A O H H H 8 H Scheme 2 General procedure: 20 Step 1: To a solution of compound 6 in DCM is added a solution of oxalyl chloride (2 eq.) and few drops of DMF. The reaction mixture is stirred for 1 to 2 hours at room temperature and evaporated in vacuo to yield the acid chloride used as crude. Step 2: To a mixture of acid chloride in DCM is added the amine R 2
NHR
3 (1.1 to 3 eq.) and a base such as triethylamine or diisopropylamine (1.1 to 3 eq.). The reaction is stirred at room temperature until, completion (microwaves at 150 C for WO 2009/082818 PCT/CA2008/002290 40 20 minutes in DCE is used for amines with low reactivity). The crude is purified by flash chromatography on silica gel to yield the amide 7. Step 3: The amide 7 is deprotected in solvents such as methanol, THF or dioxane using an aqueous solution of inorganic base such as sodium hydroxide or potassium hydroxide (10 to 20 eq.) at temperature ranging from 20 to 60'C to give the alcohol 8. Step 4: To the alcohol 8 in pyridine is added a cyclic anhydride and DMAP (3 to 10 10 equivalents). The reaction mixture is heated at temperature ranging from 90 to 140"C until completion to yield after standard acidic aqueous work up and purification by flash chromatography on silica gel the acid 9. 310--(3',3'-Dimethylsucciny)-21-oxolup-18-en-28-oic acid N-benzylamide 9-1 0 H N 0 0 HO 0 Step 1: To a solution of compound 6 (500 mg, 0.975 mmol) in 5 mL of anhydrous DCM is added a solution of oxalyl chloride (2M in DCM, 0.975 mL, 1.95 mmol) and 2 drops of DMF. The reaction mixture is stirred for 1 hour at room temperature and 20 evaporated in vacuo to yield 3fi-acetoxy-21-oxolup-18-en-28-oic acid chloride as an orange solid used as crude material. Step 2: To a solution of previously prepared 3fl-acetoxy-21-oxolup-18-en-28-oic acid chloride in 5 mL of anhydrous DCM is added triethylamine (150 pL, 1.073 mmol) and benzylamine (112 pL, 1.024 mmol). The reaction mixture is stirred at room temperature until completion, diluted with DCM, washed with HCL 1N and dried over sodium sulfate. The crude is purified by flash chromatography (Biotage) on silica gel (ethyl acetate / hexanes 0 to 50%) to yield 3/acetoxy-21-oxolup-18 en-28-oic acid N-benzylamide 7-1 (574 mg, 98%) as a colorless solid. 30 1H NMR (400 MHz, CDCl 3 ): 6 [ppm] 7.34 - 7.21 (m, 5H), 5.61 (m, 1H), 4.59 (d x d, 1H), 4.46 (d x d, 1H), 4.19 (d x d, 1H), 3.20 (sept., 1H), 2.65 - 2.54 (m, 2H), 2.46 WO 2009/082818 PCT/CA2008/002290 41 (d, 1H), 2.17 (d, 1H), 2.03 (s, 3H), 1.88 - 0.82 (m, 16H), 1.20 (d, 3H), 1.18 (d, 3H), 0.90 (br s, 6H), 0.88 (s, 3H), 0.84 (s, 3H), 0.83 (s, 3H), 0.77 (m, 1H). Step 3: To a solution of 3/3-acetoxy-21-oxolup-18-en-28-oic acid N-benzylamide (574 mg, 0.953 mmol) in a 4:1 mixture of dioxane / water (25 mL) is added an aqueous solution of 4N NaOH (2.38 mL). The mixture is stirred for 4 hours at 50'C, then HCI 4N (2.38 mL) is added and dioxane is evaporated in vacuo. The remaining aqueous solution is extracted with ethyl acetate (3x) and the combined organic layers are washed with brine, dried over sodium sulfate, filtered and concentrated. 10 The crude material is purified by flash chromatography (Biotage) on silica gel (ethyl acetate / hexanes 0 to 80%) to isolate 3/hydroxy-21-oxolup-18-en-28-oic acid N benzylamide 8-1 (307 mg, 58%) as a white solid. 1H NMR (400 MHz, CDCl 3 ): S [ppm] 7.34 - 7.21 (m, 5H), 5.62 (m, 1H), 4.59 (d x d, 1H), 4.20 (d x d, 1H), 3.19 (sept., 2H), 2.65 - 2.55 (m, 2H), 2.46 (d, 1H), 2.16 (d, 1H), 1.88 - 0.82 (m, 16H), 1.20 (d, 3H), 1.17 (d, 3H), 0.95 (s, 3H), 0.90 (s, 3H), 0.88 (s, 3H), 0.85 (s, 3H), 0.75 (s, 3H), 0.67 (m, 1H). Step 4: To a solution of 3fhydroxy-21-oxolup-18-en-28-oic acid N-benzylamide (110 mg, 0.196 mmol) in 3 mL of pyridine is added 2,2-dimethyl succinic anhydride 20 (75.3 mg, 0.588 mmol) and DMAP (28.6 mg, 0.235 mmol). The reaction mixture is stirred overnight under reflux. Then 75.3 mg of 2,2-dimethyl succinic anhydride is added twice every 3 hours to complete the reaction. The solvent is evaporated in vacuo and the residue is taken up with ethyl acetate (50 mL) and HCl 1N (10 mL). The organic layer is washed with water (2 x 30 mL), brine (30 mL) and dried over sodium sulfate. The crude material is purified by flash chromatography (Biotage) on silica gel (ethyl acetate / hexanes 0 to 50%) to give the title compound 9-1 (118.6 mg, 88%) as a colorless solid. 1H NMR (400 MHz, CDCl 3 ): 5 [ppm] 7.34 - 7.21 (m, 5H), 5.61 (d x d, 1H), 4.59 (d x d, 1H), 4.50 (d x d, 1H), 4.20 (d x d, 1H), 3.19 (sept., 1H), 2.67 (d, 1H), 2.65 - 2.54 30 (m, 2H), 2.56 (d, 1H), 2.45 (d, 1H), 2.17 (1H), 1.85 - 0.74 (m, 18H), 1.3 (s, 3H), 1.29 (s, 3H), 1.2 (d, 3H), 1.18 (d, 3H), 0.89 (br s, 6H), 0.86 (s, 3H), 0.82 (s, 3H), 0.8 (s, 3H). LC/MS: m/z = 688.68 (M+H*). The compounds of the present invention wherein Y is C(O) can be prepared as generally described in schemes 3 or 4.
WO 2009/082818 PCT/CA2008/002290 42 0 0 H / SeO 2 H / 0 0 dioxane H0 - N 0 0 - R N HO A O HO A O H H 9 10 Scheme 3 General procedure: Selenium dioxide (4 to 6 eq.) is added to a solution of compound 9 previously dissolved in dioxane, acetic acid and acetic anhydride. The reaction mixture is refluxed overnight, then cooled to room temperature and filtered through Celite. 10 The residue is dissolved in DCM, washed with water, brine, dried over sodium sulfate and evaporated to dryness. The crude material is purified by flash chromatography on silica geL to yield the compound 10. 0 0 H / SeO 2 H / NaOH or KOH O= N. dioxane O N Solvent H R 2
R
3 H - R 2
R
3 0 0 H H 7 0 0 0 o H/ H 0 O H O 0 0 - - N. HO R N. Pyridine, DMAP HO H R R 3 H~~ - 3 HO A 0 HO -H H 12 10 Scheme 4 General procedure: WO 2009/082818 PCT/CA2008/002290 43 Step 1: Selenium dioxide (4 to 6 eq.) is added to a solution of compound 7 previously dissolved in dioxane, acetic acid and acetic anhydride. The reaction mixture is refluxed overnight, then cooled to room temperature and filtered through Celite. The residue is dissolved in DCM, washed with water, brine, dried over sodium sulfate and evaporated to dryness. The crude material is purified by flash chromatography on silica geL to yield the compound 11. Step 2: The ester 11 is deprotected in solvents such as methanol, THF or dioxane using an aqueous solution of inorganic base such as sodium hydroxide or potassium 10 hydroxide (10 to 20 eq.) at temperature ranging from 20 to 60*C to give the alcohol 12. Step 3: To the alcohol 12 in pyridine is added a cyclic anhydride (5 to 10 eq.) and DMAP (1.1 to 2 eq.). The reaction mixture is heated at temperature ranging from 90 to 140 C until completion to yield after standard acidic aqueous work up and purification by flash chromatography on silica gel the acid 10. Tables 1, 2 and 3 of compounds illustrate some of the compounds of the present invention which may be synthesized using the procedures described in scheme 2. 20 Retention time (tR) for each compound are measured using the standard analytical HPLC or LC/MS methods described above. Table 1. Cpd Structure Compound name 0 3p-0-Acetoxy-21 -oxoLup-1 8-en-28-oic acid N methylamide H H 7-2 N H 0 3p-O-Acetoxy-21 -oxoLup-1 8-en-28-oic acid N H' H isopropylamide 7-3 N 0 H0 0 WO 2009/082818 PCT/CA2008/002290 44 o 3p6-0-Acetoxy-21 -oxotup-1 8-en-28-oic acid N cyclohexylamide H/ H 7-4 N 0 33-0-Acetoxy-21 -oxoLup-1 8-en-28-oic acid N cyclohexyl methylamide H H 7-5 N o 0 0 33-0-Acetoxy-21 -oxoLup-1 8-en-28-oic acid N piperidiny acetamide 7-6 N o 0 Ao H 0 o 3p-0-Acetoxy-21-oxotup-18-en-28-oic acid N morpholyl acetamide H 0 7-7 N H 0 0 0 3p-0-Acetoxy-21-oxolup-18-en-28-oic acid N-(4 acetyl piperazinyL) acetamide HI N 7-8 N o 0 3p8-0-Acetoxy-21-oxoLup-18-en-28-oic acid N-(4 methyl piperaziny) acetamide 79 N 7-9 NJ o 0 o 3,p-0-Acetoxy-21-oxoLup-18-en-28-oic acid N benzamide H H 7-10 N 0 H 3 WO 2009/082818 PCT/CA2008/002290 45 0 33-0-Acetoxy-21 -oxolup-1 8-en-28-oic acid N methyl-N-benzylamide H! 7-11 N 0 H0g. 0 H o 3p?-0-Acetoxy-21-oxotup-18-en-28-oic acid N-2 chloro-benzylamide H! H 7-12 N o H o 3p-0-Acetoxy-21-oxolup-18-en-28-oic acid N-3 chloro-benzylamide H! H 7-13 N H CI o 3p8-0-Acetoxy-21-oxolup-18-en-28-oic acid N-4 H / H chloro-benzylamide N 7-14 Cl o 3p6-0-Acetoxy-21-oxolup-18-en-28-oic acid N-4 methoxy-benzyLamide H! H N 7-15
A
0 0 Ao H ,10 0 3,-0-Acetoxy-21-oxotup-18-en-28-oic acid N pyridin-2-ylmethylamide H H 0 7-16 0N6 0 H 0 3p6-0-Acetoxy-21 -oxolup-1 8-en-28-oic acid N pyridin-3-ytmethylamide H H 7-17 N 0 p
H
WO 2009/082818 PCT/CA2008/002290 46 3p6-0-Acetoxy-21 -oxolup-1 8-en-28-oic acid N pyridin-4-ylmethylamide H H 7-18 N H : 0 H N 3,p-0-Acetoxy-21-oxolup-18-en-28-oic acid N-[2- (4 methoxy- phenyL)-ethyl] -acetamide H/ H N 7-19 O H : 0 oI H0 0 3,-0-Acetoxy-21-oxolup-18-en-28-oic acid N-(2 acetylamino-ethyl)-carbamic acid tert-butyt ester H H N 7-20 NH AO H - NH o 3p8-0-Acetoxy-21-oxolup-18-en-28-oic acid N pyridin-2-yl-acetamide H H 7-21 N 0 H - 0 N o 3pJ-0-Acetoxy-21-oxolup-18-en-28-oic acid N pyridin-3-y-acetamide H H 7-22 N H N O 0 3/3-0-Acetoxy-21-oxoLup-18-en-28-oic acid N-1 acetyl-piperazine-4-carboxylic acid tert-butyl H N O ester 7-23 N H : 3p6-0-Acetoxy-21-oxotup-18-en-28-oic acid N- 1-(4 o tert-butyl-dimethyl-silanyloxy-piperidin-1-yl) o acetamide 7-24 N H 0 0O WO 2009/082818 PCT/CA2008/002290 47 3p8-0-Acetoxy-21-oxolup-18-en-28-oic acid N-1 acetylamino-piperidine-4-carboxylic acid tert H H butyl ester 7-25 N o = 0 N o o H0 3p-0-Acetoxy-21-oxolup-18-en-28-oic acid N-(1 0 phenyl-ethyl)-acetamide H/ H 7-26 N o - o o H 0 3j-0-Acetoxy-21-oxotup-18-en-28-oic acid N-(1 methyl-1 -phenyl-ethyl)-acetamide H H 7-27 N 3p8-0-Acetoxy-21-oxoiup-18-en-28-oic acid N-(tert butyl)-acetamide H H 7-28 N 0 0 3p-0-Acetoxy-21-oxotup-18-en-28-oic acid N-(8 amino-3,8-diaza-bicyclo[3.2. 1 ]octane-3 H N benzamide)-acetamide 7-29N 0 H 3p6-0-Acetoxy-21-oxoLup-18-en-28-oic acid N-4 piperazi-2-one-acetamide H NH 7-30 N o H 0 3p8-0-Acetoxy-21-oxolup-18-en-28-oic acid N pyrimidin-2-yi-acetamide H H 7-31 N N H 0 N / o
H
WO 2009/082818 PCT/CA2008/002290 48 3p8-0-Acetoxy-21-oxotup-18-en-28-oic acid N-(4 H amino carboxylic acid tert-butyl- ester-1 H N piperidine)-acetamide 7-32N 0 0 0 A0 3p-0-Acetoxy-21-oxoLup-18-en-28-oic acid N-4-(1 0 methyl-piperazi-2-one)-acetamide *H N 733 N LC/MS: 7.92 min. 03 (Method b) H 0 M+H* 609.43 0 H o 3p8-0-Acetoxy-21-oxolup-18-en-28-oic acid N-2 methyl-phen-1 -yl acetamide H H 7-34 N 0 - o o H 0 0 3p8-0-Acetoxy-21-oxoLup-18-en-28-oic acid N-3 methyl-phen-1-yl acetamide H H 7-35 N 0 0 0 33-0-Acetoxy-21-oxotup-18-en-28-oic acid N-4 methyl-phen-1-yl acetamide H H 7-36 N AO H 0 0 3p8-0-Acetoxy-21-oxoLup-18-en-28-oic acid N-8 acetylamino-3,8-diaza-bicyclo[3.2.1]oc H / N O tane-3-carboxylic acid tert-butyl ester 7-37N 0 o 3p-0-Acetoxy-21-oxoLup-18-en-28-oic acid N pyrimidin-5-y-acetamide H H 7-38 N N LC/MS: 10.12 min. 0 H 0 (Method b) H N M+H* 590.35 0K WO 2009/082818 PCT/CA2008/002290 49 0 33-0-Acetoxy-21 -oxolup-1 8-en-28-oic acid N pyridin-4-yl-acetamide H H 7-39 N LC/MS: 11.63 min. 0 0 N (Method a) H M+H* 589.4 3p-0-Acetoxy-21-oxoLup-18-en-28-oic acid N-3 o amino-1 -methyl-1 H-pyrazole-acetamide H/ H N LC/MS: 10.29 min. 7-40 NN (Method b) o 0 M+H* 592.42 ko H 3p6-0-Acetoxy-21-oxolup-18-en-28-oic acid N-5 0 amino-1 -methyl-1 H-pyrazole-acetamide H H LC/MS: 9.44 min. 7-41 N N (Method b) o 0 M+H* 592.41 3p6-0-Acetoxy-21-oxolup-18-en-28-oic acid N-4 0 methyl-pyrimidin-5-yl-acetamide H H 7-42 N 0 3p-0-Acetoxy-21-oxolup-18-en-28-oic acid N-4 o methyl-pyrimidin-2-y-acetamide H H 7-43 N N A0o N H H 3,6-0-Acetoxy-21-oxoLup-18-en-28-oic acid N-4 0 amino-1 -methyl-1 H-pyrazole-acetamide H H 7-44 N H - N 0 0
HN
