AU2012200273A1 - Heterocyclic aspartyl protease inhibitors - Google Patents

Abstract

Disclosed are compounds of the formula (1) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof. Also disclosed is the 5 method of inhibiting aspartyl protease, and in particular, the methods of treating cardiovascular diseases, cognitive and neurodegenerative diseases, and the methods of inhibiting of Human Immunodeficiency Virus, plasmepins, cathespin D and protozoal enzymes. Also disclosed are methods of treating cognitive or neurodegenerative diseases using the compounds of formula (1) 10 in combination with a chlolinesterase inhibitor or a muscarinic antagonist. 3077055 1 (GHMatters) P60878.AU.1

Description

AUSTRALIA Patents Act 1990 COMPLETE SPECIFICATION Standard Patent Applicants: SCHERING CORPORATION and PHARMACOPEIA, INC. Invention Title: HETEROCYCLIC ASPARTYL PROTEASE INHIBITORS The following statement is a full description of this invention, including the best method for performing it known to me/us: -lA 5 HETEROCYCLIC ASPARTYL PROTEASE INHIBITORS 10 FIELD OF THE INVENTION This invention relates to heterocyclic aspartyl protease inhibitors, pharmaceutical compositions comprising said compounds, their use in the treatment 15 of cardiovascular diseases, cognitive and neurodegenerative diseases, and their use as inhibitors of the Human Immunodeficiency Virus, plasmepsins, cathepsin D and protozoal enzymes. BACKGROUND 20 Eight human aspartic proteases of the Al (pepsin-like) family are known to date: pepsin A and C, renin, BACE, BACE 2, Napsin A, cathepsin D in pathological conditions. The role of renin-angiotensin system (RAS) in regulation of blood pressure and fluid electrolyte has been well established (Oparil, S, etal. N Engl J Med 1974; 25 291:381-401/446-57). The octapeptide Angiotensin-Il, a potent vasoconstrictor and stimulator for release of adrenal aldosterone, was processed from the precursor decapeptide Angiotensin-1, which in turn was processed from angiotensinogen by the renin enzyme. Angiotensin-l was also found to play roles in vascular smooth muscle cell growth, inflammation, reactive oxygen species generation and thrombosis, 30 influence atherogenesis and vascular damage. Clinically, the benefit of interruption of the generation of angiotensin-II through antagonism of conversion of angiotensin has been well known and there are a number of ACE inhibitor drugs on the market. The blockade of the earlier conversion of angiotensinogen to angiotensin-1, i.e.the inhibition of renin enzyme, is expected to have similar but not identical effects. Since 35 renin is an aspartyl protease whose only natural substrate is angiotensinogen, it is -2 believed that there would be less frequent adverse effect for controlling high blood pressure and related symptoms regulated by angiotensin-Il through its inhibition. Another protease, Cathespin-D, is involved in lysosomal biogenesis and protein targeting, and may also be involved in antigen processing and presentation of 5 peptide fragments. It has been linked to numerous diseases including, Alzheimers, disease, connective tissue disease, muscular dystrophy and breast cancer. Alzheimer's disease (AD) is a progressive neurodegenerative disease that is ultimately fatal. Disease progression is associated with gradual loss of cognitive function related to memory, reasoning, orientation and judgment. Behavioral 10 changes including confusion, depression and aggression also manifest as the disease progresses. The cognitive and behavioral dysfunction is believed to result from altered neuronal function and neuronal loss in the hippocampus and cerebral cortex. The currently available AD treatments are palliative, and while they ameliorate the cognitive and behavioral disorders, they do not prevent disease 15 progression. Therefore there is an unmet medical need for AD treatments that halt disease progression. Pathological hallmarks of AD are the deposition of extracellular p-amyloid (AP) plaques and intracellular neurofibrillary tangles comprised of abnormally phosphorylated protein tau. Individuals with AD exhibit characteristic AB deposits, in 20 brain regions known to be important for memory and cognition. It is believed that AO is the fundamental causative agent of neuronal cell loss and dysfunction which is associated with cognitive and behavioral decline. Amyloid plaques consist predominantly of As peptides comprised of 40 - 42 amino acid residues, which are derived from processing of amyloid precursor protein (APP). APP is processed by 25 multiple distinct protease activities. As peptides result from the cleavage of APP by O-secretase at the position corresponding to the N-terminus of As, and at the C terminus by y-secretase activity. APP is also cleaved by a-secretase activity resulting in the secreted, non-amyloidogenic fragment known as soluble APP. An aspartyl protease known as BACE-1 has been identified as the s-secretase 30 activity responsible for cleavage of APP at the position corresponding to the N terminus of AO peptides. Accumulated biochemical and genetic evidence supports a central role of AD in the etiology of AD. For example, Ap has been shown to be toxic to neuronal cells in -3 vitro and when injected Into rodent brains. Furthermore inherited forms of early-onset AD are known in which well-defined mutations of APP or the presenilins are present. These mutations enhance the production of As and are considered causative of AD. Since As peptides are formed as a result p-secretase activity, inhibition of 5 BACE-1 should inhibit formation of AP peptides. Thus inhibition of BACE-1 is a therapeutic approach to the treatment of AD and other cognitive and neurodegenerative diseases caused by As plaque deposition. Human immunodeficiency virus (HIV), is the causative agent of acquired immune deficiency syndrome (AIDS). It has been clinically demonstrated that 10 compounds such as indinavir, ritonavir and saquinavir which are inhibitors of the HIV aspartyl protease result in lowering of viral load. As such, the compounds described herein would be expected to be useful for the treatment of AIDS. Traditionally, a major target for researchers has been HIV-1 protease, an aspartyl protease related to renin. 15 In addition, Human T-cell leukemia virus type I (HTLV-1) is a human retrovirus that has been clinically associated with adult T-cell leukemia and other chronic diseases. Like other retroviruses, HTLV-1 requires an aspartyl protease to process viral precursor proteins, which produce mature virions. This makes the protease an attractive target for inhibitor design. Moore, et al. Purification of HTLV-l Protease and 20 Synthesis of Inhibitors for the treatment of HTLV-l Infection 55"' Southeast Regional Meeting of the American Chemical Society, Atlanta, GA, US November 16-19, 2003 (2003), 1073. CODEN; 69EUCH Conference, AN 2004:137641 CAPLUS. Plasmepsins are essential aspartyl protease enzymes of the malarial parasite. Compounds for the inhibition of aspartyl proteases plasmepsins, particularly 1, 11, IV 25 and HAP, are in development for the treatment of malaria. Freire, et al. WO 2002074719. Na Byoung-Kuk, et al. Aspartic proteases of Plasmodium vivax are highly conserved in wild isolates Korean Journal of Prasitology (2004 June), 42(2) 61 6. Journal code: 9435800 Furthermore, compounds used to target aspartyl proteases plasmepsins (e.g. 1, 11, IV and HAP), have been used to kill malarial 30 parasites, thus treating patients thus afflicted. Certain compounds also exhibited inhibitory activity against Cathespin D. SUMMARY OF THE INVENTION -4 The present invention relates to compounds having the structural formula I NR2 k R' X N I R 3 1 1W R4 or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein 5 W is a bond, -C(=S)-, -S(O)-, -S(0) 2 -, -C(=O)-, -0-, -C(R 6

)(R

7 )-, -N(R5)- or -C(=N(R6 X is -0-, -N(R 5 )- or -C(R 6

)(R

7 )-; provided that when X is -0-, U is not -0-, -S(O)-, -S(0) 2 -, -C(=O)- or -C(=NR 5 )-; U is a bond, -S(O)-, -S(O) 2 -, -C(O)-, -0-, -P(O)(OR' 5 )-, -C(=NR 5 )-, 10 -(C(R 6

)(R

7 ))b- or -N(R6)-; wherein b is 1 or 2; provided that when W is -S(O)-, -S(0) 2 -, -0-, or -N(R 5 )-, U is not -S(O)-, -S(0) 2 -, -0-, or -N(R 5 )-; provided that when X is N(R 5 )- and W is -S(O)-, -S(0) 2 -, -0-, or -N(R 5 )-, then U is not a bond; R', R 2 and R 5 are independently selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, 15 arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, -OR' 5 , -CN, -C(O)R', -C(0)OR 9 ,

-S(O)R'

1 , -S(O) 2

R'

1 , -C(O)N(R')(R 2), -S(O)N(R")(R 2 ), -S(O) 2

N(R")(R

2 ),

-NO

2 , -N=C(R 8

)

2 and -N(R 8

)

2 , provided that R 1 and R 5 are not both selected from

-NO

2 , -N=C(R 8

)

2 and -N(R 8

)

2 ;

R

3 , R 4 , R 6 and R 7 are independently selected from the group consisting of H, 20 alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, -CH 2 -0-Si(R)(R' 0

)(R'

9 ), -SH, -CN, -OR 9 , -C(O)R 8 ,

-C(O)OR

9 , -C(O)N(R'l)(R1 2 ), -SR' 9 , -S(O)N(R 1 )(R1 2 ), -S(O) 2

N(R

11

)(R'

2 ), -N(R')(R' 2 ),

-N(R

1

)C(O)R

8 , -N(R')S(O)R1 0 , -N(R")C(O)N(R1 2

)(R

3 ), -N(R")C(0)OR 9 and

-C(=NOH)R

8 ; provided that when U is -0- or -N(R 5 )-, then R 3 , R 4 , R6 and R 7 are not 25 halo, -SH, -OR1, -SR 19 , -S(O)N(R")(R 2 ), -S(O) 2

N(R

1 )(R1 2 ), -N(R 1 )(R1 2 ), -N(R")C(O)R", -N(R')S(O)R' 0 , -N(R")C(O)N(R 12

)(RI

3 ), or -N(R")C(0)OR' ; provided that when W is -0- or -N(Rs)-, then R 3 and R 4 are not halo, -SH, -OR 9 , -SR 19 , -S(O)N(R 1

)(R'

2 ), -S(O) 2

N(R")(R'

2 ), -N(R")(R1 2 ),

-N(R")C(O)R

8 , -N(R')S(O)R' 0 , -N(R 1

)C(O)N(R

12

)(R

13 ), or -N(R"l)C(O)OR'; -5 and provided that when X is -N(Rs)-, W is -C(O)- and U is a bond, R 3 , R 4 , R 6 and R 7 are not halo, -CN, -SH, -OR 9 , -SR' 9 , -S(O)N(R 1

)(R'

2 ) or -S(O) 2

N(R)(R

1 2 ); or R 3 , R 4 ,

R

6 and R 7 , together with the carbon to which they are attached, form a 3-7 membered cycloalkyl group optionally substituted by R 14 or a 3-7 membered cycloalkylether 5 optionally substituted by R 14 ; or R and R 4 or Rr and R together with the carbon to which they are attached, are combined to form multicyclic groups such as A B or A 14 R4 R" R 14

R

14 M q 10 wherein M is -CH 2 -, S, -N(R 1 ")- or 0, A and B are independently aryl or heteroaryl and q is 0, 1 or 2 provided that when q is 2, one M must be a carbon atom and when q is 2, M is optionally a double bond; and with the proviso that when R 3 , R 4 , R 6 and R 7 form said multicyclic groups A B or A R q R 14

R

4 M q 15 then adjacent R 3 and R 4 or R 6 and R 7 groups cannot be combined to form said multicyclic groups;

R

8 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -OR" 5 , -N(R' 5 )(R 1 6), 20 -N(R" 5 )C(O)Rl', -N(R' 5

)S(O)R

6 , -N(R 15 )S(0) 2

R

16 , -N(R 15 )S(0) 2

N(R'

6

)(R

17 ),

-N(R'

5

)S(O)N(R

16 )(R1 7 ), -N(R' 5

)C(O)N(R

16

)(R

17 ) and -N(R 15

)C(O)OR'

6 ;

R

9 is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl; -6

R'

0 is independently selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl and -N(R' 5

)(R

16 ); R1, R1 2 and R 3 are independently selected from the group consisting of H, 5 alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -C(O)R 8 , -C(0)OR 9 , -S(O)R' 0 , -S(0) 2

R'

1 , -C(O)N(R' 5 )(RI), -S(O)N(R' )(R ), -S(O) 2

N(R')(R

16 ) and -CN;

R

14 is 1-5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, 10 heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, -CN, -OR 5 ,

-C(O)R

15 , -C(O)OR's, -C(O)N(R 15 )(R16), -SR' 5 , -S(O)N(R's)(R 16 ), -S(O) 2

N(R'

5 )(R),

-C(=NOR

5

)R'

8 , -P(O)(OR' 5 )(OR 1), -N(R 15

)(R

1 '), -N(R 15

)C(O)R'

6 , -N(R' 5 )S(O)R1 8 ,

-N(R'S)S(O)

2 R 16 , -N(R'S)S(0) 2

N(R

6

)(R

17 ), -N(R' 5

)S(O)N(R

6

)(R

17 ), -N(R 1 5 )C(O)N(R1 6 ) (R1 7 ) and -N(R 15 )C(O)OR 16; 15 R' 5 , R' 6 and R 17 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, arylheterocycloalky, R 1 -alkyl, R13-cycloalkyl, R '-cycloalkylalkyl, R 1 -heterocycloalkyl,

R

18 -heterocycloalkylalkyl, R 18 -aryl, R 18 -arylalkyl, R 18 -heteroaryl and R 1 8 20 heteroarylalkyl; or

R'

5 , R' 6 and R' 7 are R2

R

23

R

23 0 N Oor NA . wherein R 2 3 numbers 0 to 5 substituents, m is 0 to 6 and n is 1 to 5; R18 is 1-5 substituents independently selected from the group consisting of 25 alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, -NO 2 , halo, heteroaryl, HO alkyoxyalkyl, -CF 3 , -CN, alkyl-CN, -C(O)R 19 , -C(O)OH, -C(O)OR' 9 , -C(O)NHR 20

-C(O)NH

2 , -C(O)NH 2 -C(O)N(alkyl) 2 , -C(O)N(alkyl)(aryl), -C(O)N(alkyl)(heteroaryl),

-SR'

9 , -S(O) 2

R

2 0 , -S(O)NH 2 , -S(O)NH(alkyl), -S(O)N(alkyl)(alkyl), -S(O)NH(aryl),

-S(O)

2

NH

2 , -S(0) 2

NHR'

9 , -S(0) 2 NH(heterocycloalkyl), -S(0) 2 N(alkyl) 2 , 30 -S(O) 2 N(alkyl)(aryl), -OCF 3 , -OH, -OR 20 , -0-heterocycloalkyl, -0-cycloalkylalkyl, -0- -7 heterocycloalkylalkyl, -NH 2 , -NHR 20, -N(alkyl) 2 , -N(arylalkyl) 2 , -N(arylalkyl) (heteroarylalkyl), -NHC(O)R20, -NHC(O)NH 2 , -NHC(O)NH(alkyl), -NHC(O)N(alkyl)(alkyl), -N(alkyl)C(O)NH(alkyl), -N(alkyl)C(O)N(alkyl)(alkyl), -NHS(0) 2

R

20 , -NHS(0) 2 NH(alkyl), -NHS(O) 2 N(alkyl)(alkyl), -N(alkyl)S(0) 2 NH(alkyl) 5 and -N(alkyl)S(0) 2 N(alkyl)(alkyl); or two R 18 moieties on adjacent carbons can be linked together to form O or S0 ; R1 9 is alkyl, cycloalkyl, aryl, arylalkyl or heteroarylalkyl; R20 is alkyl, cycloalkyl, aryl, halo substituted aryl, arylalkyl, heteroaryl or 10 heteroarylalkyl; and wherein each of the alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl 1 2 3 4 65 1 14 groups in R1, R2, R , R , R5, R , R , R8, R9, R' , R", R1 2 , R and R are independently unsubstituted or substituted by 1 to 5 R21 groups independently 15 selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, -CN, -OR 5 , -C(O)R 5 , -C(O)OR 15 , -C(O)N(R 1 5 )(R1 6 ), -SR, 15 -S(O)N(R1 5

)(R

16 ), -CH(R' 5 )(R), -S(0) 2 N(Rl 5

)(R

16 ), -C(=NOR 5 )R,

-P(O)(OR

15 )(OR'), -N(R' 1 )(R1 6 ), -alkyl-N(R' 5

)(R

16 ), -N(Rls)C(O)R 16 , -CH 2 20 N(R 1

)C(O)R

16 , -CH 2

-N(R

15

)C(O)N(R')(R

17 ), -CH 2

-R'

5 ; -CH 2

N(R'

5

)(R

16 ),

-N(R

1 ")S(O)R', -N(R 15 )S(0) 2

R'

6 , -CH 2

-N(R'

5

)S(O)

2 R1 6 , -N(R' 5

)S(O)

2

N(R'

6

)(R

17 ),

-N(R

1 5

)S(O)N(R

16

)(RI

7 ), -N(R 1 5 )C(O)N(R1 6

)(R

17 ), -CH 2

-N(R

15

)C(O)N(R

1 )(R' 7 ),

-N(R'

5

)C(O)OR'

6 , -CH 2

-N(R'

5

)C(O)OR'

6 , -S(O)R 15 , =NOR' 5 , -N 3 , -NO 2 and -S(O) 2

R'

5 ; and wherein each of the alkyl, cycloalkenyl, cycloalkyl, cycloalkylalkyl, 25 heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl groups in R21 are independently unsubstituted or substituted by 1 to 5 R22 groups independently selected from the group consisting of alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, halo, -CF 3 , -CN,

-OR'

5 , -C(O)R' 5 , -C(O)OR' 5 , -alkyl-C(O)OR1 5 , C(O)N(R 15 )(R1 6 ), -SR 15 , 30 -S(O)N(R' 5

)(R'

6 ), -S(O) 2 N(R1 5 )(R1 6 ), -C(=NOR' 5

)R

6 , -P(O)(OR'")(OR 16 ), -N(R'5)(R'"), -alkyl-N(R' 5

)(R'

6 ), -N(R' 5

)C(O)R

16 , -CH 2

-N(R'

5 )C(O)Rl', -N(R 1 5

)S(O)R

16 ,

-N(R'

5 )S(0) 2

R

6 , -CH 2

-N(R'

5 )S(0) 2 R1 6 , -N(R' 5

)S(O)

2

N(R'

6 )(R1 7

),

-8

-N(R'

5

)S(O)N(R

16

)(R

17 ), -N(R' 5 )C(O)N(R1 6

)(R'

7 ), -CH 2

-N(R'

5 )C(O)N(R'")(R"), -N(R1 5 )C(O)OR', -CH 2

-N(R

15

)C(O)OR'

6 , -N 3 , =NOR's, -NO 2 , -S(O)R' 5 and -S(0) 2

R'

5 ; or two R21 or two R 22 moieties on adjacent carbons can be linked together to formI , P or 5 and when R21 or R2 are selected from the group consisting of -C(=NOR'")R"', -N(R' 5

)C(O)R

6 , -CH 2

-N(R'")C(O)R'

6 , -N(R' 5 )S(O)R"',

-N(R'

5

)S(O)

2 R"', -CH 2

-N(R'

1 )S(0) 2

R'

6 , -N(R'S)S(O) 2 N(R1 6

)(R

7 ), -N(R 5 )S(O)N(R1 6

)(R'

7 ), -N(R' 5

)C(O)N(RI

6 )(R1 7 ), -CH 2

-N(R'

5 )C(O)N(R )(R 7),

-N(R'

5

)C(O)OR'

6 and -CH 2

-N(R'")C(O)OR'

6 , R 15 and R' 6 together can be a C2 to C4 10 chain wherein, optionally, one, two or three ring carbons can be replaced by -C(0) or -N(H)- and R' 5 and R' 6 , together with the atoms to which they are attached, form a 5 to 7 membered ring, optionally substituted by R2; R2 is 1 to 5 groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, 15 heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, -CN, -OR 24 , -C(0)R 24 , -C(0)OR 24 , -C(O)N(R 24 )(R 2 ), -SR 24 , -S(O)N(R 24

)(R

2 1), -S(0) 2

N(R

2 4

)(R

25 ),

-C(=NOR

24

)R

25 , -P(O)(OR 24

)(OR

2 5 ), -N(R 24

)(R

25 ), -alkyl-N(R 24

)(R

2 5 ), -N(R 24

)C(O)R

25 ,

-CH

2

-N(R

24 )C(0)R 2 5 , -N(R 24

)S(O)R

25 , -N(R 24 )S(0) 2

R

25 , -CH 2

-N(R

24

)S(O)

2

R

25 ,

-N(R

24 )S(0) 2

N(R

2 5 )(R 2 ), -N(R 2 4

)S(O)N(R

25

)(R

2 6 ), -N(R 24

)C(O)N(R

2 5

)(R

26 ), 20 -CH 2

-N(R

24

)C(O)N(R

2 5

)(R

26 ), -N(R 24

)C(O)OR

25 , -CH 2

-N(R

24

)C(O)OR

2 5 , -S(O)R 24 and

-S(O)

2

R

24 ; and wherein each of the alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl groups in R2 are independently unsubstituted or substituted by 1 to 5 R groups independently selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, 25 aryl, heteroaryl, halo, -CF 3 , -CN, -OR 24 , -C(O)R 24 , -C(O)OR 24 , alkyl-C(O)OR 24 C(O)N(R 24)(R ), -SR 24 , -S(O)N(R 24

)(R

2 s), -S(O) 2 N(R24)(R 2 5 ), -C(=NOR 24

)R

25 ,

-P(O)(OR

24

)(OR

2 5 ), -N(R 24)(R 25 ), -alkyl-N(R 4)(R 2 3), -N(R 24

)C(O)R

2 5 ,

-CH

2

-N(R

24

)C(O)R

25 , -N(R 24 )S(O) R 25 , -N(R 24

)S(O)

2

R

2 5 , -CH 2

-N(R

24 )S(0) 2

R

2 5

-N(R

24 )S(0) 2

N(R

25 )(R2), -N(R 24

)S(O)N(R

25

)(R

26 ), -N(R 24

)C(O)N(R

2 5 )(R 2 ), 30 -CH 2

-N(R

24 )C(O)N(R2s 26), -N(R 24 )C(0)OR 25 , -CH 2

-N(R

24 )C(0)OR 25 , -S(O)R 24 and -S(O)2R 24; -9 R24, R" and R" are independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylakyl, arylcycloalkyl, R 27 -alkyl, R 27 -cycloalkyl, R 27 -cycloalkylalkyl,

R

27 -heterocycloalkyl, R 2 7 -heterocycloalkylalkyl, R 27 -aryl, R 27 -arylalkyl, R 27 -heteroaryl 5 and R 27-heteroarylalkyl;

R

2 7 is 1-5 substituents independently selected from the group consisting of alkyl, aryl, arylalkyl, -NO 2 , halo, -CF 3 , -CN, alkyl-CN, -C(O)R , -C(O)OH, -C(O)OR 2 , -C(O)NHR , -C(0)N(alkyl) 2 , -C(O)N(alkyl)(aryl), -C(O)N(alkyl)(heteroaryl), -SR 2 , -S(0) 2

R

29 , -S(O)NH 2 , -S(O)NH(alkyl), -S(O)N(alkyl)(alkyl), -S(O)NH(aryl), -S(O) 2

NH

2 , 10 -S(O) 2

NHR

2 8 , -S(O) 2 NH(aryl), -S(O) 2 NH(heterocycloalkyl), -S(0) 2 N(alkyl) 2 , -S(0) 2 N(alkyl)(aryl), -OH, -OR 29 , -0-heterocycloalkyl, -0-cycloalkylalkyl, -0-heterocycloalkylalkyl, -NH 2 , -NHR", -N(alkyl) 2 , -N(arylalkyl) 2 , -N(arylalkyl)(heteroarylalkyl), -NHC(O)R2, -NHC(O)NH 2 , -NHC(O)NH(alkyl), -NHC(O)N(alkyl)(alkyl), -N(alkyl)C(O)NH(alkyl), -N(alkyl)C(O)N(alkyl)(alkyl), 15 -NHS(O) 2 R", -NHS(O) 2 NH(alkyl), -NHS(O) 2 N(alkyl)(alkyl), -N(alkyl)S(O) 2 NH(alkyl) and -N(alkyl)S(O) 2 N(alkyl)(alkyl);

R

28 is alkyl, cycloalkyl, arylalkyl or heteroarylalkyl; and

R

29 is alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; provided that when W is -C(0)- and U is a bond, R' is not optionally 20 substituted phenyl, and that when U is -C(0)- and W is a bond, R 5 is not optionally substituted phenyl; provided that neither R' nor R 5 is -C(O)-alkyl-azetidinone or alkyl di-substituted with (-COOR 15 or -C(O)N(R- 5

)(R'

6 )) and (-N(R' 5

)(R

16 ), -N(R' 5

)C(O)R'

6 ,

-N(R'

5

)S(O)R

16 , -N(R 15 )S(0) 2

R'

6 , -N(R 1 5

)S(O)

2

N(R

1

)(R'

7 ), -N(R' 5

)S(O)N(R

6

)(R

17 ), 25 -N(R' 5

)C(O)N(R'

6

)(R'

7 ), or -N(R 1 5 )C(0)OR 16 ); provided that when R' is methyl, X is -N(R 5 )-, R 2 is H, W is -C(0)- and U is a bond, (R 3 , R 4 ) is not (H, H), (phenyl, phenyl), (H, phenyl), (benzyl, H), (benzyl, phenyl), (i-butyl, H), (i-butyl, phenyl), (OH-phenyl, phenyl), (halo-phenyl, phenyl), or

(CH

3 0-phenyl, N0 2 -phenyl); and when W is a bond and U is -C(O)-, (R 3 , R 4 ) is not 30 (H, H), (phenyl, phenyl), (H, phenyl), (benzyl, H), (benzyl, phenyl), (i-butyl, H), (i-butyl, phenyl), (OH-phenyl, phenyl), (halo-phenyl, phenyl), or (CH 3 0-phenyl, NO2-phenyl); provided that when X is -N(R 5 )-, R 1 and R 5 are each H, W is -C(0)- and U is a bond, (R 3 , R 4 ) is not (optionally substituted phenyl, optionally substituted benzyl), (optionally substituted phenyl, heteroarylalkyl) or (heteroaryl, heteroarylalkyl); - 10 provided that when U Is a bond, W is -C(0)-, and R 3 and R 4 form a ring with the carbon to which they are attached, R' is not 2-CF 3 -3-CN-phenyl; provided that when X is -N(Rs)-, U is -0- and W is a bond or -C(Rr)(R'h

(R

3

,R

4 ) is not (H, -NHC(0)-alkyl-heteroaryl) or (H, alkyl-NHC(O)-alkyl-heteroaryl); and 5 provided that when X is -N(R 5 )-, R' and R 5 are not -alkylaryl-aryl-S0 2 N(R 15

)(R'

6 ) wherein R 15 is H and R 16 is heteroaryl; provided that when R' is R 2 1 -aryl or R21-arylalkyl, wherein R21 is -OCF 3 ,

-S(O)CF

3 , -S(0) 2

CF

3 , -S(O)alkyl, -S(0) 2 alkyl , -S(0)2CHF 2 , -S(0) 2

CF

2

CF

3 ,

-OCF

2

CHF

2 , -OCHF 2 , -OCH 2

CF

3 , -SF 5 or -S(0) 2

NR'

5 R'r' 10 wherein R 15 and R 16 are independently selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, R1 8 -alkyl, R' 8 -cycloalkyl, R' 8 heterocycloalkyl, R' 8 -aryl and R' 8 -heteroaryl; U is a bond or -CH 2 ; and X is -N(R 5 )_; then R 5 is H; provided that when U is a bond, 15 R 3 and R 4 are alkyl, CNI orx R1 R 2R 21 where R 2 1 is halo, -CN, alkyl, alkoxy, haloalkyl or haloalkoxy, or R 3 and R 4 , together with the carbon to which they are attached, form a 3-7 membered cycloalkyl group, and R' is 0 A 22

N-R

2 1a N R22 H N,R21a Or a N ' 21a 20 R where a is 0 to 6 and R 22 is alkyl, alkoxy, halo, -CN, -OH, -NO 2 or haloalkyl; -11 then R 2 1 a is not H, -C(0) 2 R 5 , wherein R 15 is selected from the group consisting of alkyl, cycloalkyl and alkyl substituted with phenyl, alkyl or alkyl-R2, wherein R2 is selected from the group consisting of phenyl, 5 phenyl substituted with alkyl, and( wherein R2 is selected from the group consisting of H, methoxy, nitro, oxo, -OH, halo and alkyl, NO R22O R 22 S

R

22 0/ and N 10 In another aspect, the invention relates to a pharmaceutical composition comprising at least one compound of formula I and a pharmaceutically acceptable carrier. In another aspect, the invention comprises the method of inhibiting aspartyl protease comprising administering at least one compound of formula I to a patient in 15 need of such treatment. More specifically, the invention comprises: the method of treating a cardiovascular disease such as hypertension, renal failure, or a disease modulated by renin inhibition; the method of treating Human Immunodeficiency Virus; the method of treating a cognitive or neurodegenerative disease such as Alzheimer's Disease; -12 the method of inhibiting plasmepins I and Il for treatment of malaria; the method of inhibiting Cathepsin D for the treatment of Alzheimer's Disease, breast cancer, and ovarian cancer; and the method of inhibiting protozoal enzymes, for example inhibition of plasmodium falciparnum, for the treatment of fungal infections. Said 5 method of treatment comprise administering at least one compound of formula I to a patient in need of such treatment. In particular, the invention comprises the method of treating Alzheimer's disease comprising administering at least one compound of formula I to a patient in need of such treatment. In another aspect, the invention comprises the method of treating Alzheimer's 10 disease comprising administering to a patient I need of such treatment a combination of at least one compound of formula I and a cholinesterase inhibitor or a muscarinic antagonist. In a final aspect, the invention relates to a kit comprising in separate containers in a single package pharmaceutical compositions for use in combination, 15 in which one container comprises a compound of formula I in a pharmaceutically acceptable carrier and a second container comprises a cholinesterase inhibitor or a muscarinic antagonist in a pharmaceutically acceptable carrier, the combined quantities being an effective amount to treat a cognitive disease or neurodegenerative disease such as Alzheimer's disease. 20 DETAILED DESCRIPTION: Compounds of formula I wherein X, W and U are as defined above include the following independently preferred structures: N.R2 N.R2 N.R2 N.R2 NN N R.N NR1 RNN N R NRN I R 3 I I R 3 I R 3 I T R 3 I U * S(0)1-2 U O U * U LJ S(0)1-2 R4 R4 R4 R4 25 IA IB IC ID

N-R

2 N.R2 R . R 6 R R 1 R~ R RR N R RR R N RiR3 N R3I \N '"N N R U U - U OU U-- 3 U- R3 R4 R4 R4 R4 - 13 IE IF IG IH In compounds of formulas IA to IF, U is preferably a bond or -C(R 6

)(R

7 )-. In compounds of formula IG and IH, U is preferably -C(O)-. It will be understood that since the definition of R 1 is the same as the definition 5 of R 5 , when X is -N(R 5 )-, compounds of formula I wherein W is a bond and U is a bond, -S(0)-, -S(0)2-, -C(0)-, -0-, -C(R 6

)(R

7 )- or -N(R 5 )- are equivalent to compounds of formula I wherein U is a bond and W is a bond, -S(0)-, -S(0)2-, -C(0)-, -0-, -C(R )(R )- or -N(R 5 )_. More preferred compounds of the invention are those of formula IB wherein U 10 is a bond or those of formula IB wherein U is -C(R 6

)(R

7 )-. Another group of preferred compounds of formula I is that wherein R 2 is H.

R

3 , R 4 , R and R are preferably selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, -CH 2 -0-Si(R 9

)(R')(R'

9 ), -SH, -CN, -OR 9 , -C(O)R , 15 -C(O)OR 9 , -C(O)N(R")(R ), -SR' , -S(O)N(R")(R1 2 ), -S(O) 2

N(R")(R

12 ), -N(R'l)(R 12 ), -N(R")C(O)R", -N(R')S(O)R', -N(R 1

)C(O)N(R

12 )(R 1 3), -N(R")C(0)OR 9 and

-C(=NOH)R

8 .

