PATENT ABSTRACT
Disclosed are compounds of the formula I 
                                 
or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein W, X, U, R 1 , R 2 , R 3 , and R 4 , are as defined herein, and pharmaceutical compositions comprising the compounds of formula I. Also disclosed is the 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, cathepsin D and protozoal enzymes. Also disclosed are methods of treating cognitive or neurodegenerative diseases using the compounds of formula I in combination with a cholinesterase inhibitor or a muscarinic antagonist.

PATENT DESCRIPTION
CROSS-REFERENCE TO RELATED APPLICATIONS 
     The present application is a divisional of application U.S. Ser. No. 12/480,391, filed Jun. 8, 2009 now U.S. Pat. No. 8,178,513, which is a divisional of application U.S. Ser. No. 11/010,772, filed Dec. 13, 2004, now U.S. Pat. No. 7,592,348, which claims the benefit of priority to U.S. Provisional Application No. 60/529,535, filed Dec. 15, 2003, each of which is incorporated herein by reference. 
    
    
     FIELD OF THE INVENTION 
     This invention relates to heterocyclic aspartyl protease inhibitors, pharmaceutical compositions comprising said compounds, their use in the treatment of cardiovascular diseases, cognitive and neurodegenerative diseases, and their use as inhibitors of the Human Immunodeficiency Virus, plasmepsins, cathepsin D and protozoal enzymes. 
     BACKGROUND 
     Eight human aspartic proteases of the A1 (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, et al. N Engl J Med 1974; 291:381-401/446-57). The octapeptide Angiotensin-II, a potent vasoconstrictor and stimulator for release of adrenal aldosterone, was processed from the precursor decapeptide Angiotensin-I, which in turn was processed from angiotensinogen by the renin enzyme. Angiotensin-II was also found to play roles in vascular smooth muscle cell growth, inflammation, reactive oxygen species generation and thrombosis, influence atherogenesis and vascular damage. Clinically, the benefit of interruption of the generation of angiotensin-II through antagonism of conversion of angiotensin-I 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-I, i.e. the inhibition of renin enzyme, is expected to have similar but not identical effects. Since renin is an aspartyl protease whose only natural substrate is angiotensinogen, it is believed that there would be less frequent adverse effect for controlling high blood pressure and related symptoms regulated by angiotensin-II 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 peptide fragments. It has been linked to numerous diseases including, Alzheimers, disease, connective tissue disease, muscular dystrophy and breast cancer. 
     Alzheimer&#39;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 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 progression. Therefore there is an unmet medical need for AD treatments that halt disease progression. 
     Pathological hallmarks of AD are the deposition of extracellular β-amyloid (Aβ) plaques and intracellular neurofibrillary tangles comprised of abnormally phosphorylated protein tau. Individuals with AD exhibit characteristic Aβ deposits, in brain regions known to be important for memory and cognition. It is believed that Aβ is the fundamental causative agent of neuronal cell loss and dysfunction which is associated with cognitive and behavioral decline. Amyloid plaques consist predominantly of Aβ peptides comprised of 40-42 amino acid residues, which are derived from processing of amyloid precursor protein (APP). APP is processed by multiple distinct protease activities. Aβ peptides result from the cleavage of APP by β-secretase at the position corresponding to the N-terminus of Aβ, and at the C-terminus by γ-secretase activity. APP is also cleaved by α-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 β-secretase activity responsible for cleavage of APP at the position corresponding to the N-terminus of Aβ peptides. 
     Accumulated biochemical and genetic evidence supports a central role of Aβ in the etiology of AD. For example, Aβ has been shown to be toxic to neuronal cells in 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 Aβ and are considered causative of AD. 
     Since Aβ peptides are formed as a result β-secretase activity, inhibition of BACE-1 should inhibit formation of Aβ peptides. Thus inhibition of BACE-1 is a therapeutic approach to the treatment of AD and other cognitive and neurodegenerative diseases caused by Aβ plaque deposition. 
     Human immunodeficiency virus (HIV), is the causative agent of acquired immune deficiency syndrome (AIDS). It has been clinically demonstrated that 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. 
     In addition, Human T-cell leukemia virus type I (HTLV-I) is a human retrovirus that has been clinically associated with adult T-cell leukemia and other chronic diseases. Like other retroviruses, HTLV-I 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-I Protease and Synthesis of Inhibitors for the treatment of HTLV-I Infection 55 th  Southeast Regional Meeting of the American Chemical Society, Atlanta, Ga., US Nov. 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 I, II, IV 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. I, II, IV and HAP), have been used to kill malarial parasites, thus treating patients thus afflicted. Certain compounds also exhibited inhibitory activity against Cathespin D. 
     SUMMARY OF THE INVENTION 
     The present invention relates to compounds having the structural formula I 
                                