WO 2009/082818 PCT/CA2008/002290 50 3p8-0-Acetoxy-21-oxoLup-18-en-28-oic acid N-4,6 o dimethyl-pyrimidin-2-yL-acetamide H H 7-45 N N o 0 N o H 3p6-0-Acetoxy-21-oxolup-18-en-28-oic acid N o pyrazin-2-yt-acetamide H H SN LC/MS: 11.71 min. 7-46 (Method b) HN M+H' 590.27 o 3p-0-Acetoxy-21-oxolup-18-en-28-oic acid N quinoLin-3-y-acetamide H H 7-47 N LC/MS: 11.15 min. o - (Method b) M+H* 639.47 o 3p8-0-Acetoxy-21-oxotup-18-en-28-oic acid N-(2 pyrrolidin-1 -y-ethyl)-acetami H de 7-48 N N LC/MS: 11.19 min. H a(Method a) M+H* 609.4 o 3p8-0-Acetoxy-21-oxotup-18-en-28-oic acid N-(5 methyl-[1,3,4]oxadiazol-2-y) H acetamide 7-49 N 0 LC/MS: 16.26 min. o 0 N- N (Method a) M+H* 594.22 0 o 3p6-0-Acetoxy-21-oxoLup-18-en-28-oic acid N isoquinoLin-4-y-acetamide H H 7-50 N LC/MS: 15.26 min. o -No(Method a) H0 - N' M+H* 639.44 o 3p8-0-Acetoxy-21-oxoLup-18-en-28-oic acid N pyrimidin-4-yt-acetamide H H 7-51 N H 0 N N A0H WO 2009/082818 PCT/CA2008/002290 51 0 3p-0-Acetoxy-21-oxoLup-18-en-28-oic acid N-2 F F trifluoromethyl-phen- 1-yl acetamide H H 7-52 N LC/MS: 15.87 min. 0 01 (Method b) H : M+H* 656.56 0 3p8-0-Acetoxy-21-oxoLup-18-en-28-oic acid N-(1 methyl-1 H-tetrazol-5-yl)-acetamide H 7-53 N N LC/MS: 17.22 min. 0 NI N (Method a) O H M+H* 594.34 H 0 3p8-0-Acetoxy-21-oxoLup-18-en-28-oic acid N cycLopropylmethyl acetamide HI 7-54 N LC/MS: 12 min. 0 0 (Method b) HO M+ 565.84 0 3p8-0-Acetoxy-21-oxoLup-18-en-28-oic acid N azetidine-1 acetamide H/ D 7-55 N LC/MS: 9.61 min. 0 0(Method b) 0 H 0 M+H* 552.37 0 3,p-0-Acetoxy-21-oxoLup-18-en-28-oic acid N (2,2,2-trifluoro-ethyl)-acetamide HI 7-56 N LC/MS: 12.35 min. 0 F Fo(Method b) H FFF M+H* 594.45 0 3,-0-Acetoxy-21-oxoLup-18-en-28-oic acid N-4 F triftuoro-pyrimidin-2-yL-acetamide H/ H FF N N 7-57 NI F LC/MS: 19.21 min. 0 0 N (Method a) 0 M+H* 658.68 0 3,6-0-Acetoxy-21-oxolup-18-en-28-oic acid N-(1 cyclopropyl-1 -methyl-ethyL)-acetamide 7-58 N LC/MS: 15.38 min. (Method b) 0 HM+H* 594.5 WO 2009/082818 PCT/CA2008/002290 52 o 3p8-0-Acetoxy-21-oxoLup-18-en-28-oic acid N-(4 Ns dimethylamino-piperidin-1 -yL)-acetamide H 7-59 N LC/MS: 10.83 min. o o (Method a) M+H* 623.65 o 3p8-0-Acetoxy-21-oxolup-18-en-28-oic acid N (2,2,2-trifluoro-1 -methyl-ethyl)-acetamide H H F 7-60 N F LC/MS: 19.84 min. o o (Method a) o gM+H* 608.5 o 3p6-0-Acetoxy-21-oxotup-18-en-28-oic acid N-(5 H methyl-[1,3,4]thiadiazol-2-yL)-acetamide 7-61 N S LC/MS: 18 min. o H 0 O N (Method a) M+H* 610.47 o 0 3,-0-Acetoxy-21-oxolup-18-en-28-oic acid N (2,2,2-trifluoro- 1,1 -dimethyl-ethyl)-acetamide 7-62 LC/MS: 15.04 min. 0- HNt (Method b) U 0M+H* 622.54 F F F 0 3p8-0-Acetoxy-21-oxolup-18-en-28-oic acid N-tert butyl-N-methyl-acetamide 7-63 0 LC/MS: 15.07 min. 0 N (Method b) o 1M+H* 582.47 0 3,-0-Acetoxy-21-oxoLup-18-en-28-oic acid N-(R) 2-acetylaminomethyl-pyrrolidine 0 -1-carboxylic acid tert-butyl ester 7-64 o HN, o NO 3p6-0-Acetoxy-21-oxolup-18-en-28-oic acid N-(S)-2 acetylaminomethyl-pyrrolidine o -1-carboxytic acid tert-buty ester 7-65 o HN NA
O
WO 2009/082818 PCT/CA2008/002290 53 o 3p8-0-Acetoxy-21-oxolup-18-en-28-oic acid N-(4,4 H difluoro-cycLohexyl) acetamide 7-66 0 HN HPLC: 30.02 min. (B) O H HN F LC/MS: M+H* 630.65 0 F F o 3,p-0-Acetoxy-21-oxotup-18-en-28-oic acid N-2 chloro-phen-1-yl acetamide 7-67 0 o - HN C1 o 3p-0-Acetoxy-21-oxolup-18-en-28-oic acid N-2 isopropyl-phen- 1-yl acetamide 0 7-68 o- HN 0 33-0-Acetoxy-21-oxolup-18-en-28-oic acid N-4 fluoro-phen-1 -yl acetamide 7-69 0 0 HN AO F 0 3,-0-Acetoxy-21-oxoLup-18-en-28-oic acid N quinazolin-2-y acetamide 7-70 0 o HN N - N o 3p6-0-Acetoxy-21-oxotup-18-en-28-oic acid N-(1 methyl-1 H-tetrazoL-3-yL)-acetamide 7-71 0 0- HN NN o N N 0 33-0-Acetoxy-21-oxotup-18-en-28-oic acid N-(5 methyl-isoxazol-3-yl)-acetamide 7-72 0 o - HN 3p-0-Acetoxy-21-oxolup-18-en-28-oic acid N-(1,3 dihydro-isoindol-2-yL)-acetamide 7-73 0N
K
0 WO 2009/082818 PCT/CA2008/002290 54 3p8-0-Acetoxy-21-oxoLup-18-en-28-oic acid N-(4,4 difluoro-cyclohexylmethyl) -acetamide 0 HPLC: 30.45 min. (B) 7-74 HN LC/MS: M+H* 644.73 F F 3p-0-Acetoxy-21-oxotup-18-en-28-oic acid N-4,4 O H difluoro-piperidine acetamide 0 HPLC: 31.38 min. (B) 5N LC/MS: M+H 616.58 H F F WO 2009/082818 PCT/CA2008/002290 55 Table 2. pd # Structure Compound name Analytical data 3p8-0-Hydroxy-21 oxolup-18-en-28 H H oic acid N- LC/MS: 5.84 min. 8-2 methylamide (Method b) M+H* 484.57 HO H 0 38-0-Hydroxy-21 oxoLup-18-en-28 H H oic acid N- LC/MS: 8.41 min. 8-3 N isopropylamide (Method b) o M+H* 512.64 HO H O 3p-0-Hydroxy-21 oxolup-18-en-28 H H oic acid N- LC/MS: 11.36 min. 8-4 N cyclohexylamide (Method b) M+H* 552.66 HO 0 33-0-Hydroxy-21 oxolup-18-en-28- 1H NMR (400 MHz, CDCl 3 ): 8 H H oic acid N- [ppm] 5.38 (t, 1H), 3.74 (m, 8-5 N cyclohexyl 2H), 3.23 (m, 3H), 2.87 (d x methylamide d, 1H), 2.64 (m, 1H), 2.62 H 0 (m, 1H), 2.40 (d, 1H), 2.17 HO (d, 1H), 2.00-0.68 (m, 47H) 3p8-0-Hydroxy-21 0 oxolup-18-en-28 H / oic acid N- LC/MS: 10.05 min. 8-6 N piperidinyl (Method b) H 0 acetamide M+H* 538.61 HO 3,6-0-Hydroxy-21 0 oxotup-18-en-28 H / 0 oic acid N- LC/MS: 6.95 min. 8-7 N morpholyL (Method b) H o acetamide M+H* 540.6
HO
WO 2009/082818 PCT/CA2008/002290 56 O 0 3p-0-Hydroxy-21 oxolup-18-en-28 H / N Oic acid N-(4-acetyl LC/MS: 4.4 min. 8-8 N piperazinyl) (Method b) acetamide M+H* 581.69 HO O 38-0- Hydroxy-21 oxotup-18-en-28 H / N oic acid N-(4- LC/MS: 0.81 min. 8-9 N methyl piperazinyl) (Method b) acetamide M+H* 553.64 HO O 3p-0-Hydroxy-21 oxolup- 18-en-28 H H oic acid N- LC/MS: 10.92 min. 8-10 N benzamide (Method b) 0 .M+H* 546.65 HO Ho O 3p8-0-Hydroxy-21 oxolup-18-en-28 H Ioic acid N-methyl- LC/MS: 11.22 min. 8-11 N N-benzylamide (Method b) M+H* 574.63 HO O 38-0-Hydroxy-21 oxolup-18-en-28 H H oic acid N-2- LC/MS: 11.27 min. 8-12 N chloro- (Method b) o ci benzylamide M+ 594.58 HO 3p-0-Hydroxy-21- 1H NMR (400 MHz, CDCL 3 ): 5 0 oxotup-18-en-28- [ppm] 7.25-7.22 (m, 3H), H / H oic acid N-3- 7.13 (m, 1H), 5.64 (t, 1H), 8-13 N chtoro- 4.64 (d x d, 1H), 4.10 (d x d, benzylamide 1H), 3.74 (m, 1H), 3.21 (m, H 0 2H), 2.60 (m, 2H), 2.45 (d, HO e 1H), 2.18 (d, 1H), 1.95-0.62 H CI (m, 36H) O 3p8-0-Hydroxy-21 oxolup-18-en-28 oic acid N-4- LC/MS: 11.45 min. 8-14 chloro- (Method b) o benzylamide M+ 594 HO C1 WO 2009/082818 PCT/CA2008/002290 57 3p8-0-Hydroxy-21 oxotup-18-en-28 H H oic acid N-4- LC/MS: 9.26 mi. N ~methoxy- (ehdb 8-15 (Method b) H 0 benzylamide M+H* 590.69 HO ,o0 HOH H 38-0-Hydroxy-21- 1H NMR (400 MHz, CDCL 3 ): 8 0 oxolup-18-en-28- [ppm] 8.45 (i, 1H), 7.67 (t, oic acid N-pyridin- IH), 7.25 (i, 1H), 7.20 (i, H H 2-ylmethylamide 1H), 6.93 (br s, 1H), 4.61 (d 8-16 N x d, 1H), 4.39 (d x d, 1 H), H) 3.78 (in, H), 3.22 (i, 2H), HO) 2.70 (in, 2H), 2.45 (d, 1 H), O H 2.19 (d, 1H), 2.04 (m, 1H), 1.94-0.62 (m, 36H) 3p8-0-Hydroxy-21- 1H NMR (400 MHz, CDCI 3 ): 6 O oxolup-18-en-28- [ppm] 8.60 (s, 1H), 8.54 (d, H/ H oic acid N-pyridin- 1H), 7.71 (d, 1H), 7.31 (m, 8-17 N 3-ylmethylamide 1H), 5.92 (br t, 1H), 4.57 (d x d, 1H), 4.30 (d x d, 1H), 3.20 (m, 2H), 2.55 (m, 2H), HO Q N 2.40 (d, 1H), 2.16 (d, 1H), 1.95-0.60 (m, 38H) 0 3,-0-Hydroxy-21 0 oxolup-18-en-28 H H oic acid N-pyridin- LC/MS: 9.9 min. 8-18 N 4-ylimethylamide (Method a) H M+H* 561.55 HO H N O 3p-0-Hydroxy-21 oxolup-18-en-28 H H oic acid N-[2-(4- LC/MS: 9.69 min. 8-19 N methoxy-phenyl)- (Method b) o ethyt]-acetamide M+H* 604.71 HO A O 3p6-0-Hydroxy-21 oxolup-18-en-28 H H oic acid N-(2 N acetylamino- LC/MS: 7.96 min. 8-20 ethyl)-carbamic (Method b) - NH acid tert-butyl M-Boc+H* 513.59 HO O)O ester 0 3p6-0-Hydroxy-21 oxoLup-18-en-28 H H oic acid N-pyridin- LC/MS: 8.02 mi. 8-21 N 2-y-acetamide (Method b) 0 0 NA M+H* 547.58
HO
WO 2009/082818 PCT/CA2008/002290 58 0 3p8- 0-Hydroxy-21 oxolup-18-en-28 H H oic acid N-pyridin- LC/MS: 2.47 min. 8-22 N 3-y[-acetamide (Method b) O N M+H* 547.59 HO O 0 3p8-0-Hydroxy-21 oxolup-18-en-28 H / N oic acid N-1-acetyl- LC/MS: 10.37 min. 8-23 N piperazine-4- (Method b) carboxylic acid M+H* b) H 0 tert-butyt ester M+H 639.69 HO H 3p8-0-Hydroxy-21 O Si 7 oxotup-18-en-28 H oic acid N- 1-(4- LC/MS: 17.65 min. 8-24 H tert-buty- (Method b) N9 dimethyt- M+H 669.81 O silanyloxy-M+*698 HO piperidin-1-yL) H acetamide O 3p-0-Hydroxy-21 oxolup-1 8-en-28 H H oic acid N-1- LC/MS: 10.6 min. 8-25 N. acetylamino- (Method b) N O piperidine-4- M+H* 653.72 H- carboxytic acid HO H O tert-buty ester 3p-0-Hydroxy-21 0 oxolup-18-en-28 H H oic acid N-(1- LCMS: 10.44 min. 8-26 N phenyl-ethyl)- (Method b) acetamide M+H* 574.56 HO 0 33-0-Hydroxy-21 oxotup-18-en-28 H H oic acid N-(1- LC/MS: 11.95 min. 8-27 N methyl-1-pheny- (Method b) ethyl)-acetamide M+H* 588.58 HO Ho 0 3p-0-Hydroxy-21 0 oxolup-18-en-28 H H oic acid N-(tert- LC/MS: 10.52 min. 8-28 N butyl)-acetamide (Method b) M+H* 526.54
HO
WO 2009/082818 PCT/CA2008/002290 59 O 0 3p8-0-Hydroxy-21 oxoLup-18-en-28 H N oic acid N-(8- LC/MS: 8.08 min. 8-29 N amino-3,8-diaza- (Method b) - o bicyclo[3.2.1]octan M+H 669.62 H : e-3-benzamide) HO H acetamide 3p-0-Hydroxy-21 oxotup- 1 8-en-28 H / NH oic acid N-4- LC/MS: 12.4 min. 8-30 N O piperazi-2-one- (Method a) 0 acetamide M+H* 553.31 HON HO 3p8-0-Hydroxy-21- 1H NMR (400 MHz, CDCL 3 ): 8 0 oxolup-18-en-28- [ppm] 8.60 (d, 2H), 7.74 (s, H I H oic -acid N- 1H), 7.03 (t, 1H), 3.32 (i, 831 N N pyrimidin-2-yl- 1H), 3.20 (i, 1H), 2.75 (i, 8m acetamide 2H), 2.63 (d, 1H), 2.22 (d, H E N) -~1H), 2.05 (t, 1H), 1.94 (m, HO 2H), 1.72 (m, 1H), 1.70-0.65 H (, 34H) H oxotup-1 8-en-28 oic acid N-(4- [ppm] 4.52 (mi, 1H), 3.88 / ~ O(ml4H N o amino carboxylic (m, 1H), 3.25 (m, 1H), 3.15 8-32 acid tert-butyl- (d x d, 1H), 2.95 (m, 1H), 0 ester-1- 2.72 (m, 2H), 2.46 (d, 1H), HO piperidine)- 220 (m, 1H), 2.00-0.70 (m, acetamide 3 O-Hydroxy-21- 1H NMR (400 MHz, CDCI 3 ): 8 NH [ppm] 4.49 (s, 1H), 4.33 (d x H rN oic acid N-4-(1- (d, 1H),3.60 (m, 1H), 3.27 (d 8-33 N ethyl.-piperazi-2- x d, 1H), 3.14 (d x d, 1H), H 0 one)-acetamide 3.08-2.94 (m, 5H), 2.60 (d, 1H), 2.30 (d, 1H), 2.15 (m, HO H 3H), 1.75-0.60 (m, 38H) O 38-0-Hydroxy-21 oxolup-1 8-en-28 H H oic acid N-2- LC/MS: 10.82 min. 8-34 N N methy[-phen-1-yl (Method b) H acetamide M+H* 560.35 HO H 0 3p8-0-Hydroxy-21 0 oxolup-18-en-28 H H oic acid N-3- LC/MS: 11.9 min. 8-35 N methyl-phen-1-yi (Method b) H acetamide M+H* 560.33
HO
WO 2009/082818 PCT/CA2008/002290 60 3,p-0-Hydroxy-21 oxolup- 1 8-en-28 H H oic acid N-4- LC/MS: 11.71 min. 8-36 N methyl-phen-1-y (Method b) o acetamide M+H* 560.34 HO H 3p8-0-Hydroxy-21- 1 H NMR (400 MHz, CDCl 3 ): 5 o o oxoLup-18-en-28- [ppm] 4.8 (br s, 1H), 3.84 N 0 oic acid N-8- (m, 2H), 3.17 (m, 2H), 3.02 H acetylamino-3,8- 2.68 (m, 3H), 2.25 (m, 2H), 8-37 N diaza- 2.03 (m, 1H), 1.86-1.51 (m, a bicyclo[3.2.1]oc 10H), 1.43-1.13 (m, 27H) tane-3-carboxylic 0.99 (br s, 3H), 0.95 (s, 6H), HO H acid tert-butyl 0.85 (s, 3H), 0.74 (s, 3H), ester 0.68 (br d, 1H) O 38-0-Hydroxy-21- 1H NMR (400 MHz, CDCl 3 ): 8 oxolup-18-en-28- [ppm] 8.98 (s, 1H), 8.86 (s, H H oic acid N- 1H), 6.92 (s, 1H), 3.31 (m, 8-38 N pyrimidin-5-yl- 1H), 3.20 (m, 1H), 2.70 (m, O acetamide 2H), 2.55 (d, 1H), 2.30 (d, HN 1H), 1.95 (m, 2H), 1.80-0.65 HO (m, 36H) O 3p8-0-Hydroxy-21 oxolup-18-en-28 H H oic acid N-pyridin- LC/MS: 10.27 min. 8-39 N 4-y[-acetamide (Method a) O N M+H* 547.23 HO 3p8-0-Hydroxy-21 oxolup-1 8-en-28 H H oic acid N-3-amino- LC/MS: 14.91 min. 8-40 N N 1-methyl-1H- Method a) 8-40 N N- pyrazole- (ehda 0 N aet d M+H* 550.25 HON 38-0-Hydroxy-21 oxotup-1 8-en-28 oic acid N-5-amino H H / 1-methyl-1H- LC/MS: 14.3 mi. 8-41 N pyraZole- (Method a) Ho / acetamide M+H 550.25
HO
WO 2009/082818 PCT/CA2008/002290 61 3/p-0-Hydroxy-21- 1H NMR (400 MHz, CDCL 3 ): 8 oxoLup-18-en-28- [ppm] 9.22 (s, 1H), 8.88 (s, oic acid N-4- 1H), 6.92 (s, IH), 3.31-3.34 0 methyl-pyrimidin- (m, 1H), 3.17-3.21 (d x d, 5-yI-acetamide 1H), 2.70-2.74 (m, 2H), 2.57 H H (d, 1H), 2.43 (s, 3H), 2.31 8-42 N (d, 1H), 1.84-2.03 (m, 3H), 1.72-1.75 (m, 1H), 1.28 (d, H 3H), 1.25 (d, 3H), 1.19-1.04 (m, 11H), 1.01 (s, 3H), 0.97 (sH 3H), 0.96 (s, 3H), 0.90 0.80 (m, 1H), 0.85 (s, 3H), 0.74 (s, 3H), 0.68-0.71 (m, 1H) 3p8-0-Hydroxy-21- 1H NMR (400 MHz, CDCL 3 ): 6 oxolup-18-en-28- [ppm] 8.46 (d, 1H), 7.85 (br oic acid N-4- d, 1H), 7.89 (d, 1H), 6.89 methyl-pyrimidin- (d, 1H), 3.34-3.30 (m, 1H), 0 2-yi-acetamide 3.21-3.17 (m, 1H), 2.76-2.73 (br d, 1H), 2.62 (d, 1H), H H 2.47 (s, 3H), 2.24 (d, 1H), 8-43 N, N2.10 (br d, 1H), 1.94 (m, o0 ND ~2H), 1.73 (m, 1H), 1.64-1.43 (m, 6H), 1.42-1.20 (m, 7H), HO H 1.32 (d, 3H), 1.24 (d, 3H), 1.0 (s, 3H), 0.96 (s, 6H), 0.90-0.80 (m, 1H), 0.83 (s, 3H), 0.73 (s, 3H), 0.68 (m, 1 H) 3p8-0-Hydroxy-21- 1H NMR (400 MHz, CDCl 3 ): 5 oxolup-18-en-28- [ppm] 7.85 (s, 1H), 7.29 (s, oic acid N-4-amino- 1H), 6.82 (s, 1H), 3.85 (s, 1-methyl-1H- 3H), 3.30-3.27 (m, 1H), O pyrazole- 3.21-3.17 (d x d, 1H), 2.70 acetamide 2.62 (m, 2H), 2.50 (d, IH), H 2.22 (d, 1H), 2.12 (br d, 8-44 N 1H), 2.03-1.82 (m, 2H), 1.73 o N (m, 1H), 1.66-1.45 (m, 7H), H : N 1.42-1.20 (m, 6H), 1.27 (d, HO H 3H), 1.23 (d, 3H), 0.98 (s, 3H), 0.95 (s, 3H), 0.94 (s, 3H), 0.95 (m, 1H), 0.84 (s, 3H), 0.74 (s, 3H), 0.69 (m, 1 H) 3p8-0-Hydroxy-21- 1H NMR (400 MHz, CDCl 3 ): 6 oxoLup-18-en-28- [ppm] 7.67 (br s, 1H), 6.74 oic acid N-4,6- (s, 1H), 3.32 (m, 1 H), 3.19 O dimethyl- (d x d, 1H), 2.75 (m, 2H), pyrimidin-2-yi- 2.63 (d, 1H), 2.42 (s, 6H), H H acetamide 2.21 (d, 1H), 2.10 (br d, 8-45 N N 1H), 2.03-1.90 (m, 2H), 1.74 O N (i, 1H), 1.66-1.45 (m, 6H), 1.41-1.17 (m, 7H), 1.31 (d, HO H 3H), 1.24 (d, 3H), 1.0 (s, 3H), 0.95 (s, 6H), 0.85 (m, 1H), 0.84 (s, 3H), 0.73 (s, 3H), 0.69 (m, 1H) WO 2009/082818 PCT/CA2008/002290 62 38-0- Hydroxy-21 0 oxoup-18-en-28 H H oic acid N-pyrazin- LC/MS: 15.85 min. 8-46 N N 2-yi-acetamide (Method a) H NM+H* 548.17
-