R

3 , R 4 , R and R are preferably selected from the group consisting of aryl, heteroaryl, heteroarylalkyl, arylalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, 20 alkyl and cycloalkylalkyl. In a group of preferred compounds U is a bond or -C(O)-; W is a bond or -C(0)-; X is -N(R 5 )-; 25 R' is H, alkyl, R 2 1 -alkyl, arylalkyl, R 2 1 -arylalkyl, cycloalkylalkyl, R 21 _ cycloalkylalkyl, heterocycloalkyalkyl or R 2 1 -heterocycloalkylalkyl, R2 is H;

R

3 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R 2 1 -alkyl, R 2 1 _ cycloalkylalkyl, R 2 1 -cycloalkyl, R 21 -aryl or R 2 1 -arylalkyl; 30 R 4 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R 21 -alkyl, R 2 1 _ cycloalkylalkyl, R 2 1 -cycloalkyl, R 21 -aryl or R 2 1 -arylalkyl;

R

5 is H, alkyl, R 2 1 -alkyl, arylalkyl, R 2 1 -arylalkyl, cycloalkylalkyl, R 21 _ cycloalkylalkyl, heterocycloalkyalkyl or R 21 -heterocycloalkylalkyl; -14

R

6 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R 21 -alkyl, R 2 1 cycloalkylalkyl, R 21 -cycloalkyl, R 21 -aryl or R 21 -arylalkyl;

R

7 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R 21 -alkyl, R 21 . cycloalkylalkyl, R 21 -cycloalkyl, R21-aryl or R 2 1 -arylalkyl; R30 5 R', R' and R' is H, R' -alkyl, alkyl or M

R

2 1 is alkyl, aryl, halo, -OR 5 , -NO 2 , -C(O)R 5 , -CH 2

-N(R

5

)C(O)N(R')(R

17 ) or

-CH(R

15

)(R

1 6); n is 1; m is 1; 10 R' 8 is -OR20 1020 R20 is aryl; and R23 is alkyl. In a group of preferred compounds 15 R 3 , R 4 , R 6 and R 7 are or and R and R 5 is H, CH 3 , / N O /),0 / 21 . or 20 In an additional group of preferred compounds; U is a bond or -C(O)-; W is a bond or -C(0)-; X is -N(Rs)-; -15

R

1 is H, alkyl, R 2 1 -alkyl, arylalkyl, R 21-arylalkyl, cycloalkylalkyl, R 21 _ cycloalkylalkyl, heterocycloalkyalkyl or R 2 1 -heterocycloalkylalkyl, R2 is H;

R

3 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyt, R21-alkyl, R 21 _ 5 cycloalkylalkyl, R 2 1 -cycloalkyl, R 2 1 -aryl, R 21 -arylalkyl, heteroarylalkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl, R 2 1 -heteroarylalkyl, R 21 -heteroaryl, R 21 . heterocycloalkyl or R 2 1 -heterocycloalkylalkyl;

R

4 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R 2 1 -alkyl, R 2 1 _ cycloalkylalkyl, R 2 1 -cycloalkyl, R 21 -aryl, R 2 1 -arylalkyl, heteroarylalkyl, heteroaryl, 10 heterocycloalkyl, heterocycloalkylalkyl, R 2 1 -heteroarylalkyl, R 21 -heteroaryl, R 2 1 . heterocycloalkyl or R 21 -heterocycloalkylalkyl;

R

5 is H, alkyl, R 21 -alkyl, arylalkyl, R 2 1 -arylalkyl, cycloalkylalkyl, R21_ cycloalkylalkyl, heterocycloalkyakyl or R 21-heterocycloalkylalkyl;

R

6 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R 2 1 -alkyl, R 2 1 _ 15 cycloalkylalkyl, R 2 1 -cycloalkyl, R 2 1 -aryl, R 2 1 -arylalkyl, heteroarylalkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl, R21 -heteroarylalkyl, R 2 1 -heteroaryl, R 21 _ heterocycloalkyl or R 2 1 -heterocycloalkylalkyl;

R

7 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R 2 1 -alkyl, R 21 _ cycloalkylalkyl, R 2 1 -cycloalkyl, R 21 -aryl, R 21 -arylalkyl, heteroarylalkyl, heteroaryl, 20 heterocycloalkyl, heterocycloalkylalkyl, R 21 -heteroarylalkyl, R 2 1 -heteroaryl, R- 21 heterocycloalkyl or R -heterocycloalkylalkyl; Rl 5 , R' 6 and R 7 is H, cycloalkyl, cycloalkylalkyl, R1 8 -alkyl, alkyl, aryl, R 18 -aryl,

R

23 R23 N~ R 8-arylalkyl, arylalkyl, m or -m; n is 1 or 2; 25 m is 0 or 1;

R

18 is -OR 20 or halo; R2 is aryl or halo substituted aryl;

R

2 1 is alkyl, aryl, heteroaryl, R2-alkyl, R 22 -aryl, R 22 -heteroaryl, halo, heterocycloalkyt, -N(R' 5 )(R"), -OR" 5 , -NO 2 , -C(O)R' 5 , -N(R' 5

)C(O)R

16

,

-16

-N(R

1 )S(0) 2

R

16 , -CH 2

-N(R'

5 )C(O)N(R1 6

)(R'

7 ), -N(R')C(O)N(R)(R 17 ) or

-CH(R

1

)(R'

6 ); R22 is -OR 15 or halo and 5 R 23 is H or alkyl. As used above, and throughout the specification, the following terms, unless otherwise indicated, shall be understood to have the following meanings: "Patient" includes both human and animals. "Mammal" means humans and other mammalian animals. 10 "Alkyl" means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a 15 linear alkyl chain. "Lower alkyl" means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n pentyl, heptyl, nonyl and decyl. R 32 -substituted alkyl groups include fluoromethyl, trifluoromethyl and cyclopropylmethyl . 20 "Alkenyl" means an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such 25 as methyl, ethyl or propyl, are attached to a linear alkenyl chain. "Lower alkenyl" means about 2 to about 6 carbon atoms in the chain which may be straight or branched. Non-limiting examples of suitable alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl. "Alkynyl" means an aliphatic hydrocarbon group containing at least one 30 carbon-carbon triple bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyl chain. "Lower alkynyl" -17 means about 2 to about 6 carbon atoms In the chain which may be straight or branched. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, 2-butynyl, 3-methylbutynyl, n-pentynyl, and decynyl. "Aryl" means an aromatic monocyclic or multicyclic ring system comprising 5 about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms. The aryl group can be optionally substituted with one or more substituents (e.g., R's, R 21 R22, etc.) which may be the same or different, and are as defined herein or two substituents on adjacent carbons can be linked together to form S') o or SoQ. Non-limiting examples of suitable aryl groups include 10 phenyl and naphthyl. "Heteroaryl" means an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one to four of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain 15 about 5 to about 6 ring atoms. The "heteroaryl" can be optionally substituted by one or more R21 substituents which may be the same or different, and are as defined herein. The prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom. A nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. Non 20 limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-blthiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, 25 thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4 triazinyl, benzothiazoyl and the like. "Cycloalkyl" means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7 ring atoms. The 30 cycloalkyl can be optionally substituted with one or more R 2 1 substituents which may be the same or different, and are as defined above. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and -18 the like. Non-limiting examples of suitable multicyclic cycloalkyls include 1-decalin, norbornyl, adamantyl and the like. Further non-limiting examples of cycloalkyl include the following JJ'AAP and 5 "Cycloalkylether" means a non-aromatic ring of 3 to 7 members comprising an oxygen atom and 2 to 7 carbon atoms. Ring carbon atoms can be substituted, provided that substituents adjacent to the ring oxygen do not include halo or substituents joined to the ring through an oxygen, nitrogen or sulfur atom. "Cycloalkenyl" means a non-aromatic mono or multicyclic ring system 10 comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms which contains at least one carbon-carbon double bond. The cycloalkenyl ring - 19 can be optionally substituted with one or more R 21 substituents which may be the same or different, and are as defined above. Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms. Non-limiting examples of suitable monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like. Non 5 limiting example of a suitable multicyclic cycloalkenyl is norbornylenyl. "Heterocyclenyl" means a non-aromatic monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur atom, alone or in combination, and which 10 contains at least one carbon-carbon double bond or carbon-nitrogen double bond. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclenyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The heterocyclenyl can 15 be optionally substituted by one or more ring system substituents, wherein "ring system substituent" is as defined above. The nitrogen or sulfur atom of the heterocyclenyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitable monocyclic azaheterocyclenyl groups include 1,2,3,4- tetrahydropyridine, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6 20 tetrahydropyridine, 1,4,5,6-tetrahydropyrimidine, 2-pyrrolinyl, 3-pyrrolinyl, 2 imidazolinyl, 2-pyrazolinyl, and the like. Non-limiting examples of suitable oxaheterocyclenyl groups include 3,4-dihydro-2H-pyran, dihydrofuranyl, fluorodihydrofuranyl, and the like. Non-limiting example of a suitable multicyclic oxaheterocyclenyl group is 7-oxabicyclo[2.2.1)heptenyl. Non-limiting examples of 25 suitable monocyclic thiaheterocyclenyl rings include dihydrothiophenyl, dihydrothiopyranyl, and the like. "Halo" means fluoro, chloro, bromo, or iodo groups. Preferred are fluoro, chloro or bromo, and more preferred are fluoro and chloro. 30 "Haloalkyl" means an alkyl as defined above wherein one or more hydrogen atoms on the alkyl is replaced by a halo group defined above. "Heterocyclyl" (or heterocycloalkyl) means a non-aromatic saturated monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which 1-3, preferably 1 or 2 of the atoms -20 in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclyls contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclyl root name means that at 5 least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The heterocyclyl can be optionally substituted by one or more R 2 1 substituents which may be the same or different, and are as defined herein. The nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S dioxide. Non-limiting examples of suitable monocyclic heterocyclyl rings include 10 piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3 dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like. "Arylalkyl" means an aryl-alkyl- group in which the aryl and alkyl are as previously described. Preferred aralkyls comprise a lower alkyl group. Non-limiting 15 examples of suitable aralkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl. The bond to the parent moiety is through the alkyl. "Arylcycloalkyl" means a group derived from a fused aryl and cycloalkyl as defined herein. Preferred arylcycloalkyls are those wherein aryl is phenyl and cycloalkyl consists of about 5 to about 6 ring atoms. The arylcycloalkyl can be 20 optionally substituted by 1-5 R 21 substituents. Non-limiting examples of suitable arylcycloalkyls include indanyl and 1,2,3,4-tetrahydronaphthyl and the like. The bond to the parent moiety is through a non-aromatic carbon atom. "Arylheterocycloalkyl" means a group derived from a fused aryl and heterocycloalkyl as defined herein. Preferred arylcycloalkyls are those wherein aryl is 25 phenyl and heterocycloalkyl consists of about 5 to about 6 ring atoms. The arylheterocycloalkyl can be optionally substituted by 1-5 R 21 substituents. Non limiting examples of suitable arylheterocycloalkyls include / 0 0 I andO The bond to the parent moiety is through a non-aromatic carbon atom. 30 Similarly, "heteroarylakyl" "cycloalkylalkyl" and "heterocycloalkylalkyl" mean a heteroaryl-, cycloalkyl- or heterocycloalkyl-alkyl- group in which the heteroaryl, -21 cycloalkyl, heterocycloalkyl and alkyl are as previously described. Preferred groups contain a lower alkyl group. The bond to the parent moiety is through the alkyl. "Acyl" means an H-C(O)-, alkyl-C(O)-, alkenyl-C(O)-, alkynyl-C(O)- or cycloalkyl-C(O)- group in which the various groups are as previously described. The 5 bond to the parent moiety is through the carbonyl. Preferred acyls contain a lower alkyl. Non-limiting examples of suitable acyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl, butanoyl and cyclohexanoyl. "Alkoxy" means an alkyl-O- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, 10 n-propoxy, isopropoxy, n-butoxy and heptoxy. The bond to the parent moiety is through the ether oxygen. "Alkyoxyalkyl" means a group derived from an alkoxy and alkyl as defined herein. The bond to the parent moiety is through the alkyl. "Arylalkenyl" means a group derived from an aryl and alkenyl as defined 15 herein. Preferred arylalkenyls are those wherein aryl is phenyl and the alkenyl consists of about 3 to about 6 atoms. The arylalkenyl can be optionally substituted by one or more R 27 substituents. The bond to the parent moiety is through a non aromatic carbon atom. "Arylalkynyl" means a group derived from a aryl and alkenyl as defined herein. 20 Preferred arylalkynyls are those wherein aryl is phenyl and the alkynyl consists of about 3 to about 6 atoms. The arylalkynyl can be optionally substituted by one or more R 27 substituents. The bond to the parent moiety is through a non-aromatic carbon atom. 25 The suffix "ene" on alkyl, aryl, hetercycloalkyl, etc. indicates a divalent moiety, e.g., -CH 2

CH

2 - is ethylene, and is para-phenylene. The term "optionally substituted" means optional substitution with the specified groups, radicals or moieties, in available position or positions. Substitution on a cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, or 30 heteroarylalkyl moiety includes substitution on the ring portion and/or on the alkyl portion of the group.

- 22 When a variable appears more than once in a group, e.g., Ra in -N(R 8

)

2 , or a variable appears more than once in the structure of formula 1, e.g., R 15 may appear in both R 1 and Ra, the variables can be the same or different. With reference to the number of moieties (e.g., substituents, groups or rings) in 5 a compound, unless otherwise defined, the phrases "one or more" and "at least one" mean that there can be as many moieties as chemically permitted, and the determination of the maximum number of such moieties is well within the knowledge of those skilled in the art. With respect to the compositions and methods comprising the use of "at least one compound of formula I," one to three compounds of formula I 10 can be administered at the same time, preferably one. As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. 15 The wavy line 'fv-n as a bond generally indicates a mixture of, or either of, the possible isomers, e.g., containing (R)- and (S)- stereochemistry. For example, OH -OH .OH means containing both and N N N H H H Lines drawn into the ring systems, such as, for example: 20 indicate that the indicated line (bond) may be attached to any of the substitutable ring carbon atoms. As well known in the art, a bond drawn from a particular atom wherein no moiety is depicted at the terminal end of the bond indicates a methyl group bound through that bond to the atom, unless stated otherwise. For example:

CH

3 N represents N OH 25 -23 It should also be noted that any heteroatom with unsatisfied valences in the text, schemes, examples, structural formulae, and any Tables herein is assumed to have the hydrogen atom or atoms to satisfy the valences. Those skilled in the art will recognize that certain compounds of formula I are 5 tautomeric, and all such tautomeric forms are contemplated herein as part of the present invention. For example, a compound wherein X is -N(R)- and R' and R 5 are each H can be represented by any of the following structures:

R

2 - R 2

R

2 N R 1 HN' HN

R

5 N N N N Re R5N N I R 3 I | R 3 | | R 3 I

R

4 , R4 or R4 When R21 and R 22 , are, for example, -N(R' 5 )C(O)N(R'")(R 17 ) and R' 5 and R' 6 0 0 N NILN N 10 form a ring , the moiety formed, is, for example, R23 or R23 Prodrugs and solvates of the compounds of the invention are also contemplated herein. The term "prodrug", as employed herein, denotes a compound that is a drug precursor which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of formula I or a 15 salt and/or solvate thereof. A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) Volume 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press, both of which are incorporated herein by reference thereto. 20 "Solvate" means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate" encompasses 25 both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. "Hydrate" is a solvate wherein the solvent molecule is H 2 0.

-24 "Effective amount" or "therapeutically effective amount" is meant to describe an amount of compound or a composition of the present invention effective in inhibiting aspartyl protease and/or inhibiting BACE-1 and thus producing the desired therapeutic effect in a suitable patient. 5 The compounds of formula I form salts which are also within the scope of this invention. Reference to a compound of formula I herein is understood to include reference to salts thereof, unless otherwise indicated. The term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, when a 10 compound of formula I contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term "salt(s)" as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful. Salts of the 15 compounds of the formula I may be formed, for example, by reacting a compound of formula I with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization. Acids (and bases) which are generally considered suitable for the formation of pharmaceutically useful salts from basic (or acidic) pharmaceutical 20 compounds are discussed, for example, by S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, Intemational J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; in The Orange Book (Food & Drug Administration, Washington, D.C. on their website); and P. Heinrich Stahl, Camille G. Wermuth (Eds.), Handbook 25 of Pharmaceutical Salts: Properties, Selection, and Use, (2002) Int'l. Union of Pure and Applied Chemistry, pp. 330-331. These disclosures are incorporated herein by reference thereto. Exemplary acid addition salts include acetates, adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, 30 citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates, methanesulfonates, methyl sulfates, 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pamoates, -25 pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates, sulfonates (such as those mentioned herein), tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) undecanoates, and the like. 5 Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, aluminum salts, zinc salts, salts with organic bases (for example, organic amines) such as benzathines, diethylamine, dicyclohexylamines, hydrabamines (formed with N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D 10 glucamines, N-methyl-D-glucamides, t-butyl amines, piperazine, phenylcyclohexylamine, choline, tromethamine, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides (e.g. methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, dibutyl, and diamyl 15 sulfates), long chain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others. All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are 20 considered equivalent to the free forms of the corresponding compounds for purposes of the invention. All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates and prodrugs of the compounds as well as the salts and solvates of the prodrugs), such as those 25 which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention. Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for 30 example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the /UPAC 1974 Recommendations. The use of the terms "salt", "solvate" "prodrug" and the like, is intended to equally apply to the salt, solvate and prodrug of enantiomers, -26 stereoisomers, rotamers, tautomers, racemates or prodrugs of the inventive compounds. Polymorphic forms of the compounds of formula 1, and of the salts, solvates and prodrugs of the compounds of formula I, are intended to be included in the 5 present invention Compounds of formula I can be made using procedures known in the art. Preparative methods for preparing starting materials and compounds of formula I are show below as general reaction schemes (Method A, Method B, etc.) followed by specific procedures, but those skilled in the art will recognize that other procedures 10 can also be suitable. In the Schemes and in the Examples below, the following abbreviations are used: methyl: Me; ethyl: Et; propyl: Pr; butyl: Bu; benzyl: Bn; tertiary butyloxycarbonyl: Boc or BOC high pressure liquid chromatography: HPLC 15 liquid chromatography mass spectroscopy: LCMS room temperature: RT or rt day: d; hour: h; minute: min retention time: Rt microwave: gW 20 saturated: sat.; anhydrous: anhyd. 1 -hydroxybenzotriazole: HOBt 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride: EDCI ethyl acetate: EtOAc Benzyloxycarbonyl: CBZ 25 [1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2] octane bis(tetrafluoro borate)]: Selectfluor 1,8-diazabicyclo[5,4,0]undec-7-ene: DBU tetrahydrofuran: THF; N,N-dimethylformamide: DMF; methanol: MeOH; diethyl ether: Et 2 0; acetic acid: AcOH; acetonitrile: MeCN; trifluoroacetic acid: TFA; 30 dichloromethane: DCM; dimethoxyethane: DME; diphenylphosphinoferrocene (dppf); n-butyllithium: n-BuLi; lithium diisopropylamide: LDA 1-hydroxy-7-azabenzotriazole: HOAt 4-N,N-dimethylaminopyridine: DMAP; diisopropylethylamine: DIEA; N-methylmorpholine: NMM -27 Microporous Toluene sulfonic acid resin (MP-TsOH resin) tris-(2-aminoethyl)aminomethyl polystyrene (PS-trisamine) methylisocyanate polystyrene (PS-NCO) Saturated (sat.); anhydrous. (anhyd); room temperature (rt); hour (h); 5 Minutes (Min), Retention Time (Rt); molecular weight (MW); milliliter (mL); gram (g). milligram (mg); equivalent (eq); day (d); microwave (pW); microliter(pL); All NMR data were collected on 400 MHz NMR spectrometers unless otherwise indicated. LC-Electrospray-Mass spectroscopy with a C-1 8 column and 5% to 95% MeCN in water as the mobile phase was used to determine the molecular 10 mass and retention time. The tables contain the compounds with retention time/observed MW and/or NMR data. For internal consistency in the reaction schemes shown in Methods A to AA, the product of each method is shown as structure A4, B4, C3, etc., wherein certain variables are as defined for that method, but it will be apparent that, for example, A4 15 has the same structure as C3. That is, different methods can be used to prepare similar compounds. The compounds in the invention may be produced by processes known to those skilled in the art and as shown in the following reaction schemes and in the preparations and examples described below. Table I contains the 20 compounds with observed m/e values from mass spectrascopy and/or NMR data. These compounds can be obtained with synthetic methods similar to these listed in the last column using appropriate reagents. Method A N N s R 2

NH

2 NR2 0 0 R t

NH

2

R

1 (CHCO A H2N S=C=N HN N' HN N

R

4

R

3 THF R CH 3 0H R 25 Al A2 A3 A4 Method A, Step 1: To a solution of Al (R 3 = CH 3 & R 4 = CH 2

CH(CH

3

)

2 ) (10 mmol, 1 eq) in 30ml of anhyd. CH 2

CI

2 was added thiocarbonyl dipyridone (1.2 eq). After stirring -28 overnight the solution was diluted with CH 2 Cl 2 , washed with 1 N HCI, H 2 0 (2x), and a saturated aqueous NaCl solution (2x). The organic solution was dried over Na 2

SO

4 , filtered and concentrated. The crude material was purified via flash chromatography to afford A2 (R 3 = CH 3 & R 4 = CH 2

CH(CH

3

)

2 ). 5 Method A, Step 2: A solution of 3,5-difluorobenzyl amine (0.15 mmol, 1.5 eq) in THF (0.15 mL) was added to a solution of A2 (R 3 = CH 3 & R 4 = CH 2

CH(CH

3

)

2 ) (0.1 mmol, 1 eq) in anhydrous CH 2 Cl 2 (1 mL). The reaction mixture was refluxed overnight. The reaction solution was added to MP-TsOH resin (2-3 eq) and diluted with 10 CH 3 CN. The suspension was agitated overnight. The mixture was filtered and the filtrate was concentrated to afford A3 (R 1 =3,5-difluorobenzyl, R 3 = CH 3 , & R 4 = CH 2

CH(CH

3

)

2 ). Method A, Step 3: 15 To a solution of A3 (R' = 3,5-difluorobenzyl, R 3 = CH 3 , & R 4=

CH

2

CH(CH

3

)

2 ) (10 mg) in CH 3 0H (1 mL) was added NH 4 0H (0.44 mL) and t butyl hydrogen peroxide (0.1 mL) and the reaction mixture was agitated for 2 d. The solution was concentrated, the resulting residue was dissolved in CH 3 0H (1.2 mL) and was treated with sulfonic acid resin. The suspension was agitated 20 overnight and the resin was washed with CH 3 0H (4 x 10 min) before it was treated with 2 N NH 3 in CH 3 0H for 1 h. The suspension was filtered and the filtrate was concentrated to give the crude material which was purified by preparative HPLC/LCMS eluting with a CH 3

CN/H

2 0 gradient to afford A4 (R 1 = 3,5-difluorobenzyl, R 2 = H, R 3 = CH 3 , & R 4 = CH 2

CH(CH

3

)

2 ). NMR (CD 3 0D): 25 86.9, m, 3H; 84.8-4.9, m; 81.75, d, 2H; 81.5, m, 1 H; 81.42, s, 3H; 80.85, d, 3H; 80.65, d, 3H. ES_LCMS (m/e) 296.1. The following compounds were synthesized using similar methods: Obs. Obs. Structure MW #Structure MW m/e m/e -29 1 O NH 2202 4 H HN SNH 223 224 94 H 363 364 0 NH HN<( 2 N H 223 224 95 363 364 NH N H N NH 3 0 NH 125 226 96 NH 369 370 0 0N NH H 4 NH 225 226 97 374 375 NHN NOf NH 0 NH -30 oHN 5 NH 227 228 98 375 376 6 O H 237 238 99 H 375 376 0 HN=( N 7 239 240 100 H 377 378 NH 0N N NH 239 240 101 HN 377 378 HHO .N ,H3NH.N3 NH HN=( 9 = NH 239 240 102 377 378 -31 NH N NH O NH 10 0 H 240 241 103 381 382 0I N NNH 11 O H 241 242 104 382 383 NH 24 24y.jH 8 8 o NH 0NN 0 N-fNH 12 NH 241 242 105 NH 385 386 NfNH HN=< 14 NH 251 252 106 385 387 O - N NH H0 NH 14 253 254 107 386 387 0N,/NH

NH

-32 N-. 0 N- NH HN<( 15 NH 254 255 108 389 390 OH H NH NHf 16 NH 255 256 109 391 392 HH55 26 1 HO NH N--f HN=( 17 07 255 256 110 391 392 -33 18 H K OH 255 256 111 391 392 , N- NH HN- 3 3 19 NH 260 261 112 391 392 20 260 261 113 H 393 394 N H 21 265 266 114 ; 393 394 0 N-f H 1Q - NH 22 NH 265 266 115 NH 400 401 -34 24 fNH 267 2601 N 0 0 23 H 268 269 118 H 401 402 26 O N NH 265 266 1196 NNO . 0 NH Q N 0 HN(< 24 267 268 117 401 402 \2 0 SNH HN=( 25 0268 269 118 401 402 -N/ 26 N-NH268 269 119 HN=( 401 402 -35 HOP 27 H 269 270 120 H 403 404 HO 28 O H 273 274 121 HN 403 404 NH HQ QNH 2 0 N-f ~HN<(N 29 NH 273 274 122N40 44 -36 N 0 30 0 H 274 275 123 F -0 405 406 NH /~ N0 NH HN=( 31 274 275 124 H 405 406 NHN 32 0 274 275 125 409 410 NH NN 33 NH 277 278 126 H 409 410 -37 NH 0N 34 279 280 127 409 410 N-=< 5 0 NH 280 281 128 409 410 SNH N 36 0 280 281 129 0 411 412 P - NH 37 0 NH 280 281 130 413 414 -38 NON 38 NH 280 281 131 413 414 0 00 N O NrNH 39 NH 281 282 132 414 415 NN NH NH 40 0 -NHf 282 283 133 415 416 4 NH 282 283 13 41 0 H 282 283 134 0415 416 -39 N-0 42 0 282 283 135 415 416 NOH HN=( 43 o NH 283 284 136 417 418 NH

NH

4 0 285 286 137 -.-- 41 419 420 NH 2 N H HN=( 45 0 NH 287 288 138 N421 422 -40 4 0:,NH 287 288 13942 44 0 HN=(0 47 289 290 140 H 425 426 N~~ NH 0\NH 48 293 294 141 =N 425 426 09 NO 49 NH 294 295 142 HN=( 425 426 -41 Q F 50 ON NH 294 295 143 HN(N 427 428 NH F N NH 52 0 296 297 145 430 431 NNH 53 NH 301 302 146 f - 430 431 -42 0 F F NIfNH N. NH 54N 303 304 147 0 NH 431 432 -P 0-N 55 N-H 304 305 148 433 434 0 N-fHN=(N 56 NH 304 305 149 9 -K 437 438 57 3 3 N9NH C;305 306 150 HN=( 3 4 -43 a 20 58 NH 307 308 151 440 441 a NHN 59NH 307 308 152 440 441 qS HN NH 0 N-f 60 NH 308 309 153 441 442 60 NH N 61 N H 310 311 154 441 442 -44 0 0 NH 62 N -f 317 318 155 442 443 NH NH F 63 319 320 156 447 448 ND . N H 322 323 157 449 450 NH NH NH 65 0 324 325 158 N )N 455 456 0" NH N NH 07 -45 NH 6 O NH 327628 164H 66 327 328 159 H F F F NH a6 3 3 1 HN( 67 0 NH 327 328 160 463 464 a 68 0 H 327 328 161 471 472 F F F 0 69 oNH 327 328 162 5 IFK) 473 474 -46 70 328 329 163 481 482 "IN NNH NHN N-N N NH 71 NH 330 331 164 481 482 Br 0 NO0 72 331 332 165 HN O 487 488

NH

-47 - 0 73 'NH 331 332 166 488 489 0 NH 0 74 335 336 167 _N 0 499 500 H 75300 75 335 336 168 N7H50 55 N H -48 NH NH 76 NH 337 338 169 523 524 NH NH 78 H 42 43 71 NH 52 526 77 337 338 170 525 526 pO 0B NH 0 78 0= 342 343 171 f 0" 525 526 N H 0 N 79 HN(345 346 172 527 528 0

N

-49 NH 80 345 346 173 N H Br 528 529 0 N O NHN 82 349 350 175 535 536 835 krH351 352 17653 56 -50 Br 0 NH 84 NH 351 352 177 )535 536 F HN=(N 85 351 352 178 550 551 O N H NH 86 359 360 179 554 555 NH

N-

-51 87 361 362 180 NrNH 556 557 0 88 HN ~ 361 362 181 - 569 570 H 0~ r.1N 89 HN=( 361 362 182 N 581 582 Brs - -52 1.NNH74 N 90 N 363 364 183 374 NA NO N NH 0 0 91 iFj=( 363 364 184 388 NA D: NH Br HN<( 0 PNH 92 363 364 185 0 H337 NMR -53 0 HOO 93 363 364 156 351 NMR NH Method B S 0 + KSCN R'' NASNH RINH2 + RSk R 4 +0 'N--C- CH30H R3 H4 B1 B5 60 *C R 4 N B2 S NR2 HCI, pW R1'N ANH R 2

NH

2 R'N ANH

CH

3

CH

2 OH RR 0 R 0 160 *C B3 B4 5 A modified literature procedure was used (Ugi, I. Angew. Chem. 1962, 74 9-22). Method B, Step 1: To a solution of B1 (HCI salt, R' = 3-chlorophenethyl) (1.1 g, 5.73 mmol) in anhydrous CH 3 0H (15 mL) was added potassium thiocyanate (0.56 g, 5.73 10 mmol). The reaction mixture was heated to 60 *C for 1 h. The suspension was filtered and the filtrate was added to B5 (Ra=Me, R 4 ='Bu) (0.72 mL, 5.73 mmol) and benzyl isocyanide (0.77 mL, 6.3 mmol). The mixture was stirred overnight before the solution was concentrated and the residue was purified via flash -54 chromatography eluting with ethyl acetate in hexane to yield 0.28 g of B2 (R 3

CH

3 , R 4 = CH 2

CH(CH

3 )2, and RI = 3-Chlorophenethyl). Method B, Step 2: 5 A solution of 40% concentrated HCI in CH 3

CH

2 OH was added to B2 (R 3 _

CH

3 , R 4 = CH 2

CH(CH

3

)

2 , and R' =3-Chlorophenethyl) and the solution was heated in a microwave at 160 *C for 30 min. The solution was concentrated and purified via reverse phase preparative HPLC eluting with a CH 3

CN/H

2 0 (with 0.1% formic acid) gradient to afford B3 (R 3 = CH 3 , R 4 = CH 2

CH(CH

3

)

2 , and R' = 10 3-Chlorophenethyl). Method B, Step 3: Compound B4 (R 2 = H, R 3 = CH 3 , R 4 = CH 2

CH(CH

3

)

2 , and R' =3 Chlorophenethyl) was prepared from B3 (R 3 = CH 3 , R 4 = CH 2

CH(CH

3

)

2 , and R, 15 =3-Chlorophenethyl) following a procedure similar to Method A, Step 3.

NMR(CD

3 0D): 8 8.1, br, 1H; 8 7.35, s, 1H; 8 7.25, m, 3H; 8 3.6, m, 1H; 8 3.4, m, 1 H; 8 3.0, m, 1H; 8 2.8, m, 1 H; 8 1.75, m, 1H; 8 1.6, m, 1H; 8 1.35, m, 1H; 8 1.2 s, 3H; 8 0.8, m, 6H. ESLCMS (mle): 308.1 20 The following compounds were prepared using similar methods Obs. Obs. # Structure MW # Structure MW W/e m/e O NH 545 251 252 549 a 371 372 ONN 546 293 294 550 a 413 -55 0 NH NH 547 a 307 308 551 265 548 I 357 358 Method C 0 N=C=S S N'R2 H2N Ri HN N'RR HN N-R'

R

4 RO THF

R

4 0

R

4 0 C1 C2 C3 5 Method C, Step 1: A solution of C1 (R 3 = R = CH 2

CH

2

CH

2

CH

3 ) (50 mg, 0.25 mmol) and C4 (R'=3-chlorophenyl) (38 pL, 0.26 mmol) was refluxed overnight. Trisamine resin (2 eq) and polystyrene isocyanate resin (2 eq) was added and the mixture was 10 agitated. After 3 h, the suspension was filtered and the resin was washed with

CH

2

CI

2 (3x) and CH 3 0H (3x). The filtrate was concentrated to afford C2 (R 1 = 3 Cl-C 6

H

4 , R 3 = R4= CH 2

CH

2

CH

2

CH

3 ) (60 mg, 68%). Method C, Step 2: Compound C3 (R' = 3-Cl-C 6

H

4 , R 2 = H, R 3 = R4 = CH 2

CH

2

CH

2

CH

3 ) was 15 prepared from C2 (R' = 3-Cl-C 6

H

4 , R 3 = R4 = CH 2

CH

2

CH

2

CH

3 ) following a - 56 procedure similar to Method A, Step 3. NMR(CDCI3): 8 7.4, m, 2H; 8 7.2, m, 2H; 8 5.0, s, 2H; 8 1.7, m, 4H; 8 1.1, m, 8H; 8 0.7; m, 6H. ES-LCMS (m/e): 336.1. The following compounds were prepared using similar method. Obs. Obs. # Structure MW # Structure MW Wle W/e NH A 'N NH '" OH 641 0 209 210 655 329 330 NH NH A~--f N NH NH HO 642 211 212 656 H 329 330 NH N NH O0 NrNH 643 215 216 657 NH 335 336 NH HN N H -N 0 H 644 225 226 658 (J335 336

HO

-57 NH NH -N NH O NOH 645 239 240 659 H 335 336 OH NH H N H N NH O \ 646 245 246 660 H 335 336 OH NH HN N H N 0 0 647 N 246 247 661 H 335 336 NH NH N NH N NH 0 648 251 252 662 0 O 352 353 0 NH 0 NN NH 649 N NH 267 268 663 0 352 353 - s 0

HOK

-58 NH 650 N NH 309 310 664 Br377 378 0 0 O OH NH 0 NH 651 317 318 665 385 386 SNH 0 N -NH ONH N 652 319 320 666 0 391 392 N BNH 33 0 NH 0NH 653 /N\ Br 323 324 667 6N420 421 -59 NH NNNH ANH Br 654 N 324 325 668 420 421 Method D KCN o

(NH

4

)

2 Co 3 HN NH IN KOH HN TMSCHN 2

H

2 N 0 RA__R4______ H 2 N - 1HX

R

3

R

4

H

2 0,JW R 4

R

3 OH CH 3 OH R 4

R

3

CH

3

CH

2

OHIH

2 O R 5 D1 02 D3 D4 Method D, Step 1: A mixture of D1 (R 3 = R4 = CH 2

C

6

H

5 ) (20 g), potassium cyanide (40 g) and ammonium carbonate (15 g) in ethanol (100 mL) and H 2 0 (200 mL) was heated in a sealed flask at 130 "C overnight to yield 25 g of D2 (R 3 = R4= 10 CH2C 6

H

5 ) after filtration followed by washing with water. Method D, Step 2: A solution of 2 N KOH (3eq) was- added to D2 (R 3 = R4 = CH 2

C

6 Hs) (1 eq) and irradiated via microwave at 185 0C for 3h followed by addition of 15 concentrated HCI to the solution until a pH = 2-3 was obtained. The solid was filtered and washed with water to afford D3 (R 3 = R 4 = CH 2

C

6

H

5 ). Method D, Step 3: A solution of trimethylsilyldiazomethane in hexane (2 N) (2 eq) was added 20 drop wise to a solution of D3 (R 3 = R4 = CH 2

C

6

H

5 ) (1 eq) in anhydrous CH 3 0H (30 mL). After 1 h, an additional 2 eq of trimethylsilyldiazomethane in hexane (2 N) was added and the reaction was stirred for 20 minutes before it was was concentrated. The residue was dissolved in a 0.2 N HCI solution (25 mL) and -60 washed with ether (3x). A saturated solution of Na 2

CO

3 was added to the aqueous phase until the pH of the solution was basic. The solution was extracted with ethyl acetate (3x). The organic extracts were combined, dried over Na 2

SO

4 , and concentrated to afford D4 (R 3 = R = CH 2 CeHs). 5 The following amino esters were prepared using a similar method. o o 0 o- 0

H

2 N O H 2 N O H 2 N NH 2

NH

2 Br D5 D6 D7 D8 D9

NH

2

NH

2 0 Br Br N D10 D11 D12 D13 0~

NH

2 D14 Method E 10 -61 HB U 0- R 4 X 0 0 P N OO O Ph LIN(SI(CH 3

)

3

)

2 O (> Ph Rs SOC1 2 -N HMPA R 4 'CBZ ZnC 2

R

3 'CBZ THF/Hexane THF El E2 E3

H

2

LIOCH

3 H Pd(OH) 2 /C ' CBZ'N O/ H 2 N CH30H HCI 4 R

R

4

R

3 H0HRCHROHR 40 psi E4 E5 Method E, Step 1: 5 Thionyl chloride (0.47, 6.38 mmol) was added drop wise to a solution of El (R 3 = CH 2

CH

2

C

6 Hs) (2g, 6.38 mmol) and benzaldehyde dimethyl acetal (0.96 mL, 6.38 mmol) in anhydrous THF at 0*C under N 2 . After 5 min, ZnCl 2 (0.87 g, 6.38 mmol) was added and the reaction mixture was stirred at 0 *C. After 3 h, an additional amount of ZnC 2 (0.18 g, 1.28 mmol) and thionyl chloride (0.1 mL, 10 1.28 mmol) were added and stirred for 1 h at 0 *C. The reaction mixture was poured into a stirred suspension of ice/H 2 0. The mixture was stirred occasionally until the ice melted. The aqueous solution was extracted with ether (3x). The combined organic extracts were washed with H 2 0 (3x), a sat. aqueous solution of NaHCO 3 (1x), and H 2 0 (2x). The organic solution was dried over 15 Na 2

SO

4 , filtered and concentrated. The crude material was purified via flash chromatography eluting with ethyl acetate in hexane to yield compound E2 (R=

CH

2

CH

2

C

6 Hs). Method E, Step 2: 20 A solution of lithium hexamethyldisilazide in hexane (1.0 M, 1.65 mL, 1.64 mmol) was added drop wise to a solution of E2 (R 3 = CH 2

CH

2

C

6

H

5 ) (600 mg, 1.49 mmol) and HMPA (0.85 mL) in THF (6.5 mL) cooled at -78 0C under N 2 . After 15 min, isobutyl iodide (0.52 mL, 4.48 mmol) was added drop wise and the reaction mixture was stirred at -78 0C for 3 h. The reaction was warmed to -65 25 *C, stirred for 2 h and warmed to rt overnight. The reaction solution was poured -62 into a mixture of sat. NaHCO 3 (aq)/ether/ice. The aqueous layer was extracted with ether (3x). The organic extracts were combined and washed with brine (2x). The organic solution was dried over Na 2

SO

4 , filtered and concentrated. The crude material was purified via flash chromatography eluting with ethyl acetate in 5 hexane to yield compound E3 (R 3 = CH 2

CH

2

C

6

H

5 , R 4 = CH 2

CH(CH

3

)

2 ). Method E, Step 3: A solution of lithium methoxide (1 N in CH 3 0H) (0.36 mL, 0.36 mmol) was added to compound E3 (R 3 = CH 2

CH

2

C

6 Hs, R 4 = CH 2

CH(CH

3

)

2 ). The reaction 10 mixture was shaken at rt for 50 min. An additional 0.55 eq of lithium methoxide were added. After 2.5 h, a sat. aqueous solution of NaHSO 3 (0.75 mL) and ethyl acetate (3 mL) was added to the reaction mixture and shaken for 15 min. The suspension was filtered. The resulting white solid was washed with a sat. aqueous solution of NaHSO 3 (1x) and ethyl acetate (1x). The aqueous phase of 15 the filtrate was separated and extracted with ethyl acetate (2x). The organic extracts were combined and washed with a sat. aqueous solution of NaHSO 3 (8x). The organic solution was dried over Na 2

SO

4 , filtered and concentrated to afford E4 (R 3 = CH 2

CH

2

C

6

H

5 , R 4 = CH 2

CH(CH

3

)

2 ) (109 mg, 87%). 20 Method E, Step 4: To a solution of E4 (R 3 = CH 2

CH

2

CBH

5 , R 4

=CH

2

CH(CH

3

)

2 ) (109 mg, 0.28 mmol) in CH 3 0H (4 mL) was added 1 N HCI (0.28 mL, 0.28 mmol) and 20% palladium hydroxide on carbon (22 mg). The reaction mixture was hydrogenated at 40 psi. After 2.5 h, the reaction was filtered and the catalyst was washed with 25 CH 3 0H (3x). The filtrate was concentrated to afford E5 (R 3 = CH 2

CH

2

C

6

H

5 , R 4 =

CH

2

CH(CH

3

)

2 ) (78 mg, 96%). The following aminoesters were prepared using similar method.