or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein
 
     W is a bond, —C(═S)—, —S(O)—, —S(O) 2 —, —C(═O)—, —O—, —C(R 6 )(R 7 )—, —N(R 5 )— or —C(═N(R 5 ))—; 
     X is —O—, —N(R 5 )— or —C(R 6 )(R 7 )—; provided that when X is —O—, U is not —O—, —S(O)—, —S(O) 2 —, —C(═O)— or —C(═NR 5 )—; 
     U is a bond, —S(O)—, —S(O) 2 —, —C(O)—, —O—, —P(O)(OR 15 )—, —C(═NR 5 )—, —(C(R 6 )(R 7 )) b — or —N(R 5 )—; wherein b is 1 or 2; provided that when W is —S(O)—, —S(O) 2 —, —O—, or —N(R 5 )—, U is not —S(O)—, —S(O) 2 —, —O—, or —N(R 5 )—; provided that when X is —N(R 5 )— and W is —S(O)—, —S(O) 2 —, —O—, or —N(R 5 )—, then U is not a bond; 
     R 1 , R 2  and R 5  are independently selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, —OR 15 : —CN, —C(O)R 8 , —C(O)OR 9 , —S(O)R 10 , —S(O) 2 R 10 , —C(O)N(R 11 )(R 12 ), —S(O)N(R 11 )(R 12 ), —S(O) 2 N(R 11 )(R 12 ), —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, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —CH 2 —O—Si(R 9 )(R 10 )(R 19 ), —SH, —CN, —OR 9 , —C(O)R 8 , —C(O)OR 9 , —C(O)N(R 11 )(R 12 ), —SR 19 , —S(O)N(R 11 )(R 12 ), —S(O) 2 N(R 11 )(R 12 ), —N(R 11 )(R 12 ), —N(R 11 )C(O)R 8 , —N(R 11 )S(O)R 10 , —N(R 11 )C(O)N(R 12 )(R 13 ), —N(R 11 )C(O)OR 9  and —C(═NOH)R 8 ; provided that when U is —O— or —N(R 5 )—, then R 3 , R 4 , R 6  and R 7  are not halo, —SH, —OR 9 , —SR 19 , —S(O)N(R 11 )(R 12 ), —S(O) 2 N(R 11 )(R 12 ), —N(R 11 )(R 12 ), —N(R 11 )C(O)R 8 , —N(R 11 )S(O)R 10 , —N(R 11 )C(O)N(R 12 )(R 13 ), or —N(R 11 )C(O)OR 9 ; provided that when W is —O— or —N(R 5 )—, then R 3  and R 4  are not halo, —SH, —OR 9 , —SR 19 , —S(O)N(R 11 )(R 12 ), —S(O) 2 N(R 11 )(R 12 ), —N(R 11 )(R 12 ), —N(R 11 )C(O)R 8 , —N(R 11 )S(O)R 10 , —N(R 11 )C(O)N(R 12 )(R 13 ), or —N(R 11 )C(O)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  are not halo, —CN, —SH, —OR 9 , —SR 19 , —S(O)N(R 11 )(R 12 ) or —S(O) 2 N(R 11 )(R 12 ); 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 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, are combined to form multicyclic groups such as 
                                
wherein M is —CH 2 —, S, —N(R 19 )— or O, 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
 
                                
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 15 , —N(R 15 )(R 16 ), —N(R 15 )C(O)R 16 , —N(R 15 )S(O)R 16 , —N(R 15 )S(O) 2 R 16 , —N(R 15 )S(O) 2 N(R 16 )(R 17 ), —N(R 15 )S(O)N(R 16 )(R 17 ), —N(R 15 )C(O)N(R 16 )(R 17 ) and —N(R 15 )C(O)OR 16 ; 
     R 9  is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl; 
     R 10  is independently selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl and —N(R 15 )(R 16 ); 
     R 11 , 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 9 , —S(O)R 10 , —S(O) 2 R 10 , —C(O)N(R 15 )(R 16 ), —S(O)N(R 15 )(R 16 ), —S(O) 2 N(R 15 )(R 16 ) 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 15 , —C(O)R 15 , —C(O)OR 15 , —C(O)N(R 15 )(R 16 ), —SR 15 , —S(O)N(R 15 )(R 16 ), —S(O) 2 N(R 15 )(R 16 ), —C(═NOR 15 )R 16 , —P(O)(OR 15 )(OR 16 ), —N(R 15 )(R 16 ), —N(R 15 )C(O)R 16 , —N(R 15 )S(O)R 16 , —N(R 15 )S(O) 2 R 16 , —N(R 15 )S(O) 2 N(R 16 )(R 17 ), —N(R 15 )S(O)N(R 16 )(R 17 ), —N(R 15 )C(O)N(R 16 )(R 17 ) and —N(R 15 )C(O)OR 16 ; 
     R 15 , R 16  and R 17  are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, arylheterocycloalkyl, R 18 -alkyl, R 18 -cycloalkyl, R 18 -cycloalkylalkyl, R 18 -heterocycloalkyl, R 18 -heterocycloalkylalkyl, R 18 -aryl, R 18 -arylalkyl, R 18 -heteroaryl and R 18 -heteroarylalkyl; or 
     R 15 , R 16  and R 17  are 
                                
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 19 , —C(O)OH, —C(O)OR 19 , —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 19 , —S(O) 2 R 20 , —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 19 , —S(O) 2 NH(heterocycloalkyl), —S(O) 2 N(alkyl) 2 , —S(O) 2 N(alkyl)(aryl), —OCF 3 , —OH, —OR 20 , —O-heterocycloalkyl, —O-cycloalkylalkyl, —O-heterocycloalkylalkyl, —NH 2 , —NHR 20 , —N(alkyl) 2 , —N(arylalkyl) 2 , —N(arylalkyl)-(heteroarylalkyl), —NHC(O)R 20 , —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 20 , —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); 
     or two R 18  moieties on adjacent carbons can be linked together to form 
     
       
                 
         
             
             
         
      
     