N) HH 3p8-0-Hydroxy-21- 1 H NMR (400 MHz, CDCl 3 ): 8 oxolup-18-en-28- [ppm] 8.70 (br s, 2H), 8.02 oic acid N-quinolin- (br d, 1H), 7.76 (d, 1H), 3-yl-acetamide 7.61 (m, 1H), 7.52 (m, 1H), O hydrochloride 3.30 (m, 1H), 3.14 (d x d, 1H), 2.72 (m, 2H), 2.58 (d, H H 1H), 2.28 (d, 1H), 2.03 (br 8-47 N d, 1H), 1.90 (m, 2H), 1.68 H o (m, 1H), 1.61-1.33 (m, 6H), 1.39-1.08 (m, 7H), 1.28 (d, H 3H), 1.22 (d, 3H), 0.95 (s, 3H), 0.93 (s, 3H), 0.90 (s, 3H), 0.85 (m, 1H), 0.78 (s, 3H), 0.68 (s, 3H), 0.65 (m, 1 H) 3p8-0-Hydroxy-21 oxoLup-18-en-28- 1H NMR (400 MHz, CDCL 3 ): 8 oic acid N-(2- [ppm] 3.46 (br s, 1H), 3.22 o pyrrolidin-1-yi- (m, 3H), 2.66 (m, 6H), 2.39 H ethyl)-acetami (d, 1H), 2.15 (d, 1H), 2.0 8-48 N de (m, 1H), 1.91-1.72 (m, 7H), 1.69-1.24 (m, 5H), 1.22 (d, H 3H), 1.20 (d, 3H), 1.19-1.08 HO H (m, 9H), 1.0 (s, 3H), 0.95 (s, 3H), 0.91 (s, 3H), 0.88-0.81 (m, 1H), 0.86 (s, 3H), 0.74 (s, 3H), 0.68 (m, 1H) 0 33-0-Hydroxy-21 oxotup- 1 8-en-28 H H oic acid N-(5- LC/MS: 13.7 min. 8-49 N 0 methyl- (Method a) 0 N ON [1,3,4]oxadiazol-2- M+H* 552.11 H N yl) HO H acetamide 3pI-0-Hydroxy-21- 1H NMR (400 MHz, CDCl 3 ): 6 oxoLup-18-en-28- [ppm] 9.30 (s, 1H), 9.24 (s, oic acid N- 1H), 8.29 (d, 1H), 8.07 (t, isoquinoin-4-y- 1H), 7.92 (t, 1H), 7.66 (d, 0 acetamide 1H), 3.34 (m, 1H), 3.14 (d x H / d, 1H), 2.78 (m, 1H), 2.70 8-50 N (m, 1H), 2.63 (d, 1H), 2.37 (d, 1H), 1.99-1.81 (m, 3H), H O 1 N 1.68-1.10 (m, 14H), 1.34 (d, HO 3H), 1.24 (d, 3H), 0.97 (s, 3H), 0.96 (s, 3H), 0.91 (s, 3H), 0.91-0.79 (m, 1H), 0.78 (s, 3H), 0.69 (s, 3H), 0.64 (m, IH) WO 2009/082818 PCT/CA2008/002290 63 3p8-0-Hydroxy-21 oxolup-18-en-28- 1H NMR (400 MHz, CDCI 3 ): 6 oic acid N- [ppm] 8.86 (s, 1H), 8.61 (br pyrimidin-4-y- s, 1H), 8.28 (br s, 1H), 7.92 0 acetamide (br s, 1H), 3.31 (m, 1H), H / CIH 3.14 (m, 1H), 2.49 (d, 1H), 8-51 N 2.68-2.37 (m, 3H), 2.24 (d, 5 I,,,,1H), 2.04-1.77 (m, 5H), H 0 N N 1.68 (m, 1H), 1.61-1.11 (m, HO 9H), 1.26 (d, 3H), 1.19 (d, 3H), 0.93 (s, 3H), 0.91 (s, 3H), 0.91 (s, 3H), 0.91-0.79 (m, 1H), 0.78 (s, 3H), 0.69 (s, 3H), 0.64 (m, 1H) 3p6-0-Hydroxy-21 oxolup-18-en-28- 1H NMR (400 MHz, CDC1 3 ): 8 oic acid N-2- [ppm] 8.06 (d, 1H), 7.52 (m, trifluoromethyt- 2H), 7.43 (s, 1H), 7.15 (m, O phen-1-yl 1H), 3.26 (m, 1H), 3.14 (m, F F acetamide 1H), 2.72 (m, 1H), 2.53 (d, H H 1H), 2.21 (d, 1H), 2.01 (m, 8-52 N 1H), 1.93-1.75 (m, 2H), H 0 1.69 (m, 1H), 1.63-1.40 (m, HO 6H), 1.36-1.10 (m, 7H), 1.20 H (d, 3H), 1.18 (d, 3H), 0.92 (s, 3H), 0.91 (s, 3H), 0.90 (s, 3H), 0.96-0.76 (m, 1H), 0.79 (s, 3H), 0.69 (s, 3H), 0.64 (m, 1H) 0 33-0-Hydroxy-21 oxolup-18-en-28- 1H NMR (400 MHz, CDCL 3 ): 8 H / H / oic . acid N-(1- [ppm] 3.30-3.00 (, 6H), 8-53 N N, methyl-1H- 2.70-0.62 (m, 12H), 1.20 (d, I N tetrazol-5-yl)- 3H), 1.16 (d, 3H), 0.91 (br s, HO H N acetamide 9H), 0.83 (s, 3H), 0.70 (s, HO 3H) 3,-0-Iyd roxy- 21 - 1H NMR (400 MHz, CDCl 3 ): 6 oxolup-18-en-28- [ppm] 5.23 (t, 1H), 3.2-3.02 0 oic acid N- (in, 3H), 2.81 (in, 1H), 2.57 H cyclopropylmethyt (d x d, 1 H), 2.48 (in, 1 H), N acetamide 2.28 (d, 1H), 2.0 (d, 1H), 8-5 1.92-1.31 (in, 12H), 1.24 H - 0 1.06 (in, 10H), 0.78-0.67 (in, HO 14H), 0.60 (s, 3H), 0.54 (br d, 1H), 0.33 (, 2H), 0.02 (in, 2H) 3p8-0-Hydroxy-21- 1H NMR (400 MHz, CDCIA: 6 0 oxoLup-18-en-28- [ppm] 3.19 (m, 2H), 2.64 oic acid N- (i, 2H), 2.47 (d, 1H), 2.21 azetidine-1 2.13 (in, 3H), 2.03-1.86 (i, 8-55 N~J acetamide 5H), 1.74 (i, 1H), 1.68-1.4 H0 (, 8H), 1.36-1.24 ((M , 4H), 1.2-1.14 (, 8H), 1.04 (s, HO H 3H), 1.0-0.86 (i, 1OH), 0.75 (s, 3H), 0.68 (brd, 1H) WO 2009/082818 PCT/CA2008/002290 64 0 3p-0-Hydroxy-21 oxolup-18-en-28 H H oic acid N-(2,2,2- HPLC: 24.46 min. 8-56 N trifluoro-ethyl)- (Method A) F F acetamide LCMS: M+H* 552.3 F HO H HOO 3p8-0-Hydroxy-21- 1H NMR (400 MHz, CDCI 3 ): 8 0 oxolup-18-en-28- [ppm] 8.82 (d, 1H), 7.85 (s, H I F oic acid N-4- 1H), 7.29 (d, 1H), 6.93 (br s, 8-57 N N trifluoro-pyrimidin- 1H), 3.31-3.26 (i, 1H), 3.14 2-yl-acetamide (i, 1H), 2.68 (br d, 1H), [ppm](d, 1 H), 2.24-1.24 (s, HO H 23H), 1.00-0.83 (m, 13H), 0.73 (s, 3H), 0.68 (d, 1H) 0 3p6-0-Hydroxy-21 oxolup-18-en-28 H H oic acid N-(1- LC/MS: 11.39 min. 8-58 N 8-58 N cyclopropyl- 1- (Method b) O methyl-ethyl)- M+H* 552.41 acetamide HO 0 3/-0-Hydroxy-21 N oxoLup-18-en-28 H / oic acid N- (4- LC/MS: 9.17 min. 8-59 N dimethylamino- (Method a) O piperidin-1-yl)- M+H* 581.49 acetamide HO O 3p6-0-Hydroxy-21 oxolup-18-en-28 H H F oic acid N-(2,2,2- LC/MS: 10.26 min. 8-60 N F trifluoro-1 -methyl- (Method b) S ethyl)-acetamide M+H* 566.32 HO z HO 38-0-Hydroxy-21 0 oxoLup-18-en-28 H H oic acid N-(5- LC/MS: 7.06 min. 8-61 N s ehl (Method b) I N [1,3,4]thiadiazol-2- H* 568.31 H = N yl)-acetamide HO -HH 0 33-0-Hydroxy-21 oxolup-18-en-28 oic acid N-(2,2,2- LC/MS: 11.51 min. 8-62 0trifluoro-1,1- (Method b) HN: dimethyl-ethyl)- M+H* 580.42 HO acetamide F F F 3p-0-Hydroxy-21 oxolup-18-en-28 oic acid N-tert- LC/MS: 11 min. 8-63 0 butyl-N-methyl- (Method b) N, acetamide M+H* 540.39
HO
WO 2009/082818 PCT/CA2008/002290 65 3pl-0-Hydroxy-21- 1H NMR (400 MHz, CDC1 3 ): 8 0 oxolup-18-en-28- [ppm] 7.4 (br s, 1H), 3.8 (br oic acid N-(R)-2- m, 1H), 3.58 (i, 1H), 3.37 0 acetylaminomethyl (i, 1H), 3.29-3.16 (i, 3H), 8-64 HN, -pyrrolidine 3.0 (i, 1H), 2.8 (br d, 1H), HO 0 -1-carboxylic acid 2.57 (i, 1H), 2.37 (d, 1H), ( jN AO tert-butyl ester 2.13-2.02 (in, 2H), 1.87-1.16 (in, 33H), 1.0-0.79 (in, 14H), _______________________0.74 (s, 3H), 0.68 (br d, 1H) 3,8-0-Hydroxy-21 - 1H NMR (400 MHz, CDC1 3 ): 5 0 oxotup-18-en-28- [ppm] 7.4 (br s, 1H), 3.8 (br oic acid N-(S)-2- m, 1H), 3.58 (m, 1H), 3.37 acetylaminomethyL (m, 1H), 3.29-3.16 (m, 3H), 8-65 -pyrrolidine 3.06 (m, 1H), 2.71 (br d, -1-carboxytic acid 1H), 2.56 (mi, 1H), 2.39 (d, H tert-butyl ester 1H), 2.13-2.02 (, 2H), ( )1.87-1.16 (in, 33H), 1.0-0.79 (i, 14H), 0.74 (s, 3H), 0.68 (brd, 1 H) 0 33-0-Hydroxy-21 H oxolup-18-en-28- HPLC: 27.12 mi. 86 4 .00oic acid N-(4,4 -66 ~~difluoro- (ehdA H HN>cyclohexyl)LCM:MH582 H acetamide 0 3,8-O-Hydroxy-21 oxotup-1 8-en-28 oic acid N-2- LCMS: 19.18 mi. 8-67 0chlorophenl1 l(Method a) - HN aeai M+H+ 580.34 HO N O 0 3,8-O-Hydroxy-21 oxotup-1 8-en-28 0oic acid N-2- LC/MS: 18.67 min. 8-68 HNisopropyl-phen- 1-yt (Method a) - Nacetamide M+HW 588.44 3,6-O-Hydroxy-21- 1H NMR (400 MHz, CDCl 3 ): 8 oxotup-18-en-28- [ppm] 7.33 (d x d, 2H), 7.0 0 oic acid N-4-fluoro- (d x d, 2H), 6.92 (s, 1H), phen-1-yL 3.30 (sept., 1H), 3.18 (d x d, 8-69 0 acetamide 1H), 2.71 (m, 2H), 2.55 (d, trHNtu 1H), 2.23 (d, 1H), 2.03-1.85 HOV (mn, 3H), 1.74-1.22 (mn, 15H), F 1.0-0.93 (m, 13H), 0.86-0.81 (m, 7H), 0.74 (s, 3H), 0.69 (b, 1H) O 3-0-Hydroxy-21 oxoLup-18-en-28- HPLC: 22.01 mi. 8-70 . oic - acid N- (Method A) HN quinazoin-2-yL LC/MS: M+H* 598.41 HO F acetamide HO N WO 2009/082818 PCT/CA2008/002290 66 O 3p8-0-Hydroxy-21 oxolup-18-en-28- HPLC: 16.12 min. 8-71 0 oic acid N-(1- (Method A) - HN methyl-i H HN N tetrazol-3-yi)- LC/MS: M+H* 552.3 HO N N acetamide o 3p6-0-Hydroxy-21 oxolup-18-en-28- LC/MS: 14.9 min. 8-72 - oic acid N-(5- (Method a) HN ~~methyl-isoxazol-3- MH 5. HI/ H yi)-acetamide MH 5. HO
-
N 3p-0-Hydroxy-21- 1H NMR (400 MHz, CDCL 3 : 8 oxolup-18-en-28- [ppm] 7.25-7.18 (i, 4H), oic acid N-(1,3- 7.05 (d, 1H), 4.83 (d x d, dihydro-isoindol-2- 2H), 4.40 (d x d, 2H), 3.21 yL)-acetamide (sept., 1H), 3.13 (i, 1H), 8-73 0 2.75 (, 1H), 2.52 (br d, 7 H), 2.48 (d, 1H), 2.19 (d, 1H), 1.97 (d, 2H), 1.80 (in, 1H), 1.66 (i, 1H), 1.61-1.18 (in, 13H), 0.94-0.88 (m, 10H), 0.85-0.76 (m, 7H), 0.68 (s, 3H), 0.63 (m, 1H) o 3p8-0-Hydroxy-21 oxolup-18-en-28 0 oic acid N-(4,4- HPLC: 27.54 mi. difluoro- HPLC: 2 m 8-74 HN cyclohexylmethyl)- (Method A) HO acetamide LC/MS: M+H* 602.58 F F 3pl-0-Hydroxy-21 0 oxolup-18-en-28 H /oic acid N-4,4- HPLC: 28.62 min. difluoro-piperidine (Method A) 8-75 acetainide (ehdA H a N LC/MS: M+H* 574.47 HO F F Table 3. Cpd# Structure Compound name tR (min.) M+/M+H* (Method) O 3p8-0-(3',3' Dimethylsuccinyl)-21 H H oxolup-18-en-28-oic 9-2 N acid N-methylamide 24.7 612.70 HO 0NHi 0 (A) 0 0 WO 2009/082818 PCT/CA2008/002290 67 O 3,-0-(3',3' Dimethylsuccinyl)-21 H H oxoLup-18-en-28-oic 9-3 N acid N-isopropylamide 31.86 640.59 HO (A) 0 0 O 3p8-0-(3',3' Dimethylsuccinyl)-21 H H oxolup-18-en-28-oic 9-4 N acid N- 30.78 680.78 HO H 0 cyclohexylamide (B) 0 0 O3p-0-(3',3' DimethylsuccinyL)-21 H H oxolup-18-en-28-oic N 9-5 acid N-cyclohexyl 32.35 694.83 O o methylamide (B) HO .0 O 3p-0-(3',3' Dimethylsuccinyl)-21 H oxolup-18-en-28-oic 9-6 N acid N-piperidiny 28.63 ND O 0 acetamide (B) HO 0 o 3,8-0- (3', 3' H Dimethylsuccinyl)-21 OXOlup-18-en-28-oic 9-7 acid N-morpholyl 20.17 668.75 HO H 0 acetamide (B) 0 0 0 3,8-0-(3',3' Dimethylsuccinyl)-21 H N oxolup-18-en-28-oic 9-8 N acid N-(4-acetyl 20.53 709.56 0 0 piperazinyl) -o0 acetamide(A o f 0 0 3#l-0-(3',3' H/ N Dimethylsuccinyl)-21 N oxoLup-18-en-28-oic 9-9 acid N-(4-methy 18.13 681.80 HO H HO 0 H3 0piperazinyL) (C) O acetamide 0 0 3pl-0-(3',3' Dimethylsuccinyl)-21 H H oxoLup-18-en-28-oic 9-10 N 0 N ' acid N-benzamide 36.48 674.56 HO 0 H 0 (A) o WO 2009/082818 PCT/CA2008/002290 68 O 3p8-0-(3',3' Dimethylsucciny)-21 H oxolup-18-en-28-oic N 9-11 acid N-methyl-N- 29.85 702.74 O 0 HO O benzylamide (B) O O 0 O 3p-0-(3',3' Dimethylsuccinyl)-21 H H oxolup-18-en-28-oic 9-12 O acid N-2-chloro- 28.65 722.41 HO 0 H CI benzylamide (B) O 0 O 3p8-0-(3',3' DimethylsuccinyL)-21 H H oxoLup-18-en-28-oic 9-13 N 9-13 acid N-3-chloro- 27.88 722.75 HO 0 H O C benzylamide (B) O CI 0 O 38-0-(3',3' Dimethylsuccinyl)-21 H H oxotup-18-en-28-oic 9-14 acid N-4-chloro- 37.46 722.68 HO 0 O benzylamide (A) OO 0 C O 3,p-0-(3',3' DimethylsuccinyL)-21 H H oxolup-18-en-28-oic N 9-15 H acid N-4-methoxy- 32.24 718.71 HO O benzylamide (A) 0 O 3p8-0-(3',3' Dimethylsucciny)-21 H H oxolup-18-en-28-oic N 9-16 acid N-pyridin-2- 23.68 689.67 HO O O N ytmethytamide (C) O 0 O 3p8-0-(3',3' DimethylsuccinyL)-21 H H oxoLup-18-en-28-oic 9-17 N acid N-pyridin-3- 24.03 689.76 0 HO 0 N ylmethylamide (C) 0N 0 WO 2009/082818 PCT/CA2008/002290 69 O3p-0-(3',3' DimethylsuccinyL)-21 H H oxoLup-18-en-28-oic N 9-18 acid N-pyridin-4- 21.4 689.74 HO H ylmethylamide (C) 0 o3p8-0- (3', 3' Dimethylsucciny)-21 H H oxotup-18-en-28-oic 9-19 N acid N-[2-(4-methoxy- 34.24 732.69 0 H o phenyl)-ethyl]- (A) O = acetamide 0 O OO o 3p8-0-(3',3' Dimethylsuccinyl)-21 H H oxolup-18-en-28-oic N 9-20 0 acid N-(2- 29.39 641.91 HO NH acetylamino-ethyl)- (A) (M-Boc) O 0)o carbamic acid tert 0 butyl ester O 3)6-0-(3',3' H H DimethylsuccinyL)-21 H H oxolup-18-en-28-oic 9-21 N acid N-(2-amino- 26.23 641.68 S H 0 NH 2 CH ethyl)-acetamide (D) HO O hydrochloride 0 O 3p-0-(3',3' DimethylsuccinyL)-21 H H oxolup-18-en-28-oic 9-22 N acid N-(2- 9.60 683.50 o 0 HOH HOO NH acetylamnino- ethyl) - (B) H 0 acetamide 0 O 3p-0-(3',3' Dimethylsuccinyl)-21 H H oxolup-18-en-28-oic 9-23N acid N-[2-(3-isopropyl oNH ureido)-ethyl]- 12.44 726.67 O0 1 NH acetamide (B) O 36-0-(3',3' Dimethylsuccinyl)-21 H H oxolup-18-en-28-oic N 9-24 acid N-(2- 20.90 699.65 HO H NH acetylamino-ethyl)- (A) 0 o'0 carbamic acid methyl ester WO 2009/082818 PCT/CA2008/002290 70 O 3p8-0-(3',3' Dimethylsuccinyl)-21 H H oxoLup-18-en-28-oic 9-25 N acid N-pyridin-2-yl- 29.51 675.63 HO 0 N acetamide (A) 0 0 3f-0-(3',3' DimethylsuccinyL)-21 H H oxoLup-18-en-28-oic 9-26 N 1 acid N-pyridin-3-y- 30.29 675.66 HO O O N acetamide (C) O 0 0 0 3p8-0-(3',3' AN Dimethylsuccinyl)-21 H / N o oxolup-18-en-28-oic 9-27 N acid N-1-acetyl- 37.78 767.75 O 0 piperazine-4- (A) HO carboxylic acid tert obutyl ester IO o3p8-0- (3',3' Dimethylsuccinyl)-21 H NH oxolup-18-en-28-oic 9-28 N OH acid N-piperazinyl- 28.08 667.92 o 0 acetamide H O hydrochloride 0 O 3p8-0-(3',3' OH Dimethylsuccinyl)-21 H N oxoLup-18-en-28-oic 9-29 acid N-1-(4-hydroxy- 29.72 682.69 0 o piperidin-1-yl)- (E) HO O acetamide 0 0 3p6-0-(3',3' Dimethylsuccinyl)-21 H H oxoLup-18-en-28-oic O O N O acid N-1-acetylamino- (A) (M-Boc) 0 H 0 NO (-Bc HY piperidine-4 0H 0 carboxylic acid tert 0 butyl ester o 36-0-(3',3' Dimethylsucciny)-21 H oxoLup-18-en-28-oic 9-31 N acid N-(4- 27.23 681.61 0 )o NH aH aminopiperidine)- (D) 0 pacetamide 0 hydrochloride WO 2009/082818 PCT/CA2008/002290 71 ,3p-0-(3',3' Dimethylsuccinyt)-21 H H oxoLup-18-en-28-oic 9-32 N acid N-(1-acetyl-4- 28.07 723.65 o H o N aminopiperidine)- (E) 0 0 acetamide 0 O 3p8-0-(3',3' Dimethylsuccinyl)-21 H H OXOlup-18-en-28-Oic 9-33 N acid N-(1-phenyl- 37.72 702.55 O 0 ethyl)-acetamide (A) HO o 0 3p-0-(3',3 DimethylsuccinyL)-21 H oxoLup-18-en-28-oic N 9-34 acid N-(1-methyl-1- 41.07 716.53 0 H 0 phenyl-ethyl)- (A) Ho O acetamide 0 O 38-0-(3',3' DimethylsuccinyL)-21 H H oxolup-18-en-28-oic 9-35 acid N-(tert-butyl)- 39.85 654.59 HO 0 acetamide (A) 0 0 38-0-(3',3' O 0 Dimethylsuccinyl)-21 H N oxolup-18-en-28-oic 9-36 N acid N-(8-amino-3,8- 31.16 797.67 O 0 diaza 0 -bicyclo[3.2. 