-63 0 0 00 HNF H 2 N F_ H 2 N 0' H -eN H2NF 0 F F E6 E7 E8 E9 0 0 0 0

H

2 N O H 2 N O H 2 N 0 H 2 N O ElO Eli E12 E13 0 0 0 0

H

2 N 0 H 2 N H 2 N 0 H 2 N OTBS 0 Boc NBoc E14 E15 E16 E17 H 0 H 0 CbzN 0 Cbz' 0 E18 E19 5 Method F 0 0 0 Rh/Pt H 2 N -n O n D5 Fl A 500 mL methanol solution of 20 g of D5 (R 3 = benzyl, n = 1) with 1.5 eq of HCI was hydrogenated with 1 g of Rh/C (5% w/w) and 2 g of Pt/C (5% w/w) at 60 psi for 2 days. The solid was filtered and washed with excessive methanol.

-64 The combined solution was evaporated to give 20 g of F1 (Ra cyclohexylmethyl, n = 1) as HCI salt. The following amino esters were examples prepared using similar method. 5 o 0 oO,

H

2 N

H

2 N O H2N

H

2 N NH2 F2 F3 F4 F5 F6 o 0

H

2 N 0 H 2 N 0 HO F7 F8 F9 FI Method G

R'

5

R

16 NH

R

3 O LIOH O PS-EDC HO .<H HOHf HOBT O HNN'R1 CH 3

CH

2 OH 0 HN N'R1 THF/CH 3 CN H20 S S G1 G2

R

15

R

15 0 O R 2

NH

2 I R O 0 HN N'R1 0 HN N-R1 S R2 N 10 G3 G4 Method G, Step 1: To a solution of G1 (R 1 = CH 2 (3-CICeH 4 ) and R 3 = CH 3 ) (400 mg, 1.23 mmol, generated following a procedure similar to Method C, Step 1) in ethanol (5 15 mL) was added lithium hydroxide monohydrate (100 mg, 2.45 mmol) in H 2 0 (0.5 -65 mL). After 2.5 h, another portion of lithium hydroxide monohydrate (100 mg, 2.45 mmol) was added. After 5.5 h, the reaction mixture was diluted with H 2 0 (15 mL) and extracted with ether (2x). A solution of 30% HCI was added to the aqueous phase until its pH = 1 to 2. The solution was saturated with NaCl and 5 extracted with ethyl acetate (3x). The organic solution was dried over Na 2

SO

4 , filtered and concentrated to afford G2 (R' = CH 2 (3-CIC 6

H

4 ) and R 3 = CH 3 ) (357 mg, 93%). Method G, Step 2: 10 A solution of benzyl amine (1.2 eq) was added to G2 (R 1 = CH 2 (3-CIC 6

H

4 ) and R 3 = CH 3 ) (1 eq), HOBT (1.5 eq) and polystyrene EDC resin (94 mg, 1.53 mmol/g, 3eq) in 1:1 THF:CH 3 CN (1 mL). The reaction mixture was shaken overnight at rt. Trisamine resin (85 mg, 3.38 mmol/g, 6 eq) and isocyanate resin (100 mg, 1.47 mmol/g, 3 eq) was added. After 6 h, the suspension was filtered 15 and the filtrate was concentrated to afford G3 (R' = CH 2 (3-CIC 6

H

4 ), R 3 = CH 3 , R15 = CH 2

C

6

H

5 and Re = H). Method G, Step 3: 2 Compound G4 (R 1 = CH 2 (3-CIC6H 4 ), R =H, R 3 = CH 3 , R's = CH 2

C

6 Hs 20 and R's = H) was prepared from G3 (R 1 = CH 2 (3-CICeH 4 ), R 3 = CH 3 , R 15 CH 2

C

6

H

5 and R'6 = H) following a procedure similar to Method A, Step 3. The following compounds were prepared using similar methods. Obs. Obs. # Structure MW # Structure MW mle m/e 0 NH a 669 O NH 322 323 682 412 413

NH

-66 NH a 670 NH 334 335 683 414 415 671 348 349 684 414 415 00 NH NH 673 364 365 686 421 422 -67 Q NHNH 674 0 364 365 687 O NH 428 429 = O= NH 0 ~,Q-~NH 675 aI K NH 376 377 688 434 435 63 8 82 0-0 -68 NH N NH 677 390 391 690 0 449 450 W§ NH 678 393 394 691 461 462 0 NH 679 398 399 692 0' o511 512 -69 Nf NH NH O NH 680 398 399 693 NH 511 512 =0 NH 0 N-2 =Q-O 681 406 407 Method H 0 H2NOHR=C=S HO O3 0. C 2 0 H

H

2 N ~ R HO'_____ 1 -'"~4 ___ HO'-". 0.5 M N8HCO 3 HO{# HO R 3 0.5 M NaHCO 3 HN N'R1 HN N'R1 THF/CH30H HN N'RI

CH

3

CH

2 OH Y NH N 'Boc H1 H2 H3 H4 TV20 T R 3 0 R21-H R21 3TFA 21 0 2,6-Lutidine HN N'R' CH2CI 2 HN N'RI CH2Cl2 HN N-R1 CH1 2 C N'Boc N 'oc NH H5 H6 H7 5 Method H, Step 1: To a solution of H1 (R 3 = CH 3 ) (5 g, 39 mmol) in a 1:1 mixture of 0.5 M NaHCO 3

:CH

3

CH

2 OH was added R'-NCS (R'=3-chlorobenzyl) (11.5 mL, 78 - 70 mmol). The reaction mixture was heated at 50 *C overnight. The reaction was cooled and diluted with water. The aqueous phase was extracted with ethyl acetate (5x). The organic extracts were combined, washed with water (2x) and dried over Na 2

SO

4 . The solution was filtered and solvent was removed to give a 5 small volume of solution. Hexane was added and the resulting suspension was filtered to yield 6.8 g of a solid H2 (R 3 = CH 3 , R' = CH 2 (3-CIC 6

H

4 )) (61%). Method H, Step 2: Compound H3 (R 3 = CH 3 , R' = CH 2 (3-CIC 6

H

4 ))was synthesized from H2 10 (R 3 = CH 3 , R' = CH 2 (3-CIC 6 H4)) following a procedure similar to Method A, Step 3. Method H, Step 3: To a solution of crude H3 (R 3 = CH 3 , R' = CH 2 (3-CCrH 4 )) (14 mmol) in a 15 1:3 mixture of CH 3 0H:THF was added 0.5 M NaHCO 3 in H 2 0 (28 mL, 14 mmol) and di-tert-butyl dicarbonate (3.69 g, 16.9 mmol). The reaction was stirred at rt for 2.5 h and then stored at -10 *C overnight. The reaction was diluted with brine and extracted with ethyl acetate (4x). The organic extracts were combined and washed with brine (1x). The organic solution was dried over Na 2

SO

4 , 20 filtered and concentrated. The crude material was purified via flash chromatography eluting with ethyl acetate in hexane to afford 1.5 g of H4 (R' =

CH

2 (3-CIC 6

H

4 ) and R 3 = CH 3 ). Method H, Step 4: 25 A solution of triflic anhydride (128 pL, 0.76 mmol) in CH 2 Cl 2 (5 mL) was added drop wise to a solution of H4 (R' = CH 2 (3-CIC6H 4 ) and R 3 = CH 3 ) (200 mg, 0.55 mmol) and 2,6-lutidine (176 pL, 2.18 mmol) at -30 *C. The reaction mixture was stirred for 1.5 h. Water (10 mL) was added at -20 *C and the ice bath was removed. The reaction was stirred until it reached 0 *C. The organic layer was 30 separated, dried over Na 2

SO

4 , filtered and concentrated to afford 310 mg of H5 (R' = CH 2 (3-CIC6H 4 ) and R 3 = CH 3 ). Method H, Step 5: -71 A solution of crude H5 (R' = CH 2 (3-CIC 6

H

4 ) and R 3 = CH 3 ) (0.11 mmol) and 7N ammonia in Methanol (R 21 -H = NH 2 -H) (10 eq) was stirred overnight at rt. The reaction solution was concentrated. The crude material was purified using reverse phase preparative HPLC eluting with a CH 3

CN/H

2 0 gradient with 0.1% 5 formic acid to yield H6 (R' = CH 2 (3-CIC 6 H4), R 3 = CH 3 , R21 = NH 2 ). Method H, Step 6: A solution of 50% trifluoroacetic acid in CH 2 Cl 2 (2 mL) was added to H6 (R' = CH 2 (3-CICeH 4 ), R 3 = CH 3 , R21 = NH 2 ). After 40 min the solvent was 10 evaporated and residue purified by preparative HPLC/LCMS eluting with a

CH

3

CN/H

2 0 gradient to afford H7 (R' = CH 2 (3-CIC 6

H

4 ), R 3 = CH 3 , R 21 = NH2). NMR (CDC13), 8 7.45, m, 3H; 8 7.35, m, 1 H; 5 4.9, m, 2H; 5 3.5, m, 2H; 8 1.65, s, 3H. ESLCMS (mle) 267.07. 15 The following compounds were prepared using similar methods. Obs. Obs. # Structure MW # Structure MW We m/e HN H o N NH 694 238 239 702 320 321 NH NNH 695 N 248 249 703 328 329 HN NNH 69A NH.- 2 696 Y, D257 258 704 0 334 335 0 -72 N NH ' NH 697 O N.NN- 264 265 705 342 343 698 O NH 266 267 706 354 355 NH P 699 292 293 707 372 373 NH j~NH NH 0 N3 3 'N NHN 700 O308 309 708 H @ 418 419 -73 p NH NH N H0 NH NH 701 314 315 709 483 484 Method I R 3 0 R 3 0 FA 9 0 R 1'N (N R R - CO2 N1 N R - TFAN H HN HOBT R1 5 16 HN-\ CH 2

C

2

R

5 N N NBG PS-EDC R N-BOG HCI ' R 16 HNH N'BcNBoc NH 11 12 13 5 Method I, Step 1: Diethylaminomethyl polystyrene resin (5 eq) was added to a solution of the formate salt of 11 (R' = CH 2 (3-CIC 6

H

4 ), R 3 = CH 3 and R' 6 =H) in CH 2 Cl 2 and the suspension was agitated. After 15 min, the mixture was filtered and the resin was washed with CH 2

CI

2 (4x). The filtrate was concentrated to afford the 10 free base 11(R' = CH 2 (3-CICsH4), R 3 = CH 3 and R' =H). A solution of R 15 COOH (R' 5 =Phenethyl) (1.3 eq) was added to a mixture of EDC resin (41 mg, 1.53 mmol/g, 3eq), HOBT (1.5 eq), and the free base of 11 (R' = CH 2 (3-ClC1H4), R 3 = CH 3 and R 1 "=H) (0.021 mmol) in 1:1 CH 3 CN:THF. The suspension was agitated overnight. Polystyrene isocyanate resin (45 mg, 3 15 eq), polystyrene trisamine resin (40 mg, 6 eq) and a 1:1 mixture of CH 3 CN:THF (0.5 mL) was added. The mixture was agitated for 6 h. The suspension was filtered and the filtrate was concentrated to afford 12 (R' = CH 2 (3-CIC1H 4 ), R 3 =

CH

3 , R'"=H and R 15 = CH 2

CH

2

C

6

H

5

).

-74 Method I, Step 2: 13 (R' = CH 2 (3-CIC 6

H

4 ), R 3 = CH 3 , R'"=H and R's = CH 2

CH

2

C

6

H

5 ) was prepared from 12 (R' = CH 2 (3-CICH 4 ), R 3 = CH 3 , R' 6 =H and R" 5 = CH 2

CH

2

C

6 Hs) 5 using method similar to method H step 6. The following compounds were prepared using similar method. M Obs. Obs. # Structure # Structure MW W Wes We NH -N NH N ~H 710 O O 280 281 718 398 399 C1NH aNH H0 F NH F 711 308 309 719 406 407 O F NH N H NH 712 308 309 720 410 o 1 -75 NH NH N N 713 334 335 721 o 410 b13 NH N NH NH 715 342 343 722 F 414 15 NH 715 362 363 723 o 420 15 0 21 F 716 372 373 724 o 428 -76 p NrH ~NH 'N O' NH 717 376 377 725 HN - 511 0 12 -/N Method J 30 R'sR30 /- N:C:0 'N 0JR H2N HN-R OHC RI'- N ' N-R ' 1's. N NR

CH

2 CI H H HNR N H N-Boc N-Boc NH J1 J2 J3 5 Method J, Step 1: Diethylaminomethyl polystyrene resin (5 eq) was added to a solution of J1 (TFA salt, R 1 = CH 2 (3-CIC 6

H

4 ) and R 3 = CH 3 ) in CH 2

CI

2 and the suspension was agitated. After 15 min, the mixture was filtered and the resin was washed with 10 CH 2 Cl 2 (4x). The filtrate was concentrated to afford the free base. A solution of

R'

5 NCO (R 15 = butyl) (2 eq) in CH 2 Cl 2 was added to the free base of J1 (R' =

CH

2 (3-CIC 6

H

4 ) and R 3 = CH 3 ) (0.021 mmol) in 1:1 CH 3 CN:THF. The suspension was agitated overnight. Polystyrene isocyanate resin (45 mg, 3 eq), polystyrene trisamine resin (40 mg, 6 eq) and a 1:1 mixture of CH 3 CN:THF (0.5 mL) was 15 added. The mixture was agitated for 6 h. The suspension was filtered and the filtrate was concentrated to afford J2 (R' = CH 2 (3-CIC 6

H

4 ), R 3 = CH 3 , and R 15 =

CH

2 CH2CH 2

CH

3 ). Method J, Step 2: -77 Compound J3 (R' = CH 2 (3-CIC 6 H4), R 3 = CH 3 , and R' =

CH

2

CH

2

CH

2

CH

3 ) was prepared from J2 (R' = CH 2 (3-CIC 6

H

4 ), R 3 = CH 3 , and R 15 = CH 2

CH

2

CH

2 CH3) following the procedure described in Method H, Step 2. 5 The following compounds were prepared using similar method. Obs. Obs. # Structure MW # Structure MW m/e W/e N O 726 323 324 731 377 378 ONNH 727 337 338 732 413 414 O 0 NH 728 352 733 417 418

F

-78 N H 729 0 358 734421 422 F 730 a NH~ 45 2 730 365 366 735 425 426 Method K R3 R' 5 S0 2 CI 0 0P R 3 0 0 0 R 3 0 H2NPS-DIPEA R15 R15 N HN N'R' HN N' H HN N-Ri N,Boc N'Boc NH K1 K2 K3 5 Method K, Step 1: A solution of propyl R' 5 S0 2 CI (R' 5 =Propyl)(1.5 eq) was added to a suspension of polystyrene diisopropylethylamine resin (18 mg, 3.45 mmol/g, 3 eq) and the free base of KI prepared using method H (R' = CH 2 (3-CIC 6

H

4 ) and 10 R 3 = CH 3 ) (0.021 mmol) in 1:1 CH 3 CN:THF. The suspension was agitated overnight. Polystyrene isocyanate resin (45 mg, 3 eq), polystyrene trisamine resin (40 mg, 6 eq) and a 1:1 mixture of CH 3 CN:THF (0.5 mL) was added. The mixture was agitated for 6 h. The suspension was filtered and the filtrate was -79 concentrated to afford K2 (R' = CH 2 (3-CIC 6

H

4 ), Ra = CH 3 , and R 15

=CH

2

CH

2

CH

3 ). Method K, Step 2: 5 Compound K3 (R' = CH 2 (3-CIC 6

H

4 ), R 3 = CH 3 , and R 15 = CH 2

CH

2

CH

3 ) was prepared from K2 (R' = CH 2 (3-CIC 6

H

4 ), Ra = CH 3 , and R 1 5 = CH 2

CH

2

CH

3 ) following the procedure described in Method H, Step 6. The following compounds were prepared using similar method. Obs. Obs. Structure MW # Structure MW NH 'N NH ,0 \ NH

-

C 736 0 0 316 317 740 - 442 443 NH 737 344 345 741 Si 454 455 0 Ws| -80 NH O= Nf NH ~~NH a NH HNO 738 372373 42 0 492 493 NNH 738 O 372 373 742 0 0 Method L (1) NH S NH 2

OH

2 N' HN N'Z R 15

CO

2 H N PS-EDC

R

4

R

3 (2) TFA R 4 0 HOBT 7 911 12 00 L1ho L2 H ) R o NH R2 RNH HN N' ' HN N-Z R3 PS-EDC

R

4 R3 ()F R 0 HS L4 5 (In the scheme, -Z-NH-C(0)R 16 - is equivalent to R' substituted by R 21 , or 2515 R' Subsitituted by alkyl-R22, wherein R 21 and R 22 are -N(R' 5

)C(O)R

16 and R15 is H, and wherein Z is optionally substituted alkylene-arylenen, alkylene-arylene- -81 alkylene, alkylene-heteroarylene, alkylene-heteroarylene-alkylene, alkylene cycloalkylene, alkylene-cycloalkylene-alkylene, alkylene-heterocycloalkylene, alkylene-heterocycloalkylene-alkylene, arylene, heteroarylene, cycloalkylene or heterocycloalkylene) 5 Method L, Step 1: A solution of L1 (R 3 = CH 3 and R 4 = CH 2

CH(CH

3

)

2 ) (1 eq) and Z = -para methylene-benzyl) (1.05 eq) in CH 2 C1 2 was stirred at rt. The reaction solution was concentrated and purified via flash chromatography. The material was 10 treated with 50% trifluoroacetic acid in CH 2 Cl 2 for 30 min. The solution was concentrated. The residue was dissolved in 1 N HCI (1 OmL) and washed with ether (2x). A saturated solution of Na 2

CO

3 in H 2 0 was added to the aqueous phase until the solution became basic. The solution was extracted with CH 2

CI

2 (3x). The CH 2 Cl 2 extracts were combined, dried over Na 2

SO

4 , filtered and 15 concentrated to yield L2 (R 3 = CH 3 , R 4 = CH 2

CH(CH

3

)

2 , Z = para

(CH

2

)C

6

H

4

(CH

2 )-). Method L, Step 2: Compound L3 (R 3 = CH 3 , R 4 = CH 2

CH(CH

3

)

2 , Z = para-(CH 2

)C

6

H

4

(CH

2 )-, 20 R '= CH 2

CH

2

CH

2

CH

3 ) was prepared from L2 (R 3 = CH 3 , R 4 = CH 2

CH(CH

3

)

2 , Z = para-(CH 2

)C

6

H

4

(CH

2 )-) following the procedure described in Method I, Step 1. Method L, Step 3: Compound L4 (R 3 = CH 3 , R 4 = CH 2

CH(CH

3

)

2 , Z = para-(CH 2

)C

6

H

4

(CH

2 )-, 25 R' = CH 2

CH

2

CH

2

CH

3 ) was prepared from (R 3 = CH 3 , R 4 = CH 2

CH(CH

3

)

2 , Z = para-(CH 2

)C

6

H

4

(CH

2 )-, R' 6 = CH 2

CH

2

CH

2

CH

3 ) following the procedure described in Method A, Step 3. The following compounds were prepared using similar method. 30 -82 Obs. Obs. Structure MW # Structure MW Obs NNNH 743 0 316 317 761 0 450 451 NH o NH NH 744 N NH 316 317 762 N 450 451

-

NH 740 N 330 331 763 450 451 746 0 330 331 764 NH 450 451 -83 NH NH 747 344 345 765 464 465 TNHH 749 358 359 767 470 471 -84 NHH NH 750 358 39 768 478 47 751 386 387 769 478 479 NHH 752 0 386 387 70 8 8 753 0 386 387 771 NH 484 485 NH -f -85 754 400 401 772 492 493 755 NH 400 401 773M 492 493 756 420 421 774 519 520

NH

-86 0 758 434 435 776 53 3 759 0 436 437 777 533 534 760 0 436 437 -87 Method M S sH R2 )k ',NH 2 ,N:: R5 " NRls HN N-Z R 15 HN N-Z HN N-Z' R 3 4-4 R 3 _~~ 0 R- 0

R

4 0 R 4 0 R 4 0 M1 M2 M3 (In the scheme, -Z-NH-C(O)-NHR' 5 - is equivalent to R' substituted by 5 R 2 1, or Ri Subsitituted by alkyl-R 22 , wherein R 2 1 and R22 are -N(R' 6

)-C(O)-NHR'

5 and R1 6 is H, and wherein Z is optionally substituted alkylene-arylenene, alkylene-arylene-alkylene, alkylene-heteroarylene, alkylene-heteroarylene alkylene, alkylene-cycloalkylene, alkylene-cycloalkylene-alkylene, alkylene heterocycloalkylene, alkylene-heterocycloalkylene-alkylene, arylene, 10 heteroarylene, cycloalkylene or heterocycloalkylene) Method M, Step 1: Compound M2 (R 3 = CH 3 , R 4 = CH 2

CH(CH

3

)

2 , Z = para-(CH 2

)C

8

H

4 (CH2)- , R= 3,4-difluorophenyl) was prepared from M1 (R 3 = CH 3 , R 4 = CH 2

CH(CH

3

)

2 , 15 Z = para-(CH 2

)C

6

H

4 (CH2)-) following the procedure described in Method J, Step 1. Method M, Step 2: Compound M3 (R 3 = CH 3 , R 4 = CH 2

CH(CH

3

)

2 , Z = para-(CH 2

)C

6

H

4

(CH

2 )-, 20 R' 5 = 3,4-difluorophenyl) was prepared from M2 (R 3 = CH 3 , R 4 = CH 2

CH(CH

3

)

2 , Z = para-(CH 2 )C6H 4 (CH2)- , R' 5 = 3,4-difluorophenyl) following the procedure described in Method A, Step 3. NMR(CD 3 0D) 8 7.45, m, 1 H; 8 7.26, m, 4H; 7.24, m, 1 H; 6 6.96, m, 1 H; 8 4.8, m; 8 4.3, s, 2H; 8 1.69, m, 2H; 8 1.44, m, 1 H; 8 1,37, s, 3H; 8 0.8, m, 3H; 8 0.63, m, 3H. ES_LCMS (m/e) 430.27 25 The following compounds were prepared using similar method. Obs. Obs. # Structure MW # Structure MW Wle rn/s -88 778 NH 331 332 870 461 462 NN 779 359 360 871 461 462 NH NH 0 0a 780 359 360 872 a > 461 462 781 NH 373 374 873 461 462 NH -fNH

NNH

-89 782 373 374 874 NH 463 464 783 NH 373 374 87546 47 HO

HN

0 785 387 388 877 467 468 NH

N

-90 786 387 388 878 469 470 387 388 878N-f NH NH 787 387 388 879 469 470 -91 aI HO HN 788 \NH 387 318 MO 471 472 NNH NH NHH 789 NH 401 402 881 471 472 790 401 402 882 472 473 -92 NNH 791 F45406 883 NH 472 473 792 NH 407 408 884 475 476 NH 47 40 HN0 793 47408 885 NH475 476 0 -93 Q a HN HN HN O0 0 794 407 408 886 475 476 NH HN HN o NHH NH 796 9 N H 413 414 888 475 476 -94 a a 797 418 419 889 NH 475 476 HN H NH 798 NH 418 419 890 475 476 HNHb H o HN HN HN o 799 H 421 422 891 475 476 0N

NH

-95 800 421 422 892 475 476 a HN 801 421 422 893 475 476 NH N HN a 802 421 422 894 475 476 SNNH 0 NH -96 ovv 803 NH 421 422 895 f 475 476 HN \ HN HNHN HN 804 421 422 896 NH 477 478 NH O NH NH N HN 805 421 422 897 477 478

NH

-97 HN HN 806 421 422 898 479 480 N NH NH 0 b HN HN o 807 0JNf 423 424 899 479 480 0 N-f NH NH O NH 808 NrNH 423 424 900 0yJ 480 481 -98 809 423 424 901 483 484 810 ~ L< 423 424 90248 44 HN HN Br

HN

0 H HN O HN o 811 425 426 903 485 486 HNH NH

NH

-99 F Br HN HN HN o HN 812 425 426 904 485 486 0 NfNH N N H NHNH HN HN o 813 o 427 428 905 485 486 0 N--NH NH HN HN O, 814 429 430 906 485 486 N NH O

NH

-100 F *9 815 429 430 907 485 486 816 F 429 430 908 489 490 0a 04 HN 4 4HN 818432 433 90 489 490

NH

- 101 HNN 819 432 433 911 491 492 HNH 0 NH .K\NH F F F F HN HN 820 0 433 434 912 493 494 NH

NH

- 102 F F F HN H OF - oHN 821 NH 433 434 913 493 494 NH NH F 822 435 436 914 0 493 494 ' NH 823 435 436 915 F 4 494 - 103 0 824 435 436 916 496 497 HN HN O NH 825 435 436 917 496 497 NH HN HN NH 826 435 436 918 497 498

NH

- 104 HN N

HN

0

HN_

0 827 435 436 919 497 498 0 -fNH 0 N-fNH NH NH 828 435 436 920 499 500 829 NH 437 438 921 501 502 o=

K

-105 830 437 438 922 NH 501 502 0H HNZ HN O 831 437 438 923 N 502 503 NH 0 NH F F FN HA 0~ ~ 832 437 438 924 502 503 FQ

F

- 106 0 HN'2 NNH .3N 437 438 925 N N 502 503 HNH O NH F HN 0 0 HN00

HN

0 F 835 - 437 438 927 N 503 504 ONH

N

- 107 F HN HN~ HNH 836 439 440 928 NH 505 506 NH NH F F Fq W HN HN :zO HN 837 439 440 929 NH 507 508 NHH N FH FF 838 439 440 930 507 508 a a -108 839 NH 441 442 931 N 507 508 HNQ HN 0uNH 840 N 441 442 932 509 510 NH ( HN HN O 841 441 442 933 N NH 509 510 NH =1NH 0 - 109 c HN HN o N 842 441 442 934 509 510 N H F 843 443 444 935 510 511 ... NH 4 936 NH 511 512 - 110 F HN HN 845 443 444 937 NH 511 512 Ngf N-NH 0 NH O NH 846 NH 447 448 938 N-fNH 514 515 H0 HN 847 447 448 939 515 516 N0 NH 01

NH

848 449 450 940 Nf515 516 -0 849 450 451 941 519 520 0 NH 850 N 450 451 94251 52 - 112 N HN N NH NH 851 450 451 943 NH 522 523 0 NH NH 852N 451 452 944 523 524 a a HN HN O 853 451 452 945 523 524 O NfNH

NH

- 113 0 >=o 0 '- NH HN 854 451 452 946 525 526 NH 0 HN O HN HN 855 452 453 947 \ NH 527 528 NH 0 NH 08NH F 856 453 454 948 NfH 529 530 - 114 NK NH 857 F 453 454 949 533 534 NH 5 F NH 858 455 456 950 537 538 ,- NNH NH 859 455 456 951 539 540 NH 860 NH 455 456 952 543 544 -115 HN ~HNO HN 861 457 458 953 NH 545 546 N NH NH NHH NHi O NH F6 F HN HN O 862 457 458 954 F-C 545 546 O NH F F

F

- 116 HN 863 N NH 457 458 955 547 548 0 ~NH F F N Or NH 864 ( 458 459 956 549 550 HNH 865 NH 58 459957 0 a\ 5354 - 117 HN6 HN O 866 460 461 958 NH 555 556 o<NH F 867 o461 462 959 559 560 00 a a H 0 0 HN O ' NH 868 o 461 462 960 559 560 N NH F NH 6F

F

- 118 a 0 0 869 NH 461 462 961 r 38 Method N 0 0 s : R . NH2 HN' R16 R HN' 16 HN ) NH N N HZW' H R 16 S0 2 CI HN NZ HN N'Z R 4 \0 Rl 0 R 4 0 Ni N2 N3 5 (In the scheme, -Z-NH-S(0) 2 R* - is equivalent to R' substituted by R 21 , or R' Subsitituted by alkyl-R22, wherein R 21 and R22 are -N(R' 6 )-C(O)-NHR 15 and R 16 is H, and wherein Z is optionally substituted alkylene-arylenen, alkylene arylene-alkylene, alkylene-heteroarylene, alkylene-heteroarylene-alkylene, alkylene-cycloalkylene, alkylene-cycloalkylene-alkylene, alkylene 10 heterocycloalkylene, alkylene-heterocycloalkylene-alkylene, arylene, heteroarylene, cycloalkylene or heterocycloalkylene) Method N, Step 1: Compound N2 (R 3 = CH 3 , R 4 = CH 2

CH(CH

3

)

2 , Z = para-(CH 2 )CeH 4

(CH

2 )-, 15 R 16 = CH 2

CH(CH

3

)

2 ) was prepared from N1 (R 3 = CH 3 , R 4 = CH 2

CH(CH

3

)

2 , Z = para-(CH 2

)C

6

H

4

(CH

2 )-) following the procedure described in Method K, Step 1. Method N, Step 2: Compound N3 (R 3 = CH 3 , R 4 = CH 2

CH(CH

3

)

2 , Z = para-(CH 2

)CH

4

(CH

2 )-, 20 R' 6 = CH 2

CH(CH

3

)

2 ) was prepared from N2 (R 3 = CH 3 , R 4 = CH 2

CH(CH

3

)

2 , Z = - 119 para-(CH 2 )CeH 4

(CH

2 )-, R 1 = CH 2

CH(CH

3

)

2 ) following the procedure described in Method A, Step 3. The following compounds were prepared using similar method. Obs. Obs. # Structure MW Structure MW n/e W/e o=~4j.0 962N NH 380 381 967 484 485 NHN 963 0 ~~380 381 968 484 485 NH v 395 98 964 394 395 969 0( 498 499 - 120 O~ NHfN 965 394 395 970 498 N O HNO 966 - 451 452 0N-fNH NH Method 0 - 121 TBSCI .BuLl N Imidazole TBSO THF TB H CH 2

CI

2 -78 "C SO 01 02 03 BuLlO(O SO2 rS0C - T B S O . O2N T S OS THF

CH

2 C2 .. -78 'C 0157o o 'C 04 05 S TBAF - TBSO -T CH2C THF S O

CH

2

CI

2 S 06 07 SOC SlLI2 - NaN 3 N, S C N CH30H 0

CH

2

CI

2 4HO 08 09 H2 H 2 N SO' LIOH H 2 N S PdC %O CH 3

H/H

2 0 H

HCVCH

3 0H 010 011 Method 0, Step 1: A solution of indole-6-methanol (400 mg, 2.72 mmol), tert 5 butyldimethysilyl choride (816 mg, 5.41 mmol) and imidazole (740 mg, 10.9 mmol) in CH 2 C1 2 was stirred at rt. overnight before the solvent was evaporated and residue chromatographed using ethylacetate/hexane to give product 02.

