AU2008342537A1 - Novel lupane derivatives - Google Patents

Description

WO 2009/082819 PCT/CA2008/002291 1 NOVEL LUPANE DERIVATIVES This application is related to application Serial No. 61/018,759, filed January 3, 2008, and to application Serial No. 61/039,660, filed March 26, 2008, the entire disclosure of which is incorporated 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-Pol 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 2009/082819 PCT/CA2008/002291 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 (1.-C. Sun, et al. Bioorg. Med. Chem. Lett. 1998, 8, 1267-1272) derivatives were 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, 30 46, 5402-5414; 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 2009/082819 PCT/CA2008/002291 3 The present invention relates to a compound of formula (1):

CH

3 H3C O HGC

CH

3

CH

3 X

CH

3 R O

H

3 C CH. (I) wherein; R' is H, hydroxy protecting group or O O HO A A is C 1 - alkyl, C 2

-

8 alkenyL, or -(CH 2

)

1

-

2 0(CH 2

)

1

-

2 -; Y is C=O or C-Ry1Ry2 10 Ry 1 and Ry 2 are each independently H or -CH 3 ; X is NR 2

R

3 ; R R R' R 2 12 13C 0 N N R N N, R N,, R 0 0 0 5 R RR3,N-R3' R O R6 N YR4 N N O , or 0

R

2 is H, C.

12 alkyl which is unsubstituted or substituted one or more times by R 1 0 , C 212 alkenyl which is unsubstituted or substituted one or more times by R 1 0 , or C 2

-

12 alkynyl which is unsubstituted or substituted one or more times by R 1 0 ;

R

3 and R 3 ' are each independently H, C 1

.

12 alkyl which is unsubstituted or substituted one or more times by R 1 0 , C 2

.

1 2 alkenyl which is unsubstituted or substituted one or more times by R 1 0 , C 21 2 alkynyl which is unsubstituted or WO 2009/082819 PCT/CA2008/002291 4 substituted one or more times by R 1 0 , C 6

.

14 aryl which is unsubstituted or substituted one or more times by R 1 1 , C 7

.

16 aralkyl which is unsubstituted or substituted one or more times by R 1 1 , 5-12 member heteroaryl which is unsubstituted or substituted one or more times by R 1 1 , 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 1 2 , or 4-18 member heterocycle-alkyl which is unsubstituted or substituted one or more times by R 1 2 ; 10 R 3 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

R

4 is Cyl aLkyL which is unsubstituted or substituted one or more times by

R

1 0 , C 2 -1 aLkenyl which is unsubstituted or substituted one or more times by R 1 ", C 2 1 aLkynyl which is unsubstituted or substituted one or more times by R 1 0 , C2.

14 aryt 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 1 1 , 6-18 member 20 heteroaraLkyL which is unsubstituted or substituted one or more times by R 1 1 , 3-12 member heterocycLe which is unsubstituted or substituted one or more times by

R

1 , or 4-18 member heterocycle-alkyL which is unsubstituted or substituted one or more times by R 1 2 ;

R

5 and R 6 are each independently C 11 2 alkyl which is unsubstituted or substituted one or more times by R 1 0 , C 2

.

1 2 alkenyl which is unsubstituted or substituted one or more times by R 1 0 , C 2

.

1 2 alkynyl which is unsubstituted or substituted one or more times by R 1 0 , C 6

.

14 aryl which is unsubstituted or substituted one or more times by R 1 1 , C 7

.

1 6 aralkyL which is unsubstituted or 30 substituted one or more times by R 1 1 , 5-12 member heteroaryL which is unsubstituted or substituted one or more times by R 1 1 , 6-18 member heteroaraLkyl which is unsubstituted or substituted one or more times by R 1 1 , 3-12 member heterocycle which is unsubstituted or substituted one or more times by R", or 4-18 member heterocycle-akyL which is unsubstituted or substituted one or more times by R 1 2

;

WO 2009/082819 PCT/CA2008/002291 5

R

10 is halogen, oxo, 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.

4 alkyl) 2 , -NHC(O)H, -N(C 1

.

4 akyl)C(O)H, -N(C 14 alkyl)C(0)C 1 4 alkyl, -NHC(O)C 1

.

4 alkyl, -NHC(O)OC- 4 alkyl, -N(C 14 alkyl)C(0)OC 1 4 alkyl, -NHC(O)NH 2 , ,-N(C 1

.

4 alkyl)C(O)NH 2 , -NHC(O)NHC 1

.

4 atkyl, -N(C 1

.

4 alkyl)C(O)NHC 1

.

4 alkyl,-N(C 14 alkyl)C(O)N(C 1

.

4 alkyl) 2 , NHC(O)N(C 1 4 alkyl) 2 , -C(O)H, -C(O)C- 4 alkyl, C(O)OH, -C(0)OC 1 4 alkyl, OC(O)C 14 alkyl, -OC(O)NH(C 14 aLkyt), -OC(O)N(C 1 4 alkyl) 2 , -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

.

3 H, -S(0) 0

.

3

C

1

.

4 alkyl, -SO 2

NH

2 , -SO 2

NH(CI

4 alkyt), -SO 2

N(C

1

.

4 10 alkyL) 2 , -N(C 14 alkyl)S0 2

C

1 4 alkyl, -NHS0 2

C

14 alkyl, -P(O)(OH) 2 , -P(O)(OC 1 . 4 alkyl)OH, -P(O)(OCl- 4 atkyl) 2 , amidino, or guanidino; R" is halogen, C 1

.

6 alkyl, halogenated C 1

.

6 akyl, C 2

.

6 alkenyl, C 2

.

6 alkynyl, C 1

.

6 alkoxy, NH 2 , -NH(C 1 4 alkyl), -N(Cl 4 alkyl) 2 , -C(O)NH 2 , -C(O)NH(C 14 akyl), -C(O)N(Cl- 4 alkyL) 2 , -NHC(O)H, -N(C.

4 alkyl)C(O)H, -N(C 1 4 alkyl)C(O)C 14 alkyl, -NHC(O)Cl. 4 alkyl, -NHC(O)0C 1 4 alkyl, -N(C 1 4 alkyl)C(O)0C.

4 alkyl, -NHC(O)NH 2 , ,-N(CI- 4 alkyl)C(O)NH 2 , -NHC(O)NHC.

4 alkyl, -N(C 1

.

4 atkyl)C(O)NHC 1

.

4 alkyl,-N(C 1 .4 alkyl)C(O)N(C 1 4 alkyL) 2 , -NHC(O)N(C 14 alkyl) 2 , -C(O)H, -C(O)C 1 4 alkyl, C(O)OH, -C(0)OC 1 4 aLkyl, -OC(O)C 1

.

4 alkyl, -OC(O)NH(C 1

.

4 alkyl), -OC(O)N(Cl.

4 20 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) 03 H, -S(0) 0

.

3

C.

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, -P(O)(OH) 2 , -P(O)(OC 1 4 alkyl)OH, -P(O)(OC 1

.

4 akyl) 2 , amidino, or guanidino; 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(C.

4 alkyl) 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 14 alkyl)C(O)H, -N(C 14 alkyl)C(O)C 14 alkyl, 30 NHC(O)C 1 4 alkyl, -NHC(0)OCI.

4 alkyL, -N(C 1 4 alkyl)C(O)0C 1

.

4 alkyl, NHC(O)NH 2 , ,-N(Cl 4 alkyL)C(O)NH 2 , -NHC(O)NHC,- 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 alkyl) 2 , C(O)H, -C(O)C 1

.

4 alkyl, C(O)OH, -C(O)0C 1

.

4 alkyl, -OC(O)CI.

4 alkyl, OC(O)NH(C 14 alkyl), -OC(O)N(Cl.

4 alkyl) 2 , -C(NOH)C- 4 alkyl, -C(NOH)H, C(NOC 14 alkyl)C 14 alkyl, -C(NOC.

4 alkyL)H, hydroxyl, nitro, azido, cyano, S(0) 0

.

3 H, -S(0) 0

.

3 Cl.

4 alkyl, -SO 2

NH

2 , -S0 2

NH(C-

4 alkyl), -SO 2

N(C

1 4 alkyL) 2 , - WO 2009/082819 PCT/CA2008/002291 6

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 alkyl)OH, P(O)(OC1.

4 alkyl) 2 , amidino, or guanidino; or a pharmaceutically acceptable salt thereof. In further embodiments, the compounds of the inventions are represented by formula (I) wherein the following embodiments are present alone or in combination: 10 Y is C=0. Y is C-Ry 1 Ry 2 and Ry 1 and Ry 2 are each -CH 3 . Y is C-Ry 1 Ry 2 and Ry 1 and Ry 2 are each H.

R

1 is o 0 0 HOOC 0 ; HOOC 0; HOOC 0 o 0 HOOC"kj HOOC O ; HOOCNN-1 O HOOC HOOC 0 HOOC ,O 0 0 HOOC 0 or HOOC O WO 2009/082819 PCT/CA2008/002291 7

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.

R

1 is succinyl, glutaryl, 3-methylglutaryl, 3'-methylsuccinyl, T,3' dimethylsuccinyl, 3,3'- dimethylglutaryl, 2',2'-dimethylmalonyl, 2',3' dihydroxysuccinyl, 2',2',3',3'-tetramethylsuccinyl or 2',2'- dimethylsuccinyl. 10 R 1 is 3',3'-dimethylsuccinyt. In a further embodiment, R 1 is H, or a hydroxy protecting group. In a further embodiment, R 1 is H.

R

2 is H or C- 1 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 20 by R' 0 .

R

2 is H, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

R

2 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butyl.

R

2 is H.

R

3 ' is H. 30

R

3 and R 3 ' can also be taken together to 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 .

R

3 and R 3 ' can also be taken together to form a piperidyl, a piperazinyl, or a morpholinyl which is unsubstituted or substituted one or more times by R".

WO 2009/082819 PCT/CA2008/002291 8

R

3 is C- 1 2 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 , C 2 . 12 alkynyl 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 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 10 R 12 , or 4-18 member heterocycle-alkyl which is unsubstituted or substituted one or more times by R 1 .

R

3 is C 1

.

1 2 alkyl which is unsubstituted or substituted one or more times by

RI

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 20 one or more times by R 1 .

R

3 is C1.

6 alkyl which is 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 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 . 30

R

4 is C 1

.

2 alkyl which is unsubstituted or substituted one or more times by RIO, C 2

.

1 2 alkenyl which is unsubstituted or substituted one or more times by RIO, C 2 . 12 alkynyl which is unsubstituted or substituted one or more times by RIO, 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 1 , 5-12 member heteroaryl which is unsubstituted or substituted one or more times by R", 6-18 member WO 2009/082819 PCT/CA2008/002291 9 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'.

R

4 is Cl 1 2 alkyl which is unsubstituted or substituted one or more times by

R

1 ", C 6 aryl which is unsubstituted or substituted one or more times by R 1 1 , C 7

.

9 aralkyl which is unsubstituted or substituted one or more times by R 1 1 , 5-6 member heteroaryl 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 1 2 , or 7-8 member heterocycle-alkyl which is unsubstituted or substituted one or more times by R'.

R

4 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 which is unsubstituted or substituted one or more times by R 1 1 , 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 20 R", 5-6 member heterocycle which is unsubstituted or substituted one or more times by R1 2 , or 7-8 member heterocycle-alkyl which is unsubstituted or substituted one or more times by R 12 .

R

3 , R 4 , R 5 or R 6 are Cl 1

,

2 alkyl which is unsubstituted or substituted one or more times by R 1 0 .

R

3 , R 4 , R 5 or R 6 are C 1

.

6 alkyl which is unsubstituted or substituted one or more times by R 1 0 . 30 R 3 , R 4 , R 5 or R 6 are each independently methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyt.

R

3 , R 4 , R 5 or R 6 are each independently is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butyl.

WO 2009/082819 PCT/CA2008/002291 10

R

3 , R 4 , R 5 or R 6 are phenyl which is unsubstituted or substituted one or more times by R 1 1 .

R

3 , R 4 , R 5 or R 6 are phenyl.

R

3 , R 4 , R 5 or R 6 are 5-6 member heteroaryl which is unsubstituted or substituted one or more times by R".

R

3 , R 4 , R 5 or R 6 are is pyridyt which is unsubstituted or substituted one or 10 more times by R".

R

3 , R 4 , R 5 or R 6 are is 7-8 member heteroaralkyl which is unsubstituted or substituted one or more times by R".

R

3 , R 4 , R 5 or R 6 are -CH 2 -pyridyt which is unsubstituted or substituted one or more times by R".

R

3 , R 4 , R 5 or R 6 are 5-6 member heterocycle which is unsubstituted or substituted one or more times by R 1 . 20

R

3 , R 4 , R 5 or R 6 are piperidine which is unsubstituted or substituted one or more times by R".

R

3 , R 4 , R 5 or R 6 are 7-8 member heterocycle-alky which is unsubstituted or substituted one or more times by R 1 2

R

3 , R 4 , R 5 or R 6 are -CH 2 -piperidine which is unsubstituted or substituted one or more times by R 1 . 30 R 3 , R 4 , R 5 or R 6 are each independently ethyl, iso-propyl, tert-butyl, cyclopentyl, -CH 2 -cyclopentyl, cyclohexyl, -CH 2 -cyclohexyL, phenyl, benzyl, pyridinyl, -CH 2 -pyridinyL, piperidynyl, piperazinyl, thienyL, morpholino, oxadiazole, pyrimidinyt, pyranyt, pyrazinyt,.thiazole, and pyrazole, which are unsubstituted or substituted by one or more substituents chosen from a halogen, C 1

.

4 alkyl, C 1

.

4 alkyloxy, CF 3 , COC1.

4 alkyl, COOH, COOC 1

.

4 alkyl, cyano, NH 2 , nitro, NH(C 1

.

6 alkyl), and N(C 1

.

6 alkyl) 2

.

WO 2009/082819 PCT/CA2008/002291 11

R

3 is 5-6 member heteroaryl which is unsubstituted or substituted one or 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 pyridine which is unsubstituted or substituted one or more times by halogen, C 1 -3 alkyl, C 1 .3 alkoxy, or halogenated C 1

.

3 alkyl. 10

R

3 is pyrimidine which is unsubstituted or substituted one or more times by halogen, C 1

.

3 alkyl, C 1

.

3 alkoxy, or halogenated C 1

.

3 alkyl.

R

3 is pyrazole which is unsubstituted or substituted one or more times by halogen, C 1

.

3 alkyl, C 1

.

3 alkoxy, or halogenated CI- 3 alkyl.

R

3 is phenyl which is unsubstituted or substituted one or more times by halogen, C 1

.

3 alkyl, C 1

.

3 alkoxy, or halogenated C 1

.

3 alkyl. 20 R 3 is benzyl which is unsubstituted or substituted one or more times by halogen, C 1

.

3 alkyl, C 1

.

3 alkoxy, or halogenated C 1

.

3 alkyl.

R

3 is oxadiazole which is unsubstituted or substituted one or more times by halogen, C 1

-

3 alkyl, C 1

.

3 alkoxy, or halogenated C 1

.

3 alkyl.

R

3 is imidazole which is unsubstituted or substituted one or more times by halogen, C 1

.

3 alkyl, C 1

.

3 alkoxy, or halogenated C 1

.

3 alkyl.

R

3 is pyrrolidine which is unsubstituted or substituted one or more times by 30 halogen, C 1

.

3 alkyl, C 1

.

3 alkoxy, or halogenated C 1

.

3 alkyl.

R

3 is piperidine which is unsubstituted or substituted one or more times by halogen, C 1

.

3 alkyl, C 1

.

3 alkoxy, or halogenated C 1

.

3 alkyl.

R

3 is cyclohexyl which is unsubstituted or substituted one or more times by halogen, C 1

.

3 alkyl, C 1

.

3 alkoxy, or halogenated C 1

.

3 alkyl.

WO 2009/082819 PCT/CA2008/002291 12

R

3 is pyridine.

R

3 is methylpyridine.

R

3 is pyrimidine.

R

3 is pyrazine. 10 R 3 is pyrazole.

R

3 is methylpyrazole.

R

3 is thiadiazole.

R

3 is methylthiadiazole.

R

3 is oxadiazole. 20 R 3 is methyloxadiazole.

R

3 is piperidine.

R

3 is methylpiperidine.

R

3 is N-acetyL piperidine.

R

3 is cyclohexyt. 30 R 3 is difluorocyclohexyl.

R

4 is 5-6 member heteroaryl which is unsubstituted or substituted one or more times by R".

R

4 is 5-6 member heterocycle which is unsubstituted or substituted one or more times by R 1

.

WO 2009/082819 PCT/CA2008/002291 13

R

4 is pyridine which is unsubstituted or substituted one or more times by halogen, C 1 .3 alkyl, C 1

.

3 alkoxy, or halogenated C 1

.

3 alkyl.

R

4 is pyrimidine which is unsubstituted or substituted one or more times by halogen, C 1

.

3 alkyl, C 1

.

3 alkoxy, or halogenated C 1

.

3 alkyL.

R

4 is pyrazine which which is unsubstituted or substituted one or more times by halogen, C 1

.

3 alkyl, C 1

.

3 alkoxy, or halogenated C 1

.

3 alkyl. 10

R

4 is pyrazole which is unsubstituted or substituted one or more times by halogen, C 1

.

3 alkyl, C 1

.

3 alkoxy, or halogenated C 1

.

3 alkyl.

R

4 is phenyl which is unsubstituted or substituted one or more times by halogen, C 1

.

3 alkyl, C 1

.

3 alkoxy, or halogenated C 1

.

3 alkyl.

R

4 is benzyl which is unsubstituted or substituted one or more times by halogen, C 1

.

3 alkyl, C 1

.

3 alkoxy, or halogenated C 1

.

3 alkyl. 20 R 4 is thiazole which is unsubstituted or substituted one or more times by halogen, C 1

.

3 alkyl, C 1

.

3 aLkoxy, or halogenated C 1

.

3 alkyl.

R

4 is oxadiazole which is unsubstituted or substituted one or more times by halogen, C 1

.

3 aLkyl, C 1

.

3 alkoxy, or halogenated C 1

.

3 alkyl.

R

4 is imidazole which is unsubstituted or substituted one or more times by halogen, C 1 3 aLkyl, C 1

.

3 alkoxy, or halogenated C 1

.

3 alkyl.

R

4 is pyrrolidine which is unsubstituted or substituted one or more times by 30 halogen, C 1

.

3 alkyl, C 1

.

3 alkoxy, or halogenated C 1

.

3 aLkyl.

R

4 is piperidine which is unsubstituted or substituted one or more times by halogen, C 1

.

3 alkyl, C 1

.

3 alkoxy, or halogenated C 1

.

3 alkyl.

R

4 is cyclohexyl which is unsubstituted or substituted one or more times by halogen, C 1

.

3 alkyl, C 1

.

3 alkoxy, or halogenated C 1

.

3 alkyl.

WO 2009/082819 PCT/CA2008/002291 14

R

4 is pyridine.

R

4 is methylpyridine.

R

4 is pyrimidine.

R

4 is pyrazine. 10 R 4 is pyrazole.

R

4 is methylpyrazole.

R

4 is phenyl.

R

4 is fluorophenyL.

R

4 is benzyl. 20 R 4 is fluorobenzyl.

R

4 is thiazole.

R

4 is methylthiazole.

R

4 is oxadiazole.

R

4 is methyLoxadiazole. 30 R 4 is imidazole.

R

4 is methylimidazole.

R

4 is piperidine.

R

4 is methylpiperidine.

WO 2009/082819 PCT/CA2008/002291 15

R

4 is N-acetyl piperidine.

R

4 is thienyl.

R

5 is C 11 2 alkyl which is unsubstituted or substituted one or more times by

R

1 0 .

R

5 is C 1

.

6 alkyl which is unsubstituted or substituted one or more times by 10 R 0 .

R

5 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

R

5 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butyl.

R

6 is C 1

.

1 2 alkyl which is unsubstituted or substituted one or more times by

R

1 0 . 20 R 6 is C 1

.

6 alkyl which is unsubstituted or substituted one or more times by

R

1 0 .

R

6 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

R

6 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butyl.

R

1 0 is halogen, oxo, 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(C 1

.

4 alkyl) 2 , -NHCOH, -N(C 1

.

4 alkyl)COH, -N(C 1

.

4 alkyl)COC 1

.

4 30 ,alkyl, -NHCOC 1

.

4 alkyl, -NHCOOC 1

.

4 alkyl, -NHCONHC 1

.

4 alkyl, -N(C 1

.

4 alkyl)CONHC 1

.

4 alkyl,-N(C 1

.

4 alkyl)CON(C 1

.

4 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 1

.

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

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

1

.

4 alkyl, -NHS0 2

C

1

.

4 alkyl, P(O)(OH) 2 or P(O)(OC 1

.

4 alkyl) 2

;

WO 2009/082819 PCT/CA2008/002291 16 R1 0 is halogen, oxo, C 16 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 14 alkyl)COC 14 alkyl, -NHCOC 1

.

4 alkyl, -NHCOOC 14 alkyL, -NHCONHC 1 4 alkyl, -N(C 1 4 alkyl)CONHC 1 4 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(0)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

C

1 4 alkyl, -S0 2

NH

2 , -SO 2

NH(C

1

.

4 alkyl), SO 2

N(C

14 alkyl) 2 , -N(C 1 4 alkyl)S0 2

C

1 .4 alkyl, -NHS0 2

C

14 alkyl, or -P(O)(OH) 2 .

R

1 0 is halogen, oxo, -NH 2 , -NH(C 14 alkyt), -N(C 1

.

4 alkyt) 2 , -CONH 2 , -CONH(C 1 .4 10 alkyl), -CON(C 1 4 alkyt) 2 , -NHCOH, -N(C 14 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 alkyt, carboxy, -C(O)0C.4 alkyl, hydroxyl, C 1

.

4 alkoxy, nitro, nitroso, azido, or cyano. R1 0 is halogen, oxo, -NH 2 , -NH(C 1 4 alkyl), -N(Cl.

4 alkyL) 2 , -CONH 2 , -CONH(C 14 alkyl), -CON(C 14 alkyl) 2 , -NHCOH, -N(C 1 4 alkyl)COH, --N(C 1

.

4 alkyL)COC,.

4 alkyl, NHCOC 1

.

4 alkyl, -NHCo0C 1

.

4 alkyl, -NHCONHC 1 4 alkyl, -C(O)H, -C(O)C 1

.

4 aLkyl, carboxy, -C(0)OC 1 4 aLkyL, hydroxyl, C 1

.

4 alkoxy, nitro, azido, or cyano.

R

1 0 is halogen, oxo, -NH 2 , -NH(C 1 4 aLkyl), -N(C 1

.

4 alkyt) 2 , -CONH 2 , -CONH(C 14 20 alkyl), -CON(C 1

.

4 alkyl) 2 , -NHCOH, -N(C 14 alkyl)COH, -N(C 1 4 alkyl)COC 1 4 alkyl, NHCOC 1

.

4 alkyl, -NHCOOC 1 4 alkyl, -NHCONHC,.

4 alkyl, -C(O)H, -C(O)C 1

.

4 alkyl, carboxy, -C(O)0CI-4 alkyl, hydroxyl, or C 1 .4 alkoxy.

R

1 0 is halogen, oxo, -NH 2 , -NH(C 14 alkyl), -N(C 14 alkyl) 2 , -CONH 2 , -CONH(C 1

.

4 alkyL), -CON(C 1

.

4 alkyl) 2 , -N(C 1 4 alkyL)COC 1

.

4 alkyl, -NHCOC 1 4 alkyl, carboxy, C(O)0C 1 .4 alkyl, hydroxyl, C 1

.

4 alkoxy, or cyano. 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 1

.

4 alkyl), -CON(C 1

.

4 30 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.

4 alkyl, -N(C 1

.

4 alkyl)CONHC.

4 aLkyl, -N(C 1

.

4 alkyl)CON(Cl.

4 alkyL) 2 , -NHCON(C 1

.

4 alkyl) 2 , -C(O)H, -C(O)C.

4 alkyl, carboxy, C(O)0CI- 4 alkyl, -C(NOH)C 1

.

4 alkyl, -C(NOH)H, -C(NOCI.

4 alkyl)C 1

.

4 alkyL, -C(NOC 1

.

4 alkyL)H, hydroxyl, nitro, azido, cyano, -S(O)o.

2 H, -S(0) 0

.

2 Cl.

4 alkyl, -SO 2

NH

2 , SO 2

NH(C

1

.

4 alkyl), -SO 2 N(Cl.

4 atkyL) 2 , -N(C 1

.

4 alkyl)S0 2

C

1

.

4 alkyl, -NHSO 2

C

1

.

4 aLkyL, P(O)(OH) 2 or P(O)(OC 1

.

4 alkyl) 2

;

WO 2009/082819 PCT/CA2008/002291 17 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 14 alkyl) 2 , -CONH 2 , -CONH(C.

4 alkyl), -CON(C 1 . 4 alkyl) 2 , -NHCOH, -N(C 14 alkyl)COH, -N(C 1

.

4 alkyl)COC 1

.

4 alkyl, -NHCOC.

4 alkyl, NHCO0CI- 4 alkyl, -NHCONHC.

4 alkyl, -N(C 1

.

4 alkyl)CONHC,- 4 alkyl, -N(C 1 4 alkyl)CON(C 14 alkyl) 2 , -NHCON(Cj.

4 aLkyl) 2 , -C(0)H, -C(O)C 1

.

4 alkyl, carboxy, C(0)O C 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(CI-

4 alkyl), -S0 2

N(C

14 alkyl) 2 , -N(C 1 4 alkyl)S0 2

C

1

.

4 alkyl, -NHS0 2

C

1 4 alkyl, or -P(O)(OH) 2 . 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 14 alkyl), -N(C 1 4 alkyL) 2 , -CONH 2 , -CONH(C 1

.

4 alkyl), -CON(C 4 alkyl) 2 , -NHCOH, N(C 14 alkyl)COH, -N(C 14 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(0)OC 1 4 alkyl, hydroxyl, C 1

.

6 atkoxy, nitro, nitroso, 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(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 14 alkyl, -NHCOOC 1

.

4 alkyl, 20 NHCONHCj- 4 alkyl, -C(O)H, -C(O)C 1

.

4 alkyl, carboxy, -C(O)0C 1

.

4 alkyl, hydroxyl, C1.

6 alkoxy, nitro, azido, or cyano.

R

1 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 14 atkyl) 2 , -CONH 2 , -CONH(C 1

.

4 alkyl), -CON(C 1

.

4 alkyl) 2 , -NHCOH,

-N(C

14 alkyl)COH, -N(Cl.

4 alkyl)COC 1

.

4 alkyl, -NHCOC 1

.

4 alkyl, -NHCOOC 1

.

4 alkyl, NHCONHC 14 alkyl, -C(O)H, -C(O)C 14 alkyl, carboxy, -C(0)OCI.

4 alkyl, hydroxyl, or C 1

.

6 alkoxy. R" is halogen, C 1

.

6 alkyl, halogenated C 1

.

6 alkyl, C 2

.

6 alkenyl, C 2

.

6 alkynyl, -NH 2 , 30 -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 14 alkyL)COC,.

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, C 2

.

6 alkenyl, C 2

.

6 alkynyl,

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 1

.

4 alkyl) 2 , -NHCOH, -N(C 1

.

4 alkyl)COH, -N(C 1

.

4 alkyL)COC 1 4 ,atkyl, -NHCOC 1 4 alkyl, - WO 2009/082819 PCT/CA2008/002291 18

NHCOOC

1

.

4 alkyl, -NHCONHC 1 4 alkyl, -N(C 14 alkyl)CONHC 1

.

4 alkyl, -N(C 1 .4 alky)CON(C 1 4 alkyl) 2 , -NHCON(C 1

.

4 alkyt) 2 , -C(O)H, -C(O)C 1

.

4 alkyl, carboxy, C(O)0C 1 4 alkyl, -C(NOH)C 14 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

-

2 H, -S(0) 0

.

2

C

1

.

4 alkyl, -SO 2

NH

2 , SO 2

NH(C

14 alkyl), -S0 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 or P(O)(OC.

4 alkyl) 2 .

R'

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.

4 atkyl) 2 , -CONH 2 , -CONH(C 1

.

4 10 alkyl), -CON(CI.

4 alkyL) 2 , -NHCOH, -N(C 1

.

4 alkyl)COH, -N(C 1

.

4 alkyl)COC 1

.

4 ,alkyl, NHCOC 14 alkyl, -NHCOOC 14 alkyl, -NHCONHC 1

.

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 alkyL) 2 , -C(O)H, -C(O)C.

4 alkyl, carboxy, -C(0)0 C 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

C

14 alkyl, -SO 2

NH

2 , -SO 2 NH(Cl 4 alkyl), -SO 2

N(C

1

.

4 alkyl) 2 ,

-N(C

1

.

4 alkyl)SO 2

C.

4 alkyl, -NHS0 2

C

1 4 alkyl, or -P(O)(OH) 2 .

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.

4 alkyl), -N(C 1

.

4 alkyL) 2 , -CONH 2 , -CONH(C.

4 alkyt), -CON(C 1

.

4 alkyl) 2 , NHCOH, -N(C 1

.

4 alkyl)COH, -N(C 1

.

4 alkyl)COC 1

.

4 alkyl, -NHCOC.

4 alkyl, -NHCOOC.

4 20 alkyl, -NHCONHC 14 alkyl, -C(O)H, -C(O)C.

4 alkyl, carboxy, -C(0)OCI- 4 alkyl, hydroxyl, C 1

.

6 alkoxy, nitro, nitroso, azido, or cyano. R1 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.

4 alkyl), -N(C 1

.

4 atkyl) 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.

4 alkyl, -NHCOOC 1

.

4 alkyl, -NHCONHC 1

.

4 alkyl, -C(O)H, -C(O)Cl.

4 alkyl, carboxy, -C(0)OC 1 4 alkyl, hydroxyl, C 1 .6 alkoxy, nitro, azido, or cyano. R1 2 is halogen, oxo, C 1

.

6 alkyl, halogenated C 1

.

6 alkyl, C 2

.

6 alkenyl, C 2

-

6 alkynyl, 30 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 14 alkyl)COC 1

.

4 alkyl, -NHCOC 1 4 alkyl, -NHCOOC.

4 alkyl, -NHCONHC 1

.

4 alkyl, -C(O)H, -C(O)C 1

.

4 alkyl, carboxy, -C(O)0C 1

.

4 alkyl, hydroxyl, or C 1

.

6 alkoxy.

WO 2009/082819 PCT/CA2008/002291 19

R

1 2 is halogen, oxo, C 1

.

6 alkyl, halogenated C 1

.

6 alkyl, -NH 2 , -NH(C 14 alkyl), N(C 14 alkyl) 2 , -CONH 2 , -CONH(C 1 4 alkyl), -CON(C 1

.

4 alkyl) 2 , -N(C 14 alkyl)COC 1

.

4 alkyl, NHCOC 14 alkyl, carboxy, -C(0)OC 14 alkyl, hydroxyl, or C 16 alkoxy. In a further embodiment, the present invention relates to a compound of formula (II) or formula (Ila): CH3 CH3 H3C HC O Y R 1 CH, CH, N N CH, CH, N R3' R2 Ra' R 2 0 RO, - CH3 RO - CH3 H3C CH, HC CH, (01) (Ila) or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , and R 3 ' 10 are defined above. In a further embodiment, the present invention relates to a compound of formula (II) :

CH

3

H

3 C O CHs CH3I I

CH

3

H

3 C

CH

3 or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , and R 3 ' are defined above. In a further embodiment, the present invention relates to a compound of formula (Ill) : WO 2009/082819 PCT/CA2008/002291 20

CH

3 H3C O

H

3 C O Y

CH

3

CH

3 N R 4 - CH 3

H

3 C

CH

3 (Ill) or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , and R 4 are defined above. In a further embodiment, the present invention relates to a compound of formula (IV)

CH

3 H3C 0

H

3 C / O Y

-R

6

CH

3

CH

3 N 0 RO - CH 3

H

3 C CH. (IV) or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , and R 6 are defined above. 10 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. 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 20 (-) enantiomers). All such enantiomers and mixtures thereof including racemic mixtures are included within the scope of the invention. The single optical isomers WO 2009/082819 PCT/CA2008/002291 21 or enantiomers can be obtained by methods well known in the art, such as chiral HPLC, enzymatic resolution and chiral auxiliary. 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. 10 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 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. 20 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 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, 30 hydrobromic, suLphuric, nitric, perchloric, fumaric, maLeic, phosphoric, glycolLic, lactic, salicylic, succinic, toluene-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.

WO 2009/082819 PCT/CA2008/002291 22 Salts derived from amino acids are also included (e.g. L-Arginine, L-Lysine). 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. 10 In one embodiment of the invention, the pharmaceutically acceptable salt is a sodium salt. 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. 20 In one embodiment of the invention, the pharmaceutically acceptable salt is a tromethamine salt. In one embodiment of the invention, the pharmaceutically acceptable salt is an L-Arginine salt. In one embodiment of the invention, the pharmaceutically acceptable salt is a meglumine salt. It will be appreciated by those skilled in the art that the compounds in 30 accordance with the present invention can exist in different polymorphic forms. As 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 WO 2009/082819 PCT/CA2008/002291 23 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 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. 10 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 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 20 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, pentenyL, pentadienyL, hexenyl, hexadienyL, hexatrienyL, heptenyl, heptadienyL, heptatrienyl, octenyL, octadienyL, octatrienyL, octatetraenyL, propynyl, butynyL, pentynyl, hexynyL, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexenyt, cyclohexdienyL 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 30 hydrogen atom is replaced by a halogen, e.g., an alkythaLide. Examples of haloalkyls include but are not limited to trifluoromethyl, difluoromethyl, 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, WO 2009/082819 PCT/CA2008/002291 24 carboxy, -C(=NRd)NReRf, azido, cyano, C 1

.

6 alkyloxy, C 2

-

6 alkenyloxy, C 2

.

6 alkynyloxy, --N(Rd)C(=NRe)-NRfRg, hydroxyl, nitro, nitroso, -N(Rh)CONRiRj, -S(O)o- 2 Ra, -C(O)Ra, C(O)ORa , -SO2NRaRb, -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 terms "cycloalkyl" and "cycloalkenyl" 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), 10 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, 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 (-0-alkyl), alkenyloxy (-0-alkenyl) and alkynyloxy (-0-alkynyl) groups can also be optionally substituted. Examples include but are not limited to methoxy, ethoxy, propoxy, isopropoxy, butoxy, 20 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(=NR)NReRf, azido, cyano, -N(Rd)C(=NRe)NRRg, hydroxyl, nitro, nitroso, C 1

.

6 alkyl, 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. 30 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 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, - WO 2009/082819 PCT/CA2008/002291 25 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, 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, -OCONReRf and/or -NRaCOORb, wherein Ra-Rj are each independently H, C 1

.

4 alkyl, C 2

.

4 alkenyl, or C 2

.