     R 19  is alkyl, cycloalkyl, aryl, arylalkyl or heteroarylalkyl; 
     R 20  is alkyl, cycloalkyl, aryl, halo substituted aryl, arylalkyl, heteroaryl or heteroarylalkyl; 
     and wherein each of the alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl groups in R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13  and R 14  are independently unsubstituted or substituted by 1 to 5 R 21  groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —CN, —OR 15 , —C(O)R 15 , —C(O)OR 15 , —C(O)N(R 15 )(R 16 ), —SR 15 , —S(O)N(R 15 )(R 16 ), —CH(R 15 )(R 16 ), —S(O) 2 N(R 15 )(R 16 ), —C(═NOR 15 )R 16 , —P(O)(OR 15 )(OR 16 ), —N(R 15 )(R 16 ), -alkyl-N(R 15 )(R 16 ), —N(R 15 )C(O)R 16 , —CH 2 —N(R 15 )C(O)R 16 , —CH 2 —N(R 15 )C(O)N(R 16 )(R 17 ), —CH 2 —R 15 ; —CH 2 N(R 15 )(R 16 ), —N(R 15 )S(O)R 16 , —N(R 15 )S(O) 2 R 16 , —CH 2 —N(R 15 )S(O) 2 R 16 , —N(R 15 )S(O) 2 N(R 16 )(R 17 ), —N(R 15 )S(O)N(R 16 )(R 17 ), —N(R 15 )C(O)N(R 16 )(R 17 ), —CH 2 —N(R 15 )C(O)N(R 16 )(R 17 ), —N(R 15 )C(O)OR 16 , —CH 2 —N(R 15 )C(O)OR 16 , —S(O)R 15 , ═NOR 15 , —N 3 , —NO 2  and —S(O) 2 R 15 ; and wherein each of the alkyl, cycloalkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl groups in R 21  are independently unsubstituted or substituted by 1 to 5 R 22  groups independently selected from the group consisting of alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, halo, —CF 3 , —CN, —OR 15 , —C(O)R 15 , —C(O)OR 15 , -alkyl-C(O)OR 15 , C(O)N(R 15 )(R 16 ), —SR 15 , —S(O)N(R 15 )(R 16 ), —S(O) 2 N(R 15 )(R 16 ), —C(═NOR 15 )R 16 , —P(O)(OR 15 )(OR 16 ), —N(R 15 )(R 16 ), -alkyl-N(R 15 )(R 16 ), —N(R 15 )C(O)R 16 , —CH 2 —N(R 15 )C(O)R 16 , —N(R 15 )S(O)R 16 , —N(R 15 )S(O) 2 R 16 , —CH 2 —N(R 15 )S(O) 2 R 16 , —N(R 15 )S(O) 2 N(R 16 )(R 17 ), —N(R 15 )S(O)N(R 16 )(R 17 ), —N(R 15 )C(O)N(R 16 )(R 17 ), —CH 2 —N(R 15 )C(O)N(R 16 )(R 17 ), —N(R 15 )C(O)OR 16 , —CH 2 —N(R 15 )C(O)OR 16 , —N 3 , ═NOR 15 , —NO 2 , —S(O)R 15  and —S(O) 2 R 15 ; 
     or two R 21  or two R 22  moieties on adjacent carbons can be linked together to form 
     
       
                 
         
             
             
         
      
     
     and when R 21  or R 22  are selected from the group consisting of —C(═NOR 15 )R 16 , —N(R 15 )C(O)R 16 , —CH 2 —N(R 15 )C(O)R 16 , —N(R 15 )S(O)R 16 , —N(R 15 )S(O) 2 R 16 , —CH 2 —N(R 15 )S(O) 2 R 16 , —N(R 15 )S(O) 2 N(R 16 )(R 17 ), —N(R 15 )S(O)N(R 16 )(R 17 ), —N(R 15 )C(O)N(R 16 )(R 17 ), —CH 2 —N(R 15 )C(O)N(R 16 )(R 17 ), —N(R 15 )C(O)OR 16  and —CH 2 —N(R 15 )C(O)OR 16 , R 15  and R 16  together can be a C 2  to C 4  chain wherein, optionally, one, two or three ring carbons can be replaced by —C(O)— or —N(H)— and R 15  and R 16 , together with the atoms to which they are attached, form a 5 to 7 membered ring, optionally substituted by R 23 ; 
     R 23  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 25 ), —SR 24 , —S(O)N(R 24 )(R 25 ), —S(O) 2 N(R 24 )(R 25 ), —C(═NOR 24 )R 25 , —P(O)(OR 24 )(OR 25 ), —N(R 24 )(R 25 ), -alkyl-N(R 24 )(R 25 ), —N(R 24 )C(O)R 25 , —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 25 , —N(R 24 )S(O) 2 N(R 25 )(R 26 ), —N(R 24 )S(O)N(R 25 )(R 26 ), —N(R 24 )C(O)N(R 25 )(R 26 ), —CH 2 —N(R 24 )C(O)N(R 25 )(R 26 ), —N(R 24 )C(O)OR 25 , —CH 2 —N(R 24 )C(O)OR 25 , —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 R 23  are independently unsubstituted or substituted by 1 to 5 R 27  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 25 ), —SR 24 , —S(O)N(R 24 )(R 25 ), —S(O) 2 N(R 24 )(R 25 ), —C(═NOR 24 )R 25 , —P(O)(OR 24 )(OR 25 ), —N(R 24 )(R 25 ), -alkyl-N(R 24 )(R 25 ), —N(R 24 )C(O)R 25 , —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 25 , —N(R 24 )S(O) 2 N(R 25 )(R 26 ), —N(R 24 )S(O)N(R 25 )(R 26 ), —N(R 24 )C(O)N(R 25 )(R 26 ), —CH 2 —N(R 24 )C(O)N(R 25 )(R 26 ), —N(R 24 )C(O)OR 25 , —CH 2 —N(R 24 )C(O)OR 25 , —S(O)R 24  and —S(O) 2 R 24 ; 
     R 24 , R 25  and R 26  are independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, 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 -heteroarylalkyl; 
     R 27  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 28 , —C(O)OH, —C(O)OR 28 , —C(O)NHR 29 , —C(O)N(alkyl) 2 , —C(O)N(alkyl)(aryl), —C(O)N(alkyl)(heteroaryl), —SR 28 , —S(O) 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 28 , —S(O) 2 NH(aryl), —S(O) 2 NH(heterocycloalkyl), —S(O) 2 N(alkyl) 2 , —S(O) 2 N(alkyl)(aryl), —OH, —OR 29 , —O-heterocycloalkyl, —O-cycloalkylalkyl, —O-heterocycloalkylalkyl, —NH 2 , —NHR 29 , —N(alkyl) 2 , —N(arylalkyl) 2 , —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(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(O)— and U is a bond, R 1  is not optionally substituted phenyl, and that when U is —C(O)— and W is a bond, R 5  is not optionally substituted phenyl; 
     provided that neither R 1  nor R 5  is —C(O)-alkyl-azetidinone or alkyl di-substituted with (—COOR 15  or —C(O)N(R 15 )(R 16 )) and (—N(R 15 )(R 16 ), —N(R 15 )C(O)R 16 , —N(R 15 )S(O)R 16 , —N(R 15 )S(O) 2 R 16 , —N(R 15 )S(O) 2 N(R 16 )(R 17 ), —N(R 15 )S(O)N(R 16 )(R 17 ), —N(R 15 )C(O)N(R 16 )(R 17 ), or —N(R 15 )C(O)OR 16 ); 
     provided that when R 1  is methyl, X is —N(R 5 )—, R 2  is H, W is —C(O)— 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 O-phenyl, NO 2 -phenyl); and when W is a bond and U is —C(O)—, (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 O-phenyl, NO 2 -phenyl); 
     provided that when X is —N(R 5 )—, R 1  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(O)—, and R 3  and R 4  form a ring with the carbon to which they are attached, R 1  is not 2-CF 3 -3-CN-phenyl; 
     provided that when X is —N(R 5 )—, U is —O— and W is a bond or —C(R 6 )(R 7 )—, (R 3 , R 4 ) is not (H, —NHC(O)-alkyl-heteroaryl) or (H, alkyl-NHC(O)-alkyl-heteroaryl); and 
     provided that when X is —N(R 5 )—, R 1  and R 5  are not -alkylaryl-aryl-SO 2 —N(R 15 )(R 16 ) wherein R 15  is H and R 16  is heteroaryl; 
     provided that when R 1  is R 21 -aryl or R 21 -arylalkyl, wherein R 21  is —OCF 3 , —S(O)CF 3 , —S(O) 2 CF 3 , —S(O)alkyl, —S(O) 2 alkyl, —S(O) 2 CHF 2 , —S(O) 2 CF 2 CF 3 , —OCF 2 CHF 2 , —OCHF 2 , —OCH 2 CF 3 , —SF 5  or —S(O) 2 NR 15 R 16 ; 
     wherein R 15  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 18 -heterocycloalkyl, R 18 -aryl and R 18 -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, 
                                