1]octane- (A) 0 H3-benzamide) acetamide 0 3,6-0-(3', 3' H / NH Dimethylsuccinyt)-21 937NH 0 oxoLup-18-en-28-oic 9-37 N o acid N-4-piperazi-2- 4.43 681.81 H O one-acetamide (F) HO 0 O 3p8-0-(3',3' Dimethylsucciny)-21 H H oxoLup-18-en-28-oic 9-38 NTN acid N-pyrimidin-2-y- 22.09 676.54 HO H acetamide (A) "0 0 WO 2009/082818 PCT/CA2008/002290 72 o o 3p-0-(3',3' N NH DimethylsuccinyL)-21 H rN E oxoLup-18-en-28-oic 9-39 N acid N-(4-N'- 24.34 752.70 o isopropylureido-1- (A) Ho 0 piperaZine)-aCetamide 0H 0 o 0 38-0-(3',3' NA Dimethylsuccinyl)-21 9-0N oxoLup-18-en-28-oic 9-40 acid N-1-acetyl- 27.92 726.03 H o piperazine-4- (A) H 4 carboxylic acid methyl 0 ester 38-0-(3',3'- 1H NMR (400 MHz, Dimethylsuccinyl)-21- CDCl 3 ): 8 [ppm] 4.49 oxolup-18-en-28-oic (m, 3H), 3.65 (m, 1H), acid N-(4-amino 3.16 (m, 1H), 3.07 carboxylic acid tert- 2.60 (m, 6H), 2.68 (d, 0 Hbutyl-ester-1- 1H), 2.56 (d, 1H), Ho piperidine)-acetamide 2.43 (d, 1H), 2.22 (d, N 1H), 2.15-1.83 (m, 9-41 0 8H), 1.76-1.55 (m, H 9H), 1.52-1.47 (m, O H 1H), 1.42 (s, 9H), 1.29 0 (s, 3H), 1.28 (s, 3H), 1.22 (d, 3H), 1.37-1.16 (m, 3H), 1.13 (d, 3H), 0.99 (s, 3H), 0.95 (m, 3H), 0.88 (s, 3H), 0.83 (s, 3H), 0.80 (s, 3H) o 3p-0-(3',3' DimethylsuccinyL)-21 H oxoLup-18-en-28-oic 9-42 N F acid N-(4-amino-1- 17.47 681.83 0 F piperidine)-acetamide H :F triftuoroacetic acid H 0 O 3p-0-(3',3' r r Dimethylsuccinyl)-21 H N oxoLup-18-en-28-oic 9-43 acid N-(4- 5.23 ND O 0 acetylamino-1- (F) H piperidine)-acetamide 0 o 3p0-0- (3', 3' N N Dimethylsuccinyt)-21 N H N oxotup-18-en-28-oic 9-44 acid N-[(4-amino-N'- 32.19 767.33 O H 0 isopropylureido)-1- (E) O 0piperidine]-acetamide 0 WO 2009/082818 PCT/CA2008/002290 73 H 3p8-0-(3',3' NO, Dimethylsuccinyl)-21 H N y oxotup-18-en-28-oic 9-45 acid N-(4- amino 34.86 740.09 H carboxylic acid methyl (E) H ester-1-piperidine) 0 acetamide o 3p8-0- (3', 3' N'~ Dimethylsuccinyt)-21 H oxoLup-18-en-28-oic 9-46 0 acid N-4-(1 -methyl- 29.21 695.85 H o piperazi-2-one)- (E) HO O acetamide 0 O 3p8-0-(3',3' Dimethylsuccinyl)-21 H H oxolup-18-en-28-oic 947 N 9-47 acid N-2-methyl-phen- 36.94 688.89 HO H -yl acetamide (A) 0 O 3p-0-(3',3' Dimethylsuccinyl)-21 H H oxoLup-18-en-28-oic 9-48 N acid N-3-methyl-phen- 39.06 688.81 0 0 1-yl acetamide (A) HoO 0 O 3,#-0-(3',3' Dimethylsuccinyl)-21 H OXOlup-18-en-28-Oic 9-49 N acid N-4-methyt-phen- 38.63 688.81 0 o 1-yl acetamide (A) * 0 H 0 3p8-0-(3',3' O o Dimethylsuccinyl)-21 H / N 0 oxolup-18-en-28-oic 9-50 N acid N-8-acetylamino- 30.02 ND 0 0 3,8-diaza- (B) 0 bicyc[o[3.2.1]oc 0 tane-3-carboxylic acid tert-butyl ester O 3p8-0-(3',3' Dimethylsucciny)-21 H H oxotup-18-en-28-oic 9-51 1 N acid N-pyrimidin-5-yt- 24.8 676.79 HO o 0 N acetamide (A) HOH 0 O 3p8-0-(3',3' Dimethylsuccinyt)-21 oxolup-18-en-28-oic 9-52 O N acid N-pyridin-4-yt- 22.21 675.72 HO acetamide (C) 0 0 WO 2009/082818 PCT/CA2008/002290 74 O3p-0-(3',3' Dimethylsuccinyt)-21 H H oxolup-18-en-28-oic 9-53 N NN_ acid N-3-amino-1- 26.79 678.74 H o methyt-1H-pyrazole- (A) HO acetamide HO O 0 O 3p-0-(3',3' Ha Dimethylsuccinyl)-21 H H / oxoLup-18-en-28-oic 9-54 N NN acid N-5-amino-1- 6.77 678.59 H o methyl-1H-pyrazole (F) HO acetamide o H hydrochloride O3p-0-(3',3' Dimethytsucciny)-21 H H OH oxolup-18-en-28-oic 9-55 N N acid N-4-methyl- 23.92 690.78 O a o N-) pyrimidin-5-yl- (A) HO acetamide 0 H hydrochloride O 38-0-(3',3' OH Dimethylsuccinyl)-21 H H oxotup-18-en-28-oic 9-56 N N acid N-4-methyl- 24.1 690.77 o 0 N / pyrimidin-2-yl- (A) o acetamide 0 hydrochloride o 3p-0-(3',3' aH Dimethylsuccinyl)-21 H H oxotup-18-en-28-oic 957 N 9-57 N N- acid N-4-amino-1- 23.1 678.67 oN, methyl-1H-pyrazole (A) HO O acetamide O H hydrochloride o 3p-0-(3',3' CH Dimethylsuccinyl)-21 H oxolup-18-en-28-oic 9-58 N acid N-4,6-dimethyl- 26.18 704.83 o N pyrimidin-2-y- (A) o acetamide 0 hydrochloride o 36-0- (3',3' Dimethylsuccinyl)-21 H H oxolup-18-en-28-oic 9-59 N N acid N-pyrazin-2-yl- 30.74 676.67 H O - acetamide (A) HO 0 WO 2009/082818 PCT/CA2008/002290 75 o 3p-0-(3',3' Dimethylsuccinyl)-21 H H oxolup-18-en-28-oic 9-60 N N N acid N-quinolin-3-y- 11.63 724.99 o = o acetamide (G) HH N hydrochloride 0 o 38-0-(3',3' H / H Dimethylsuccinyl)-21 H H oxoLup-18-en-28-oic 9-61 N N acid N-(2-pyrrolidin-1- 19.22 695.83 o 0 y-ethyt)-acetamide (C) H hydrochloride 0 o 38-0-(3', 3' Dimethylsuccinyl)-21 H H oxoLup-18-en-28-oic 9-62 N 0 acid N-(5-methyl- 9.28 680.69 o 0 N'N [1,3,4]oxadiazol-2-yl)- (G) H acetamide 0 o 3p-0-(3',3' Dimethylsuccinyl)-21 H oxolup-18-en-28-oic 9-63 N acid N-isoquinolin-4- 8.37 725.99 o o N yl-acetamide (G) Ho OH hydrochloride 0 o 3p-0-(3',3' CIH Dimethylsucciny)-21 HH OH oxolup-18-en-28-oic 9-64 acid N-pyrimidin-4-yl- 11.25 676.68 O N N acetamide (G) H hydrochloride 0 o 3p6-0-(3',3' F F Dimethylsuccinyl)-21 H 96H oxolup-18-en-28-oic 9-65 N acid 31.23 HO o O trifluoromethyl-phen- (B) A 1 -yl acetamide 0 o 3p-0-(3',3' Dimethylsuccinyl)-21 H H / oxolup-18-en-28-oic 24.28 9-66 N N N acid N-(1-methyl-1H- 680.76 HO O0O N_' tetrazol-5-yl)- (A) 0 acetamide 0 H Dimethylsuccinyl)-21 H N oxolup-18-en-28-oic 967 acid N-(4-amino 19.22 7.54.17 H carboxylic acid ethyl (B) 0 H ester-1-piperidine) acetamide WO 2009/082818 PCT/CA2008/002290 76 3p6-0-(3',3' Dimethylsuccinyl)-21 H 9-8 oxoLup-18-en-28-oic 9-68 N 0 acid N-(4-amino (B) 768.33 0 carboxylic acid (B) 0 H isopropyl ester-1 - Opiperidine)-acetamide o 3p-0-(3', 3' H / Dimethylsuccinyl)-21 9-69 N oxolup-18-en-28-oic 22.90 acid N- (B) 652.69 HO 0 H 0 cyclopropylmethy o acetamide 0 0 3p-0-(3',3' DimethylsuccinyL)-21 H / I oxotup-18-en-28-oic 9-70 N- acid N-azetidine-1 18.56 638.61 o 0 acetamide (B) HO O O 3p8-0-(3',3' H F Dimethylsuccinyt)-21 9-71 H F oxoLup-18-en-28-oic 31.30 o =i F acid N-(2,2,2- (A) 680.80 HO 0 H : 0 trifluoro-ethyl) O H acetamide 0 3- 0-(3',3' H F DimethylsuccinyL)-21 9-7F oxotup-18-en-28-oic 9HN F acid N-4-trifluoro- 745.18 Spyrimidin 0 acetamide 0 OO o 3p8-0-(3',3' Dimethylsuccinyt)-21 973 N oxotup-18-en-28-oic 32. o-73 o acid N-(1-cycLopropy- (B) 680.83 HO H 01-methyl-ethyl) O H acetamide 3p8-0-(3',3' Dimethy(succiny)-21 H N oxoLup-18-en-28-oic 09H740acid N-(4- (C) 710.01 HO o H 0 dimethylamino-P Ho j O pjperidin-1-y() 0 acetamide 0 3p6-0-(3',3' H / F Dimethylsuccinyl)-21 9-75 H F oxoLup-18-en-28-oic F acid N-(2,2,2- (H) 694.88 HO H : trifluoro-1 -methyl 0 H ethyl)-acetamide WO 2009/082818 PCT/CA2008/002290 77 0 3p-0-(3',3' Dimethylsuccinyt)-21 H H oxolup-18-en-28-oic 9.01 9-76 N acid N-(5-methyl- ('H) 696.92 O O N-N [1,3,4]thiadiazol-2 O yl)-acetamide 0 3,-0-(3',3' Dimethylsuccinyl)-21 0 oxolup-1 8-en-28-oic 9-77 acid N-(2,2,2- 30.11 709.02 O HN trifluoro-1,1-dimethy- (B) HO O F ethyl)-acetamide - Yj F ,F O F O 3p-0-(3',3' Dimethylsuccinyl)-21 0 oxolup-18-en-28-oic 9-78 0 acid N-tert-butyl-N- 14.91 668.76 O N methyl-acetamide (H) HO O 4 HO 0 3-0-(3',3'-1H NMR (400 MHz, Dimethylsuccinyt)-21- CDCL 3 ): 5 [ppm] 7.50 0 oxolup-18-en-28-oic (i, 1H), 4.49 (i, 1H), acid N-(R)-2- 3.81 (m, 1H), 3.58 (i, acetylaminomethyl- 1H), 3.38 (m, 1H), 9-79 HO 0 0 HN pyrrolidine 3.25 (m, 2H), 3.01 (i, HO yj -1-carboxylic acid 1H), 2.80 (br d, 1H), 0 0 tert-butyl ester 2.61 (mn, 3H), 2.37 (d, 1 H), 2.07 (in, 3H), 1.45 (in, 35H), 0.99 ______________________________________(in, 4H), 0. 81 (mn, 1 H) 3fl-O-(3',3'- 1H NMR (400 MHz, Dimethylsucciny)-21 - CDCl 3 ): 6 [ppm] 7.41 0 oxotup-18-en-28-oic (m, 1H), 4.48 (d x d, acid N-(S)-2- 1H), 3.74 (m, IH), 0 acetylaininonethyl- 3.57 (m, 1H), 3.92 (m, 9-80 0 pyrrolidine 1H), 3.24 (in, 2H), HO 04N 0 -1- carboxyLic acid 3.06 (mn, 1 H), 2.71 (br O 0 tert-butyl ester d,1 H), 2.60 (m, 3H), 41 2.40 (d, 1 H), 2.04 (in, 3H), 1.73 (m, 9H), 1.46 (m, 14H), 1.26 (m, 45H), 0.86 (m, 2H) O 0 ~ 3p-0-(3',3' DimethylsuccinyL)-21 9o81 0 0 oxoLup-18-en-28-oic 18.71 981 0 - HN> F~lI acid N-((R)-2- 681.92 HO YIU0 HN,,- F F pyrrolidine2 trifluoroacetic acid WO 2009/082818 PCT/CA2008/002290 78 3p8-0-(3',3' Dimethylsuccinyl)-21 0 0 oxoLup-18-en-28-oic 18.60 9-82 OHHN OH acid N-((S)-1- 681.93 HO O F pyrrolidin-2 0NH ylmethyl)-acetamide trifluoroacetic acid O 3p-0-(3',3' Dimethylsucciny)-21 oxolup-18-en-28-oic 9-83 acid N-((R)-1-methyl- 19.04 695.99 SHN pyrrolidin-2-ymeth (C) HO O yl)-acetamide 0 N O 3,-0-(3',3' Dimethytsuccinyt)-21 0 oxotup-18-en-28-oic 9-84 acid N-((S)-1-methy- 19.01 696 O HN pyrrolidin-2-ytmeth (C) HOY ON' yl)-acetamide OO O 3p8-0- (3', 3' H Dimethylsucciny)-21 9-85 0 oxolup-18-en-28-oic 11.57 9-85 acid N-(4,4-difluoro- (H)711 HO O - cyclohexyl) acetamide 0 H 0 F O 38-0-(3',3' Dimethylsuccinyl)-21 oxoLup-18-en-28-oic 9-86 acid N-2-chloro-phen- 15.20 708.92 0 - HN 1-yl acetamide (H) HO O 0 O 3p-0-(3',3' Dimethylsuccinyt)-21 oxolup-18-en-28-oic 9-87 acid N-2-isopropyl- 14.11 717.05 HO O HN phen-1-y acetamide (H) HOO . O 0 O 3p-0-(3',3' DimethylsuccinyL)-21 9-88 0 oxotup-18-en-28-oic 35.60 acid N-4-fluoro-phen- 693 HOz HNa(A HO - HN F 1-yl acetamide 0 F O 38-0-(3',3' Dimethylsuccinyl)-21 9-89 0 oxolup-18-en-28-oic 29.02 727.08 N acid N-quinazolin-2-yl (A) HO acetamide O 0 Nj 0 WO 2009/082818 PCT/CA2008/002290 79 0 3p-0-(3',3' DimethylsuccinyL)-21 9-90 0 oxoLup-18-en-28-oic 31.85 9 £ acid N-(1-methy-1H- (E) 680.80 HO O HN N tetrazol-3-y) O N N acetamide 0 O 3p-0-(3',3' DimethylsuccinyL)-21 9-91 0 oxoLup-18-en-28-oic 11.36 acid N-(5-methyl- 679.81 HO I isoxazol-3-yL) O N'o acetamide 0 DimethylsuccinyL)-21 / oxotup-18-en-28-bic 0 acid N-(1,3-dihydro- 13.17 701.07 9 N isoindot-2-yl)- (H) HO O acetamide a 0 DimethylsuccinyL)-21 0 oxoLup-18-en-28-oic O acid N-(4,4-difluoro 9-93 a HN cyclohexyLmethyl)- 11.6 731.22 HO 0 acetamide (H) 0 F F 0 3p-0-(3',3' DimethylsuccinyL)-21 H oxoLup-18-en-28-oic 9-94 0 acid N-4,4-difluoro- 12.24 703.02 N0- piperidine acetamide (H) H N-H HO 0 - Yj H 0 F F 0 3p8-0-(3',3' DimethylsuccinyL)-21 / oxoLup-18-en-28-oic 9-95 0 acid N-8-acetylamino- 31.4 O N 3,8-diaza- (E) 736,20 HO bicyclo[3.2.1]oc 0 N tane-3-acetamide 00 HIV Replication Activity HIV-1 Replication in MT2 ceL line with and without 30% human serum: The ceLLs are infected at a Multiciplicity of Infection (MOI) of 0.5 for 3h and then washed twice WO 2009/082818 PCT/CA2008/002290 80 with complete media to remove residual virus. Cells are then resuspended at 0.5 x 10 6 /ml in complete medium (RPMI, 10% FBS, 1% sodium pyruvate), and seeded into 96-well plates (6.25 x 10 4 /well). The cells are cultured in the presence or absence of various concentrations of test compounds in serial dilutions for 3 days at 37*C. The test compounds are serially diluted in complete medium supplemented or not with 30% human serum. After 3 days, 100 pL of cultured medium with cells are replaced with 120 pL of freshly diluted test compounds in complete medium containing or not 30% Human serum. The level of HIV-1 replication is determined at days 5 after infection by the presence of viral RT activity in harvested supernatant 10 fluid. The IC 5 0 and IC 9 0 values for the virus replication are determined by using GRAPHPAD PRISM software. The IC 50 of the compounds tested in accordance with the HIV replication activity assay MT-2 (HIVI1IB) are represented in Table 4 (without HS) and Table 5 (with 30% HS) Table 4 Cpd # MT-2 (HIVIIIB)
IC
50 range 9-1 +++ 9-2 +++ 9-3 +++ 9-4 +++ 9-5 +++ 9-13 +++ 9-19 +++ Table 5 MT-2 (HIVIIIB) with MT-2 (HIVIIIB) with Cpd # 30% HS Cpd # 30% HS
IC
5 0 range IC 5 0 range 9-6 +++ 9-52 +++ 9-7 +++ 9-53 +++ 9-8 +++ 9-54 +++ 9-9 +++ 9-55 +++ 9-10 +++ 9-56 +++ 9-11 +++ 9-57 +++ 9-12 +++ 9-58 +++ WO 2009/082818 PCT/CA2008/002290 81 9-14 +++ 9-59 +++ 9-15 +++ 9-60 +++ 9-16 +++ 9-61 +++ 9-17 +++ 9-62 ++ 9-18 +++ 9-63 +++ 9-20 +++ 9-64 +++ 9-21 +++ 9-65 +++ 9-22 +++ 9-66 ++ 9-23 +++ 9-67 +++ 9-24 +++ 9-68 +++ 9-25 +++ 9-69 +++ 9-26 +++ 9-70 +++ 9-27 +++ 9-71 +++ 9-28 +++ 9-72 +++ 9-29 +++ 9-73 +++ 9-30 +++ 9-74 +++ 9-31 ++ 9-75 +++ 9-32 +++ 9-76 +++ 9-33 +++ 9-77 +++ 9-34 +++ 9-78 +++ 9-35 +++ 9-79 +++ 9-36 +++ 9-80 +++ 9-37 +++ 9-81 +++ 9-38 +++ 9-82 +++ 9-39 +++ 9-83 +++ 9-40 +++ 9-84 +++ 9-41 +++ 9-85 +++ 9-42 +++ 9-86 +++ 9-43 +++ 9-87 ++ 9-44 +++ 9-88 +++ 9-45 +++ 9-89 +++ 9-46 +++ 9-90 +++ 9-47 +++ 9-91 +++ 9-48 +++ 9-92 +++ 9-49 +++ 9-93 +++ WO 2009/082818 PCT/CA2008/002290 82 9-50 +++ 9-94 +++ 9-51 +++ 9-95 +++ When the compounds are tested more than once, the average IC 50 is provided. MT2 (HIVIIB) IC50 + >1000nM ++ 200-999 nM +++ < 199 nM PBMCs are separated from healthy donors' blood by standard density gradient centrifugation, resuspended at a cell density of 1.5 X 106 ceLLs/ml in culture 10 medium containing 2 pg/mL of phytohaemagglutinin (PHA), and thereafter incubated for 3 days at 37 *C in a humidified 5% CO 2 atmosphere. The PHA stimulated PBMCs are adjusted at a concentration of 5x10 6 /mL and then infected with HIV-11iB at a MOI of 5.0 for 3 hours at 37 "C in a humidified 5% CO 2 atmosphere and then washed to remove any residual virus. Thereafter, cells are resuspended in culture medium supplemented with interleukin-2 (IL-2) at a concentration of 50 units/mL (2X) and seeded at a density of 0.2 X 106 cells/well into 96-well plates in the absence or presence of various concentrations of the test compound. Then, infected-cells are cultured for 4 days at 37 "C in a humidified 5% CO 2 atmosphere in the absence or presence of 30% human serum after which an aliquot of cultured 20 medium supernatant is replaced with fresh medium supplemented with human serum (when necessary) containing the serially diluted test compound. The IC 50 and IC 9 0 values for the virus replication are determined at day 6 post-infection by measuring the reverse transcriptase activity in the harvested supernatant by using GRAPHPAD PRISM software. The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples. 30 While the invention has been illustrated with respect to the production and of particular compounds, it is apparent that variations and modifications of the invention can be made without departing from the spirit or scope of the invention.