4 alkynyL. 10 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 (-0-aryl) 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)NRRg, hydroxyl, nitro, -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(O)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, 20 NRaSO 2 Rb, NRaSO 2 NRbRc, CRaN=ORb, -OCONR.Rf 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 optionally substituted by, for example, halogens, NRdRe, -CONRdRe, -NRdCORe, carboxy, -C(=NRd)NR.Rf, azido, cyano, 30 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, -NRaS0 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 2009/082819 PCT/CA2008/002291 26 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 limited to azetidinyl, dioxolanyl, morpholinyl, morpholino, oxetanyl, piperazinyl, piperidyl, piperidino, cyclopentapyrazolyl, 10 cyclopentaoxazinyl, cyclopentafuranyl, tetrahydrofuranyl, tetrahydrothiofuranyl, tetrahydrothiofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl dioxyde, thiazolinyl, oxazolinyl, pyranyt, thiopyranyl, aziridinyl, azepinyl, dioxazepinyt, diazepinyt, oxyranyl, oxazinyl, pyrrolidinyl, thiopyranyl, thiolane, pyrazolidinyl, dioxanyl, and imidazolidinyt. Where indicated, the heterocyclic groups can be optionally substituted by, for example, halogens, oxo, -NRdRe, -CONRdRe, =NO-Re, NRdCORe, carboxy, -C(=NRd)NR.Rf, azido, cyano, -N(Rd)C(=NRe)NRfRg, hydroxyl, nitro, nitroso, -N(Rh)CONRiRj, C 1

.

6 alkyl, C 2

.

6 alkenyt, C 2

.

6 alkynyt, C 7

.

1 2 aralkyl,

C

6

.

12 aryl, C 1

.

6 alkyloxy, C 2

-

6 alkenyloxy, C 2

-

6 alkynyloxy, S(0)o.

2 Ra, C 6

.

1 o aryl, C 6

.

1 0 20 aryloxy, C 7

.

1 0 arylalkyl, C 6

.

1 0 aryl-C 1

.

10 alkyloxy, -C(0)Ra, -C(0)ORa, -SO 2 NRaRb, NRaS0 2 Rb, -NRaS0 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 "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 heterocycle-alkyl 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, the following groups are encompassed by a 7 30 member heterocycle-alkyl (* represents the attachment point): N N CH 3 S 0 * * * * WO 2009/082819 PCT/CA2008/002291 27 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)NRRg, hydroxyl, nitro, nitroso, -N(Rh)CONRiRj, C 1

.

6 alkyl, C 2

.

6 alkenyl, C 2

.

6 alkynyt, C 1

.

6 alkyloxy, C 2

.

6 alkenyloxy, C 2

.

6 alkynyloxy, S(O)o.

2 Ra, C 6

.

1 0 aryl, C 6

.

1 0 aryloxy, C 710 arylalkyl, C 6 . 10 aryl-C 1 .1o 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

.

4 alkyl, C 2

.

4 alkenyt or C 2 .4 alkynyt. 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, pyrimidinyt, pyridyt, pyrazolyl, pyrrolyl, thiatriazolyl, tetrazolyl, thiadiazolyl, triazolyt, thiazolyl, thienyl, tetrazinyt, thiadiazinyt, triazinyt, thiazinyt, 20 furoisoxazolyl, imidazothiazolyl, thienoisothiazolyl, thienothiazoyl, imidazopyrazolyl, pyrrolopyrrolyl, thienothienyl, thiadiazolopyrimidinyl, thiazolothiazinyl, thiazolopyrimidinyl, thiazolopyridinyl, oxazolopyrimidinyl, oxazolopyridyl, benzoxazolyl, benzisothiazolyl, benzothiazolyl, imidazopyrazinyl, purinyl, pyrazolopyrimidinyl, imidazopyridinyl, benzimidazoyl, indazolyl, benzoxathiolyl, benzodioxolyl, benzodithiolyl, indolizinyl, indolinyl, isoindolinyl, furopyrimidinyl, furopyridyl, benzofuranyl, isobenzofuranyl, thienopyrimidinyl, thienopyridyl, benzothienyl, benzoxazinyt, benzothiazinyt, quinazolinyt, naphthyridinyt, quinolinyt, isoquinolinyt, benzopyranyt, pyridopyridazinyl and pyridopyrimidinyt. Where 30 indicated the heteroaryl groups can be optionally substituted by, for example, halogens, -NRdRe, -CONRdRe, -NRdCORe, carboxy, -C(=NRd)NR.Rf, azido, cyano, -N(Rd)C(=NRe)NRfRg, 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) 0

-

2 Ra, C 6

.

1 0 aryl, C 6

.

1 0 aryloxy, C 7

.

1 0 arylalkyl, C 6 .1o aryl-C 1

.

1 o alkyloxy, C(0)Ra, -C(0)ORa, -S0 2 NRaRb, -NRaSO 2 Rb, -NRaS0 2 NRbRe, -CRaN=ORb, -OCONReRf WO 2009/082819 PCT/CA2008/002291 28 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 "heteroaralkyl" 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,-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, 10 C 2

-

6 alkynyloxy, S(0)o.

2 Ra, C 6

.

1 0 aryl, C 6

.

1 0 aryloxy, C 7

.

1 0 arylalkyl, C 6

.

1 0 aryl-C 1

.

1 0 alkyloxy, -C(O)Ra, -C(O)ORa, -SO 2 NRaRb, -NRaSO2Rb, -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. It is understood that in a 6-18 member heteroaralkyl moiety, the 5-18 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 * * * * 20 "Halogen atom" is specifically a fluorine atom, chlorine atom, bromine atom or iodine atom. 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. - 30 may be either a single or double bond.

WO 2009/082819 PCT/CA2008/002291 29 The term "guanidino" represents -N(Rd)C(=NRe)NRfRg wherein Rd, Re, Rf 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 aryt, and C 7

.

1 2 aralkyl, or Rf and Rg 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. The term "amidino" represents -C(=NRd)NRRf wherein Rd, Re and Rf are each independently selected from H, C 11 0 alkyl, C2- 1 0 alkenyl, C 2 .10 alkynyl, C 6

-

1 2 aryl, and C 7

.

1 2 aralkyl, or Re and Rf are taken together with the 10 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 "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 pulbication, 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. 20 When there is a sulfur atom present, the sulfur atom can be at different oxidation levels, i.e., S, SO, or S02. All such oxidation levels are within the scope of the present invention. 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 30 formula (1) or 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 administering to the subject a therapeutically effective amount of a compound of formula (I) or composition of the invention.

WO 2009/082819 PCT/CA2008/002291 30 In another embodiment, there is provided the use of a compound, composition or combination of the invention for the manufacture of a medicament for treating or preventing HIV infections in a subject in need of such treatment. In another embodiment, there is provided the use of a compound, composition or combination of the invention for the manufacture of a medicament for blocking cellular entry of HIV in a subject. In another embodiment, there is provided the use of a compound, 10 composition or combination of the invention for the manufacture of a medicament for delaying the onset of AIDS or treating AIDS in a subject in need of such treatment. 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 pharmaceutical combination comprising at least one compound of formula (I) and at least one further therapeutic agent. 20 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 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 30 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 analog reverse transcriptase inhibitors chosen from 3TC (lamivudine, Epivir@), AZT WO 2009/082819 PCT/CA2008/002291 31 (zidovudine, Retrovir@), Emtricitabine (Coviracil@, formerly FTC), d4T (2',3' dideoxy-2',3'-didehydro-thymidine, stavudine and Zerit®), tenofovir (Vireado), 2',3'-dideoxyinosine (ddl, didanosine, Videx®), 2',3'-dideoxycytidine (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, 10 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-y]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, 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 20 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 (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. 30 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), TBR-652 (formerly TAK-652), PF-232798, Maraviroc (Selzentry@, UK-427,857) or WO 2009/082819 PCT/CA2008/002291 32 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. 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. 10 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). In another embodiment, the pharmaceutical combination of this invention may contain at least one other antiviral agent which is an antisense drug and is 20 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), erythropoietin, Mutikine, AmpLigen, thymomodulin, thymopentin, foscarnet, HE2000, Reticulose, Murabutide, Resveratrol,. HRG214, HIV-1 Immunogen (Remune), WF1O and EP HIV-1090. 30 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.

WO 2009/082819 PCT/CA2008/002291 33 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, 10 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. 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 20 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. In a further embodiment, the compound of formula (1) and at least one further therapeutic agent are administered sequentially. 30 In a further embodiment, the compound of formula (1) and at least one further therapeutic agent are administered simultaneously. Thus, a further embodiment of the invention is a kit for use in administering a combination, 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 WO 2009/082819 PCT/CA2008/002291 34 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 (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. 10 The terms "host" or "patient" or "subject" means a human, male or female, for example, a child, an adolescent, or an adult. 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 20 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. 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. 30 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 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 WO 2009/082819 PCT/CA2008/002291 35 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 as or differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art. 10 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 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. 20 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 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. 30 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 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 WO 2009/082819 PCT/CA2008/002291 36 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. The compounds according to the invention may also be formulated for parenteral administration (e.g. by injection, for example, bolus injection or 10 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 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 20 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 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 30 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 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 WO 2009/082819 PCT/CA2008/002291 37 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 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. 10 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 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, 20 trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be 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 30 insufflator. 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: WO 2009/082819 PCT/CA2008/002291 38 Cpd# Name 14-1 3p-0-(3', 3'-Dimethylsuccinyl)- 1 7pi-tert-butyloxycarbonylamino 21-oxolup-18-ene; 14-2 3p-0-(cis-Cyclohexane-3'-carboxylic acid-i'-carboxyl) -17p3 [N-tert-butyloxycarbonyL-amino]-21-oxoLup-18-ene; 3p-O-[(1'R,3'S)-1',2',2'-Trimethyl-cyclopentane-3'-carboxylic 14-3 acid-i'-carboxyl]-17p3-[N-tert-butyloxycarbonyL-amino]-21 oxolup-18-ene; 15-1 3p8-0-(3',3'-Dimethylsucciny)-17p8-amino-21-oxotup-18-ene; 15-2 3p-0- (cis-Cyclohexane-3 '-carboxylic acid-i'-carboxyl)- 1 7/ amino-21 -oxolup-1 8-ene; 15-3 3p6-0-[(1'R,3'S)-1',2',2'-Trimethyl-cyclopentane-3'-carboxylic acid-i '-carboxyl]-1 7p6-amino-21 -oxolup-1 8-ene; 16-1 3p8-0-(3',3'-Dimethylsucciny)-17p8-(1-tert butyloxycarbonylpiperidine-4-amino]-21-oxoLup-18-end; 16-2 3p-0-(3',3'-Dimethylsucciny)-17p-(methylamino)-21-oxoLup 18-ene; 17-1 3p-0-(3',3'-Dimethylsucciny)-17p-[N'-(benzyl)ureido]-21 oxoLup-18-ene; 17-2 3p6-0-(3',3'-Dimethylsucciny)-17p-[N'-(ethyl)ureido]-21 oxotup-18-ene; 17-3 3p8-0-(3',3'-Dimethylsucciny)-17p-[N'-(phenyt)ureido]-21 oxolup-18-ene; 17-4 3p-0-(3',3'-Dimethylsucciny)-17p-[N'-(isopropyL)ureido]-21 oxotup-18-ene; 17-5 3p-0-(3',3'-Dimethylsucciny)-17p-[N'-(tert-butyl)ureido]-21 oxoLup-18-ene; 17-6 3p-0-(3',3'-Dimethylsucciny)-17p-[N'-(pyridin-3-yt)ureido]-21 oxoLup-18-ene; 17-7 3p-0-(3',3'-Dimethylsucciny)-17p-[N'-(cyclohexyl)ureido]-21 oxolup-18-ene; WO 2009/082819 PCT/CA2008/002291 39 17-8 3p-O-(3',3'-Dimethylsucciny)-1 7#-[N' (cyclohexylmethyl)ureido]-21 -oxoLup-1 8-ene; 17-9 3p-O-(3',3'-Dimethysuccinyl)-17p-[N'-(1 -tert butyloxycarbonyl-piperidin-4-yl)-ureido]-21 -oxoLup- 1 8-ene; 17-10 3p-0-(3',3'-Dimethylsucciny)-1 7p-(N'-piperidin-4-yl-ureido) 21 -oxolup-1 8-ene; 17-11 3p-O-(3',3'-Dimethylsuccinyl)-1 7p-[N'-(1 -acetylpiperidin-4-yl) ureido]-21 -oxolup-1 8-ene; 17-12 3p-0-(3',3'-Dimethylsucciny)-1 7p8-[N'-(pyridin-3 ylmethyl)ureido] -21 -oxotup- 1 8-ene; 17-13 38-0-(3',3'-Dimethylsucciny)-17p8-[(morpholine-4-carbony) amino]-21 -oxolup-1 8-ene; 17-14 3p-0- (3', 3'-Dimethylsuccinyt)- 17p- [(4-tert-butyloxycarbonyt piperazine-1 -carbonyt)-amino]-21 -oxoLup-1 8-ene; 17-15 3p9-0-(3',3'-Dimethylsuccinyl)-1 7p-[(piperazine-1 -carbonyt) amino]-21 -oxotup-1 8-ene; 17-16 3p8-0-(3',3'-Dimethylsuccinyt)-1 7p-[(4-methyl-piperazine-1 carbonyl)-amino]-21 -oxoLup-1 8-ene; 17-17 3p-0-(3',3'-Dimethylsuccinyt)-1 7p8-[(4-acetyl-piperazine-1 carbonyt)-amino]-21 -oxotup-1 8-ene; 17-18 3p6-0-(3', 3'-Dimethylsuccinyt)- 17p3-[N'-isopropyl-N'-methyl ureido]-21 -oxotup-1 8-ene; 17-19 3p-0-(3',3'-Dimethylsuccinyl)-1 7p-(N'-5-methyl [1,3,4]oxadiazol-2-yl-ureido)-21 -oxotup-1 8-ene; 3p6-0- (3', 3'-Dimethylsuccinyl)- 1 7p-[(4-tert 17-20 butoxycarbonylamino-piperidine-1 -carbonyt)-amino]-21 oxoLup-18-ene; 17-21 3-0- (3', 3'-Dimethylsuccinyt)- 17p8- (N'-cyclopropylmethyl ureido)-21 -oxotup-18-ene; 17-22 3p-0-(3',3'-Dimethylsuccinyt)-1 7p-(N'-cyctopropyl-ureido)-21 oxotup-18-ene; 17-23 3p-0-(3',3'-Dimethylsuccinyl)-1 7p-[(4-amino-piperidine-1 carbonyt)-amino]-21-oxotup-18-ene trifluoroacetate; WO 2009/082819 PCT/CA2008/002291 -40 17-24 3/3-O-(3',3'-Dimethysucciny)-1 7,8-[(4-amino-piperidine-1I carbonyL)-amino] -21 -oxolup- 1 8-ene; 17-25 3,-O-(3',3'-Dimethy~succiny)-1 7/J-(N'-pyridin-2-yL-ureido)-21 oxotup- 18-ene; 17-26 3,8--(3',3'-Dimethylsuccinyt)-1 7fr-(N'-pyridin-4-yL-ureido)-21 oxolup-1I8-ene; 17-27 3/3-0-(3',3-Dimethylsucciny)-1 7/3-[N'-(pyridin-2 ytmethyL)ureido]-21 -oxotup-1 8-ene; 17-28 3/--(3',3'-Dimethytsuccinyt)-1 7fi-[N'-(1 -methyl-piperidin-4 y~methyl)-ureido] -21 -oxotup- 1 8-ene; 17-29 3,8-O-(3',3'-Dimethylsucciny[)-1 7/3-[(4-isopropyl-piperazine-1 carbonyt)-aminoj-21 -oxotup-1 8-ene; 17-30 3,8-O-(3',3'-Dimethy~succinyl)-1 7/3-[N'-(1 -methyl-piperidin-4 yl)- ureido]-21 -oxotup-1 8-ene; 17-31 3,8-0-(3',3'-DimethyLsuccinyl)-173-[N'-(pyridin-4 y~methyL)ureido] -21 -oxotup-l18-ene; 17-32 3,8-O-(3' ,3'-Dimethylsuccinyl)-1 7f-(N'-pyrimidin-2-yL-ureido) 21 -oxotup-1I8-ene; 17-33 3,8O-(3',3'-Dimethylsuccinyt)-1 7,8-[N'-(1-tert butyLoxycarbonyL-azetidi n-3-yL)- ureido] -21 -oxotup- 18-ene; 3,8-0-(3',3'-DimethyLsuccinyt)-1 7,8- [(3-(S)-1 -tert 17-34 butyLoxycarbonyL- pyrrolidin-2-yimethyL)- ureido] -21 -oxotup- 18 ene; 17-35 3,6-0-(3',3'-Dimethysuccinyt)-1 7,-[azetidin-3-yL-ureido)]-21 oxotup- 18-ene; 3,8-0- (3', 3'- DimethyLsuccinyL)- 17,8- [(4- (tert-butyLoxycarbonyL 17-36 methyt-amino)-piperidine-l1-carbonyL)-amino] -21 -oxoiup- 18 ene; 17-37 3,8-O-(3',3'-DimethyLsuccinyL)-1 7/3[N'-(1-methyL-i H-pyrazoL-4 yt)ureido]-21 -oxolup-18-ene; 17-38 3/3O-(3',3'-DimethyLsucciny)-1 7/3-(3-(S)-1 -pyrrotidin-2 y~methyL-ureido)-21 -oxotup- 1 8-ene; 17-39 3,6-0- (3', 3'- DimethyLsuccinyL)- 17,8-[(4-methyLamino-piperidine 1 -carbonyL)-amino] -21 -oxotup- 1 8-ene; WO 2009/082819 PCT/CA2008/002291 41 3p1-0- (3',3'-Dimethylsucciny)-1 7#-[((R)-3-tert 17-40 butyloxycarbonyl amino- pyrrolidine- 1 -carbonyl)-amino]-21 oxotup-18-ene; 3#-0- (3', 3'-Dimethylsuccinyl)- 1 7p-[((S)-3- tert 17-41 butyloxycarbonyl amino- pyrrolidine- 1-carbonyt)-amino]-21 oxolup-18-ene; 17-42 3P/O-(3',3'-Dimethylsuccinyt)-17p-[((R)-3-amino-pyrrolidine-1 carbonyt)-amino]-21 -oxotup-1 8-ene; 17-43 3p-0-(3',3'-Dimethylsuccinyt)-1 7p6-[((S)-3-amino-pyrrolidine-1 carbonyt)-amino]-21 -oxotup-18-ene; 17-44 3pl-0-(3',3'-Dimethylsucciny)-1 7p-(N'-pyrimidin-5-yl-ureido) 21 -oxotup-1 8-ene; 17-45 3#-0-(3',3'-Dimethylsuccinyt)-1 7p-(N'-5-methyl [1,3,4]thiadiazo-2-y-ureido)-21 -oxolup-1 8-ene; 17-46 3p8-0- (3',3'-Dimethylsuccinyt)-17p1-(N'-pyrimidin-4-yl-ureido) 21 -oxotup-18-ene; 17-47 3#-0- (3',3'-Dimethylsuccinyt)-17p1-(N'-2-methylpyridin-4-yl ureido)-21 -oxotup-18-ene; 17-48 3p-0-(3',3'-Dimethylsuccinyt)-17p1-[N'N'-dimethyl-ureido]-21 oxolup-18-ene; 17-50 3p-0-(3',3'-Dimethylsuccinyl)-1 7p-[N'-((S)-2,2,2-trifluoro-1 methyl-ethyl)-ureido]-21 -oxoLup-1 8-ene; 17-51 3p-0-(3',3'-Dimethylsuccinyt)-1 7p-[N'-((R)-2,2,2-trifluoro-1 methyl-ethyl)-ureido] -21 -oxoLup-1 8-ene; 17-52 3p--(3',3'-Dimethylsuccinyt)-1 7,8-[N'-(pyrimidin-4 ylmethyl)ureido]-21 -oxotup-1 8-ene; 17-53 3p-0-(3',3'-Dimethylsuccinyl)-1 7p-[N'-(1 -methyl-1 -pyridin-2 yl-ethyl)ureido]-21 -oxotup-18-ene; 17-54 3p-0-(3',3'-Dimethylsuccinyl)-1 7/1-[N'-((S)-1 -cyclohexyl ethyl)ureido]-21 -oxotup-18-ene; 17-55 3p-0-(3',3'-Dimethylsuccinyl)-1 7p-[N'-((R)-1 -cyclohexyl ethyl)ureido] -21 -oxolup- 1 8-ene; 17-56 3p-0-(3',3'-Dimethylsuccinyl)-17p-[N'-(2,2,2-trifluoro-1 ,1 dimethyl-ethyl)ureido]-21 -oxotup-1 8-ene; WO 2009/082819 PCT/CA2008/002291 -42 17-57 3fl-O-(3',3'-Dimethylsuccinyl)-1 7/3-[N'-(4,4 difluorocyclohexyi)ureido] -21 -oxotup- 1 8-ene; 17-58 3fl-O-(3',3'-Dimethylsucciny)-1 7/3-(3,3-difluoro-pyrrolidine-1 carbonyL)-amino] -21 -oxotup- 1 8-ene; 17-59 3A3O-(3',3'-Dimethylsucciny)-1 7,6-[(4,4-dif tuoro-piperidine-1 carbonyt)-amino]-21 -oxotup-1 8-ene; 17-60 3f6-O- (3', 3'- Dimethylsucci nyl)- 1 7l- [N' -(4,4-difluoro-cyclohexyL methyl)ureido] -21 -oxotup- 1 8-ene; 17-61 3/3-O-(3',3'-Dimethylsucciny[)-1 7/3-[N'-((S)-1 -phenyl-ethyt) ureido]-21 -oxotup-1 8-ene; 17-62 3/5-O-(3' ,3'-Dimethytsuccinyl)-1 7/3-[N'-((R)-1 -phenyl -ethyl) ureido]-21 -oxotup-1 8-ene; 17-63 3,8--(3',3'-Dimethytsuccinyt)-1 71-[N'-(1 -methyl-i -phenyt ethyl)- ureido] -21 -oxotup-1 8-ene; 17-64 3/--(3',3'-Dimethytsuccinyt)-1 7f6-[N'-(thiophen-2-ylmethy[) ureido]-21 -oxotup-1 8-ene; 17-65 3fr0O-(3',3'-Dimethysucciny[)-1 7/3-[N'-(2-methyl [1 ,3,4]oxadiazot-2-ytmethyt)-ureido]-21 -oxotup-1 8-ene; 17-66 3/-O-(3',3'-Dimethylsuccinyl)-1 7/3-[N'-(1 -phenyt-cyclopropyt) ureido]-21 -oxotup-1 8-ene; 17-67 3#.-O-(3',3'-Dimethylsuccinyl)-1 7,8-[N'-(pyrimidin-2 ytmethyl)ureido] -21 -oxotup- 1 8-ene; 17-68 3/3-O-(3',3'-Dimethylsuccinyl)-1 7/-[N'-(pyrimidin-5 ylmethyl)ureido] -21 -oxotup- 1 8-ene; 17-69 3/3&O-(3', 3'-Dimethylsuccinyt)-1 7/3-[N'-(1 -pyridin-2-yL cyclopropyt)-ureido]-21 -oxotup-1 8-ene; 17-70 3/3-O-(3',3'-Dimethylsuccinyt)-1 7p-[N'-(1 -methyl-I -cyclohexyl ethyl) -ureido] -21 -oxotup-1 8-ene; 17-72 3fr-0-(3',3'-Dimethysuccinyt)-1 7AO[N'-(1 -pyridin-2-yL-ethyl) ureido]-21 -oxotup-1 8-ene; 17-73 3AlO-(3',3'-Dimethysuccinyl)-1 7/3[N'-(1 -methyl-i H-imidazol 2-y-methyt)-ureido]-21 -oxotup-1 8-ene; WO 2009/082819 PCT/CA2008/002291 -43 1774 3#3-O-(3', 3'-Dimethylsuccinyt)- I 7/3-[N'-(4-methyl-4H [1, 2,4]triazoL-3-yL-methyL)-ureido] -21 -oxotup- 1 8-ene; 17-75 3/3-O-(3',3'-Dimethy~succiny)-1 7/3-[N'-(thiophen-3-ytmethyl) ureido]-21 -oxotup-1 8-ene; 17-76 3/3-O-(3',3'-Dimethy~succiny)-1 7A3[N'-(2-methyL-2H-pyrazoL-3 yi-methyl)-ureido]-21 -oxotup-1 8-ene; 18-1 3,8-0- (3', 3' -Dimethylsuccinyt)- 1 7fl-methylsulfonylamino-2 1 oxotup-1 8-ene; 19-1 3fl-O-(3' ,3'-Dimethysucciny)-1 7fi-acetylamino-21 -oxotup-1 8 ene; 19-2 3/3-0-(3',3'-Dimethysuccinyl)-1 7fl-benzamido-21 -oxotup-1 8 ene; 19-3 3/3-0,1 7/-N-bis(3',3'-dimethyLsuccinyt)-21 -oxotup-1 8-ene; 19-4 3/3O-(3',3'-Dimethytsucciny[)-1 7A3(5-methyl [1 ,3,4]oxadiazote-2-amido)-21 -oxotup-1 8-ene; 19-5 3fi-0-(3',3'-Dimethy~succiny)-1 7/3-(1 -tert butytoxycarbonytpiperidine-4-amido)-2 1 -oxotup- 1 8-ene; 19-6 3fl-O-(3',3'-Dimethytsuccinyl)-1 7/3-(piperidine-4-amido)-21 oxotup- 18-ene; 19-7 3/-0-(3',3'-Dimethysucciny)-1 7/3-(1 -acetyipiperidine-4 amido)-21 -oxotup-1 8-ene; 19-8 3/3--(3',3'-Dimethysucciny)-1 7,8-(pyridin-3-yL)amido-21 oxolup- 18-ene; 19-9 3/3-0- (3', 3'- Dimethytsuccinyl)- 1 7/3-(4-f tuorobenzyt)amido-21 oxotup- 18-ene; 19-10 3A3O-(3',3'-Dimethytsuccinyl)-1 7A3benzamido-21 -oxotup-1 8 ene; 19-11 3fl-O-(3',3'-Dimethy~succinyt)-1 7/3-(2-ftuorobenzamido)-21 oxotup- 18-ene; 19-12 3fl-O-(3',3'-Dimethysuccinyl)-1 71-(3-ftuorobenzamido)-21 oxotup- 18-ene; WO 2009/082819 PCT/CA2008/002291 4-4 19-13 3fl-O-(3',3'-Dimethylsucciny)-1 7,0-(4-f tuorobenzamido)-21 oxolup- 18-ene; 19-14 3fr0-(3',3'-Dimethy~succinyl)-1 7p6-(pyridin4-yL)amido-21 oxotup- 18-ene; 19-15 3fl-O-(3',3'-Dimethylsucciny)- I 7#-(pyridin-2-yl)amido-21 oxotup- 1 8-ene; 19-16 3l-O0- (3', 3'- Di methylsucciny) -1 7f6-(pyrazi n-2-yl)amido-21 oxolup-1 8-ene; 19-17 3,8-0- (3', 3'- Di methylsucci ny) -1 7fl- (1 -methyl-i1 H -pyrazole-3 amido)-21 -oxotup-18-ene; 19-18 3,& --(3', 3'- Di methylsucciyl)- 1 7,8-(1 -methyl-i1 H -imidazole-5 amido) -21 -oxotup- 18-ene; 19-19 3l- 0- 3', 3'- Di methylsucci ny)- 1 7,8-(1 -methyl-i1 H -imidazole-4 amido) -21 -oxotup- 18-ene; 19-20 3,8-0- (3', 3'- Di methylsucci nyL) -1 7,8-(2 -thiophene)amido-21 oxolup- 18-ene; 19-21 3,8-0- (3', 3'- Di methylsucci ny)- 1 7,8-(1,3-thiazole-2-amido) -21 oxolup- 18-ene; 19-22 3#-0- (3', 3'- Di methylsucci ny) -1 7Ai-(pyri midi ne-2-amido) -21 oxotup-1 8-ene; 19-23 3,6-0- (3', 3'- Di methylsucci ny) -1 7fi- (pyri midi ne- 5-amido) -21 oxotup- 18-ene; 19-24 3fi-0- (3', 3'- Di methy~succi nyl) -17,8- (5 -methylisoxazole-3 amido) -21 -oxotup- 18-ene; 19-25 38-O0- (3', 3'- Di methylsucci ny)-1 7f6- (pyri midi ne-4- amido)-21 oxolup- 18-ene; 19-26 3f-0- (3', 3'- Di methyLsucci nyL) -1 7/3- (1 -methyl-i1 H -imidazole-2 amido)-21 -oxolup- 18-ene; 19-27 3,8-0- (3', 3'- Di methylsucci ny) -1 7#-(1, 3-thiazole-4-amido) -21 oxolup- 18-ene; 19-28 3fl-0- (3', 3'- Di methylsucciny) -177/&-(1, 3-thiazole- 5- amido)-21 oxolup-1 8-ene; WO 2009/082819 PCT/CA2008/002291 45 19-29 3P0- (3',3'-Dimethylsuccinyl)-17/-phenylacetamido-21 -oxolup 18-ene; 19-30 3#-0-(3', 3'-Dimethylsuccinyt)- 1 7#-tetrahydro-pyran-4 carbonylamino-21 -oxoLup- 1 8-ene; 19-31 3/30- (3',3'-Dimethylsuccinyl)-1 7/3-isopropylamido-21 -oxolup 18-ene; 19-32 3/O-(3',3'-DimethylsuccinyL)-1 7/3tert-butylamido-21 -oxotup 18-ene; 19-33 3/0-(3',3'-DimethyLsuccinyL)-1 7/3-cyclohexylamido-21 -oxolup 18-ene; 19-34 3fl-0-(3',3'-Dimethysucciny)-1 7,8-(1 -methyl-1 H-pyrazole-5 amido)-21 -oxolup-1 8-ene; 19-35 3/3O-(3',3'-Dimethylsucciny)-17p-(1 -methyl-1 H-pyrazole-4 amido)-21 -oxolup-1 8-ene; 19-36 3P/O-(3',3'-Dimethylsucciny)-1 7/8-(1 -methylpiperidine-4 amido)-21 -oxolup-1 8-ene; 19-37 3fl-0-(3',3'-Dimethysucciny)-1 7/(3-pyrrolidin-1 -yl propionamido)-21 -oxolup-1 8-ene; 19-38 3AO-(3',3'-Dimethysucciny)-1 7/3-(2-pyrrolidin-1 -yl acetamido)-21 -oxolup-1 8-ene; 19-39 3,8-0-(3',3'-Dimethylsuccinyt)-1 7#-(4-pyrrolidin-1 -yl butyramido)-21 -oxotup-1 8-ene; 19-40 3AO-(3',3'-Dimethysuccinyl)-1 7/3(3-piperidin-1 -yl propionamido)-21 -oxolup-1 8-ene; 19-41 3/3-0-(3',3'-Dimethylsucciny)-1 7/3-[3-(2-oxo-pyrrotidin-1 -yl) propionamido]-21 -oxolup-18-ene; 19-42 3fl-0-(3',3'-Dimethysucciny)-1 7/-(S)-1 -methyl-pyrrolidine-2 amido]-21 -oxotup-1 8-ene; 19-43 3/-0-(3',3'-DimethylsuccinyL)- 173- (4-methytbenzamido)-21 oxolup-18-ene; 19-44 3fl-0-(3',3'-Dimethysucciny)-1 7A(3-methylbenzamido)-21 oxolup-18-ene; WO 2009/082819 PCT/CA2008/002291 -46 19-45 3fl-0- (3', 3' -Dimethylsuccinyl)-1 17/3-(2-methylbenzamido)-21 oxotup- 18-ene; 19-46 3#3-0- (3', 3'-Dimethylsuccinyt)-1I 7/3-(2-methylpyridin-3 yl)amido-21 -oxotup- 18-ene; 19-47 3/3-0-(3' ,3'-DimethyLsuccinyt)-1 7/3-(5-methylpyridin-3 yL)amido-21 -oxotup- 1 8-ene; 19-48 3/3--(3' ,3'-DimethyLsuccinyL)-1 7/3-(6-methytpyridin-3 yl)amido-21 -oxotup-1I8-ene; 19-49 3/-0-(3',3'-Dimethysucciny)-1 7/-(4-miethyLpyridin-3 yt)amido-21 -oxotup- 1 8-ene; 19-50 3fl-0- (3', 3'- Dimethylsucciny)- 1 7,6-(4-hydroxypyridin- 3 ytamido-21 -oxotup- 1 8-ene; 19-51 3/3-0- (3', 3'- Dimethylsucciny)- 1 7,8-(2-hydroxypyridin- 3 yt)amido-21 -oxotup-1I8-ene; 19-52 3#-0- (3', 3'- Dimethysuccinyt)- 1 7fl- (2-methylpyridin-4 yt)amido-21 -oxotup-1I8-ene; 19-53 3fl-0- (3', 3'- DimethylsuccinyL)- 1 7A3-(2-di methylamino acetamido)-21 -oxotup- 1 8-ene; 19-54 3,6-0- (3', 3'-Dimethylsucciny)- 1 7fl- (4- methylpi perazine-1I acetamido)-21 -oxotup- 1 8-ene; 19-55 3,6-0- (3', 3' -DimethytsuccinyL)- 177/&(R)- 1 -methyl-pyrrolidine-2 amido] -21 -oxotup-1 8-ene; 19-56 3/3-0- (3', 3'- Dimethylsuccinyt)- 1 7A3 (S)- 1 -isopropyl- pyrrotidine 2-amido]-Zi -oxotup-1 8-ene; 19-57 33-0- (3', 3'- Dimethytsuccinyt)- 1 7/3- (S)- 1 -tert-butyoxycarbonyL pyrrotidine-2-amido] -21 -oxotup- 1 8-ene; 19-58 3/1-0-(3', 3'- Dimethylsuccinyt)-l 17,-(R)- 1 -tert-butyoxycarbonyt pyrroLidi ne-2-amido] -21 -oxotup- 1 8-ene; 19-59 3/-0-(3',3'-Dimethylsucciny()-1 7/1-((RS)-2-dimethytamino propionamido)-21 -oxotup-1 8-ene; 19-60 3/-0-(3',3'-Dimethytsucciny[)-1 7/1&(1 -imidazole-acetamido)-21 oxotup- 18-ene; WO 2009/082819 PCT/CA2008/002291 -47 19-61 3/3O-(3',3'-DimethyLsucciny)-1 7/3(2-carboxy-benzamido)-21 oxotup- 18-ene; 19-62 3fi-O-(3',3'-Dimethysucciny)-1 7f-(5-cyclopropyl [1 ,3,4]oxadiazoLe-2-amido)-21 -oxotup-18-ene; 19-63 3,6-O:(3',3'-DimethyLsucciny)-1 7,8-(5-phenyL-[1 ,3,4]oxadiazoLe 2-amido)-21 -oxotup-18-ene; 19-64 3/-O-(3',3'-Dimethylsuccinyt)-1 7/-(2,6-dimethyLpyridin-4 yl)amido-21 -oxolup- 1 8-ene; 19-65 3fi-O-(3',3'-Dimethysucciny)-1 7fi((S)-1 -methyipiperidine-2 amido)-21 -oxotup- 18-ene; 19-66 3/3-O-(3',3'-DimethyLsucciny)-1 7fr((R)-1 -methyLpiperidine-2 amido)-21 -oxotup-18-ene; 19-67 3/5-O-(3',3'-DimethyLsucciny)-1 7#-(3-methyL [1 ,2,4]oxadiazole-5-amido)-21 -oxotup-1 8-ene; 19-68 3,8--(3',3'-Dimethysucciny)-1 7,8-(5-methyl [1 ,2,4]oxadiazole-3-amido)-21 -oxotup-1 8-ene; 19-69 3,6-O-(3',3'-Dimethylsuc cinyl)-1 7/3-(5-methyt [1 ,3,4]oxadiazoLe-2-methyL-amido)-21 -oxotup-1 8-ene; 19-70 3/?-O-(3',3'-Dimethy~succiny)-1 7/3-(8,Q-oxa bicycto[3.2. 1 ]octane- 3-amido) -2 t-oxotup- 1 8-ene; 19-71 3fl-O-(3',3'-Dimethy~succinyl)-1 7fl-(8a-oxa bicycto[3.2. 1 ]octane- 3-amido) -21 -oxotup-1 8-ene; 19-72 3A3O-(3',3'-Dimethy~succinyl)-1 7,3-(2-methyt-1 ,3-thiazole-4 amido)-2 1 -oxotup- 1 8-ene; 19-73 3,--(3',3'-DimethyLsuccinyL)-1 7,8- (1 -azetidin-acetamido)-21 oxotup- 1 8-ene; 19-74 3,8-0- (3', 3'- Di methylsucci nyl) -1 7A8(N', N'-di methyl-oxalamido) 21 -oxotup- 1 8-ene; 19-75 3fl-- (3', 3'- Dimethylglutaryt) -1 7fi- (5- methyl- [1, 3,4]oxadiazote 2-amido) -21 -oxotup-1I8-ene; 19-76 3A --(3', 3'- Di methylsuccinyl) -1 7,& (2- methyl-i 1,3-oxazole-4 amido) -21 -oxotup-1I8-ene; WO 2009/082819 PCT/CA2008/002291 48 19-77 3p-0-(3',3'-Dimethylsuccinyl)-1 7p-(5-methyl-thiophene-2 amido)-21 -oxolup-18-ene; 19-78 3p-O-(3',3'-Dimethylsucciny)-1 7p8-(thiophene-3-amido)-21 oxolup-18-ene; 19-79 3p-0-(3',3'-Dimethylsucciny)-1 7-(5-ethyl-[1,3,4]-oxadiazole 2-amido)-21 -oxolup-1 8-ene; 19-80 3pl-0-(3',3'-Dimethylsucciny)-1 7p8-(5-methyl-[1,3]-oxazole-2 amido)-21 -oxolup-18-ene; 19-81 38-0-(cis-Cyclohexane-3'-carboxyic acid-i '-carboxy)- 17p8-[(5 methyl-[1,3,4]oxadiazol-2-carbonyt)-amino]-21-oxoLup-18-ene; 19-82 3p-O-(3',3'-Dimethylsucciny)-17p8-(1H-pyrazole-4-amido)-21 oxotup-18-ene; 19-84 3p-0-(3',3'-Dimethylsucciny)-17p-(5-isopropyt-[1,3,4] oxadiazole-2-amido)-21 -oxoLup- 1 8-ene; 20-1 3p-0-(3',3'-Dimethylsuccinyt)-17p-methoxycarbonytamino-21 oxoLup-18-ene; 20-2 3p-0-(3',3'-Dimethylsuccinyt)-17p8-isopropytoxycarbonylamino 21 -oxotup-18-ene; 20-3 3p8-0-(3',3'-Dimethylsuccinyt)-17p cyclopropylmethoxycarbonylamino-21-oxotup-18-ene; 20-4 3p-O-(3',3'-Dimethylsuccinyt)-17p6 cyclopentyloxycarbonylamino-21-oxolup-18-ene; 20-5 3p-0-(3',3'-Dimethylsuccinyt)-17p cyclohexyloxycarbonylamino-21-oxolup-18-ene; 20-6 3p-0-(3',3'-DimethyLsuccinyt)-17p-[(1-carboxylic acid tert butyt ester)-piperidine-4-oxycarbonylamino] -21 -oxoLup- 1 8-ene; 20-7 3p-0-(3',3'-Dimethylsuccinyt)-17 cyclohexylmethoxycarbonylamino-21 -oxolup-1 8-ene; 20-8 3p-0-(3',3'-Dimethylsuccinyt)-17p-benzyloxycarbonylamino-21 oxoLup- 1 8-ene; 20-9 3pl-0-(3',3'-Dimethysuccinyl)-1 7p3 cyclobutyloxycarbonylamino-21 -oxotup-1 8-ene; WO 2009/082819 PCT/CA2008/002291 49 20-10 3p--(3',3'-Dimethylsuccinyl)-17-(1 cyclopropylethoxycarbonylamino)-21 -oxolup-1 8-ene; 20-11 3p-0-(3',3'-Dimethysucciny)-1 7p8-(1 -methyl cyclopropylmethoxycarbonylamino)-21 -oxolup- 1 8-ene; 20-12 3pi-0-(3',3'-Dimethylsuccinyl)-1 7pl-(1 -amino cyclopropytmethoxycarbonylamino)-21 -oxolup-1 8-ene; 20-13 3p-0-(3',3'-Dimethylsucciny)-1 7p8-((R)-1 -methylpyrrolidine-3 oxycarbonylamino)-21 -oxoLup-1 8-ene; 20-14 3p-0- (3',3'-Dimethylsuccinyl)-1 7p3- (tetrahydro-thiopyran-4 oxycarbonylamino)-21 -oxoLup- 1 8-ene; 20-15 3p-0-(3',3'-Dimethysuccinyl)-1 7/3-(1,1 -dioxo-tetrahydro thiopyran-4-oxycarbonylamino)-21 -oxoLup-1 8-ene; 20-16 3p-0-(3',3'-Dimethylsucciny)-1 7p-(piperidine-4 oxycarbonylamino)-21 -oxolup-1 8-ene; 20-17 3p3-0-(3',3'-DimethylsuccinyL)-1 7p8-(1 -methylpiperidine-4 oxycarbonylamino)-21 -oxoLup- 1 8-ene; 20-18 3p-0-(3',3'-DimethyLsuccinyL)-17p-(1 -methylpiperidine-4 methoxycarbonylamino)-21 -oxolup-1 8-ene; 20-19 3p-0-(3',3'-Dimethylsucciny)-1 7p-(1 -methylpiperidine-3 methoxycarbonylamino)-21 -oxoLup-1 8-ene; 20-20 3p-0-(3',3'-Dimethylsucciny)-1 7p-((S)1 -methylpyrrolidine-2 methoxycarbonylamino)-21 -oxolup-1 8-ene; 20-21 33-0-(3',3'-DimethyLsuccinyL)- 173-(1 -methylpyrrolidine-3 methoxycarbonylamino)-21 -oxolup-1 8-ene; 20-22 3/-0-(3',3'-DimethylsuccinyL)- 17-(2-cyclopropy- 1 ethoxycarbonylamino)-21 -oxotup-1 8-ene; 20-23 3p-0-(3',3'-Dimethylsucciny)-1 7-(2-pyrrolidin-1 ethoxycarbonylamino)-21 -oxolup-1 8-ene; 20-24 3p-0-(3',3'-Dimethylsucciny)-1 7p-(2-(2-oxo-pyrrolidin)-1 ethoxycarbonylamino)-21 -oxoLup-1 8-ene; 24-1 17p-Benzamido-3p3-hydroxy-21 -oxoLup-1 8-ene; WO 2009/082819 PCT/CA2008/002291 50 24-2 17p-(pyridin-2-yl)amido-3p-hydroxy-21-oxolup-18-ene; and 25-1 17p-(isopropylcarbonylamino)-3p8-hydroxy-21-oxolup-18-ene; and pharmaceutically acceptable salts thereof.