-122 Method 0, Step 2: To a solution of 02 (200 mg, 0.77 mmol) in THF (10 mL) at -78 *C was added butyl lithium (1.2 eq). The solution was stirred at -78 *C for 5 min and then warmed to rt. The reaction mixture was cooled to -78 0C and p 5 toluenesulfonyl chloride was added. The solution was warmed to rt and stirred overnight. The reaction was quenched with a saturated aqueous K 2 CO3 solution, extracted with ethyl acetate and CH 2

CI

2 . The crude material was purified via flash chromatography using ethylacetate/hexane to afford 360 mg of 03. 10 Method 0, Step 3: A solution butyl lithium (1.2 eq) was added to a solution of 03 (340 mg, 0.829 mmol) in THF (20 mL). The reaction mixture was stirred for 15 min at -78 0C then sulfur dioxide was bubbled through the solution for 15 min. Hexane 15 (100 mL) was added to the reaction mixture. The reaction mixture was evaporated to afford 04 which was used in the next step without further purification. Method 0, Step 4: 20 To a solution of 04 (0.829 mmol) in CH 2 Cl 2 cooled to 0 *C was added N chlorosuccinimide (220 mg, 1.66 mmol). After 2 h of stirring, the solution was filtered through a Celite plug. The filtrate was concentrated to afford 05. Method 0, Step 5: 25 To a solution of 05 in anhydrous pyridine (3 mL) was added butyl amine (100 pL). The reaction was agitated at rt for 4 d. The reaction mixture was partitioned between 1 N HCI and CH 2 0 2 . The organic layer was separated and washed with 1 N HCI (3x). The organic solution was dried over Na 2

SO

4 , filtered and concentrated. The crude material was purified via flash chromatography 30 using ethylacetate/hexane to yield 06. Method 0, Step 6: - 123 To a solution of 06 (70 mg) in THF was added TBAF. The reaction was stirred at rt. before the reaction mixture was chromatographed using ethylacetate/hexane to afforded 50 mg of 07 (95%). 5 Method 0, Step 7: To a solution of 07 (50 mg) in CH 2 Cl 2 (5 mL) was added thionyl chloride (1 mL) the reaction was stirred for 5 min and then evaporated to afford 08. Method 0, Step 8: 10 To a solution of 08 in CH 3 OH (5 mL) was added sodium azide (50 mg). The solution was stirred at rt overnight and solvent evaporated. The residue was chromatographed using ethylacetate/hexane to afforded 09 after purification. Method 0, Step 9: 15 To a suspension of 09 (70 mg) in CH 3 0H was added 1 eq HCI (aq) and palladium on carbon. The reaction mixture was hydrogenated at 1 atm for 20 min to yield 90 mg of crude product 010. Method 0, Step 10: 20 A solution of lithium hydroxide (30 mg) in H 2 0 was added to a solution of 010 (40 mg) in CH 3 0H (3 mL). The reaction was stirred at rt for 2 h and an additional portion of LiOH (40 mg) was added and solution was stirred for 2 more hours. The solvent was evaporated and residue chromatographed using ethylacetate/hexane to afforded 011. 25 Method P - 124 R2N3rHN N H.. HNCb Cbz Cbz 'BoC NH 2 C P1 P2 P3 P4 I R23 N HNA - K-NH 2 0 PS Method P, Step 1: A 300 mL of THF solution of 100 g of P1 (R"=n-Pr) was added to a 5 suspension of 38 g of LAH in 2 L of anhydrous THF at 0 C. The reaction mixture is stirred at r.t. for 1 h before 30 ml of H 2 0, 90 ml of 15% NaOH was added at 0 *C. The mixture was stirred at r.t. for one hour before Na 2

SO

4 (anh) was added, the mixture was filtered, and the solution evaporated to give a product which was dried under vacuo overnight. This product was dissolved in 600 ml of DCM and 10 the solution was added into a solution of oxalyl chloride (37.3 ml) and DMSO (60.8 ml) in 1.4 L of DCM at -78 *C over 40 min before Diisopropylethylamine (299 ml) was added at -78 *C. The reaction was allowed to reach -10 *C. The reaction was quenched with 1 L H 2 0 at -10 0C and the mixture was extracted with DCM. After removal of solvent, P2 (R"=Pr, 106 g) was obtained. The 15 crude material was used for next step without purification. Method P, Step 2: To a 1.5 L DCM solution of P2 (R2=Pr, 106 g) was added p-Boc aminomethylbenzylamine (1.1 eq) and sodium triacetoxyborohydride (1.1 eq) and the reaction was stirred at r.t. overnight. The reaction was quenched with 20 H 2 0 and content extracted with DCM. After removal of solvents the residue was chromatographed using a silica gel column eluted with 3% MeOH in DCM to give 42.5 g of P3 (R =Pr). Method P, Step 3: 25 A 10 ml MeOH solution of P3 (R 23 =Pr, 110 mg) was hydrogenated using Pd/C (5%, 11 mg) at 1 atm of hydrogen to give product P4 (R 23 =Pr) after removal of solvent and catalyst.

-125 Method P, Step 4: To a 10 ml DCM solution of P4 at 0 OC (R 2 3 =Pr) was added triphosgene ( 1.2 eq) and triethylamine (2.4 eq) and the solution was stirred at 0 C for 2 h before the reaction was extracted with DCM/H20. After removal of the solvent, 5 the residue was chromatographed using a silica gel column eluted with EtOAc/Hexane to give a white solid which was treated with 2N HCI in dioxane for 2 h. After removal of the solvent, compound P5 (R 2 3 =Pr) as a white solid was obtained (80 mg). 10 The following compounds were synthesized using similar methods: - NH 2

NH

2 HNA'. NH 2 > 11 NH 2 P5 P6 P7 P8 Method 0 15

R

4 om01

R

4 0 R4 0, R4 m 1 MRaO m=0,1 R2NH 2 R3m= + H 2 N Njf Z .-2 HN N ',' flOItH n=,1,2 R n01,2 ROH n=0,1,2 01 08 02 03 (Boc) 2 0 DIEA

CH

2

CI

2 R4 M R4 0 =O R4 0 -' N N fNC(O)R5 OtD N N H 10%Pd-CL N N 1,2 p=0,1,2 yH 2 __P-,, N p=,, PSEDC N 1.2n=,1,2 Bc.R Boc' 'R 2 Boc R 2 'R 06 05 04 1 TFA W 0 HN N N-C(O)RI5 N' R2 n=0,1,2 07 -126 Method 0, Step 1 At room temperature, 01 (R 3 =Me; R 4 = iBu) (1.00 g) and 08 (n=1, p=2, m=1) (1.24 g) in dichloromethane (30 mL) were stirred for 42 h. This mixture was concentrated in vacuo to give an amber oil which was purified on a column of 5 silica gel (200 mL) eluted with ethylacetate/hexane to give 02 (n=1, p=2, m=1,

R

3 =Me; R 4 = iBu), a colorless oil (1.59 g). Method 0, Step 2 Compound 03 (n=1, p=2, m=1, R 2=H, R =Me; R 4= iBu) was prepared 0 from 02 (n=1, p=2, m=1, R 3 =Me; R 4 = iBu) using method similar to method A step 3. Method 0, Step 3 Compound Q3 (n=1, p= 2 , m=1, R 2 =H, R 3 =Me; R 4 = iBu) (1.37 g) in 5 anhydrous dichloromethane (25 mL) was treated with di-tert-butyl bicarbonate (0.68 g, 1.1 equiv.) and diisopropylethylamine (0.66 mL, 1.1.equiv.). The resulting solution was stirred at room temperature for 20 h before it was diluted with dichloromethane and washed with 1 N hydrochloric acid. The dried dichloromethane solution was concentrated in vacuo to give a colorless film 10 (1.32 g) which was purified on a column of silica gel (125 mL) and eluted with hexane : ethyl acetate to give compound 04 (n=1, p=2, m=1, R 2 =H, R 3 =Me; R 4 = i-Bu ) as a white foam (0.74 g). Method 0, Step 4 5 Compound 04 (n=1, p=2, m=1, R 2 =H, R 3 =Me; R 4 = 'Bu) (0.540 g) in absolute EtOH (20 mL) was hydrogenated with 10% Pd/C (0.400 g) at 1 atm for 2 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give 05 (n=1, p=2, m=1, R 2 =H, R 3 =Me; R 4 = 'Bu) as a colorless oil (0.35 g). 0 Method 0, Step 5 Compound 05 (n=1, p= 2 , m=1, R 2 =H, R 3 =Me; R 4 = iBu) (0.012 g) and HOBt (0.005 g) dissolved in acetonitrile (0.8 mL) and tetrahydrofuran (0.25 mL) was treated with EDC resin (0.080 g, 3 eq., 1.53 mmoVg) in a microtiter plate - 127 well followed by addition of a 1 M dichloroethane solution (40uL, 1.25 eq.). After the well was capped and shaken for 18 h, the mixture was filtered and the resin washed with acetonitrile (0.5 mL). The combined solution was treated with Trisamine resin (0.050 g, 6 eq., 4.23 mmol/g) and Isocyanate resin (0.067 g, 3 5 eq., 1.53 mmoVg) for 18 h before the solution was filtered and the solvent was removed in vacuo to give 06 (n=1, p=2, m=1, R 2 =H, R 3 =Me; R 4 = 'Bu, R 15 = Me). Method Q, Step 6. A dichloromethane solution (1.0 mL) of 06 (n=1, p=2, m=1, R 2 =H, 10 R 3 =Me; R 4 ='Bu, R1 6 = Me) was mixed with trifluoroacetic acid (1.0 mL) and the solution was shaken for 2 h before it was concentrated. Diethyl ether (0.5 mL) was added and then concentrated in vacuo to give a residue, which was was purified on a Prep LCMS unit to give 07 (=1, p=2, m=1, R2=H, R 3 =Me; R 4 = iBu,

R

15 = Me). NMR (CDCl 3 ): 8 8.38, br, 2H; 8 4.56, m, 1 H; 8 3.79, m, 1 H; 8 3.57, m, 15 2H; 8 2.99, m, 1H; 8 2.48, m, 1H; 8 2.04, s, 3H; 8 1.95, m, 1H; 8 1.5-1.8, m, 5H; 8 1.5, s, 3H; 1.25, m, 2H; 5 0.95, m, 3H; 8 0.85, m, 3H. ESLCMS (m/e) 309.17. The following compounds were prepared using similar methods: Obs. Obs. # Structure MW # Structure MW N NH N 971 NN 308 309 1074 428 429 NH NHH NfNH - 128 0 NN SN NH 0 -0o 972. NH 308 309 1075 Ni-i 428 429 0< N 973 NH 310 311 1076 N28 429 0 N 974 N NH 322 323 1077 128 429 0 NH4.N 975 324 325 1078 0 N NH 428 429

NH

- 129 0 0 - NH 976 N NH 334 335 1079 NH 430 431 o= NH 977 NH 336 337 1080 0 NH 430 431 0 NH 0 NNH NH 978 N H 348 349 1081 N NH 430 431 0 NH 01NH - 130 s NH 979 N 348 349 1082 o NfNH 432 433 NH HN 980 0 N .NH 0 351 1083 432 433 NH 1084 981 0 350 351 432 433 N C NCN NH 982 350 351 1085 432 433 N NH

O

- 131 N 983 360 361 1086 432 433 N N NH 984 NH360 361 1087 Nf 432 433 N 986 362 363 1089 438 439 N 9865 N 362 363 1088 438 439 N-.(O NH NH NHNH NNH 0 N-f N -132 0 0 N NH 987 364 365 1090 438 439 0 988 NH 364 365 1091 438 439 989 NH364 365 1092 NH 438 439 N O NH 990 N NH 370 371 1093 440 441 O HNH -133 991 N NH 370 371 1094 440 441 N 992 s 376 377 1095 440 441 994 s 376 377 1097 442 443 0H 0 10 N 994 376 377 1097 442 43

NH

- 134 O 9 N 3 N 995 O N NH 378 379 1098 442 443 0 NH NN NN 996 /NH 378 379 1099 NH 442 443 Of H 997 O NH 378 379 1100 442 443 0 0 - 135 Qo HN N 998 N NH 378 379 1101 442 443 0 0 N NH 999 ifNH 379 380 1102 N444 445 NNH 0 O Os NN 1000 384 385 1103 444 445

NNH

- 136 1001 N o N- 8 8 14044 45 NH HNH 1003 05N N386 387 1105 H~ 446 447 0 QNH 1004 388 3897 1744 4 -137 N NH 10065 NHN 3890 391 1109 451 452 1007 N NH 390 391 1110 O H 452 453 NH

NHN

-138 0 1008 390 391 1111 N NH 452 453 N- NH N NH 1009 NH 39 391 1112 N N NH 452 453 o 0O 1010 390 391 1113 NH 456 457 O NH 1011 NH 390 391 1114 456 457 - 139 1012 390 391 1115 \N 456 457 o o 9 1013 390 391 1116 458 459 0 1014 o 390 391 1117 460 461 SNNH 0NNH NH NH \ &_ N H 1015 392 393 1118 \0 460 461 0 NH -140 1016 392 331119 N 6046 0 1019 NH 392 393 1120 N N 460 461 0 NyN0 NHH NNH N N 101H 398 399 112H 462 463 0N-f 0~N NH 0 -NH 0 N - 141 0P 100 98 39 12 42N6 -~ ~ p-NH 383912 6 6 0 NNH 1021 NH 398 399 1124 0 462 463 NH 1022 N 398 399 1125 _ Q 462 463 - 142 0 NH 1023 398 399 1126 NH 464 465 0 NH O 0 O N 1024 400 401 1127 0 466 467 P.H 0 NH 0 N N 1025 (S) 400 401 1128 466 467 0 N-fNH

NH

- 143 0 0 1026 NH 400 401 1129 470 471 0N-.NH NH 0 NH N 1027 N 400 401 1130 472 473 0 NH\ 00 NHQ 1028 NH 400 401 1131 474 475 N-f NH 0 NH 0 NH - 144 0 1029 NH400 401 113247 45 1030 0 400 401 1133 476 477 NH 0 NHN 1031 0 0 401 1134 0 - N.,NH 476 477 o~(NHNH 0NH - 145 0 0 NH O O NH 1032 NH 402 403 1135 478 479 0 NH0N fH NH Ot NH 1033 402 403 113648 43 1034 404 405 1137 ~ K 482 483 0N-fNH

NH

- 146 N 1035 NH 404 405 1138 482 483 0 N hQ N 1036 NfNH 404 405 1139 0 NH 488 489 N 1037 O NH 404 405 1140 0 490 491 - 147 NH 1038 H404 405 1141 M - 0DF500 501 N 0 NH NHH 1040 ? o 404 405 1143 502 503 NH 1041 zi 404 405 1144 0 504 505 - 148 1042 NH 409 410 1145 504 505 1043 410 411 1146 504 505

-

~ ~ ~ -9 0 4, ,4 N51 1 $NH 1044 0 411 1147 f 511 512 1045 . 410 411 1148 512 513 - 149 0 N N 1046 NH 412 413 1149 N NH 512 513 0 0 NH 51 53 1047 412 413 1150 520 521 1048 412 413 1151 520 521 - 150 0 0 N N 1049 41 4 415 1152 NNH 520 521 NH Qo o 1N5 1050 0 - H414 415 1153 NfH 52 51 =5)N NH 52 51 NH 1051 '= NH414 415 115452 53 - 151 0 N 1052 414 415 1155 NH 522 523 1052 ) N. 'H 0 N0 NH NHN 1053 414 415 1156 536 537 0 k0 N o NH 1054 414 415 1157 536 537

NHH

- 152 0 -0 1055 NH 414 415 1158 0 11 fNH 536 537 NNH Ol 9 0 'NH NH 1057 0 NH 416 417 1160 NH 8 53 0NH0 -N f~lt

NH

-153 <>F NH5 417 418 1161 INH 540 541 Q O p NH NHN 1059 N NH 418 419 1162 N H Br 541 542 0 NH 0 N 1060 NH 418 419 1163 542 543 0 - 154 N NH 1061 NH 418 419 1164 546 547 OH N 1062 418 419 1165 NH 546 547 N3 4 07 f 0NH 103418 419 1166 550 551 -155 N 1064 420 421 1167 NH 550 551 N 0NH 1065 N 423 424 1168 N H 569 570 0 0 N NH 1066 NH 424 425 1169 582 583 N= 1066 82 NH -156 o1 N 1067 424 425 1170 NNH 582 583 0 0 N 1068 NH 426 427 1171 584 585 0 NNH N O O 1069 NH 426 427 1172 N H 584 585 -157 Q - NH 1070 426 427 1174 594 595 *-- *1 NH 1072 426 427 1173 596 597 1071 426 427 1174 -fN 596 597 00 - 158 N 1073 427 428 oNH Method R R 3 m=,1 R0 m ,1 Ris R O rn,1 R1R NH R N N N C0)-NH HN N., N(C NH N~N 4 p=0,1,2 lp0,1,2 TE& NIA l, Bo N n=0,,2 NBoc n=,,2 NR2 n=0,1,2 5 R1 R2 R3 Method R, Step 1. A solution of R' (n=1, p=2, m=1, R 2=H, R 3=Me; R 4= 'Bu) (0.010 g) in acetonitrile (0.85 mL) and dichloroethane (0.15 mL) was put into a microtiter 10 plate well followed by addition of 0.12 ml of 0.5M phenylisocyanate solution in dichloroethane. The well was sealed and the plate shaken for 20 h before the mixture was filtered and the solid washed with acetonitrile (0.5ml). The combined solution was treated with Trisamine resin (0.050 g, 6 eq., 4.23 mmoVg) and Isocyanate resin (0.067 g, 3 eq., 1.53 mmol/g) and the mixture was 15 shaken for 18 h. The mixture was filtered and the solution was evaporated to give the R2 (n=1, p=2, m=1, R 2 =H, R 3 =Me; R 4 = 'Bu and R' 5 =Ph). Method R, Step 2.

-159 Procedure similar to Method Q, step 6 was used for the transformation of R2 (n=1, p=2, m=1, R 2 =H, R 3 =Me; R 4 = 'Bu and R" 5 =Ph) to R3 (n=1, p=2, m=1,

R

2 =H, R 3 =Me; R 4 = 'Bu and R" 5 =Ph). 5 The following compounds were prepared using similar methods: Obs. Obs. # Structure MW # Structure MW ml~e mfLe oNHN NN NH 1176 O N-N 309 310 1215 419 420 NH 1177 NH 309 310 1216 419 420 1178 o 311 312 1217 421 422 N- F N 1179 o 325 326 1218 421 422 -160 NNH 1180 0 337 338 1219 0 0 425 426 1181 0 346 347 1220 427 428 N 0 3 1182 351 352 1221 427 428 O NH 1184 351 352 1223 429 430 - 161 NH N 0 H2N O NH 1185 36 6 24431 432 0 N-fNH 35 36 12 N NH FN 0 NH 1156 365 366 1225 0 N NH 431 432 8 NH 1187 365 366 1226 433 434 1188 367 368 1227 435 436 0 - 162 NH 1189 377 378 1228 441 442 NH 1190 381 382 1229 441 442 0 HNH 1191 385 386 1230 441 442 N NH 1192 391 392 1231 445 446 - 163 NHO 1193 393 394 1232 a 449 450 1194 395 396 1233 453 454 NH O F NH 1195 399 400 1234 453 454 0 N-fNH NH H 33 1196 o~ 399 400 1235 7 453. 454 -164 NH NH 1197 399 400 1236 453 454 NH N 1198 399 400 1237 453 454 NH 1199 399 400 1238 455 456 1200 0 401 402 1239 455 456 N NH 1201 7 403 404 1240 457 458 -165 F N H NQ N 1202 403 404 1241 \ 461 462 b N 1203 407 408 1242 463 464 N NH 1204 407 408 1243 a 467 468 N H N H 125410 411 1244 a 467 468 N2NH 4 14 1206 410 411 1245 e l 471 472 - 166 NH 1207 413 414 1246 475 476

-

NH NH NH 1208 413 414 1247 NL477 478 0 NH 1209 ii)415 416 1248 477 478 NH 1210 0 415 416 1249 487 488 - 167 HN 0 N 1211 415 416 1250 N- NH 487 488 NH 121 415 416 1251 F F 87 488 1213 N -168 OLN 1214 419 420 Method S

R

4 0 R 0 m=0,1 R 4 0 R3-) NSOR' RF 3.. NR3OR N. N NH R1 5 S0 2 CI TFA N N NSo2R5 p=0,1,2 p=0,1,2 Y p=0,1,2 Boc'N,R2 n=0,1,2 Boc'N'R2 n=0,1,2 Boc'N,R2 n=0,1,2 SI S2 S3 5 Method S, Step 1. A solution of S1 (n=1, p=2, m=1, R 2 =H, R 3 =Me; R 4 = iBu) (0.010 g) in acetonitrile (0.85 mL) and dichloroethane (0.15 mL) was put into a microtiter plate followed by addition of DIPEA-MP resin (0.030 g, 4 eq) and phenylsulfonyl 10 chloride in dioxane (1 M, 45 sL, 0.045 mmol. The well was capped and shaken for 18 h before it was filtered and residue washed with acetonitrile (0.5 mL). The combined solution was treated with Trisamine resin (0.040 g, 6 eq., 4.23 mmoVg) and Isocyanate resin (0.060 g, 3 equiv., 1.53 mmoVg) and shaken for 18 h before the mixture was filtered and the solvent removed to give S2 (n=1, 15 p=2, m=1, R 2 =H, R 3 =Me; R 4 = iBu and R' 5 =Ph). Method S, Step 2. Procedure similar to Method Q, step 6 was used for the transformation of S2 to S3 (n=1, p=2, m=1, R2=H, R 3 =Me; R4= 'Bu and R 15 =Ph). 20 The following compounds were prepared using similar methods: Obs. Obs. # Structure MW # Structure MW We m/e -169 OA 0 1253 N NH 344 345 1293 NH 448 449 0 - N NH NH 0 N H 1254 34 345 1294 454 455 N 1255 N NH 358 359 1295 0 456 457 NH N NH

O=

1256 358 359 1296 0 NH 456 457 -170 0 O 'NH O& NH 1257 0 N NH 360 361 1297 NH 458 459 NH\ 0 ~s-z 0l NH F N O N NH 1258 o NH 372 373 1298 aN458 459 0 NH NH 1259 NH 372 373 1299 N 458 459 0 N NH 1260 0 386 387 1300 462 463 0e - 171 OA 1261 ON NH 4 0 10 464 465 NH HN 0-pN 1262 NfNH 406 407 1302 466 467 o NH 0 N 0 0 NH NH 1263 NH 406 407 1303 0 H 466 467 NNH 1264 412 413 1304 ,o 466 467 - 172 NNH 1265 o 416 417 1305 o46 47 NHH 1266 NH 420 421 1306 470 471 o = 126 NH 40 41 107N N a7 7 NN NH N 1268 420 421 1308 474 475 -173 N N N NH 1269 H 420 421 1309 F 474 475 F NC NH NH 1270 420 421 1310 FF F 7 474 475 F 0 , N a NH ON NH O-~ j 4 ~ 1271 420 421 1311 474 475 0 F N a NN NH N 0 0 N NH 1272 424 425 1312 a 474 475 0 0~0 F--6 00 1273 7 424 425 1313 a 47447 - 174 0-gN a OziN O fNH - O N NH 1274 F 424 425 1314 474 475 NN N 1276 C -z 432 433 13165 474 475 0 1276 432 433 1316 474 475 O~ O N NHa 1277 NH 434 435 1317 0 NH 476 477 NH O-~NC a< NCk 1278 01434 435 1318 a 480 481 -175 0 o-N NH -N NH 1279 436 437 1319 - 482 483 O -NO N O NH NH 1280 436 437 1320 r 484 485 0 0 Nr NH NNH 1281 F 438 439 1321 484 485 00 1282 440 441 1322 NH 488 489 NH NHN 12 3 4 N 1283440 441 1323 Ff H 49 9 F F - 176 O -gN S-N' O N NH NH 1284 NH 440 441 1324 FO 490 491 NH0 1285 442 443 1325 492 493 0 F S-N NcN 1286 F O 442 443 1326 0- 498 499 0 0 F 0' N Nl0-9 F O NH ON NH F 0 0NQ 1287 442 443 1327 a a 508 509 SN -N NH 1288 442 443 1328 F F 508 509 F1 - 177 0 0 '-N O 0S N NH F 0Ny NH 0O H 50 0 1289 F 442 443 1329 a 50N0 b\ N- O N a0 1290 446 447 1330 a 508 509 6 - NH F N NH NH F F NH 1291 448 449 1331 F F 542 543 FjF 1292 448 449 1332 6 fNH 557 558 Method T -178 RS o Rm=,1 R A RaR o m=0,1 R 0 m=0 N N NHo, N N NMR6 N N N R 4 2 p=0,1,2 =,12 p=0,1,2 N n=0,1,2

BOC'N'R

2 n=0,1,2 N n-0,1,2 T1 T2 T3 Method T, Step 1. To a microtiter plate well containing 1 ml solution of T1 (n=1, p=2, m=1, 5 R 2=H, R 3=Me; R 4 = iBu) in DCM (0.010 g) and R 1 5 C(O)R 6 (5 equiv, R 15 =H,

R'

6 =Ph) was added Sodium cyanoborohydride in dichloroethane (14.3 mg / mL, 2 equiv.). The well was capped and shaken for 20h before MP-TsOH Resin (100 mg, 1.29 mmol/g) was added to the well followed by additional MP-TsOH resin (50 mg) after 2 h. After the mixture was shaken for another 1 h, the mixture 10 was filtered and the resin washed with dichloroethane (1 mL) (3 X), then MeOH (1 mL) (2 X).The resin was treated with 7N ammonia in MeOH (1 mL) for 30 min (2X) followed by filtration and evaporation of solvent to give T2 (n=1, p=2, m=1,

R

2 =H, R 3 =Me; R 4 = 'Bu and R'" 5 =Ph and R'6=H). 15 Method T, Step 2. Procedure similar to Method Q, step 6 was used for the transformation of T2 (n=1, p=2, m=1, R 2 =H, R 3 =Me; R 4 = iBu and R' 5 =Ph and R' 6 =H) to T3 (n=1, p=2, m=1, R 2 =H, R 3 =Me; R 4 = 'Bu and R 15 =Ph and R'r=H). 20 The following compounds were prepared using similar methods: Obs. Obs. # Structure MW Structure MW m/e m/e N NH NH 1333 348 349 1339 384 385 - 179 N NH NH 1334 350 351 1340 3B4 385 _/-N N N ,NH N-0 1335 A 1< 350 351 1341 N 400 401 N N NH NNH 1336 356 357 1342 446 447 N N NH N fNH 1337 362 363 1343 448 449 NH 1338 370 371 Method U -180 NR2 R 2 1B(OH) 2 N'R2 'J!, Pd(dppf)C1 2 j11 HN N H ' ' -''

R

3 -- -rtoluene, HIO NR21 Br K 2 C0 3 R 3 4- / R 2 R 0) ' microwave U1 U2 In a microwave vial was charged U1 (R 2 = H; R 3 = i-Bu, R 4 = Me) (0.025 g) 5 in toluene (4 mL), potassium carbonate (0.035 g), Pd(dppf)C1 2 (0.020 g). water (0.02 mL) and R 21

B(OH)

2 (R21 = m-Methoxyphenyl) (3 eq.) were placed. The vial was placed in a microwave for 10 min. at 150 0 C. The reaction mixture was diluted with dichloromethane and extracted with 2.5N NaOH. The dried (MgSO4) dichloromethane solution was concentrated in vacuo to give a brown residue 10 which was purified via a RP Prep LCMS system to give product U2 (R 2 = H; R 3 = 'Bu: R 4 = Me; R 21 = m-methoxyphenyl). The following compounds were prepared using similar methods: 15 Obs. Obs. # Structure MW Structure MW m/e m/e \ NH N-f o 2NH 1344 / /\ 279 280 1381 N. NH 365 366 0

NH

- 181 N NH o NH NH 1345 285 286 1382 365 366 \NH /P -N N NHC o,; NH 0N-.fNH 1346 O \293 294 1383 NH 366 367 NH HN jHN 1347 0 299 300 1384 0 371 372

.

F F/\ H N H 1348 0 299 300 1385 N NH 371 372 = NH F 3 7 1349 N 304 305 1386 F N-f~ 371 372 - 182 NH NfNH HNA o NH / 1350 309 310 1387 -0 \ 372 373 0 -N NH \ NH HN o NH 0 1351 313 314 1388 372 373 a -N jH NH NHN N NH 0 1352 0 318 319 1389 375 376 a 0 1353 323 324 1390 / NH 377 378 0 NH

NH

-183 0 \ NH NH 0 1354 323 324 1391 N- NH 377 378 0 NH NH 0 NH NfN 1355 323 324 1392 377 378 NH O4 NH 1356 329 330 1393 o=fN 377 378 -184 0 AH NH r N NH 1358 s 335 336 1395 0 NHf 379 380 Ao NH N NH HN N-f 0 N 1359 337 338 1396 380 381 0 N H NH 1360 343 344 1397 H N 381 382 a - 185 NH NH HN N' N-f' o NH F 1 1361 347 348 1398 383 384 0 NH 132 \ N-f'~ NH4 19 HN A 1362 a\ 34 4819 384 385 NH H HN o NH a) 1363 /\ '' 347 348 1400 385 386 a 0 HN 'N H 0 1364 o C, 347 348 1401 *-385 386 NH 1365 0347a 348 1402 NH 386 387 -186 H 1366 NH 349 350 1403 387 388 1367 34 3010 0 NH NH NH N N N0 NH N-f NH 1367 O NH 349 350 1404 389 390 F SNH N~fNH NF-L 0 NH 1368 05 5 46OO N 9 9 130 NH 350 351 1405 389 390 F NH 1369 NH 351 352 1406 0N~f NH 0 : NH 39 33 0 NH 1370 -352 353 1407 0 395 396

N

-187 F NHF 0= NH 1371 357 358 1408 403 404 SS F NH NH HN NF NHH 1372 359 360 1409 403 404 F NH 1373 F 360 361 1410 406 406 F 1374 360 361 1411 01406 407 1375 360 361 1412 0 413 414 N NH -188 NH HN NH0 1376 o H 360 361 1413 419 420 1 3 7 NH 1377 N 360 361 1414 497 498 N- ~ NH HN~r 0 NH 1378 I I 360 361 1415 0398 TBD -HN0 NHO 1 365 366 1416 9 399 TBD 0 - 189 0 1380 ' NH 365 366 NH Method V

R

3 R R OHR4H 1) TFA RJ( R A Boc. OH<i Boc N N RI 2) CSCI 2 R N-R1 -N-R S R2'N 5 V1 V2 V3 V4 Method V, Step 1: Compound VI (R 3 = R4 = Me) (14.76mmole), EDCI (14.76mmole), HOAt (14.76mmole), and DIEA (14.76mmole) were mixed with 36 ml DCM. This mixture was stirred at RT for 15min before 3-chlorobenzylamine was added. o After the reaction solution was stirred at RT overnight, it was washed with sodium carbonate (3X), water, 1 N HCI (4 X), and aq sodium bicarbonate and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified on flash column to give the amide product V2 (R' = 3 chlorobenzyl; R 3 = R4 = Me). 5 Method V, step 2 Compound V2 (R 1 = 3-chlorobenzyl; R 3 = R4 = Me) (8.33mmole) was dissolved in 35 ml anhydrous DCM, and cooled to 0-5 2 C. Thiophosgene (9.16mmole) in 1Oml DCM was added dropwise under N 2 followed by addition of 0 DIEA (11.96mmole). The solution was stirred in ice bath for 0.5 h before the reaction mixture was washed with saturated sodium bicarbonate (3 X), brine, -190 and dried over anhydrous sodium sulfate. The solvent was evaporated and residue purified on flash column using ethylacetate/hexane to give the thiohydantoin V3 (R' = 3-chlorobenzyl; R 3 = R 4 = Me). 5 Method V, step 3: The thiohydantoin V3 (R 1 = 3-chlorobenzyl; R 3 = R4 = Me) was treated with t-butyl hydroperoxide and ammonium hydroxide in MeOH at RT for 48 h to give compound V4 (R' = 3-chlorobenzyl; R 2 = H; R 3 = R4= Me). The following compounds were prepared using similar method. 0 Obs. Obs. # Structure MW # Structure MW We m~e 1417 N NH 251 252 1420 0 307 308 NH b-NH N NH NH N. N 1418NH 265 266 1421 NH 357 358 0 NH O NH 1419 0 293 294 1422 NH 371 372 NH N 3 - 191 Method W 0 0 -R2 MeO HO -R2 W1 W2 Compound WI obtained using method A (n=1, R 2 =m-Cl-Bn, R 3 =Me) was 5 hydrolyzed to W2 (n=1, R 2 =m-Cl-Bn, R 3 =Me) using two equivalent of LiOH in MeOH. The following compounds were synthesized in similar fashion: Obs. Obs. # Structure MW s # Structure MW Wie Wle NH 1423 O 295 296 1426 0 411 412 ~NH O OH N N 1424 0 311 312 1427 425 426 0 1425 r: 325 326 -192 Method X S Hs

HN-R

1 7 0 N' R2 0(

NH

2 NCO R S HN N'R17 HN NR7 HN N-Z HNN'Z HN N' R 16 _--. HN N R 16 R4A R3 R 3 +~{ F1 3 -4 R R4 O R4 x1 X2 X3 X4 (In the scheme, -Z-NH-C(O)-N(R 16 )(R") - is equivalent to R 1 substituted 5 by R 21 , or R 1 Subsitituted by alkyl-R 22 , wherein R 21 and R22 are -NH-C(O)

N(R'

1

)(R'

7 ) and R's is H, and wherein Z is optionally substituted alkylene arylenen, alkylene-arylene-alkylene, alkylene-heteroarylene, alkylene heteroarylene-alkylene, alkylene-cycloalkylene, alkylene-cycloalkylene-alkylene, alkylene-heterocycloalkylene, alkylene-heterocycloalkylene-alkylene, arylene, 10 heteroarylene, cycloalkylene or heterocycloalkylene) Method X, Step1: To a mixture of the amine X1 obtained using method L (R 3 = Me; R4 = ' Bu; Z = para-(CH 2

)C

6

H

4

(CH

2 )-) (10 mg) in DCM and sat. NaHCO 3 (1:1 by 15 volume) was added triphosgene (0.33 eq) at r.t. The solution was stirred vigorously for 40 minutes before the organic layer was separated and dried over anhydrous Na 2

SO

4 . The organic solution was evaporated to give compound X2

(R

3 = Me; R 4 = i-Bu; Z = para-(CH 2

)C

6

H

4

(CH

2 )-). 20 Method X, Step2: Compound X3 (R' 5 = H; R 16 = cyclopropylmethyl; R 3 = Me; R 4 ='Bu; Z = para-(CH 2

)CH

4

(CH

2 )-) was prepared from X2 (R 3 = Me; R 4 = i-Bu; Z = para

(CH

2

)C

6

H

4

(CH

2 )- ) using method similar to method M, step 1. 25 Method X, Step3: Compound X4 (R 16 = H; R = cyclopropylmethyl; R 2 = H; R 3 = Me; R4= 'Bu; Z= para-(CH 2

)C

6

H

4

(CH

2 )-) was prepared from X3 (R' 6 = H; R 17 = cyclopropylmethyl; R 2= H; R3 = Me; R4 = 'Bu; Z = para-(CH 2

)C

6

H

4

(CH

2 )-) using method similar to method A Step 3. NMR (CD 3 0D): 8 7.25, s, 4H; 6 4.8, m, 2H; 30 8 4.25, s, 2H; 8 2.9, m, 2H; 8 1.68, m, 2H; S 1.44, m, 1 H; 8 1.36, s, 3H; 8 0.9, m, - 193 1H; 5 0.82, m, 3H; 8 0.66, m, 3H; 8 0.4, m, 2H; 8 0.12, m, 2H. ESLCMS (m/e) 386.1. The following compounds were prepared using a similar method. Obs. Obs. # Structure MW # Structure MW m/e m/e HNN 1428 N NH 385 386 1443 518 519 HNH NH 1429 NH 401 402 1444 a 518 519 HN H 1430 N 401 402 1445 524 525 N-fH 52452 -194 HN 1431 NH 415 416 1446 N 524 525 9 o 00 HNN N 1433 435 436 1448 0 532 533 -195 HN 1434 N 435 436 1449 o 533 534 1436~~ 44 40 45 57 3 NH 1435 N 44 44 150537 538 1436 449~N 450 1451 053753 - 196 1437 463 464 1452 545 5 00 070 1438 471 472 1453 559 560 1439 485 486 1454 570 571 - 197 1440 496 497 1455 572 573 1441 504 505 1456 N 598 599 1442 O4 513 514 Method Y 40(I N H R3!" R~~~1) H 40 0R -z R23 !42 2 PS-EDC R 3 23~ R3R< N-Z + HOAX HO T RJN2 R N O ,NH (2) H N2 -- H -' HN- BOC TFA It NI 2 ()N~0o N.. NH40HMeOH Y1 Y2 Y3 Y4 5 - 198 H R 23 Ot& R23 (in the scheme, z' - is equivalent to RI substituted by R 21 , or R1 Subsitituted by alkyl-R22, wherein R and R22 are -N(R' 5

)-C(O)-N(R'

6

)(RI

7 ) and R's and R 16 form a ring as defined above, and wherein Z is optionally substituted alkylene-arylenen, alkylene-arylene-alkylene, alkylene-heteroarylene, alkylene 5 heteroarylene-alkylene, alkylene-cycloalkylene, alkylene-cycloalkylene-alkylene, alkylene-heterocycloalkylene, alkylene-heterocycloalkylene-alkylene, arylene, heteroarylene, cycloalkylene or heterocycloalkylene) Method Y, Step 1: 10 The reaction mixture of compound Y1 obtained from Method L (R 3 = Me; R4 = i-Bu; Z = para-(CH 2

)C

6

H

4

(CH

2 )-) (0.1639mmole), Y2 (R2 = H; R 23 = Pr) (0.1967mmole), PS-EDC resin (0.4917mmole) and HOBT (0.2459mmole) in 3.5 ml of mixture of THF, MeCN and DMF (1:1:0.3) was shaken overnight at RT before 6 eq of PS-trisamine resin 3 eq of PS-isocyanate resin were added. After 15 6hrs the reaction mixture was filtered and the resin was washed with THF, DCM and MeOH. The combined filtrate was evaporated and the crude was treated with 40% TFA in DCM for 40 min before the solvent was evaporated and residue purified on RP HPLC system to give product Y3 (R 3 = Me; R 4 = i-Bu; Z = para

(CH

2

)C

6

H

4 (CH2)-, R 23 = H; R 23 = Pr). 20 Method Y, Step 2: The reaction solution of Y3 (R 3 = Me; R 4 = i-Bu; Z = para-(CH 2

)C

6

H

4

(CH

2

)

, = H; R 23 = Pr) (0.030mmole), carbonyl diimidazole (0.032mmole), and DIEA (0.09mmole) in 0.5 ml DCM was shaken overweekend at RT. The crude was 25 then purified on reverse column to give the thiohydantoin product which was converted into Y4 (R 2 = H; R 3 = Me; R 4 = 'Bu; Z = para-(CH 2 )CeH 4 (CH2)-, R H; R 23 = Pr).