where R 21  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 1  is 
                                
where a is 0 to 6 and R 22  is alkyl, alkoxy, halo, —CN, —OH, —NO 2  or haloalkyl;
 
     then R 21a  is not H, —C(O) 2 R 15 , wherein R 15  is selected from the group consisting of alkyl, cycloalkyl and alkyl substituted with phenyl, alkyl or alkyl-R 22 , wherein R 22  is selected from the group consisting of 
     phenyl, 
     phenyl substituted with alkyl, 
     and 
                                
wherein R 22  is selected from the group consisting of H, methoxy, nitro, oxo, —OH, halo and alkyl,
 
     
       
                 
         
             
             
         
      
     
     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 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&#39;s Disease; the method of inhibiting plasmepins I and II for treatment of malaria; the method of inhibiting Cathepsin D for the treatment of Alzheimer&#39;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 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&#39;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&#39;s 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, 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&#39;s disease. 
    
    
     DETAILED DESCRIPTION 
     Compounds of formula I wherein X, W and U are as defined above include the following independently preferred structures: 
     
       
                 
         
             
             
         
      
     
     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 of R 5 , when X is —N(R 5 )—, compounds of formula I wherein W is a bond and U is a bond, —S(O)—, —S(O) 2 —, —C(O)—, —O—, —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(O)—, —S(O) 2 —, —C(O)—, —O—, —C(R 6 )(R 7 )— or —N(R 5 )—. 
     More preferred compounds of the invention are those of formula IB wherein U 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 6  and R 7  are preferably selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —CH 2 —O—Si(R 9 )(R 10 )(R 19 ), —SH, —CN, —OR 9 , —C(O)R 8 , —C(O)OR 9 , —C(O)N(R 11 )(R 12 ), —SR 19 , —S(O)N(R 11 )(R 12 ), —S(O) 2 N(R 11 )(R 12 ), —N(R 11 )(R 12 ), —N(R 11 )C(O)R 8 , —N(R 11 )S(O)R 10 , —N(R 11 )C(O)N(R 12 )(R 13 ), —N(R 11 )C(O)OR 9  and —C(═NOH)R 8 . 
     R 3 , R 4 , R 6  and R 7  are preferably selected from the group consisting of aryl, heteroaryl, heteroarylalkyl, arylalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, alkyl and cycloalkylalkyl. 
     In a group of preferred compounds 
     U is a bond or —C(O)—; 
     W is a bond or —C(O)—; 
     X is —N(R 5 )—; 
     R 1  is H, alkyl, R 21 -alkyl, arylalkyl, R 21 -arylalkyl, cycloalkylalkyl, R 21 -cycloalkylalkyl, heterocycloalkyalkyl or R 21 -heterocycloalkylalkyl, 
     R 2  is H; 
     R 3  is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R 21 -alkyl, R 21 -cycloalkylalkyl, R 21 -cycloalkyl, R 21 -aryl or R 21 -arylalkyl; 
     R 4  is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R 21 -alkyl, R 21 -cycloalkylalkyl, R 21 -cycloalkyl, R 21 -aryl or R 21 -arylalkyl; 
     R 5  is H, alkyl, R 21 -alkyl, arylalkyl, R 21 -arylalkyl, cycloalkylalkyl, R 21 -cycloalkylalkyl, heterocycloalkyalkyl or R 21 -heterocycloalkylalkyl; 
     R 6  is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R 21 -alkyl, R 21 -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, R 21 -aryl or R 21 -arylalkyl; 
     R 15 , R 16  and R 17  is H, R 18 -alkyl, alkyl or 
     
       
                 
         
             
             
         
      
     
     R 21  is alkyl, aryl, halo, —OR 15 , —NO 2 , —C(O)R 15 , —CH 2 —N(R 15 )C(O)N(R 16 )(R 17 ) or —CH(R 15 )(R 16 ); 
     n is 1; 
     m is 1; 
     R 18  is —OR 20    
     R 20  is aryl; 
     and 
     R 23  is alkyl. 
     In a group of preferred compounds 
     R 3 , R 4 , R 6  and R 7  are 
                                
and
 
     R 1  and R 5  is H, CH 3 , 
     
       
                 
         
             
             
         
      
     