WO 2009/082819 PCT/CA2008/002291 51 EXAMPLES The following general schemes and examples are provided to illustrate various embodiments of the present invention and shall not be considered as limiting in scope. It will be appreciated by those of skill in the art that other compounds of the present invention can be obtained by substituting the generically or specifically described reactants and/or operating conditions used in the following examples. 10 In the foregoing and in the following examples, all temperatures are set forth uncorrected in degrees Celsius; and, unless otherwise indicated, all parts and percentages are by weight. Analytical HPLC is carried out under standard conditions using a Phenomenex Gemini C18 column, 250 x 4.6 mm, 3 pim, 110A for the methods A, B, C, D and E, a Varian pursuit XRs C18 column, 50 x 4.6 mm, 3 ptm, for the methods F, G, H and I and a Waters SymmetryShield C18 column, 250 x 4.6 mm, 5 ptm for the method J. Elution is performed using a linear gradient with a flow rate of 1 20 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% over 40 min over 40 min over 40 min over 40 min over 40 min Methods F G H I J Solvent B 50 to 95% 15 to 45% 30 to 75% 15 to 60% 80 to 90% over 15 min over 15 min over 15 min over 15 min over 20 min The following abbreviations may be used as follows: Ac acetyl AcOEt Ethyl acetate AcOH Acetic acid Ac 2 0 Acetic anhydride (Boc)20 di-tert-butyldicarbonate br broad 30 DABCO 1,4-diazabicyclo[2.2.2]octane WO 2009/082819 PCT/CA2008/002291 52 DCM dichloromethane DIPEA Diisopropylethylamine DMAP 4-Dimethylaminopyridine DPPA Diphenylphosphoryl azide NaOAc Sodium acetate PCC Pyridinium chlorochromate q Quadruplet Sept. Septuplet TEA Triethylamine 10 TFA TrifLuoroacetic acid THF Tetrahydrofuran Hal Halogen H H -H Pyridine, Ac 2 O H HBr/AcOH OH DMAP 0 -0 - O Toluene, AcOH, Ac 2 O HO 0 H 0 H 1 H 2 2O 0 H Na 2 Cr 2

O

7 .2H 2 0 H H .

Toluene, NaOAc, AcOH, Ac 2 0 H 0 0 0 O 0 KOH H RuO 2

.H

2 0, NalO 4 H/ Toluene, EtOH AcOEt, H20, TFA 0 - - OH O- OH 5 H 6 0 0o O O KOH H /O2PPA, TEA H MeOH, THF Toluene NCO - - OH 0 H -H HO HO 8 HH Scheme 1 WO 2009/082819 PCT/CA2008/002291 53 Lup-20(29)-ene-3,6,28-diyl diacetate 2 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 IN (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 10 (102.35 g, 86.3%) as a colorless solid. Lup-18-ene-3,3,28-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 20 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. 21 -Oxo-lup-1 8-ene-3,6,28-diyl diacetate 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 30 200 mL), dried over sodium sulfate and concentrated in vacuum. The gummy yellow solid is triturated with methanol and filtered off to yield the title compound 4 (21.41 g, 94.8%) as a colorless solid.

WO 2009/082819 PCT/CA2008/002291 54 28-Hydroxy-21 -oxolup-1 8-en-3,y-vl 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 HCl 1 N (27 mL) and evaporated to dryness. The solid is taken up with water and a 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. 10 31-Acetoxy-21-oxolup-18-en-28-oic acid 6 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 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. 20 31-Hydroxy-21-oxolup-18-en-28-oic acid 7 To a solution of compound 6 (300 mg, 0.58 mmol) in 3 mL of methanol and 10 mL of THF is added an aqueous 4N solution of potassium hydroxide (1.45 mL, 5.8 mmol). The reaction mixture is stirred for 2 days at room temperature, neutralized with HCl 1 N (6 mL) and extracted with DCM (20 mL). The organic layer is washed with water (3 x 20 mL), brine (20 mL) and dried over sodium sulfate to yield the title compound 7 (201.4 mg, 73.7%). 'H NMR (400 MHz, CDCI 3 ): 5 [ppm] 3.20 (m, 2H), 2.74 (d x d, 1H), 2.57 (d, 1H), 2.46 (m, 1H), 2.17 (d, 1H), 2.06 (br d, 1H), 1.90 - 1.24 (m, 15H), 1.21 (s, 3H), 1.19 (s, 30 3H), 1.04 (s, 3H), 0.98 - 0.83 (m, 2H), 0.96 (s, 3H), 0.93 (s, 3H), 0.87 (s, 3H), 0.76 (s, 3H), 0.70 (br d, 1H). LC/MS: m/z = 471.46 (M+H*). 30- Hydroxy-21 -oxolup- 18-en-1 70isocyanate 8 WO 2009/082819 PCT/CA2008/002291 55 To a stirring suspension of compound 7 (124 mg, 0.26 mmol) in dry toluene (2.2 mL) is added TEA (40 ptL, 0.32 mmol) and DPPA (68 pL, 0.32 mmol). The mixture is stirred for 24 hours at room temperature and concentrated to dryness. The residue is purified by flash chromatography on silica gel (ethyl acetate/hexanes 0% to 20%) to afford the title compound 8 (70.3 mg, 57%) as a white solid. 'H NMR (400 MHz, CDCl 3 ): 6 [ppm] 3.19 (m, 1H), 3.11 (m, 1H), 3.01 (d x d, 1H), 2.58 (d, 1H), 2.40 (d x d, 1H), 2.11 - 1.22 (m, 17H), 1.17 (m, 9H), 0.96 (s, 3H), 0.90 (s, 3H), 0.89 (s, 3H), 0.76 (s, 3H), 0.68 (m, 1H). LC/MS: m/z = 468.57 (M+H*). 10 0 0 H/ H/ 0 DPPA, TEA O Toluene 0- OH toluene - N 3 O H 0 H H H 6 9 o o H/ H/ HCI KOH NCO NH 2 HCI 0 DCM O MeOH, THF H H O 0 0f 0 H H 0, 0=>=0

NH

2 HCI (Boc) 2 0, TEA NHBOC A DCM Pyridine HO HO H 12 H 13 0 0 H/ H/ HCI NHBOC NH 2 HCI O O Dioxane O O 0 0 0= HO A O HO A O 14 15 WO 2009/082819 PCT/CA2008/002291 56 Scheme 2 30-Acetoxy-21 -oxolup- 1 8-en-28-oic acid azide 9 To a stirring suspension of compound 6 (1.11 g, 2.17 mmol) in dry toluene (16 mL) is added TEA (0.33 mL, 2.6 mmol) and DPPA (0.56 mL, 2.6 mmol). The mixture is stirred for 3 hours at room temperature and concentrated to dryness. The residue is purified by flash chromatography on silica geL (ethyl acetate/hexanes 0% to 20%) to afford the title compound 9 (967 mg, 83%) as a white solid. 1H NMR (400 MHz, CDCL 3 ): 6 [ppm] 4.45(d x d, 1H), 3.18 (m, 1H), 2.60 (d x d, 1H), 10 2.48 (d, 1H), 2.44 (m, 1H), 2.11 (d, 1H), 2.21 (s, 3H), 2.0 (m, 1H), 1.92 - 1.22 (m, 14H), 1.20 (d, 3H), 1.18 (d, 3H), 1.04 (m, 1H), 1.03 (s, 3H), 0.90 (s, 3H), 0.89 (s, 3H), 0.83 (s, 3H), 0.82 (s, 3H), 0.79 (m, 1H). LC/MS: m/z = 538.58 (M+H*). 3i-Acetoxy-21-oxolup-18-en-172-isocyanate 10 A solution of compound 9 (960 mg, 1.78 mmol) in toluene (18 mL) is stirred at 80*C for 2 hours and concentrated to dryness to afford the title compound 10 (784 mg, 86%) as a white solid. 'H NMR (400 MHz, CDCl 3 ): 8 [ppm] 4.46(d x d, 1H), 3.11 (m, 1H), 3.01 (d x d, 1H), 20 2.58 (d, 1H), 2.41 (d, 1H), 2.09 (m, 1H), 2.04 (s, 3H), 2.0 - 1.24 (m, 15H), 1.18 (d, 3H), 1.70 (m, 6H), 1.04 (m, 1H), 0.92 (s, 3H), 0.89 (s, 3H), 0.84 (s, 3H), 0.83 (s, 3H), 0.80 (m, 1H). LC/MS: m/z = 510.48 (M+H*). 30-Acetoxy- 1 7,6-amino-21 -oxoLup- 1 8-ene hydrochloride 11 To a stirring solution of compound 10 (784 mg, 1.54 mmol) in DCM (15 mL) is added concentrated HCl (5 mL). The biphasic mixture is stirred 48 hours at room temperature, and then concentrated to dryness to give the title compound 11 (765 mg, 96%) as a white solid. 30 'H NMR (400 MHz, DMSO-d 6 ): 5 [ppm] 8.40 (br s, 2H), 4.37(d x d, 1H), 3.16 (m, 1H), 2.83 (d x d, 1H), 2.43 (m, 2H), 2.08 (m, 1H), 1.97 (s, 3H), 1.92 - 1.0 (m, 25H), 0.86 (s, 3H), 0.82 (s, 3H), 0.81 (m, 1H), 0.77 (s, 6H). 17,3-Amino-3/-hydroxy-21-oxolup-18-ene hydrochloride 12 WO 2009/082819 PCT/CA2008/002291 57 To a solution of compound 11 (760 mg, 1.46 mmol) in 3.8 mL of methanol and 11.2 mL of THF is added an aqueous 4N solution of potassium hydroxide (3.6 mL, 14.6 mmol). The reaction mixture is stirred for 24 hours at room temperature and acidified with 4N HCL The precipitate formed is collected by filtration to yield the title compound 12 (705 mg, 100%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ): 6 [ppm] 4.28 (d x d, 1H), 3.14 (m, 1H), 2.95 (m, 1H), 2.86 (br d, 1H), 2.48 (m, 2H), 2.42 (d, 2H), 2.06 (m, 1H), 1.90 - 1.07 (m, 24H), 0.91 (m, 1H), 0.84 (s, 3H), 0.81 (s, 3H), 0.80 (s, 3H), 0.65 (m, 1H), 0.63 (s, 3H). LC/MS: m/z = 442.56 (M+H*). 10 171-tert-Butyloxycarbonylamino-31-hydroxy-21-oxolup-18-ene 13 To a stirring suspension of compound 12 (600 mg, 1.25 mmol) in DCM (13 mL) is added successively TEA (0.4 mL, 3.14 mmol) and (Boc) 2 0 (411 mg, 1.88 mmol). The solution is stirred overnight at room temperature then another 1.56 mmol of TEA and 0.94 mmol of (Boc) 2 0 is added and stirring is continued for 3 hours. The mixture is diluted with DCM and washed with HCI (1N) and water, dried over sodium sulfate and concentrated to dryness. The residue is purified by flash chromatography on silica gel (methanol/DCM 0% to 8%) to afford the title compound 13 as foam (564 mg, 83%). 20 1 H NMR (400 MHz, CDC1 3 ): 6 [ppm] 4.62 (br s, 1H), 3.19 (d x d, 1H), 3.11 (m, 1H), 2.83 (br d, 1H), 2.62 (d, 1H), 2.23 (br d, 1H), 1.88 (m, 3H), 1.73 (m, 1H), 1.68 1.10 (m, 30H), 0.98 (m, 1H), 0.96 (s, 3H), 0.92 (s, 3H), 0.88 (s, 3H), 0.76 (s, 3H), 0.70 (m, 1H). LC/MS: m/z = 542.61 (M+H*). 3-(3', 3'-Dimethylsuccinvl)-171tert-butyloxvcarbonvlamino-21-oxolup-18-ene 14-1 0 H /0

NH

HH 0 H HOO 0 A stirring solution of compound 13 (557 mg, 1.03 mmol), DMAP (151 mg, 1.23 30 mmol) and 2,2-dimethylsuccinic anhydride (527 mg, 4.12 mmol) in dry pyridine (11 mL) is heated overnight at 120'C. Another 3.12 mmol of 2,2-dimethylsuccinic WO 2009/082819 PCT/CA2008/002291 58 anhydride is added and heating at 120*C is continued for 4 hours. The mixture is cooled down to room temperature and concentrated to dryness. The residue is diluted in ethyl acetate, washed twice with HCI 1N, water and brine, dried over sodium sulfate and concentrated to dryness. The residue is purified by flash column chromatography on silica gel (ethyl acetate/hexanes 0% to 40%) to yield the title compound 14-1 as a white solid (467 mg, 68%). 'H NMR (400 MHz, CDC1 3 ): S [ppm] 4.50 (d x d, 1H), 3.11 (m, 1H), 2.84 (br s, 1H), 2.60 (m, 3H), 2.24 (br s, 1H), 1.98 - 0.95 (m, 39H), 0.92 (s, 3H), 0.90 (s, 3H), 0.83 (s, 3H), 0.80 (s, 3H), 0.79 (m, 2H). 10 LC/MS: m/z = 670.69 (M+H*). 3#-0-(3',3'-Dimethylsuccinyl)-17f-amino-21-oxolup-18-ene hydrochloride 15-1 0

NH

2 CIH 0 H HO 0 To a stirring solution of compound 14-1 (414 mg, 0.62 mmol) in dioxane (5 mL) is added 4N HCI in dioxane (1.5 mL). The mixture is stirred 24 hours at room temperature. Another 1.5 mL of 4N HCI in dioxane is added and the mixture is stirred for 2 days and then concentrated to dryness to give the title compound 15 1 (390 mg, 100%) as a white solid. An aliquot (80 mg) is purified by flash column chromatography on silica gel (methanol/DCM 0% to 10%) to give the title compound 20 15-1 as a white solid (38 mg). 'H NMR (400 MHz, DMSO-d 6 ): 6 [ppm] 4.36 (d x d, 1H), 3.18 (d x d, 1H), 3.05 (m, 1H), 2.48 (m, 2H), 2.13 (d, 2H), 2.0 - 1.18 (m, 16H), 1.17 - 0.94 (m, 17H), 0.84 (s, 3H), 0.82 (s, 3H), 0.76 (s, 6H). LC/MS: m/z = 570.59 (M+H*).

WO 2009/082819 PCT/CA2008/002291 59 0 O R2 H O H / reductive H/ amination -R2 O N3 Z 0 H E or H= HO A 0 HOR X HO 0A1 H R 2 -X H base 15 where X= Br, I, CI, OMs, OTs, 16 Scheme 3 General procedure for the preparation of compound 16: An alkyl R 2 group is introduced to compound 15 by conventional reductive amination with an aldehyde or a ketone (see A.F. Abdel-Magid, et al. J. Org. Chem. (1996), 61, 3849-3862) or by alkylation with an alkyl halide in presence of a base such as TEA, DIPEA or NaH in a solvent such as THF or DMF to give compound 16. 10 31-0-(3',3'-Dimethylsuccinyl)-171-(1 -tert-butyloxycarbonylpiperidine-4-aminol 21-oxolup-18-ene 16-1 0 O H/ NKO H 0 HO 0 To a stirring suspension of compound 15-1 (54.6 mg, 0.09 mmol) and N-Boc-4 piperidine (21.5 mg, 0.11 mmol) in dichloroethane (0.6 mL) is added TEA (17 gL, 0.13 mmol). After stirring the mixture at room temperature for 1 hour, sodium triacetoxyborohydride (28.6 mg, 0.13 mmol) is added and the reaction is stirred for 24 hours at room temperature. The mixture is diluted with ethyl acetate, washed with aqueous sodium bicarbonate, water and brine, dried over sodium sulfate and 20 concentrated to dryness. The residue is purified by flash column chromatography on silica gel (methanol/DCM 0% to 10%) to give the title compound 16-1 as a white solid (39 mg, 68%). 1 H NMR (400 MHz, DMSO-d 6 ): 8 [ppm] 4.49 (m, 1H), 4.10 (q, 1H), 3.90 (m, 4H), 3.18 (m, 1H), 3.0 (t, 1H), 2.77 (m, 1H), 2.60 (m, 2H), 2.35 (m, 1H), 2.08 (m, 2H), 1.84 (m, 3H), 1.78 - 0.94 (m, 47H), 0.90 (s, 3H), 0.88 (s, 3H), 0.81 (m, 7H). LC/MS: m/z = 753.7 (M+H').

WO 2009/082819 PCT/CA2008/002291 60 0 H /0 N NR3 0 0 HO A O R2 R3 H 17

R

3 NCO 0 or H O/ 90/ R3'R3NCOCI

R

5

SO

2 CI N' R5 0 0I HO A 0 H/ H N-R2 18 HH HO A 0 H H0

R

4 COCI H I 0 15 or 16 R 2 = H or alkyl or R 4 COOH N R4 ao R2 or R4, 0 R4 HO A O

R

6 OCOCI 419 or R4 0 R4 0 H / N 0-R6 0 0 1 O R2 HO AO 20 Scheme 4 General procedures Ureas 17 are made by treatment of compound 15 or 16 with an isocyanate (1 to 3 eq.), carbamoyl chloride or phosgene or triphosgene followed by an amine in a solvent such as toluene or THF. 10 Sulfonamides 18 are obtained by coupling compound 15 or 16 with the appropriate sulfonyl chloride (1 to 3 eq.) in solvents such as THF or DCM and in the presence of a base such as TEA or DIPEA.

WO 2009/082819 PCT/CA2008/002291 61 Amides 19 are prepared by coupling compound 15 or 16 with the appropriate acyl chloride (1 to 3 eq.), preactivated carboxylic acid, mixed anhydride or anhydride in solvents such as THF or DCM and in the presence of a base such as TEA or DIPEA. Carbamates 20 are obtained by reacting compound 15 or 16 with the appropriate chloroformate (1 to 3 eq.) in solvents such as THF or DCM and in the presence of a base such as TEA or DIPEA. 3,-0-(3',3'-Dimethylsuccinyl)-17p-[N'-(benzvl)ureidol-21-oxolup-18-ene 17-1 0 H/ 0 N 'KN'O 0H H HO HO "' O 10 To a stirring suspension of compound 15-1 (49.2 mg, 0.08 mmol) in DCM (1 mL) is added TEA (23 piL, 0.18 mmol) and benzyl isocyanate (15 ptL, 0.12 mmol). The mixture is stirred for 24 hours at room temperature, diluted with DCM, washed twice with water and brine, dried over sodium sulfate and concentrated to dryness. The residue is purified by flash column chromatography on silica gel (methanol/DCM 0% to 10%) to give the title compound 17-1 as a white solid (39 mg, 68%). 1 H NMR (400 MHz, DMSO-d 6 ): 6 [ppm] 12.2 (br s, 1H), 7.25 (m, 2H), 7.20 (m, 3H), 6.28 (s, 1H), 6.21 (t, 1H), 4.35 (d x d, 1H), 4.20 (d x d, 1H), 4.07 (d x d, 1H), 3.04 20 (m, 1H), 2.83 (d x d, 1H), 2.43 (m, 2H), 2.09 (d, 2H), 1.90 (m, 2H), 1.75 - 0.94 (m, 30H), 0.87 (s, 3H), 0.85 (s, 3H), 0.80 (m, 1H), 0.76 (s, 6H). LC/MS: m/z = 703.68 (M+H*). 3p-0-(3',3'-Dimethylsuccinyl)-17,-methylsulfonylamino-21-oxolup-18-ene 18-1 0 H 00 \\ /,0 0 - - H HO =I : H HO O 0 H WO 2009/082819 PCT/CA2008/002291 62 A solution of compound 15-1 (48.6 mg, 0.08 mmol) in DCM (0.8 mL) is treated with TEA (51 jtL, 0.4 mmol) and methanesulfonyl chloride (25 pL, 0.128 mmol). The mixture is stirred in microwave at 100*C for 5 minutes. The mixture is diluted with DCM, washed twice with water and brine, dried over sodium sulfate. The residue is purified by flash column chromatography on silica gel (methanol/DCM 0% to 10%) to yield the title compound 18-1 (26.5 mg, 51%) as a pale yellow solid. 'H NMR (400 MHz, CDCla): 8 [ppm] 4.62 (s, 1H), 4.48 (d x d, 1H), 3.14 (m, 1H), 3.05 (m, 1H), 2.98 (s, 3H), 2.88 (d, 1H), 2.60 (q, 2H), 2.33 (d, 1H), 2.27 (br d, 1H), 2.02 - 1.82 (m, 2H), 1.78 - 1.1 (m, 28H), 1.02 (m, 1H), 0.91 (s, 3H), 0.90 (s, 3H), 0.81 10 (m, 7H). LC/MS: m/z = 648.6 (M+H*). 3,6-0-(3',3'-Dimethylsuccinyl)-17,6-acetylamino-21-oxolup-18-ene 19-1 0 H/ 0 N HO O H HH OH 0 To a stirring solution of compound 15-1 (50 mg, 0.08 mmol) in THF (1 mL) is added TEA (23 ptL, 0.18 mmol) and acetyl chloride (9 p1, 0.12 mmol). The mixture is stirred for 2 hours at room temperature, diluted with ethyl acetate, washed twice with water and brine, dried over sodium sulfate and concentrated to dryness. The residue is purified by flash column chromatography on silica gel (methanol/DCM 0% 20 to 5%) to give the title compound 19-1 as a white solid (25 mg, 50%). 'H NMR (400 MHz, CDCl 3 ): 6 [ppm] 5.43 (s, 1H), 4.48 (d x d, 1H), 3.12 (m, 1H), 2.75 (t, 1H), 2.69 (d, 1H), 2.65 (d, 1H), 2.55 (d, 1H), 2.30 (m, 2H), 1.97 (s, 3H), 1.94 1.12 (m, 28H), 1.10 (s, 3H), 1.01 (m, 1H), 0.92 (s, 3H), 0.89 (s, 3H), 0.83 (s, 3H), 0.81 (s, 3H). LC/MS: m/z = 612.64 (M+H*). 31-0-(3',3'-Dimethylsuccinyl)-171-methoxycarbonylamino-21-oxolup-18-ene 20-1 WO 2009/082819 PCT/CA2008/002291 63 0 H /0 N 0 HO 0 To a stirring suspension of compound 15-1 (51.6 mg, 0.085 mmol) in DCM (1 mL) is added TEA (24 p1, 0.19 mmol) and methylchloroformate (10 iL, 0.13 mmol). The mixture is stirred for 2 hours at room temperature, diluted with DCM, washed twice with water and brine, dried over sodium sulfate and concentrated to dryness. The residue is purified by flash column chromatography on silica gel (methanol/DCM 0% to 10%) and repurified by reverse-phase HPLC (55 to 85% CH 3 CN in H 2 0 (3 mmol HCL) over 60 min at 244 nm) to give the title compound 20-1 as a 10 white solid (1.5 mg, 3%). 1 H NMR (400 MHz, CDCl 3 ): 6 [ppm] 4.73 (br s, 1H), 4.44 (d x d, 1H), 3.55 (s, 3H), 3.07 (m, 1H), 2.76 (t, 1H), 2.54 (m, 3H), 2.17 (m, 2H), 1.90 - 1.08 (m, 27H), 1.05 (s, 3H), 0.95 (m, 1H), 0.86 (s, 3H), 0.84 (s, 3H), 0.77 (s, 3H), 0.75 (s, 3H), 0.74 (m, 1 H). LC/MS: m/z = 628.64 (M+H*).

WO 2009/082819 PCT/CA2008/002291 64 0 H/ H 0 AcCI, MeOH NH; CI N 0 -- 0 0- O aH )IJ~H S Hz 0 A 0 HO A O H A35 14

R

2 -X R H or base reductive where X= Br, I, CI, OMs amination O 0 H /OH/ NN- N O 0 H LiOH O O H Al' .H E I_ _ HO A O H 0 A 0 H H 16 36 0 0 CI R4 or HO R4 0 H / N~ R4 HO A 0 H 19 Scheme 5 General procedure for the preparation of compound 19: Step 1: Compound 14 is treated with acetyl chloride in methanol and stirred at room temperature to give compound 35. Step 2: An alkyl R 2 group is introduced to compound 35 by conventional reductive amination with an aldehyde or a ketone or by alkylation with an alkyl halide in 10 presence of a base such as TEA, DIPEA or NaH in a solvent such as THF or DMF to give compound 36. Step 3: The deprotection of the ester group occurs in solvents such as methanol, THF or dioxane using an aqueous solution of inorganic base such as lithium hydroxide or potassium hydroxide (3 to 10 eq.) at temperature ranging from 20 to 60*C.