Claims (44)

1. A compound of formula (1) or a pharmaceutically acceptable salt thereof: CH 3 H 3 C /Y CH 3 CH 3 X R1, - CH 3 H3C CH 3 (I) wherein R' is O O HO A * 10 A is C 1 - alkyl, C 2 8 alkenyL, or -(CH 2 ) 1 . 2 0(CH 2 ) 12 -; Y is C=O or C-Ry1Ry 2 ; Ry 1 and Ry 2 are each independently H or -CH 3 ; WO 2009/082818 PCT/CA2008/002290 84 Xis R2 , 1 N'R 0 R 2 is H, C 1 . 12 alkyl which is unsubstituted or substituted one or more times by R 1 0 , C 2 - 12 alkenyl which is unsubstituted or substituted one or more times by RIO, or C 2 . 12 alkynyl which is unsubstituted or substituted one or more times by R0*; R 3 is H, C 1 . 1 2 alkyl which is unsubstituted or substituted one or more times by R 1 0 , 10 C 2 12 alkenyl which is unsubstituted or substituted one or more times by RIO, C 2 . 1 2 alkynyt which is unsubstituted or substituted one or more times by R' 0 , C 6 . 14 aryl which is unsubstituted or substituted one or more times by R" , C. 16 aralkyl which is unsubstituted or substituted one or more times by R" 1 , 5 12 member heteroaryl which is unsubstituted or substituted one or more times by R', 6-18 member heteroaralkyl which is unsubstituted or substituted one or more times by R", 3-12 member heterocycle which is unsubstituted or substituted one or more times by R 12 , or 4-18 member heterocycle-alkyl which is unsubstituted or substituted one or more times by R 12 ; 20 R 2 and R 3 can also be taken together to form 5-12 member heteroaryl which is unsubstituted or substituted one or more times by R", or a 3-12 member heterocycle which is unsubstituted or substituted one or more times by R 2 ; RI 0 is halogen, oxo, C 1 . 6 alkoxy, -NH 2 , -NH(C 1 . 4 alkyl), -N(C 1 . 4 alkyt) 2 , -C(O)NH 2 , C(O)NH(C 1 . 4 alkyl), -C(0)N(C 1 4 alkyL) 2 , -NHC(O)H, -N(C 1 . 4 alkyl)C(0)H, -N(C 1 . 4 alkyl)C(O)C 1 . 4 alkyl, -NHC(O)C 1 . 4 alkyl, -NHC(O)OC 1 . 4 alkyl, -N(C 1 . 4 alkyl)C(0)0C 1 . 4 alkyl, -NHC(O)NH 2 , ,-N(C 1 . 4 alkyl)C(O)NH 2 , -NHC(O)NHC 1 . 4 alkyl, -N(C 1 . 4 alkyl)C(O)NHC 1 . 4 alkyl,-N(C 1 . 4 alkyl)C(O)N(C 1 . 4 alkyt) 2 , 30 NHC(0)N(C 1 . 4 alkyl) 2 , -C(O)H, -C(O)C 1 . 4 alkyl, C(O)OH, -C(O)0C 1 . 4 alkyl, OC(O)C 1 . 4 alkyl, -OC(0)NH(C 1 . 4 alkyl), -OC(0)N(C 14 alkyl) 2 , -C(NOH)C 1 4 alkyL, C(NOH)H, -C(NOC 14 alkyl)C 1 . 4 alkyl, -C(NOC 1 . 4 alkyL)H, hydroxyl, nitro, azido, cyano, -S(0) 0 . 3 H, -S(0) 0 . 3 C 1 . 4 alkyl, -SO 2 NH 2 , -SO 2 NH(C 1 . 4 alkyl), -SO 2 N(C 1 . 4 WO 2009/082818 PCT/CA2008/002290 85 alkyl) 2 , -N(C 1 . 4 alkyl)S0 2 C 1 . 4 alkyl, -NHSO 2 C 1 . 4 alkyl, -P(O)(OH) 2 , -P(O)(0C 1 . 4 alkyl)OH, -P(O)(OC 1 . 4 alkyl) 2 , amidino, or guanidino; R' is halogen, C 1 . 6 alkyl, halogenated C 1 . 6 alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 1 . 6 alkoxy, NH 2 , -NH(C 1 . 4 alkyl), -N(C 1 . 4 alkyt) 2 , -C(O)NH 2 , -C(O)NH(C 1 . 4 alkyl), -C(O)N(C 1 . 4 alkyl) 2 , -NHC(O)H, -N(C 1 . 4 alkyl)C(O)H, -N(C 1 . 4 akyl)C(O)C 1 . 4 alkyl, -NHC(O)C 1 . 4 alkyl, -NHC(O)OC 1 . 4 alkyl, -N(C 1 . 4 alkyl)C(O)OC 1 . 4 alkyl, -NHC(O)NH 2 , ,-N(C 1 . 4 alkyl)C(O)NH 2 , -NHC(O)NHC 1 . 4 alkyl, -N(C 1 . 4 alkyl)C(O)NHC 1 . 4 alkyl,-N(C 1 . 4 alkyl)C(O)N(C 1 . 4 alkyL) 2 , -NHC(O)N(C 1 . 4 alkyt) 2 , -C(O)H, -C(O)C 1 . 4 alkyl, 10 C(O)OH, -C(O)0C 1 . 4 aLkyl, -OC(O)C 1 . 4 alkyl, -OC(O)NH(C 1 . 4 aLkyl), -OC(O)N(C 1 . 4 alkyt) 2 , -C(NOH)C 1 . 4 alkyl, -C(NOH)H, -C(NOC 1 . 4 alkyl)C 1 . 4 alkyl, -C(NOC 1 . 4 alkyl)H, hydroxyl, nitro, azido, cyano, -S(0) 0 . 3 H, -S(0)o. 3 C 1 . 4 alkyl, -SO 2 NH 2 , SO 2 NH(C 1 . 4 alkyl), -SO 2 N(C 1 . 4 alkyt) 2 , -N(C 1 . 4 'alkyl)S0 2 C 1 . 4 alkyl, -NHSO 2 C 1 . 4 alkyl, -P(O)(OH) 2 , -P(O)(OC 1 . 4 alkyl)OH, -P(O)(OC 1 . 4 aky) 2 , amidino, or guanidino; and R1 2 is halogen, oxo, C 1 . 6 alkyl, halogenated C 1 . 6 alkyl, C 2 . 6 alkenyl, C 2 - 6 alkynyL, C 1 . 6 alkoxy, -NH 2 , -NH(C. 4 aLkyl), -N(C 1 . 4 alkyl) 2 , -C(O)NH 2 , -C(O)NH(C 1 . 4 alkyL), 20 C(O)N(C 1 4 alkyL) 2 , -NHC(O)H, -N(C 1 . 4 alkyl)C(O)H, -N(C 1 . 4 alkyt)C(O)C 1 . 4 akyl, NHC(O)C 1 . 4 alkyl, -NHC(O)OC 1 . 4 aLkyl, -N(C 1 . 4 alkyt)C(O)OC 1 . 4 alkyl, NHC(O)NH 2 , ,-N(C 1 . 4 alkyl)C(O)NH 2 , -NHC(O)NHC 1 . 4 alkyl, -N(C 1 . 4 alkyt)C(O)NHC 1 4 alkyt,-N(C 1 . 4 alkyl)C(O)N(C 1 . 4 alkyL) 2 , -NHC(O)N(C 1 . 4 alkyl) 2 , C(O)H, -C(O)C 1 . 4 alkyl, C(O)OH, -C(O)0C 1 . 4 alkyL, -OC(O)C 1 . 4 alkyL, OC(O)NH(C 1 . 4 alkyl), -OC(O)N(C 1 . 4 alkyt) 2 , -C(NOH)C 1 . 4 alkyt, -C(NOH)H, C(NOC 1 . 4 alkyt)C 1 . 4 alkyL, -C(NOC 1 . 4 aLkyL)H, hydroxyL, nitro, azido, cyano, S(0) 0 . 3 H, -S(0)o.3C1.4 alkyl, -S0 2 NH 2 , -SO 2 NH(C 1 . 4 alkyl), -S0 2 N(C 1 . 4 atkyl) 2 , N(C 1 . 4 alkyl)SO 2 C 1 . 4 alkyl, -NHS0 2 C 1 . 4 akyl, -P(O)(OH) 2 , -P(O)(OC 1 . 4 alkyl)OH, P(O)(OC1. 4 alkyt) 2 , amidino, or guanidino. 30
2. A compound according to claim 1, wherein Y is C=0.
3. A compound according to claim 1 wherein Y is C-Ry 1 Ry 2 and Ry 1 and Ry2 are -CH 3 . WO 2009/082818 PCT/CA2008/002290 86
4. A compound according to claim 1, wherein wherein Y is C-Ry 1 Ry 2 and Ry 1 and Ry 2 are H.
5. A compound according to anyone of claims 1 to 4, wherein R 1 is succinyl, glutaryl, 3'-methylglutaryl, 3-methylsuccinyl, 3',3'-dimethylsuccinyl, 3',3'- dimethylglutaryl, 2',2'-dimethylmalonyl, 2',3'-dihydroxysuccinyl, 2',3'-dimethylsuccinyL, 2',2',3',3'-tetramethylsuccinyL, 2'-methylsuccinyL, or 2',2'- dimethylsuccinyl. 10 6. A compound according to claim 5, wherein R 1 is 3',3'-dimethylsuccinyl.
7. A compound as defined in anyone of claims 1 to 6, wherein R 2 is H or C 1 12 alkyl which is unsubstituted or substituted one or more times by R 1 0 .
8. A compound as defined in claim 7, wherein R 2 is H or C 1 . 6 alkyl which is unsubstituted or substituted one or more times by R 1 0 .
9. A compound as defined in claim 7, wherein R 2 is H, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, 20 cyclopentyl, or cyclohexyl.
10. A compound according to claim 7, wherein R 2 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butyl.
11. A compound according to claim 7, wherein R 2 is methyl.
12. A compound according to claim 7, wherein R 2 is H.
13. A compound according to any one of claims 1 to 6, wherein R 2 and R 3 30 taken together form a 5-6 member heteroaryl which is unsubstituted or substituted one or more times by R" or a 5-6 member heterocycle which is unsubstituted or substituted one or more times by R 1 .
14. A compound according to claim 13, wherein R 2 and R 3 taken together form a piperidyt, a piperazinyl, or a morpholinyl which is unsubstituted or substituted one or more times by R".. WO 2009/082818 PCT/CA2008/002290 87
15. A compound according to any one of claims 1 to 6, wherein R 2 and R 3 taken together form a diazabicyclo[3.2.1]octane which is unsubstituted or substituted one or more times by R"..
16. A compound according to anyone of claims 1 to 12, wherein R 3 is C 112 alkyl which is unsubstituted or substituted one or more times by R"4, C 2 . 12 alkenyl which is unsubstituted or substituted one or more times by R 1 0 , C 2 12 alkynyt which is unsubstituted or substituted one or more times 10 by R'", C 6 . 14 aryl which is unsubstituted or substituted one or more times by R", C 7 . 1 6 aralkyl which is unsubstituted or substituted one or more times by R", 5-12 member heteroaryl which is unsubstituted or substituted one or more times by R", 6-18 member heteroaralkyl which is unsubstituted or substituted one or more times by R", 3-12 member heterocycle which is unsubstituted or substituted one or more times by R 12 , or 4-18 member heterocycle-alkyl which is unsubstituted or substituted one or more times by R 1 .
17. A compound according to claim 16, wherein R 3 is C 1 . 1 2 alkyl which is 20 unsubstituted or substituted one or more times by R 1 0 , C 6 aryl which is unsubstituted or substituted one or more times by R", C 7 - 9 aralkyl which is unsubstituted or substituted one or more times by R", 5-6 member heteroaryl which is unsubstituted or substituted one or more times by R", 7-8 member heteroaralkyl which is unsubstituted or substituted one or more times by R", 5-6 member heterocycle which is unsubstituted or substituted one or more times by R 1 2 , or 7-8 member heterocycle-alkyl which is unsubstituted or substituted one or more times by R 1 .
18. A compound according to claim 16, wherein R 3 is C 1 . 6 alkyl which is 30 unsubstituted or substituted one or more times by R' 0 , phenyl which is unsubstituted or substituted one or more times by R", benzyl which is unsubstituted or substituted one or more times by R", 5-6 member heteroaryl which is unsubstituted or substituted one or more times by R", 7-8 member heteroaralky which is unsubstituted or substituted one or more times by R", 5-6 member heterocycle which is unsubstituted or WO 2009/082818 PCT/CA2008/002290 88 substituted one or more times by R", or 7-8 member heterocycle-alkyl which is unsubstituted or substituted one or more times by R 1 .
19. A compound according to claim 16, wherein R 3 is C 1 . 6 alkyl which is unsubstituted or substituted one or more times by R 1 0 , benzyl which is unsubstituted or substituted one or more times by R 1 1 , 7-8 member heteroaralkyl which is unsubstituted or substituted one or more times by R 1 1 , 5-6 member heterocycle which is unsubstituted or substituted one or more times by R 1 2 , or 7-8 member heterocycle-alkyl which is 10 unsubstituted or substituted one or more times by R 1 2 .
20. A compound according to claim 16, wherein R 3 is C 1 . 6 alkyl which is unsubstituted or substituted one or more times by R 1 0 , benzyl which is unsubstituted or substituted one or more times by R 1 1 , 7-8 member heteroaralkyl which is unsubstituted or substituted one or more times by RI 1 , or 7-8 member heterocycle-alkyl which is unsubstituted or substituted one or more times by R 1 2 .
21. A compound according to claim 16, wherein R 3 is C 1 . 6 alkyl which is 20 unsubstituted or substituted one or more times by R 10 , benzyl which is unsubstituted or substituted one or more times by RII, or 7-8 member heterocycle-alkyl which is unsubstituted or substituted one or more times by R 1 2 .
22. A compound according to claim 16, wherein R 3 is methyl, ethyl, propyl, isopropyl, butyL, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cylcohexyLmethyl.
23. A compound according to claim 16, wherein R 3 is benzyl which is 30 unsubstituted or substituted one or more times by R 1 1 .
24. A compound according to claim 16, wherein R 3 is benzyl.
25. A compound according to claim 16, wherein R 3 is pyridinyl(CH 2 )- which is unsubstituted or substituted one or more times by R 1 1 . WO 2009/082818 PCT/CA2008/002290 89
26. A compound according to claim 16, wherein R 3 is pyridinyl(CH 2 )-.
27. A compound according to claim 16, wherein R 3 is piperidiny which is unsubstituted or substituted one or more times by R 1 .
28. A compound according to claim 16, wherein R 3 is piperidinyt.
29. A compound according to claim 16, wherein R 3 is pyrimidinyl which is unsubstituted or substituted one or more times by R". 10
30. A compound according to claim 16, wherein R 3 is pyrimidinyl.
31. A compound according to claim 16, wherein R 3 is pyridine which is unsubstituted or substituted one or more times by R".
32. A compound according to claim 16, wherein R 3 is pyridine.
33. A compound according to claim 16, wherein R 3 is pyrazole which is unsubstituted or substituted one or more times by R". 20
34. A compound according to claim 16, wherein R 3 is methyl pyrazole.
35. A compound according to claim 16, wherein R 3 is pyperazinyl.
36. A compound according to claim 16, wherein R 3 is phenyl which is unsubstituted or substituted one or more times by R".
37. A compound according to claim 16, wherein R 3 is fluorophenyl. 30 38. A compound according to claim 16, wherein R 3 is phenyl.
39. A compound according to claim 16, wherein R 3 is cyclohexyl(CH 2 )- which is unsubstituted or substituted one or more times by R' 0 .
40. A compound according to claim 16, wherein R 3 is cyclohexyl(CH 2 )- which is unsubstituted or substituted one or more times by halogen. WO 2009/082818 PCT/CA2008/002290 90
41. A compound according to anyone of claims 1 to 40, wherein R 1 " is halogen, oxo, C 1 . 6 alkoxy,-NH 2 , -NH(C 1 . 4 alkyl), -N(C 1 . 4 alkyl) 2 , -CONH 2 , CONH(C 14 alkyL), -CON(C 1 4 alkyl) 2 , -NHCOH, -N(C 1 . 4 alkyl)COH, -N(Cl. 4 alkyl)COC 1 . 4 alkyl, -NHCOC 1 . 4 alkyl, -NHCOOC 1 . 4 alkyL, -NHCONHC 1 . 4 alkyl, N(C 1 4 alkyl)CONHC 14 alkyl,-N(C 1 4 alkyL)CON(C 1 . 4 alkyl) 2 , -NHCON(C 14 alkyl) 2 , C(O)H, -C(O)C 1 4 alkyl, carboxy, -C(0)OC 1 4 alkyl, -C(NOH)C 1 4 alkyl, C(NOH)H, -C(NOC 1 . 4 alkyl)C. 4 alkyl, -C(NOC 1 . 4 alkyL)H, hydroxyl, nitro, azido, 10 cyano, -S(0) 0 - 2 H, -S(0) 0 - 2 C 1 4 alkyl, -SO 2 NH 2 , -SO 2 NH(CI. 4 alkyl), -SO 2 N(C 1 .4 alkyL) 2 , -N(C 1 4 alkyL)SO 2 C 14 alkyl, -NHSO 2 C- 4 alkyl, -P(O)(OH) 2 or P(O)(OC 1 . 4 alkyl) 2 ; R" is halogen, C 1 . 6 alkyl, halogenated C 1 . 6 alkyl, C 2 - 6 alkenyl, C 2 . 6 alkynyl, C 1 . 6 alkoxy, NH 2 , -NH(C 1 4 alkyl), -N(C 1 . 4 alkyt) 2 , -CONH 2 , -CONH(C 1 . 4 alkyl), -CON(C 1 4 alkyl) 2 , -NHCOH, -N(C 14 alkyl)COH, -N(C 1 . 4 alkyl)COC 14 alkyl, -NHCOC 1 . 4 alkyl, -NHCOOC 14 aLkyl, -NHCONHC,. 4 alkyl, -N(C 1 4 alkyl)CONHC,. 4 alkyl, -N(C 1 4 alkyL)CON(Cl. 4 alkyt) 2 , -NHCON(C 14 alkyL) 2 , -C(O)H, -C(O)C 1 4 alkyl, carboxy, C(0)OC 1 4 alkyl, -C(NOH)C- 4 alkyl, -C(NOH)H, -C(NOC 1 4 alkyL)C 14 alkyl, 20 C(NOC 14 alkyL)H, hydroxyl, nitro, azido, cyano, -S(0) 0 . 2 H, -S(0) 0 . 2 C 1 4 alkyl, SO 2 NH 2 , -SO 2 NH(CI- 4 alkyl), -SO 2 N(C 1 . 4 alkyl) 2 , -N(C. 4 alkyL)SO 2 CI- 4 alkyl, NHSO 2 C 1 4 alkyl, -P(O)(OH) 2 or P(O)(OC 4 alkyL) 2 ; and R 12 is halogen, oxo, C 1 . 6 alkyl, halogenated C 1 . 6 alkyl, C 2 . 6 alkenyl, C 2 - 6 aLkynyl,, C 1 . 6 alkoxy,-NH 2 , -NH(C 14 alkyl), -N(Ca. 4 alkyl) 2 , -CONH 2 , -CONH(Cl. 4 alkyl), CON(C 14 alkyL) 2 , -NHCOH, -N(C 1 . 4 alkyL)COH, -N(C 14 alkyl)COC 1 . 4 alkyl, NHCOC 14 alkyl, -NHCOOC 14 alkyl, -NHCONHC 1 . 4 alkyL, -N(Cl. 4 alkyL)CONHC 1 .4 alkyl, -N(C 1 . 4 alkyL)CON(Cl. 4 alkyL) 2 , -NHCON(C 1 . 4 alkyl) 2 , -C(O)H, -C(O)C 1 . 4 alkyl, carboxy, -C(0)OC 1 - 4 alkyl,-C(NOH)C 14 alkyl, -C(NOH)H, -C(NOC 1 . 4 30 alkyl)C 14 alkyl, -C(NOC 1 . 4 alkyL)H, hydroxyl, nitro, azido, cyano, -S(0) 0 - 2 H, S(0) 0 - 2 C 1 . 4 alkyl, -SO 2 NH 2 , -SO 2 NH(C 1 . 4 alkyl), -SO 2 N(CI- 4 alkyL) 2 , -N(Cl- 4 alky[)S0 2 CI. 4 alkyl, -NHSO 2 C 1 .4 alkyl, -P(O)(OH) 2 or P(O)(OC. 4 akyL) 2 .
42. A compound according to claim 41, wherein WO 2009/082818 PCT/CA2008/002290 91 R 1 0 is halogen, oxo, C 1 . 6 alkoxy,-NH 2 , -NH(C 14 alkyl), -N(C 1 . 4 alkyl) 2 , -CONH 2 , CONH(C 1 . 4 alkyl), -CON(C 14 alkyl) 2 , -NHCOH, -N(C 1 4 alkyl)COH, -N(C 14 alkyl)COC 1 . 4 alkyl, -NHCOC- 4 alkyl, -NHCOOC,. 4 alkyl, -NHCONHC 1 4 alkyl, N(C 1 4 alkyl)CONHC 1 4 alkyl,-N(C 1 4 alkyl)CON(C 14 alkyl) 2 , -NHCON(C 14 alkyl) 2 , C(O)H, -C(O)C- 4 aLkyl, carboxy, -C(O)OC. 4 alkyl,-C(NOH)C 1 4 alkyl,-C(NOH)H, hydroxyl, nitro, azido, cyano, -S(0) 0 - 2 H, -S(0) 0 . 2 C 1 . 4 alkyl, -SO 2 NH 2 , SO 2 NH(C 1 - 4 alkyl), -SO 2 N(C 1 - 4 alkyl) 2 , -N(C 1 4 alkyl)S0 2 C 14 alkyl, -NHS0 2 C 1 4 alkyl, or -P(O)(OH) 2 ; 10 R" is halogen, C 1 . 6 alkyl, halogenated C 1 . alkyl, C 26 alkenyl, C 2 . 6 aLkynyl, C 1 6 alkoxy, NH 2 , -NH(C 1 4 alkyl), -N(C 1 . 4 alkyl) 2 , -CONH 2 , -CONH(C 1 4 alkyl), -CON(CI. 4 alkyl) 2 , -NHCOH, -N(C 1 4 alkyl)COH, -N(C 1 . 4 alkyl)COC 4 alkyl, -NHCOC 1 . 4 alkyl, -NHCOOC 14 alkyl, -NHCONHC 1 4 alkyl, -N(C 1 . 4 alkyl)CONHC 14 alkyl, -N(C 1 .4 alkyl)CON(C 1 . 4 alkyl) 2 , -NHCON(C 1 . 4 alkyl) 2 , -C(O)H, -C(O)Cl- 4 atkyl, carboxy, C(O)OCI 4 alkyl, -C(NOH)CI 4 akyl, -C(NOH)H, hydroxyl, nitro, azido, cyano, S(0) 0 - 2 H, -S(0) 0 - 2 C 1 4 alkyl, -SO 2 NH 2 , -SO 2 NH(C- 4 alkyl), -SO 2 N(C 14 alkyL) 2 , N(C 1 . 4 alkyl)S0 2 C 14 alkyl, -NHS0 2 C 1 . 4 aLkyl, or -P(0)(OH) 2 ; and R" is halogen, oxo, C 1 . 6 alkyl, halogenated C 1 . 6 alkyl, C 2 . 6 alkenyL, C 2 . 6 alkynyL,, C 1 . 6 20 alkoxy,-NH 2 , -NH(C 1 . 4 alkyl), -N(C 1 . 4 alkyL) 2 , -CONH 2 , -CONH(C 14 alkyl), CON(C 14 alkyl) 2 , -NHCOH, -N(C 14 alkyl)COH, -N(C 1 . 4 alkyl)COC 1 . 4 alkyl, NHCOC 1 . 4 alkyl, -NHCOOC. 4 alkyl, -NHCONHC 1 . 4 alkyl, -N(C 1 . 4 alkyl)CONHC. 4 alkyl, -N(C 1 . 4 alkyl)CON(Cl. 4 alkyt) 2 , -NHCON(C 1 . 4 alkyl) 2 , -C(O)H, -C(O)C 1 . 4 alkyl, carboxy, -C(O)0CI- 4 alkyL,-C(NOH)C 1 . 4 alkyl, -C(NOH)H, hydroxyl, nitro, azido, cyano, -S(0) 0 - 2 H, -S(0) 0 . 2 C 1 . 4 atkyl, -SO 2 NH 2 , -SO 2 NH(C 1 . 4 alkyl), SO 2 N(C 4 alkyl) 2 , -N(C 1 . 4 alkyl)SO 2 CI. 4a lkyt, -NHSO 2 CI. 4 alkyl, and -P(O)(OH) 2 .