     In an additional group of preferred compounds; 
     U is a bond or —C(O)—; 
     W is a bond or —C(O)—; 
     X is —N(R 5 )—; 
     R 1  is H, alkyl, R 21 -alkyl, arylalkyl, R 21 -arylalkyl, cycloalkylalkyl, R 21 -cycloalkylalkyl, heterocycloalkyalkyl or R 21 -heterocycloalkylalkyl, 
     R 2  is H; 
     R 3  is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R 21 -alkyl, R 21 -cycloalkylalkyl, R 21 -cycloalkyl, R 21 -aryl, R 21 -arylalkyl, heteroarylalkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl, R 21 -heteroarylalkyl, R 21 -heteroaryl, R 21 -heterocycloalkyl or R 21 -heterocycloalkylalkyl; 
     R 4  is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R 21 -alkyl, R 21 -cycloalkylalkyl, R 21 -cycloalkyl, R 21 -aryl, R 21 -arylalkyl, heteroarylalkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl, R 21 -heteroarylalkyl, R 21 -heteroaryl, R 21 -heterocycloalkyl or R 21 -heterocycloalkylalkyl; 
     R 5  is H, alkyl, R 21 -alkyl, arylalkyl, R 21 -arylalkyl, cycloalkylalkyl, R 21 -cycloalkylalkyl, heterocycloalkyalkyl or R 21 -heterocycloalkylalkyl; 
     R 6  is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R 21 -alkyl, R 21 -cycloalkylalkyl, R 21 -cycloalkyl, R 21 -aryl, R 21 -arylalkyl, heteroarylalkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl, R 21 -heteroarylalkyl, R 21 -heteroaryl, R 21 -heterocycloalkyl or R 21 -heterocycloalkylalkyl; 
     R 7  is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R 21 -alkyl, R 21 -cycloalkylalkyl, R 21 -cycloalkyl, R 21 -aryl, R 21 -arylalkyl, heteroarylalkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl, R 21 -heteroarylalkyl, R 21 -heteroaryl, R 21 -heterocycloalkyl or R 21 -heterocycloalkylalkyl; 
     R 15 , R 16  and R 17  is H, cycloalkyl, cycloalkylalkyl, R 18 -alkyl, alkyl, aryl, R 18 -aryl, 
     R 18 -arylalkyl, arylalkyl, 
     
       
                 
         
             
             
         
      
     
     n is 1 or 2; 
     m is 0 or 1; 
     R 18  is —OR 20  or halo; 
     R 20  is aryl or halo substituted aryl; 
     R 21  is alkyl, aryl, heteroaryl, R 22 -alkyl, R 22 -aryl, R 22 -heteroaryl, halo, heterocycloalkyl, —N(R 15 )(R 16 ), —OR 15 , —NO 2 , —C(O)R 15 , —N(R 15 )C(O)R 16 , —N(R 15 )S(O) 2 R 16 , —CH 2 —N(R 15 )C(O)N(R 16 )(R 17 ), —N(R 15 )C(O)N(R 16 )(R 17 ) or —CH(R 15 )(R 16 ); 
     R 22  is —OR 15  or halo 
     and 
     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. 
     “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 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. 
     “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 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 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” 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 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 18 , R 21 , R 22 , 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 
                                
Non-limiting examples of suitable aryl groups include 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 about 5 to about 6 ring atoms. The “heteroaryl” can be optionally substituted by one or more R 21  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-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-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl, benzothiazolyl 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 cycloalkyl can be optionally substituted with one or more R 21  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 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 
     
       
                 
         
             
             
         
      
     
     “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 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 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-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 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 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-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 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. 
     “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 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 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 21  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 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 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 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 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 
     
       
                 
         
             
             
         
      
     
     The bond to the parent moiety is through a non-aromatic carbon atom. 
     Similarly, “heteroarylalkyl” “cycloalkylalkyl” and “heterocycloalkylalkyl” mean a heteroaryl-, cycloalkyl- or heterocycloalkyl-alkyl-group in which the heteroaryl, 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 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, 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 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. 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. 
     The suffix “ene” on alkyl, aryl, heterocycloalkyl, 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 heteroarylalkyl moiety includes substitution on the ring portion and/or on the alkyl portion of the group. 
     When a variable appears more than once in a group, e.g., R 8  in —N(R 8 ) 2 , or a variable appears more than once in the structure of formula I, e.g., R 15  may appear in both R 1  and R 3 , the variables can be the same or different. 
     With reference to the number of moieties (e.g., substituents, groups or rings) in 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 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. 
     The wavy line             as a bond generally indicates a mixture of, or either of, the possible isomers, e.g., containing (R)— and (S)-stereochemistry. For example,
                                
means containing both
 
     
       
                 
         
             
             
         
      
     
     Lines drawn into the ring systems, such as, for example: 
                                
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: 
     
       
                 
         
             
             
         
      
     
     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 tautomeric, and all such tautomeric forms are contemplated herein as part of the present invention. For example, a compound wherein X is —N(R 5 )— and R 1  and R 5  are each H can be represented by any of the following structures: 
     
       
                 
         
             
             
         
      
     
     When R 21  and R 22 , are, for example, —N(R 15 )C(O)N(R 16 )(R 17 ) and R 15  and R 16  form a ring, the moiety formed, is, for example, 
     
       
                 
         
             
             
         
      
     
     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 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. 
     “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 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 O. 
     “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. 
     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 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 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 compounds are discussed, for example, by S. Berge et al,  Journal of Pharmaceutical Sciences  (1977) 66(1) 1-19; P. Gould,  International 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 &amp; Drug Administration, Washington, D.C. on their website); and P. Heinrich Stahl, Camille G. Wermuth (Eds.),  Handbook of Pharmaceutical Salts: Properties, Selection, and Use , (2002) Int&#39;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, 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, 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. 
     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-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 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 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 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 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 IUPAC 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, stereoisomers, rotamers, tautomers, racemates or prodrugs of the inventive compounds. 
     Polymorphic forms of the compounds of formula I, and of the salts, solvates and prodrugs of the compounds of formula I, are intended to be included in the 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 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 
     liquid chromatography mass spectroscopy: LCMS 
     room temperature: RT or rt 
     day: d; hour: h; minute: min 
     retention time: Rt 
     microwave: μW 
     saturated: sat.; anhydrous: anhyd. 
     1-hydroxybenzotriazole: HOBt 
     1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride: EDCl 
     ethyl acetate: EtOAc 
     Benzyloxycarbonyl: CBZ 
     [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 O; acetic acid: AcOH; acetonitrile: MeCN; trifluoroacetic acid: TFA; 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 
     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); Minutes (Min), Retention Time (R t ); molecular weight (MW); milliliter (mL); gram (g). milligram (mg); equivalent (eq); day (d); microwave (μW); microliter (μL); 
     All NMR data were collected on 400 MHz NMR spectrometers unless otherwise indicated. LC-Electrospray-Mass spectroscopy with a C-18 column and 5% to 95% MeCN in water as the mobile phase was used to determine the molecular 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 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 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 
     