WO 2009/082819 PCT/CA2008/002291 65 Step 4: Amides 19 are prepared by coupling compound 16 with the appropriate acyl chloride (1 to 3 eq.), preactivated carboxylic acid, mixed anhydride or anhydride in solvents such as THF, DMF or DCM and in the presence of a base such as TEA or DIPEA. 3/3O-(3',3'-Dimethylsucciny)-17,8-[methyl-(5-methyl-[1,3,4]oxadiazole-2 carbonyL)-amino]-21-oxolup-18-ene 19-69 0 H 0 o N 0 HO O N HO 0H 10 Step 1: To an ice-cold stirring suspension of 14-1 (146.8 mg, 0.22 mmol) in MeOH (2 mL) is added acetyl chloride (0.16 mL, 2.19 mmol). The mixture is stirred at room temperature overnight and the solvent is removed by evaporation. The residue is purified by flash column chromatography on silica gel (methanol/DCM 0% to 8%) to yield the title compound 3/0- (3', 3'- Dimethylsuccinyl-methyl-ester)- 17,8 amino-21-oxolup-18-ene hydrochloride 35-1 (118 mg, 86%). 1H NMR (400 MHz, CDCI): 8 [ppm] 4.48 (d x d, 1H), 3.67 (s, 3H), 3.30 (m, 2H), 2.58 (q, 2H), 2.45 (q, 2H), 2.00-1.20 (m, 15H), 1.25 (s, 3H), 1.24 (s, 3H), 1.17 (d, 3H), 1.15 (d, 3H), 1.14 (s, 3H), 1.00 (m, 1H), 0.82 (s, 3H), 0.80 (s, 3H), 0.79 (m, 1H). 20 Step 2: To an ice-cold stirring solution of 35-1 (101 mg, 0.164 mmol) in dry THF (1.6 mL) is added sodium hydride (14 mg, 0.345 mmol, as a 60% dispersion in mineral oil). The mixture is stirred 15 minutes at 0 0 C then methyl iodide (0.012 mL, 0.196 mmol) is added. The resulting mixture is stirred at 0"C for 30 minutes then at room temperature overnight. The mixture is diluted with ethyl acetate, washed with aqueous ammonium chloride, water, aqueous sodium thiosulfate 5% and brine, dried over sodium sulfate. The residue is purified by flash column chromatography on silica gel (methanol/DCM 0% to 5%) to yield 3f&0-(3',3' Dimethylsuccinyl-methyl-ester)-17/3-N-methyl-amino-21-oxolup-18-ene 30 hydrochloride 36-1 (30 mg, 30%) as an oil. 1H NMR (400 MHz, CDCI 3 ): 8 [ppm] 4.48 (d x d, 1H), 3.67 (s, 2H), 3.13 (sept., 1H), 2.62 (d, 1H), 2.55 (d, 1H), 2.37 (d, 1H), 2.11 (s, 3H), 1.98 (d, 1H), 1.97 (t x d, 1H), 1.87 (m, 3H), 1.72 (d x t, 1H), 1.68-0.70 (m, 14H), 1.26 (s, 3H), 1.25 (s, 3H), 1.19 WO 2009/082819 PCT/CA2008/002291 66 (d, 3H), 1.17 (d, 3H), 1.13 (s, 3H), 0.90 (s, 3H), 0.89 (s, 3H), 0.82 (s, 3H), 0.80 (s, 3H). LC/MS: m/z = 598.45 (M+H+). Step 3: To a stirring solution of 36-1 (80 mg, 0.134 mmol) in 1,4-dioxane (1 mL) and water (0.5 mL) is added LiOH 1N (0.401 mL, 0.401 mmol). The mixture is stirred overnight at room temperature, neutralized to pH 7 with HCI 1 N, extracted with ethyl acetate (1X), DCM (containing few drops of methanol) (3X). The organic extracts are combined and dried over sodium sulfate. The residue is purified by 10 flash column chromatography on silica gel (methanol/DCM 0% to 10%) to yield 16-2 (43 mg, 55%) as a white solid. 1H NMR (400 MHz, CD 3 0D): 8 [ppm] 4.46 (d x d, 1H), 3.25 (sept., 1H), 2.89 (m, 1H), 2.58 (d, 1H), 2.53 (d, 1H), 2.38 (d, 1H), 2.12 (s, 3H), 2.07 (d, 1H), 2.01-1.93 (m, 4H), 1.79 (d x t, 1H), 1.70-1.27 (m, 11H), 1.24 (s, 3H), 1.23 (s, 3H), 1.20 (s, 3H), 1.18 (d, 3H), 1.17 (d, 3H), 1.14-0.98 (m, 2H), 0.96 (s, 6H), 0.86 (s, 3H), 0.85 (s, 3H), 0.84 (m, 1H). LC/MS: m/z = 584.52 (M+H+). HPLC (D) RT = 26.63 min. 20 Step 4: To an ice-cold stirring solution of potassium 5-methyl-[1,3,4]oxadiazole-2 carboxylate (13.4 mg, 0.081 mmol) in dry acetonitrile (1.0 mL) is added a catalytic amount of DMF followed by oxalyl chloride (0.037 mL, 0.074 mmol). The mixture is stirred 50 minutes at 0 "C, it is then added to an ice-cold stirring suspension of 16 2 (42.9 mg, 0.074 mmol) and TEA (0.021 mL, 0.147 mmol) in dry THF (1.3 mL). The resulting mixture is stirred 3.5 hours at room temperature, diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate. The residue is purified by flash column chromatography on silica gel (methanol/DCM 0% to 10%) to yield the title compound 19-69 (8.2 mg, 16%) as white solid. 1H NMR (400 MHz, CDCl 3 ): 6 [ppm] 4.48 (d x d, 1H), 3.89 (br s, 3H), 3.16 (sept., 30 1H), 2.64 (d, 2H), 2.59 (s, 3H), 2.54(d, 1H), 2.44 (br s, 2H), 2.00-0.70 (m, 19H), 1.29 (s, 3H), 1.28 (s, 3H), 1.22 (t, 6H), 1.05 (s, 3H), 0.90 (s, 3H), 0.84 (s, 3H), 0.82 (s, 3H), 0.79 (s, 3H). LC/MS:+ m/z = 694.97 (M+H+). HPLC (A) RT = 24.93 min.

WO 2009/082819 PCT/CA2008/002291 67 0 0 H/ H/

NH

3 CI HO R4 N' R4 0H 0 OH 0 O H or H 0 A 0 0 H 0A 37 35 R4 LiOH 0 N R4 0 0 H *H 0 A 0 H 19 SScheme 6 General procedure Step 1: Amides 19 are prepared by coupling compound 35 with the appropriate acyl chloride, preactivated carboxylic acid, mixed anhydride or anhydride in solvents such as THF, DCM or DMF and in the presence of a base such as TEA or DIPEA. 10 Step 2: The deprotection occurs in solvents such as methanol, THF or dioxane using an aqueous solution of inorganic base such as lithium hydroxide or potassium hydroxide (3 to 10 eq.) at temperature ranging from 20 to 60*C. 32-0- (3',3'-Dimethylsuccinyl)-172-(4-hydroxypyridine-3-yl)amido-21-oxolup-18-ene 19-50 0 H / OOH N HO H Y H 0 Step 1: To a stirring suspension of compound 35-1 (85.3 mg, 0.14 mmol) and 4 hydroxynicotinic acid (28.7 mg, 0.21 mmol) in DMF (1.5 mL) is added TEA (53 piL, 0.41 mmol) and HATU (78.4 mg, 0.21 mmol). The mixture is stirred for 2 hours at 20 room temperature. Water is added slowly and the precipitate formed is collected WO 2009/082819 PCT/CA2008/002291 68 by filtration and purified by flash column chromatography on silica geL (methanol/DCM 0% to 8%) to yield the title compound 3fl-0-(3',3'-DimethVlsuccinVl methyl-ester)- 170- (4-hydroxypyridine-3-yl)amido-21 -oxolup- 1 8-ene 37-1 (70 mg). 'H NMR (400 MHz, CDCI 3 ): 8 [ppm] 11.6 (br s, 1H), 10.92 (br s, 1H), 8.80 (s, 1H), 7.61 (d, 1H), 6.57 (m, 1H), 4.44 (d x d, 1H), 3.66 (s, 3H), 3.15 (m, 1H), 2.89 (t, 1H), 2.79 (d, 1H), 2.57 (q, 2H), 2.24 (m, 3H), 1.88 (m, 2H), 1.74-0.72 (m, 14H), 1.24 (s, 3H), 1.23 (s, 3H), 1.18 (d, 3H), 1.15 (d, 3H), 1.08 (s, 3H), 0.94 (s, 3H), 0.83 (s, 3H), 0.81 (s, 3H), 0.78 (s, 3H). LC/MS: m/z = 705.98 (M+H*). 10 Step 2: To a stirring solution of 37-1 (70 mg, 0.10 mmol) in 1,4-dioxane (0.8 mL) and water (0.2 mL) is added LiOH-H 2 0 (12.5 mg, 0.30 mmol). The mixture is stirred overnight at room temperature, acidifed to pH 3 with HCL 1N, and the precipitate formed is collected by filtration. The product is purified by flash column chromatography on silica geL (methanol/DCM 0% to 15%) to yield 19-50 (31 mg) as a white solid. 'H NMR (400 MHz, CDCL 3 ): 6 [ppm] 11.7 (br s, 1H), 10.80 (s, 1H), 8.42 (d x d, 1H), 7.38 (m, 1H), 6.52 (d x d, 1H), 4.42 (d x d, 1H), 3.12 (m, 1H), 2.93 (m, 1H), 2.80 (d, 1H), 2.54 (q, 2H), 2.40 (m, 1H), 2.29 (d, 1H), 2.07 (m, 5H), 1.88 (m, 2H), 1.70 20 0.70 (m, 10H), 1.22 (s, 3H), 1.21 (s, 3H), 1.18 (d, 3H), 1.16 (d, 3H), 1.03 (s, 3H), 0.90 (s, 3H), 0.80 (s, 3H), 0.78 (s, 3H), 0.76 (s, 3H). LC/MS: m/z = 691.86 (M+H*).

WO 2009/082819 PCT/CA2008/002291 69 0 0 H/ H/

NH

2 N-0 0 0 HClH 000 HO A 0 H A H H HO A 0 15 H 26

R

3

'R

3 NH 0 H / N NR3 0 0 H 3 1 HO A 0 H 17 Scheme 7 Isocyanates 26 are made by treatment of compound 15 with phosgene or triphosgene. Ureas 17 are obtained by treatment of the isocyanates 26 with an amine in a solvent such as toluene or THF in the presence of a base such as TEA or DIPEA. 3p-0-(3',3'-DimethylsuccinyL)-17p8-[N'-(1 -tert-butyloxycarbony-piperidin-4-yl) 10 ureido]-21-oxolup-18-ene 17-9 o 0 H/ O N tN o H H HO O HO 0 Y H 0 Step 1: To an ice-cold stirring solution of triphosgene (335 mg, 1.129 mmol) in dry THF (5 mL) is added drop wise over 10 minutes a solution of compound 15-1 (456 mg, 0.753 mmol) and DIPEA (0.33 mL, 1.881 mmol) in dry THF (6 mL). The resulting mixture is stirred at room temperature for 3 hours. Water is added drop wise at 0"C and the mixture is diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate. The residue is purified by flash column chromatography WO 2009/082819 PCT/CA2008/002291 70 on silica gel (ethyl acetate/hexanes 0% to 80%) to yield 3#-0-(3',3' dimethylsuccinyl)-21-oxolup-18-ene-17p-isocyanate 26-1 (419 mg) as a foam. 'H NMR (400 MHz, CDCl): 6 [ppm] 4.49 (d x d, 1H), 3.11 (sept., 1H), 2.99 (d x d, 1H), 2.67 (d, 1H), 2.59 (d, 1H), 2.54 (d, 1H), 2.41 (d, 1H), 2.10 (m, 1H), 2.04-1.80 (m, 3H), 1.75 (d x t, 1H), 1.70-1.46 (m, 6H), 1.39-1.24 (m, 5H), 1.30 (s, 3H), 1.28 (s, 3H), 1.18 (d, 3H), 1.17 (d, 3H), 1.16 (s, 3H), 1.01 (t x d, 1H), 0.91 (s, 3H), 0.89 (s, 3H), 0.83 (s, 3H), 0.81 (s, 3H), 0.78 (m, 1H). IR (v, cm"): 2257 (NCO). 10 Step 2: To a stirring solution of 3#-O-(3',3'-dimethylsuccinyl)-21-oxolup-18-ene 17/-isocyanate 26-1 (151 mg, 0.253 mmol) in dry toluene (6 mL) is added 4-amino 1-Boc-piperidine (203 mg, 1.014 mmol). The mixture is stirred 2 hours at 80*C, cooled down and diluted with ethyl acetate, washed with HCL 1 N, water and brine, dried over sodium sulfate. The residue is purified by flash column chromatography on silica gel (methanol/DCM 0% to 10%) to yield the title compound 17-9 (173 mg) as a white solid. 'H NMR (400 MHz, CDCl 3 ): 8 [ppm] 5.40 (br s, 1H), 4.56 (br s, 1H), 4.47 (d x d, 1H), 3.97 (br s, 2H), 3.66 (br s, 1H), 3.16 (sept., 1H), 2.91 (d, 1H), 2.78 (t, 2H), 2.66 (d, 1H), 2.59 (d, 1H), 2.52 (d, 1H), 2.28 (d, 1H), 2.13 (d, 1H), 1.99 (m, 1H), 1.90-0.70 20 (m, 19H), 1.42 (s, 9H), 1.28 (s, 3H), 1.27 (s, 3H), 1.21 (d, 3H), 1.17 (d, 3H), 1.10 (s, 3H), 0.92 (s, 3H), 0.89 (s, 3H), 0.82 (s, 3H), 0.80 (s, 3H). LC/MS: m/z = 797.44 (M+H*). HPLC (Method A) RT = 29.8 min.

WO 2009/082819 PCT/CA2008/002291 71 0 0 H 1) R 2 CHO H

NH

2 NH CIH or R H - 2) R 2 X (X =Hal, OMs, OTs) H Ro 11 or RO 21 H 1 lorl12 H R1 = H, Ac 0 0 O0

R

3 NCO or R , R3 1) KOH if R1= Ac N/ N R 3 11 or 12 N N or 21 R 3 O2 2) Pyridine, DMAP - R 2

R'

3

R

3

R

3 'NCOCI R 2

R

3 H RO 22 0 O HO A Ro H H H 7 A O 0 H /H 0 HIC '-0 1) KOH if RI= Ac S' ll2 RSO 2 CI 11_____, 11or12 N - , N R 5 o 2 2) Pyridine, DMAP O O R 2 H - 2 H R O0 HO A O R 1 0 H 23 ~ \, O A 0 H .18 A 0 0 H O R4COOH or H 1) KOH if R1 = Ac N R or21 R 4 COCor 2 4 2) Pyridine, DMAP R2

R

4 C00COR 4 24 0 0 0 HO A 0 RO H H 19 A 0 0 H/ 0 H 0 11orl12 ROCC0o N O 1) KOH if R1 = Ac NO or 21 ROCOOCOR, H 2 R 6 2) Pyridine, DMAP O 0 R 2

R

6 RO 25 0 HO A 0 H H 2 A Scheme 8 General procedure for the preparation of compound 21: An alkyl R 2 group is introduced to compound 11 or 12 by conventional reductive amination with an aldehyde (see A.F. Abdel-Magid, et al. J. Org. Chem. (1996), 61, 3849-3862) or by alkylation with an alkyl halide in presence of a base such as TEA, DIPEA or NaH in a solvent such as THF or DMF to give compound 21. 10 General procedure for the synthesis of ureas 17 WO 2009/082819 PCT/CA2008/002291 72 Step 1: A solution of compound 11, 12 or 21 and the appropriate isocyanate or carbamoyl chloride in solvents such as toluene, dichloromethane or chloroform is stirred for 4 to 20 hours at room temperature or under reflux. The residue obtained is purified by flash column chromatography. If R1 = Ac then deprotection occurs 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 22 (R1 = H). 10 Step 2: A solution of urea 22 (R1 = H), a base such as DMAP, TEA, DABCO or DIPEA and the appropriate anhydride (2 to 10 equivalents) in solvents such as pyridine, TEA or toluene (0.2-1.0 M) is heated from 90 to 120*C for 4 to 24 hours. The mixture is concentrated, washed with acid and purified by flash column chromatography on silica gel to yield compound 17. General procedure for the synthesis of sulfonamides 18 Step 1: A solution of compound 11, 12 or 21 and the appropriate- sulfonyl chloride in solvents such as THF or DCM and in the presence of a base such as TEA or DIPEA is stirred for 4 to 20 hours at room temperature or under reflux. The residue 20 obtained is purified by flash chromatography on silica gel to afford the desired amide 23. If R1 = Ac then deprotection occurs 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 23 (RI = H). Step 2: A solution of sulfonamide 23 (R1 = H), a base such as DMAP, TEA, DABCO or DIPEA and the appropriate anhydride (2 to 10 equivalents) in solvents such as pyridine, TEA or toluene (0.2-1.0 M) is heated from 90 to 120 C for 4 to 24 hours. 30 The mixture is concentrated, washed with acid and purified by flash column chromatography on silica gel to yield compound 18. General procedure for the synthesis of amides 19 Step 1: A solution of compound 11, 12 or 21 and the appropriate acyl chloride or anhydride in solvents such as THF or DCM and in the presence of a base such as TEA or DIPEA is stirred for 4 to 20 hours at room temperature or under reflux. The WO 2009/082819 PCT/CA2008/002291 73 residue obtained is purified by flash chromatography on silica gel to afford the desired amide 24. If R1 = Ac then deprotection occurs 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 24 (RI = H). Step 2:. A solution of amide 24 (R1 = H), a base such as DMAP, TEA, DABCO or DIPEA and the appropriate anhydride (2 to 10 equivalents) in solvents such as pyridine, 10 TEA or toluene (0.2-1.0 M) is heated from 90 to 120*C for 4 to 24 hours. The mixture is concentrated, washed with acid and purified by flash column chromatography on silica geL to yield compound 19. General procedure for the synthesis of carbamates 20 Step 1: To a stirring solution of compound 11, 12 or 21 in toluene or benzene is added the desired chloroformate or anhydride (3 equivalents). The resulting mixture is stirred 2 to 4 hours under reflux. After standard acidic workup, the residue obtained is purified by flash chromatography on silica gel to afford the desired carbamate 25. 20 If R1 = Ac then deprotection occurs 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 25 (R1 = H). Step 2: A stirring solution of carbamate 25 (RI = H), a base such as DMAP, TEA, DABCO or DIPEA and the appropriate anhydride (2 to 10 equivalents) in solvents such as pyridine, TEA or toluene (0.2-1.0 M) is heated from 90 to 120'C for 4 to 24 hours. The mixture is concentrated, washed with acid and purified by flash column chromatography on silica gel to yield compound 20. 30 17I-Benzamido-3#-hydroxy-21-oxolup-18-ene 24-1 WO 2009/082819 PCT/CA2008/002291 74 0 H 0 N HH H HO H To a stirring suspension of compound 12 (62.7 mg, 0.13 mmol) in THF (1.3 mL) is added TEA (37 pL, 0.28 mmol) and benzoyl chloride (23 jAL, 0.20 mmol). The mixture is stirred for 3 hours at room temperature, diluted with ethyl acetate, washed twice with 1N HCl, water and brine, dried over sodium sulfate and concentrated to dryness. The residue is purified by flash column chromatography on silica geL (methanol/DCM 0% to 4%) to give the title compound 24-1 as a white solid (55 mg, 77%). 'H NMR (400 MHz, CDCl 3 ): 8 [ppm] 7.73 (m, 2H), 7.50 (m, 1H), 7.43 (m, 2H), 6.13 10 (s, 1H), 3.19 (m, 2H), 2.90 (m, 1H), 2.87 (d, 1H), 2.40 (m, 1H), 2.35 (d, 1H), 1.94 (m, 2H), 1.80 - 1.20 (m, 20H), 1.14 (s, 3H), 0.96 (m, 6H), 0.86 (m, 3H), 0.75 (s, 3H), 0.70 (m, 1H). 3,6-0-(3',3'-Dimethylsucciny)-17p6-benzamido-21-oxolup-18-ene 19-2 0 OH H

N

HO 0 H 0 A stirring solution of compound 24-1 (55 mg, 0.10 mmoL), DMAP (14.8 mg, 0.12 mmoL) and 2,2-dimethylsuccinic anhydride (38.7 mg, 0.30 mmoL) in dry pyridine (1.0 mL) is heated at 120"C for 4 hours. Another 0.30 mmol of 2,2-dimethylsuccinic 20 anhydride is added and heating at 120*C is continued for 24 hours. The mixture is cooled down to room temperature and concentrated to dryness. The residue is diluted in ethyl acetate, washed twice with HCl 1N, water and brine, dried over sodium sulfate and concentrated to dryness. The residue is purified by flash column chromatography on silica geL (methanol/DCM 0% to 10%) to yield the title compound 19-2 as a white solid (48 mg, 71%).

WO 2009/082819 PCT/CA2008/002291 75 'H NMR (400 MHz, CDCl 3 ): 8 [ppm] 7.71 (m, 2H), 7.50 (m, 1H), 7.42 (m, 2H), 6.11 (s, 1H), 4.48 (d x d, 1H), 3.17 (m, 1H), 2.90 (d, 1H), 2.83 (d, 1H), 2.66 (d, 1H), 2.55 (d, 1H), 2.41 (d, 1H), 2.36 (d, 1H), 1.95 (m, 3H), 1.76 - 1.16 (m, 26H), 1.13 (s, 3H), 0.97 (s, 3H), 0.87 (s, 3H), 0.83 (s, 3H), 0.79 (s, 3H). LC/MS: m/z = 674.70 (M+H*). 176- (pyridin-2-yl)amido-33-hydroxy-21-oxolup-18-ene 24-2 0 H/ 0 N_ N H H H HO H To a stirring suspension of compound 12 (107.7 mg, 0.22 mmol) and picolinic acid 10 (41.3 mg, 0.34 mmol) in DMF (2.2 mL) is added TEA (71 pL, 0.56 mmol) and HATU (127.6 mg, 0.34 mmol). The mixture is stirred for 2 hours at room temperature. Water is added slowly and the precipitate formed is collected by filtration to give the title compound 24-2 as an off-white solid (120 mg). 'H NMR (400 MHz, CDCl 3 ): 8 [ppm] 8.54 (m, 1H), 8.33 (br s, 1H), 8.13 (m, 1H), 7.83 (t x d, 1H), 7.43 (d x d, 1H), 3.19 (m, 2H), 2.86 (t, 2H), 2.47 (m, 1H), 2.37 (d, 1H), 1.96 (m, 3H), 1.76-1.16 (m, 18H), 1.04-0.86 (m, 1OH), 0.83 (s, 3H), 0.78 - 0.66 (m, 4H). 3P-O-(3',3'-Dimethylsuccinyl)-1713(pyridin-2-vl)amido-21-oxolup-18-ene 20 hydrochloride 19-15 0 H / O CIH N 0 H N HO OH HO 0 A stirring solution of compound 24-2 (113 mg, 0.21 mmol), DMAP (30.3 mg, 0.25 mmol) and 2,2-dimethylsuccinic anhydride (105.9 mg, 0.83 mmol) in dry pyridine (2.0 mL) is heated at 130*C for 4 hours. Another 0.42 mmol of 2,2-dimethylsuccinic WO 2009/082819 PCT/CA2008/002291 76 anhydride is added and heating at 130"C is continued for 24 hours. The mixture is cooled down to room temperature and concentrated to dryness. The residue is diluted in ethyl acetate, washed twice with HCI 1N, water and brine, dried over sodium sulfate and concentrated to dryness. The residue is purified by flash column chromatography on silica gel (methanol/DCM 0% to 10%) to yield the title compound 19-15 as a pale yellow solid (137.6 mg). 'H NMR (400 MHz, CDCI 3 ): 6 [ppm] 8.52 (m, 1H), 8.32 (br s, 1H), 8.12 (m, 1H), 7.82 (t x d, 1H), 7.42 (d x d, 1H), 4.46 (d x d, 1H), 3.17 (m, 1H), 2.85 (m, 2H), 2.60 (q, 2H), 2.47 (m, 1H), 2.37 (d, 1H), 1.96 (m, 3H), 1.74-1.16 (m, 24H), 1.02-0.98 (m, 10 4H), 0.95 (s, 3H), 0.84 - 0.72 (m, 10H). LC/MS: m/z = 675.7 (M+H*). Ureas 17 and carbamates 20 can also be prepared from the isocyanate 8 as described in scheme 9. 0 H/ NCO H Rio 1 H

.H

R'NR 8 or 10 1) R 6 OH R2 R 3 1 R1 =H, Ac 2) KOH if RI = Ac 2) KOH if R1 = Ac 0 0 H / O0 N N'.R3 N O-R6 H IH H R3, H HO 22 HO H H2 25 0 0 0 Pyridine 0 0 0 Pyridine A DMAP A 0 0 H/ 0 H/ 0 N N R 3 N 0-R6 0 0 H I - H H 3 ' H HO A 0 H HO A 0 17 20 WO 2009/082819 PCT/CA2008/002291 77 Scheme 9 General procedure for the synthesis of ureas 17 Step 1: A solution of isocyanate 8 or 10 and the desired amine R 3

'R

3 NH in solvents such as benzene, toluene or chloroform is stirred for 4 to 20 hours at room temperature or under reflux. The residue obtained is purified by flash chromatography on silica gel to afford the desired urea intermediate 22. If RI = Ac then deprotection occurs 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 22 (R1 = H). Step 2: A solution of urea 22 (RI = H), a base such as DMAP, TEA, DABCO or DIPEA and the appropriate anhydride (2 to 10 equivalents) in solvents such as pyridine, TEA or toluene (0.2-1.0 M) is heated from 90 to 120'C for 10 to 24 hours. The mixture is concentrated, washed with acid and purified by flash column chromatography on silica gel to yield compound 17. General procedure for the synthesis of carbamates 20 20 Step 1: To a stirring solution of isocyanate 8 or 10 in toluene or benzene is added the desired alcohol (3 to 10 equivalents) and a catalyst such as titanium (IV) tert butoxide. The resulting mixture is stirred 2 to 4 hours at room temperature. After standard workup, the residue obtained is purified by flash chromatography on silica gel to afford the desired carbamate intermediate 25. If R1 = Ac then deprotection occurs 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 25 (R1 = H). 30 Step 2: A stirring solution of carbamate 25 (R1 = H), a base such as DMAP, TEA, DABCO or DIPEA and the appropriate anhydride (2 to 10 equivalents) in solvents such as pyridine, TEA or toluene (0.2-1.0 M) is heated from 90 to 120 C for 10 to 24 hours. The mixture is concentrated, washed with acid and purified by flash column chromatography on silica gel to yield compound 20. 171-(isopropylcarbonylamino)-3p-hydroxy-21-oxolup-18-ene 25-1 WO 2009/082819 PCT/CA2008/002291 78 0 H 0 N O H H E HO H Step 1: To a stirring solution of compound 10 (300 mg, 0.59 mmol) in toluene (3 mL) is added isopropanol (68 1, 0.88 mmol) and titanium (IV) tert-butoxide (23 p1, 0.06 mmoL). The mixture is stirred for 1 hour at room temperature. A saturated solution of ammonium chloride and ethyl acetate are added and the organic layer is dried over sodium sulfate and concentrated to dryness. The residue is purified by flash column chromatography on silica gel (ethyl acetate/hexanes 0% to 50%) to yield the 17/-(isopropylcarbonylamino)-3-acetoxy-21-oxolup-18-ene as white foam 10 (349 mg). 'H NMR (400 MHz, CDCl 3 ): S [ppm] 4.85 (m, 1H), 4.73 (br s, 1H) 4.45 (d x d, 1H), 3.12 (m, 1H), 2.83 (m, 1H), 2.59 (m, 1H), 2.23 (d, 1H), 2.02 (s, 3H), 1.88 (m, 3H), 1.78-1.13 (m, 25H), 1.11 (s, 3H), 1.03 (m, 1H), 0.91 (s, 3H), 0.90 (s, 3H), 0.83 .(s, 3H), 0.82 (s, 3H), 0.79 (m, 1H). Step 2: To a solution of 17/-(isopropylcarbonylamino)-3lacetoxy-21-oxolup-18-ene (349 mg, 0.6 mmol) in 2 mL of methanol and 6 mL of THF is added an aqueous 4N solution of potassium hydroxide (1.5 mL, 6 mmol). The reaction mixture is stirred for 24 hours at room temperature, acidified with 4N HCl and extracted with ethyl 20 acetate. The organic layer is dried over sodium sulfate and concentrated to dryness to yield the title compound 25-1 (330 mg). 'H NMR (400 MHz, CDCl 3 ): S [ppm] 4.80 (br s, 1H), 4.65 (br s, 1H) 3.15 (d x d, 1H), 3.05 (m, 1H), 2.80 (m, 1H), 2.55 (m, 1H), 2.20 (d, 1H), 1.85 (m, 4H), 1.60-1.08 (m, 27H), 1.06 (s, 3H), 0.94 (m, 1H), 0.91 (s, 3H), 0.88 (s, 3H), 0.83 (s, 3H), 0.70 (s, 3H), 0.65 (m, 1H). 3/-0-(3',3'-Dimethylsuccinyl)-17-(isopropylcarbonvlamino)-21-oxolup-18-ene 20-2 WO 2009/082819 PCT/CA2008/002291 79 0 NO H / O N ) Oj HH HO H 0 A stirring solution of compound 25-1 (327 mg, 0.6 mmol), DMAP (91 mg, 0.74 mmol) and 2,2-dimethylsuccinic anhydride (476 mg, 3.7 mmol) in dry pyridine (6.0 mL) is heated at 130*C for 24 hours. The mixture is cooled down to room temperature and concentrated to dryness. The residue is diluted in ethyl acetate, washed twice with HCI 1 N, water and brine, dried over sodium sulfate and concentrated to dryness. The residue is purified by flash column chromatography on silica gel (methanol/DCM 0% to 10%) and crystallized in water/methanol to yield 10 the title compound 20-2 as a white solid (286 mg). 'H NMR (400 MHz, CDCI 3 ): 8 [ppm] 4.87 (br s, 1H), 4.70 (br s, 1H), 4.48 (d x d, 1H), 3.12 (m, 1H), 2.83 (m, 1H), 2.60 (m, 3H), 2.25 (m, 1H), 1.89 (m, 3H), 1.76-0.94 (m, 39H), 0.92 (s, 3H), 0.89 (s, 3H), 0.85-0.75 (m, 7H). LC/MS: m/z = 656.7 (M+H*). Table 1 illustrates some intermediateswhich are synthesized using the procedures described herein. cpd# Structure Name Analytical data 0 3p-O-acetyL-17p 11 NH2HCI 100 21-oxotup- LC/MS (M*/M+H*): 485.56 18-ene O H hydrochLoride 0 H / 3p-hydroxy-17p-. 12 NH2HCI amino-21-oxoLup- LC/MS (M*/M+H*): 442.56 18-ene HO 'HHhydrochloride

H

WO 2009/082819 PCT/CA2008/002291 80 0 H / 3p-hydroxy-17p 22-1 H1 N'^ [N' 22-10 H nzlUed]2-LC/MS (M*/M+H*): 575.66 H (benzyt)ureido]-21 H oxoLup-18-ene 3p-hydroxy-17p H 0O [N'-3p-hydroxy 22-2 H oxolup-18-ene LC/MS (M*/M+H*): 911.39 H 17p-ureido]-21 H oxolup-18-ene 1 H NMR (400 MHz, CDCI 3 ): S [ppm] 7.73 0 (m, 2H), 7.50 (m, 1H), 7.43 (m, 2H), 6.13 24-1 N 3f3.hydoy-2- (s, 1H), 3.19 (m, 2H), 2.90 (m, 1H), 2.87 24-1 H I ben idroy-217- (d, 1H), 2.40 (m, 1H), 2.35 (d, 1H), 1.94 oxotup-iB-ene (m, 2H), 1.80-1.20 (m, 20H), 1.14 (s, 3H), HO 0.96 (m, 6H), 0.86 (m, 3H), 0.75 (s, 3H), 0.70 (m, 1H). 1 H NMR (400 MHz, CDCl 3 ): S [ppm] 8.54 0 (m, 1H), 8.33 (br s, 1H), 8.12 (m, 1H), H 3p-hydroxy-176- 7.83 (m, 1H), 7.43 (m, 1H), 3.19 (m, 2H), (pyridin-2- 2.86 (m, 2H), 2.47 (m, 1H), 2.38 (d, 1H), y)amido-21 - 1.96 (m, 3H), 1.78-0.64 (m, 14H), 1.25 (d, H (inen HO oxoLup-18-ene 3H), 1.23 (d, 3H), 1.03 (s, 3H), 0.97 (s, H 3H), 0.95 (s, 3H), 0.83 (s, 3H), 0.73 (s, 3H). 0 3p-hydroxy-17p-(5 H N methyl- HPLC : 24.98 24-3 N [1,3,4]oxadiazoLe- Method (E) O- 2-amido)-21- LC/MS (M*/M+H*): 552.34 HO oxotup-18-ene 0 0 3p-hydroxy-17p-(1 H tert 24-4 HuoXyCarbonyLpi LC/MS (M*/M+H*): 553.61 No peridine-4-amido)- (-Boc) HO 0 21-oxoLup-18-ene 0 H/ 3p-hydroxy-17p 24-5 yrid- 1- LC/MS (M*/M+H*): 547.50 HO N oxolup-18-ene H 0 HF H N F 3p-hydroxy-17p-(4 24-6 fluorobenzyt)amido LC/MS (M*/M+H*): 578.50 -21 -oxotup-18-ene HO H 0 1 H NMR (400 MHz, CDCI 3 ): 5 [ppm] 8.74 H / 3p-hydroxy-17p3 (- , 2H), 7.55 (m, 2H),6.21 (brs, 1M), 3.18 24-7 N (pyridin-4. (m, 2H), 2.86 (i, 2H), 2.40 (m, 2H), 1.9 H N yL)aiido.21- (m, 3H), 1.79-0.68 (m , 14H), 1.23 (d, 3H), HO H - oxotup-18-ene 1.21 (d, 3H), 1.13 (s, 3H), 0.98 (s, 3H), H 0.96 (s, 3H), 0.86 (s, 3H), 0.75 (s, 3H).

WO 2009/082819 PCT/CA2008/002291 81 0H NMR (400 MHz, CDCl 3 ): 8 [ppm] 9.35 (d, 1 H), 8.75 (d, 1H), 7.52 (d x d, 1H), 3.18 (m, 2H), 2.83 (m, 2H), 2.46 (m, 1 H), 2.38 24-8 / N~~~~~~ (pyrazin-2- (,a.,1.i~,~1,.2~,i) 24-8 m(d, 1H), 1.94 (m, 3H), 1.78-0.68 (m, 14H), N 1.25 (d, 3H), 1.23 (d, 3H), 1.02 (s, 3H), HO p 0.98 (s, 3H), 0.95 (s, 3H), 0.83 (s, 3H), 0.74 (s, 3H). 111 NMR (400 MHz, CDCL 3 ): 8 [ppm] 7.33 (br 0 s, 1H), 6.95 (br s, 1H), 6.73 (br s, 1H), HH H 3p-hydroxy-17p-(1- 3,90H(, 7.1 (, 1), 5.2 ( , 1H) H / 0 / methyl-1H- 38 s 1) .7(n H,28 i,2) 24-10H imedazo[-5 2.38 (in, 2H1), 1.92 (in, 3H), 1.78-0.66 (in, pyrazole-3-amido) H N mio21xou- 143H), 1.22 (d, 3H), 1.21 (d, 3H), 1.12 (s, HO 21-oxolup-18-ene HO1-n 3H1), 0.95 (s, 6H), 0.86 (s, 3H), 0.75 (s, 3H). 3H NMR (400 MHz, CDCla): 6 [ppm] 7.45 (br H 3ethyL y-i - s, 1H), 7.33 (br s, 1H), 7.18 (br s, 11H), H 0>1 imidote-- 3.70 (s, 3H), 3.16 (m, 2H), 2.83 (m, 2H), 24-11H amidzo)- - 2.38 (m, 2H), 1.93 (m, 3H), 1.78-0.68 (m, N O H 18id)-ene - 14H), 1.22 (d, 3H), 1.21 (d, 3H), 1.94 (s, H 3H), 0.95 (s, 6H), 0.8 (s, 3H), 0.7 (s, 3H). 0H NMR (400 MHz, CDCl 3 ): 5 [ppm 7.48 (br H 3phyd - 1 - s, 1H), 7.46 (br s, 1H), 7.6 (br s, 1H), H / 0 mithydlo-H- 3.97 (s, 3H), 3.17 (m, 2H), 2.83 (m, 2H), 24-10 imidoe-5ai- 2.38 (m, 2H), 1.9 5 (m, 3H), 1.78-0.68 (m, N 21- oxo p- 14H), 1.22 (s, 3H), 1.21 (s, 3H), 1.11 (s, HO H h o 3H), 0.9 (s, 3H), 0.95 (s, 3H), 0.85 (s, _________ ________ ________3H), .74 (,3 1-H NMR (400 MHz, CDCI): 6 [ppm] 7.4 (d, H /(hyl-1- s, 1H), 7.6 (, , 7.41 7.18 (br 1, 1H), 24-1 N N 3-hidazole-- (.97 (sHs, 2.85 3.1 (m, 2.40 2.8 (m, 1.9, H N4/ amido)-21-oxolup- 2.3H), 21., 1. (m, 3H), 1.78-0.6 (, HO H18-ene 1 ( , 4 H), 1.2 1 (s, 3H), 1 . 98 (s, 3H), 0 .9 ( H (s, 3H), 0.8 (s, 3H), 0.7 (s, 3H) . OH NMR (400 MHz, CDCl 3 ): 6 [ppm] 7.34 (, H ~ 3j3-hydroxy-173- 1 H),7.6 (, H), .13 (brs, 1 H), 3.17, 24-15 N (pthihene-m 2H), 2.8 (m, 2H), 2.4 (m, 2H), 1.95n, Saido)-2-oxoup- (mH), 1.8-0.6 (, 15H), 1.23 (s, 3H), NHO8en 12 (s, 3H), .5 (s, 31), 0.9 8 (s, 3H), 8 s H

O

1 H NMR (400 MHz, CDCla 3 ): S [ppm] 6.86 (b, 3p-hydroxy-1703-(- , 1), .38 (d, 1), .17 (in, 1H), 2.817 24-16 ~ ~ (1,3thisazole-- (in, 2H), 2.46 (, 3H), 2.38 (in, 211), 1.92 ainido)-21-oxolup- (in, 2H), 1.780-0.66 (in, 14H), 1.23 (s, 3H1), 18-ene 1.21 (s, 3H), 1.12 (s, 3H), 0.98 (s, 3H), HO 0.94 (s, 3H), 0.83 (s, 3H), 0.73 (s, 3H). 0 3P-0-acetyl-17p H N (5-methyl- HPLC : 39.41. 24-14 H0AN [1,3,4]oXadiaZole- Method (E) H 2-amido)-21 - LC/MS (M*/M+H*): 594.33 O0 oxolup-18-ene HO 0 l~H NMR (400 MHz, CDCl3): 8 [ppm] 9.33 (s 0 ~ 3p-hydroxy-170- 1 H), 9.06 (s, 2H), 6.13 (br s, 1 H), 3.17 (m, 24-15N) rN (pyrimidine-5- 2H), 2.80 (m, 2H), 2.41 (m, 2H), 1.95 (m, H ~ amido)-21 -oxolup- 2H), 1.78-0.66 (m, 15H), 1.23 (s, 3H), HO N 18-ene 1.21 (s, 3H), 1.05 (s, 3H), 0.98 (s, 3H), 0.96 (s, 3H), 0.86 (s, 3H), 0.75 (s, 3H). 0 'H'NMR (400 MHz, CDCla): 8 [ppm] 6.86 (1r 0 ~3p-hydroxy-17p-(5- s, 1 H), 6.38 (d, 1 H), 3.17 (m, 2H), 2.81 24-16N , methylisoxazole-3- (m, 2H), 2.46 (s, 3H), 2.38 (m, 2H), 1.92 H ~ amido)-21 -oxolup- (m, 2H), 1.78-0.66 (m, 14H), 1.23 (s, 3H), HO 18-ene 1.20 (s, 3H), 1.07 (s, 3H), 0.95 (s, 6H), 0.84 (s, 3H), 0.74 (s, 3H).