43. A compound according to claim 41, wherein R 1 0 is halogen, oxo, -NH 2 , -NH(C 1 . 4 alkyl), -N(C 14 alkyL) 2 , -CONH 2 , -CONH(C 1 . 4 alkyl), 30 CON(C 1 . 4 alkyl) 2 , -NHCOH, -N(C 1 . 4 alkyl)COH, -N(Cl. 4 alkyL)COC,. 4 alkyl, NHCOC 1 . 4 alkyl, -NHCOOCj. 4 alkyl, -NHCONHC 1 . 4 alkyl, -C(O)H, -C(O)C 1 . 4 alkyl, carboxy, -C(O)0C 1 . 4 alkyL, hydroxyl, C 1 . 4 alkoxy, nitro, azido, or cyano; R" is halogen, C 1 . 6 alkyl, halogenated C 1 . 6 alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl,-NH 2 , -NH(CI. 4 alkyl), -N(Cj- 4a lkyL) 2 , -CONH 2 , -CONH(C 1 4 alkyl), -CON(Cl. 4 a lkyl) 2 , -NHCOH, N(Cl. 4 alkyL)COH, -N(C 1 4 alkyl)COC. 4 alkyl, -NHCOCj. 4 alkyl, -NHCOOCj. 4 alkyl, WO 2009/082818 PCT/CA2008/002290 92 -NHCONHC 1 . 4 alkyl, -C(O)H, -C(O)C 1 . 4 alkyl, carboxy, -C(0)O C 1 . 4 alkyl, hydroxyl, C 1 . 6 alkoxy, nitro, azido, or cyano; and R 12 is halogen, oxo, C 1 . 6 alkyl, halogenated C 1 . 6 alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, -NH 2 , NH(C 1 . 4 alkyl), -N(C 1 . 4 alkyl) 2 , -CONH 2 , -CONH(C 1 . 4 alkyl), -CON(C 1 . 4 alkyl) 2 , NHCOH, -N(C 1 . 4 alkyl)COH, -N(C 1 . 4 alkyl)COC 1 . 4 alkyl, -NHCOC 1 . 4 alkyl, NHCOOC 1 . 4 alkyl, -NHCONHC 1 . 4 alkyl, -C(O)H, -C(O)C 1 . 4 alkyl, carboxy, C(O)OC 1 . 4 alkyl, hydroxyl, C 1 . 6 alkoxy, nitro, azido, or cyano. 10 44. A compound according to claim 41, wherein R 1 0 is halogen, oxo, -NH 2 , -NH(C 1 . 4 alkyl), -N(C 1 . 4 alkyl) 2 , -CONH 2 , -CONH(C 1 . 4 alkyl), CON(C 1 . 4 alkyL) 2 , -NHCOH, -N(C 1 . 4 , alkyl)COH, -N(C 1 . 4 alkyl)COC 1 . 4 alkyl, NHCOC 1 . 4 alkyL, -NHCOOC,. 4 alkyl, -NHCONHC 1 . 4 alkyL -C(O)H, -C(O)C. 4 alkyl, carboxy, -C(O)0C 1 . 4 alkyl, hydroxyl, or C 1 . 4 alkoxy; R" is halogen, C 1 . 6 alkyl, halogenated C 1 . 6 alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, -NH 2 , -NH(C 1 . 4 alkyl), -N(C 1 . 4 alkyl) 2 , -CONH 2 , -CONH(C 1 . 4 alkyl), -CON(C 1 . 4 alkyl) 2 , -NHCOH, -N(C 1 . 4 alkyl)COH, -N(C 1 . 4 alkyl)COC 1 . 4 alkyl, -NHCOC 1 . 4 alkyl, -NHCOOC 1 . 4 alkyl, -NHCONHC 1 . 4 alkyl, -C(O)H, -C(O)C 1 . 4 alkyl, carboxy, -C(O)0C 1 . 4 alkyl, 20 hydroxyl, or C 1 . 6 alkoxy; and R 1 2 is halogen, oxo, C 1 . 6 alkyl, halogenated C. alkyl, C 2 - alkenyl, C 2 .6alkynyl, -NH 2 , NH(C 1 . 4 alkyl), -N(C 1 . 4 alkyl) 2 , -CONH 2 , -CONH(C 1 . 4 alkyl), -CON(C 1 . 4 alkyl) 2 , NHCOH, -N(C 1 . 4 alkyl)COH, -N(C 1 . 4 alkyl)COC 1 . 4 alkyl, -NHCOC 1 . 4 alkyl, NHCOOCI- 4 alkyl, -NHCONHC,. 4 alkyl, -C(O)H, -C(O)C 1 . 4 alkyl, carboxy, C(O)0C 1 . 4 alkyl, hydroxyl, or C 1 . 6 alkoxy.
45. A compound according to claim 41, wherein 30 R 1 0 is halogen, oxo, -NH 2 , -NH(C 1 . 4 alkyl), -N(Cl. 4 alkyl) 2 , -CONH 2 , -CONH(C. 4 alkyl), -CON(C 1 . 4 alkyl) 2 , -N(C. 4 alkyl)COC. 4 alkyl, -NHCOCj. 4 alkyl, carboxy, C(O)0C.4 alkyl, hydroxyl, C 1 . 4 alkoxy, or cyano. R 1 is halogen, C 1 . 6 alkyl, halogenated C 1 . 6 alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, -NH 2 , -NH(C. 4 alkyl), -N(C 1 . 4 alkyl) 2 , -CONH 2 , -CONH(C. 4 alkyl), -CON(C. 4 alkyl) 2 , -N(C 1 . 4 WO 2009/082818 PCT/CA2008/002290 93 alkyl)COC 1 . 4 alkyl, -NHCOC 1 . 4 alkyl, carboxy, -C(O)0C 1 4 alkyl, hydroxyl, or C 1 . 6 alkoxy. R 1 2 is halogen, oxo, C 1 . 6 alkyl, haLogenated C 1 . 6 alkyl, -NH 2 , -NH(C 14 alkyl), N(C 1 . 4 alkyl) 2 , -CONH 2 , -CONH(C- 4 alkyl), -CON(C 1 4 alkyl) 2 , -N(C 1 4 alkyl)COC 1 a alkyl, NHCOC 14 alkyt, carboxy, -C(O)0Cl.4alkyl, hydroxyl, or C 1 . 6 alkoxy.
46. A compound according to claim 1, wherein said .compound is selected from:
360-(3',3'-Dimethylsucciny)-21-oxolup-18-en-28-oic acid N-benzylamide; 3/-0-(3',3'-Dimethylsuccinyl)-21-oxotup-18-en-28-oic acid N-methylamide; 3P0- (3',3'-Dimethylsuccinyl)-21-oxolup-18-en-28-oic acid N-isopropylamide; 3#0- (3',3'-Dimethylsuccinyl)-21 -oxoLup-1 8-en-28-oic acid N-cyclohexylamide; 3/3O-(3',3'-Dimethylsuccinyl)-21-oxolup-18-en-28-oic acid N-cyclohexyl methylamide; 3P/O-(3',3'-Dimethylsucciny)-21-oxolup-18-en-28-oic acid N-piperidinyl acetamide; 3,-0-(3',3'-Dimethylsuccinyl)-21-oxolup-18-en-28-oic acid N-morpholyl acetamide; 36O-(3',3'-Dimethylsuccinyl)-21-oxolup-18-en-28-oic acid N-(4-acetyl piperazinyl) acetamide; 3P-O-(3',3'-Dimethylsucciny)-21-oxolup-18-en-28-oic acid N-(4-methyl piperazinyl) acetamide; 3P-0-(3',3'-Dimethylsucciny)-21-oxolup-18-en-28-oic acid N-benzamide; 360-(3',3'-Dimethylsuccinyl)-21-oxolup-18-en-28-oic acid N-methyl-N benzylamide; 3/30-(3',3'-Dimethylsuccinyl)-21-oxolup-18-en-28-oic acid N-2-chloro benzylamide; 3P--(3',3'-Dimethylsucciny)-21-oxolup-18-en-28-oic acid N-3-chloro benzylamide; WO 2009/082818 PCT/CA2008/002290 94 3p-O-(3',3'-Dimethylsucciny)-21 -oxolup-1 8-en-28-oic acid N-4-chloro benzylamide; 3P-O-(3',3'-Dimethylsuccinyt)-21 -oxoLup-1 8-en-28-oic acid N-4-methoxy benzylamide; 3-O-(3',3'-Dimethylsucciny)-21 -oxolup-1 8-en-28-oic acid N-pyridin-2 ylmethylamide; 3P-O-(3',3'-Dimethylsucciny)-21 -oxolup-1 8-en-28-oic acid N-pyridin-3 ylmethylamide; 3fr0-(3',3'-Dimethylsucciny)-21 -oxolup-1 8-en-28-oic acid N-pyridin-4 ylmethylamide; 3-O-(3',3'-Dimethylsucciny)-21 -oxolup-1 8-en-28-oic acid N-[2-(4-methoxy phenyl)-ethyl] -acetamide; 3,O-(3',3'-Dimethylsucciny)-21 -oxoLup-1 8-en-28-oic acid N-(2-acetylamino ethyl)-carbamic acid tert-butyl ester; 3P-O-(3',3'-Dimethylsuccinyt)-21-oxolup-18-en-28-oic acid N-(2-amino-ethyL) acetamide; 3/3O-(3',3'-Dimethylsucciny)-21 -oxolup-18-en-28-oic acid N-(2-acetylamino ethyl)-acetamide; 3/O-(3',3'-Dimethylsuccinyt)-21-oxolup-18-en-28-oic acid N-[2-(3-isopropyl ureido)-ethyl]-acetamide; 3f-O-(3',3'-Dimethylsucciny)-21-oxolup-18-en-28-oic acid N-(2-acetylamino ethyl)-carbamic acid methyl ester; 3/3O-(3',3'-Dimethysucciny)-21-oxoLup-18-en-28-oic acid N-pyridin-2-yL acetamide; 3pO-(3',3'-Dimethysuccinyl)-21 -oxoLup-18-en-28-oic acid N-pyridin-3-yL acetamide; 3/O-(3',3'-Dimethylsucciny)-21-oxoLup-18-en-28-oic acid N-i-acetyL-piperazine 4-carboxylic acid tert-butyl ester; 3/3-0-(3',3'-Dimethylsucciny)-21-oxotup-18-en-28-oic acid N-piperazinyl acetamide; 3/O-(3',3'-Dimethylsucciny)-21-oxoLup-18-en-28-oic acid N-i -(4-hydroxy piperidin-1 -y)-acetamide; 3A O-(3',3'-Dimethylsuccinyl)-21 -oxoLup-1 8-en-28-oic acid N-i-acetyLamino piperidine-4-carboxyLic acid tert-butyL ester; WO 2009/082818 PCT/CA2008/002290 95 3P-O-(3',3'-Dimethylsuccinyl)-21-oxolup-18-en-28-oic acid N-(4-aminopiperidine) acetamide; 3P-O-(3',3'-Dimethylsucciny)-21-oxotup-18-en-28-oic acid N-(4-amino-N-1-acetyl piperidine)-acetamide; 3,-O-(3',3'-Dimethylsuccinyl)-21-oxolup-18-en-28-oic acid N-(1 -phenyl-ethyl) acetamide; 3P-O-(3',3'-Dimethylsucciny)-21-oxolup-18-en-28-oic acid N-(1-methyl-1-phenyl ethyl) -acetamide; 3-O-(3',3'-Dimethylsucciny)-21-oxolup-18-en-28-oic acid N-(tert-butyl) acetamide; 3P-O-(3',3'-Dimethylsucciny)-21-oxolup-18-en-28-oic acid N-(8-amino-3,8-diaza bicyclo[3.2.1 ]octane-3-benzamide)-acetamide; 3#-0-(3',3'-Dimethylsucciny)-21 -oxolup-1 8-en-28-oic acid N-4-piperazi-2-one acetamide; 3P-O-(3',3'-Dimethylsuccinyl)-21 -oxolup-1 8-en-28-oic acid N-pyrimidin-2-yl acetamide; 3,&-O-(3',3'-Dimethylsuccinyl)-21 -oxolup-1 8-en-28-oic acid N-(4-N' isopropylureido-1 -piperazine)-acetamide; 3#-O-(3',3'-Dimethylsucciny)-21 -oxolup-1 8-en-28-oic acid N-1-acetyl-piperazine 4-carboxylic acid methyl ester; 3P-O-(3',3'-Dimethylsucciny)-21 -oxolup-18-en-28-oic acid N-(4-amino carboxylic acid tert-butyl-ester-1-piperidine)-acetamide; 3P-O-(3',3'-Dimethylsuccinyl)-21 -oxolup-18-en-28-oic acid N-(4-amino-1 piperidine)-acetamide; 3f-O-(3',3'-Dimethysucciny)-21-oxolup-18-en-28-oic acid N-(4-acetylamino-1 piperidine)-acetamide; 3/-O-(3',3'-Dimethylsucciny)-21-oxolup-18-en-28-oic acid N-[(4-amino-N' isopropylureido)-1 -piperidine]-acetamide; 3f-O-(3',3'-Dimethylsuccinyl)-21-oxolup-18-en-28-oic acid N-(4- amino carboxylic acid methyl ester-i -piperidine)-acetamide; 3/3O-(3',3'-Dimethylsuccinyl)-21-oxolup-18-en-28-oic acid N-4-(1-methyl-piperazi 2-one)-acetamide; 3O-(3',3'-Dimethylsuccinyl)-21-oxolup-18-en-28-oic acid N-2-methyl-phen-1-yl acetamide; WO 2009/082818 PCT/CA2008/002290 96 3-O-(3',3'-Dimethylsucciny)-21-oxolup-18-en-28-oic acid N-3-methyl-phen-1-yL acetamide; 3-O-(3',3'-Dimethylsucciny)-21-oxolup-18-en-28-oic acid N-4-methyl-phen-1-yL acetamide; 3P-O-(3',3'-Dimethylsucciny)-21-oxolup-18-en-28-oic acid N-8-acetylamino-3,8 diaza-bicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester; 3P-O-(3',3'-Dimethylsucciny)-21-oxolup-18-en-28-oic acid N-pyrimidin-5-y acetamide; 3/3O-(3',3'-Dimethylsucciny)-21-oxolup-18-en-28-oic acid N-pyridin-4-yl acetamide; 3/3O-(3',3'-Dimethylsucciny)-21-oxolup-18-en-28-oic acid N-3-amino-1-methyl 1 H-pyrazole-acetamide; 3-O-(3',3'-Dimethysucciny)-21-oxolup-18-en-28-oic acid N-5-amino-1-methyl 1 H-pyrazole acetamide; 3#-O-(3',3'-Dimethylsucciny)-21-oxolup-18-en-28-oic acid N-4-methyl-pyrimidin-5 yl-acetamide; 3-O-(3',3'-Dimethylsucciny)-21 -oxolup-1 8-en-28-oic acid N-4-methyl-pyrimidin-2 yl-acetamide; 3#-O-(3',3'-Dimethysucciny)-21-oxolup-18-en-28-oic acid N-4-amino-1-methyL 1H-pyrazoLe acetamide; 3#-O-(3',3'-Dimethylsucciny)-21-oxolup-18-en-28-oic acid N-4,6-dimethyl pyrimidin-2-y-acetamide; 3#-O-(3',3'-Dimethylsucciny)-21-oxolup-18-en-28-oic acid N-pyrazin-2-yi acetamide; 3#-O-(3',3'-Dimethytsuccinyt)-21-oxolup-18-en-28-oic acid N-quinolin-3-yl acetamide; 3/O-(3',3'-Dimethysucciny)-21-oxolup-18-en-28-oic acid N-(2-pyrrolidin-1 -yl ethyl)-acetamide; 3P-O-(3',3'-Dimethysucciny)-21 -oxolup-18-en-28-oic acid N-(5-methyl [1,3,4]oxadiazol-2-yL)-acetamide; 3AO-(3',3'-Dimethylsuccinyl)-21 -oxolup-1 8-en-28-oic acid N-isoquinoin-4-y acetamide; 3#-O-(3',3'-Dimethysucciny)-21 -oxolup-18-en-28-oic acid N-pyrimidin-4-y acetamide; WO 2009/082818 PCT/CA2008/002290 97 3/3O-(3',3'-Dimethylsucciny)-21-oxolup-18-en-28-oic acid N-2-trifluoromethyl phen-1 -yl acetamide; 3-O-(3',3'-Dimethylsucciny)-21-oxolup-18-en-28-oic acid N-(1-methyl-1H tetrazol-5-yl)-acetamide; 3-O-(3',3'-Dimethylsucciny)-21-oxolup-18-en-28-oic acid N-(4-amino carboxylic acid ethyl ester-1-piperidine)-acetamide; 3-O-(3',3'-Dimethylsucciny)-21-oxolup-18-en-28-oic acid N-(4-amino carboxylic acid isopropyl ester-1-piperidine)-acetamide; 3/-0-(3',3'-Dimethylsuccinyl)-21-oxolup-18-en-28-oic acid N-cyclopropylmethyl acetamide; 3/30-(3',3'-Dimethylsucciny)-21-oxolup-18-en-28-oic acid N-azetidine-1 acetamide; 3/3-O-(3',3'-Dimethylsuccinyl)-21-oxolup-18-en-28-oic acid N-(2,2,2-trifluoro ethyl)-acetamide; 3-O-(3',3'-Dimethylsucciny)-21-oxolup-18-en-28-oic acid N-4-trifluoro-pyrimidin 2-yl-acetamide; 3-O-(3',3'-Dimethylsucciny)-21-oxolup-18-en-28-oic acid N-(1 -cyclopropyl-1 methyl-ethyl)-acetamide; 3flO-(3',3'-Dimethylsucciny)-21-oxolup-18-en-28-oic acid N-(4-dimethylamino piperidin-1-y)-acetamide; 3-O-(3',3'-Dimethylsucciny)-21-oxolup-18-en-28-oic acid N-(2,2,2-trifluoro-1 methyl-ethyl)-acetamide; 3/3O-(3',3'-Dimethylsuccinyl)-21-oxolup-18-en-28-oic acid N-(5-methyl [1,3,4]thiadiazol-2-yl)-acetamide; 3-O-(3',3'-Dimethylsucciny)-21-oxolup-18-en-28-oic acid N-(2,2,2-trifluoro-1,1 dimethyl-ethyl)-acetamide; 330- (3',3'-Dimethylsuccinyl)-21-oxoLup-18-en-28-oic acid N-tert-butyl-N-methyl acetamide; 3#-0-(3',3'-Dimethylsucciny)-21-oxotup-18-en-28-oic acid N-(R)-2 acetyLaminomethyl-pyrrolidine-1-carboxyLic acid tert-butyl ester; 3/3O-(3',3'-Dimethylsucciny)-21-oxolup-18-en-28-oic acid N-(S)-2 acetyLaminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester; 3fO-(3',3'-Dimethylsuccinyl)-21-oxoLup-18-en-28-oic acid N-((R)-1-pyrrolidin-2 ylmethyl)-acetamide; WO 2009/082818 PCT/CA2008/002290 98 3P-O-(3',3'-Dimethylsuccinyl)-21-oxolup-18-en-28-oic acid N-((S)-1-pyrrolidin-2 ylmethyl)-acetamide; 3/O-(3',3'-Dimethylsuccinyt)-21 -oxolup-1 8-en-28-oic acid N-((R)-1 -methyl pyrrolidi n-2-ylmethyl)-acetamide; 3/O-(3',3'-Dimethysucciny)-21 -oxolup-1 8-en-28-oic acid N-((S)-1 -methy pyrrolidi n-2-ylmethyl)-acetamide; 3-O-(3',3'-Dimethylsucciny)-21 -oxolup-1 8-en-28-oic acid N-(4,4-difluoro cyclohexyl) acetamide; 3fO-(3',3'-Dimethylsucciny)-21-oxolup-18-en-28-oic acid N-2-chloro-phen-1-yl acetamide; 3,OO-(3',3'-Dimethylsucciny)-21-oxolup-18-en-28-oic acid N-2-isopropyl-phen-1-yL acetamide; 3/-O-(3',3'-Dimethylsucciny)-21-oxolup-18-en-28-oic acid N-4-fluoro-phen-1-yL acetamide; 3/3O-(3',3'-Dimethylsuccinyt)-21-oxolup-18-en-28-oic acid N-quinazolin-2-y acetamide; 3-O-(3',3'-Dimethysucciny)-21-oxolup-18-en-28-oic acid N-(1-methyL-1H tetrazol-3-y)-acetamide; 3/O-(3',3'-Dimethysucciny)-21-oxoLup-18-en-28-oic acid N-(5-methyL-isoxazol-3 yl)-acetamide; 3/O-(3',3'-Dimethylsucciny)-21-oxotup-18-en-28-oic acid N-(1,3-dihydro-isoindo 2-yL)-acetamide; 3/-O-(3',3'-Dimethylsucciny)-21-oxolup-18-en-28-oic acid N-(4,4-diftuoro cyctohexylmethyl)-acetamide; 3-O-(3',3'-Dimethylsucciny)-21-oxoLup-18-en-28-oic acid N-4,4-difluoro piperidine acetamide; 3-O-(3',3'-Dimethysucciny)-21-oxoLup-18-en-28-oic acid N-8-acetylamino-3,8 diaza- bicyclo[3.2.1 ]octane-3-acetamide; and and pharmaceutically acceptable salts thereof. 47. A compound according to claim 27, wherein said compound is selected from: 3/3-0-(3',3'-Dimethylsucciny)-21-oxoLup-18-en-28-oic acid N-piperazinyl-acetamide hydrochloride salt; WO 2009/082818 PCT/CA2008/002290 99 3,6-0-(3',3'-Dimethylsucciny)-21-oxolup-18-en-28-oic acid N-(4-aminopiperidine) acetamide hydrochloride salt; 3-O-(3',3'-Dimethylsucciny)-21-oxolup-18-en-28-oic acid N-(2-amino-ethyl) acetamide hydrochloride salt; 3/-O-(3',3'-Dimethylsucciny)-21-oxolup-18-en-28-oic acid N-5-amino-1-methyL-1H pyrazole-acetamide hydrochloride salt; 3P-O-(3',3'-Dimethylsucciny)-21-oxolup-18-en-28-oic acid N-4-methyl-pyrimidin-5 yl-acetamide hydrochloride salt; 3P-O-(3',3'-Dimethylsuccinyl)-21-oxolup-18-en-28-oic acid N-4-methyl-pyrimidin-2 10 yl-acetamide hydrochloride salt; 3-O-(3',3'-Dimethylsuccinyt)-21-oxolup-18-en-28-oic acid N-4-amino-1-methyL-1H pyrazole-acetamide hydrochloride salt; and 3fO-(3',3'-Dimethylsucciny)-21 -oxolup-18-en-28-oic acid N-4,6-dimethyl pyrimidin-2-y-acetamide hydrochloride salt. 48. A compound according to claim 1, wherein said compound is selected from: 3/3O-(3',3'-Dimethylsucciny)-21-oxolup-18-en-28-oic acid N-benzylamide; 3-O-(3',3'-Dimethylsucciny)-21-oxolup-18-en-28-oic acid N-piperidinyl acetamide; 3/O-(3',3'-Dimethylsucciny)-21-oxoLup-18-en-28-oic acid N-benzamide; 3fO-(3',3'-Dimethylsucciny)-21-oxolup-18-en-28-oic acid N-1-acetylamino piperidine-4-carboxylic acid tert-butyl ester; 3f-O-(3',3'-Dimethylsucciny)-21-oxolup-18-en-28-oic acid N-(8-amino-3,8-diaza bicyclo[3.2.1 ]octane-3- benzamide)-acetamide; 3#-O-(3',3'-Dimethylsucciny)-21-oxolup-18-en-28-oic acid N-pyrimidin-2-yl acetamide; 3-O-(3',3'-Dimethylsucciny)-21-oxoLup-18-en-28-oic acid N-1-acetyl piperazine-4-carboxylic acid methyl ester; 3P-O-(3',3'-Dimethylsucciny)-21 -oxolup-18-en-28-oic acid N-2-methyl-phen-1-yL acetamide; 3P-O-(3',3'-Dimethylsucciny)-21-oxolup-18-en-28-oic acid N-(2,2,2-trifluoro-1 methyl-ethyl)-acetamide; WO 2009/082818 PCT/CA2008/002290 100 3-O-(3',3'-Dimethylsuccinyl)-21 -oxolup-1 8-en-28-oic acid N-(4,4-difluoro cyclohexylmethyl)-acetamide; 3AO-(3',3'-Dimethylsucciny)-21 -oxolup-1 8-en-28-oic acid N-4,4-difluoro piperidine acetamide; and and pharmaceutically acceptable salts thereof. 49. A compound selected from: 3f-O-Acetoxy-21-oxoLup-18-en-28-oic acid N-methylamide; 3,-O-Acetoxy-21-oxoLup-18-en-28-oic acid N-isopropylamide; 3f-O-Acetoxy-21-oxoLup-18-en-28-oic acid N-cyclohexylamide; 3/3-O-Acetoxy-21-oxoLup-18-en-28-oic acid N-cyclohexyl methylamide; 3/O-Acetoxy-21-oxoLup-18-en-28-oic acid N-piperidinyl acetamide; 3fi-O-Acetoxy-21 -oxoLup-1 8-en-28-oic acid N-morphoLyl acetamide; 3/-O-Acetoxy-21-oxoLup-18-en-28-oic acid N-(4-acetyl piperazinyl) acetamide; 3,GO-Acetoxy-21-oxolup-18-en-28-oic acid N-(4-methyl piperaziny) acetamide; 3f-O-Acetoxy-21 -oxolup-1 8-en-28-oic acid N-benzamide; 3f-O-Acetoxy-21 -oxoLup-1 8-en-28-oic acid N-methyl-N-benzylamide; 3p-O-Acetoxy-21-oxoLup-18-en-28-oic acid N-2-chloro-benzyLamide; 33O-Acetoxy-21-oxolup-18-en-28-oic acid N-3-chloro-benzyLamide; 38O-Acetoxy-21-oxoLup-18-en-28-oic acid N-4-chloro-benzyLamide; 3-O-Acetoxy-21-oxoLup-18-en-28-oic acid N-4-methoxy-benzyLamide; 3/O-Acetoxy-21-oxoLup-18-en-28-oic acid N-pyridin-2-ylmethylamide; 3p-O-Acetoxy-21-oxoLup-18-en-28-oic acid N-pyridin-3-yLmethylamide; 3flO-Acetoxy-21 -oxoLup-1 8-en-28-oic acid N-pyridin-4-yLmethytamide; 3/3O-Acetoxy-21-oxoLup-18-en-28-oic acid N- [2- (4-methoxy-pheny)-ethyl] -acetamide; WO 2009/082818 PCT/CA2008/002290 101 3,6-O-Acetoxy-21-oxolup-18-en-28-oic acid N- (2-acetylami no-ethyl)-carbamic acid tert butyl ester; 3P-O-Acetoxy-21-oxolup-18-en-28-oic acid N-pyridin-2-y-acetamide; 3/3O-Acetoxy-21-oxoLup-18-en-28-oic acid N-pyridin-3-yl-acetamide; 3,6-O-Acetoxy-21-oxotup-18-en-28-oic acid N-1-acetyl-piperazine-4-carboxylic acid tert-butyt ester; 3f-O-Acetoxy-21-oxolup-18-en-28-oic acid N- 1-(4-tert-butyl-dimethyl-siLanytoxy piperidin-1-y)-acetamide; 3/O-Acetoxy-21-oxotup-18-en-28-oic acid N-1-acetylamino-piperidine-4-carboxylic acid tert-butyl ester; 3/-O-Acetoxy-21-oxotup-18-en-28-oic acid N-(1- phenyt-ethyl)-acetamide; 3/-O-Acetoxy-21-oxotup-18-en-28-oic acid N-(1-methyl-1-phenyt-ethyl)-acetamide; 3,6-O-Acetoxy-21-oxotup-18-en-28-oic acid N-(tert-butyl)-acetamide; 3/-O-Acetoxy-21-oxotup-18-en-28-oic acid N-(8-amino-3,8-diaza-bicyclo[3.2. 