       
                 
         
             
             
         
      
     
     Method A, Step 1: 
     To a solution of A1 (R 3 =CH 3  &amp; R 4 =CH 2 CH(CH 3 ) 2 ) (10 mmol, 1 eq) in 30 ml of anhyd. CH 2 Cl 2  was added thiocarbonyl dipyridone (1.2 eq). After stirring overnight the solution was diluted with CH 2 Cl 2 , washed with 1N HCl, H 2 O (2×), and a saturated aqueous NaCl solution (2×). 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  &amp; R 4 =CH 2 CH(CH 3 ) 2 ). 
     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  &amp; 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 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 , &amp; R 4 =CH 2 CH(CH 3 ) 2 ). 
     Method A, Step 3: 
     To a solution of A3 (R 1 =3,5-difluorobenzyl, R 3 =CH 3 , &amp; R 4 =CH 2 CH(CH 3 ) 2 ) (10 mg) in CH 3 OH (1 mL) was added NH 4 OH (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 OH (1.2 mL) and was treated with sulfonic acid resin. The suspension was agitated overnight and the resin was washed with CH 3 OH (4×10 min) before it was treated with 2 N NH 3  in CH 3 OH 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 O gradient to afford A4 (R 1 =3,5-difluorobenzyl, R 2 =H, R 3 =CH 3 , &amp; R 4 =CH 2 CH(CH 3 ) 2 ). NMR (CD 3 OD): δ6.9, m, 3H; δ4.8-4.9, m; δ1.75, d, 2H; δ1.5, m, 1H; δ1.42, s, 3H; δ0.85, d, 3H, δ0.65, d, 3H. ES_LCMS (m/e) 296.1. 
     The following compounds were synthesized using similar methods: 
     
       
         
               
               
               
               
             
               
               
               
               
             
           
               
                   
               
               
                   
                   
                   
                 Obs.  
               
               
                 # 
                 Structure 
                 MW 
                 m/e 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 1 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 223 
                 224 
               
               
                   
               
               
                 2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 223 
                 224 
               
               
                   
               
               
                 3 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 225 
                 226 
               
               
                   
               
               
                 4 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 225 
                 226 
               
               
                   
               
               
                 5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 227 
                 228 
               
               
                   
               
               
                 6 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 237 
                 238 
               
               
                   
               
               
                 7 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 239 
                 240 
               
               
                   
               
               
                 8 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 239 
                 240 
               
               
                   
               
               
                 9 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 239 
                 240 
               
               
                   
               
               
                 10 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 240 
                 241 
               
               
                   
               
               
                 11 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 241 
                 242 
               
               
                   
               
               
                 12 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 241 
                 242 
               
               
                   
               
               
                 13 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 251 
                 252 
               
               
                   
               
               
                 14 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 253 
                 254 
               
               
                   
               
               
                 15 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 254 
                 255 
               
               
                   
               
               
                 16 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 255 
                 256 
               
               
                   
               
               
                 17 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 255 
                 256 
               
               
                   
               
               
                 18 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 255 
                 256 
               
               
                   
               
               
                 19 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 260 
                 261 
               
               
                   
               
               
                 20 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 260 
                 261 
               
               
                   
               
               
                 21 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 265 
                 266 
               
               
                   
               
               
                 22 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 265 
                 266 
               
               
                   
               
               
                 23 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 265 
                 266 
               
               
                   
               
               
                 24 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 267 
                 268 
               
               
                   
               
               
                 25 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 268 
                 269 
               
               
                   
               
               
                 26 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 268 
                 269 
               
               
                   
               
               
                 27 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 269 
                 270 
               
               
                   
               
               
                 28 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 273 
                 274 
               
               
                   
               
               
                 29 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 273 
                 274 
               
               
                   
               
               
                 30 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 274 
                 275 
               
               
                   
               
               
                 31 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 274 
                 275 
               
               
                   
               
               
                 32 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 274 
                 275 
               
               
                   
               
               
                 33 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 277 
                 278 
               
               
                   
               
               
                 34 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 279 
                 280 
               
               
                   
               
               
                 35 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 280 
                 281 
               
               
                   
               
               
                 36 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 280 
                 281 
               
               
                   
               
               
                 37 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 280 
                 281 
               
               
                   
               
               
                 38 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 280 
                 281 
               
               
                   
               
               
                 39 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 281 
                 282 
               
               
                   
               
               
                 40 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 282 
                 283 
               
               
                   
               
               
                 41 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 282 
                 283 
               
               
                   
               
               
                 42 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 282 
                 283 
               
               
                   
               
               
                 43 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 283 
                 284 
               
               
                   
               
               
                 44 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 285 
                 286 
               
               
                   
               
               
                 45 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 287 
                 288 
               
               
                   
               
               
                 46 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 287 
                 288 
               
               
                   
               
               
                 47 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 289 
                 290 
               
               
                   
               
               
                 48 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 293 
                 294 
               
               
                   
               
               
                 49 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 294 
                 295 
               
               
                   
               
               
                 50 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 294 
                 295 
               
               
                   
               
               
                 51 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 295 
                 296 
               
               
                   
               
               
                 52 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 296 
                 297 
               
               
                   
               
               
                 53 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 301 
                 302 
               
               
                   
               
               
                 54 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 303 
                 304 
               
               
                   
               
               
                 55 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 304 
                 305 
               
               
                   
               
               
                 56 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 304 
                 305 
               
               
                   
               
               
                 57 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 305 
                 306 
               
               
                   
               
               
                 58 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 307 
                 308 
               
               
                   
               
               
                 59 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 307 
                 308 
               
               
                   
               
               
                 60 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 308 
                 309 
               
               
                   
               
               
                 61 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 310 
                 311 
               
               
                   
               
               
                 62 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 317 
                 318 
               