WO 2009/082819 PCT/CA2008/002291 82 'H NMR (400 MHz, CDCI): 8 [ppm] 9.24 (d, O 1H), 8.96 (d, 1H), 8.22 (br s, 1H), 8.05 (d O3-hydroxy-173- x d, 1H), 3.18 (m, 2H), 2.83 (m, 2H), 2.41 24-17 (pyrimidine-xoup- (m, 2H), 1.95 (m, 2H), 1.80-0.66 (m, N N md-2o p 15H), 1.24 (s, 3H), 1.22 (s, 3H), 1.03 (s, HO 3H), 0.97 (s, 3H), 0.95 (s, 3H), 0.83 (s, 3H), 0.74 (s, 3H). HNMR (400 MHz, CDCL 3 ): 6 [ppm] 7.53 (b 0 3p-hydroxy-17p-(1- s, 1H), 6.96 (d, 1H), 6.93 (d, 1H), 4.00 (s, 0 a / methyl-1H- 3H), 3.16 (i, 2H), 2.89 (i, 1H), 2.80 (d, 24-18 N N imidazole-2- 1H), 2.53 (i, 1H), 2.38 (d, 1H), 1.94 (i, N amido)-21-oxoLup- 3H), 1.78-0.68 (i, 14H), 1.22 (d, 3H), H 0 18-ene 1.20 (d, 3H), 1.09 (s, 3H), 0.95 (s, 6H), 0.85 (s, 3H), 0.74 (s, 3H). 0H NMR (400 MHz, CDC1 3 ): 8 [ppm] 8.73 (d, 3p-hydroxy-17- IH), 8.11 (d, 2H), 7.56 (br s, 1H), 3.1 24-19 N (1,3-thiazote-4- (in, 2H), 2.83 (m, 2H), 2.39 ( , 2H), 1.95 > amido)-21-oxotup- (in, 3H), 1.79-0.66 (m, 14H), 1.24 (s, 3H), S 18-ene 1.22 (s, 3H), 1.04 (s, 3H), 0.96 (s, 3H), 0.95 (s, 3M), 0.83 (s, 3), 0.74 (s, 3H). 0H NMR (400 MHz, CDCL): 8 [ppm] 8.87 (s, 0 3p-hydroxy-17p- 1 H), 8.11 (, 1 H), .56 (br s, 1 H), 3.17m (1,3-thiazole-5- 2H), 2.83 (i, 2H), 2.38 (i, 2H), 1.95 (9, 2 S IN namido)-21-oxolup- 3H), 1.79-0.66 (m, 14H), 1.23 (s, 3H), S-/ 18-ene 1.21 (s, 3H), 1.10 (s, 3H), 0.97 (s, 3H), 0.95 (s, 3H), 0.85 (s, 3H), 0.74 (s, 3H). OH NMR (400 MHz, CDCL 3 ): 8 [ppm] 7.43 (d, O o H), 6.46 (d, 1H), 5.97 (br s, 1H), 4.10 (s, H 3p-hydroxy-517p(1 -3H), 3.18 (m, 3H), 2.83 (m, 2H), 2.38 (m, 24-21 amo)-21-mxo- 2H), 1.94 (i, 3.), 1.78-0.66 (, 14H), 1 8-e o 1.23 (d, 3H), 1.21 (d, 3H), 1.13 (s, 3H), HO 0.96 (s, 3H), 0.95 (s, 3H), 0.87 (s, 3H),

H

______________ 0.75 (s, 3H). O0 1 NMR (400 MHz, CDC1 3 ): 6 [ppm] 7.78 (s, H 33-hydroxy-17p-(1- 1H), 7.66 (d, 1H), 5.73 (br s, IH), 3.90 (s, 24-22 N- methyl-1H- 3H), 3.17 (i, 2H), 2.83 (i, 2H), 2.34 (i, pyrazole-5-amido)- 2H), 1.93 (i, 3H), 1.78-0.66 (i, 14H), HH HO 21 -oxolup-i-ene 1.23 (d, 3H), 1.21 (d, 3H), 1.07 (s, 3H), H 21-oxolup-18-ene H 0.96 (s, 3H), 0.95 (s, 3H), 0.7 (s, 3), H / (2,6 roy7p(- HPLC :136.51 24-22 N 24-24 -- Idmethytpyrzaido.- Method (C)

H

HOado21-oxtp1-n LCMS (M'/M4-H*): 575.49 0 3p-hydroxy-17p8 H 242 O IN (2,6)1 HPLC : 16.512.(1) 225H dmethyLppridine- Method (D) HMaRido(-21- L40MS (M/M+H): 567.51 H 1 oxotup-18-ene 0.9 (s,)1 H), 02.84 ; (s23),0.7(s,). H 3p-hydroXy-1 7p-(-HL:369 24-23 methylbiezaido)e- Method (E) 21-oxou-21-en LC/MS (M*/M+H*): 560.32

HO

WO 2009/082819 PCT/CA2008/002291 83 H N'1H NMR (400 MHz, CDCL 3 ): 6 [ppm] 7.21 (s, r (4 drx1f3[- 2H), 3.18 (in, 4H), 2.93 (d, 3H), 2.70 (n, 3p-hydroXy-17p-[2- H), . (i, 2H), 2.4 (, ), 2.0 ( 24-26 methylpiperazin-1- 3H), 2.25 (i, 2H), 2.00-0.68 (i, 18H), yL)-acetamido]-21- 1.21 (d, 3H), 1.20 (d, 3H), 1.05 (s, 31), HO oxotup-18-ene 0.96 (s, 3H), 0.93 (s, 3H), 0.87 (s, 3H), HO0.75 (s, 3H). 0 11H NMR (400 MHz, CDCl 3 ): S [ppm] 7.24 (s, H 0 1H), 3.18 (m, 2H), 2.88 (d, 2H), 2.78 (m, 3p-hydroxy173.(2- 1H), 2.70 (d, 14H), 2.35 (m, 2H), 2.31 (s, 24-27 dimethylamino- -0.68 (m , 17H), 1.21 (d, 3H), H acetamido)-21 1.20 (d, 3H), 1.09 (s, 3H), 0.96 (s, 3H), OoXoup-18-ene 0.93 (s, 3H), 0.87 (s, 3H), 0.75 (s, 3H). 0 H H 3p-hydroxy-170(2- MHPLC : 20.69 24-28 i -: methyapyridin-4- ~ , ( H2 () eyl)amido-21- 6H), 2 8) Ho- 1.20 d,3H),eL .0MS (Ms/M,H)): 561.44 H O oXolup-18-ene . 0 . 3 ( ,3 ) 0 . 7 ( ,3 ) 0 75 s, H . O H 0 24-29 ((RS)2- Method (C) dimethylamino S propionamido)-21- LC/MS (M*/M+H*): 541.40 HOO F oxotup-18-ene H 0I[2N 3p-hydroxy-17p- (2- HPLC : 11.44 24-30 imidazoL-1 -yl- Method (C) acetainmido)-21- LC/MS (M*/M+H*): 550.39 HO oxoLup-18-ene 0 H 3p-hydroxy-17p-(6- HPLC :13.96 N methylpyridin-3- Method (E) 24-3 H I y)amido-21 HO HN oa LCMS (M*/M+H*): 561.32 H 0 H / 0 3p-hydroxy-17p-(4- HPLC : 12.53 methylpyridin-3 24-32 N yaido2.Method (E) Nyl)amido-21 HO oxoLup- 1 8-ene LC/MS (M*/M+H*): 561.32 H 0 H / 3p-hydroxy-17p-(5- HPLC : 17.94 N methylpyridin-3- Method 2433 - H hyl)amido21 (E) HO HoXoLup-18-ene LC/MS (M*/M+H*): 561.31 H 0 H / O 30-hydroxy-17p-(2- HPLC : 10.57 24-34 N enthylpyridin-3- Method (E) - N yl)amido-21 HON oxotup-18-ene LC/MS (IK/M+H+): 561.31 WO 2009/082819 PCT/CA2008/002291 84 0 H / O 3p-hydroxy-17p-(2- HPLC : 35.40 24-35 N methylbenzamido)- Method (E) 21-oxolup-18-ene LC/MS (M*/M+H*): 560.30 FK) HO O -fH NMR (400 MHz, CDCL 3 ): 8 [ppm] 9.30 (br s, 1H), 3.18 (d x d, 1H), 3.12 (m, 1H), H - - -2.73 (in, 3H), 2.55 (in, 3H), 2.32 (in, 3H), 24-36 N I<IN pyrroiidin-1-y- 2.28 (m, 4H), 2.05 (s, 3H), 1.94-0.66 (m, roXolup-18-ene 24H), 1.20 (d, 3H), 1.17 (d, 3H), 1.10 (s, HO 3H), 0.96 (s, 3H), 0.91 (s, 3H), 0.87 (s, 3H), 0.75 (s, 3H). O H / O 3,6-hydroxy-17p8-(2- 1 H NMR (400 MHz, CDC1 3 ): 5 [ppm] 7.30 (br 24-37 N N pyrrolidin-1-yl- s, 1H), 3.19 (m, 2H), 3.02 (d, 2H), 2.69 H acetamido)-21- (m, 2H), 2.58 (m, 4H), 2.26 (m, 2H), 1.95 HO -H oxoLup-18-ene 0.62 (m, 42H). H 0 H 0 3p8-hydroxy-17,8-(4- 1 H NMR (400 MHz, CDCL 3 ): 6 [ppm] 6.83 (br 24-38 N pyrrolidin-1-yi- s, 1H), 3.19 (m, 1H), 3.11 (m, 1H), 2.77 H H Hbutyramido)-21- (in, 1H), 2.66 (d, 1H), 2.48 (n, 5H), 2.28 HO oxolup-18-ene (m, 3H), 2.05 (s, 3H), 2.00-0.66 (m, 46H). H 0H NMR (400 MHz, CDCL 3 ): 8 [ppm] 9.30 (br H 0 N ' 3pl-hydroxy-17p6-(3- s, 1H), 3.15 (m, 2H), 2.84 (m, IH), 2.70 2-H ND piperidin-1-y- 2.26 (m, 10H), 1.92 (m, 3H), 1.78-0.66 propionamido)-21- (m, 21H), 1.20 (d, 3H), 1.18 (d, 3H), 1.09 H HO oxoLup-18-ene (s, 3H), 0.96 (s, 3H.), 0.92 (s, 3H), 0.87 (s, HH 3H), 0.75 (s, 3H). 0 'H NMR (400 MHz, CDCL 3 ): 6 [ppm] 6.63 (br H / 3p8-hydroxy-17,6-[3- s, 1H), 3.62-3.38 (m, 4H), 3.18 (m, 5H), N (2-oxo-pyrroLidin-1- 2.60 (d, 1H), 2.48 (m, 2H), 2.32 (m, 3H), 244 0D Hyl)-propionamido]- 1.94-0.66 (m, 18H), 1.19 (d, 3H), 1.17 (d, HO H 21-oxoLup-18-ene 3H), 1.09 (s, 3H), 0.95 (s, 3H), 0.91 (s, H 3H), 0.87 (s, 3H), 0.75 (s, 3H). O 3f-hydroxy-17p8 H N [(S)-1-methyl 24-41 pyrrolidine-2- LC/MS (M*/M+H*): 553.27 H amido}-21-oxoLup HOO 0 H O 3p8-hydroxy-17p0-(1 24-42 N isopropyiazetidine- LC/MS (M/M+H*): 567.30 H NT 3-amido)-21 HO H oxolup-18-ene H 0 H /03p-hydroxy-170-(3 24-43 thiophene)amido- LC/MS (M*/M+H*): 552.41 S 21-oxolup-18-ene HO H WO 2009/082819 PCT/CA2008/002291 85 H 30-hydroxy-17p-(5- HPLC : 30.83 24-44 mezol -i- Method (E) H o / oxazote-2-amido)-LCM MM )51.4 HO H 21-xlp1eeLC/MS (M*/M+H*): 551.41 HO 2-oxotup-18-ene H O 30-hydroxy-170- HPLC : 11.62 25-1 N'kO isopropyloxycarbon Method(J) 8 aino-21-oxoLup- J):528.26 HO H 0 3p-O-acetyl-17p H 0 tert 25-2 NO-/ butyloxycarbonyla LCIMS (M*/M+H*): 584.68 mino]-21-oxolup 18-ene 0 3p-hydroxy-17p 0 tert 25-3 butyloxycarbonyla LC/MS (M*/M+H*): 542.61 H Imino]-21-oxolup NO 18-ene 0 25-46N spoyoyabnL/S(V+~:545 H 'H NMR (400 MHz, CDCW 3 : 5 (ppm] 4.83 (br H (0--aeA-73 s, 1iH) 4.48 (d x d, 1KH), 3.83 (d, 2H), 3.14 0cyc-opropylmethox (in, 1KH), 2.85 (in, 1t-H), 2.66 (d, 1 H), 2.26 25- N'1 yclorboyamo (d, IH), 2.04 (s, 3H), 1.91-0.80 (in, 19H), 21-oxrotup-18-ene 1.22 (s, 3H), 1.21 (s, 3H), 1.13 (s, 3H), 21-oxtup-1-ene 0.93 (s, 3H), 0.92 (s, 3H), 0.85 (s, 3H), 0.84 (s, 3H), 0.53 (d, 2H), 0.25 (d, 2H). lH NMR (400 MHz, CDCL3): 5 [ppm] 5.04 (0 31--acetyL-170- (mn, I1-H), 4.74 (br s, I1-H) 4.44 (d x d, I H), Q cyctopentyloxycarb 3.10 (in, 1H), 2.82(m, 1K), 2.60 (d, 1K), 25-6 IN 0 2.22 (d, 1H), 2.02 (s, 3H), 1.89-0.77 (in, 0onylamino-21 - 27H), 1.16 (s, 3H), 1.13 (s, 3H), 1.10 (s, A'Ooxolup-18-ene 3H), 0.90 (s, 3M), 0.89 (s, 3M), 0.82 (s, 3M), 0.81 (s, 3H). lH NMR (400 MHz, CDCW 3 : 8 [ppm] 5.04 3I3-hydroxy-17p3- (in, 1 H), 4.75 (br s, 1 H), 3.15 (in, 2H), 257ccoetlxcr 2.84(m, 1H), 2.60 (d, 1H), 2.22 (d, 1H), 25-7 ~N .0 copnyxyab 1.89-0.77 (in, 26H), 1.18 (d, 3H), 1.16 (d, - HonyLamn-1- 3H-), 1.10 (s, 3M), 0.90 (s, 3M), 0.89 (s, HO oxtup-1-ene 3H), 0.82 (s, 3H), 0.81 (s, 3H), 0.70 (in, 1 H). 'H NMR (400 MHz, CDCt 3 ): 8 [ppm] 4.72 (s, (0 33-0-acetyl-17p- 1H), 4.60 (i, 1 H) 4.45 (d x d, 1H), 3.11 cycloproyeto (m, 1H), 2.82(m, 1H), 2.62 (d, 1H), 2.23 25-8 N (d, 1H), 2.02 (s, 3H), 1.90-0.77 (m, 29H), nylamino-1e- 1.20 (s, 3H), 1.19 (s, 3H), 1.10 (s, 3H), oxotup-18-ene 0.91 (s, 3H), 0.89 (s, 3H), 0.83 (s, 3H), S0.82 (s, 3H).

WO 2009/082819 PCT/CA2008/002291 86 'H NMR (400 MHz, CDC 3 ): S [ppm] 4.57 (b s, 1H), 3.17 (d x d, 1H), 3.11 (m, 1H), H3p-hydroxy-17p- 2.83 (m, 1H), 2.62 (d, 1H), 2.22 (d, 1H), 25-9 N A~OIi cyclohexytoxycarbo 2.02 (s, 3H), 1.88-1.20 (m, 29H), 1.18 (s, nylamino-21- 3H), 1.16 (s, 3H), 1.09 (s, 3H), 0.94 (s, HO oxotup-18-ene 3H), 0.91 (s, 3H), 0.86 (s, 3H), 0.74 (s, 3H). IH NMR (400 MHz, CDCI 3 ): 8 Ippm] 4.76 (s, o3-0-acetyl-17p- I 1H), 4.74 (i, 1H) 4.45 (d x d, 1H), 3.72 ' 0 (1-tert- Im, 2H), 3.13 (i, 1H), 3.12 (m, 2H), 210 N but xycarbonypipe| 2.80(m, 1H), 2.61 (d, 1H), 2.25 (d, 1H), -0 ytoxycarbonylamin 2.03 (s, 3H), 1.89-0.78 (m, 23H), 1.42 (s, yoy2abonytamin 18- 9H), 1.20 (s, 3H), 1.18 (s, 3H), 1.10 (s, o)-21-oxolup-18- 3H), 0.92 (s, 3H), 0.90 (s, 3H), 0.83 (s, ene 3H), 0.82 (s, 3H). 'H NMR (400 MHz, CDCl3): 6 [ppm] 4.76 (s, (o 3j-O-ac IetyL-17p- 1H), 4.45 (d x d, 1H), 3.81 (d, 2H), 3.41 3 (d, 1H), 3.11 (m, 1H), 2.82(m, 1H), 2.62 25-11 N-K cyciohexytmethoxy (d, 1H), 2.24 (d, 1H), 2.01 (s, 3H), 1.89 H 0- carbonylamino-21 - 0.78 (m, 29H), 1.20 (s, 3H), 1.18 (s, 3H), oxoLup-18-ene 1.10 (s, 3H), 0.91 (s, 3H), 0.89 (s, 3H), 0.83 (s, 3H), 0.82 (s, 3H). 'H1 NMR (400 MHz, CDCL 3 ): 6 [ppm] 4.82 (s, o phdoy10 1 H), 3.81 (d, 2H1), 3.40 (d, 111), 3.18 (d x 3cyroxym17ox d, 111), 3. 10 (in, 1H), 2.82(m, 1H1), 2.62 25-12y m (d IM), 2.24 (d, 1H), 1.87-0.78 (m, 29H), H ~carbonylamino-21 25 H12 0box o nlauo 1.18 (s, 3 ), 1 .17 (s, 3), 1.09 (s, 3), oxu e 0.94 (s, 3M), 0.91 (s, 3), 0.86 (s, 3M), 0.74 (s, 3M). H NMR (400 MHz, CDC 3 ): 5 [ppm] 7.32, oH (i, 51), 5.03 (s, 2H), 4.84 (b ,11H), 4.45 (d x d, 1H), 3.11 (m, 1H), 2.80 (m , 11), 25-13 N 0 t o 2.63 (d, 1H , 2.25 (d, 1H ), 2.03 (s, 3H), min-1 1.87-0.77 ( , 1911), 1.20 (s, 3), 1.18 (s, 3), 1.06 (s, 3H), 0.91 (s, 3H), 0.90 (s, 30), 0.83 (s, 3H), 0.82 (s, 3M). 'H NMR (400 MHz, CDCl): 8 [ppm] 4.77 (b 0 3PO-actyt-7p- (m, 5H), 5.03 (s, 2H), 4.4 (d, 1H), 4.45 ( 0 s, 1( x4.48 (d x d, 1H), 4.15 (m, 11), 3.15 3~-Q-cety-17 ~ 2.(in 111, 1H2. (d11, 1H2. (si, 2.26 251I cyclopropytmethox (d, 111), 2.05 (s, 3M), 1.94-0.81 (in, 1911), 0 1.63-077H( , 19 .2 (s, 3H), 1. (s, 2K 21-oxotup-18-ene 1.14 (s, 3H), 0.95 (s, 3H), 0.93 (s, 3H), 0.86 (s, 3H), 0.85 (s, 3H), 0.39 (i, 3H), 0. 21 (m, 111). 'H NMR (400 MHz, CDC 3 ): [ppm] 4.85 (br s, 11H) 4.48 (d x d, 11H), 3.83 (s, 21), S0 3f(O-acetyt-17p- 3.15 (in, 11), 2.82 (mi, 1 (), 2.69 (d, 1), cyclopropytmethox 2.28 (d, 11 ), 2.04 (s, 3H , 1.93-0.80 (m , ycarbonylamino- 181), 1.23 (s, 3H), 1.21 (s, 3H), 1.14 (s, 21-oxoLup-18-ene 3M), 1.09 (s, 3H), 0.94 (s, 3H), 0.92 (s, 3H), 0.85 (s, 3H), 0.84 (s, 3H), 0.45 (d, 2), 0.33 (d, 21H). 'H NMR (400 M~z, CDCI 3 ): 6 [ppm] 4.87 O 3p0-acetoxy-17p8- (i, 111), 4.78 (br s,111) 4.44 (d x d, 111), 2516/ JJ ycobtyoxcab 3.11 (mn, 111), 2.82(m, 111), 2.62 (d, 111), N cyclo ylox 2.22 (d, 1), 2.01 (s, 3), 2.00-0.77 (, 0 H c a25m), 1.14 (s, 3), 1.11 (s, 3o-), 1.10 (s 2e -oxoup-18-ene 3H), 0.90 (s, 31), 0.89 (s, 31), 0.82 (s, (b s), 0. 81 (s, 32 ).

WO 2009/082819 PCT/CA2008/002291 87 'H NMR (400 MHz, CDCL 3 ): 5 [ppm] 4.87 (s, 346-acetoxy-17p6- 1H), 4.60 (m, IH) 4.43 (d x d, 1H), 3.60 o as tetrahydro- (m, 1H), 3.10 (m, 1H), 2.80(m, 1H), 2.60 25-17 N thiopyran-4- (m, 3H), 2.53 (d, 1H), 2.23(d, 1H), 2.01 0 H ytoxycarbonylamin (s, 3H), 1.87-0.76 (m, 23H), 1.18 (s, 3H), o-21-oxotup-18-ene 1.16 (s, 3H), 1.08 (s, 3H), 0.90 (s, 3H), 0.88 (s, 3H), 0.81 (s, 3H), 0.80 (s, 3H). 'H NMR (400 MHz, CDCl 3 ): 8 [ppm] 4.77 (s, 0o,-ctxy1,-l 1H), 4.47 (in, 1H) 4.45 (di x d, 1H), 3.11 S N 3-acetoXy-17-(1- H), 2.81 (, 1H), 2.64 (, 1H), 2.59 methyl-piperidin-4- (d, 1H), 2.26 (d, 1H), 2.24(s, 3H), 2.14 2518 H ytoxycarbonylamin (i, 2H), 2.02 (s, 3M), 1.88-0.77 (i, 23H), 'O' o)-21-oxolup-18- 1.20 (s, 3H), 1.18 (s, 3H), 1.10 (s, 3H), ene 0.91 (s, 3), 0.89 (s, 3H), 0.82 (s, 3H), 0.81 (s, 3H). 1 _H NMR (400 MHz, MOOL 3 : 5 [ppm] 4.96 (br 0 ((S)-1 -Methyl- (d x d, 1H), 3.13 (i, 2H), 2.80 (, 1), 25-19 N pyrrotidin-2-yL)- 2.60 (d, 1H), 2.35 (s, 4H), 2.11 (in, 2H),), H i(ethoxycarbonyta 2.01 (s, 3H), 1.90-0.77 ( m, 21H), 1.19 (d, r~ mino-21-oxotup-18- 3H), 1.17 ( 8, 3H), 1.08 (s, 3H), 0.90 (s, 0ene 3M), 0.89 (s, 3), 0.82 (s, 3H), 0.81 (s, 3M). 'H NMR (400 MHz, CDCL 3 ): 6 [ppm] 5.20 (br 0 3p-acetoxy-17pr(2- s, 1H), 4.46 ( x d, 1M), 4.15 (hr s, 2H), pyrrolidin-1- 3.14 (in, 1), 2.85 (n, H), 2.65 (, 7H), 2 0 ylethoxycarbonyla 2.28 (i, 4H), 2.05 (s, 3M), 1.88-0.80 (i, mino)-21-oxolup- 19), 1.22 (, 3M), 1.20 (, 3H), 1.11 (s, 0Ns 18-ene 3H), 0.93 (s, 3M), 0.92 (s, 3H), 0.85 (s, 3H), 0.84 (s, 3m). 'NMR (400 M~z, CDCL 3 ): 5 [ppm] 4.74 (s, (O iM-ctxy1,- 1) 4.43 (di x di, 1H), 4.04 (di, 2H), 3.10 0.0 ( , ), 2.81 ( s, 1H), 2.61 (m, 1M), 2.2 25-21 IN c ( , ), 2.00 (s, 3), 1.86-0.77 (m2 , 21), arbonylamino-21 1.18 (s, 3M), 1.16 (s, 3H), 1.08 (s, 3M), oxoup-1 8-ene 0.89 (s, 3H), 0.87 (s, 3H), 0.80 (s, 3M), 0.79 (s, 3M), 0.38 (i, 2H), 0.00 (i, 2H). 3/3--aceyt-1fr H NMR (400 MHz, CDCI.

3 ): 6 [ppm] 4.86 (br aty(1--1tert- s, 1H) 4.45 (d x d, 1H), 3.55 ( r, 2M), 3.12 N 0 NA butoxycarbonylamni (i, 1iM), 2.82 (i, 1iM), 2.64 (d, IMH), 2.25360 a ey-7l HN R(0 ~,C C3:8[p ]48 b 25p22 y no i (d, 14), 2.02 (s, 3M), 1.89-1.16 (m, 18H), cyclopropymethox 1.41 (s, 9H) 1.20 (s, 3H), 1.18 (s, 3M), ycarbonytamino)- 1.11 (s, 3M), , 0.92 (s, 3M), 0.89 (s, 3M), 21-oxotup- -ene 0.83 (s, 3 H), 0.82 (s, 3M), 0.80 (, 4M). o 3pl-acetoxy-17pi-(1 H NMR (400 M~z, CDCL,): 6 [ppm] 5.26 N' 0 o 3- 3.1'1 (in, 1H), 2.85 (mn, 2M), 2.60 (di, 1H), 25-2H 2.45-2.20 (, ), 2.02 (s, 3M), 1.92-0.72 yloxycarbonyamin ( , 22M), 1.19 (s, 3M), 1.17 (s, 3M), 1.08 o)-21-oxoup-18- (s, 3M), 0.90 (s, 3M), 0.89 (s, 3M), 0.82 (s, ene 3MH), 0. 81 (s 3M). 0 3p-O-acetyl-17p- 'H NMR (400 MHz, CDCI,): 6 [ppm] 4.83 (b 0 4o s, 1H), 4.48 ((t x d, I), 3.88 (r, 2t), 25-24 2 e - 3.12 (m, 1M), 2.85 (, 3M), 2.60 (, 1H), ycamin o)-ethoxonyL 1.99-0.77 (m, 24M), 1.19 (d, 3M), 1.17 (d, o)-21-oxoLup- 3), 1.09 (s, 3), 0.90 (s, 3), 0.89 (s, eH), 0.82 (s, 3MH), 0.81 (s, 3M).

WO 2009/082819 PCT/CA2008/002291 88 11H NMR (400 MHz, CDCL 3 ): 5 [ppm] 4.88 (br 25-25 IH 252 oHylmethoxycarbonyl 2.02 (s, 3H), 1 .99-0.75 (mn, 2411), 1.19 (d, 0/0amino)-21 -oxolup- 3H), 1.17 (d, 311), 1.10 (s, 311), 0.90 (s, 18-ene 3H), 0.88 (s, 311), 0.82 (s, 3H-), 0.81 (s, 3H). 0 3,-aceoxy-7,6-l- IH NMR (400 MHz, CDCL 3 ): 8 [ppm] 5.75 (br o-aetoy-17fl-(- s, 1H), 4.45 (dx d, 1-e), 3.90 (n, 2-p) 3.2 S-methylpridin- (, 1), 2.85 (, 1H), 2.75-2.40 (, 7H), 25-26 N~ 0 2.35 (s, 3H), 2.20 (in, 411), 2.00 (s, 3H-), 0H ymethoxycarbony a H - meth2 oxarbony8a 1.*99-0.76 (in, 1611), 1.18 (s, 3H), 1.16 (s, 0 mNmno- 311), 1.09 (s, 3H), 0.89 (s, 31), 0.88 (s, -31), 0.81 (s, 3 ), 0.80 (s, 311). 0 111 NMR (400 MHz, CDCL 3 ): 8 [ppm] 4.86 (br 0s, 111), 4.45 (d x d, 1H), 4.15 (i, 2) 3.43 o Metl-pyrrolidin-- (m, 41), 3.12 (i, 111), 2.80 (i, 111), 2.6 25-27 N (2-oXo-pyrroLidin-1-(, 1), 2.25 (, 2), 2.02 H ~yl)-propionamido]- ,1 ) 0Lmd (s, 31H), 2.00-0.77 (, 201H), 1.20 (s, 31H), AO o- N 21-oxo3up-18-ene 1.18 (s, 3H), 1.10 (s, 3H), 0.90 (s, 3H), )0.89 (s, 3 ), 0.83 (s, 311), 0.82 (s, 31). 00 H 3) H N (40 NHBOC NHBOC 0HOC' H + 0 H .3HO H 0 ( , HO (,H 14-101. H 09 ( 3 . H 8 HCI H),08s H, .0(,3) 00 00 H 0 HO H H 15N1 Scheme 10 3fl-o- (3', 3'- DimethysuccinyL)- 1 71-tert-butyloxcarbonlamino-21 -oxotup- 1 8-ene 14-1 0 H 0 H 0 HO 0 O H H / Hl 0 To a stirring mixture of compound 13 (43 g, 0.079 mot), DMAP (11.7 g, 0.095 mot) in TEA (396 mL) is added 2,2-dimethyltsuccinic anhydride (25.4 g, 0.198 mo). The WO 2009/082819 PCT/CA2008/002291 89 reaction mixture is heated at 95*C overnight. The mixture is cooled down to room temperature and concentrated to dryness. The residue is dissolved in ethyl acetate (400 mL) and washed twice with a saturated solution of NaHCO 3 (100 mL). The mixture is diluted with 100 mL of EtOAc and 1N HCI (100 mL) is added while stirring. The mixture is cooled in an ice-bath and stirred for 30 min. The precipitate formed is collected by filtration to yield the title compound 14-1 as a white solid (39 g) in a ratio of 97:3 of 14-1:14-4 respectively. The organic layer of the filtrate is dried over sodium sulfate and concentrated to dryness. The solid obtained (16 g) is recristallized twice with ethyl methyl ketone to give the title 10 compound 14-1 (3.6g) in a ratio of 98:2 of 14-1:14-4 respectively. HPLC analysis: 14-1 RT: 13.4 min, 14-4 RT: 14.1 min using method (J) 30-0-(3',3'-Dimethylsuccinyl)-17p-amino-21-oxolup-18-ene hydrochloride 15-1 0

NH

2 CIH 0 H HO 0 YV~j H 0 A solution of compound 14-1 (53.6 g, 0.08 mol) in 4N HCl in dioxane (536 mL) is stirred at room temperature overnight. The mixture is concentrated to dryness and triturated with hexanes to give the title compound 15-1 (46 g, 95%) as a white solid. 'H NMR (400 MHz, DMSO-d 6 ): 6 [ppm] 4.36 (d x d, 1H), 3.18 (d x d, 1H), 3.05 (m, 20 1H), 2.48 (m, 2H), 2.13 (d, 2H), 2.0 - 1.18 (m, 16H), 1.17 - 0.94 (m, 17H), 0.84 (s, 3H), 0.82 (s, 3H), 0.76 (s, 6H). The compounds of the present invention wherein Y is C(O) can be prepared as generally described in schemes 11, 12, 13 or 14.

WO 2009/082819 PCT/CA2008/002291 90 0 0 H / SeO 2 H / NH dioxane NH HO A O - - HO A O 14 27 H /0 HCI

NH

2 HCI 0H - HO A 0 H 28 Scheme 11 General procedure: Step 1: Selenium dioxide (4 to 6 eq.) is added to a solution of compound 14 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 10 over sodium sulfate and evaporated to dryness. The crude material is purified by flash chromatography on silica get to yield the compound 27. Step 2: The compound 27 is deprotected in solvents such as THF or dioxane and 4N HCL. The mixture is stirred for 12 to 24 hours at room temperature then concentrated to dryness to give 28.