1 ]octane 3-benzamide)-acetamide; 3p--Acetoxy-21 -oxoLup-1 8-en-28-oic acid N-4-piperazi-2-one-acetamide; 3p-O-Acetoxy-21 -oxotup-1 8-en-28-oic acid N-pyrimidin-2-yl-acetamide; 3p-O-Acetoxy-21-oxolup-18-en-28-oic acid N-(4- amino carboxylic acid tert-butyl ester-1 -piperidine)-acetamide; 3f-O-Acetoxy-21-oxoLup-18-en-28-oic acid N-4-(1-methyl-piperazi-2-one)-acetamide; 3fi-O-Acetoxy-21 -oxoLup- 1 8-en-28-oic acid N-2-methyl-phen- 1 -yl acetamide; 3fl-O-Acetoxy-21-oxotup-18-en-28-oic acid N-3-methyl-phen-1-yi acetamide; 3/-O-Acetoxy-21-oxoLup-18-en-28-oic acid N-4-methyl-phen-1-yL acetamide; 3pi-0-Acetoxy-21 -oxoLup-1 8-en-28-oic acid N-8-acetylamino-3,8-diaza-bicyclo[3.2.1 ]oc tane-3-carboxylic acid tert-butyl ester; 3p-O-Acetoxy-21-oxoLup-18-en-28-oic acid N-pyrimidin-5-yl-acetamide; 3/3-O-Acetoxy-21-oxoLup-18-en-28-oic acid N-pyridin-4-yL-acetamide; 3/-O-Acetoxy-21 -oxotup-1 8-en-28-oic acid N-3-amino-1 -methyl-1 H-pyrazole acetamide; 3p-O-Acetoxy-21 -oxoLup- 1 8-en-28-oic acid N-5-amino-1 -methyl-1 H-pyrazole acetamide; 3O-Acetoxy-21-oxoLup-18-en-28-oic acid N-4-methyl-pyrimidin-5-y-acetamide; WO 2009/082818 PCT/CA2008/002290 102 3p-0-Acetoxy-21-oxolup-18-en-28-oic acid N-4-methyl-pyrimidin-2-yl-acetamide; 3pl-O-Acetoxy-21 -oxolup-18-en-28-oic acid N-4-amino-1-methyl-1 H-pyrazole acetamide; 3pl-0-Acetoxy-21-oxoLup-18-en-28-oic acid N-4,6-dimethyl-pyrimidin-2-y-acetamide; 3#-O-Acetoxy-21-oxoLup-18-en-28-oic acid N-pyrazin-2-y-acetamide; 3p-O-Acetoxy-21-oxolup-18-en-28-oic acid N-quinoLin-3-y-acetamide; 3p-O-Acetoxy-21-oxotup-18-en-28-oic acid N-(2-pyrrolidin-1-yl-ethyl)-acetamide; 3p-O-Acetoxy-21 -oxolup-1 8-en-28-oic acid N-(5-methy-[1,3,4]oxadiazol-2-y) acetamide; 3f-0-Acetoxy-21-oxoLup-18-en-28-oic acid N-isoquinoin-4-y-acetamide; 3p-O-Acetoxy-21-oxoLup-18-en-28-oic acid N-pyrimidin-4-yl-acetamide; 3p-O-Acetoxy-21-oxoLup-18-en-28-oic acid N-2-trifluoromethyl-phen-1-yL acetamide; 3p-O-Acetoxy-21-oxoLup-18-en-28-oic acid N-(1-methyL-1H-tetrazol-5-yl)-acetamide; 3f-0-Acetoxy-21-oxoLup-18-en-28-oic acid N-cyclopropylmethyl acetamide; 3pi-O-Acetoxy-21 -oxoLup-1 8-en-28-oic acid N-azetidine-1 acetamide; 3p-O-Acetoxy-21-oxoLup-18-en-28-oic acid N-(2,2,2-trifluoro-ethyl)-acetamide; 3/O-Acetoxy-21-oxoLup-18-en-28-oic acid N-4-trifluoro-pyrimidin-2-yl-acetamide; 3p-O-Acetoxy-21 -oxoLup- 1 8-en-28-oic acid N-(1-cyclopropyl-1-methyl-ethyl) acetamide; 3p-O-Acetoxy-21 -oxoLup-1 8-en-28-oic acid N-(4-dimethylamino-piperidin-1-yl) acetamide; 3p-O-Acetoxy-21-oxoLup-18-en-28-oic acid N-(2,2,2-trifluoro-1-methyl-ethyl) acetamide; 3/O-Acetoxy-21 -oxoLup-1 8-en-28-oic acid N-(5-methyL-[1,3,4]thiadiazol-2-y) acetamide; 3fi-O-Acetoxy-21 -oxoLup-1 8-en-28-oic acid N-(2,2,2-trifluoro-1, 1 -dimethyl-ethyl) acetamide; 3,O-Acetoxy-21-oxoLup-18-en-28-oic acid N-tert-butyl-N-methyl-acetamide; 3p-O-Acetoxy-21-oxoLup-18-en-28-oic acid N-(R)-2-acetylaminomethyl-pyrrolidine -1-carboxylic acid tert-butyl ester; 3/O-Acetoxy-21-oxolup-18-en-28-oic acid N-(S)-2-acetylaminomethyl-pyrrolidine -1-carboxylic acid tert-butyl ester; WO 2009/082818 PCT/CA2008/002290 103 3-O-Acetoxy-21 -oxotup- 1 8-en-28-oic acid N- (4,4-difluoro-cyclohexyl) acetamide; 3/-O-Acetoxy-21-oxoLup-18-en-28-oic acid N-2-chloro-phen-1-yl acetamide; 3-O-Acetoxy-21-oxolup-18-en-28-oic acid N-2-isopropyl-phen-1-yL acetamide; 3fl-0-Acetoxy-21 -oxotup- 1 8-en-28-oic acid N-4-fluoro-phen- 1 -yl acetamide; 3/-0-Acetoxy-21 -oxolup- 1 8-en-28-oic acid N-qui nazolin-2-yl acetamide; 3/3O-Acetoxy-21-oxoLup-18-en-28-oic acid N-(1-methyl-1H-tetrazol-3-yl)-acetamide; 3/3-0-Acetoxy-21-oxoLup-18-en-28-oic acid N-(5-methyl-isoxazot-3-yl)-acetamide; 3/O-Acetoxy-21-oxolup-18-en-28-oic acid N-(1,3-dihydro-isoindol-2-yl)-acetamide; 3/O-Acetoxy-21 -oxoLup-1 8-en-28-oic acid N- (4,4-difluoro-cyclohexylmethyl) acetamide; 3AO-Acetoxy-21 -oxotup-1 8-en-28-oic acid N-4,4-difluoro-piperidine acetamide; and pharmaceutically acceptable salts thereof. 50. A compound selected from: 3fl-0-Hydroxy-21 -oxolup-1 8-en-28-oic acid N-methylamide; 3/3-O-Hydroxy-21-oxoLup-18-en-28-oic acid N-isopropylamide; 3/3-O-Hydroxy-21-oxoLup-18-en-28-oic acid N-cyclohexylamide; 3/0- Hydroxy-21-oxolup-18-en-28-oic acid N-cyclohexyl methylamide; 36O-Hydroxy-21-oxoLup-18-en-28-oic acid N-piperidinyl acetamide; 3/3-0-Hydroxy-21-oxoLup-18-en-28-oic acid N-morpholyl acetamide; 3/3-0-Hydroxy-21-oxolup-18-en-28-oic acid N-(4-acetyl piperazinyl) acetamide; 3-O-Hydroxy-21-oxolup-18-en-28-oic acid N-(4-methyl piperazinyl) acetamide; 3/-O-Hydroxy-21-oxolup-18-en-28-oic acid N-benzamide; 3-O-Hydroxy-21-oxoLup-18-en-28-oic acid N-methyl-N-benzylamide; 3/3O-Hydroxy-21 -oxolup-1 8-en-28-oic acid N-2-chloro-benzylamide; WO 2009/082818 PCT/CA2008/002290 104 3pO-Hydroxy-21-oxotup-18-en-28-oic acid N-3-chloro-benzylamide; 3f8-O-Hydroxy-21-oxolup-18-en-28-oic acid N-4-chloro-benzyLamide; 3-O-Hydroxy-21-oxolup-18-en-28-oic acid N-4-methoxy-benzylamide; 3#-O-Hydroxy-21-oxoLup-18-en-28-oic acid N-pyridin-2-ylmethylamide; 3-O-Hydroxy-21-oxoLup-18-en-28-oic acid N-pyridin-3-ylmethylamide; 3frO-Hydroxy-21 -oxolup-1 8-en-28-oic acid N-pyridin-4-ylmethylamide; 3fl-0-Hydroxy-21 -oxolup- 1 8-en-28-oic acid N- [2- (4-methoxy-phenyl)-ethyl] acetamide; 3fO-Hydroxy-21-oxoLup-18-en-28-oic acid N- (2-acetylamino-ethyl)-carbamic acid tert-butyl ester; 3fr0-Hydroxy-21 -oxolup-18-en-28-oic acid N-pyridin-2-yl-acetamide; 3,O-Hydroxy-21 -oxolup-1 8-en-28-oic acid N-pyridin-3-yl-acetamide; 3fiO-Hydroxy-21-oxoLup-18-en-28-oic acid N-1-acetyl-piperazine-4-carboxylic acid tert-butyl ester; 3frO-Hydroxy-21-oxolup-18-en-28-oic acid N- 1-(4-tert-butyl-dimethyl-siLanyLoxy piperidin-1-y)-acetamide; 36-O-Hydroxy-21-oxotup-18-en-28-oic acid N-1-acetylamino-piperidine-4-carboxylic acid tert-butyl ester; 3/O-Hydroxy-21-oxolup-18-en-28-oic acid N-(1 -phenyl-ethyl)-acetamide; 3#-0-Hydroxy-21-oxolup-18-en-28-oic acid N-(1-methyl-i-phenyt-ethyl)-acetamide; 3/-O-Hydroxy-21-oxoLup-18-en-28-oic acid N-(tert-butyl)-acetamide; 3#-O-Hydroxy-21 -oxolup-1 8-en-28-oic acid N-(8-amino-3,8-diaza bicyclo[3.2.1 ]octane-3-benzamide)-acetamide; 3,6O-Hydroxy-21-oxotup-18-en-28-oic acid N-4-piperazi-2-one-acetamide; 3/-O-Hydroxy-21-oxolup-18-en-28-oic acid N-pyrimidin-2-yl-acetamide; 3P-O-Hydroxy-21-oxoLup-18-en-28-oic acid N-(4- amino carboxylic acid tert-buty ester-1 -piperidine)-acetamide; 3#-O-Hydroxy-21-oxolup-18-en-28-oic acid N-4-(1-methyl-piperazi-2-one)-acetamide; 3/-O-Hydroxy-21-oxoLup-18-en-28-oic acid N-2-methyl-phen-1-yL acetamide; 3,-O-Hydroxy-21-oxoLup-18-en-28-oic acid N-3-methyl-phen-1-yl acetamide; WO 2009/082818 PCT/CA2008/002290 105 3/3-O-Hydroxy-21-oxolup-18-en-28-oic acid N-4-methyl-phen-1-yl acetamide; 3fl-O-Hydroxy-21 -oxoLup- 1 8-en-28-oic acid N-8-acetylamino- 3,8-diaza bicyclo[3.2.1 ]octane-3-carboxylic acid tert-butyl ester; 3/-O-Hydroxy-21-oxolup-18-en-28-oic acid N-pyrimidin-5-yl-acetamide; 3fi-O-Hydroxy-21 -oxolup-1 8-en-28-oic acid N-pyridin-4-yl-acetamide; 3/O-Hydroxy-21 -oxoLup- 1 8-en-28-oic acid N-3-amino-1 -methyl-1 H-pyrazole acetamide; 3/3O-Hydroxy-21 -oxolup-1 8-en-28-oic acid N-5-amino-1 -methyl-1 H-pyrazole acetamide; 3/3-O-Hydroxy-21-oxotup-18-en-28-oic acid N-4-methyl-pyrimidin-5-y-acetamide; 3/O-Hydroxy-21 -oxoLup-1 8-en-28-oic acid N-4-methyl-pyrimidin-2-yL-acetamide; 3/O-Hydroxy-21 -oxoLup-1 8-en-28-oic acid N-4-amino-1 -methyl-1 H-pyrazole acetamide; 3/3-O-Hydroxy-21-oxoLup-18-en-28-oic acid N-4,6-dimethyl-pyrimidin-2-yL-acetamide; 3fi-O-Hydroxy-21 -oxoLup- 1 8-en-28-oic acid N-pyrazin-2-y-acetamide; 3-O-Hydroxy-21-oxotup-18-en-28-oic acid N-quinotin-3-yL-acetamide; 3-O-Hydroxy-21-oxoLup-18-en-28-oic acid N-(2-pyrrolidin-1-y-ethyl)-acetamide; 3fl-O-Hydroxy-21-oxoLup-18-en-28-oic acid N-(5-methy-[1,3,4]oxadiazol-2-y) acetamide; 3/-O-Hydroxy-21-oxoLup-18-en-28-oic acid N-isoquinoin-4-y-acetamide; 3/3O-Hydroxy-21 -oxoLup-1 8-en-28-oic acid N-pyrimidin-4-yL-acetamide; 33-O-Hydroxy-21-oxoLup-18-en-28-oic acid N-2-trifluoromethyl-phen-1-yL acetamide; 3/3O-Hydroxy-21-oxolup-18-en-28-oic acid N-(1-methyL-1H-tetrazol-5-yL)-acetamide; 3,00- Hydroxy-21 -oxoLup- 1 8-en-28-oic acid N-cyclopropyLmethyl acetamide; 3-O-Hydroxy-21-oxoLup-18-en-28-oic acid N-azetidine-1 acetamide; 3/3-0-Hydroxy-21-oxoLup-18-en-28-oic acid N-(2,2,2-trifluoro-ethyL)-acetamide; 3/-O-Hydroxy-21-oxotup-18-en-28-oic acid N-4-trifluoro-pyrimidin-2-yL-acetamide; 3/3-O-Hydroxy-21-oxotup-18-en-28-oic acid N-(1-cyctopropyl-1-methyL-ethyL) acetamide; WO 2009/082818 PCT/CA2008/002290 106 3f-O-Hydroxy-21 -oxolup-1 8-en-28-oic acid N-(4-dimethylamino-piperidin-1 -yl) acetamide; 3#-O-Hydroxy-21 -oxolup-1 8-en-28-oic acid N-(2,2,2-trifluoro-1 -methyL-ethyl) acetamide; 3fl-O-Hydroxy-21 -oxolup-1 8-en-28-oic acid N-(5-methyt-[1,3,4]thiadiazol-2-yl) acetamide; 3,6-O-Hydroxy-21-oxotup-18-en-28-oic acid N-(2,2,2-trifluoro-1,1-dimethyl-ethyt) acetamide; 3p-O-Hydroxy-21-oxolup-18-en-28-oic acid N-tert-butyl-N-methyl-acetamide; 3/3O-Hydroxy-21-oxoLup-18-en-28-oic acid N-(R)-2-acetylaminomethyl-pyrroLidine -1-carboxylic acid tert-butyl ester; 3fl-0-Hydroxy-21 -oxoLup-1 8-en-28-oic acid N-(S)-2-acetylaminomethy-pyrrolidine -1 -carboxylic acid tert-butyl ester; 3,O-Hydroxy-21-oxotup-18-en-28-oic acid N-(4,4-difluoro-cyclohexy) acetamide; 3-O-Hydroxy-21-oxolup-18-en-28-oic acid N-2-chloro-phen-1-yl acetamide; 3/3-O-Hydroxy-21 -oxoLup- 1 8-en-28-oic acid N-2-isopropyl-phen- 1 -yl acetamide; 3fO-Hydroxy-21 -oxoLup- 1 8-en-28-oic acid N-4-fluoro-phen- 1 -yl acetamide; 3/-O-Hydroxy-21-oxolup-18-en-28-oic acid N-quinazotin-2-y acetamide; 3-O-Hydroxy-21 -oxolup-1 8-en-28-oic acid N-(1 -methyl-1 H-tetrazol-3-yl)-acetamide; 3/3-O-Hydroxy-21-oxoLup-18-en-28-oic acid N-(5-methyl-isoxazol-3-y)-acetamide; 3-O-Hydroxy-21-oxolup-18-en-28-oic acid N-(1,3-dihydro-isoindol-2-yl)-acetamide; 3fi-O-Hydroxy-21-oxoLup-18-en-28-oic - acid N- (4,4-difluoro-cyclohexyLmethy) acetamide; 3EA0-Hydroxy-21-oxoLup-18-en-28-oic acid N-4,4-difluoro-piperidine acetamide; and pharmaceutically acceptable salts thereof. 51. A compound according to any one of claims 1 to 50, wherein said compound is in the form of a pharmaceutically acceptable salt selected from hydrochloride salts, sodium salts, lithium salts, potassium salts, tromethamine salts, meglumine and L-arginine salts. 10 WO 2009/082818 PCT/CA2008/002290 107 52. A compound according to any one of claims 1 to 51 wherein the compound is in the form of the (+) enantiomer or the (-) enantiomer or a mixture thereof. 53. A pharmaceutical combination comprising a compound according to any one of claims 1 to 52 and at least one further antiviral agent. 54. The pharmaceutical combination according to claim 53, wherein said at least one further antiviral agent is a nucleoside reverse transcriptase 10 inhibitor, non-nucleoside reverse transcriptase inhibitor, protease inhibitor, attachment and fusion inhibitor, integrase inhibitor, or maturation inhibitor. 55. The pharmaceutical combination according to claim 54, wherein said at least one further antiviral agent is a nucleoside reverse transcriptase inhibitor chosen from 3TC (lamivudine, Epivir@), AZT (zidovudine, Retrovir@), Emtricitabine (Coviracil@, formerly FTC), d4T (2',3'-dideoxy 2',3'-didehydro-thymidine, stavudine and Zerit®), tenofovir (Viread®), 2',3'-dideoxyinosine (ddl, didanosine, Videx®), 2',3'-dideoxycytidine 20 (ddC, zalcitabine, Hivid®), Combivir@ (AZT/3TC or zidovudine/Lamivudine combination), Trivizir® (AZT/3TC/abacavir or zidovudine/lamivudine/abacavir combination), abacavir (1592U89, Ziagen®), Epzicom@ (abacavir and lamivudine), Truvada® (Tenofovir and emtricitabine), SPD-754 (apricitabine), Elvucitabine (ACH-126,443, (Beta-L-Fd4C), ALovudine (MIV-310), DAPD (amdoxovir), Racivir, phosphazid, stampidine, CMX-157, PPI-801/802 (formerly MIV-410), MIV 210, fozivudine tidoxil, KP-,1461, Fosalvudine (HDP 99.0003), 9-[(2 hydroxymethyL)-1,3-dioxoLan-4-yL]guanine, and 2-amino-9-[(2 hydroxymethyl)-1,3-dioxolan-4-yt]adenine. 30 56. The pharmaceutical combination according to claim 54, wherein said at least one further antiviral agent is a non-nucleoside reverse transcriptase inhibitor chosen Nevirapine (Viramune®, NVP, BI-RG-587), deLavirdine (Rescriptor®, DLV), efavirenz (DMP 266, Sustiva®), (+) Catanolide A, Capravirine (AG1549, formerly S-1153), DPCO83, MIV-150, TMC120, Intelence (etravirine®, TMC125), TMC-278 or BHAP (delavirdine), calanoLides, GW695634, RDEA806, RDEA427, RDEA640, UK- WO 2009/082818 PCT/CA2008/002290 108 453061, BILR355, VRX 840773 and L-697,661 (2-Pyridinone 3benzoxazoMeNH derivative). 57. The pharmaceutical combination according to claim 54, wherein said at least one further antiviral agent is a protease inhibitor chosen from nelfinavir (Viracepto, NFV), amprenavir (141W94, Agenerase®), indinavir (MK-639, IDV, Crixivan@), saquinavir (Invirase@, Fortovase@, SQV), ritonavir (Norvir®, RTV), lopinavir (ABT-378, Kaletra@), Atazanavir (Reyataz®, BMS232632), mozenavir (DMP-450), fosamprenavir 10 (GW433908), R0033-4649, Tipranavir (Aptivus®, PNU-140690), Darunavir (Prezista®, TMC114), SPI-256, Brecanavir (GW640385), P-1946, MK-8122 (formerly PPL-100) and VX-385. 58. The pharmaceutical combination according to claim 54, wherein said at least one further antiviral agent is a attachment and fusion inhibitor chosen from T-20 (enfuvirtide, Fuzeon@), T-1249, TRI-999, TRI-1144, Schering C (SCH-C), Vicriviroc (Schering D, SCH-D), FP21399, PRO-140, PRO 542, PRO 452, TNX-355, Aplaviroc (GW873140, AK602), TBR-220 (formerly TAK-220), TBR-652 (formerly TAK-652), PF-232798, Maraviroc 20 (Selzentry@, UK-427,857) or soluble CD4, CD4 fragments, CD4-hybrid molecules, BMS-806, BMS-488043, AMD3100, AMD070, AMD887, INCB9471, INCB15050, KRH-2731, KRH-3140, SJ-3366, SP-01A, sifuvirtide, and KRH-3955. 59. The pharmaceutical combination according to claim 54, wherein said at least one further antiviral agent is a integrase inhibitor chosen from S 1360, L-870,810, elvitegravir (GS9137, JKT 303), GS9137, L-870,812, raLtegravir (Isentresso, MK-0518), MK-2048, GSK1349572, and C-2507. 30 60. The pharmaceutical combination according to claim 54, wherein said at least one further antiviral agent is a maturation inhibitor chosen from Vivecon (MPC-9055) and Bevirimat PA-457. 61. The pharmaceutical combination according to claim 53, wherein said at least one further antiviral agent which is a zinc finger inhibitor and is azodicarbonamide (ADA). WO 2009/082818 PCT/CA2008/002290 109 62. The pharmaceutical combination according to claim 53, wherein said at least one further antiviral agent which is an antisense drug and is HGTV43. 63. The pharmaceutical combination according to claim 53, wherein said at least one further antiviral agent which is an immunomodulator, immune stimulator or cytokine chosen from interleukin-2 (IL-2, AldesLeukin, Proleukin), granulocyte macrophage colony stimulating factor (GM-CSF), 10 erythropoietin, Multikine, Ampligen, thymomodulin, thymopentin, foscarnet, HE2000, Reticulose, Murabutide, Resveratrol, HRG214, HIV-1 Immunogen (Remune), WF1O and EP HIV-1090. 64. The pharmaceutical combination according to claim 53, wherein said at least one further antiviral agent is chosen from 2',3'-dideoxyadenosine, 3'-deoxythymidine, 2',3'-dideoxy-2',3'-didehydrocytidine and ribavirin; acyclic nucleosides such as acyclovir and ganciclovir; interferons such as alpha-, beta-and gamma-interferon; glucuronation inhibitors such as probenecid; and TIBO drugs, HEPT, Pictovir@ (VGX-410) and TSAO 20 derivatives. 65. A pharmaceutical combination comprising a compound according to any one of claims 1 to 52 and an inhibitor of the cytochrome P450. 66. The pharmaceutical combination according to claim 65, wherein said inhibitor of the cytochrome P450 is atazanavir, clarithromycin, indinavir, itraconazoLe, ketoconazoLe, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, amprenavir, erythromycin, fluconazole, 30 fosamprenavir, grapefruit juice, fluvoxamine, fLuoxetine, macrolide antibiotics, sertraLine suLfaphenazoLe, TroLeandomycin, cycLosporine, cLomethiazoLe, atazanavir, mibefradil, vitamin E, bergamottin, or dihydroxybergamottin, or a pharmaceutically acceptable salt thereof. 67. The pharmaceutical combination according to claim 65, wherein the inhibitor of the cytochrome P450 is ritonavir or a pharmaceutical acceptable salt thereof. WO 2009/082818 PCT/CA2008/002290 110 68. A pharmaceutical combination according to anyone of claims 53 to 67, wherein the individual components of such combination are administered sequentially. 69. A pharmaceutical combination according to anyone of claims 53 to 67, wherein the individual components of such combination are administered simultaneously. 10 70. The pharmaceutical combination of anyone of claims 53 to 67 wherein said combination further comprises one or more pharmaceutically acceptable carrier. 71. A pharmaceutical composition comprising a compound according to anyone of claims 1 to 52 together with one or more pharmaceutically acceptable carrier. 72. A method for prevention or treatment of HIV infections in a subject in need of such treatment comprising administering to the subject a 20 therapeutically effective amount of a compound according to anyone of claims 1 to 52.
AU2008342536A 2008-01-03 2008-12-23 Novel C-21-keto lupane derivatives preparation and use thereof Abandoned AU2008342536A1 (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US1876608P 2008-01-03 2008-01-03
US61/018,766 2008-01-03
US3968008P 2008-03-26 2008-03-26
US61/039,680 2008-03-26
PCT/CA2008/002290 WO2009082818A1 (en) 2008-01-03 2008-12-23 Novel c-21-keto lupane derivatives preparation and use thereof