               
                   
               
               
                 63 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 319 
                 320 
               
               
                   
               
               
                 64 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 322 
                 323 
               
               
                   
               
               
                 65 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 324 
                 325 
               
               
                   
               
               
                 66 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 327 
                 328 
               
               
                   
               
               
                 67 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 327 
                 328 
               
               
                   
               
               
                 68 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 327 
                 328 
               
               
                   
               
               
                 69 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 327 
                 328 
               
               
                   
               
               
                 70 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 328 
                 329 
               
               
                   
               
               
                 71 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 330 
                 331 
               
               
                   
               
               
                 72 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 331 
                 332 
               
               
                   
               
               
                 73 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 331 
                 332 
               
               
                   
               
               
                 74 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 335 
                 336 
               
               
                   
               
               
                 75 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 335 
                 336 
               
               
                   
               
               
                 76 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 337 
                 338 
               
               
                   
               
               
                 77 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 337 
                 338 
               
               
                   
               
               
                 78 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 342 
                 343 
               
               
                   
               
               
                 79 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 345 
                 346 
               
               
                   
               
               
                 80 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 345 
                 346 
               
               
                   
               
               
                 81 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 349 
                 350 
               
               
                   
               
               
                 82 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 349 
                 350 
               
               
                   
               
               
                 83 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 351 
                 352 
               
               
                   
               
               
                 84 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 351 
                 352 
               
               
                   
               
               
                 85 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 351 
                 352 
               
               
                   
               
               
                 86 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 359 
                 360 
               
               
                   
               
               
                 87 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 361 
                 362 
               
               
                   
               
               
                 88 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 361 
                 362 
               
               
                   
               
               
                 89 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 361 
                 362 
               
               
                   
               
               
                 90 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 363 
                 364 
               
               
                   
               
               
                 91 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 363 
                 364 
               
               
                   
               
               
                 92 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 363 
                 364 
               
               
                   
               
               
                 93 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 363 
                 364 
               
               
                   
               
               
                 94 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 363 
                 364 
               
               
                   
               
               
                 95 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 363 
                 364 
               
               
                   
               
               
                 96 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 369 
                 370 
               
               
                   
               
               
                 97 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 374 
                 375 
               
               
                   
               
               
                 98 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 375 
                 376 
               
               
                   
               
               
                 99 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 375 
                 376 
               
               
                   
               
               
                 100 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 377 
                 378 
               
               
                   
               
               
                 101 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 377 
                 378 
               
               
                   
               
               
                 102 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 377 
                 378 
               
               
                   
               
               
                 103 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 381 
                 382 
               
               
                   
               
               
                 104 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 382 
                 383 
               
               
                   
               
               
                 105 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 385 
                 386 
               
               
                   
               
               
                 106 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 385 
                 386 
               
               
                   
               
               
                 107 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 386 
                 387 
               
               
                   
               
               
                 108 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 389 
                 390 
               
               
                   
               
               
                 109 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 391 
                 392 
               
               
                   
               
               
                 110 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 391 
                 392 
               
               
                   
               
               
                 111 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 391 
                 392 
               
               
                   
               
               
                 112 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 391 
                 392 
               
               
                   
               
               
                 113 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 393 
                 394 
               
               
                   
               
               
                 114 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 393 
                 394 
               
               
                   
               
               
                 115 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 400 
                 401 
               
               
                   
               
               
                 116 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 401 
                 402 
               
               
                   
               
               
                 117 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 401 
                 402 
               
               
                   
               
               
                 118 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 401 
                 402 
               
               
                   
               
               
                 119 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 401 
                 402 
               
               
                   
               
               
                 120 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 403 
                 404 
               
               
                   
               
               
                 121 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 403 
                 404 
               
               
                   
               
               
                 122 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 403 
                 404 
               
               
                   
               
               
                 123 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 405 
                 406 
               
               
                   
               
               
                 124 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 405 
                 406 
               
               
                   
               
               
                 125 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 409 
                 410 
               
               
                   
               
               
                 126 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 409 
                 410 
               
               
                   
               
               
                 127 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 409 
                 410 
               
               
                   
               
               
                 128 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 409 
                 410 
               
               
                   
               
               
                 129 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 411 
                 412 
               
               
                   
               
               
                 130 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 413 
                 414 
               
               
                   
               
               
                 131 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 413 
                 414 
               
               
                   
               
               
                 132 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 414 
                 415 
               
               
                   
               
               
                 133 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 415 
                 416 
               
               
                   
               
               
                 134 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 415 
                 416 
               
               
                   
               
               
                 135 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 415 
                 416 
               
               
                   
               
               
                 136 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 417 
                 418 
               
               
                   
               
               
                 137 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 419 
                 420 
               
               
                   
               
               
                 138 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 421 
                 422 
               
               
                   
               
               
                 139 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 423 
                 424 
               
               
                   
               
               
                 140 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 425 
                 426 
               
               
                   
               
               
                 141 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 425 
                 426 
               
               
                   
               
               
                 142 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 425 
                 426 
               
               
                   
               
               
                 143 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 427 
                 428 
               
               
                   
               
               
                 144 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 429 
                 430 
               
               
                   
               
               
                 145 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 430 
                 431 
               
               
                   
               
               
                 146 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 430 
                 431 
               
               
                   
               
               
                 147 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 431 
                 432 
               
               
                   
               
               
                 148 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 433 
                 434 
               
               
                   
               
               
                 149 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 437 
                 438 
               
               
                   
               
               
                 150 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 439 
                 440 
               
               
                   
               
               
                 151 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 440 
                 441 
               
               
                   
               
               
                 152 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 440 
                 441 
               
               
                   
               
               
                 153 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 441 
                 442 
               
               
                   
               
               
                 154 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 441 
                 442 
               
               
                   
               
               
                 155 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 442 
                 443 
               
               
                   
               
               
                 156 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 447 
                 448 
               
               
                   
               
               
                 157 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 449 
                 450 
               
               
                   
               
               
                 158 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 455 
                 456 
               
               
                   
               
               
                 159 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 463 
                 464 
               
               
                   
               
               
                 160 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 463 
                 464 
               
               
                   