WO 2009/082819 PCT/CA2008/002291 91 0 H / O NH 0AO 0 R 3 HO A O .% H R 3 29

R

3 NCO 0 or H/ O

R

3

R

3

'NH

2 R 5 So 2 CI NH 0 0 0 O HO A O O0'R H / O 30

-NH

2 HO A O O H0 28 R 4 COCI H / O or R 4 COOH NH 0 0 or 0 0 OA0 R4 HOA O R4 0 R4

R

6 OCOCI 31 0 H/ 0 NH H E00 HO A 0 O 1O H R6 32 Scheme 12 General procedures: Ureas 29 are made by treatment of compound 28 with an isocyanate (1 to 3 eq.) or phosgene or triphosgene followed by an amine (R 3

R

3

'NH

2 ) in a solvent such as toluene or THF. 10 Sulfonamides 30 are obtained by coupling compound 28 with the appropriate sulfonyl chloride (1 to 3 eq.) in solvents such as THF or DCM and in the presence of a base such as TEA or DIPEA.

WO 2009/082819 PCT/CA2008/002291 92 Amides 31 are prepared by coupling compound 28 with the appropriate acyl chloride (1 to 3 eq.), preactivated carboxylic acid, mixed anhydride or anhydride in solvents such as THF or DCM and in the presence of a base such as TEA or DIPEA. Carbamates 32 are obtained by reacting compound 28 with the appropriate chloroformate (1 to 3 eq.) in solvents such as THF or DCM and in the presence of a base such as TEA or DIPEA. 0 0 H / SeO2 H / 0 X dioxane X 0 0 0 0 H H -- ' HO A O - HO A 0 H H 17-20 29-32 10 Scheme 13 General procedure: Selenium dioxide (4 to 6 eq.) is added to a solution of compound 17, 18, 19 or 20 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 20 flash chromatography on silica geL to yield the compound 29, 30, 31 or 32, respectively.

WO 2009/082819 PCT/CA2008/002291 93 0 0 H /SeO2 H O NaOH or KOH x x H dioxane O Solvent O H -- O H - H H 22, 23, 24 or 25 33 0 0 H 0 0 0 H/ 0 A -4 x 0 Pyridine, DMAP H HO A O HO -H H 34 29-32 Scheme 14 General procedure: Step 1: Selenium dioxide (4 to 6 eq.) is added to a solution of compound 22, 23, 24 or 25 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, 10 dried over sodium sulfate and evaporated to dryness. The crude material is purified by flash chromatography on silica gel to yield the compound 33. Step 2: The ester 33 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 34. Step 3: To the alcohol 34 in solvents such as pyridine, TEA or toluene (0.2-1.0 M) is added a cyclic anhydride (2 to 10 eq.) and base such as DMAP, TEA, DABCO or 20 DIPEA (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 get the acid 29, 30, 31 or 32. HIV Replication Activity WO 2009/082819 PCT/CA2008/002291 94 HIV-1 Replication in MT2 cell 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 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 10 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 fluid. The IC 50 and IC 9 0 values for the virus replication are determined by using GRAPHPAD PRISM software. 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 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 20 with HIV-11IIB 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 cetls/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 medium supernatant is replaced with fresh medium supplemented with human serum (when necessary) containing the serially diluted test compound. The IC 5 0 and IC 9 0 values for the virus replication are determined at day 6 post-infection by 30 measuring the reverse transcriptase activity in the harvested supernatant by using GRAPHPAD PRISM software. The IC50 of the compounds tested in accordance with the HIV replication activity assay MT2 (HIViiiB) are represented in Table 1. Table 2 of compounds illustrates some of the compounds of the present invention which are synthesized and tested using the procedures described herein.

WO 2009/082819 PCT/CA2008/002291 95 Retention time (tR) for each compound are measured using the standard analytical HPLC methods described above. Table 2. MT2 MT2 (HIVIIIB) Cpd# Structure (HIVIIIB) with HS 30% thom ) M*/M+H* IC50 range IC50 range 0 Hf 0 14-1 H V o +++ +++ 670.69 HOH O HOH HOH 'H NMR (400 MHz,

CH

3 0D): 8 [ppm] 6.90 (br s, IH), 4.46 (dxd, IH), 3.17 (sept., 1H), 2.96 (dxd, I H), 2.50 (d, 0 IH), 2.37 (m, IH), 2.18 H (d, 1 H), 2.17 (br s, 2H), 14-2 NH + 2.04-1.81 (m, 5H), 1.78 0 0 (dxt, 1H), 1.74-0.80 (m, HO O H19H), 1.40 (s, 9H), 1.18 (t, 9H), 0.99 (s, 3H), 0.96 (s, 3H), 0.88 (s, 3H), 0.85 (s, 3H). o H 14-3 NH (++ 34'99 725.16 Ho (B) 0 0 C+H HO 0 Hf 15-1 NH 2 CIH 570.59 H HO H 0 15-2 /NH2 + 579.42 0 0 MN2 HO 0 Cu.' 0 15-3 NH2 +++ 20.56 625.55 HO 0 CIH WO 2009/082819 PCT/CA2008/002291 96 0 16-1 H N 753.7 H HO 0 H 0 0 16-2 H 584.5 0 (D) H 0 17-1 HN N ++++++703.68 HO O H H H H 17-2 H +++H+++21.6 641.6 HO O 0O 0 0 H 17-3 +H ++ 30.9 689.6 0 (A) H 0 OH /0O 17-4 N~ N ++++7'63 655.7 H H (F) HO HO 0 YO 0 HOO O 17-5 N N +++ 91 65.9 0 H H (F) HO O0 00 0 17-6 N UN .. . 36 691.9 0 H H CIH (G) 0 0 /0 17-7 N N O..98 695.9 o H H(F HO 01 WO 2009/082819 PCT/CA2008/002291 97 0 17-8 N . 7099 0 H H (F) HO 0 o 0 17-9 + 797.44 HOH 00 17-10 HoH + 26.69 696.73 o H H(D) HO Y O CIH 0 0 I 0 17-11 NN 33.92 739.06 H H (C) HO 01 0 0 H /H HO O N 0 0 H/ 0 17-13 N N ++20.92 683.81 O H HO O (A) HO 0 0 H / 17-16 N N +++ 26.77 68.86 HO H () H O 0 H 0 17-17 N N 26.29 72.8 HO H N H (D) HOy~ 0CH H 00 H/ 0 17-16 N N 26.50.696.86 HO 0 H H Ny (A) 750 HOY 'X WO 2009/082819 PCT/CA2008/002291 98 0 17-18 N N'... 298 669.63 0 H (A) HO 'u~ 0 00 0 17-19 ~N 0-O3 1 657 0 H H (E) 657 HO Y 4 0 00 0 N7-20 NNa 19.49 O72 H H. 974 HO NH(B 0 0 0 /0 17-21 N N ++ 17.12 676 0OYU H H- (B) 676 HO 4 " 00 00 17-22 N " N.. 15."72 653.60 0 H H (B) HO U 01 0 0 / 0 17-23 N~ Na+ 26.1 0O H NH +(D) 696.83 0 Oj;TFA~i 0 0 / 0 17-24 0 2 Y Ha ++ 12.53 696.96 HO- H H (G) H U O I CIH H 0 0 Hf 0 17-25 N N N. 30.3 Ho-Y - HH H H (E) 690.81 0 Hf 0 N 17 -26 N l No 20.22 H H .. 690.4 HO o (C) 0 00 17-27 N 11N--- 21.45 N(C) 704 HO 0j __________ 0 WO 2009/082819 PCT/CA2008/002291 99 0 /0 17-28 N 11 5 724.97 O H H HO OO 0 0 H /0 17-29 N t N-- +++ 724.5 HOy~ O H 0 17-30 N N N8 724.5 O H: H NHG HOO OO 17-31 N )N 1876 7 H H H O04.88 HO 0 00 HOO H 0 0 0 0 17-3 NN T 25.9 7 9. HO2 H H HO1 H (A) 69 . OH 00 17 -3 6 N N O H H N2.95 7693.3 HO H (A) 0 0 0 H H H 2(D) HOy~ H 00 0 17-35 19.12.68.85 HO UN(B / 0 17-36 N NH 123.5 H ... 811731 HOrj 0 H 2 /(H) 0 N-N H OH

/N

WO 2009/082819 PCT/CA2008/002291 100 0 OH ~CIHH 17-38 N N N..28.20 697.05 HO H _____0_____H 0 /0 17-39 N NO ++ 16.15 711.13 HO H C 0 CMh 00 0 17-40 HO H.. 26.03 783.57 HO 0= NH (A) 0 0 / 0 17-41 0 HN... 26.28 783.58 HO ou0 J0< NH (A) 0 0 0 17-42 N NQ\+ 15.39 629 HO HUoNH (C) 0 0 I 0 17-43 N N~c 15.57 629 HOj (C) HO 0 H NH 2 0 N Hf 0 17-44 N I N N. 6.00 HO2 2 H H (F) 691.96 )r0 0 0 0 0 -,> 17-45 N N 30.73 720 0H H .. (E) 720 HO j 0 0 H 0 0 -' 17-46 N ) NI" . 13.25 HO 0 H H (H) 692.03 0v -H 0 0 -C. 17-47 N 11N .. 8.85 750 HOIl H (H) 0 WO 2009/082819 PCT/CA2008/002291 101 0 17-48 HO NO 8.11 641.78 0 O F / 0 F4 F 17-50 N-39 710.06 H H (F) H-OO HO O 00 F 0 F F 17-51 HF H 9.)3 710.06 0 O HO 01 0 0 CIH 17 -5 2 NN . 24 .0 8 17-54 -N (E) HOO /0 17-53 N 24.08 70. 0 H H (F) HO HO ~ FE 0I 0 0 /0 17-54 N N 28.20 724.22 0 H H (F) HO 10 00 0 17-5 N'1 N .. 26.47 724.23 0 H H'(B) HO yi 0 00 0 17-56 N N .. 10.80 724.19 0 - H H (F) HO yi 01 0 0 F 17-57 N 11N 732.275 0 H H (F) HO U 0 00 17-58 0 A, N . ~ 9.20 740 H ... F).0 HO UFF(F 0 WO 2009/082819 PCT/CA2008/002291 102 0 17-59 H O 28.13 718.14 H (A) HO O F 0 0 0 2 6 17-60 0 27.66 746.33 HON N oH H J F (A) O HO F 0 00 0 17-61 +++ 10.48 718.19 0 H H I,(F) HO YjO 4 O O 0 17-63 +++ .. 100 732.29 0 0 O 0 HO yv O x O 0 17-65 N +++ 710.1 1760 H H I (F) HO UO O O 00 00 /0 17-66 H +9++ 730.27 H H O (F) HO O 00 / CIH 17-67 N 5.52 706.11 176 H H N (A) HO -Y O HO O 00 0 CIH 17-68 0N ++ 2 9 706.04 HO O HO WO 2009/082819 PCT/CA2008/002291 103 0 /0 17-69 N N 17.10 731.26 O H H (E) HO O CIH O1 0O 00 / 0 17-70 N N + 31 66 738.28 0 H H (B) HO a1 0 0 17-72 N 10.00 719.18 HO CIH (H) 0 0 O H a 17-73 N NH +++ 12.45 708.07 HORV, a H N (I) O CIH O0 H/ 0 17-74, )l10.03 17-74 N NH + 709.07 HO O CIH N (H) HO /0 17-75 N++ N 9.04 710.01 0H H(G HO Y- o-Ol G HO 0 a0 O H 0 17-76 N NH 5.76 708.08 HO O H H (G) ON 0 H 0 O 18-1 N +++ +++ 648.6 HO H 19-1 Y~.Q H / + + ,6 HO H OH 0 19-1 N+ +++ 612.64 H O H H 0 Hf 19-2 N ..... 674.70 0

H

WO 2009/082819 PCT/CA2008/002291 104 0 Hf 0 OH 19-3 H 0 21.8 698.8 H (A) HO 0 00 H 0 N 19-4 N +++ +++ 32.5 680.6 HO O O(E) 0 H 00 H 0t 19-5 N N +++ ++ 31.8 681.7 HO 0 (A) (M-Boc) F-c 0 H0 0 0 H 0 19-6 N + 26.4 681.6 H O (D) HH/O 0 H 00 19-7 NH O ++0+ 4, , 0 Hf F 19-9 + +++ 24.9 723.6 HO O (E) SOA 0H 0 Hf 19-0 +++ +++ 675.6 O O (E )

O

H 00 F H 0 1 F 19-11 +++ m 29.9 706.6 HO O ((+) O 00 H (A HOH 0 -0 0 HH 00 Hf 0 F HN + 33.6 691.0 111 HO H(A) (M+) 0 WO 2009/082819 PCT/CA2008/002291 105 0 H /0 19-12 F 32.4 H . 692.8 H (A) HO O 0 H /0 19-13 N ++. 31.8 691.0 O HOO H 0 O H 0 H / C 19-14 N 24.4 H +++ 675.7 IN (E) HOO H 0 CIH H/ 0 19-15 N-++.7 H 0 HH CIH ON H / O 19-19 HN 381 HO 00 H CIH 19-17 N N 2569 H(N- 678.8 HO O H YJ0 H 0 H 0 19-18 N N 3. 7.1 HOHNHH 678.7 HOH O H 0 1H1 .. 10.9 678.7 (H) HO H CIH \ H 00 H 0 19-20 N -30.2 0H /I®n.. A 680.7 HO~y H HO 0 H 00 H 0 19-21 N -~32.7 H 681.7 HOH 0 WO 2009/082819 PCT/CA2008/002291 106 0 / O CIH 19-22 +++22 676.7 0 H N"(E) HO O HO 00 19-23 1 N +++ +++30. 676.8 HO N 0 0 / 0 19-24 N +++. 30.5 679.8 HO O Of O 19-25 Nk' CH. 67*. 0 HN_ N (E) HO 0I 0 0 /0 9-26 N 35.5 678.8 HO OCIH 19-27 N -A) OH 0 HO 00 00 19-28 N +++ 239 681.7 O s/ (A) HO 0 00 0 19-29 N +++ 688.8 O H () HO O 0 0 0 0 /0 03 6 HO 01 WO 2009/082819 PCT/CA2008/002291 107 0 19-31 N (8.32 640.5 H OH() HO 0 HO 0 0 /0 19-32 N++ +++ 97 654.2 HO 0 H (F) HO -j0 O1 0 /0 19-33 N 10.37 680.75 HO 0 0O 00 Hf 19-34 + +++ 2 3N 678.7 - H /(E) HO O H CIH 0 0 N CI 28.3 19-35 N +++ 678.7 HO H H O H HO HN HO 0O H /N 0 Hf 19-37 28.7 69.8 O (C) O 0 H 0 0 N 1902 19-38 681.70.7 H (C) HOH Hfi 0 WO 2009/082819 PCT/CA2008/002291 108 0 N - N) 20.2 19-40 H + 709.9 H(C) HOH HO 0O 0 H 0 N N\11.2 19-41 H (H 709.9 HOO H 00 19-42 H+18.0 681.7 OH N .. h. (C) 61. HOy ~ O H HO 00 Hf 0 19-43 H )7 688.4 143N (A) H HO 00 H 0 19-44 H +2+ 688.8 N (B) HO O H HO 00 Hf 0 1945N 32.4 145H .. 688.8 O0: (A) HO H H 0 H / 0 C 19-46N ~N 9.2 68. 0 (A) HO " y H 00 H / 0 HCI 19-47 H (E) . 689.8 HOH HOH 00 H 0 H N HCI 1. 19-4 H-'21. 689.7 N94 (E) HOH Y-j H 00 H / HCI 1949N N 19.6 H94 E 689.9 HO

H

WO 2009/082819 PCT/CA2008/002291 109 0 19-50 N 25.4 691.9 H O (E) HO H HO 0 0 O H 19-51 +++ 8.0 691.9 O (E) HO 0 H 0 H 0 19-52 H .14 689.9 0N1 I (E) H HO 00 O H 0 19-53 N 27.1 655.8 H (D) HO 19-56 N

.

1. HO HO 0 0 / N 19-584M H366 671.75 HO O 00 00 19-55 N 8. .92 681.09 0H HOH 0 00 0 19-57 N .. 7.20 701.09 HO 0 0 / 0 19-8 1 - .. 32.08 667.71 O * J A) (M-Bac) HO OU 0 00 WO 2009/082819 PCT/CA2008/002291 110 0 17.64 /0 and 19-59 N +++ 18.01 669.86 0 H ++(C7 HO 0O 0 /0 19-60 N OH 17.92 678.87 OH O(C) HO O 0 0 0 OH 19-61 + - 718.98 0 H N HO 0+ 0 0 /0 19-62 +++ 0> 707.09 Na O H N-N HO 0O 0H 0 /0 19-63 743.31 0 O H HO 0 00 H/ 0 19-64 H N ++ 704.06 N " - (C) 0 Na0 H 00 H/ 0 N96 + 28.56 660 Na'O 0 H D 00 H 0 19-66 NH ... 7.9 696.06 0 0~ (D) NaO 0 / 0 19-67 N, . 27.57 680.9 0 H (A) HO 00 0 /06 -'-, N .. 25.38 680.9 0 N-0 (A) HO YI 0I WO 2009/082819 PCT/CA2008/002291 111 0 19-69 H O0 +++3 694.9 1N + 2-N7 H+7 0 0 19-70 N 26.87 709.15 0 (A) 0 0 0 19-71 N 26.06 709.15 OH (A) HO 0 I 0 0 0 0 3. 19-72 N 696. 0H(A) 69. HO 17 O0 0 0 /0 19-73 N++ 17.28 667.93 0 N(C) 0 0O HO 0 19-74 N ... 20 669.9 00(A HO 0 0 4O7 /0 25.0 0 0 N- N(A U7U 0 / 0 19-76 N N 9.68 67. 097 H (F) 67. 0 1 0 HO Y o 0 00 0 19-77 N .. 9.07 695.0 0 H 11 -i-(F) HO -/ 0 WO 2009/082819 PCT/CA2008/002291 112 0 19-78 + 0 29.3 680.9 N H-1 (A) 0s HO O HO 00 19-79 25.9 695.0 19-80 +++Y 381 67. N- H N (A) HO y 0I 00 0 ++ 38.1 7.9 19-80 N+++ 679.92 HO O O 00 00 / 0 19-81 +++ 10.4 ++ 706.96 O O N NF HO 0/ 20-1 ~ -o N0- -+ ++686 HO- ; O H 0 /0 19-82 N +++ 24.12 664.82 OH 'N (E) HO H 0+ 0 0 19-84 0 -j .. 1.4 709.07 N- N (F) HO Tyoo 0 00 H 0 H01N0 + . 628.64 H 0 20- N 0. . 33.3 656.6 0HH (A) HO0 H 00 0 20-3 N A-v .. 0. 668.73 HOH 0 WO 2009/082819 PCT/CA2008/002291 113 0 20-4 N 0 682.83 H H HO 0 00 0 20-5 N 0 696.93 HO O HO 0 0 0 0 20-6 N + + 798.50 0 0 0 0 /0 20-7 N O+711.03 H 0 H HO 0 00 0 O 0 20-11 0+ 704.9 0 0 00 00 0 20-9 + 1fO 32. 668.65 HO 0O 0 0 /0 20-10 N O N 13.84 682.5 H (E) 0 0 00 0 HO O 20-11 N 0 - 682.79 0 0 00 0 20-12 N (0o ... 12.32 683-5 HO HC 0 0 20-13 INO t0. 29.0 679 0 I (E) vi0 WO 2009/082819 PCT/CA2008/002291 114 0 / 0 S 20-14 NUO- 714.87 0 H HO YU0 0 0 0 201 0 O . 6.53 747.17 201 NH (F) HOH HO j 0 0 C / 0 N H 20-16 N~ . 12.03 697.8 0 (G) 0 - j0 0 0 20-17 N~ (G1.3 711.93 o-

(G)

0 00 00 20-18 N lO.. 19.87 726.13 0 H OO,(C) HO lj0; 00 0 20-19 N* ... 19.43 726.12 0H (C) 0N HO ) 0r 00 0 20-20 N o . 29.73 711.93 HOH HO 0 1 N D 00 0 20-21 N~ 0I .. 712.04 0 H HO l o 0 0 / 0 20-22 N~ 0-"n .. 682.73 0 H HO 0 01 0 / 0 20-23 N 0--N) ~ 29.6 711.84 0 H (D) HO x 0 WO 2009/082819 PCT/CA2008/002291 115 0 / 0 20-24 N0- N. 6.19 726.06 0H 0(F) HO 0 When the compounds are tested more than once, the average IC50 is provided. MT2 (HIVIIIB) IC50 with or without HS + > 1000 nM ++ 200-999 nM +++ <199 nM 10 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. 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 (79)

1. A compound of formula (1): CH 3 H3C O HGC CH 3 CH 3 X CH 3 H 3 C CH 3 (I) wherein R' is O 0 HO A A is C 1 - alkyl, C 2 - alkenyl, or -(CH 2 ) 1 . 2 0(CH2)1-; Y is C=O or C-Ry 1 Ry2; 10 Ry 1 and Ry 2 are each independently H or -CH 3 ; X is NR 2 R 3 ; R R R R 2 12 P 120 N O N Ns Ns / 0 0 0 R 3 R 3 R R R2R NR3 R O 2 N 1 N YNR 4 N O N O , O or O0 R 2 is H, C 11 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 1 0 , or C 2 - 12 alkynyl which is unsubstituted or substituted one or more times by R 1 0 ; R 3 and R 3 ' are each independently H, C 112 alkyl which is unsubstituted or substituted one or more times by R 1 0 , C 2 -1 2 alkenyl which is unsubstituted or substituted one or more times by R 1 0 , C 2 - 12 alkynyl which is unsubstituted or WO 2009/082819 PCT/CA2008/002291 117 substituted one or more times by R 1 0 , 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' 2 , or 4-18 member heterocycle-alkyl which is unsubstituted or substituted one or more times by R 12 ; 10 R 3 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. 1 2 R 4 is Cle alkyL which is unsubstituted or substituted one or more times by R 1 0 , C 2 -C1 aLkenyl which is unsubstituted or substituted one or more times by R 1 0 , C 2 . 1 alkynyl which is unsubstituted or substituted one or more times by R 1 0 , C . 1 4 aryL which is unsubstituted or substituted one or more times by R1, C 716 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 20 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 1 , or 4-18 member heterocycle-aLkyl which is unsubstituted or substituted one or more times by R 12 ; R 5 and R 6 are each independently C- 1 2 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 , C 2 . 1 2 alkynyl which is unsubstituted or substituted one or more times by R 1 0 , C 6 . 14 aryl which is unsubstituted or substituted one or more times by R', C 7 . 16 aralkyl which is unsubstituted or 30 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 2 ; WO 2009/082819 PCT/CA2008/002291 118 R 1 0 is halogen, oxo, C 1 - 6 alkoxy, -NH 2 , -NH(C 1 . 4 alkyt), -N(C 1 . 4 alkyt) 2 , -C(O)NH 2 , C(O)NH(Cl. 4 alkyl), -C(O)N(Cl 14 aLkyL) 2 , -NHC(O)H, -N(C 1 . 4 atky[)C(O)H, -N(C 1 . 4 atkyt)C(O)C 1 - 4 alkyl, -NHC(O)C 1 - 4 aLkyt, -NHC(O)0C 1 - 4 alkyl, -N(Cl 14 atkyt)C(O)0CI. 4 alkyt, -NHC(O)NH 2 , ,-N(CI- 4 atkyl)C(O)NH 2 , -NHC(O)NHC, 14 alkyl, -N(Cl- 4 alky[)C(O)NHC 1 . 4 atkyt,-N(C 1 . 4 atkyt)C(O)N(Cl. 4 alkyt) 2 , NHC(O)N(C 1 . 4 atkyl) 2 , -C(O)H, -C(O)C- 4 alkyl, C(O)OH, -C(O)0CI. 4 alkyl, OC(O)C 1 . 4 alkyt, -OC(O)NH(C. 4 a~kyl), -OC(O)N(C 1 - 4 atkyt) 2 , -C(NOH)CI. 4 atkyl, C(NOH)H, -C(N0C 14 alkyt)C. 4 alkyL, -C(N0C 14 atky[)H, hydroxyl, nitro, azido, cyano, -S(O) 0 . 3 H, -S(O) 0 - 3 C 1 . 4 alkyt, -SO 2 NH 2 , -SO 2 NH(C 1 . 4 alkyl), -SO 2 N(CI- 4 10 a~kyt) 2 , -N(C 1 - 4 atkyl)S0 2 C 1 . 4 atkyL, -NH50 2 C 1 . 4 alkyl, -P(O)(OH) 2 , -P(O)(0C 1 4 alkyl)OH, - P(O) (00,. 4 atkyL) 2 , amidino, or guanidino; R 1 1 is halogen, C 1 - 6 alkyl, halogenated C 1 . 6 alkyl, C 2 - 6 aLkenyL, C 2 . 6 atkynyl, C 1 . 6 alkoxy, NH 2 , -NH(C 1 . 4 atkyL), -N(C 1 . 4 atkyt) 2 , -C(0)NH 2 , -C(0)NH(Cl. 4 alkyl), -C(0)N(C 1 - 4 atkyt) 2 , -NHC(O)H, -N(Cl 14 alky[)C(0)H, -N(Cj- 4 alky[)C(0)C 1 . 4 alkyl, -NHC(0)Cl. 4 alkyt, -NHC(O)OCI- 4 alkyl, -N(C 1 - 4 alky[)C(0)0C 1 . 4 alkyl, -NHC(0)NH 2 , ,-N(Cl- 4 atkyl)C(0)NH 2 , -NHC(0)NHC,. 4 alkyl, -N(CIA alkyL)C(0)NHC 1 - 4 alkyt,-N(C 1 - 4 alky[)C(0)N(Cl. 4 atkyt) 2 , -NHC(0)N(C- 4 atkyt) 2 , -C(0)H, -C(0)C 1 - 4 alkyt, C(0)OH, -C(0)0C 1 . 4 alkyl, -OC(0)C. 4 atkyt, -OC(0)NH(C. 4 aLkyt), -OC(0)N(Cl 14 20 alkyt) 2 , -C(NOH)C 1 . 4 alkyl, -C(NOH)H, -C(N0Cj 14 alkyt)C 1 - 4 alkyl, -C(NOCj 14 aLkyL)H, hydroxyl, nitro, azido, cyano, -S(0) 0 - 3 H, -S(0) 0 - 3 C 1 - 4 atky[, -S0 2 NH 2 , SO 2 NH(C 1 . 4 atkyt), -S0 2 N(C- 4 alkyl) 2 , -N(C 1 . 4 alky[)S0 2 C, 14 alkyl, -NHS0 2 C 1 . 4 alkyl, -P(0)(OH) 2 , -P(0)(OC 1 - 4 atkyt)OH, -P(0)(CI 4 alkyl) 2 , amidino, or guanidino; and R'1 2 is halogen, oxo, C 1 - 6 alkyl, halogenated C 1 - 6 alkyL, C 2 - 6 atkenyL, C 2 - 6 alkynyl, C 1 - 6 alkoxy, -NH 2 , -NH(Cl 14 atkyl), -N(C 1 . 4 atkyt) 2 , -C(0)NH 2 , -C(0)NH(C 1 . 4 atkyL), C(0)N(C 14 atkyt) 2 , -NHC(0)H, -N(C. 4 atkyl)C(0)H, -N(C 1 . 4 atkyt)C(0)C 1 . 4 atkyL, 30 NHC(0)C 1 - 4 atkyL, -NHC(0)OCI. 4 atkyL, -N(C 1 - 4 atkyt)C(O)OCI- 4 atkyt, NHC(0)NH 2 , ,-N(C 1 . 4 atkyt)C(0)NH 2 , -NHC(0)NHC- 4 alkyt, -N(C 1 - 4 atkyL)C(0)NHC,. 4 atkyt,-N(C 1 . 4 atkyt)C(O)N(C 1 . 4 atkyl) 2 , -NHC(0)N(Cl. 4 atkyL) 2 , C (0) H, .C(0)C 1 . 4 atkyL, C(0)OH, -C(O)OCI- 4 atkyL, -0C(O)C 1 - 4 atkyt, OC(0)NH(Cl 14 alkyt), -OC(O)N(Cl. 4 atkyt) 2 , -C(NOH)Cl. 4 atkyt, -C(NOH)H, C(N0C 14 atky[)C 1 . 4 atkyL, -C(NOC,. 4 atkyt)H, hydroxyt, nitro, azido, cyano, S(0) 0 . 3 H, -S(0) 0 - 3 C 1 . 4 atkyt, -SO 2 NH 2 , -S0 2 NH(Cj- 4 atkyL), -SO 2 N(C 1 - 4 atkyt) 2 , - WO 2009/082819 PCT/CA2008/002291 119 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 alkyl)OH, P(O)(C, 4 alkyl) 2 , amidino, or guanidino; or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1, wherein Y is C=O

3. A compound according to claim 1, wherein Y is -C(CH 3 ) 2 - 10 4. A compound according to claim 1, wherein Y is -CH 2 -.

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'-dimethyLmalonyt, 2',3'-dihydroxysuccinyl, 2',3' dimethylsuccinyl, 2',2',3',3'-tetramethylsucciny, 2'-methylsuccinyL, or 2',2' dimethylsuccinyl.

6. A compound according to claim 5, wherein R 1 is 3',3'-dimethylsucciny. 20 7. A compound according to any one of claims 1 to 6, wherein R 2 is H or C 1 . 1 2 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, cyclopentyl, or cyclohexyl. 30 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 H.

12. A compound according to anyone of claims 1 to 11, wherein WO 2009/082819 PCT/CA2008/002291 120 R 1 0 is halogen, oxo, C 1 . 6 alkoxy,-NH 2 , -NH(Cl. 4 alkyl), -N(C 14 akyl) 2 , -CONH 2 , -CONH(C 14 alkyt), -CON(C 1 . 4 alkyl) 2 , -NHCOH, -N(C 1 4 alkyl)COH, -N(C 14 alkyl)COCj- 4 ,alkyl, -NHCOC 1 . 4 aLkyl, -NHCOOC 14 alkyl, -NHCONHC 14 alkyl, -N(C- 4 alkyl)CONHC 1 .4 alkyl,-N(C 1 . 4 alkyl)CON(C 14 alkyl) 2 , -NHCON(Cl- 4 atkyt) 2 , -C(O)H, -C(O)C 1 . 4 alkyl, carboxy, -C(O)OCI- 4 alkyl, -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 . 2 H, -S(0) 0 - 2 C 1 4 alkyl, -SO 2 NH 2 , -SO 2 NH(CI- 4 alkyl), -S0 2 N(C- 4 atkyl) 2 , -N(C 1 4 alkyl)S0 2 C 14 alkyl, -NHS0 2 C 1 4 alkyl, P(O)(OH) 2 or P(O)(OC 4 akyl) 2 ; 10 R" is halogen, C 1 . 6 alkyl, halogenated C 1 . 6 alkyl, C2- 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 alkyt) 2 , -NHCOH, -N(C 1 4 alkyl)COH, -N(C. 4 alkyl)COC- 4 ,alkyl, -NHCOC 14 alkyL, NHCOOC 1 . 4 alkyl, -NHCONHC 14 alkyl, -N(C 14 alkyl)CONHC 1 4 alkyl, -N(C 14 alkyl)CON(C 1 . 4 alkyt) 2 , -NHCON(C 14 alkyl) 2 , -C(O)H, -C(O)C 1 . 4 alkyl, carboxy, C(O)OCI 4 alkyl, -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 - 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 1 . 4 alkyl) 2 , -N(C 1 A alkyl)S0 2 C 1 4 aLkyl, -NHSO 2 C 1 - 4 alkyl, P(O)(OH) 2 or P(O)(OC 1 . 4 alkyl) 2 ; and 20 R 1 2 is halogen, oxo, C 1 . 6 alkyl, halogenated C 1 . 6 alkyl, C 2 . 6 atkenyl, C 2 . 6 alkynyl,, C 1 . 6 alkoxy, -NH 2 , -NH(C- 4a lkyl), -N(C 14 alkyl) 2 , -CONH 2 , -CONH(C. 4 aLkyl), CON(C 14 alkyl) 2 , -NHCOH, -N(C 1 . 4 alkyl)COH, -N(C 14 alkyl)COC 14 ,alkyl, -NHCOC 14 alkyl, -NHCOOCj. 4 alkyl, -NHCONHC 1 . 4 alkyl, -N(C 1 4 alkyl)CONHC 1 . 4 aLkyl, -N(C 1 4 atkyl)CON(ClA alkyt) 2 , -NHCON(C 14 alkyl) 2 , -C(O)H, -C(0)C- 4 alkyl, carboxy, C(O)OC 1 - 4 alky,-C(NOH)C 1 . 4 alkyl, -C(NOH)H, -C(NOC 14 alky[)C. 4 alkyl, -C(NOC 1 4 alky()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(CIA alkyl), -SO 2 N(C- 4 alkyl) 2 , -N(C 1 4 alkyl)S0 2 CI 4 alkyl, -NHS0 2 C 1 . 4 alkyl, P(O)(OH) 2 or P(O)(OCI. 4 alkyl) 2 ; 30 13. A compound according to anyone of claims 1 to 11, wherein 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(Cl 4 alkyl) 2 , -NHCOH, -N(C- 4 aLkyL)COH, -N(C 1 . 4 alkyL)COC,. 4 alkyl, -NHCOC- 4 alkyl, -NHCOOC 1 . 4 aLkyl, -NHCONHC 1 . 4 aLkyl, -N(Cl- 4 alkyL)CONHC 1 . 4 alkyl,-N(C 1 . 4 atkyl)CON(C 14 alkyl) 2 , -NHCON(Cl- 4 alkyl) 2 , -C(O)H, -C(O)C 1 . 4 alkyl, carboxy, -C(O)0C 1 4 alkyl, -C(NOH)C 14 aLkyL,-C(NOH)H, hydroxyl, nitro, azido, cyano, WO 2009/082819 PCT/CA2008/002291 121 -S(O)o- 2 H, -S(0) 0 - 2 Cl- 4 alkyl, -50 2 NH 2 , -SO 2 NH(CI. 4 alkyl), -S0 2 N(C 14 alkyl) 2 , -N(C 1 .4 alkyl)S0 2 C 1 . 4 alkyl, -NHS0 2 C 1 . 4 aLkyl, or -P(O)(OH)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 14 alkyl), -N(C 1 4 alkyl) 2 , -CONH 2 , -CONH(C 14 alkyl), -CON(Cl- 4 alkyl) 2 , -NHCOH, -N(C 1 4 alkyl)COH, -N(CI 4 alkyl)COCI. 4 alkyl, -NHCOC 1 . 4 alkyl, NHCOOCj- 4 alkyl, -NHCONHC 14 alkyl, -N(C 1 4 alkyl)CONHC 1 . 4 alkyl, -N(C. 4 alkyl)CON(C 14 alkyl) 2 , -NHCON(C 14 alkyl) 2 , -C(O)H, -C(O)C 1 . 4 alkyl, carboxy, -C(0)O C 1 . 4 alkyl,-C(NOH) C 14 alkyl, -C(NOH)H, hydroxyl, nitro, azido, cyano, -S(0) 0 - 2 H, 10 S(0) 0 . 2 C 1 . 4 alkyl, -SO 2 NH 2 , -S0 2 NH(C 1 4 alkyl), -SO 2 N(C- 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 ; and R 1 2 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 1 a alkyl), -N(C 1 a alkyl) 2 , -CONH 2 , -CONH(C 1 . 4 alkyl), -CON(C 1 . 4 alkyl) 2 , -NHCOH, -N(Cl- 4 alkyl)COH, -N(C 1 . 4 alkyl)COC 1 4 alkyll, -NHCOC 14 alkyl, NHCOOC 1 . 4 alkyl, -NHCONHC 14 alkyl, -N(C 14 alkyl)CONHC,. 4 alkyl, -N(C 1 .4 alkyl)CON(C 1 . alkyl) 2 , -NHCON(C. 4 alkyl) 2 , -C(O)H, -C(O)C 14 alkyl, carboxy, -C(0)O C 1 . alkyl, -C(NOH) CIA 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 14 alkyl), -SO 2 N(C 14 alkyl) 2 , -N(C 14 alkyl)SO 2 C,. 4 20 alkyl, -NHSO 2 C 14 alkyl, or -P(O)(OH) 2 .