Publications (1)

Publication Number Publication Date
AU2008342536A1 true AU2008342536A1 (en) 2009-07-09

Family

ID=40823728

Family Applications (1)

Application Number Title Priority Date Filing Date
AU2008342536A Abandoned AU2008342536A1 (en) 2008-01-03 2008-12-23 Novel C-21-keto lupane derivatives preparation and use thereof

Country Status (7)

Country Link
EP (1) EP2240504A1 (en)
JP (1) JP2011508747A (en)
CN (1) CN101977924A (en)
AU (1) AU2008342536A1 (en)
CA (1) CA2711420A1 (en)
MX (1) MX2010007374A (en)
WO (1) WO2009082818A1 (en)

Families Citing this family (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2572631T3 (en) * 2008-01-25 2016-06-01 Chimerix, Inc. Methods of treating viral infections
US9067966B2 (en) 2009-07-14 2015-06-30 Hetero Research Foundation, Hetero Drugs Ltd. Lupeol-type triterpene derivatives as antivirals
LT3494972T (en) 2010-01-27 2024-03-12 Viiv Healthcare Company Combinations of dolutegravir and lamivudine for the treatment of hiv infection
EA201290632A1 (en) * 2010-02-11 2013-03-29 ГЛАКСОСМИТКЛАЙН ЭлЭлСи DERIVATIVES OF BETULINA
PL2534150T3 (en) 2010-02-12 2017-09-29 Chimerix, Inc. Methods of treating viral infection
AU2011248620B2 (en) 2010-04-26 2015-11-26 Chimerix, Inc. Methods of treating retroviral infections and related dosage regimes
WO2013020245A1 (en) * 2011-08-08 2013-02-14 Glaxosmithkline Llc Carbonyl derivatives of betulin
CN104844679B (en) * 2011-12-16 2017-03-01 葛兰素史克有限责任公司 The derivant of betulin
JO3387B1 (en) 2011-12-16 2019-03-13 Glaxosmithkline Llc Derivatives of betulin
CN103242413B (en) 2012-02-08 2015-08-26 江西青峰药业有限公司 Lupane triterpene system's derivative and pharmaceutical use thereof
EA201590862A1 (en) 2012-12-14 2016-05-31 ГЛАКСОСМИТКЛАЙН ЭлЭлСи PHARMACEUTICAL COMPOSITIONS
US9637516B2 (en) 2012-12-31 2017-05-02 Hetero Research Foundation Betulinic acid proline derivatives as HIV inhibitors
US20170129916A1 (en) 2014-06-26 2017-05-11 Hetero Research Foundation Novel betulinic proline imidazole derivatives as hiv inhibitors
SG11201702379TA (en) 2014-09-26 2017-04-27 Glaxosmithkline Ip No 2 Ltd Long acting pharmaceutical compositions
MA40886B1 (en) 2015-02-09 2020-03-31 Hetero Research Foundation Novel c-3 triterpenone with c-28 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
WO2017115329A1 (en) * 2015-12-30 2017-07-06 Hetero Research Foundation C-3 novel triterpenone derivatives as hiv inhibitors
US11116737B1 (en) 2020-04-10 2021-09-14 University Of Georgia Research Foundation, Inc. Methods of using probenecid for treatment of coronavirus infections

Also Published As

Publication number Publication date
CA2711420A1 (en) 2009-07-09
JP2011508747A (en) 2011-03-17
CN101977924A (en) 2011-02-16
MX2010007374A (en) 2010-10-05
WO2009082818A1 (en) 2009-07-09
EP2240504A1 (en) 2010-10-20
WO2009082818A8 (en) 2009-09-03

Similar Documents

Publication Publication Date Title
AU2008342536A1 (en) Novel C-21-keto lupane derivatives preparation and use thereof
EP2250185A1 (en) Novel lupane derivatives
US20110077251A1 (en) Novel 17 beta lupane derivatives
JP5755731B2 (en) Modified C-3 betulinic acid derivative C-28 amide as an HIV maturation inhibitor
US9505800B2 (en) Extended triterpene derivatives
CN103429607B (en) There is the triterpenoid that C-17 and C-3 of HIV maturation inhibit activities is modified
AU2016381072B2 (en) Fused Tricyclic Heterocyclic compounds as HIV integrase inhibitors
JP6186010B2 (en) C-19 modified triterpenoids having HIV maturation inhibitory activity
ES2957767T3 (en) Triterpenoids modified at C-3 and C-17 as HIV-1 inhibitors
MX2010011437A (en) Antioxidant inflammation modulators: oleanolic acid derivatives with saturation in the c-ring.
CA2634499A1 (en) Hydroxydihydropyridopy razine-1,8-diones and methods for inhibiting hiv integrase
US8431556B2 (en) C-21-keto lupane derivatives preparation and use thereof
AU2018225556A1 (en) Chemokine CXCR4 receptor modulators and uses related thereto
CA3101643C (en) Triterpene amine derivatives
WO2005023810A1 (en) Spirohydantoin compounds and methods for the modulation of chemokine receptor activity
HK1151030A (en) Novel c-21-keto lupane derivatives preparation and use thereof
HK1149019A (en) Novel lupane derivatives
WO2006000096A1 (en) Spirohydantoin compounds and methods for the modulation of chemokine receptor activity
WO2007065256A1 (en) Novel spiropiperidine compounds and methods for the modulation of chemokine receptor activity
HK1116775A (en) Novel spirotropane compounds and methods for the modulation of chemokine receptor activity

Legal Events

Date Code Title Description
MK1 Application lapsed section 142(2)(a) - no request for examination in relevant period