- 199 The following compounds were prepared using similar method. M Obs. Obs. # Structure Structure MW W m/e m/e H4 H HN O 1457 413 414 1459 N 427 428 H N HNNQ OJ 1458 413 414 O N_.NH NH 5I Method Z

NH

2 S S HHN R1 N' -(R16 HN N-Z 'fH i7 HN NN 1 H N H N N' Ri7 H N N R R

R

4 Resin R O R3

R

3 Zi Z2 Z3 Z4 - 200 (in the scheme, -Z-NH-C(O)-N(R 16

)(R

17 ) - is equivalent to R' substituted by R 2 1 , or R' Subsitituted by alkyl-R22, wherein R 21 and R22 are -N(R' 5

)-C(O)

N(R'

1

)(R

17 ) and R' 5 is H, and wherein Z is optionally substituted alkylene arylenen, alkylene-arylene-alkylene, alkylene-heteroarylene, alkylene 5 heteroarylene-alkylene, alkylene-cycloalkylene, alkylene-cycloalkylene-alkylene, alkylene-heterocycloalkylene, alkylene-heterocycloalkylene-alkylene, arylene, heteroarylene, cycloalkylene or heterocycloalkylene) Method Z, Step 1: To the solution of the PhoximeTM resin (1.23 mmoVg) in DCM was added 10 the amine Z1 obtained from method L (R 3 = Me; R 4 = 'Bu; Z = para

(CH

2

)C

6

H

4

(CH

2 )-) (2 eq). The mixture was shaken overnight before the resin was filtered and washed with DCM, MeOH, THF (3 cycles), then DCM (x2), dried in vacuum to get resin Z2 (R 3 = Me; R 4 = 'Bu; Z = para-(CH 2

)C

6

H

4

(CH

2 )-). Method Z, Step 2: 15 To the resin Z2 (R 3 = Me; R 4 = 'Bu; Z = para-(CH 2 )C6H 4

(CH

2 )-), swelled in DCM, in toluene was added N-methylbenzylamine (4 eq). The mixture was heated at 80-90 0 C overnight before MP-TSOH resin (1.3 mmol/g, 12 eq) was added. The mixture was shaken for 1.5 hours, the solution was filtered and the resin washed with DCM and MeOH. The combined organic solution was 20 concentrated in vacuo to get Z3 (R 3 = Me; R 4 = 'Bu; Z = para-(CH 2

)C

6

H

4

(CH

2 )-; R'"= Me; R 17 = Bn). Method Z, Step 3: Compound Z4 (R 3 = Me; R 4 = 'Bu; Z = para-(CH 2 )CeH 4

(CH

2 )-; R 16 = Me; 25 R 17 = Bn) was generated from Z3 (R 3 = Me; R 4 = 'Bu; Z = para-(CH 2

)CH

4

(CH

2 )-;

R'

6 = Me; R 17 = Bn) using method similar to Method A step 3.

- 201 The following compounds were prepared using similar method. Obs. Obs. # Structure MW # Structure MW mle Wie 1460NH 457 458 1474 531 532 MNN 1461 469 470 1475 0 533 534 OH 16N 4 2' 1462 0471 472 1476 533 534 - 202 N-fNH 1463 0 471 472 1477 538 539 1464 483 484 1478 545 546 1465 0 485 486 1479 0 547 548 HO 146 0 485 486 1480 0 547 548 -203 NH 1467 o N-N 495 496 1481 N 547 548 00 1468 NH 499 500 1482 NH 551 552 1469 501 502 1483 568 569 -204 ) PN 1470 P H 507 508 1484 571 572 N HN O 1471 509 510 1485 593 594 NH NH 0 1472 517 518 1486 596 597 - 205 NHN 1473 517 518 1487 0 607 608 7k) 1488 364 365 NY0 HN 1489 /\0 377 377 1490 * 513 514 Method AA cCl H N" H + C 0 N HN + N.Bo Cl N HN N, N, N NH AA1 AA2 AA3 - 206 8,11 -Dichloro-6,11 -dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (AA2) (18 mg) was reacted with AA, obtained from method 0, and diisopropylethylamine (14 uL) in acetonitrile (2.5 mL). The resulting mixture was heated at 65 *C for 18 h. The reaction mixture was placed on a preparative silica 5 gel plate and eluted with hexane : ethyl acetate 3:1 to give the desired product which was treated with 40% TFA. Evaporation of the solvent followed by purification afforded compound AA3. Obs. Obs # Structure MW # Structure MW Wle W/e N N 187 0 NH 491 492 188 0 N N 493 494 The following compounds were prepared using similar method. 10 Method AB

R

3

R

4 1.(R)(+)- tBuSONH 2 , R R 4 0 CSC1 2

R

4 0 0 0 2. CH 3

CO

2

CH

3 , LDA, NaHCO 3 , SCN OCH 3 AB1 CITI(OI-Pr) 3 , THF AB2 CH 2 Cl 2 AB3 3. HCI, MeOH RiR

R*NH

2 0 S tBuOOH, NH 4 0H, MeOH 0 N NH NH DIEA, CH 3 CN R R 4 NH Rl R 4 AB4 AB5 Method AB, Step 1: - 207 To a solution of (R)-(+)-2-methyl-2-propane sulfonamide (1.0 g, 8.3 mmol, 1 eq) and AB1 (R 3 =Ph, R 4 = n-Bu) (3 mL, 9.1 mmol, 1.1eq) in anhydrous THF (30 mL) at room temperature was added Ti(OEt) 4 (7 mL, 17 mmol, 2 eq). The mixture was heated at 70 *C for 24 h. After cooling to room temperature, the 5 mixture was poured into 30 mL of brine under vigourous stirring. The resulting suspension was filtered through a pad of Celite and the solid was washed with EtOAc (2 x 20 mL). The filtrate was washed with brine (30 mL), dried (Na 2

SO

4 ), and concentrated in vacuo. The residue was chromatographed on silica by eluting with hexane/Et 2 O (5:1) to give 1.9 g (85%) of (R)-2-methyl-N-(1 10 phenylpentylidene)propane-2-sulfinamide. 1 HNMR (CDCI 3 , 300 MHz): S 7.91 (m, 2H), 7.52-7.37 (m, 3H), 3.27 (m, 1H), 3.15 (m, 1H), 1.73-1.61 (m, 2H), 1.47-1.38 (m, 2H), 1.31 (s, 9H), 0.95 (m, 3H). MS(ESI): MH* = 265.9. HPLC tR =7.24, 7.58 min (E/Z = 5.5:1). To a solution of methyl acetate (0.6 mL, 6.9 mmol, 2 eq) in THF (5 mL), 15 LDA (2M in heptane/THF, 3.4 mL, 6.9 mmol, 2 eq) was added dropwise via a syringe at -78 *C. After stirring at -78 *C for 30 min, a solution of CITi(Oi-Pr) 3 (1.8 mL, 7.6 mmol, 2.2 eq) in THF (5 mL) was added dropwise. After stirring for another 30 min, a solution of (R)-2-methyl-N-(1-phenylpentylidene)propane-2 sulfinamide (0.9 g, 3.4 mmol, 1 eq) in THF (2 mL) was added dropwise via a 20 syringe. The mixture was stirred at -78 *C for 3 h and TLC showed no starting material left. A saturated aqueous solution of NH 4 CI (10 eq) was added and the suspension was warmed to room temperature. The mixture was diluted with H 2 0 (50 mL) and stirred for 10 min. The mixture was then partitioned between H 2 0 (50 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous 25 layer was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried (MgSO 4 ) and concentrated to give 1.1 g of a brown oil. Chromatography on silica gel using 50% EtOAc/hexanes as eluent gave 0.8 g (76%) of methyl 3-((R)-2-methylpropan-2-ylsulfinamido)-3-phenylheptanoate as a yellow oil. 'HNMR (CDCI 3 , 300 MHz): 8 7.15-7.07 (m, 5H), 3.35 (s, 1H), 3.19 30 (dd, J=16, 5.6Hz, 1H), 3.01 (dd, J=1 5.8, 5.5Hz, 1H), 2.07 (m, 2H), 1.71 (m, 2H), 1.35-1.26 (m,4H), 1.17 (s, 9H), 0.89 (m, 3H). MS(ESI): MH* = 339.9. HPLC tR = 7.50, 7.6 min (E/Z = 1.5:1) - 208 To a solution of methyl 3-((R)-2-methylpropan-2-ylsulfinamido)-3 phenylheptanoate (0.4 g, 1.1 mmol) in 12 mL of MeOH was added 16 mL of 4N HCI/dioxane. After stirring for 30 min, the volatiles were removed in vacuo. The residue was re-dissolved in MeOH (6 mL), stirred for 5 min, and evaporated 5 again to afford 0.30 g (97%) of AB2 (R 3 =Ph, R 4 = n-Bu) as a yellow solid. 1 HNMR (CDCl 3 , 300 MHz): 8 9.01 (br s, 2H), 7.37-7.12 (m, 5H), 3.64 (m, 1 H), 3.54 (s, 3H), 3.31 (m, 1 H), 2.09 (m, 2H), 1.8 (m, 2H), 1.1 (m,4H), 1.07 (s, 9H), 0.7 (m, 3H). MS(ESI): MH* = 235.9. HPLC tR = 4.72 min. 10 Method AB, Step 2: Treatment of compound AB2 (R 3 =Ph, R 4 =n-butyl) with thiophosgene in

CH

2 Cl 2 in the presence of aqueous NaHCO 3 at 0 *C generates isothiocyanate AB3 (R 3 =Ph, R 4 =n-butyl) which was converted into final product using method similar to Method A Step 2 and Method A Step 3 to give product AB5 (R 3 =Ph, 15 R 4 =n-butyl, R'=Me). . 'HNMR (CDCI 3 , 300 MHz): 8 10.4 (br s, 1H), 7.25-7.11 (m, 5H), 3.23 (dd, J = 16, 5.6 Hz, 1H), 3.03 (s, 3H), 2.8 (dd, J = 15.8, 5.5 Hz, 1H), 2.49 (s, 1H), 1.78 (m, 2H), 1.1-1.0 (m, 4H), 0.99 (m, 3H). MS(ESI): MH* = 260.2. HPLC tA = 5.09 min. 20 The following compounds were synthesized using similar methods: Obs. Obs # Structure MW # Structure MW ni/e Wie NH ) 1.10 0 NH HN N NH 189 239 240 195 443 444 0 - 209 NH 01NH HN N"O NH 190 253 254 196 463 464 N-H /HN" N 191 0 259 260 197 537 538 HNK 192 333 334 198 537 538 -210 H N O HN NH H 0 193 333 334 199 295 296 Br a y0 HN 194 349 350 200 295 296 Br Method AC R NH 0 N RAR3+ RNHOH + H 2 NCN 0 NH ACI AC2

R

3

R

4 AC3 5 The synthesis was adapted from a procedure by Hull, R. et al, J. Chem. Soc. 1963, 6028-6033. Thus, to a solution of AC2 (R 1 =Benzyl) (0.72 g, 5.9 mmol) in ACI (R 4 =Me, R 3 =Me) (1.4 mL) was added a 50% aqueous solution of cyanamide (0.31 mL, 8.0 mmol). The reaction was heated with stirring at reflux (-40 *C) for 0.5 h, then cooled to 25 *C and stirred for an additional 16 h. The 10 volatiles were removed in vacuo and the residue was partitioned between ether and H 2 0. The organic layer was dried over Na 2

SO

4 , filtered and the volatiles were removed in vacuo. The residue was purified by column chromatography using 5-10% CH 3 0H/CH 2

CI

2 as eluent followed by reverse phase preparative HPLC to give 0.15 g (8.0%) of AC3 (R'=benzyl, R 4 =Me and R 3 =Me) as a white 15 solid. 'H NMR (CH 3 0H, 300 MHz): S 7.35-7.33 (m, 5H), 4.71 (s, 2H), 1.46 (s, 6H); 13C NMR (CDCl 3 , 75 MHz) 8 157.8, 135.6, 129.1, 128.5, 127.9, 104.2, 59.6, 28.8. MS (ESI) m/e 206.1 (M+H)*. 20 -211 # Structure MW Obs. m/e HN--<P N-O 201 205 206 Method AD NH \ NH

NH

2 NCS 1. NBS, CCl 4 , hv N N

R

4

R

3

R

4

R

3 2. CH 3 NHOH, NH ' NH Et 3 N, THF R4 R 3

R

4

R

3 AD1 AD2 AD3 AD4 5 Method AD, Step 1: AD2 (R 3 =Ph, R 4 =tButyl) was prepared from ADI using method similar to Method AB, step 2. 0 Method AD, Step 2: The synthesis was adapted from a procedure by Hussein, A. Q. et al, Chem. Ber. 1979, 112, 1948-1955. Thus, to a mixture of AD2 (R 3 =Ph, R 4 =tert Butyl) (0.56 g, 2.7 mmol) and boiling chips in CC1 4 (25 mL) was added N bromosuccinimide (0.49 g, 2.7 mmol). The mixture was irradiated with a 200 watt 5 light source for 1 h. The reaction was cooled, the solid filtered off and the volatiles were removed in vacuo. Chromatography on silica gel by eluting with 5% EtOAc/hexane gave 0.57 g (73%) of 1-(1-bromo-1-isothiocyanato-2,2 dimethylpropyl)benzene as a beige powder. 'H NMR (CDCl 3 , 300 MHz): 8 7.63 7.61 (m, 2H), 7.37-7.26 (m, 3H), 1.17 (s, 9H); 13C NMR (CDCl 3 , 75 MHz): S 0 139.1, 129.0, 128.9, 128.6, 127.5, 91.2, 45.6, 26.6. MS (ESI) m/e 284.9 (M+H)*. To a solution of 1-(l-bromo-1-isothiocyanato-2,2-dimethylpropyl)benzene (0.13 g, 0.47 mmol) and the hydrochloride salt of N-methylhydroxylamine (0.047 g, 0.57 mmol) in THF (3 mL) was added triethylamine (0.18 mL, 1.32 mmol). The mixture was stirred at 25 "C for 16 h, filtered and the volatiles were removed in 5 vacuo. The residue was purified by column chromatography using

CH

3 0H/CH 2

CI

2 as eluent to give 0.050 g (42%) of AD3 (R 3 =Ph, R 4 =tert-Butyl) as -212 a glassy solid. 'H NMR (CDCl 3 , 300 MHz): 8 7.35-7.26 (m, 5H), 3.38 (s, 3H), 1.0 (s, 9H); MS (ESI) m/e 251.1 (M+H)*. Method AD, Step 2: 5 To a solution of AD3 (R 3 =Ph, R 4 =tert-Butyl) (0.065 g, 0.26 mmol) in

CH

3 0H (5 mL) at 0 *C was added a solution of aqueous ammonia (2 mL) followed by a 70% aqueous solution of t-butylhydroperoxide (2 mL). The reaction was allowed to warm to 25 *C and stirred for 16 h, The volatiles were removed and the residue was purified by reverse phase HPLC to give 2.0 mg (2.2%) of 10 AD4 (R 3 =Ph, R 4 =tert-Butyl) as a colorless oil. 'H NMR (CDCl 3 , 300 MHz) 5 7.47 7.43 (m, 2H), 7.39-7.35 (m, 3H), 3.23 (s, 3H), 1.0 (s, 9H); MS (ESI) m/e 234.2 (M+H)*. The following compounds were synthesized using similar methods: Obs. Obs. # Structure MW # Structure MW mle m/e NJ NH NH O OQNH 202 213 214 204 309 310 NH -N NH 203 233 234 15 Method AE -213 S S NBoc NBOC N- TBS-Cl R'N - 1) tBuooH N 2,6-utidine RNA NH Imidazole o NH 2)H H H DC - J NH N 3 M DCM 0 ~2) TFAIDMAOHR ~ OH OTBS 3) BOC 2 O OH oTf H2 AE2 AE3 AE4 I DIEA/THF NH NBoc ANH .1)R 15 0H/HBF4 N 2)TFA/DCM R O-R 15 AE5 AES Method AE, Step 1: TBDMS-Cl (5.3g, 35.19mmole) and imidazole (2.4g, 35.19mmole) were 5 added to a suspension of H2 (R'=Me, R 3 =cyclohexylmethyl) (8.2g, 31.99mmole) in 220 ml DCM. The reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered, and the filtrate was diluted with 1200ml EtOAc. The organic phase was washed with saturated NaHCO 3 3X and brine 3X, and dried over anhydrous Na 2

SO

4 to give 12g of AE2 (R'=Me, R 3 =cyclohexylmethyl), 10 which was used for next step without further purification. Method AE, Step 2: AE2 (R'=Me, R 3 =cyclohexylmethyl; 12 grams crude) was converted to iminohydantoin using conditions similar to Method A Step 3, which was 15 subsequently treated with 75% TFA in DCM at room temperature for 24 hrs. The solvent was evaporated in vacuo to give 13.6g of a product that was reacted with Boc anhydride to give 5.8g AE3 (R'=Me, R 3 =cyclohexylmethyl) after column purification. 20 Method AE, Step 3: AE4 (R'=Me, R 3 =cyclohexylmethyl )(8.2 g) was obtained from AE3 (5.8g) according to the step 4 of the method H. Method AE, Step 4: 25 To a solution of AE4 (R'=Me, R 3 =cyclohexylmethyl) ((3.95 g, 8.38 mmol) in anhydrous THF (98 mL) was added diisopropylethylamine (7 mL, 40 mmol).

-214 The reaction was stirred under N 2 (gas) at room temperature. After 5.5 h, the reaction was concentrated and the crude material was purified via flash chromatography eluting with a gradient of 0 to 75% ethyl acetate in hexane to afford AE5 (R'=Me, R 3 =cyclohexylmethyl) (2.48 g, 92%). 5 Method AE, Step 4: To a solution of R 15 0H (R 15 =cyclobutyl) (10 sII) and HBF 4 (1 equiv) in anhydrous methylene chloride (0.5 mL) was added a solution of AE5 (R'=Me,

R

3 =cyclohexylmethyl) (20 mg, 0.062 mmol) in methylene chloride (0.5 mL). The 0 reaction was agitated overnight at rt. Trifluoroacetic acid (1 mL) was added to the reaction mixture and the solution was agitated for 1 h at rt. The reaction was concentrated and the crude material was purified via reverse phase preparative HPLC/MS eluting with a 7 min gradient of 5 to 95% CH 3 CN in H 2 0 with 0.1% formic acid to afford AE5 (R'=Me, R 3 =cyclohexylmethyl, R 15 = cyclobutyl). 5 The following compounds were synthesized using similar method: Obs. Obs. Structure MW # Structure MW We m~e NH HN / N N NHO-/ HN 0 205 0 267 268 226 335 336 HN / HN / -N \ N HN 0 HN O O O 206 293 294 227 335 336 -215 \ NH 0 0NH a. 207 295 296 228 O 335 336 HN C HN HN O HN O O 1 0 208 295 296 229 335 336 HN HN HN O HN O 0 O 209 295 296 230 335 336 HN* NH HN O -- N AlHO_ O~a 0N H 0 210 295 296 231 0 335 336 HN HN H O HN 211 0305 306 232 0335 336 -216 N-- NH NH 0 NH NAN 212 307 308 233 337 338 HN HN HN O HO H 0 213 307 308 234 337 338 HN a- HN -N H -N 214 309 310 235 349 350 HN / "" HN 0 0 H N 215 309 310 236 349 350 HN HN HN O H 216 . O309 310 237 0349 350 -217 HN HN HN O HN 0 217 309 310 238 349 350 HN NH HN O HN 0 N N 218 0 321 322 239 O 353 354 HN NH HN O 00N 219 321 322 240 0 361 362 NH HN NA H 'N H HN O 220 0 0D 321 322 241 363 364 NH NHH 0 NH 36 221 322 323 242 363 364 -218 H HN / ~N H 0/ H 222 329 330 243 363 364 HN QrNH O 223 333 334 244 389 390 F F HN HN 4-N 4-N HN O HN O 224 -0335 336 245 321 NA HN HN O 225 335 336 Method AF NBoc R N NH N-k NH 1) ArOH/tBuOK 1LN O THF 0 O ROTf 2) 50%TFA/DCM R15 AE4 AF4 5 To a solution of tBuOK (9.5mg, 0.0848mmole) in 0.5ml anhydrous THF was added ArOH (Ar=m-Chlorophenyl)(13pl, 0.1273mmole) in 0.5ml anhydrous -219 THF followed by addition of AE4 (R'=Me, R 3 =cyclohexylmethyl) (20mg, 0.0424mmole) in 0.5ml anhydrous THF. The reaction mixture was stirred at room temperature for 2 days before it was diluted with 1 ml MeCN, treated with 100mg MP-TsOH resin and 100mg Amberlyst A26 resin. The resin was 5 removed by filtration and the filtrate was evaporated down to give a product that was treated with 50% TFA for 1 hr. After evaporation of TFA in vacuo, the residue was dissolved in 2ml MeCN, and treated with 100mg MP-TsOH resin. The resin was washed thoroughly with THF, MeCN and MeOH, and then treated with 2M NH 3 in MeoH to give AF2 (R'=Me, R 3 =cyclohexylmethyl and R' 5 =3 0 chlorophenyl). The following compounds were synthesized using similar method: Obs. Obs. # Structure MW m/e # Structure MW m/e NH NH 'N NH 'N NH 246 O 316 317 309 365 366 ~N'NHQ Hc 0 247 316 317 310 365 366 0NH N NHNH 0 30 248 0 o 316 317 311 366 367 - 220 NH o .NH 'N H 249 329 330 312 0 366 367 0 -N NH 250 329 330 313 366 367 o H NH NHO 251 329 330 314 366 367 H lNHN N N OH ,'N NH 253 0 331 332 316 366 367 - 221 NO 'N H N NH 254 331 332 317 o 366 367 NH N NH N H NH 255 333 334 318 367 368 a NH 256 o(j 333 334 319 FiI 6 6 o NNH NN NH~ 0 0 O) 257 333 334 320 367 368 F o 33 3432 N39N7 258 333 334 3201 369 370 - 222 N NH o1NH 259 333 334 322 371 372 N NH 0 N NH NH NH 260 N 340 341 323 371 372 NH O0 NH N NH NHNH 261 340 341 324 371 372 N HQ NH -N 262 340 341 325 0 372 373 0 N H O NH 263 0 343 344 326 372 373 O NH - 223 N NH 0N N H 264 343 344 327 372 373 NHH NNH 00N 265 343 344 328 372 373 I ~NfNH N NH 266 343 344 329 373 374 HN HN 267 0 344 345 330 ( C ) 373 374 o N NH NH N NH 0 ,/ NH 268 344 345 331 r 375 376 "0 - 224 0 N-fNH 0NH ONNH NH 270 0 345 346 333 375 376 HO NkNH N 271 345 346 334 q 377 378 ~ol0 o NrNH NHH 271 0~l 345 346 335 0 ) 0 377 378 NH N N NyNH F NH 273 347 348 336 C) 0 37 378 - 225 JH 0 N.NH N NH a NH 274 F O 347 348 337 383 384 NH N NHON N NH o N NH NH 275 O O 349 350 338 383 384 LH ONrNH A 0 277 - 349 350 340 0 383 384 N H 28 H 03 3 3H 276 - - 349 350 339 383 384 bF 0N- NH NI H 0 NH 278 0 0-0 349 350 341 a P03834 - 226 279 351 352 342 F 383 384 NH N NH IN HH F NH 280 O 351 352 344 383 384 F NH NH 0 O r o N H NNH 281 351 352 344 383 384 F o NNH 0 N H NH NH 282 351 352 3445 ;: 3813 384 F c o y NNH 0 N- NH NH NH 282 351 352 346 itII*i-0 383 384 F-aa - 227 NH NH 284 F O7N 385 386 0 ~Nr -NHZ 285 Y F 351 352 348 385 386 F o N NH N NH 286 351 352 349 _/ 386 387 F

NH

2 0 N NH NH NS NH 0N Q3 NHO38 287 355 356 350 387 388 'NN 28 38 288 0355 356 351 387 388 - 228 NNH Nf NH O0 N NH NNH 289 357 358 353 393 394 Br N NH N0H N NH NH T NH 290 357 358 353 Br 0393 394 o N HNH 291 357 358 354 F 3994 \ HO NH 292 o 357 358 355 393 394 293 0~~( 358 359 356 399H 400 FkO

F

- 229 NH N NH F N NH 294 358 359 357 0 399 400 NH \N H NH ~0 0 295 N 358 359 358 400 401 0 o N NH 296 o 35 35400 401 297 ~~359 360 360H O4090 NN~ o ONN NH * NH 297 0359 360 360 H 0400 401 NHN NH NH '-fNH 298 359 360 361 401 402 F F - 230 299 359 360 362 401 402 0NrNH O N,. NH F N NH N N NH 0 300 359 360 363 401 402 NYNHI NH 0 N NH 0 XNH 301 9 0359 360 364 _0~ 405 406 Oa O r0 0NrNH 0 N,,NH kN H NH 302 0360 361 365 0 411 412 .N. - F 0o1 -231 NY NH 0 N NH O NH NH 303 360 361 366 414 415 N0 HN N-fNH 3.. o.N.O 360 361 367 417 418 -. * 6- F F F O N. NH F NN 306 0 363 364 369 421 422 F5 F

|

- 232 N N NH NHC) _ 307 0 363 364 370 0 434 435 HNO NH N NH O N H F F F 308 O 363 364 371 451 452 F FF a F Method AG NBoc R, NBoc RNH RN NH R 21 -H / NaH NA NH 50%TFA/DCM , NH THF 3 OTf 5 AE4 AG1 AG2 Method AG, Step 1:

R

21 -H (R" =PhS-) (33pl, 0.318mmole) was treated with NaH (1 0.2mg, 60% in mineral oil) in 0.5ml anhydrous THF. A solution of AE4 (R'=Me,

R

3 =Cyclohexylmethyl) (20mg, 0.0424mmol) in 0.5ml anhydrous THF was added. 10 The reaction mixture was stirred at room temperature overnight before it was partitioned between ether and saturated NaHCO 3 water solution. The aqueous phase was extracted with ether 2 times. The combined organic phase was washed with brine 2 times, and dried over anhydrous NaSO 4 . The crude was purified on flash column with EtOAc / hexane to give 9 mg of AGI (R 21 =PhS-, 15 R'=Me, R 3 =cyclohexylmethyl) (49.2 % yield).