14. A compound according to any one of claim 1 to 11, wherein R" is halogen, oxo, -NH 2 , -NH(CI. 4 alkyl), -N(Cl- 4 alkyl) 2 , -CONH 2 , -CONH(C 1 . 4 alkyl), -CON(CIA alkyl) 2 , -NHCOH, -N(C 1 . 4 alkyl)COH, -N(C- 4 alkyl)COCI. 4 alkyl, NHCOC 14 alkyl, -NHCOOC 14 alkyl, -NHCONHC 14 alkyl, -C(O)H, -C(O)C 14 alkyl, carboxy, -C(0)OC 14 alkyl, hydroxyl, C 1 . 4 alkoxy, nitro, nitroso, azido, or cyano; R" is halogen, C 1 .6alkyl, halogenated C 1 . 6 alkyl, C 2 - 6 alkenyl, C 2 . 6 alkynyl,-NH 2 , -NH(C 14 alkyl), -N(C 14 alkyl) 2 , -CONH 2 , -CONH(C 14 alkyl), -CON(C 14 alkyl) 2 , -NHCOH, 30 -N(C 1 . 4 alkyl)COH, -N(C 1 . 4 alkyl)COC 14 alkyl, -NHCOC 14 alkyl, -NHCOOC 14 alkyl, NHCONHCj. 4 alkyl, -C(O)H, -C(O)C 1 . 4 alkyl, carboxy, -C(O)0C 1 . 4 alkyl, hydroxyl, C 1 . 6 alkoxy, nitro, nitroso, 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 atkyl), -N(C 1 . 4 alkyl) 2 , -CONH 2 , -CONH(Cl. 4 alkyl), -CON(C 14 alkyl) 2 , NHCOH, -N(C 14 alkyl)COH, -N(C 14 alkyl)COC 1 . 4 alkyl, -NHCOC 14 alkyl, -NHCOOC 14 WO 2009/082819 PCT/CA2008/002291 122 alkyl, -NHCONHC,. 4 alkyl,- -C(O)H, -C(O)Cl. 4 alkyl, carboxy, -C(O)0C. 4 alkyl, hydroxyt, C1 alkoxy, nitro, nitroso, azido, or cyano.

15. A compound according to any one of claims 1 to 11, wherein R 1 0 is halogen, oxo, -NH 2 , -NH(C 14 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, NHCOCI. 4 alkyl, -NHCOOCj. 4 alkyl, -NHCONHC,. 4 alkyl, -C(O)H, -C(O)C. 4 alkyl, carboxy, -C(0)OC 1 - 4 alkyl, hydroxyl, C 1 . 4 alkoxy, nitro, 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. 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. 4 alkyl)COC 1 . 4 alkyl, -NHCOC. 4 alkyl, -NHCOOC 1 . 4 alkyl, NHCONHC. 4 alkyl, -C(O)H, -C(O)C. 4 alkyl, carboxy, -C(O)0C 1 . 4 alkyl, hydroxyl, C 1 . 6 alkoxy, nitro, azido, or cyano; and 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. 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,. 4 alkyl, -NHCOOC. 4 alkyl, -NHCONHC. 4 alkyl, -C(O)H, -C(O)Cl. 4 alkyl, carboxy, -C(0)OCI- 4 alkyl, 20 hydroxyl, C 1 . 6 alkoxy, nitro, azido, or cyano.

16. A compound according to any one of claims 1 to 11, 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,. 4 alkyl, NHCOC 1 . 4 alkyl, -NHCOOC,. 4 alkyl, -NHCONHC. 4 alkyl -C(O)H, -C(O)C 1 . 4 alkyl, carboxy, -C(0)OCI 4 alkyl, hydroxyl, or C 1 4 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(Cl. 4 alkyl), -CON(C 1 . 4 alkyl) 2 , 30 NHCOH, -N(C 1 . 4 alkyl)COH, -N(C 1 . 4 alkyl)COC. 4 alkyl, -NHCOC 1 . 4 alkyl, -NHCOOC 1 . 4 alkyl, -NHCONHC, 4 alkyl, -C(O)H, -C(O)C 1 . 4 alkyl, carboxy, -C(0)O C 1 . 4 alkyl, hydroxyl or C 1 . 6 alkoxy; and R1 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. 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. 4 alkyl, -NHCOC 1 . 4 alkyl, -NHCOOC 1 . 4 WO 2009/082819 PCT/CA2008/002291 123 alkyl, -NHCONHC 1 . 4 alkyl, -C(O)H, -C(O)C 1 . 4 alkyl, carboxy, -C(0)O C 1 . 4 alkyl, hydroxyl or C 1 . 6 alkoxy.

17. A compound according to any one of claims 1 to 11, 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 A alkyL) 2 , -N(C 1 . 4 alkyl)COC 1 . 4 alkyl, -NHCOC 1 . 4 alkyl, carboxy, C(O)0C 1 . 4 alkyl, hydroxyl, C 14 alkoxy, 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 . 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 1 4 alkyl, -NHCOC 14 alkyl, carboxy, -C(0)OCI- 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 1 . 4 alkyl), N(Cl. 4 alkyl) 2 , -CONH 2 , -CONH(C 14 alkyl), -CON(C 1 4 alkyl) 2 , -N(C 1 . 4 alkyl)COC 1 4 alkyl, NHCOCI- 4 alkyl, carboxy, -C(0)OC 1 4 alkyl, hydroxyl, or C 1 . 6 alkoxy.

18. A compound as defined in anyone of claims 1 to 17, wherein 20 R 3 , R 4 , R 5 or R 6 are each independently C 1 . 1 2 alkyl which is unsubstituted or substituted one or more times by R 1 0 , C 6 . 11 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' 2 , or 7-8 member heterocycle-alkyl which is unsubstituted or substituted one or more times by R 1 . 30 19. A compound as defined in anyone of claims 1 to 17, wherein R 3 , R 4 , R 5 or R 6 are each independently 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 1 , benzyl which is unsubstituted or substituted one or more times by R 1 , 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 1 , 5-6 member heterocycle which is unsubstituted or WO 2009/082819 PCT/CA2008/002291 124 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 .

20. A compound as defined in anyone of claims 1 to 17, wherein R 3 , R 4 , R 5 or R 6 are each independently 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 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 10 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' 2 .

21. A compound according to anyone of claims 1 to 17, wherein R 3 , R 4 , R 5 or R 6 are C 1 . 1 2 alkyl which is unsubstituted or substituted one or more times by Rio.

22. A compound according to anyone of claims 1 to 17, wherein R 3 , R 4 , R 5 or R 6 are C 1 . 6 alkyl which is unsubstituted or substituted one or more times by R 1 0 . 20 23. A compound according to anyone of claims 1 to 17, wherein R 3 , R 4 , R 5 or R 6 are each independently methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

24. A compound according to anyone of claims 1 to 17, wherein R 3 , R 4 , R 5 or R 6 are each independently is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butyl.

25. A compound according to anyone of claims 1 to 17, wherein R 3 , R 4 , R 5 or R 6 are phenyl which is unsubstituted or substituted one or more times by R 1 1 . 30

26. A compound according to anyone of claims 1 to 17, wherein R 3 , R 4 , R 5 or R 6 are phenyl.

27. A compound according to anyone of claims 1 to 17, wherein R 3 , R 4 , R 5 or R 6 are 5-6 member heteroaryl which is unsubstituted or substituted one or more times by R". WO 2009/082819 PCT/CA2008/002291 125

28. A compound according to anyone of claims 1 to 17, wherein R 3 , R 4 , R 5 or R 6 are is pyridyl which is unsubstituted or substituted one or more times by R".

29. A compound according to anyone of claims 1 to 17, wherein R 3 , R. 4 , R 5 or R 6 are is 7-8 member heteroaralkyl which is unsubstituted or substituted one or more times by R".

30. A compound according to anyone of claims 1 to 17, wherein R 3 , R 4 , R 5 10 or R 6 are -CH 2 -pyridyl which is unsubstituted or substituted one or more times by R'.

31. A compound according to anyone of claims 1 to 17, wherein R 3 , R 4 , R 5 or R 6 are 5-6 member heterocycle which is unsubstituted or substituted one or more times by R 1 .

32. A compound according to anyone of claims 1 to 17, wherein R 3 , R 4 , R 5 or R 6 are piperidine which is unsubstituted or substituted one or more times by R' 2 . 20 33. A compound according to anyone of claims 1 to 17, wherein R 3 , R 4 , R 5 or R 6 are 7-8 member heterocycle-alkyl which is unsubstituted or substituted one or more times by R"

34. A compound according to anyone of claims 1 to 17, wherein R 3 , R 4 , R 5 or R 6 are -CH 2 -piperidine which is unsubstituted or substituted one or more times by R 1 .

35. A compound according to anyone of claims 1 to 17, wherein R 3 , R 4 , R 5 or R 6 are each independently ethyl, iso-propyl, tert-butyl, cyclopentyl, -CH 2 30 cyclopentyl, cyclohexyl, -CH 2 -cyclohexyt, phenyl, benzyl, pyridinyl, -CH 2 -pyridinyl, piperidynyl, piperazinyl, thienyl, 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 1 . 4 alkyloxy, CF 3 , COC1. 4 alkyl, COOH, COOC 1 . 4 alkyl, cyano, NH 2 , nitro, NH(C 1 . 6 alkyl), and N(C 1 . 6 alkyl) 2 . WO 2009/082819 PCT/CA2008/002291 126

36. A compound according to any one of claims 5 to 17, wherein said compound is defined by formula (II) or formula (Ila) CH 3 CH 3 H 3 0 0 H3C O 0 0 R3 CH 3 CH R3 CH 3 CN N R3 R 2 R 3 R 2 0 RO - CH 3 ROH 3 C3 H 3 C CH 3 HC CH 3 (11) (Ila)

37. A compound according to claim 36, wherein said compound is defined by formula (11): CH 3 H 3C O H 3 C CH 3 H 3 3 3-I I R 2 Ra' Rj"O - CH 3 H 3 C CH 3 (II) 10

38. A compound according to any one of claims 36 or 37, wherein R 3 ' is H.

39. A compound according to anyone of claims 36 to 38, wherein R 3 is 5-6 member heteroaryl which is unsubstituted or substituted one or more times by R".

40. A compound according to anyone of claims 36 to 38, wherein R 3 is 5-6 member heterocycle which is unsubstituted or substituted one or more times by R. 1 2 20 41. A compound according to anyone of claims 36 to 38, wherein R 3 is pyrazole which is unsubstituted or substituted one or more times by halogen, C 1 . 3 alkyl, C 1 . 3 alkoxy, or halogenated C 13 alkyL. WO 2009/082819 PCT/CA2008/002291 127

42. A compound according to anyone of claims 36 to 385, wherein R 3 is piperidine which is unsubstituted or substituted one or more times by halogen, C 1 . 3 alkyl, C 1 . 3 alkoxy, or halogenated C 13 alkyl.

43. A compound according to anyone of claims 36 to 38, wherein R 3 is oxadiazole which is unsubstituted or substituted one or more times by halogen, C 1 . 3 alkyl, C 1 - 3 alkoxy, or halogenated C 13 alkyl.

44. A compound according to anyone of claims 36 to 38, wherein R 3 is 10 cyclohexyl which is unsubstituted or substituted one or more times by halogen, C 1 - 3 alkyl, C 1 . 3 alkoxy, or halogenated C- 3 alkyl.

45. A compound according to anyone of claims 36 to 38, wherein R 3 is pyridine which is unsubstituted or substituted one or more times by halogen, C 1 . 3 alkyl, C 13 alkoxy, or halogenated C 1 . 3 alkyl.

46. A compound according to anyone of claims 36 to 38, wherein R 3 is imidazole which is unsubstituted or substituted one or more times by halogen, C 1 . 3 alkyl, C 1 3 alkoxy, or halogenated C 1 - alkyl. 20

47. A compound according to anyone of claims 36 to 38, wherein R 3 is pyridine.

48. A compound according to anyone of claims 36 to 38, wherein R 3 is pyrimidine.

49. A compound according to anyone of claims 36 to 38, wherein R 3 is pyrazole. 30 50. A compound according to anyone of claims 36 to 38, wherein R 3 is methylpyrazole.

51. A compound according to anyone of claims 36 to 38, wherein R 3 is thiadiazole. WO 2009/082819 PCT/CA2008/002291 128

52. A compound according to anyone of claims 36 to 38, wherein R 3 is oxadiazole.

53. A compound according to anyone of claims 36 to 38, wherein R 3 is methyLoxadiazole.

54. A compound according to anyone of claims 36 to 38, wherein R 3 is piperidine. 10 55. A compound according to anyone of claims 36 to 38, wherein R 3 is methylpiperidine.

56. A compound according to anyone of claims 36 to 38, wherein R 3 is N acetyl piperidine.

57. A compound according to anyone of claims 36 to 38, wherein R 3 is cyclohexyl.

58. A compound according to anyone of claims 36 to 38, wherein R 3 is 20 difluorocyclohexyl.

59. A compound according to any one of claims 5 to 17, wherein said compound is defined by formula (III) : CH 3 H 3 C O Y CH CH 3 N R4 R2 - CH 3 H 3 C CH (Ill)

60. A compound according to claim 59, wherein R 4 is Cl 12 alkyl which is unsubstituted or substituted one or more times by R 1 0 , C 2 - 1 2 alkenyl which is unsubstituted or substituted one or more times by R' 0 , C 2 - 1 2 alkynyl which is WO 2009/082819 PCT/CA2008/002291 129 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 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 R1, or 4-18 member heterocycle-alkyl which is unsubstituted or substituted one or more times by R 1 2 . 10 61. A compound according to claim 59, wherein R 4 is 5-6 member heteroaryl which is unsubstituted or substituted one or more times by R".

62. A compound according to claim 59, wherein R 4 is 5-6 member heterocycle which is unsubstituted or substituted one or more times by R 1 .

63. A compound according to claim 59, wherein R 4 is pyridine which is unsubstituted or substituted one or more times by halogen, C 1 3 alkyl, C 1 . 3 alkoxy, or halogenated C 1 . 3 alkyl. 20 64. A compound according to claim 59, wherein R 4 is pyrimidine which is unsubstituted or substituted one or more times by halogen, C 13 alkyl, C 1 . 3 alkoxy, or halogenated C 1 . 3 alkyL.

65. A compound according to anyone claim 59, wherein R 4 is pyrazole which is unsubstituted or substituted one or more times by halogen, C 1 . 3 alkyl, C 1 . 3 alkoxy, or halogenated C 1 . 3 alkyL.

66. A compound according to claim 59, wherein R 4 is phenyl which is unsubstituted or substituted one or more times by halogen, C 1 . 3 alkyl, C1. 3 alkoxy, or 30 hatogenated C 1 . 3 alkyL.

67. A compound according to claim 59, wherein R 4 is benzyl which is unsubstituted or substituted one or more times by halogen, C 1 . 3 alkyl, C1.3 alkoxy, or halogenated C 1 . 3 alkyL. WO 2009/082819 PCT/CA2008/002291 130

68. A compound according to claim 59, wherein R 4 is thiazole which is unsubstituted or substituted one or more times by halogen, C 1 . 3 alkyl, C 1 . 3 alkoxy, or halogenated C 1 3 alkyl.

69. A compound according to claim 59, wherein R 4 is oxadiazole which is unsubstituted or substituted one or more times by halogen, C 1 . 3 alkyl, C 13 alkoxy, or halogenated C 1 . 3 alkyl.

70. A compound according to claim 59, wherein R 4 is imidazole which is 10 unsubstituted or substituted one or more times by halogen, C 1 3 alkyl, C 1 . 3 alkoxy, or halogenated C 13 alkyl.

71. A compound according to claim 59, wherein R 4 is piperidine which is unsubstituted or substituted one or more times by halogen, C 1 3 alkyl, C 1 . 3 alkoxy, or halogenated C 1 . 3 alkyL.

72. A compound according to claim 59, wherein R 4 is cyclohexyl which is unsubstituted or substituted one or more times by halogen, C 1 . 3 alkyl, C 1 . 3 alkoxy, or halogenated C 1 3 alkyl. 20

73. A compound according to claim 59, wherein R 4 is pyridine.

74. A compound according to claim 59, wherein R 4 is methylpyridine.

75. A compound according to claim 59, wherein R 4 is pyrimidine.

76. A compound according to claim 59, wherein R 4 is pyrazole.

77. A compound according to claim 59, wherein R 4 is methylpyrazoLe. 30

78. A compound according to claim 59, wherein R 4 is phenyl. R 4 is fLuorophenyl.

79. A compound according to claim 59, wherein R 4 is benzyl.

80. A compound according to claim 59, wherein R 4 is fluorobenzyl. WO 2009/082819 PCT/CA2008/002291 131

81. A compound according to claim 59, wherein R 4 is thiazole.

82. A compound according to claim 59, wherein R 4 is methylthiazole.

83. A compound according to claim 59, wherein R 4 is oxadiazole.

84. A compound according to claim 59, wherein R 4 is methyloxadiazole. 10 85. A compound according to claim 59, wherein R 4 is imidazole.

86. A compound according to claim 59, wherein R 4 is methylimidazole.

87. A compound according to claim 59, wherein R 4 is piperidine.

88. A compound according to claim 59, wherein R 4 is methylpiperidine.

89. A compound according to claim 59, wherein R4 is N-acetyl piperidine. 20 90. A compound according to claim 59, wherein R 4 is thienyt.

91. A compound according to any one of claims 5 to 35, wherein said compound is defined formula (IV) CH 3 H 3 C 0 Y CH 3 CH 3 - :OR2 Ri 0 CH3 H 3 C CH 3 (IV)

92. A compound selected from: 3#-O-(3',3'-Dimethylsuccinyl)-17p-tert-butyloxycarbonylamino-21-oxoLup-18-ene; WO 2009/082819 PCT/CA2008/002291 132 3/-0-(3',3'-Dimethylsuccinyl)-1 7p6-amino-21 -oxolup-1 8-ene; 3p6-0- (cis-Cyclohexane-3'-carboxylic acid-i'-carboxyl)- 1 7pl-amino-21 -oxolup- 1 8-ene; 3/3-0-{(1'R,3'S)-1',2',2'-Trimethyl-cyclopentane-3'-carboxylic acid-I '-carboxyl] 17/3- amino-21-oxolup-18-ene; 3p-0-(3',3'-DimethylsuccinyL)-17p3-(1-tert-butyloxycarbonylpiperidine-4-amino]-21 oxolup-18-ene; 3p-0-(3',3'-Dimethylsucciny)-17p8-(methylamino)-21-oxolup-18-ene; 3p-O-(3',3'-Dimethylsucciny)-17p-[N'-(benzyl)ureido]-21-oxolup-18-ene; 3pl-0-(3',3'-Dimethylsuccinyl)-1 7,6-[N'-(ethyl)ureido]-21 -oxolup-1 8-ene; 3p-0-(3',3'-Dimethysucciny)-17p-[N'-(phenyl)ureido]-21-oxolup-18-ene; 3p-0-(3',3'-Dimethylsucciny)-17p-[N'-(isopropyl)ureido]-21-oxolup-18-ene; 3p-0-(3',3'-Dimethylsucciny)-17p-[N'-(tert-butyl)ureido]-21-oxolup-18-ene; 3p-0-(3',3'-Dimethylsucciny)-17p-[N'-(pyridin-3-yL)ureido]-21-oxolup-18-ene; 3p-0-(3',3'-DimethylsuccinyL)-17p-[N'-(cyclohexyL)ureido]-21-oxoLup-18-ene; 3/-0-(3',3'-DimethylsuccinyL)-17p-{N'-(cyclohexylmethyl)ureido]-21-oxotup-18-ene; 3p-0-(3',3'-DimethyLsuccinyL)-17p3-[N'-(1-tert-butyoxycarbony-piperidin-4-y) ureido]-21 -oxotup-1 8-ene; 3/-0-(3',3'-DimethyLsuccinyL)-17p3-(N'-piperidin-4-yl-ureido)-21-oxoLup-18-ene; 3p-0-(3',3'-Dimethysuccinyt)-17p-[N'-(1-acetyl-piperidin-4-yl)-ureido]-21-oxotup-18 ene; 3p-0-(3',3'-Dimethysucciny)-17p-[N'-(pyridin-3-ylmethyL)ureido]-21-oxolup-18-ene; 3p3-0-(3',3'-DimethyLsuccinyt)-17p3-[(morpholine-4-carbonyl)-amino]-21-oxoLup-18 ene; 3p-0-(3',3'-DimethyLsuccinyt)-17p-[(4-tert-butyLoxycarbonyL-piperazine-1-carbonyL) amino] -21 -oxoLup-1 8-ene; 3p-0-(3',3'-Dimethysucciny)-17p-[(piperazine-1-carbonyl)-amino]-21-oxolup-18 ene; WO 2009/082819 PCT/CA2008/002291 133 3p3-0-(3',3'-Dimethylsuccinyl)-173-[(4-methyl-piperazine-1 -carbonyl)-amino]-21 oxolup-18-ene; 3pl-0-(3',3'-Dimethylsuccinyl)-1 7p-[(4-acetyl-piperazine-1 -carbonyl)-amino]-21 oxotup-18-ene; 3p-0-(3',3'-Dimethylsuccinyl)-17,p-[N'-isopropyl-N'-methyl-ureido]-21 -oxotup-1 8-ene; 3p8-0-(3',3'-Dimethylsucciny)-1 7p8-(N'-5-methy-[1,3,4]oxadiazol-2-yl-ureido)-21 oxotup-18-ene; 3p-0-(3',3'-Dimethylsuccinyl)-17p-[(4-tert-butoxycarbonylamino-piperidine-1 carbonyl)-amino]-21 -oxolup-1 8-ene; 3#8-0-(3',3'-Dimethylsuccinyt)-17p-(N'-cyclopropylmethyl- ureido)-21-oxolup-18-ene; 3#-0-(3',3'-Dimethylsucciny)-17p6-(N'-cyclopropyl-ureido)-21-oxolup-18-ene; 3p8-0-(3',3'-Dimethylsucciny)-1 7#- [(4-amino-piperidine-1 -carbonyl)-amino]-21 oxolup-18-ene trifluoroacetate; 3p-0-(3',3'-Dimethylsucciny)-17p-[(4-amino-piperidine-1-carbonyl)-amino]-21 oxoLup-18-ene; 3/-O-(3',3'-Dimethylsucciny)-17p-(N'-pyridin-2-yl-ureido)-21-oxolup-18-ene; 3,-0-(3',3'-Dimethylsucciny)-17#-(N'-pyridin-4-yl-ureido)-21-oxolup-18-ene; 3#-O-(3',3'-Dimethylsucciny)-17p-[N'-(pyridin-2-ylmethyl)ureido]-21-oxolup-18-ene; 3p-0-(3',3'-Dimethylsuccinyt)-17/-[N'-(1-methyl-piperidin-4-ylmethyl)-ureido]-21 oxolup-18-ene; 3p-0-(3',3'-DimethylsuccinyL)-17p-[(4-isopropyl-piperazine-1-carbonyl)-amino]-21 oxoLup-18-ene; 3p-0-(3',3'-DimethylsuccinyL)-17p3-[N'-(1-methyl-piperidin-4-y)- ureido]-21-oxolup 18-ene; 3/-0-(3',3'-DimethylsuccinyL)-17p-[N'-(pyridin-4-ylmethyt)ureido]-21-oxotup-18-ene; 3#-0-(3',3'-Dimethylsucciny)-17p-(N'-pyrimidin-2-yl-ureido)-21-oxolup-18-ene; 3p-0-(3',3'-DimethylsuccinyL)-17- [N'-(1-tert-butyloxycarbonyt-azetidin-3-y) ureido]-21 -oxotup-1 8-ene; 3/3O-(3',3'-Dimethylsuccinyt)-17p3-[(3-(S)-1-tert-butyloxycarbony-pyrrolidin-2 ylmethyl)-ureido]-21-oxolup-18-ene; 3#3-0-(3',3'-DimethylsuccinyL)-173-[azetidin-3-y-ureido)]-21-oxoLup-18-ene; WO 2009/082819 PCT/CA2008/002291 134 3p-0- (3', 3'-Dimethylsuccinyl)- 17,p- [(4-(tert-butyloxycarbonyl-methyl-amino) piperidine-1 -carbonyl)-amino]-21 -oxoLup-1 8-ene; 3/-0-(3',3'-DimethylsuccinyL)-1 7p-[N'- (1 -methyl- 1 H-pyrazol-4-yl)ureido]-21 -oxoLup 18-ene; 3p8-0-(3',3'-Dimethylsucciny)-1 7p-(3-(S)-1 -pyrrolidin-2-ylmethyl-ureido)-21 -oxolup 18-ene; 3p-0-(3',3'-Dimethylsuccinyl)-17p-[(4-methylamino-piperidine-1 -carbonyl)-amino] 21 -oxolup-18-ene; 3p-0-(3',3'-Dimethylsuccinyl)-17p-[((R)-3-tert-butyloxycarbony amino-pyrrolidine-1 carbonyl)-amino]-21 -oxolup-18-ene; 3,6O-(3',3'-DimethylsuccinyL)-17/-[((S)-3- tert-butyoxycarbony amino-pyrrolidine-1 carbonyt)-amino]-21 -oxotup-18-ene; 3p-0-(3',3'-Dimethylsucciny)-1 7p-[((R)-3-amino-pyrrolidine-1 -carbonyl)-amino]-21 oxoLup-18-ene; 3P3O-(3',3'-Dimethylsucciny)-1 7f6-[((S)-3-amino-pyrrolidine-1 -carbonyl)-amino]-21 oxotup-18-ene; 3p-0-(3',3'-Dimethylsuccinyt)-1 7p-(N'-pyrimidin-5-yl-ureido)-21 -oxolup-1 8-ene; 3p8-0-(3',3'-Dimethylsucciny)-1 7/ (N'-5-methy-[1,3,4]thiadiazol-2-yl-ureido)-21 oxolup-18-ene; 3p-0-(3',3'-DimethyLsuccinyL)-1 7p-(N'-pyrimidin-4-yl-ureido)-21 -oxoLup- 1 8-ene; 3/3O-(3',3'-Dimethysucciny)-17p8-(N'-2-methylpyridin-4-yl-ureido)-21 -oxolup-1 8 ene; 3,-0-(3',3'-Dimethylsucciny)-1 7p-[N'N'-dimethyl-ureido]-21 -oxolup-1 8-ene; 3p-0-(3',3'-Dimethylsuccinyl)-1 7pl-[N'-((S)-2,2,2-triftuoro-1 -methyl-ethyl)-ureido] 21 -oxolup-1 8-ene; 3p-0-(3',3'-Dimethylsuccinyl)-1 7p8-[N'-((R)-2,2,2-triftuoro-1 -methyt-ethyl)-ureido] 21 -oxolup-18-ene; 3p-0-(3',3'-Dimethytsucciny)-1 7p8-[N'-(pyrimidin-4-ytmethyL)ureido]-21 -oxolup-1 8 ene; 3p-0-(3',3'-Dimethylsucciny)-1 7p-[N'-(1 -methyl-1 -pyridin-2-yl-ethyL)ureido]-21 oxoLup-18-ene; 3p-0-(3',3'-Dimethysucciny)-1 7/3[N'-((S)-1 -cyclohexyl-ethyl)ureido]-21 -oxotup-1 8 ene; 3p8-0-(3',3'-Dimethysucciny)-1 7p-[N'-((R)-1 -cyctohexyl-ethyl)ureido]-21 -oxoLup-1 8 ene; 3/-0-(3',3'-Dimethylsucciny)-1 7#-[N'-(2,2,2-trifluoro-1, 1 -dimethyl-ethyl)ureido]-21 oxoLup-18-ene; WO 2009/082819 PCT/CA2008/002291 135 3/30- (3',3'-Dimethylsuccinyl)-173- [N'-(4,4-difluorocyclohexyl)ureido]-21 -oxoLup-18 ene; 3P/O-(3',3'-Dimethylsuccinyl)-17-(3,3-dif Luoro-pyrrolidine-1 -carbonyl)-amino]-21 oxolup-18-ene; 3/3-0-(3',3'-Dimethylsuccinyl)- 1 7-[(4,4-diftuoro-piperidine-1 -carbonyL)-amino]-21 oxolup-18-ene; 33-O-(3',3'-Dimethylsuccinyl)-17-[N'-(4,4-difluoro-cyclohexyl-methyl)ureido]-21 oxolup-18-ene; 3/3-0-(3',3'-Dimethylsuccinyl)-1 7p-[N'-((S)-1 -phenyl-ethyl)-ureido]-21 -oxolup-1 8 ene; 3P-0-(3',3'-Dimethylsucciny)-17/-[N'-((R)-1 -phenyl-ethyl)-ureido]-21 -oxolup-1 8 ene; 3,3-0-(3',3'-Dimethylsuccinyl)-1 7p-[N'-(1 -methyl-1 -phenyl-ethyl)-ureido]-21 -oxolup 18-ene; 33-O-(3',3'-Dimethylsuccinyl)-17p-[N'-(thiophen-2-ylmethyl)-ureido]-21 -oxoLup-18 ene; 3#-0-(3',3'-Dimethytsuccinyl)-1 7p-[N'-(2-methyl-[1,3,4]oxadiazol-2-ylmethyl) ureido]-21 -oxolup-1 8-ene; 3/3O-(3',3'-Dimethylsuccinyl)-17-[N'-(1 -phenyl-cyclopropyl)-ureido]-21 -oxoLup-18 ene; 3/3-0-(3',3'-Dimethysucciny)-1 7p-[N'-(pyrimidin-2-ylmethyl)ureido]-21 -oxotup-1 8 ene; 3/3O-(3',3'-Dimethylsuccinyl)-1 7/3-[N'-(pyrimidin-5-ylmethyl)ureido]-21 -oxolup-1 8 ene; 3/-0-(3',3'-Dimethylsucciny)-1 7p-[N'-(1 -pyridin-2-yl-cyclopropyl)-ureido]-21 oxoLup-18-ene;

330-(3',3'-Dimethylsuccinyl)-1 7p-[N'-(1 -methyl-1 -cyclohexyl-ethyl)-ureido]-21 oxoLup-18-ene; 3/-0-(3',3'-Dimethylsucciny)-1 7#-[N'-(1 -pyridin-2-yl-ethyl)-ureido]-21 -oxolup-1 8 ene; 3/3-0-(3',3'-Dimethylsuccinyl)-17/[N'-(1 -methyl-1 H-imidazol-2-yl-methyl)-ureido] 21 -oxoLup- 1 8-ene; 3,6-0-(3',3'-Dimethylsucciny)-1 7/-[N'-(4-methyl-4H-[1,2,4]triazol-3-yl-methyl) ureido]-21 -oxolup-18-ene; 3/3O-(3',3'-DimethylsuccinyL)-17p-[N'-(thiophen-3-ymethyl)-ureido]-21 -oxolup-18 ene; 3,8-0-(3',3'-Dimethylsucciny)-1 73- [N'-(2-methyl-2H-pyrazol-3-yl-methyl)-ureido]-21 oxoLup-18-ene; 3A0- (3', 3'- Dimethylsuccinyl)- 17/& methylsulfonylamino-21 -oxoLup- 1 8-ene; WO 2009/082819 PCT/CA2008/002291 136 3/30- (3',3'-Dimethylsuccinyl)-1 7f-acetylamino-21 -oxotup- 1 8-ene; 3#-0-(3', 3'-Dimethylsuccinyl)- 1 7/3benzamido-21 -oxoLup- 1 8-ene; 3P/30,1 7/3-N-bis(3',3'-dimethysucciny)-21 -oxotup-1 8-ene; 3fl-0-(3',3'-Dimethylsuccinyl)-1 7/-(5-methyl-[1,3,4]oxadiazole-2-amido)-21 -oxolup 18-ene; 3/3-0-(3',3'-Dimethylsuccinyl)-176- (1 -tert-butyLoxycarbonylpiperidine-4-amido)-21 oxoLup-18-ene; 3/30-(3',3'-Dimethysucciny)-1 7p-(piperidine-4-amido)-21 -oxolup-1 8-ene; 3/-0-(3',3'-Dimethylsuccinyt)- 17/3- (1 -acetytpiperidine-4-amido)-21 -oxotup-1 8-ene; 3/3-0-(3',3'-Dimethytsuccinyt)-1 7,8-(pyridin-3-yl)amido-21 -oxotup-1 8-ene; 3/-0-(3',3'-Dimethylsuccinyt)-17p-(4-ftuorobenzyt)amido-21 -oxotup-1 8-ene; 3/O-(3',3'-Dimethytsuccinyt)-1 7p-benzamido-21 -oxoLup-1 8-ene; 3/3-O-(3',3'-Dimethytsuccinyl)- 17/p-(2-f luorobenzamido)-21 -oxotup-1 8-ene; 3/0-(3',3'-Dimethytsuccinyt)-17p-(3-ftuorobenzamido)-21 -oxoLup-1 8-ene; 3/3O-(3',3'-Dimethylsuccinyl)-17/(4-ftuorobenzamido)-21 -oxotup-1 8-ene; 3/3-O-(3',3'-Dimethytsuccinyt)- 17/p-(pyridin4-yl)amido-21 -oxoLup- 1 8-ene; 3,-0-(3',3'-Dimethytsuccinyt)-1 7p-(pyridin-2-yt)amido-21 -oxotup-1 8-ene; 3/3-O-(3',3'-Dimethylsuccinyl)-1 7/(pyrazin-2-yl)amido-21 -oxotup-1 8-ene; 3P/O-(3',3'-Dimethylsuccinyl)-17/3(1 -methyl-1 H-pyrazole-3-amido)-21 -oxotup-1 8 ene; 3/-0-(3',3'-Dimethylsucciny)-1 7#-(1 -methyl-1 H-imidazote-5-amido)-21 -oxotup-1 8 ene; 3/3-0-(3',3'-Dimethylsucciny)-1 7p(1 -methyl-1 H-imidazote-4-amido)-21 -oxotup-1 8 ene; 3/3-0-(3',3'-Dimethytsuccinyl)-1 7p-(2-thiophene)amido-21 -oxotup-1 8-ene; WO 2009/082819 PCT/CA2008/002291 137 3p8-0-(3',3'-Dimethylsucciny)-1 7/3-(1,3-thiazole-2-amido)-21 -oxolup-1 8-ene; 3p-0-(3',3'-DimethyLsuccinyl)-17p-(pyrimidine-2-amido)-21 -oxolup-1 8-ene; 3p-O-(3',3'-Dimethysucciny)-1 7p-(pyrimidine-5-amido)-21 -oxolup-1 8-ene; 3p8-0-(3',3'-Dimethylsuccinyl)- 1 7p-(5-methylisoxazole-3-amido)-21 -oxolup-1 8-ene; 3pl-O-(3',3'-Dimethylsucciny)-1 7p8-(pyrimidine-4-amido)-21 -oxolup-1 8-ene; 3p-0-(3',3'-Dimethylsuccinyl)-1 7p-(1 -methyl-1 H-imidazole-2-amido)-21 -oxolup-1 8 ene; 3p8-0-(3',3'-Dimethylsuccinyl)-1 7p-(1,3-thiazole-4-amido)-21 -oxolup-1 8-ene; 3p-0-(3',3'-Dimethylsuccinyl)-1 7p-(1,3-thiazole-5-amido)-21 -oxolup-1 8-ene; 3p-0-(3',3'-Dimethylsuccinyl)-1 7p-phenylacetamido-21 -oxoLup-1 8-ene; 3p-0-(3',3'-Dimethylsuccinyl)-17p-tetrahydro-pyran-4-carbonylamino-21 -oxoLup-18 ene; 3p-0-(3',3'-DimethyLsuccinyl)-1 7p8-isopropylamido-21 -oxoLup-1 8-ene; 3p8-0-(3',3'-Dimethylsuccinyl)-17p-tert-butylamido-21 -oxoLup-1 8-ene; 3p-0-(3',3'-Dimethylsuccinyl)-1 7p-cyclohexylamido-21 -oxoLup-1 8-ene; 3p-O-(3',3'-Dimethysucciny)-1 7p6-(1 -methyl-i H-pyrazole-5-amido)-21 -oxolup-1 8 ene; 3p-0-(3',3'-Dimethylsuccinyl)-1 7p6-(1 -methyl-1 H-pyrazole-4-amido)-21 -oxolup-1 8 ene; 3p-0-(3',3'-DimethylsuccinyL)-17p8-(1 -methylpiperidine-4-amido)-21 -oxolup-1 8-ene; 3p-0-(3',3'-Dimethylsucciny)-17p-(3-pyrrolidin-1 -y-propionamido)-21 -oxolup-1 8 ene; 3p-0-(3',3'-Dimethylsuccinyl)-17p-(2-pyrrolidin-1 -yl-acetamido)-21 -oxolup-1 8-ene; 3p-O-(3',3'-Dimethylsuccinyl)-1 7p-(4-pyrrolidin-1 -y-butyramido)-21 -oxolup-1 8-ene; 3p-0-(3',3'-Dimethylsuccinyl)-1 7p-(3-piperidin-1 -y-propionamido)-21 -oxolup-1 8 ene; WO 2009/082819 PCT/CA2008/002291 138 3p-0-(3',3'-Dimethylsuccinyl)-.17 p-[3-(2-oxo-pyrroLidin-1 -yl)-propionamido]-21 oxolup-18-ene; 3p-0-(3',3'-Dimethylsucciny)-1 7A(S)-1 -methyl-pyrrolidine-2-amido]-21 -oxolup-18 ene; 3/3-0-(3',3'-Dimethylsuccinyt)-17p8-(4-methylbenzamido)-21 -oxoLup-1 8-ene; 3p-0-(3',3'-Dimethysucciny)-1 7p-(3-methylbenzamido)-21 -oxotup-1 8-ene; 3p-0-(3',3'-DimethyLsuccinyl)-17p-(2-methylbenzamido)-21 -oxoLup-1 8-ene; 3p6-0-(3',3'-Dimethylsuccinyt)-17p-(2-methylpyridin-3-yl)amido-21 -oxotup-1 8-ene; 3p8-0-(3',3'-Dimethylsuccinyt)-1 7p-(5-methylpyridin-3-yl)amido-21 -oxotup-1 8-ene; 3p-0-(3',3'-Dimethylsuccinyl)-1 7p-(6-methylpyridin-3-yl)amido-21 -oxoLup- I 8-ene; 3p-0-(3',3'-Dimethylsuccinyl)- 17p3-(4-methylpyridin-3-yl)amido-21 -oxolup-1 8-ene; 3/-0-(3',3'-Dimethylsuccinyl)- 17/3-(4-hydroxypyridin-3-yl)amido-21 -oxoLup-1 8-ene; 3p-0-(3',3'-Dimethylsuccinyl)-1 7p-(2-hydroxypyridin-3-yl)amido-21 -oxotup-1 8-ene; 3p-0-(3',3'-Dimethylsuccinyl)-173-(2-methylpyridin-4-yl)amido-21 -oxoLup-1 8-ene; 3p-0-(3',3'-Dimethylsuccinyl)-173-(2-dimethylamino-acetamido)-21 -oxoLup-1 8-ene; 3/-0-(3',3'-DimethylsuccinyL)-17/3-(4-methylpiperazine-1 -acetamido)-21 -oxoLup-18 ene; 3p-0-(3',3'-Dimethylsucciny)-1 7p6-(R)-1 -methyl-pyrrolidine-2-amido]-21 -oxotup-1 8 ene; 3p-0-(3',3'-Dimethylsuccinyt)-17p-(S)-1 -isopropyl-pyrrolidine-2-amido]-21 -oxotup 18-ene; 3/3-O-(3',3'-DimethyLsuccinyL)-17p-(S)-1 -tert-butyloxycarbonyl-pyrroidine-2-amido] 21 -oxolup-1 8-ene; 3p-0-(3',3'-DimethyLsuccinyL)-17/3-(R)-1 -tert-butyloxycarbony-pyrrolidine-2-amido] 21 -oxolup-1 8-ene; 3p-0-(3',3'-Dimethylsuccinyl)-17p-((RS)-2-dimethylamino- propionamido)-21-oxoLup 18-ene; 3p-0-(3',3'-Dimethylsuccinyt)-17/-(1-imidazole-acetamido)-21-oxoLup-18-ene; WO 2009/082819 PCT/CA2008/002291 139 33-0- (3', 3'- Dimethylsucciny1)- 1 73- (2-carboxy-benzamido)-21 -oxotup- 1 8-ene; 3/3-O-(3' ,3'-Dimethytsucciny[)-1 7/3-(5-cyclopropyt-[1 ,3,4]oxadiazoLe-2-amido)-21 oxotup-1 8-ene; 3fi-0-(3',3'-Dimethylsuccinyl)-1I 7/3-(5-phenyt-[1 ,3,4]oxadiazote-2-amido)-21 -oxotup 18-ene; 3/3-0- (3', 3'- Dimethytsuccinyt)-1 17/3-(2, 6-dimethytpyridin-4-yt)amido-21 -oxotup- 18 ene; 3,8-O-(3' ,3'-Dimethytsucciny[)-1I 7/3-((S)-1I -methylpiperidine-2-amido)-21 -oxotup-1 8 ene; 3/-0-(3',3'-Dimethylsucciny[)-1 7,6-((R)-1 -methytpiperidine-2-amido)-21 -oxotup-1 8 ene; 3,8-0-(3' ,3'-Dimethylsuccinyt)-1 7/3-(3-methyt-[1 ,2,4]oxadiazote-5-amido)-21 -oxotup 18-ene; 3/-0-(3',3'-Dimethytsuccinyt)-1 7,8-(5-methyl-[1 ,2,4]oxadiazote-3-amido)-21 -oxotup 18-ene; 3/3-0-(3' ,3'-Dimethytsuccinyt)-1 7/3-(5-methyt-[1 ,3,4]oxadiazote-2-methy-amido)-21 oxolup- 18-ene; 3,& 0- (3', 3'- Di methylsucci nyt) -17,8-(8fl-oxa- bicyclo[3.2. 1 ]octane- 3-amido) -21 -oxotup 18-ene; 3,8-0- (3', 3'- Dimethylsuccinyt)- 1 7fl- (8a-oxa-bicyclo[3.2. 1 ]octane- 3-amido)-21 -oxotup 18-ene; 3/-0-(3',3'-Dimethytsuccinyt)-1 7,8-(2-methyt-1 ,3-thiazote-4-amido)-21 -oxotup-1 8 ene; 3,8-0-(3',3'-Dimethysuccinyt)-1 7/-(1 -azetidin-acetamido)-21 -oxotup-1 8-ene; 3/3-0- (3', 3'- Dimethytsuccinyt)- 173- (N', N-dimethyt-oxatamido)-21 -oxotup-l18-ene; 3/-0-(3',3'-Dimethytglutaryt)-1 7/3(5-methyt-[1 ,3,4]oxadiazote-2-amido)-21 -oxotup 18-ene; 3/-0-(3',3'-Dimethytsuccinyt)-1 7,8-(2-methyl-1 ,3-oxazote-4-amido)-21 -oxotup-1 8 ene; 3/-O-(3',3'-Dimethytsuccinyt)-1 7/-(5-methyt-thiophene-2-amido)-21 -oxotup-1 8-ene; 3/3--(3' ,3'-Dimethytsuccinyt)-1 7/-(thiophene-3-amido)-21 -oxotup-1 8-ene; 3/-0-(3',3'-Dimethysuccinyt)-1 7/3(5-ethyt-[1 ,3,4]-oxadiazote-2-amido)-21 -oxotup 18-ene; 3/3-0-(3' ,3'-Dimethytsucciny)-1 7/-(5-methyt-[1 ,3]-oxazote-2-amido)-21 -oxotup-1 8 ene; WO 2009/082819 PCT/CA2008/002291 140 3,8- 0- (cis- Cyclohexane-3 Y-carboxylic acid-i' -carboxyl)- 1 7/3-((5- methyl [1 ,3,4]oxadiazoL-2-carbonyL)-amino]-21 -oxotup-iB-ene; 3,6--(3' ,3'-Dimethylsuccinyt)-1 7,6-(1 H-pyrazote-4-amido)-21 -oxolup-1 8-ene; 3,6--(3',3'-Dimethytsuccinyt)-1 7,6-(5-isopropyl-[1 ,3,4]-oxadiazole-2-amido)-21 oxotup- 18-ene; 3,6-0- (3', 3' -Dimethytsuccinyt)- 1 7,-methoxycarbonylamino-21 -oxolup- 18-ene; 36-0- (3', 3' -Dimethytsuccinyt)- 1 7/-isopropytoxycarbonylamino-21 -oxotup- 18-ene; 3,6--(3', 3'- Dimethytsuccinyt)- 1 7,-cyctopropytmethoxycarbonytamino-21 -oxolup- 18 ene; 33-0- (3', 3'- Dimethytsuccinyt)- 1 7,-cyclopentytoxycarbonytamino-21 -oxotup- 1 8ene; 3,6-0- (3', 3'- Dimethylsuccinyt)- 1 7,-cyctohexytoxycarbonytamino-21 -oxotup- 18-ene; 33A--(3', 3' -Dimethytsuccinyt)- 1 7/-[(1 -carboxylic acid tert-butyL ester) -piperidi ne-4 oxycarbonytamino]-21 -oxotup-1 8-ene; 3,6-0- (3', 3'- Di methytsuccinyL)- 1 7/-cyctohexytmethoxycarbonytamino-21 -oxotup- 18 ene; 3,6-0- (3', 3'- DimethylsuccinyL)- 1 7/3benzytoxycarbonytamino-21 -oxotup- 1 8-ene; 3,6-0- (3', 3' -Dimethytsuccinyt)- 1 7,6cyctobutyLoxycarbonytamino-21 -oxotup- 1 8-ene; 3/3-0- (3', 3'- Dimethytsuccinyt)- 17,8- (1 -cyctopropytethoxycarbonytamino)-2 1 -oxolup 18-ene; 3,6-0- (3', 3'- Dimethylsuccinyt)- 17/3-(1 -methyt-cyctopropytmethoxycarbonyamino)-21 oxotup-1 8-ene; 3,6--(3', 3'- Dimethy~succinyt)- 17,8- (1 -amino-cyclopropytmethoxycarbonyLamino)-21 oxotup- 18-ene; 3/3-0-(3', 3'- Dimethytsucciny)-l 17,6-( (R)- 1 -methylpyrrolidine-3-oxycarbonyLamino)-21 oxotup- 18-ene; 33--(3', 3'- Di methytsuccinyt)- 17,6- (tetrahydro-thiopyran-4-oxycarbonytamino)-2 1 oxotup- 18-ene; 3,6-0- (3', 3'- Dimethytsuccinyt)-I 17/3-(1,1 -dioxo-tetrahydro-thiopyran-4 oxycarbonylamino)-21 -oxotup- 1 8-ene; 3,6--(3', 3'- Di methytsuccinyL)- 17,6- (piperidine-4-oxycarbonylamino)-2 1 -oxotup- 18 ene; 3,6-0- (3', 3' -Dimethytsuccinyt)- 17/3- (1 -methytpi peridine-4-oxycarbonyamino)-21 oxotup-1 8-ene; WO 2009/082819 PCT/CA2008/002291 141 3p-0-(3',3'-Dimethylsuccinyt)-17p3-(1 -methylpiperidine-4-methoxycarbonylamino) 21 -oxolup-1 8-ene; 3p8-0-(3',3'-Dimethylsuccinyl)-17p- (1 -methylpiperidine-3-methoxycarbonylamino) 21 -oxolup-1 8-ene; 3p-0-(3',3'-Dimethylsucciny)-1 7p8-((S)1 -methylpyrrolidine-2 methoxycarbonylamino)-21 -oxoLup-1 8-ene; 3p3-0- (3', 3'-Dimethylsuccinyl)- 17p3-(1 -methylpyrrolidine-3-methoxycarbonylamino) 21 -oxolup-1 8-ene; 3p-0-(3',3'-Dimethylsuccinyl)- 173-(2-cyclopropy-1 -ethoxycarbonylamino)-21 oxolup-18-ene; 3/-0-(3',3'-Dimethylsuccinyl)-173-(2-pyrrolidin-1 -ethoxycarbonylamino)-21 -oxoLup 18-ene; 3p-0-(3',3'-Dimethylsuccinyl)-17p3-(2-(2-oxo-pyrrolidin)-1 -ethoxycarbonylamino)-21 oxolup-18-ene; 3p-0-(cis-Cyclohexane-3'-carboxylic acid-i'-carboxyl) -17p-[N - tert butyloxycarbonyL-amino]-21-oxoLup-18-ene; 3p-0-[(1'R,3'S)-1',2',2'-Trimethyl-cyclopentane-3'-carboxylic acid-i'-carboxyL] 17/3-[N-tert-butyloxycarbonyl-amino]-21-oxoLup-18-ene; 173-Benzamido-3p-hydroxy-21-oxoLup-18-ene; 17/3-(pyridin-2-yl)amido-3p-hydroxy-21-oxolup-18-ene; 173-(isopropyLcarbonylamino)-3p-hydroxy-21-oxoLup-18-ene; and pharmaceutically acceptable salts thereof. 93. A compound selected from: 3p-O-acetyl-17p-amino-21-oxoLup-18-ene; 3p-hydroxy-17p-amino-21 -oxotup-1 8-ene; 3p-hydroxy-17p-[N'-(benzyL)ureido]-21 -oxoLup-1 8-ene; 3p-hydroxy-17p-[N'-3p-hydroxy-oxoLup-18-ene 17p-ureido]-21-oxoLup-18-ene; 3p-hydroxy-17p-benzamido-21-oxoLup-18-ene; 3p-hydroxy-17p-(pyridin-2-yL)amido-21-oxoLup-18-ene; 3p-hydroxy-17p-(5-methyl-[1,3,4]oxadiazole-2-amido)-21-oxolup-18-ene; 3p-hydroxy-17p-(1-tert-butyloxycarbonylpiperidine-4-amido)-21-oxolup-18-ene; WO 2009/082819 PCT/CA2008/002291 142 3p-hydroxy-17p-(pyridin-3-yl)amido-21 -oxolup-1 8-ene; 3p-hydroxy-17p-(4-fluorobenzyl)amido-21 -oxolup-1 8-ene; 3p-hydroxy-17p-(pyridin-4-yL)amido-21 -oxolup-1 8-ene; 3p-hydroxy-1 7p-(pyrazin-2-yl)amido-21 -oxolup-1 8-ene; 3p-hydroxy-17p-(1 -methyl-i H-pyrazole-3-amido)-21 -oxolup-1 8-ene; 3p-hydroxy-17p- (1-methyl-1 H-imidazole-5-amido)-21 -oxolup-1 8-ene; 3p-hydroxy-170-(1 -methyl-1 H-imidazole-4-amido)-21 -oxolup-1 8-ene; 3p-hydroxy-1 7p-(2-thiophene)amido-21 -oxolup-1 8-ene; 3p-hydroxy-17p-(1,3-thiazole-2-amido)-21 -oxolup-1 8-ene; 3p-0-acetyl-1 7p-(5-methyl-[1,3,4]oxadiazole-2-amido)-21 -oxolup-1 8-ene; 3p-hydroxy-17p-(pyrimidine-5-amido)-21 -oxolup-1 8-ene; 3p-hydroxy-17p-(5-methyisoxazole-3-amido)-21 -oxolup-1 8-ene; 3p-hydroxy-1 7p-(pyrimidine-4-amido)-21 -oxoLup-1 8-ene; 3p-hydroxy-17p-(1 -methyl-1 H-imidazole-2-amido)-21 -oxolup-1 8-ene; 3p-hydroxy-1 7p-(1,3-thiazole-4-amido)-21 -oxolup-1 8-ene; 3p-hydroxy-1 7p-(1,3-thiazole-5-amido)-21 -oxolup-1 8-ene; 3p-hydroxy-17p-(1 -methyl-1 H-pyrazole-5-amido)-21 -oxolup-1 8-ene; 3D-hydroxy-17p-(1 -methyl-1 H-pyrazole-4-amido)-21 -oxoLup-1 8-ene; 3p-hydroxy-1 7p-(3-methylbenzamido)-21 -oxolup-1 8-ene; 3p-hydroxy-1 7p8-(2,6-dimethylpyridin-4-yl)amido-21 -oxolup-1 8-ene; 3p-hydroxy-1 7p-((RS)1 -methylpiperidine-2-amido)-21 -oxolup-1 8-ene; 3p-hydroxy-1 7p-[2-(4-methylpiperazin-1 -yl)-acetamido]-21 -oxolup-1 8-ene; 3p-hydroxy-17p-(2-dimethylamino-acetamido)-21 -oxolup-1 8-ene; 3p-hydroxy-17p-(2-methylpyridin-4-yl)amido-21 -oxolup-1 8-ene; WO 2009/082819 PCT/CA2008/002291 143 3p-hydroxy-17p-((RS)2-dimethylamino-propionamido)-21 -oxoLup-1 8-ene; 3p-hydroxy-17p-(2-imidazot-1 -y-acetamido)-21 -oxoLup-1 8-ene; 3p-hydroxy-17p-(6-methylpyridin-3-yl)amido-21 -oxolup-I 8-ene; 3p-hydroxy-17p-(4-methylpyridin-3-yL)amido-21 -oxoLup-1 8-ene; 3p-hydroxy-17p-(5-methylpyridin-3-yl)amido-21 -oxotup-1 8-ene; 3p-hydroxy-1 7p-(2-methylpyridin-3-yL)amido-21 -oxolup-1 8-ene; 3p-hydroxy-17p-(2-methylbenzamido)-21 -oxoLup-1 8-ene; 3p-hydroxy-17p3-(3-pyrrolidin-1 -y-propionamido)-21 -oxolup-1 8-ene; 3p8-hydroxy-1 7/p-(2-pyrrolidin-1 -y-acetamido)-21 -oxoLup-1 8-ene; 3p-hydroxy-17/p-(4-pyrrolidin-1 -y-butyramido)-21 -oxoLup-1 8-ene; 3p-hydroxy-1 7p3-(3-piperidin-1 -y-propionamido)-21 -oxotup-1 8-ene; 3p-hydroxy-17p3-[3-(2-oxo-pyrrolidin-1 -y)-propionamido]-21 -oxolup-1 8-ene; 3p-hydroxy-1 7p8-[(S)-1 -methyl-pyrrotidine-2-amido]-21 -oxolup-1 8-ene; 3p-hydroxy-17p8-(1 -isopropylazetidine-3-amido)-21 -oxoLup-1 8-ene; 3p-hydroxy-17p-(3-thiophene)amido-21 -oxolup-1 8-ene; 3p-hydroxy-1 7p-(5-methyl-[1,3]-oxazole-2-amido)-21 -oxoLup-1 8-ene; 3p-hydroxy-1 7p-isopropyLoxycarbonylamino-21 -oxotup-1 8-ene; 3P-0-acetyl-1 7p-tert-butyloxycarbonylamino]-21 -oxolup-1 8-ene; 3p-hydroxy-1 7p-tert-butyloxycarbonylamino]-21 -oxotup-1 8-ene; 3p-0-acetyl-1 7p-isopropyloxycarbonylamino-21 -oxoLup-1 8-ene; 3p-0-acetyl-17p.-cyclopropyLmethoxycarbonylamino-21 -oxoLup-1 8-ene; 3p-O-acetyl-1 7p-cyclopentyloxycarbonylamino-21 -oxoLup-1 8-ene; 3p-hydroxy-17p-cyclopentyloxycarbonylamino-21 -oxolup-1 8-ene; 3p-0-acetyL-17p-cyclohexyloxycarbonylamino-21 -oxoLup-1 8-ene; WO 2009/082819 PCT/CA2008/002291 144 3p-hydroxy-1 7p-cyclohexyloxycarbonylamino-21 -oxolup-1 8-ene; 3p-0-acetyl-1 7P-(1 -tert-butoxycarbonylpiperidin-4-yoxycarbonylamino)-21 -oxoLup-1 8-ene; 3p-0-acetyl-1 7p-cyclohexylmethoxycarbonylamino-21 -oxolup-1 8-ene; 3p-hydroxy-1 7p-cyclohexylmethoxycarbonylamino-21 -oxoLup-1 8-ene; 3p-0-acetyl- 1 7p-benzyloxycarbonylamino-21 -oxolup-1 8-ene; 3p-O-acetyl-1 7p-cyclopropylmethoxycarbonylamino-21 -oxolup-1 8-ene; 3p-O-acetyl-1 7p-cyclopropylmethoxycarbonylamino-21 -oxoLup-1 8-ene; 3/-acetoxy-1 7/-cyclobutyloxycarbonytamino-21 -oxolup-1 8-ene; 3p-acetoxy-1 7p6-tetrahydro-thiopyran-4-yoxycarbonylamino-21 -oxolup-1 8-ene; 3p-acetoxy-17,6-(1 -methyl-piperidin-4-yloxycarbonylamino)-21 -oxoLup-1 8-ene; 3p6-acetoxy-1 7p8-((S)-1 -Methyl-pyrrolidin-2-y)-methoxycarbonylamino-21 -oxolup-1 8-ene; 3p-acetoxy-17p3-(2-pyrrolidin-1 -ylethoxycarbonylamino)-21 -oxolup-1 8-ene; 3p-acetoxy-1 7p8-cyclopropylethoxycarbonylamino-21 -oxotup- 1 8-ene; 3p-0-acetyl-1 7p3-(1 -tert-butoxycarbonylamino-cyclopropyLmethoxycarbonylamino)-21 -oxotup-1 8-ene; 3p-acetoxy-17,3-(1 -methyl-pyrrolidin-3-yloxycarbonylamino)-21 -oxotup-1 8-ene; 3p-O-acetyl-1 7P-(1 -methylpiperidin-4-ytmethoxycarbonylamino)-21 -oxoLup-1 8-ene; 3p-0-acetyL-17p-(1 -methylpiperidin-3-ymethoxycarbonylamino)-21 -oxotup-1 8-ene; 3/-acetoxy- 17p3- (1 -Methyl-pyrrolidin-3-yL)-methoxycarbonylamino-21 -oxotup-1 8-ene; 3p-acetoxy-17p-[3-(2-oxo-pyrrolidin-1-y)-propionamido]-21-oxoLup-18-ene; and pharmaceutically acceptable salts thereof. 94. A compound according to claim 92, wherein said compound is: 3/3O-(3',3'-DimethylsuccinyL)-17p-tert-butyloxycarbonylamino-21-oxoLup-18-ene; 3P/O-(3',3'-Dimethylsuccinyl)-17p-amino-21-oxolup-18-ene; 3/-0-(3',3'-Dimethylsuccinyl)-17/-(methylamino)-21-oxolup-18-ene; 3/3O-(3',3'-Dimethylsuccinyt)-173- [N'-(cyclohexyl)ureido]-21-oxoLup-18-ene; WO 2009/082819 PCT/CA2008/002291 145 3-0- (3',3'-Dimethylsuccinyl)-17-[N'-(cyclohexylmethyl)ureido]-21 -oxolup-1 8-ene; 3,-0-(3',3'-Dimethylsuccinyl)-1 7p-[N'-(pyridin-3-ylmethyl)ureido]-21 -oxolup-1 8-ene; 3#-0-(3',3'-Dimethylsuccinyl)-1 7p-(N'-5-methyl-[1,3,4]oxadiazol-2-yl-ureido)-21 oxolup-18-ene; 3/-0-(3',3'-Dimethylsuccinyl)-1 7/3[N'-(pyridin-4-ylmethyl)ureido]-21 -oxolup-1 8-ene; 3/3-0-(3',3'-Dimethylsuccinyl)-1 7fl-benzamido-21 -oxoLup-1 8-ene; 3/3-0-(3',3'-Dimethylsuccinyl)-1 7/3-(5-methyl-[1,3,4]oxadiazole-2-amido)-21 -oxolup 18-ene; 3/3-0-(3',3'-Dimethylsuccinyl)-1 7/3(pyridin-3-yl)amido-21 -oxolup-1 8-ene; 3/3O-(3',3'-Dimethylsuccinyl)-1 7p-(pyrazin-2-yl)amido-21 -oxolup-1 8-ene; 3/3O-(3',3'-Dimethylsuccinyl)-1 7#-(1 -methyl-1 H-pyrazole-3-amido)-21 -oxolup-1 8-ene; 3fl-O-(3',3'-Dimethylsuccinyl)-1 7-(1 -methyl-1 H-imidazole-5-amido)-21 -oxolup-1 8 ene; 3f3-O-(3',3'-Dimethylsuccinyl)-1 73(1,3-thiazole-2-amido)-21 -oxolup-1 8-ene; 3P-0-(3',3'-Dimethylsuccinyl)-1 7#-(pyrimidine-2-amido)-21 -oxolup-1 8-ene; 3,-0-(3',3'-Dimethylsuccinyl)-17p-(1,3-thiazole-4-amido)-21 -oxolup-1 8-ene; 33-O-(3',3'-Dimethylsuccinyl)-1 7#-phenylacetamido-21 -oxoLup-1 8-ene; 3/-0-(3',3'-Dimethylsuccinyl)-1 7/tetrahydro-pyran-4-carbonylamino-21 -oxolup-18 ene; 3/-0-(3',3'-Dimethylsuccinyl)-1 7#-(1 -methyl-i H-pyrazole-4-amido)-21 -oxolup-1 8-ene; 33-O-(3',3'-Dimethylsuccinyl)-173- (1-methylpiperidine-4-amido)-21 -oxolup-1 8-ene; 3/3-0-(3',3'-Dimethylsuccinyl)-1 7/3isopropyloxycarbonylamino-21 -oxolup- I 8-ene; 3P0- (3',3'-Dimethylsuccinyl)-1 7/3-cyclohexyloxycarbonylamino-21 -oxoLup-1 8-ene; 3/3-0-(3',3'-Dimethylsuccinyl)-1 7/3-benzyloxycarbonylamino-21 -oxolup-1 8-ene; 3/30- (3',3'-Dimethylsuccinyl)-173-(1 -methylpiperidine-4-oxycarbonylamino)-2 1 oxolup-18-ene; and pharmaceutically acceptable salts thereof. 95. A compound according to claim 92, wherein said compound is: WO 2009/082819 PCT/CA2008/002291 146 3/3-O-(3',3'-Dimethylsuccinyl)-17/3-amino-21-oxolup-18-ene hydrochloride salt; 3p-O-(3',3'-Dimethylsuccinyl)-17/[N'-(3-pyridyl)ureido]-21-oxolup-18-ene hydrochloride salt; 3,8-0-(3',3'-Dimethylsuccinyl)-17/3(N'-piperidin-4-yl-ureido)-21 -oxolup-18 ene hydrochloride salt; 3p-0-(3',3'-Dimethylsuccinyl)-17p-(piperidine-4-amido)-21 -oxolup-18-ene hydrochloride; 3p-0-(3',3'-Dimethylsuccinyl)-17/-benzamido-21-oxoLup-18-ene sodium 10 salt; 3,-0-(3',3'-Dimethylsuccinyl)-17p-(4-pyridyl)amido-21-oxoLup-18-ene hydrochloride salt; ,3p-0-(3',3'-Dimethylsuccinyl)-17p3-(2-pyridyl)amido-21 -oxolup-18-ene hydrochloride salt; 3/O-(3',3'-Dimethylsuccinyl)-17p-(2-pyrazyl)amido-21-oxolup-18-ene hydrochloride salt; 3p-0-(3',3'-Dimethylsuccinyl)-17p-(1 -methyl-1 H-pyrazole-3-amido)-21 oxolup-18-ene hydrochloride salt; 3p-0-(3',3'-Dimethylsuccinyl)-17p-(1 -methyl-1 H-imidazole-5-amido)-21 20 oxolup-18-ene hydrochloride salt; 3p-0-(3',3'-Dimethylsuccinyl)-17p-(1 -methyl-1 H-imidazole-4-amido)-21 oxolup-18-ene hydrochloride salt; 3p-0-(3',3'-Dimethylsuccinyl)-17p8-(1 -methyl-1 H-imidazole-2-amido)-21 oxolup-18-ene hydrochloride salt; 3p8-0-(3',3'-Dimethylsuccinyl)-17o-(1 -methyl-1 H-pyrazole-5-amido)-21 oxolup-18-ene hydrochloride salt; or 3p-O-(3',3'-Dimethylsuccinyl)-1 7o-(1 -methyl-1 H-pyrazole-4-amido)-21 oxolup-18-ene hydrochloride salt. 30 96. A compound according to any one of claims 1 to 95, 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. 97. A compound according to any one of claims 1 to 96 wherein the compound is in the form of the (+) enantiomer or the (-) enantiomer or a mixture thereof. 98. A pharmaceutical combination comprising a compound according to 40 any one of claims I to 97 and at least one further antiviral agent. 99. The pharmaceutical combination according to claim 98, wherein said at least one further antiviral agent is a nucleoside reverse transcriptase inhibitor, non-nucleoside reverse transcriptase inhibitor, protease inhibitor, attachment and fusion inhibitor, integrase inhibitor, or maturation inhibitor. WO 2009/082819 PCT/CA2008/002291 147 100. The pharmaceutical combination according to claim 99, wherein said at least one further antiviral agent is a nucleoside reverse transcriptase inhibitor chosen from 3TC (lamivudine, Epivir@), AZT (zidovudine, Retrovir@), Emtricitabine (Coviracilo, 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, Hivid®), Combivir@ (AZT/3TC or zidovudine/lamivudine combination), Trivizir® (AZT/3TC/abacavir 10 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-y]adenine. 101. The pharmaceutical combination according to claim 99, wherein said 20 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®), (+)-Calanolide A, Capravirine (AG1549, formerly S-1153), DPCO83, 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). 102. The pharmaceutical combination according to claim 99, wherein said 30 at least one further antiviral agent is a protease inhibitor chosen from nelfinavir (Viracept®, NFV), amprenavir (141W94, Agenerase®), indinavir (MK-639, IDV, Crixivan®), saquinavir (Invirase®, Fortovase®, SQV), ritonavir (Norvir®, RTV), lopinavir (ABT-378, Kaletra®), Atazanavir (Reyatazo, BMS232632), mozenavir (DMP-450), fosamprenavir (GW433908), R0033-4649, Tipranavir (Aptivus@, PNU 140690), Darunavir (Prezista®, TMC 114), SPI-256, Brecanavir (GW640385), P-1946, MK-8122 (formerly PPL-100) and VX-385. WO 2009/082819 PCT/CA2008/002291 148 103. The pharmaceutical combination according to claim 99, 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 (Selzentry@, UK-427,857) or soluble CD4, CD4 fragments, CD4-hybrid molecules, BMS-806, BMS-488043, AMD3100, AMD070, AMD887, 10 INCB9471, INCB1 5050, KRH-2731, KRH-3140, SJ-3366, SP-01A, sifuvirtide, and KRH-3955. 104. The pharmaceutical combination according to claim 99, 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. 105. The pharmaceutical combination according to claim 99, wherein said at least one further antiviral agent is a maturation inhibitor chosen 20 from Vivecon (MPC-9055) and Bevirimat PA-457. 106. The pharmaceutical combination according to claim 98, wherein said at least one further antiviral agent which is a zinc finger inhibitor and is azodicarbonamide (ADA). 107. The pharmaceutical combination according to claim 98, wherein said at least one further antiviral agent which is an antisense drug and is HGTV43. 30 108. The pharmaceutical combination according to claim 98, 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), erythropoietin, Multikine, Ampligen, thymomodulin, thymopentin, foscarnet, HE2000, Reticulose, Murabutide, Resveratrol, HRG214, HIV-1 Immunogen (Remune), WF1O and EP HIV-1090. WO 2009/082819 PCT/CA2008/002291 149 109. The pharmaceutical combination according to claim 98, 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, Pictoviro (VGX-410) and TSAO derivatives. 10 110. A pharmaceutical combination comprising a compound according to any one of claims 1 to 97 and an inhibitor of the cytochrome P450. 111. The pharmaceutical combination according to claim 110, wherein said inhibitor of the cytochrome P450 is atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, amprenavir, erythromycin, fluconazole, fosamprenavir, grapefruit juice, fluvoxamine, fluoxetine, macrolide antibiotics, sertraline sulfaphenazole, Troleandomycin, cyclosporine, clomethiazole, atazanavir, mibefradil, vitamin E, 20 bergamottin, or dihydroxybergamottin, or a pharmaceutically acceptable salt thereof. 112. The pharmaceutical combination according to claim 110, wherein the inhibitor of the cytochrome P450 is ritonavir or a pharmaceutically acceptable salt thereof. 113. A pharmaceutical combination according to anyone of claims 98 to 112, wherein the individual components of such combination are administered sequentially. 30 114. A pharmaceutical combination according to anyone of claims 98 to 112, wherein the individual components of such combination are administered simultaneously. 115. The pharmaceutical combination of anyone of claims 98 to 112 wherein said combination further comprises one or more pharmaceutically acceptable carrier. WO 2009/082819 PCT/CA2008/002291 150 116. A pharmaceutical composition comprising a compound according to anyone of claims 1 to 97 together with one or more pharmaceutically acceptable carrier. 117. 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 according to anyone of claims 1 to 97. 10