- 233 Method AG, Step 2: AG1 (R 2 1 =PhS-, R'=Me, R 3 =cyclohexylmethyl) was treated with 50% TFA according to the Step 6 of the method H to give AG2 (R 2 1 =PhS-, R 1 =Me, 5 R 3 =cyclohexylmethyl). The following compounds were synthesized using similar method: Obs. Obs. # Structure MW # Structure MW Wie We NH NH N NH N H 372 315 316 374 337 338 N H 0 373 331 332 Method AH 10 0 HC , P 1) R4Br/KH -_ --o HCI Ph P NH2 N 18-Crown-6 ' O

NH

2 HCI

R

3 DCM Rs 2) 1N HCI

R

3 AHI AH2 AH3 Method AH, Step 1: Benzophenone imine (3.27g, 18.04mmole) was added to a suspension of 15 AH1 (R 3 =cyclohexylmethyl) (4g, 18.04mmole) in 65ml DCM. The reaction mixture was stirred at room temperature overnight under N 2 before the solid was filtered, and the solvent was evaporated. The residue was dissolved in 100 ml ether, washed with water 2X and dried over anhydrous MgSO 4 . The crude was - 234 purified on flash column to give 5.08 g (80.57% yield) of AH2

(R

3 =cyclohexylmethyl). Method AH, Step 2: 5 A solution of AH2 (R 3 =cyclohexylmethyl) (1g, 2.86mmole) in 12 ml anhydrous THF was added to a suspension of 18-crown-6 (0.76g, 2.86mmole) and 30% KH in mineral oil (1.16g, 8.58mmole) in 4ml anhydrous THF under N2. The mixture was cooled in ice-bath and R 4 Br (R 4 =3-pyridylmethyl, as a hydrobromide salt) was then added. The reaction mixture was stirred in ice-bath 0 for 30min and at room temperature for 2 more hrs before the reaction was quenched with 2ml of HOAc/THF/H2 O (0.25:0.75:1). The mixture was diluted with 40ml EtOAc/H2O (1:1). The aqueous phase was extracted with EtOAc 3 times. The combined organic phase was washed with brine 3 times and dried over anhydrous MgSO4. The crude was purified on flash column to give 0.44g 5 (35.14% yield) of product which was treated with1N HCI (2.2mi, 2.22mmole) in 3ml ether in ice-bath followed by stirred at r.t. overnight. The aqueous phase was evaporated and purified on C-18 reverse phase column to give 0.22g (66% yield) of AH3 (R 4 =3-pyridylmethyl;

R

3 =cyclohexylmethyl). t0 Method Al NH NH NH 5% Pd/C, H 2 NH R3 MeOH Br (~ All A12 To a solution of compound All (R'=Me, R 3 =n-Bu) (34mg, 0.105mmol) in !5 methanol (1 ml) was added 10% Pd/C (5mg). The mixture was kept under an H 2 balloon for 1 hr. After filtration of the catalyst, the filtrate was concentrated to get crude product. This residue was purified by RP HPLC to get compound A12 (R'=Me, R 3 =n-Bu) (25mg, 100%). Observed MW (M+H) 246.1; exact mass - 235 245.15. 1 H NMR (400 MHz, CDsOD): 6 = 7.59 (m, 2H), 7.36 (m, 3H), 3.17 (s, 3H), 2.17 (m, 2H), 1.27 (m, 4H), 0.86 (t, 3H, J=7.2Hz). The following compounds were synthesized using similar method: Obs. Obs. # Structure MW # Structure MW W/e m/e NH NH NNH 375 283 284 380 463 464 N NN NN 3 NH 376 285 286 381 -O 487 488 NH 377 0 H299 300 382 489 490 - 236 NH NH NH H 378 N H 450 451 383 503 504 379 - 462 463 384 516 517 Method AJ Rtl NHBoc R"N NH N NH 0O 1) BuZnBr, Pd(dPPf)C12 NH Br -I3 THF, 55* C .3 Br 2) 4N HCV/ dioxane 5 AJI AJ2 To a mixture of compound AJ1 (R'=Me, R3 =n-Bu) (70mg, 0.165mmol) and butylzincbromide (1.32ml, 0.6mmol) was added Pd(dppf)C12. The mixture - 237 was degassed, sealed and heated at 55 *C for 1 day. The mixture was diluted with CH 2 C12 and NH3/H 2 0. The organic layer was separated, dried, concentrated, and purified by RP HPLC to get product which was then treated with 4N HC/dioxane for 30min to give compound AJ2(R'=Me,

R

3 =n-Bu) (12mg, 5 25%). Observed MW (M+H) 302.1; 'H NMR (400 MHz, CD 3 0D): 6 = 7.32 (m, 3H), 7.22 (m, 1H), 3.19 (s, 3H), 2.65 (m, 2H), 2.20 (m, 2H), 1.60 (m, 2H), 1.38 (m, 4H), 1.24 (m, 2H), 0.92 (m, 6H). The following compound was synthesized in a similar fashion: Obs. Obs. # Structure MW # Structure MW mlIe Wle 0 N 386 N H 518 519 385 NH 301 302 NH 10 Method AK NH NH 4NH _Pt/C, Rh/C NH 21 3 Conc. HCI 2 R21 MeOH R2 AKI AK2 To a solution of AKI (R'=Me, R 3 =n-Butyl, R 21 =n-Bu) (9mg, 0.03mmol) in methanol (1 ml) was added 5% Pt/C (5mg), Rh/C (5mg) and conc. HCI (0.05mi). 5 The mixture was kept under H 2 (50 psi) for 2 days. After the filtration of the catalyst, the filtrate was concentrated to get compound AK2 (R'=Me, R 3 =n-butyl, - 238 R 21 =n-Bu) Observed MW (M+H) 308.1. 'H NMR (CD 3 0D): 6 = 3.16 (s, 3H), 1.80 (m, 6H), 1.26 (m, 16H), 0.88 (m, 6H). The following compounds were synthesized using similar method: Obs. Obs. # Structure MW Structure MW w/e mle NH QN 387 O 277 278 391 6 391 392 NH N NH 388 O 291 292 392 391 392 NH O ) NHN 389 305 306 393 NH 468 469 0 NH 390 NH 307 308 -239 Method AL 0 PtO 2 , NH 2 _ NH2

NH

2 Cone. HCI N8 Nc) 03 R3 R3H(I;

CH

2 C1 2 (fR N H Boc ALl AL2 AL3 5 Method AL, Step 1: To a solution of compound AL1 (R 3 =n-Bu) (418mg, 1.39mmol) in methanol (8m1) was added PtO 2 (40mg) and conc. HCI (0.4mi). The mixture was hydrogenated (50psi) for 1 day. After filtration of the catalyst, the filtrate was concentrated. The crude residue was basified to pH=11-12 by 1N NaOH. This 10 mixture was extracted with ethyl acetate. The organic layer was separated, dried and concentrated to get compound AL2 (R 3 =n-Bu) (316mg, 100%). Method AL, Step 2: To a solution of compound AL2 (R 3 =n-Bu) (300mg, 1.32mmol) in dichloromethane (6ml) was added (BOC) 2 0 (316mg, 1.45mmol). The mixture 15 was stirred at RT for 1.5hr. It was diluted with water and dichloromethane. The organic layer was separated, dried and concentrated to get compound AL3

(R

3 =n-Bu) (464mg, 100%). Method AM alNH ml NH N NH NH g NHNH N 4N HCI/ o NH R'SCOCI 0 R3 dioxane R 3

CH

2 Cl 2 N N R15. Bod H 20 AMI AM2 AM3 Method AM, Step 1: Compound AM1 (R'=Me, R 3 =n-Butyl) was treated with 4N HCI in dioxane for 2 hr. The mixture was concentrated to get compound AM2 as an HCI salt 25 (R'=Me, R 3 =n-Butyl). Observed MW (M+H) 470.1; 'H NMR (CD 3 0D): 6 = 7.28 - 240 (m, 2H), 6.96 (m, 3H), 4.80 (m, 2H), 4.56 (m, 1H), 4.00 (m, 1H), 3.64 (m, 4H), 3.37 (m, 2H), 3.12 (m, 1H), 3.00 (m, 1H), 2.90 (m, 1H), 2.72 (m, 1H), 2.38 (m, 1H), 2.12-1.62 (m, 8H), 1.35 (m, 6H), 1.12 (m, 1H), 0.91 (m, 3H). 5 Method AM, Step 2: To a solution of compound AM2 (R'=Me, R 3 =n-Butyl) (32mg, 0.068mmol) in dichloromethane (1 ml) was added acetyl chloride (5ul, 0.072mmol). The mixture was stirred for 2 hr. It was then diluted with CH 2 Cl 2 and water. The organic layer was separated, dried, concentrated and purified by RP HPLC to 0 get compound AM3 (R'=Me, R 3 =n-Butyl and R' 5 =Me) Observed MW (M+H) 512.3; 'H NMR (400 MHz, CDC1 3 ): 6 = 7.27 (m, 2H), 6.98 (m, 1H), 6.92 (m, 2H), 4.65 (s, 2H), 4.50 (m, 2H), 3.98 (m, 1 H), 3.70 (m, 1 H), 3.41 (m, 2H), 2.98 (m, 2H), 2.62 (m, 1H), 2.50 (m, 1 H), 2.47 (m, 1H), 2.02 (m, 5H), 1.75 (m, 6H), 1.26 (m, 7H), 0.84 (m, 3H). 5 The following compounds were synthesized using similar method: Obs. Obs. # Structure MW # Structure MW NH N NH 394 0 252 253 397 469 470 H 0

H

- 241 NH NH N NH H 395 O N 252 253 398 4 N NH 498 499 00 H o NN O0 NH 36NH H51 52 396N NH 456 457 399 511 512 0 Method AN NH NH Et 3 N, NH NH NaBH(OAc) 3 R' Ria 'R15 + R3 DCER N H R15R6 5 AN2 AN3 To a solution of compound AN2 (R'=4-N-(a phenoxyacetyl)piperidinylmethyl, R3=n-Butyl) (28mg, 0.06mmol) in dichloroethane (2ml) was added butyraldehyde (5.3ul, 0.06mmol), triethylamine - 242 (8.4ul, 0.06mmol) and NaBH(OAc) 3 (18mg, 0.084mmol). The mixture was stirred overnight. It was then diluted with dichloromethane and water. The organic layer was separated, dried, concentrated and purified by RP HPLC to get AN2 (R=4 N-(a-phenoxyacetyl)piperidinylmethyl,

R

3 =n-Butyl, R' 5 =propyl and R 1 6 =H) 5 (5.4mg, 17%). Observed MW (M+H) 526.1; exact mass 525.37. 'H NMR

(CD

3 0D): 6 = 7.28 (m, 2H), 6.96 (m, 3H), 4.76 (m, 2H), 4.55 (m, 1 H), 4.05 (m, 1H), 3.77 (m, 1H), 3.61 (m, 3H), 3.50 (m, 1H), 3.11 (m, 4H), 2.85 (m, 1H), 2.68 (m, 1H), 2.38 (m, 1H), 2.05 (m, 2H), 1.95 (m, 2H), 1.73 (m, 5H), 1.39 (m, 8H), 1.10 (m, 1H), 0.99 (m, 3H), 0.92 (m, 3H). 0 The following compound was synthesized using similar method: Obs. Obs. # Structure MW m/e # Structure MW /e \ NH O 400 N 308 309 402 NNH 525 526 orQ NH o ,NH 401 N 308 309 Method AO 5 - 243 RZMgC1 + RCI CuCI,LCI

R

3

R

4 0 THF 0 A01 A02 A03 A mixture of copper chloride (2.06g, 20.8mmol) and lithium chloride (1.76g, 41.6mmol) in 100ml of THF was cooled down to -78 *C. To this mixture, 5 a 2.OM solution of A01 (R 3 =n-butyl) (1Oml, 20mmol) was added gradually. The reaction was warmed up to -60 *C, and A02 (R 4 =m-Br-Ph) (2.9m, 22mmol) was injected. The mixture was stirred at -60 *C for 15 minutes and then quickly warmed up to RT by removing the dry-ice bath. The reaction was quenched with water and sat. NaHCO 3 .After addition of diethyl ether, a lot of precipitate formed 0 and was filtered. From the biphasic filtrate, the organic layer was separated, dried, concentrated and purified by silica gel chromatography (10% EtOAc/ hexane) to get ketone A03 (R 4 =m-BrPh, R 3 =n-Bu) (3.93g, 82%). Observed MW (M+H) 241.1; exact mass 240.01. 1 H NMR (400 MHz, CDCI 3 ): 6 = 8.07 (m, 1H), 7.88 (m, 1H), 7.64 (m, 1H), 7.34 (m, 1H), 2.94 (t, 3H, J=7.2Hz), 1.71 (m, 2H), 5 1.40 (m, 2H), 0.95 (t, 3H, J=7.6Hz). The following ketones were made according to Method 9: Structure Observed MW Exact mass (M+H) N 242.1 241.01 !00 Method AP

R

4 H 4 1 CuCI,LICI 3

R

4 OHR N,-/ THF 0 N RMgCI API AP2 AP3 AP4 5 Method AP, Step 1: - 244 To a solution of AP1 (R 4 =3-Bromophenyl) (5g, 25mmol) in dichloromethane (10ml) were added N,O-dimethylhydroxylamine hydrochloride (2.56g, 26.25mmol) and 4-methylmorpholine (2.95m, 26.25mmol). EDCI (5.04g, 26.25mmol) was then added portionwise. The reaction mixture was stirred at RT 5 overnight and was then quenched with 1 N HCI (60ml). The mixture was extracted with dichloromethane. The organic layer was washed with 1 N HCI and brine, dried over Na 2 SO4, and concentrated to give the Weinreb amide AP2

(R

4 =m-BromoPhenyl) (5.96g, 98%). Observed MW (M+H) 244.1; exact mass 243.99. 'H NMR (CDC1 3 ): 6 = 7.78 (m, 1H), 7.58 (m, 2H), 7.24 (m, 1H), 3.51 (s, 0 3H), 3.32 (s, 3H). This material was used in the next step without purification. Method AP, Step 2: To a suspension of magnesium turnings (1.19g, 48.8mmol) in 30ml of THF was added dropwise a solution of R 3 Br (R 3 =cyclohexylethyl) (5.73m, 36.6mmol) in 24ml of THF. After addition of half of the solution of bromide, 5 several crystals of iodine were added to initiate the reaction. The mixture became cloudy and heat evolved. The rest of the solution of bromide was added dropwise. The mixture was stirred at RT for 30 minutes and then was cooled to 0 *C, and the AP2 (R 4 =m-BromoPhenyl) (5.96g, 24.4mmol) was added. The mixture was stirred at RT for 3 hr and then quenched with 1 N HCI until no !0 residual Mg(0) was left. The phases was separated, and the water layer was extracted with ether. The combined organic layers were washed with brine, dried, and concentrated. The crude was purified by silica chromatography (15% EtOAc/hexane) to get ketone AP3 (R 4 =m-BromoPhenyl, R 3 =Cyclohexylethyl) (8.06g, 100%). Observed MW (M+H) 295.2; exact mass 294.06. 'H NMR (400 !5 MHz, CDCl 3 ): 6 = 8.18 (m, 1H), 7.85 (m, 1H), 7.64 (m, 1H), 7.33 (m, 1H), 2.94 (t, 3H, J=7.2Hz), 1.70 (m, 9H), 1.63 (m, 4H). Method AQ 10 R +CN +

R

3 R4 0 A0i A03 A04 - 245 To a -78 *C solution of AQ1 (R 4 = cyclopropyl) (2.55 g, 38.0 mmol) in diethyl ether (100 ml) was added A02 (R 3 =n-BuLi) (38 ml, 1.5 M in hexanes, 57 mmol). After 45 min, the cooling bath was removed. After 3h at RT, the reaction 5 was quenched by dropwise addition of water and then diluted further with EtOAc and water. The phases were separated and the aqueous layer was extracted with EtOAc (2X). The organic portions were combined, washed with brine, dried over MgSO 4 , and concentrated. This crude residue was subjected to column chromatography (silica gel, 0%->100% CH 2

C

2 /hexanes) to provide the desired 10 ketone AQ4 (R 4 =cyclopropyl, R 3 =n-Butyl) (2.57 g, 20.4 mmol, 54%). 1 H NMR (CDC13) 8 2.52 (t, J = 7.2 Hz, 2 H), 1.90 (m, 1 H), 1.57 (m, 2 H), 1.30 (m, 2 H), 0.98 (m, 2 H), 0.89 (t, J= 7.6 Hz, 3 H), 0.83 (m, 2 H). Method AR S N' R2 RN NH R 2

NH

2 RA' NH R 3 R tBuOOH R3 NH R N-R 5

R

4 N-RS 15 B2 AR2 Method AR: Compound B2 (R'=m-Cl-Phenethyl,

R

3 =Me, R 4 =i-butyl and

R

5 =benzyl) was converted into AR2 (R'=m-Cl-Phenethyl,

R

3 =Me, R 4 =i-butyl and 20 R 5 =benzyl) using method A step 3. The following compounds were synthesized using similar methods: Obs. Obs. # Structure MW # Structure MW Wle mle NP 403 NH 396 397 407 N NH 340 NA ~~V~~Ha6H -246 NNH 404 NH IH 354 NA 408 H 382 NA 405 477 NA 409 446 NA 0-40: 406 NH 460 NA Method AS - 247 0 R4 ASS W SOCI 2

-

Na, Thff INj~ HQaI. R3JQR

R

3 N toluene R 3 N N 4 H THFH H H3C'NN .CH R0 ASI AS2 AS3 AS4 1 2 N

NH

2 NEta, N,RI abs. EtOH AS6 HN N' R NH ASS Method AS, Step 1: To a mixture of AS1 (R 3 =Ph) (3.94 g) in toluene (10 ml) was added thionyl chloride (1.61 ml) and the resulting mixture as heated under reflux for 6 h (until 5 HCI evolution ceased). The reaction mixture was kept overnight at rt before it was concentrated in vacuo. Toluene (10 ml) was added and the mixture was concentrated in vacuo again. The reaction mixture was dissolved in CH2Cl2, solid sodium bicarbonate added, filtered and then the CH2CI2 solution was concentrated in vacuo to give AS2 (R 3 =Ph). 10 Method AS, Step 2: To AS2 (R 3 =Ph) (0.645 g) and AS5 (R 4 =4-chlorophenyl) (0.464 g), and 1,3-dimethylimidazolium iodide (0.225 g) in anhydrous THF (20 ml) was added 60% sodium hydride in oil (0.132 g). The resulting mixture was stirred at rt for 18 15 h. The reaction mixture was concentrated and partitioned between H20 and Et2O. The dried Et2O solution was concentrated in vacuo to give a yellow residue which was placed on preparative silica gel plates and eluted with CH2CI2 to give AS3 (R=Ph, R 4 =p-CIPh). (Miyashita, A., Matsuda, H., Hiagaskino, T., Chem. Pharm. Bull., 1992, 40 (10), 2627-2631). 20 Method AS, Step 3: Hydrochloric acid (1 N, 1.5 ml) was added to AS3 (R 3 =Ph, R 4 =p-CIPh) in THF (10 ml) and the resulting solution was stirred at rt for 20 h. The reaction mixture was concentrated in vacuo and then partitioned between CH2CI2 and H20. The dried CH2CI2 was concentrated in vacuo to give a residue which was -248 placed on preparative silica gel plates and eluted with CH2Cl2:hexane 1:1 to afford AS4 (R 3 =Ph, R 4 =p-CIPh). Method AS, Step 4: 5 AS4 (R 3 =Ph, R 4 =p-ClPh) (0.12 g) and methylguanidine, HCI (AS6, R'= Me) (0.055 g) were mixed in absolute EtOH (5 ml) with triethylamine (0.2 ml) and then heated under reflux for 20 h. The resulting mixture was concentrated and then partitioned between CH2CI2 and H20. The dried CH2Cl2 was concentrated in vacuo to give a residue which was placed on preparative silica 10 gel plates and eluted with CH2CI2:MeOH 9:1 to afford AS5 (R 3 =Ph, R 4 =p-ClPh and R'=Me). The following compounds were synthesized using similar methods: Obs. Obs. Structure MW # Structure MW mle W~e H a 'N 419 299 300 NH H 'N 'kN N N 411 0 265 266 420 0 0 309 310 N H

O

HN Nk\ 412 265 266 421 0 325 326 -0 - 249 NH NH Br 413 0 271 272 422 0 343 344 JH NH "N N -N N Br 41 423 343 344 414 274 42 NNH N Br 0 415 279 280 424 421 422 T Br NH 0 416 0 295 296 425 482 483 3~H 417 0 295 296 426 512 513 NH 418 0 299 300 42756 51 - 250 Method AT Boo N0 Boo, 0

R'

5 NHRs N 'OH 1) R Boc'N HN NN NaOHlMeOH iR6 Ri HNAN /n ' HN N Xn EDC resin HN Nr)n RR O R3 0 2) TFA/DCM R 3 44 R4 0R4 0R 4 0 5 ATI AT2 AT3 Method AT, Step1: ATI, prepared using a method similar to Method H, Step1,2 and 3, (n=4,

R

3

=R

4 =n-Bu) (0.146 g) in MeOH (3 ml) and 1 N NaOH (0.727 ml) were stirred 10 overnight at rt. The mixture was concentrated and then partitioned in water (pH -3, adjusted using conc. HCI) and EtOAc. The dried EtOAc layer was concentrated in vacuo to afford AT2 (n=4, R 3

=R

4 =n-Bu). Method AT, Step 2: 15 Compound AT2 (n=4, R 3

=R

4 =n-Bu) (0.012 g) in MeCN (1 ml) was treated with EDC resin (0.12 g, 1.44 mmol/g), HOBT (0.004 g) in THF (1 ml), and n butylamine (R1 5=H, R16=n-butyl) (0.007 ml). The reaction was carried out overnight at rt. before Argonaut PS-NCO resin (0.150 g), PS-polyamine resin (0.120g) and THF (2 ml) were added and the mixture shaken for 4 h. The 20 reaction mixture was filtered and resin washed with THF (2 ml). The combined organic phase was concentrated in vacuo before the residue was treated with 1 N HCI in MeOH (1 ml) for 4 h followed by evaporation of solvent to give AT3 (n=4, R 3

=R

4 =n-Bu, R 15 =H and R 16 =n-Butyl). 25 The following compounds were synthesized using similar method: Obs. Obs. # Structure MW # Structure MW m/e mle -251 0 N 60 N 428 324 325 436 400 401 429 0 325 326 437' 406 07 430 o338 339 438 414 15 403 0 432 366 367 440 420 21 002 - 252 433 368 369 441 4282 9 0 29 434 380 381 442 444 -- o0 435 382 383 443 458 59 Method AU 0 H2N NH2 50% KOH, 6H+ ?,OEtOH RA Ri - HN N R'\ / NH AU1 AU2 AU3 5 A published procedure was adapted (Varga, I.; Nagy, T.; Kovesdi, I.; Benet-Buchholz, J.; Dormab, G.; Urge, L.; Darvas, F. Tetrahedron, 2003, (59) 655-662). AU1 (R 1 "=H, R 1 "=H) (0.300 g), prepared according to procedure 10 described by Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G.; Tatchell, A. R., - 253 (Vogel's Textbook of Practical Organic Chemistry. 5*' ed. Longman: new York, 1989; pp1034-1035), AU2 (HCI salt, R'=Me) (0.237 g), 50% KOH (0.305 ml), 30% H202 (0.115 ml) and EtOH (4.6 ml) were heated in a sealed tube for 2 h. Reaction mixture was concentrated and extracted with CH2CI2. The dried organic 5 solution was concentrated in vacuo to give a residue which was placed on preparative silica gel plates eluting with CH2CI2:MeOH 9:1 to afford AU3 (R 15 =H,

R

16 =H, R'= Me). The following compounds were synthesized using similar method: Obs. Obs. # Structure MW # Structure MW mle W/e NH NH HN ',H -N NH 44 0 265 266 448 0 285 286 NH N NH 449 O Os 309 310 H H 'N NH N H 446 O 280 281 450 00- 309 310 NH -N NH 7 0 285 286 10 - 254 Method AV Boc'N Boc'N HN HNr~ >R 2 2 HN OHHN NC OH 2 R- YN R34 t~dQR22 R R4 o NRo N R R 0 AVI AV2 AV3 AV4 5 Method AV, Step 1: In a microwave tube, AVI (R 3 =Me, R 4 =Bu-i) (0.0012 g) and AV2 (R 2 2 =OPh) (0.0059 ml) in isopropanol (2 ml) was placed in a microwave at 10 125 0 C for 5 min. The reaction mixture was concentrated in vacuo to give AV3

(R

3 =Me, R 4 =i-Bu, R22=OPh). Method AV, Step 2: AV3 (R 3 =Me, R 4 =i-Bu, R22=OPh) in CH2C2 (1 ml) and TFA (1 ml) was 5 shaken for 2h and the concentrated in vacuo and purified on Prep LCMS to afford AV4 (R 3 =Me, R 4 =i-Bu, R22=OPh). The following compounds were synthesized in a simlar fashion. M Obs. M Obs. # Structure # Structure W rn/B W Wle o N NH N 451 378 379 453 416 417 4o o6 NH 452 396 397 - 255 Method AW 2~ R. N RRN 2 1

B(OH)

2 N HN N R1 Pd(dppf)C1 2 HN N'R R3- toluene, H0 , 3 n K 2 C0 3 - n microwave AW1 AW2 Method similar to Method U was used for this transformation. The following compounds were generated using similar methods. 5 The following compounds were synthesized in a similar fashion: Obs. Obs. # Structure MW # Structure MW W/e m/e NHH HN N' 454 341 342 458 347 348 NH HN N.- HN ' - , 0 455 341 342 459 - - 359 360 F NH HN N' H' 0 0 0 HN 456 342 343 460 '' 323 324 - 256 NH HN HN 0 N HN 457 342 343 461 /N . 294 295 --- N N Method AX 0 0 0 H 0 Cbz Pd/C Cbz' O 1) NaBH 4 Cbz' O Cbz R4 KC 2) AS R 4 R4 t-BuOOH ChiralPak nO n OH n''O AX1 AX2 AX3 AX4 Rh-Catalys Rh-Catalystl

H

2 H 2 H 0 H 0 Cbz'N O Cbz'N H4 R4.H H nOH n''OH 5 AX5 AX6 Method AX, Step 1. A literature procedure was adapted.(J-Q Yu and E.J. Corey, Organic Letters, 2002, 4, 2727-2730). To a 400 ml DCM solution of AX1 (n=1, R 4 =phenethyl) (52 grams) in a ice 10 bath was added 5 g of Pd/C (5% w/w), 50 g of potassium carbonate and 100 ml of anhydrous t-BuOOH. The mixture was stirred in air for overnight before it was diluted with DCM and washed with water. The residue after removal of organic solvent and drying was chromatographed using ethylacetate/hexane to give 25 g of AX2 (n=1, R 4 =phenethyl). 15 - 257 Method AX, Step 2. A solution of AX2 (4.5 g, n=1, R 4 =phenethyl) in MeOH (50 ml) was treated with 0.4 g of Sodium borohydride and the reaction was stirred for 30 min before the solvent was removed and residue chromatographed to give a mixtrue of AX3 5 (n=1, R 4 =phenethyl) and AX4 (n=1, R 4 =phenethyl) which was separated using an AS chiralpak column eluted with 8% IPA in Hexane (0.05% DEA) to give 2.1 g of AX3 (n=1, R4=phenethyl) as the first fraction and 2.2 g of AX4 (n=1,

R

4 =phenethyl) as the second fraction. 10 Method AX, Step 3. A 100 ml methanolic solution of AX4 (n=1, R 4 =phenethyl) ( 2.2 g) and 1,1'-bis(di-ipropylphosphino)ferrocene (1,5-cyclooctadiene)rhodium (1) tetrafluoroborate (0.4 g, 0.57 mmol) was hydrogenated at 55 psi overnight. The reaction was concentrated, and the brown oil was purified by silica gel 15 chromatography to yield AX6 (n=1, R 4 =phenethyl) (1.7g). The following compounds were generated using similar method. H 0 H 0 H 0 H 0 Cbz'N ,- Cbz'N ' Cbz'N Cbz' o Cbz'N H H H OH OH 'OH OH "OH AX7 AX8 AX9 AXI AXI H 0 Cbz'N 0 0 AX12 Method AY - 258 H 0 O Cbz' N O H 2 N O H RhPdIH 2 H \ / n OH n OH AYI AY2 A solution of AY1 (n = 1; 1.5g, 3.4 mmol), 5% Rh/C (1.5g), 5% Pd/C (0.5g) in AcOH (30 mL) was shaken in a Parr apparatus at 55 psi for 18 hours. The vessel was flushed with N 2 , and the reaction was filtered through a pad of 5 celite. After concentration AY2 was obtained which was carried on without purification. MS m/e: 312.0 (M+H). AY3 was generated using similar method. H 0 CbzN 0 .,%H OH AY3 10 Method AZ R N-Boc R N-Boc RI 5 NH NH N-N 1) NHAZ5 OKHO NH RO o NH

R

3 ------- 3 NaBH 3 CN R% 5 R3 + RI R 3 Ho0 n DcE, MeoH RN- n R 1-n 2) TFA AZ1 AZ2 AZ3 AZ4 Method AZ, Step 1 15 To a solution of AZI (n=1, R'=Me, R 3 =2-cyclohexylethyl) (0.441 g, 1.01 mmol), generated from AY2 using Method C and Method H Step 3, in DCM was added Dess-Martin Periodinane (0.880 g, 2.07 mmol). The reaction was stirred for 3 hours at room temperature. The reaction was quenched with H 2 0 and diluted with EtOAc. After removal of the organic phase, the aqueous layer was 20 extracted with EtOAc (3x). The combined organics were dried (Na 2 SO4), filtered, - 259 and concentrated. The residue was purified by silica gel chromatography (0 100% EtOAc/hexanes) to yield AZ2 (n=1, R'=Me, R 3 =2-cyclohexylethyl) (0.408 g, 0.94 mmol, 93% yield). MS m/e: 434.1 (M+H). Method AZ Step 2: 5 To a solution of AZ2 (n=1, R'=Me, R 3 =2-cyclohexylethyl) (0.011 g, 0.025 mmol) and AZ5 (R 15 =H and R1 6=m-pyridylmethyl) (0.0067 mL, 0.066 mmol) in DCE (1.8 mL) and MeOH (0.2 mL) was added AcOH (4 drops) and MP cycanoborohydride resin (.095 g, 2.42 mmoVg). The reaction was agitated for 40 hours at room temperature. The reaction was treated with 7N NHa/MeOH, 10 and solution was filtered. After concentration, the residue was purified by silica gel HPLC (0-4% [(5% 7N NH3/MeOH)/lMeOH/(50%DCM/hexanes) to furnish fraction 1 and fraction 2 which, after removal of solvent, were treated with 20% TFA in DCM for 3h at r.t. to give AZ4 (n=1, R'=Me, R 3 =2-cyclohexylethyl, R, 5 =H and R 16 =m-pyridylmethyl) (0.005 g, 0.009 mmol) and the AZ3 (n=1, R'=Me, 15 R 3 =2-cyclohexylethyl, R'"=H and R 16 =m-pyridylmethyl) (0.012 g, 0.022 mmol) respectively. The following compounds were generated using similar methods: Obs. Obs. # Structure MW # Structure MW nle m/e SNH 462 333 334 504 406 407 \f NH NH 463 H 348 349 505 410 411 NH NH - 260 \ NH o NH 464 H 374 375 506 410 411 \ NH O NH O NH O N)_NH 465 rjM.374 375 507 410 411 \ NH NH o NH 466 374 375 508 411 412 NH \ NH NH NH 467 374 375 509 411 412 NH NH Nf o NNH NH 376 377 5 468 376 377 510 411 412 -261 \ NH \ NH o NH 0 N 469 376 377 511 m 416 417 \NHNH NH N NH N-f 07 NH o- NH S 470 376 377 512 Mid416 417 -1 NNH NH 471 M-H376 377 513 416 417 0- NHN t i"* 0 rf-N NH 472 377 378 1514 416 417 - 262 \ NH IN O N NH

N

>~NH H2 NH 473 377 378 515 o 417 418 0~ N NH ONH NH 0 474 378 379 516 417 418 HOm O NH NH 475 378 379 517 ~y~Ki424 425 HO t N- NH \NH NH 0 NH 476 388 389 518 424 425 N NH 0 NH o-H 477 N 388 389 519 0 . 424 425 - 263 \ NJ NH N 0 NH NH 478 [2Ns{" 388 389 520 424 425 O N NH NH N NH 0 NH ( H 479 N 388 389 521 N 425 426 NH WNH NNH 0 NH 480 CNI 6 388 389 522 NH 425 426 N.NH NHH 0 NHH -f'f 481 CN 388 389 523 425 426 6 - 264 NfNH NH NNH O NH 482 388 389 524 C H 425 426 NH NH O N H o NH 53 52 483 388 389 525 425 426 NH NH NH 0 N.N 485 390 391 527 H4I 425 426 - 265 ~ yNH o HN o NH 486 390 391 528 425 426 (N N )NH HN~ ~~ ~ 39039 59 2542 HN !~NH N> 488 391 392 530 425 426 H

H

2 N 0 N NH NH H N 489 391 392 531 425 426 0 C, N H

H

2 N NH NH 49 391 392 532 425 426 - 266 N NH Nq 0 )NH 0 NH 491 0 391 392 533 428 429 HN NN NH NH 0 NH 492 392 393 534429 \ NH oNH 493 392 393 535 439 440 0 N NH NH N H 494 "I392 393 536 439 443 0 0 Ny.N f 495 392 393 537 442 443 - 267 N NH N-fH o NH 496 402 403 538 442 443 ci \ NH NH 497 0 (402 403 539 N-' 442 443 N NH o H NO NH 498 402 403 540 442 443 O N,NH 499 0-0 40540 541 W444 445 o N\-NH 0 H 500 406 407 542 WK ~445 446 - 268 oNH oN 501 0 406 407 543 459 460 0 o N-fNH NH N 502 406 407 544 459 460 NH 0 503 406 407 Method BA

CO

2 Me OH Br N N N Bn Boc Boc BA1 BA2 BA3 5 Method BA, Step 1: BA1, prepared according to a literature procedure (Terao, Y; Kotaki, H; Imai, N and Achiwa K. Chemical and Pharmaceutical Bulletin, 33 (7), 1985, 2762-2766) was converted to BA2 using a procedure described by Coldham, I; - 269 Crapnell, K.M; Fernandez, J-C; Moseley J.D. and Rabot, R. (Journal of Organic Chemistry, 67 (17), 2002, 6185-6187). 1 H NMR(CDCl 3 ) for BA2: 1.42 (s, 9H), 4.06 (d, 4H), 4.09 (s, 1H), 4.18 (s, 2H), 5.62 (d, 1H). 5 Method BA, Step 2: BA3 was generated from BA2 using a literature procedure described by Winkler J. D.; Axten J.; Hammach A. H.; Kwak, Y-S; Lengweiler, U.; Lucero, M. J.; Houk, K. N. (Tetrahedron, 54 1998, 7045-7056). Analytical data for compound BA3: MS m/e: 262.1, 264.1 (M+H). 'H NMR(CDCl 3 ) 1.43 (s, 9H), 3.98 10 (s, 2H), 4.11 (d, 4H), 5.78 (d, 1H). Method BB

R

1 S R 1 S

H

2 N 0 NH 0 NH R3 SCN-RI . R 3 +

R

3 H e Boc' Boc )n Boc'N n 551 BB2 BB3 TFA/DCM TFA/DCM R' S R' S N N9 NH 0 NH

R

3 + R 3 H.H HN n HN BB4 65 Method BB, Step 1; 15 Compound BB1 (n=1, R'=Me, R 3 =cyclohexylethyl) was converted to BB2 (n=1, R'=Me, R 3 =cyclohexylethyl) and 1B3 (n=1, R'=Me, R 3 =cyclohexylethyl) which were separated via a silica gel column eluted with EtOAc in Hexane (0 15%).

- 270 Method BB, Step 2; Compound BB4 (n=1, R'=Me, R 3 =cyclohexylethyl) was generated from BB2 (n=1, R'=Me, R 3 =cyclohexylethyl) using 20% TFA in DCM. The following compounds were generated using similar method: 5 S ~ S O NH o NH o NH H H ., HN HN HN BB5 B6 BB7 Method BC R' S R' NH R% S NN N NH 0 NH

R

3 ,3

R

3 ' H H H HN R N nR1 N n 0 0 BC1 BC2 BC3 10 Method BC, Step 1; Compound BC2 (n=1, R 1 =Me, R 3 =cyclohexylethyl and R' 5 =m-Pyridyl) was obtained from BC1 (n=1, R 2 =Me, R 3 =cyclohexylethyl) using method L step 2. Method BC, Step 2; 15 Compound BC3 (n=1, R 1 =Me, R 3 =cyclohexylethyl and R' 5 =m-Pyridyl) was obtained from BC2(n=1, R 1 =Me, R 3 =cyclohexylethyl and R' 5 =m-Pyridyl) using method L step 3. The following compounds were generated using a similar method: Obs. Obs. # Structure MW # Structure MW W/e m/ e -271 0ON :1 -NH H, 552 4y:374 375 574 411 412 H N O0 M N 0 H N 0 553 N 388 389 575 N 416 417 O 0 HN 55 N 388 389 576 416 417 555 388 389 577 416 417 - 272 N4 NH \N4 NH NH O NH 0 556 N 388 578 N 416 417 HN N O NH NH 557 N 390 391 579 424 425 0 0 NH 558 390 391 580 N 424 425 NNH HNyNo 0 0 NH 559 N 402 403 581 N 424 425 0 o0 - 273 N NH 560 N 402 403 582 N 424 425 N NH NH 0 ~N NH 5. 402 403 584 N 425 426 erNNH O NH NH 562 0 -N404 405 585 5 N 425 426 - 274 O N )NNH 564 0404 405 586 425 426 NH N NH NH 565 404 405 587 425 426 NHNH 0NH NH 0 5 566 0 b 404 405 588 0N425 426 NN HN 567 0 410 411 589 4 1 5 425 426 - 275 0 \ - HNH NH

-

NH 568 N 410 411 590N 430 431 NH xNH 0 NH NH 569 N411 412 591 0N 430 431 s NHN 00 570 0411 412 592 N ~4~2) 438 439 N 0 NHN0 N Hr N H 571 411 412 593 0N 43 439

N

- 276 O :=;NH N4NH NH 0 572 N 411 412 594 N 439 440 N 0 O NH 573 N 411 412 0 N e Method BD

R

1 S R 1 NH

R

1 , S N N N H O NH NH 0 NH R3 0R3

R

3 H H H 15 R'2,N R',5 -N H)N n Oi!og n ,Qn 0 0 5 BD1 BD2 BD3 Method BD, Step 1; Compound BD2 (n=1, R 1 =Me, R 3 =cyclohexylethyl and R' 5 =Ph) was obtained from BD1 (n=1, R 2 =Me, R 3 =cyclohexylethyl) using Method N, Step 1. Method BD, Step 2; 10 Compound BD3(n=1, R'=Me, R 3 =cyclohexylethyl and R' 5 =Ph) was obtained from BD2 (n=1, R'=Me, R 3 =cyclohexylethyl and R' 5 =m-Pyridyl) using Method N, Step 2.

- 277 The following compounds were generated using a similar method: Obs. Obs. # Structure MW # Structure MW nile m/e O NH 0 NrNH 595 0 440 441 596 1 460 461 Method BE

R

1 S RI NH

R

1 S N N NH NH O NH O NH . R3 .R3 R3 H H H 'R15 R 15 HN ) R1Ny N )n r n 0 5 BE1 BE2 BE3 Method similar to Method M was adapted for these transformations. The following compounds were generated similar methods. Obs. Obs. # Structure MW # Structure MW m/e W/e NH 597 o 405 406 598 439 440 10 Method BF - 278 RI S R' NH N R o NH 0 NH NHR RR

R

3 H BF3 H H HN ) R IN )n RIN ) n R 1 6

R

16 BF1 BF2 BF3 Method BF, Step 1: Method similar to Method T, Step 1 was used for the synthesis of BF2 (n =1, R 1 =Me and R 3 =phenethyl, R 15 =H and R' 6 =n-propyl). 5 Method BF, Step 2: Method similar to method L Step 3 was adapted for this transformation. The following compounds were generated using similar methods. Obs. Obs. # Structure MW # Structure MW Wie ff Ve \N NH 0 NH 599 MN 376 377 604 N 397 398 N \NH Nf 10 NH 0 N 600 390 391 605 N 397 398 - 279 NH O NH H NH 601 390 391 606 N 397 398 NH NH 0 NH H 602 N 390 391 607 N 411 412 N NNH O NH 603 N 397 398 Method BG 0 Nl-Z 0 H O - 0R BGI BG 2 Method BG: 5 To a solution of BG1 (n=1, R 3 =cyclohexylethyl) (0.136 g, 0.31 mmol) in

CH

2

CI

2 was added 2,6-lutidine, AgOTf, and butyl iodide. The reaction was stirred at room temperature for 96 hours. The reaction was filtered through a - 280 pad of Celite, and the solution was concentrated. The residue was purified by silica chromatography (0-100% EtOAc/hexanes) to furnish BG2 (n=1,

R

3 =cyclohexylethyl, R' 5 =n-butyl) (0.124 g, 0.25 mmol, 80% yield). MS m/e: 426.1 (M-OBu). 5 The following compound was prepared using similar method: 0 H 0 N-Z 0O6 BG3 Method BH OK -z Step1 BH1 BH2 Step 2 NH R S N-Z=( 0 NH Step oNH NH 'H R H RH Riof 0IKI 1+. ~ 57 BH5 BH4 BH3 0 Method BH, Step 1. Compound BH1 (n=1, R 3 =cyclohexylethyl and R 15 =n-butyl) (0.060 g, 0.12 mmol) and 5% Pd(OH) 2 /C (0.040 g) in EtOAc (1 mL)/MeOH (0.2 mL) was stirred under an atmosphere of H 2 for 20 hours at room temperature. The reaction was filtered through a pad of Celite, and the solution was concentrated. The crude 5 product mixture BH2 (n=1, R 3 =cyclohexylethyl and R' 5 =n-butyl) was carried on to the next step without purification. Method BH, Step 2.

- 281 A solution of BH2 (n=1, R 3 =cyclohexylethyl and R' 5 =n-butyl) was converted to a product mixture of BH4 and BH3 using a method similar to Method C Step 1. The mixture was purified by silica gel chromatography using EtOAc/hexanes to yield BH4 (n=1, R 2 =Me, R 3 =cyclohexylethyl and R 1 5 =n-butyl) 5 (0.032 g, 0.078 mmol, 56% yield) and BH3 (n=1, R 2 =Me, R 3 =cyclohexylethyl and R4=n-butyl) (0.008 g, 0.020 mmol, 14% yield). For BH4 (n=1, R 2 =Me,

R

3 =cyclohexylethyl and R' 5 =n-butyl), MS m/e: 409.1M+H). For BH3 (n=1,

R

2 =Me, R 3 =cyclohexylethyl and R 15 =n-butyl), MS m/e: 409.1 (M+H). 10 Method BH, Step 3. Compound BH4 (n=1, R 2 =Me, R 3 =cyclohexylethyl and R' 5 =n-butyl) (0.032 g, 0.078 mmol) was converted to BH5 (n=1, R 2 =Me, R 3 =cyclohexylethyl and

R'

5 =n-butyl) (0.016 g, 0.043 mmol, 57% yield)using a method similar to Method A, step 3. MS m/e: 392.1 (M+H). 15 The following compound was generated using a similar method: Obs. Obs. # Structure MW # Structure MW mle m/e 0 NrNH 0 Ny..NH 608 391 392 610 O"K 391 392 O NH 609 O"eo 391 392 Method BI -282 0 H0H 0 N, 0 N-Z B11 B12 A solution of B11 (0.020 g, 0.040 mmol) in DCM (1 mL) was degassed using freeze/pump/thaw (4x) method. At the end of the fourth cycle Crabtree's catalyst was added and the system was evacuated. While thawing, the system 5 was charged with hydrogen gas, and the reaction was stirred at room temperature for 16 hours under an H 2 atmosphere. The reaction was concentrated, and the brown oil was purified by reverse phase HPLC to furnish B12(0.011 g, 0.022 mmol, 55% yield). MS m/e: 368.2 (M+H). 10 Method BJ R0 R NH N O-, 4NH 0 N H O NH R3 R3 Br BJ1 BJ2 BJ3 Method BJ, Step 1 A mixture of 2 ml dioxane solution of BJ1 (R'=Me, R 3 =Me) (140 mg, 0.5 15 mmol) generated using Method BK Steps 1 & 2, indole (1.2 eq), potassium t Butoxide (1.4 eq), Pd 2 (dba) 3 (0.02 eq) and 2-di-t-butylphospinobiphenyl (0.04 eq) in a sealed tube was irradiated in a microwave oven at 120 *C for 10 min and the mixture was separated via a silica gel column to give BJ2(R'=Me, R 3 =Me) (0.73 mg). 20 Method BJ, Step 2 BJ2(R'=Me, R 3 =Me) was converted to BJ3 (R'=Me, R 3 =Me) using Method BK, Steps 3 & 4. Obs. Mass for BJ3 (R'=Me, R 3 =Me): 319.2.

- 283 Obs. # Structure MW NH 0 NH 614 318 319 Method BK OMe 0 Me 2 N-We( 0 Me2N \ NO</ Lawesson's 0 HN{CO, OMe egn RA R 4 (NKCN ,kNH Oe X NH R3 R 4

R

3

R

4 BK1 BK2 BK3 S N N oH, BuOOH \NNH.HCI NH + MeOHOHk,,NH 0,4~HOH 0u001IN N

R

3

R

4 R3 R 4 R3 R 4 BK4 BK5 BK6 5 Method BK, Step 1: Hydantoin BK2 (R 3 =N-benzyl-3-piperidyl, R 4 =n-Bu) was prepared according to Method D, Step 1 from the corresponding ketone BK1 (R 3

=N

benzyl-3-piperidyl, R 4 =n-Bu). Analytical data for BK2 (R 3 =N-benzyl-3-piperidyl,

R

4 =n-Bu): (M+H) = 330.1. 10 Method BK, Step 2: To a suspension of hydantoin BK2 (R 3 =N-benzyl-3-piperidyl,

R

4 =n-Bu) (138 mg, 0.419 mmol) in DMF (1.5 ml) was added dimethylformamide dimethylacetal (0.11 ml, 0.84 mmol). The resulting mixture was heated in a 100 15 *C oil bath for 16h and then cooled to RT and concentrated under vacuum. This crude residue was purified by column chromatography (MeOH/DCM) to give -284 product BK3 (R 3 =N-benzyl-3-piperidyl, R 4 =n-Bu) (140 mg, 0.408 mmol, 97%), (M+H) = 344.1. Method BK, Step 3: 5 To a solution of a portion of BK3 (R 3 =N-benzyl-3-piperidyl, R 4 =n-Bu) (70 mg, 0.20 mmol) in toluene (1 ml) was added Lawesson's reagent (107 mg, 0.26 mmol). The resulting mixture was placed in an oil bath at 60 *C for 16h and then at 100 *C for 24h. After cooling to RT, the reaction was quenched by addition of several drops of 1 N HCI and then diluted with EtOAc and 1 N KOH. The 10 phases were separated and the aqueous layer extracted with EtOAc (2X). The organic portions were combined, washed with brine, dried over MgSO 4 , filtered, and concentrated. This crude residue was purified by preparative TLC (1000 pm silica, 15% EtOAc/DCM) to give two separated diastereomers BK4 (R 3

=N

benzyl-3-piperidyl, R 4 =n-Bu) (24 mg, 0.067 mmol, 33%, MS: (M+H) = 360.2) and 15 BK5 (R 3 =N-benzyl-m-piperidyl,

R

4 =n-Bu) (22 mg, 0.062 mmol, 31%, MS: (M+H) = 360.2). Method BK, Step 4: Diastereomer BK5 (R 3 =N-benzyl-3-piperidyl,

R

4 =n-Bu) was treated 20 with NH 4 0H (2 ml) and t-butyl hydrogen peroxide (70% aqueous, 2 ml) in MeOH (4 ml) for 24 h. After concentration, the crude sample was purified by preparative TLC (1000 mm silica, 7.5% 7N NH3/MeOH in DCM). The resulting sample was dissolved in DCM (1 ml), treated with 4N HCI in dioxane for 5 min, and finally concentrated to give diastereomeric products BK7 (R 3 =N-benzyl-3 25 piperidyl, R 4 =n-Bu) (12 mg, 0.029 mmol, 43%). 'H NMR (CD 3 0D) 8 7.60 (m, 2 H), 7.49 (m, 3 H), 4.39 (ABq, JAB = 12.8 Hz, AVAB = 42.1 Hz, 2 H), 3.69 (m, 1 H), 3.39 (br d, J= 13.6 Hz, 1 H), 3.20 (s, 3 H), 2.96 (m, 2 H), 2.45 (m, 1 H), 1.99 (m, 1 H), 1.92-1.78 (m, 3 H), 1.68 (br d, J= 12.4 Hz, 1 H), 1.50 (dq, Jd = 3.6 Hz, Jq = 12.8 Hz, 1 H), 1.36-1.22 (m, 4 H), 1.03 (m, 1 H), 0.90 (t, J= 7.2 Hz, 3 H). LCMS: 30 tR (doubly protonated) = 0.52 min, (singly protonated) = 2.79 min; (M+H) for both peaks = 343.2. The following compounds were synthesized using similar methods: - 285 M Obs. # Structure W m/e NH -N NH 615 0 Br 281 282 Method BL N-Boc R NH 1 NH H2NP BU O NH NaBH 3 CN O DCE, MeOH N 2) TFA R - n BL1 BL2 To a 2ml Methanolic solution of BL1 (n=1, R 3 =cyclohexylethyl, R'=Me) 5 (10 mg) was added BL3 (HCI salt, R' 5 =H, 2 eq) and NaOAc (2 eq) and the mixture was heated to 60 C for 16 h. After removal of solvent, the residue was treated with 20% TFA in DCM for 30 min before the solvent was evaporated and residue purified using a reverse phase HPLC to give BL2 (n=1,

R

3 =cyclohexylethyl, R' = Me and R 15 = H). 10 The following compounds were synthesized using similar methods. Obs. Obs. Structure MW # Structure MW inom/e f i NHN 616 MN H 348 349 617 H 388 389 Method BM - 286 Boc, Boc Boc,

R

2 N R 2 N R 2 N O NH NH o NH 1) DPPA Z-OSu 2) TPP R 3

R

3 nOH NH2 nHN-Cbz BM1 BM2 BM3 20% TFA/DCM 20% TFA/DCM R2 NH

R

2 NH O NH o NH R3

R

3 n NH 2 fN-Cbz BM4 BM5 Method BM, Step 1: To a toulene solution (3ml) of BM1 (n=1, R 3 =cyclohexylethyl, R 2 =Me) (0.050 mg) was added 1.5 eq of diphenylphosphorylazide and 1.5 eq of DBU 5 and the solution was stirred at r.t. overnight. The reaction mixture was diluted with EtOAc and washed with 1% aq HOAc before the organic layer was dried and solvent evaporated. The residue was chromatographed using EtOAc/Hex to give a product that was treated with triphenylphosphine (2 eq) in THF (1% water) overnight to give BM2 (n=1, R 3 =cyclohexylethyl, R 2 =Me) after reverse phase 10 purification. Method BM Step 2: To a DCM solution of BM2 (n=1, R 3 =cyclohexylethyl, R 2 =Me) was added 1 eq of benzyloxycarbonyl-OSu and the reaction was stirred overnight before the solvent was evaporated and residue chromatographed to give BM3 (n=1, 15 R 3 =cyclohexylethyl,

R

2 =Me). Compound BM4 (n=1, R 3 =cyclohexylethyl, R 2 =Me) and BM5 (n=1,

R

3 =cyclohexylethyl, R 2 =Me) were generated from BM2 (n=1, R 3 =cyclohexylethyl,

R

2 =Me) and BM3 (n=1, R 3 =cyclohexylethyl, R 2 =Me) through Boc-deprotection.

- 287 The following compounds were synthesized using similar method: Obs. Obs. # Structure MW # Structure MW HN HN N H N NH 00 618 332 333 619 468 469 NN Method BN 0 0 Cbz-NH

H

2 N BN1 BN2 5 A mixture of Pd(OAc) 2 (9 mg), triethylamine (17 microliter), triethylsilane (11 microliter) and BN1 (20 mg) in DCM was hydrogenated at 1 atm at rt for 1.5 h before the reaction was filtered through a Celite pad to give BN2 after removal of solvent. 0 Method BO The following compounds were generated through boc-deprotection of the corresponding starting material using 50% TFA in DCM, rt 30 min. Obs. Obs. # Structure MW # Structure MW W~e rnle - 288 H 2 N HN o N, NH 620 NH 266 267 624 o 288 289 NH 621 O> NH 266 267 625 OH 320 321 tt NH 0 NH 622 N H 274 275 626 H320 321

NH

2 623NH 274 275 Method BP - 289 R2 BOC 1 BOC R, N R'NR Rs N'R2 N NJ O NH Ot %N O N g-R3 0 R Bp OBP3 BP1BP Method BP, Step 1 To a solution of OP1 (n=1, R =Me, R 2=H, Ra = cyclohexylethyl) (0.012 g, 0.028 mmol) in CH 2 Cl 2 (0.5 mL) was added 2,6-lutidine (0.010 mL, 5 0.086 mmol), AgOTf (0.024 g, 0.093 mmol), and benzyl bromide (0.010 mL, 0.084 mmol). The reaction was stirred at room temperature for 16 hours. The solid was filtered, and after concentration the residue was purified by reverse phase HPLC to yield BP2 (n=1, R'=Me, R 2 =H, R 3 = cyclohexylethyl) (0.010 g, 0.019 mmol). MS m/e: 526.1 (M+H). 10 Method BP, Step 2 BP3(n=1, R 1 =Me, R 2 =H, R 3 = cyclohexylethyl) was prepared from BP2(n=1, R'=Me, R 2 =H, R 3 = cyclohexylethyl) using 30% TFA/DCM. MS m/e: 426.1 (M+H). M Obs. # Structure W mle O NINH 627 425 426 15 Method B - 290 BOC BOC R2 R N'2 N R 2 R N O N O Oi NH HN Step 1 o= N3 Step 2 n 3 n ) Meo/ Me/\ 801 B02 B03 OMe OMe Method BQ Step 1: 601 was prepared according to Method AZ. 5 To a solution of BQ1 (n=1, R =Me, R 2=H, R3 = cyclohexylethyl) (0.004 g, 0.007 mmol) in CH 2 Cl 2 (0.3 mL) was added DIEA (0.007 mL, 0.040 mmol), acetic acid (0.001 mL, 0.017 mmol), HOBt (0.003 g, 0.019 mmol), and EDCI (0.003 g, 0.016 mmol). The reaction was stirred at room temperature for 16 hours. The reaction was concentrated and purified by reverse phase HPLC 10 to provide BQ2 (n=1, R'=Me, R 2 =H, R 3 = cyclohexylethyl) (0.003 g, 0.005 mmol). MS m/e: 627.1 (M+H). Method B0 Step 2: BQ2 (n=1, R'=Me, R 2 =H, R 3 = cyclohexylethyl) (0.003 g, 0.005 15 mmol) was treated with 20% TFA/CH 2

CI

2 (1 mL) in the presence of PS thiophenol resin (0.030 g, 1.42 mmoVg) for 3 hours. The solution was filtered and concentrated to produce B03 (n=1, R'=Me, R 2 =H, R 3 = cyclohexylethyl) (0.002 g, 0.005 mmol). MS m/e: 377.2 (M+H). # Structure MW Obs. m/e 0 NN 628 376 377 0 Method BR - 291 BOq Boc2 R N'R2 R N-R2 R% N O N O N O N 10. W 7 O#<NH Step I O.S,?< HN-to\,2A=S Meo/ MeO/ BRI BR2 BR3 OMe OMe Method BR, Step 1: 5 To a solution of BRI (n=1, R =Me, R 2=H, R3 = cyclohexylethyl) (0.004 g, 0.007 mmol) in pyridine (0.2 ml) was added DMAP (a few crystals) and methylsulfonyl chloride (3 drops). The reaction was stirred at room temperature for 6 days. The reaction was quenched with water and diluted with CH 2 C1 2 . The organic layer was removed, and the aqueous phase was extracted with CH 2

C

2 10 (3x). After concentration, the brown residue was purified by reverse phase HPLC to yield BR2(n=1, R 1 =Me, R 2 =H, R 3 = cyclohexylethyl) (0.003 g, 0.004 mmol). MS m/e: 663.2 (M+H). Method BR, Step 2: 15 BR3 (n=1, R'=Me, R 2 =H, R 3 = cyclohexylethyl) was prepared from BR2(n=1, R'=Me, R 2 =H, R 3 = cyclohexylethyl) following a procedure similar to Method BQ Step 2. MS m/e: 413.1 (M+H). Obs. # Structure MW O Ny.:NH .. o '" g~ll 629 412 413 0 Method BS - 292 BOC BOC N N-R 2 P'R R R Ph N % 1 /N 0 N P' NHO O N A- O 0KNH HN- z HN n )n O=< MeO O\ BS MeO e BS2 NH OMe OMe S Method BS Step 1: To a solution of BS1 (n=1, R'=Me, R 2 =H, R 3 = cyclohexylethyl) 5 (0.003 g, 0.006 mmol) in CH 2 C1 2 (0.3 mL) was added phenyl isocyanate (2 drops). The reaction was stirred at room temperature for 16 hours. The reaction was concentrated and purified by reverse phase HPLC to provide BS2 (n=1, R'=Me, R 2=H, R3 = cyclohexylethyl) (0.002 g, 0.002 mmol). MS m/e: 823.5 (M+H). 10 Method BS Step 2: Compound BS2 (n=1, R'=Me, R 2 =H, R 3 = cyclohexylethyl) was subjected to the same conditions in Method BQ Step 2. The crude mixture prepared above was treated with LiOH (0.006 g, 0.25 mmol) in MeOH (0.3 mL) for 2 hours. The 15 reaction was concentrated, and the residue was purified by reverse phase HPLC to furnish BS3 (n=1, R'=Me, R 2 =H, R 3 = cyclohexylethyl) (0.0012 g, 0.002 mmol). MS m/e: 454.1 (M+H). Obs. # Structure MW W/e Q N)NH NH . 630 W| 453 454 Method BT - 293 R NH Ro NHR3 QO R3HR Br R2 H BT1 BT2 Method BT: To a round bottom flask were added compound BT1 (R'=Me, R 3 =Me) (100 mg, 0.29 mmol), anhydrous toluene (2 ml), 3-aminopyridine (55 mg, 0.58 mmol) 5 and 2-(di-tert-butyl phosphino) biphenyl (17 mg, 0.058). The solution was then degassed by N 2 for 2 minutes before NaO-t-Bu (61 mg, 0.638 mmol) and Pd 2 (dba)3 (27 mg, 0.029 mmol) were added. The reaction was stirred at 80 *C for 22 hours. After cooling down to room temperature, the reaction was poured to cold water and extracted by CH 2

CI

2 . The combined organic layer was then dried over Na 2

SO

4 . After 10 the filtration, the concentrated residue was separated by TLC (CH 3 0H:CH 2 Cl 2 =l:10) and reverse phase HPLC (10%-100% acetonitrile in water w/0.1 %formic acid) to produce the desired compound BT2 (R'=Me, R 3 =Me and R 2 1 = m-pyridyl) as a formate salt (23.6 mg, white solid, 20%). 'HNMR (CDC1 3 ) S 7.50-6.90 (m, 13 H), 3.14 (s, 3H) MS mle 358 (M+H). Obs. Obs. # Structure MW m# Structure MW We mle NH HN HN N' 631 347 348 632 156 357 N 633 H 357 358 635 357 358 - 294 H 634 357 358 636 358 359 Method BU O N r N O N NBoc )NH NH NH TFA HN n cbz' 4 n Cbz n BU1 BU2 BU3 R1 R'R O N NH O NBoc o N Noc RNH NH MNH MeO N MeO N HN BU6 BUS BU4 5 Method BU, Step 1, To a round bottmed flask containing BU1 (m =1 , n = 1, R'=Me,

R

3 =Cyclohexylethyl) (99 mg, 0.307 mmol) of the trifluroacetic acid salt of pyrollidine derivative in 5 ml of DCM was added (86 pL, 0.614 mmol) of triethylamine followed by addition of (76 mg, 0.307 mmol) N-(benzyyloxycarbonyloxy)succinimide. Stir at room 0 temperature for 18h. Dilute the mixture with DCM and extract with sat'd NaHCO 3 soln, then water. Collect the organic portion and dry over Na 2

SO

4 , filter and concentrate in vacuo. Purify by silica gel chromatography (eluting with 0 to 60% - 295 EtOAc/hexanes) to yield BU2 (m =1 , n = 1, R'=Me, R 3 =Cyclohexylethyl) (130 mg, 0.284 mmol, 93% yield). MS m/e: 458.1 (M+H). Method BU, Step 2, 5 To a solution of BU2 (m =1 , n = 1, R'=Me, R 3 =Cyclohexylethyl) (130 mg) in 1 ml of MeOH in a reaction vial was added 0.5 ml of a solution of 70% tBuOOH in water and 0.5 ml of NH 4 0H. Seal the vial and shake at room temperature for 72h. The mixture was concentrated in vacuo. The mixture was diluted with 1 ml of MeOH and a mixture 30 mg of NaHCO 3 and Boc 2 0 (87 mg, 0.398 mmol) were added. The 10 solution mixture was stirred at room temperature for 18h before it was concentrated and the residue purified by silica gel chromatography using EtOAc/hexanes to yield the BU3 (m =1 , n = 1, R'=Me, R 3 =Cyclohexylethyl) (90 mg, 0.167 mmol, 58% yield). MS m/e: 541.1, 441.1 (M+H). 15 Method BU, Step 3, A solution of BU3 (m =1 , n = 1, R'=Me, R 3 =Cyclohexylethyl) (90mg, 0.167 mmol) in 5 ml of MeOH was hydrogenated using1O mg of Pd(OH) 2 -C (20% w/w) at 1 atm for 1 h. The reaction mixture was filtered through a pad of diatomaceous earth and the pad was washed with MeOH. Concentration of the collected organic portions !0 in vacuo yielded BU4 (m =1 , n = 1, R'=Me, R 3 =Cyclohexylethyl) (47 mg 0.116 mmol, 70% yield). MS m/e: 407.1 (M+H). Method BU, Step 4, To a vial containing 10 mg of powdered 4 4 molecular sieves was added 3 !5 methoxyphenyl boronic acid (60 mg, 0.395 mmol) then 3 ml of anhydrous MeOH. To this mixture was added pyridine (100 ml, 0.650 mmol), Cu(OAc) 2 (7 mg, 0.038 mmol), and BU4 (m =1 , n = 1, R'=Me, R 3 =Cyclohexylethyl) (7.83 mg, 0.019 mmol) and the mixture was stirred at room temperature for 96 h before it was quenched with 0.25 ml of 7N ammonia in methanol solution. The reaction mixture was extracted with water 10 and DCM and the organic layers were dried and concentrate in vacuo. The residue was purified via a reverse-phase HPLC to give a product which was treated with 5ml of 40% of TFA in DCM for 5 h. After removal of the volatiles, the residue was purified using a reverse phase HPLC system to furnish BU5 (m =1, n = 1, R'=Me, - 296 R 3=Cyclohexylethyl and R 21=m-MeOPh) as the formic acid salt (0.7 mg, 0.0015 mmol, 30.1% yield). MS m/e: 413.1 (M+H). Obs. Obs. # Structure MW m/e # Structure MW We \NH -H NH 637 N 258 359 638 0 412 413 Method BV R2 R3.CHO + S s , R3 s R R N N

)R

3

R

4 5 BV1 BV2 BV3 BV4 BV5 Method BV Step 1: The method was adapted from a literature procedure (Page et al., Tetrahedron 1992, 35, 7265-7274) 10 A hexane solution of nBuLi (4.4 mL, 11 mmol) was added to a -78 C solution of BV2 (R 4 = phenyl) (2.0 g, 10 mmol) in THF (47 mL). After 60 minutes at -78 C, a solution of BV1 (R 3 = 3-bromo-4-fluorophenyl) (2.24 g, 11 mmol) was added and the reaction slowly warmed to RT over 18 h. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with CH 2 Cl 2 (2 x), dried over 15 MgSO4 and concentrated under vacuum. The resulting oil was subjected to silica gel chromatography using 4-10% EtOAc/Hexanes to give a white solid BX3 (R 3 = 3 bromo-4-fluorophenyl and R 4 = phenyl) (1.69 g, 4.23 mmol, 42%).'H NMR (CDCl 3 ) S 7.61 (m, 2 H), 7.27 (m, 3 H), 6.94 (m, 1 H), 6.92 (m, 1 H), 6.68 (m, 1 H), 3.15 (bs, 1 H), 2.57-2.73 (m, 4 H), 1.89 (m, 2 H). 20 Method BV Step 2: - 297 A solution of BV3 (R 3 = 3-bromo-4-fluorophenyl and R 4 = phenyl) (1.69 g, 4.23 mmol) in acetone (40 mL) was slowly added via addition funnel to a 0 *C solution of N-bromosuccinimide (NBS, 11.3 g, 63.3 mmol) in acetone (200 mL) and water (7.5 mL). The mixture was slowly warmed to RT, and quenched after 60 minutes with 10% 5 aqueous Na 2

SO

3 . After diluting with CH 2

CI

2 , the layers were separated, and the organic layer washed with water (2x), brine (1x) and dried over MgSO 4 . Concentration under vacuum afforded an oil which was subjected to silica gel chromatography using 5% EtOAc/Hexanes to give a solid BV4 (R 3 = 3-bromo-4-fluorophenyl and R 4 = phenyl) (690 mg, 2.24 mmol, 53%). 1 H NMR (CDCl 3 ) & 8.19 (m, 1 H), 7.93 (m, 3 H), 10 7.66 (m, 1 H), 7.50 (m, 2 H), 7.20 (m, 1 H). Method BX Step 3: BV5 (R 3 = 3-bromo-4-fluorophenyl and R 4 = phenyl and R'=Me and R 2 = H) was prepared from BV4 (R 3 = 3-bromo-4-fluorophenyl and R 4 = phenyl) using Method 15 AS, Step 4. Obs. Obs. # Structure MW # Structure MW m/e NH NH 0 N N Br 261 362 640 B 261 NA 639 1 1 Human Cathepsin D FRET assa. 20 This assay can be run in either continuous or endpoint format. Cathepsin D is an aspartic protease that possesses low primary sequence yet significant active site homology with the human aspartic protease BACE1. BACE1 is an amyloid lowering target for Alzheimer's disease. Cathespin D knockout mice die within weeks after 25 birth due to multiple GI, immune and CNS defects.

- 298 The substrate used below has been described (Y.Yasuda et al., J. Blochem. , 125, 1137 (1999)). Substrate and enzyme are commercially available. A Km of 4 uM was determined in our lab for the substrate below under the assay conditions described and is consisitent with Yasuda et al. 5 The assay is run in a 30ul final volume using a 384 well Nunc black plate. 8 concentrationsof compound are pre-incubated with enzyme for 30mins at 37C followed by addition of substrate with continued incubation at 37C for 45 mins. The rate of increase in fluorescence is linear for over 1h and is measured at the end of the 10 incubation period using a Molecular Devices FLEX station plate reader. Kis are interpolated from the IC50s using a Km value of 4uM and the substrate concentration of 2.5uM. Reagents 15 Na-Acetate pH 5 1% Brij-35 from 10% stock (Calbiochem) DMSO Purified (>95%) human liver Cathepsin D (Athens Research & Technology Cat# 16-12 030104) !0 Peptide substrate(Km=4uM) Bachem Cat # M-2455 Pepstatin is used as a control inhibitor (Ki-0.5nM) and is available from Sigma. Nunc 384 well black plates Final Assay buffer conditions !5 100mM Na Acetate pH 5.0 0.02% Brij-35 1% DMSO Compound is diluted to 3x final concentration in assay buffer containing 3% DMSO. 0 1Oul of compound is added to 1Oul of 2.25nM enzyme(3x) diluted in assay buffer without DMSO, mixed briefly, spun, and incubated at 37C for 30mins. 3x substrate (7.5uM) is prepared in 1x assay buffer without DMSO. 10ul of substrate is added to each well mixed and spun briefly to initiate the reaction. Assay plates are incubated - 299 at 37 C for 45mins and read on 384 compatible fluorescence plate reader using a 328nm Ex and 393nm Em. Compounds of the present invention exhibit hCathD Ki data ranges from about 0.1 to about 500 nM, preferably about 0.1 to about 100 nM more preferably about 0.1 5 to about 75 nM. The following are examples of compounds that exhibit hCathD Ki data under 75 nM. structure structure 00 SHN O)O HN=H HN N O N

HN=

- 300 F HN=<N 0 Q~OO-O 2 NH0 J HBr 6 HN=<0N-N NNH N 00 o-~ro pT 0- __2 0 -301 N 0 HN-K The following compound 0 HN=< 5 has a hCath D Ki value of 0.45 nM. BA CE-1 Cloning. Protein Expession and Purification. A predicted soluble form of human BACE1 (sBACE1, corresponding to amino acids 1-454) was generated from the full length BACE1 cDNA (full length human 10 BACE1 cDNA in pCDNA4/mycHisA construct; University of Toronto) by PCR using the advantage-GC cDNA PCR kit (Clontech, Palo Alto, CA). A Hindill/Pmel fragment from pCDNA4-sBACE1 myc/His was blunt ended using Klenow and subcloned into the Stu I site of pFASTBACI(A) (Invitrogen). A sBACElmycHis recombinant bacmid was generated by transposition in DH10Bac cells(GIBCO/BRL). Subsequently, the 15 sBACE1 mycHis bacmid construct was transfected into sf9 cells using CellFectin (Invitrogen, San Diego, CA) in order to generate recombinant baculovirus. Sf9 cells were grown in SF 900-Il medium (Invitrogen) supplemented with 3% heat inactivated -302 FBS and 0.5X penicillin/streptomycin solution (Invitrogen). Five milliliters of high titer plaque purified sBACEmyc/His virus was used to infect 1 L of logarithmically growing sf9 cells for 72 hours. Intact cells were pelleted by centrifugation at 3000xg for 15 minutes. The supernatant, containing secreted sBACE1, was collected and diluted 5 50% v/v with 100 mM HEPES, pH 8.0. The diluted medium was loaded onto a Q sepharose column. The Q-sepharose column was washed with Buffer A (20 mM HEPES, pH 8.0,50 mM NaCI). Proteins, were eluted from the Q-sepharose column with Buffer B (20 mM HEPES, pH 8.0, 500 mM NaCI). The protein peaks from the Q-sepharose column 10 were pooled and loaded onto a Ni-NTA agarose column. The Ni-NTA column was then washed with Buffer C (20 mM HEPES, pH 8.0, 500 mM NaCI). Bound proteins were then eluted with Buffer D (Buffer C+250 mM imidazole). Peak protein fractions as determined by the Bradford Assay (Biorad, CA) were concentrated using a Centricon 30 concentrator (Millipore). sBACE1 purity was estimated to be -90% as 15 assessed by SDS-PAGE and Commassie Blue staining. N-terminal sequencing indicated that greater than 90% of the purified sBACE1 contained the prodomain; hence this protein is referred to as sproBACE1. Peptide Hydrolysis Assay. The inhibitor, 25 nM EuK-biotin labeled APPsw substrate (EuK 20 KTEEISEVNLDAEFRHDKC-biotin; CIS-Bio International, France), 5 pM unlabeled APPsw peptide (KTEEISEVNLDAEFRHDK; American Peptide Company, Sunnyvale, CA), 7 nM sproBACE1, 20 mM PIPES pH 5.0, 0.1%Brij-35 (protein grade, Calbiochem, San Diego, CA), and 10% glycerol were preincubated for 30 min at 30 0 C. Reactions were initiated by addition of substrate in a 5 i aliquot resulting in a 5 total volume of 25 il. After 3 hr at 30' C reactions were terminated by addition of an equal volume of 2x stop buffer containing 50 mM Tris-HCI pH 8.0, 0.5 M KF, 0.001% Brij-35, 20 pg/mI SA-XL665 (cross-linked allophycocyanin protein coupled to streptavidin; CIS-Bio International, France) (0.5 sg/well). Plates were shaken briefly and spun at 1 200xg for 10 seconds to pellet all liquid to the bottom of the plate before 30 the incubation. HTRF measurements were made on a Packard Discovery@ HTRF plate reader using 337 nm laser light to excite the sample followed by a 50 I.s delay and simultaneous measurements of both 620 nm and 665 nm emissions for 400 ts.

- 303 1Co determinations for inhibitors, (), were determined by measuring the percent change of the relative fluorescence at 665 nm divided by the relative fluorescence at 620 nm, (665/620 ratio), in the presence of varying concentrations of I and a fixed concentration of enzyme and substrate. Nonlinear regression analysis of 5 this data was performed using GraphPad Prism 3.0 software selecting four parameter logistic equation, that allows for a variable slope. Y=Bottom + (Top-Bottom)/ (1+1 0A((LogEC50-X)*Hill Slope)); X is the logarithm of concentration of 1, Y is the percent change in ratio and Y starts at bottom and goes to top with a sigmoid shape. Compounds of the present invention have an ICso range from about 0.1 to 10 about 500 p.M, preferably about 0.1 to about 100 pM, more preferably about 0.1 to about 20 pM. The last compound in Table M has an IC50 value of 0.35 pM. Examples of compounds under 1 pM are listed below: )-N NHNH N NH C NH 0- 'N

H

3 C 0 N N NN - 304 N N 0 Cp~/ TN l 0 04, H 3 C\ NH 0 NNH N CH 3 N 0N N CH 3 0,, -NC NH 0 NH go'.

N

- 305 ~~cH 3 N~N N' NH oil.

C

3 H3 F N NC H o NH NHH 0 NH NNCH N H 0 0 0 - 306 NH 0 H NN 00 ONN N H ", > NH ~~0 QN - 307 QoZH3 o N NONH 0O N HI NH H NC\ NH NN o NN N 0

H'

3 C\ / ?3H 3 C NH HH o)~ N NN

H

- 308 H 3 C " NH 0 N0 N H 0 0 N o0'ai NNH H3 NH 0 N 0N N ~0N H3NH NH 0 N HH H~ck NH 0 S NH 3 C - 0 H NO rI~J ~CN

C-I

- 309 H 3 C\ NH 0 N HN N N Human mature Renin enzyme assay: Human Renin was cloned from a human kidney cDNA library and C-terminally epitope-tagged with the V5-6His sequence into pCDNA3.1. pCNDA3.1-Renin-V5 5 6His was stably expressed in HEK293 cells and purified to >80% using standard Ni Affinity chromatography. The prodomain of the recombinant human renin-V5-6His was removed by limited proteolysis using immobilized TPCK-trypsin to give mature human renin. Renin enzymatic activity was monitored using a commercially available fluorescence resonance energy transfer(FRET) peptide substrate, RS-1 (Molecular 10 Probes, Eugene, OR) in 50mM Tris-HCI pH 8.0, 100mM NaCl, 0.1%Brij-35 and 5% DMSO buffer for 40mins at 30 degrees celsius in the presence or absence of different concentrations of test compounds. Mature human Renin was present at approximately 200nM. Inhibitory activity was defined as the percent decrease in renin induced fluorescence at the end of the 40min incubation compared to vehicle controls 15 and samples lacking enzyme. 1% of hRenin at 100 M Compound 68.8 o NH - N -310 75.3 0 * NH N In the aspect of the invention relating to a combination of a compound of formula I with a cholinesterase inhibitor, acetyl- and/or butyrylchiolinesterase inhibitors can be used. Examples of cholinesterase inhibitors are tacrine, donepezil, rivastigmine, galantamine, pyridostigmine and neostigmine, with tacrine, donepezil, 5 rivastigmine and galantamine being preferred. In the aspect of the invention relating to a combination of a compound of formula I with a muscarinic antagonist, m 1 or m 2 antagonists can be used. Examples of m 1 antagonists are known in the art. Examples of m 2 antagonists are also known in the art; in particular, m 2 antagonists are disclosed in US patents 5,883,096; 10 6,037,352; 5,889,006; 6,043,255; 5,952,349; 5,935,958; 6,066,636; 5,977,138; 6,294,554; 6,043,255; and 6,458,812; and in WO 03/031412, all of which are incorporated herein by reference. For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. 15 Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art, e.g. magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral 20 administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pennsylvania.

-311 Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal 5 administration. Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen. Also included are solid form preparations which are intended to be converted, 10 shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions. The compounds of the invention may also be deliverable transdermally. The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type 15 as are conventional in the art for this purpose. Preferably the compound is administered orally. Preferably, the pharmaceutical preparation is in a unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve 20 the desired purpose. The quantity of active compound in a unit dose of preparation may be varied or adjusted from about 1 mg to about 100 mg, preferably from about 1 mg to about 50 mg, more preferably from about 1 mg to about 25 mg, according to the particular application. 25 The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required. 30 The amount and frequency of administration of the compounds of the invention and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. A typical recommended daily dosage regimen for oral administration can range from about 1 -312 mg/day to about 300 mg/day, preferably 1 mg/day to 50 mg/day, in two to four divided doses. When a compound of formula I is used in combination with a cholinesterase inhibitor to treat cognitive disorders, these two active components may be co 5 administered simultaneously or sequentially, or a single pharmaceutical composition comprising a compound of formula I and a cholinesterase inhibitor in a pharmaceutically acceptable carrier can be administered. The components of the combination can be administered individually or together in any conventional oral or parenteral dosage form such as capsule, tablet, powder, cachet, suspension, 10 solution, suppository, nasal spray, etc. The dosage of the cholinesterase inhibitor can be determined from published material, and may range from 0.001 to 100 mg/kg body weight. When separate pharmaceutical compositions of a compound of formula I and a cholinesterase inhibitor are to be administered, they can be provided in a kit 15 comprising in a single package, one container comprising a compound of formula I in a pharmaceutically acceptable carrier, and a separate container comprising a cholinesterase inhibitor in a pharmaceutically acceptable carrier, with the compound of formula I and the cholinesterase inhibitor being present in amounts such that the combination is therapeutically effective. A kit is advantageous for administering a 20 combination when, for example, the components must be administered at different time intervals or when they are in different dosage forms. While the present invention has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications and variations thereof will be apparent to those of ordinary skill in the art. All such alternatives, 25 modifications and variations are intended to fall within the spirit and scope of the present invention.

Claims (20)

1. A compound having the structural formula NoR2 | R3 I R4 or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, 5 wherein W is a bond, -C(=S)-, -S(O)-, -S(0)2-, -C(=O)-, -0-, -C(R 6 )(R 7 )-, -N(R5)- or -C(=N(R5))-; X is -0-, -N(R 5 )- or -C(R 6 )(R 7 )-; provided that when X is -0-, U is not -0-, -S(O)-, -S(0)2-, -C(=0)- or -C(=NR 5 )_; 10 U is a bond, -S(0)-, -S(0)2-, -C(0)-, -0-, -P(O)(OR's)-, -C(=NR 5 )-, -(C(R")(R ))b- or -N(R 5 )-; wherein b is 1 or 2; provided that when W is -S(O)-, -S(0)2-, -0-, or -N(R 5 )-, U is not -S(O)-, -S(0)2-, -0-, or -N(R 5 )-; provided that when X is -N(R 5 )- and W is -S(O)-, -S(0)2-, -0-, or -N(Rs)-, then U is not a bond; R', R 2 and R 5 are independently selected from the group consisting of H, alkyl, 15 alkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, -OR 5 , -CN, -C(O)R4, -C(0)OR 9 , -S(O)R' 0 , -S(O) 2 R' 0 , -C(O)N(R")(R' 2 ), -S(O)N(R")(R 12 ), -S(O) 2 N(R')(R1 2 ), -NO 2 , -N=C(R 8 ) 2 and -N(RO) 2 , provided that R' and R 5 are not both selected from -NO 2 , -N=C(R 8 ) 2 and -N(R 8 ) 2 ; 20 R 3 , R 4 , R 6 and R 7 are independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, -CH 2 -O-Si(R 9 )(R1 0 )(R 9 ), -SH, -CN, -OR 9 , -C(0)R', -C(O)OR 9 , -C(O)N(R'l)(R1 2 ), -SR' 9 , -S(O)N(R)(R1 2 ), -S(O) 2 N(R 1 )(R1 2 ), -N(R)(R 12 ), -N(R")C(O)Ra, -N(R")S(O)Rl 0 , -N(R")C(O)N(R 12 )(R 13 ), -N(R")C(O)OR 9 and 25 -C(=NOH)R 8 ; provided that when U is -0- or -N(R 5 )-, then R 3 , R 4 , R 6 and R 7 are not halo, -SH, -OR 9 , -SR' 9 , -S(O)N(R'l)(R 12 ), -S(O) 2 N(R")(R 12 ), -N(R")(R 12 ), -N(R 1 )C(O)R", -N(R 1 )S(O)R 0 , -N(R")C(O)N(R1 2 )(R 3 ), or -N(R")C(O)OR 9 ; -314 provided that when W is -0- or -N(R 5 )-, then R 3 and R 4 are not halo, -SH, -OR', -SR' 9 , -S(O)N(R")(R 12 ), -S(0) 2 N(R 1 )(R' 2 ), -N(Rl 1 )(R 12 ), -N(R 1 )C(O)R 8 , -N(R")S(O)R", -N(R 1 )C(O)N(R1 2 )(R 13 ), or -N(R 1 )C(0)OR 9 ; and provided that when X is -N(R 5 )-, W is -- C(O)- and U is a bond, R 3 , R 4 , R 6 and R 7 5 are not halo, -CN, -SH, -OR', -SR", -S(O)N(R')(R' 2 ) or -S(0) 2 N(R)(R 2 ); or R 3 , R 4 , R 6 and R 7 , together with the carbon to which they are attached, form a 3-7 membered cycloalkyl group optionally substituted by R' 4 or a 3-7 membered cycloalkylether optionally substituted by R 14 or R 3 and R 4 or R 6 and R 7 together with the carbon to which they are attached, 10 are combined to form multicyclic groups such as A B or A SM R 14 R 1 4 R19 ; wherein M is -CH 2 -, S, -N(R' 9 )- or 0, A and B are independently aryl or heteroaryl and q is 0, 1 or 2 provided that when q is 2, one M must be a carbon atom and when 15 q is 2, M is optionally a double bond; and with the proviso that when R 3 , R 4 , R 6 and R 7 form said multicyclic groups A B or A 1 KIM),,3FR14 R 1 R 14 R 14 M then adjacent R 3 and R 4 or R 6 and R 7 groups cannot be combined to form said multicyclic groups; 20 R 8 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -OR' 5 , -N(R1 5 )(R' 6 ), -N(R' 5 )C(O)R 1 6 , -N(R' 5 )S(O)R 6 , -N(R 15 )S(O) 2 R", -N(R' 5 )S(O) 2 N(R 6 )(R 7 ), -N(R 1 )S(O)N(RI 6 )(R' 7 ), -N(R' 5 )C(O)N(R' 6 )(R 7 ) and -N(R' 5 )C(0)OR 16 ; -315 R 9 is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl; R 1 * is independently selected from the group consisting of H, alkyl, alkenyl, 5 cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl and -N(R")(R); R 1 , R 12 and R 13 are independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -C(O)R 8 , -C(O)OR', -S(O)R' 0 , -S(O) 2 R' 1 , -C(O)N(R")(R 8 ), 10 -S(O)N(R' 5 )(R 16 ), -S(O) 2 N(R' 5 )(R' 6 ) and -CN; R 14 is 1-5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, -CN, -OR's, -C(O)R 15 , -C(0)OR 15 , -C(O)N(R 5 )(R 16 ), -SR 15 , -S(O)N(R 15 )(R 16 ), -S(0) 2 N(R 5 )(R6), 15 -C(=NOR 5 )R 16 , -P(O)(0R 1 5 )(0R 1 8 ), -N(R 5 )(R 16 ), -N(R'-)C(O)R 16 , -N(R'S)S(O)R' 6 , -N(R 15 )S(O) 2 R 16 , -N(R 15 )S(O) 2 N(R 6 )(R 17 ), -N(R 15 )S(O)N(R 16 )(R 1 7 ). -N(R)C(O)N(R)(R1 7 ) and -N(R'")C(O)OR 8 ; R, 15 R 16 and R' 7 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, 20 heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, arylheterocycloalkyl, Rl 8 -alkyl, R' 8 -cycloalkyl, R 1 -cycloalkylalkyl, R1 8 -heterocycloalkyl, R -heterocycloalkylalkyl, R -aryl, R 1 "-arylalkyl, R 8-heteroaryl and R 18 heteroarylalkyl; or R' 5 , R 16 and R' 7 are R2 0 R23 R R 23 0 N or \r )Ym 4) 25 "; wherein R 23 numbers 0 to 5 substituents, m is 0 to 6 and n is 1 to 5; R 18 is 1-5 substituents independently selected from the group consisting of alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, -NO 2 , halo, heteroaryl, HO alkyoxyalkyl, -CF 3 , -CN, alkyl-CN, -C(O)R' 9 , -C(O)OH, -C(O)OR 19 , -C(O)NHR20, 30 -C(O)NH 2 , -C(O)NH 2 -C(O)N(aky) 2 , -C(O)N(alkyl)(aryl), -C(O)N(alkyl)(heteroaryl), -316 -SR'9, -S(0)2R20, -S(O)NH2, -S(0)NH(alkyl), -S(O)N(alkyl)(alkyl), -S(O)NH(aryl), -S(O) 2 NH 2 , -S(0) 2 NHR" 9 , -S(0) 2 NH(heterocycloalkyl), -S(0) 2 N(alkyl) 2 , -S(0) 2 N(alkyl)(aryl), -OCF 3 , -OH, -OR", -0-heterocycloalkyl, -0-cycloalkylalkyl, -0 heterocycloalkylalkyl, -NH 2 , -NHR 20 , -N(alkyl) 2 , -N(arylalkyl) 2 , -N(arylalkyl) 5 (heteroarylalkyl), -NHC(O)R2", -NHC(O)NH 2 , -NHC(O)NH(alkyl), -NHC(O)N(alkyl)(alkyl), -N(alkyl)C(O)NH(alkyl), -N(alkyl)C(O)N(alkyl)(alkyl), -NHS(0) 2 R 20 , -NHS(O) 2 NH(alkyl), -NHS(O) 2 N(alkyl)(alkyl), -N(alkyl)S(0) 2 NH(alkyl) and -N(alkyl)S(0) 2 N(alkyl)(alkyl); or two R 18 moieties on adjacent carbons can be linked together to form <> or 10 , 0o R 19 is alkyl, cycloalkyl, aryl, arylalkyl or heteroarylalkyl; R2 is alkyl, cycloalkyl, aryl, halo substituted aryl, arylalkyl, heteroaryl or heteroarylalkyl; and wherein each of the alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, 15 heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl groups in R', R 2 , R , R 4 , R 5 , R , R , Ra, R 9 , R 10 , R", R , R1 3 and R" are independently unsubstituted or substituted by 1 to 5 R 2 1 groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, 20 heteroarylalkyl, halo, -CN, -OR 15 , -C(O)R' 5 , -C(O)OR 1 s, -C(O)N(R")(R 16 ), -SR's, -S(O)N(R)(R 16 ), -CH(R' 5 )(R 1 ), -S(0) 2 N(R 1 5 )(R' 6 ), -C(=NOR 15 )R6, -P(O)(OR's)(OR 6 ), -N(R 15 )(R 16 ), -alkyl-N(R' 5 )(R1 6 ), -N(Rls)C(O)R1 6 , -CH 2 N(R' 5 )C(O)R 6 , -CH 2 -N(R' 5 )C(O)N(R 6 )(R 17 ), -CH 2 -R' 5 ; -CH 2 N(R' 5 )(R 16 ), -N(R' 5 )S(O)R' 6 , -N(R'.)S(O) 2 R 16 , -CH 2 -N(R' 5 )S(0) 2 R' 6 , -N(R' 5 )S(0) 2 N(RI 6 )(R4 7 ), 25 -N(R' 1 )S(O)N(R' 6 )(R' 7 ), -N(R' 5 )C(O)N(R' 6 )(R 17 ), -CH 2 -N(Rls)C(O)N(R 6 )(R 7 ), -N(R' 5 )C(O)OR' 6 , -CH 2 -N(R 15 )C(O)OR 16 , -S(O)R' 5 , =NOR 1 5 , -N 3 , -NO 2 and -S(0) 2 R' 1 ; and wherein each of the alkyl, cycloalkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl groups in R 2 1 are independently unsubstituted or substituted by 1 30 to 5 R2 groups independently selected from the group consisting of alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, halo, -CF 3 , -CN, -OR , -C(0)R'', -C(0)OR", -alkyl-C(O)OR'", C(O)N(R'')(R'6), -SR, -317 -S(O)N(R 1 5 )(R' 6 ), -S(O) 2 N(R' 5 )(R 16 ), -C(=NOR 15 )R 16 , -P(O)(ORIS)(OR 16 ), -N(R' 5 )(R 16 ), -alkyl-N(R 15 )(R 16 ), -N(R 15 )C(O)R' 6 , -CH-N(R 15 )C(O)R 6 , -N(R 15 )S(O)R' 6 , -N(R 15 )S(0) 2 R", -CH-N(Rs)S(O) 2 R 6 , -N(R 15 )S(0) 2 N(R 16 )(R' 7 ), -N(R 15 )S(O)N(R 16 )(R 17 ), -N(R 1 5 )C(O)N(R )(R 7), -CH 2 -N(R 15 )C(O)N(R, 6 )(R4), 5 -N(R 15 )C(0)ORr, -CH 2 -N(R 1 )C(0)OR 16 , -N 3 , =NOR' 5 , -NO 2 , -S(O)R' 5 and -S(0) 2 R' 5 ; or two R 2 1 or two R22 moieties on adjacent carbons can be linked together to form ' ;> and when R 2 1 or R22 are selected from the group consisting of -C(=NOR' 5 )R' 6 , -N(R3)(O)R6, -CH 2 -N(R 5 )C(O)R, -N(R' 5 )S(O)R, 10 -N(R 15 )S(0) 2 Rr, -CH 2 -N(R' 1 )S(O) 2 R 16 , -N(R 1 5 )S(O) 2 N(R' 6 )(R 7 ), -N(R 1 5)S(O)N(R 16 )(R 7 ), -N(R' 5 )C(O)N(R 1 6)(R 17 ), -CH 2 -N(R 15 )C(O)N(R 16 )(RI), -N(R 15 )C(O)OR1 6 and -CH 2 -N(R 1 5 )C(0)OR 16 , R's and R' 6 together can be a C2 to C4 chain wherein, optionally, one, two or three ring carbons can be replaced by -C(0) or -N(H)- and R 15 and R 16 , together with the atoms to which they are attached, form a 15 5 to 7 membered ring, optionally substituted by R 23 ; R2 is 1 to 5 groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, -CN, -OR 24 -C(O)R 24 , -C(O)OR 24 , -C(O)N(R 24 )(R 2 5 ), -SR 24 , -S(O)N(R 24 )(R 2 s), -S(O) 2 N(R 2 4 )(R 2 s), 20 -C(=NOR 24 )R 2 5 , -P(O)(OR 2 4 )(OR 25 ), -N(R 2 4 )(R 2 s), -alkyl-N(R 24 )(R 2 5 ), -N(R 24 )C(O)R 2 5 , -CH 2 -N(R 24 )C(O)R 25 , -N(R 24 )S(O)R 25 , -N(R 24 )S(O) 2 R 2 5 , -CH 2 -N(R 24 )S(O) 2 R 25 , -N(R 2 4 )S(O) 2 N(R 2 5 )(R 26 ), -N(R 24 )S(O)N(R 25 )(R 2 6 ), -N(R 24 )C(O)N(R 25 )(R6), -CH 2 -N(R 24 )C(O)N(R 2 5 )(R 2 6 ), -N(R 24 )C(O)OR 25 , -CH 2 -N(R 2 4 )C(0)OR 2 5 , -S(O)R 2 4 and -S(0) 2 R 24 ; and wherein each of the alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, 25 heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl groups in R 23 are independently unsubstituted or substituted by 1 to 5 R 2 7 groups independently selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, -CF 3 , -CN, -OR 24 , -C(O)R 24 , -C(O)OR 24 , alkyl-C(O)OR 24 , C(O)N(R 24 )(R 2 5 ), -SR 24 , -S(O)N(R 24)(R2), -S(O) 2 N(R 24)(R 2), -C(=NOR 24 )R 2 5 , 30 -P(O)(OR 2 4 )(OR 2 5 ), -N(R 24 )(R 2 s), -alkyl-N(R 24)(R ), -N(R 4)C(O)R 2 s, -CH 2 -N(R 24 )C(O)R 25 , -N(R 24 )S(O) R 25 , -N(R 24 )S(O) 2 R 25 , -CH 2 -N(R 24 )S(O) 2 R 2 5 , -N(R 24 )S(O) 2 N(R 25 )(R 2 6 ), -N(R 24 )S(O)N(R 2 5 )(R 26 ), -N(R 24 )C(O)N(R 2 5 )(R 2 6 ), -318 -CH 2 -N(R24)C(O)N(R2 5 )(R 26 ), -N(R 24 )C(O)OR 2 5 , -CH 2 -N(R 24 )C(O)OR 25 , -S(O)R 24 and -S(0)2 R24; R 24 , R 2 s and R 2 ' are independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, 5 heteroaryl, heteroarylalkyl, arylcycloalkyl, R 27 -alkyl, R 27 -cycloalkyl, R 27 -cycloalkylalkyl, R 27-heterocycloalkyl, R 27 -heterocycloalkylalkyl, R 27-aryl, R 27-arylalkyl, R 27 -heteroaryl and R 27 -heteroarylakyl; R 2 7 is 1-5 substituents independently selected from the group consisting of alkyl, aryl, arylalkyl, -NO 2 , halo, -CF 3 , -CN, alkyl-CN, -C(O)Ras, -C(O)OH, -C(O)ORes 10 -C(O)NHR", -C(O)N(alkyl) 2 , -C(O)N(alkyl)(aryl), -C(O)N(alkyl)(heteroaryl), -SR 28 , -S(0) 2 R 29 , -S(O)NH 2 , -S(O)NH(alkyl), -S(O)N(alkyl)(alkyl), -S(O)NH(aryl), -S(O) 2 NH 2 , -S(O) 2 NHR 2 , -S(O) 2 NH(aryl), -S(0) 2 NH(heterocycloalkyl), -S(O) 2 N(alkyl) 2 , -S(O) 2 N(alkyl)(aryl), -OH, -OR 2, -0-heterocycloalkyl, -0-cycloalkylalkyl, -0-heterocycloalkylalkyl, -NH 2 , -NHRa, -N(alkyl) 2 , -N(arylalkyl) 2 , 15 -N(arylalkyl)(heteroarylalkyl), -NHC(O)R 29 , -NHC(O)NH 2 , -NHC(O)NH(alkyl), -NHC(O)N(alkyl)(alkyl), -N(alkyl)C(O)NH(alkyl), -N(alkyl)C(O)N(alkyl)(alkyl), -NHS(O) 2 R 29 , -NHS(O) 2 NH(alkyl), -NHS(O) 2 N(alkyl)(alkyl), -N(alkyl)S(0) 2 NH(alkyl) and -N(alkyl)S(0) 2 N(alkyl)(alkyl); R 2 is alkyl, cycloalkyl, arylalkyl or heteroarylakyl; and 20 R is alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; provided that when W is -C(0)- and U is a bond, R 1 is not optionally substituted phenyl, and that when U is -C(0)- and W is a bond, R 5 is not optionally substituted phenyl; provided that neither R' nor R 5 is -C(O)-alkyl-azetidinone or alkyl di-substituted 25 with (-COOR 15 or -C(O)N(R 15 )(R 16 )) and (-N(R' 5 )(R' 8 ), -N(R' 5 )C(O)R 16 , -N(R 15 )S(O)R 6 , -N(R")S(0) 2 R 16 , -N(R 1 5 )S(0) 2 N(R 16 )(R1 7 ), -N(R' 5 )S(O)N(R)(R 17 ), -N(R'5)C(0)N(Rl)(Rl), or -N(R' 5 )C(0)OR 16 ); provided that when R 1 is methyl, X is -N(R 5 )-, R 2 is H, W is -C(0)- and U is a bond, (R 3 , R 4 ) is not (H, H), (phenyl, phenyl), (H, phenyl), (benzyl, H), (benzyl, 30 phenyl), (i-butyl, H), (i-butyl, phenyl), (OH-phenyl, phenyl), (halo-phenyl, phenyl), or (CH 3 0-phenyl, N0 2 -phenyl); and when W is a bond and U is -C(0)-, (R 3 , R 4 ) is not (H, H), (phenyl, phenyl), (H, phenyl), (benzyl, H), (benzyl, phenyl), (i-butyl, H), (i-butyl, phenyl), (OH-phenyl, phenyl), (halo-phenyl, phenyl), or (CH 3 0-phenyl, N0 2 -phenyl); -319 provided that when X is -N(R 5 )-, R' and R 5 are each H, W is -C(O)- and U is a bond, (R 3 , R 4 ) is not (optionally substituted phenyl, optionally substituted benzyl), (optionally substituted phenyl, heteroarylalkyl) or (heteroaryl, heteroarylalkyl); provided that when U is a bond, W is -C(0)-, and R 3 and R 4 form a ring with 5 the carbon to which they are attached, R' is not 2-CF 3 -3-CN-phenyl; provided that when X is -N(Rs)-, U is -0- and W is a bond or -C(R")(Rl)-, (R 3 ,R 4 ) is not (H, -NHC(0)-alkyl-heteroaryl) or (H, alkyl-NHC(0)-alkyl-heteroaryl); and provided that when X is -N(R 5 )-, R' and R 5 are not -alkylaryl-aryl-S0 2 N(R'")(R 16 ) wherein R 15 is H and R 16 is heteroaryl; 10 provided that when R' is R 2 1 -aryl or R 21 -arylalkyl, wherein R21 is -OCF 3 , -S(0)CF 3 , -S(0) 2 CF 3 , -S(0)alkyl, -S(0) 2 alkyl , -S(0) 2 CHF 2 , -S(0) 2 CF 2 CF 3 , -OCF 2 CHF 2 , -OCHF 2 , -OCH 2 CF 3 , -SF 5 or -S(0) 2 NR' 5 R'6; wherein R's and R 16 are independently selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, R 18 -alkyl, R 18 -cycloalkyl, R' 8 _ 15 heterocycloalkyl, R 18 -aryl and R' 8 -heteroaryl; U is a bond or -CH 2 ; and X is -N(R 5 )-; then R 5 is H; provided that when U is a bond, R 3 and R 4 are alkyl, or R) 1 R 2R \21 !0 where R21 is halo, -CN, alkyl, alkoxy, haloalkyl or haloalkoxy, or R 3 and R 4 , together with the carbon to which they are attached, form a 3-7 membered cycloalkyl group, and R' is - 320 N-R 2 1a <I N aR N, N , 21 a where a is 0 to 6 and R22 is alkyl, alkoxy, halo, -CN, -OH, -NO 2 or haloalkyl; then R 2 1 a is not H, -C(0) 2 R' , wherein R 15 is selected from the group consisting of alkyl, cycloalkyl and alkyl substituted with phenyl, alkyl or alkyl-R 22 5 wherein R2 is selected from the group consisting of phenyl, phenyl substituted with alkyl, and\ wherein R2 is selected from the group consisting of H, methoxy, nitro, oxo, -OH, halo and alkyl, N O R22 R and 10R2 -321

2. A compound of claim 1 having the structure N..R2 N.- R2 N..-R2 N''2 RN NR1s N NR1R N ),N R7 NR I R 3 I I R 3 I R 3 IR3 I U S(O)1. 2 U U O U S()1-2 R4 R4 R4 R4 5 IA IB IC ID R6N--N. R2 N 2N 2 R'F2 R R 6 - N R N'' R 1 NR1 R' RN ( NR R 1 N-R O U+O - R1 U R3 R4 R4 R4 R4 IE IF IG or IH

3. A compound of claim 2 wherein in structures IA to IF, U is a bond or 10 -C(R 6 )(R 7 )-.

4. A compound of claim 2 wherein in structure IB, U is a bond.

5. A compound of claim 2 of the structure IB wherein U is -C(R 6 )(R 7 )-. 15

6. A compound of claim 1 wherein R 2 is H.

7. A compound of claim 1 wherein R 3 , R 4 , R6 and R 7 are independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, 20 heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, -CH 2 -0 Si(R9)(R'")(R''), -SH, -CN, -OR?, -C(O)R8, -C(O)OR9, -C(0)N(R")(R 1), -SR19, -S(O)N(R")(R 12 ), -S(O) 2 N(R)(R 12 ), -N(R 1 )(R 12 ), -N(Rl )C(O)R 8 , -N(R 1 )S(O)R 1 0 , -N(R1')C(O)N(R1 2 )(R 13 ), -N(R')C(0)OR 9 and -C(=NOH)R". - 322

8. A compound of claim 1 wherein R 3 , R 4 , R 6 and R 7 are selected from the group consisting of aryl, heteroaryl, heteroarylalkyl, arylalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, alkyl and cycloalkylalkyl. 5

9. A compound of claim 1 wherein U is a bond or -C(O)-; W is a bond or -C(O)-; X is -N(R)-; R 1 is H, alkyl, R 21 -alkyl, arylalkyl, R 2 1 -arylalkyl, cycloalkylalkyl, R 21 10 cycloalkylalkyl, heterocycloalkyalkyl or R 2 1 -heterocycloalkylalkyl, R2 is H; R 3 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R 2 1 -alkyl, R 2 1 _ cycloalkylalkyl, R21-cycloalkyl, R 21 -aryl or R 2 1 -arylalkyl; R 4 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R 2 1 -alkyl, R 21 _ 15 cycloalkylalkyl, R 21 -cycloalkyl, R 21 -aryl or R 2 1 -arylalkyl; R' is H, alkyl, R 2 1 -alkyl, arylalkyl, R 2 1 -arylalkyl, cycloalkylalkyl, R21_ cycloalkylalkyl, heterocycloalkyalkyl or R 2 1 -heterocycloalkylalkyl; R6 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R21-alkyl, R 21 cycloalkylalkyl, R 21-cycloalkyl, R 21 -aryl or R21-arylalkyl; 20 R 7 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R21-alkyl, R 21 _ cycloalkylalkyl, R21 -cycloalkyl, R 2 1 -aryl or R 2 1 -arylalkyl; R23 N . R15 1 R , R 1 and R' 7 is H, R 18 -alkyl, alkyl or m; R 2 1 is alkyl, aryl, halo, -OR 1 5 , -NO 2 , -C(O)R 5 , -CH 2 -N(R 1 5 )C(O)N(R 1 6 )(R") or -CH(R 15)(R'); 25 n is 1; m is 1; R 18 is -OR20 R is aryl; and 30 R23 is alkyl. - 323

10. A compound of claim 9 wherein R 3 , R 4 , R' and R are R21 or 5 and R and R 5 is H, CH 3 , / N O or

11. A compound selected from the group consisting of: 10 a ON HNO HN( - 324 a ~0 0 HN=( 0 H 0N N-(' NH\ Br6 HN<(N0NN NNO HN-( 0~ - 325 N 0 0 F HN(

12. A compound of claim 1 wherein U is a bond or -C(0)-; W is a bond or -C(0)-; 5 X is -N(R)-; R' is H, alkyl, R 2 1 -alkyl, arylalkyl, R 2 1 -arylalkyl, cycloalkylalkyl, R 21_ cycloalkylalkyl, heterocycloalkyakyl or R 2 1 -heterocycloalkylalkyl, R2 is H; R 3 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R 2 1 -alkyl, R 21 10 cycloalkylalkyl, R 2 1 -cycloalkyl, R 2 1 -aryl, R 21 -arylalkyl, heteroarylalkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl, R 21-heteroarylalkyl, R 21-heteroaryl, R 21 heterocycloalkyl or R21-heterocycloalkylalkyl; R 4 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R 21 -alkyl, R 21 _ cycloalkylalkyl, R 21 -cycloalkyl, R21-aryl, R 2 1 -arylalkyl, heteroarylakyl, heteroaryl, - 326 heterocycloalkyl, heterocycloalkylalkyl, R 2 1 -heteroarylalkyl, R 2 1 -heteroaryl, R 21 _ heterocycloalkyl or R 2 1 -heterocycloalkylalkyl; R 5 is H, alkyl, R 2 1 -alkyl, arylalkyl, R21-arylalkyl, cycloalkylalkyl, R 21 . cycloalkylalkyl, heterocycloalkyalkyl or R 2 1 -heterocycloalkylalkyl; 5 R 6 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R 2 1 -alkyl, R 2 1 . cycloalkylalkyl, R 2 1 -cycloalkyl, R21 -aryl, R 21 -arylalkyl, heteroarylalkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl, R 21-heteroarylalkyl, R 21 -heteroaryl, R21 heterocycloalkyl or R 2 1 -heterocycloalkylalkyl; R 7 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R 21 -alkyl, R 21 _ 10 cycloalkylalkyl, R 2 1 -cycloalkyl, R 21 -aryl, R 21 -arylalkyl, heteroarylalkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl, R 2 1 -heteroarylalkyl, R 2 1 -heteroaryl, R 21 . heterocycloalkyl or R 2 1 -heterocycloalkylalkyl; R 15 , R" and R 17 is H, cycloalkyl, cycloalkylalkyl, R' 8 -alkyl, alkyl, aryl, R 18 -aryl, R 23 R23 (N R 18 -arylalkyl, arylalkyl, M or m; 15 n is 1 or 2; m is 0 or 1; R 1 is -OR 20 or halo; R2o is aryl or halo substituted aryl; R21 is alkyl, aryl, heteroaryl, R -alkyl, R 22 -aryl, R22 -heteroaryl, halo, 20 heterocycloalkyl, -N(R' 5 )(R1 6 ), -OR 1 5 , -NO 2 , -C(O)R 15 , -N(R' 5 )C(O)R 6 , -N(R' 5 )S(0) 2 R'", -CH 2 -N(R 15 )C(O)N(R'1)(R 17 ), -N(R' 5 )C(O)N(R, 6 )(R 17 ) or -CH(R 1 5 )(R 16 ); R2 is -OR' 5 or halo and 25 Re2 is H or alkyl.

13. A compound selected from the group consisting of: - 327 NN 0 NH N~N 0 timcc NH"' N 0 HCC NCN 0 H /\ \/ ?H3 H 3 \ NH 0 N\1 -NH N+ 0 0S - 328 ItC~ NH 0N VOH 3 Y N N 0 N NHCNH 0 N H 0 N N H 3 \ ~>NH 011. N. - 329 NH N 0 NH -O H 3 -'NN NH N 0 0 ~ NH N /kN-C 3 0 /7NN 00c F h -, N 0 - 330 N3 N N 0 0* N QONNr-NH NNN NcNl 0ac NHN o N NHI Hck NHN NO /3C \NH0 - 331 o3 NH NH 0 N "N\cN NN H 3 0\ NH 0D N 0> H ~ c N - 332 NH NH NH N .,-CH, o N -11H H F - HA NH 0 N H3C- HNN 0 HC N \ CH 3 H 3 C NH \N CH3 0 N HN N O N N' \ CH 3

14. A pharmaceutical composition comprising an effective amount of a compound of claim 1 and a pharmaceutically effective carrier. 5

15. A method of inhibiting aspartyl protease comprising administering to a patient in need of such treatment an effective amount of a compound of claim 1.

16. A method of treating cardiovascular diseases, cognitive and 10 neurodegenerative diseases, and the methods of inhibiting of Human Immunodeficiency Virus, plasmepins, cathepsin D and protozoal enzymes.comprising - 333 administering to a patient in need of such treatment an effective amount of a compound of claim 1.

17. The method of claim 16 wherein a cognitive or neurodegenerative disease is 5 treated.

18. The method of claim 17 wherein Alzheimer's disease is treated.

19. A pharmaceutical composition comprising an effective amount of a compound 10 of claim 1, and an effective amount of a cholinesterase inhibitor or a muscarinic antagonist in a pharmaceutically effective carrier.

20. A method of treating a cognitive or neurodegenerative disease comprising administering to a patient in need of such treatment an effective amount of a 15 compound of claim 1 in combination with an effective amount of a cholinesterase inhibitor.