               
               
                 161 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 471 
                 472 
               
               
                   
               
               
                 162 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 473 
                 474 
               
               
                   
               
               
                 163 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 481 
                 482 
               
               
                   
               
               
                 164 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 481 
                 482 
               
               
                   
               
               
                 165 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 487 
                 488 
               
               
                   
               
               
                 166 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 488 
                 489 
               
               
                   
               
               
                 167 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 499 
                 500 
               
               
                   
               
               
                 168 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 504 
                 505 
               
               
                   
               
               
                 169 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 523 
                 524 
               
               
                   
               
               
                 170 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 525 
                 526 
               
               
                   
               
               
                 171 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 525 
                 526 
               
               
                   
               
               
                 172 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 527 
                 528 
               
               
                   
               
               
                 173 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 528 
                 529 
               
               
                   
               
               
                 174 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 535 
                 536 
               
               
                   
               
               
                 175 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 535 
                 536 
               
               
                   
               
               
                 176 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 535 
                 536 
               
               
                   
               
               
                 177 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 535 
                 536 
               
               
                   
               
               
                 178 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 550 
                 551 
               
               
                   
               
               
                 179 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 554 
                 555 
               
               
                   
               
               
                 180 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 556 
                 557 
               
               
                   
               
               
                 181 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 569 
                 570 
               
               
                   
               
               
                 182 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 581 
                 582 
               
               
                   
               
               
                 183 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 374 
                 NA 
               
               
                   
               
               
                 184 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 388 
                 NA 
               
               
                   
               
               
                 185 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 337 
                 NMR 
               
               
                   
               
               
                 186 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 351 
                 NMR 
               
               
                   
               
             
          
         
       
     
     Method B 
                                
A modified literature procedure was used (Ugi, I.  Angew. Chem.  1962, 74 9-22).
 
     Method B, Step 1: 
     To a solution of B1 (HCl salt, R 1 =3-chlorophenethyl) (1.1 g, 5.73 mmol) in anhydrous CH 3 OH (15 mL) was added potassium thiocyanate (0.56 g, 5.73 mmol). The reaction mixture was heated to 60° C. for 1 h. The suspension was filtered and the filtrate was added to B5 (R 3 =Me, R 4 = i 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 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 R 1 =3-Chlorophenethyl). 
     Method B, Step 2: 
     A solution of 40% concentrated HCl in CH 3 CH 2 OH was added to B2 (R 3 =CH 3 , R 4 =CH 2 CH(CH 3 ) 2 , and R 1 =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 O (with 0.1% formic acid) gradient to afford B3 (R 3 =CH 3 , R 4 =CH 2 CH(CH 3 ) 2 , and R 1 =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 1 =3-Chlorophenethyl) was prepared from B3 (R 3 =CH 3 , R 4 =CH 2 CH(CH 3 ) 2 , and R 1 =3-Chlorophenethyl) following a procedure similar to Method A, Step 3. NMR (CD 3 OD): δ 8.1, br, 1H; δ 7.35, s, 1H; δ 7.25, m, 3H; δ 3.6, m, 1H; δ 3.4, m, 1 H; δ 3.0, m, 1H; δ 2.8, m, 1 H; δ 1.75, m, 1H; δ 1.6, m, 1H; δ 1.35, m, 1H; δ 1.2 s, 3H; δ 0.8, m, 6H. ES_LCMS (m/e): 308.1 
     The following compounds were prepared using similar methods 
     
       
         
               
               
               
               
             
           
               
                   
               
               
                   
                   
                   
                 Obs. 
               
               
                 # 
                 Structure 
                 MW 
                 m/e 
               
               
                   
               
             
             
               
                 545 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 251 
                 252 
               
               
                   
               
               
                 546 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 293 
                 294 
               
               
                   
               
               
                 547 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 307 
                 308 
               
               
                   
               
               
                 548 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 357 
                 358 
               
               
                   
               
               
                 549 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 371 
                 372 
               
               
                   
               
               
                 550 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 413 
                   
               
               
                   
               
               
                 551 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 265 
               
               
                   
               
             
          
         
       
     
     Method C 
     
       
                 
         
             
             
         
      
     
     Method C, Step 1: 
     A solution of C1 (R 3 =R 4 =CH 2 CH 2 CH 2 CH 3 ) (50 mg, 0.25 mmol) and C4 (R 1 =3-chlorophenyl) (38 μL, 0.26 mmol) was refluxed overnight. Trisamine resin (2 eq) and polystyrene isocyanate resin (2 eq) was added and the mixture was agitated. After 3 h, the suspension was filtered and the resin was washed with CH 2 Cl 2  (3×) and CH 3 OH (3×). The filtrate was concentrated to afford C2 (R 1 =3-Cl—C 6 H 4 , R 3 =R 4 =CH 2 CH 2 CH 2 CH 3 ) (60 mg, 68%). 
     Method C, Step 2: 
     Compound C3 (R 1 =3-Cl—C 6 H 4 , R 2 =H, R 3 =R 4 =CH 2 CH 2 CH 2 CH 3 ) was prepared from C2 (R 1 =3-Cl—C 6 H 4 , R 3 =R 4 =CH 2 CH 2 CH 2 CH 3 ) following a procedure similar to Method A, Step 3. NMR (CDCl3): δ 7.4, m, 2H; δ 7.2, m, 2H; δ 5.0, s, 2H; δ 1.7, m, 4H; δ 1.1, m, 8H; δ 0.7; m, 6H. ES-LCMS (m/e): 336.1. 
     The following compounds were prepared using similar method. 
     
       
         
               
               
               
               
             
           
               
                   
               
               
                   
                   
                   
                 Obs. 
               
               
                 # 
                 Structure 
                 MW 
                 m/e 
               
               
                   
               
             
             
               
                 641 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 209 
                 210 
               
               
                   
               
               
                 642 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 211 
                 212 
               
               
                   
               
               
                 643 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 215 
                 216 
               
               
                   
               
               
                 644 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 225 
                 226 
               
               
                   
               
               
                 645 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 239 
                 240 
               
               
                   
               
               
                 646 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 245 
                 246 
               
               
                   
               
               
                 647 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 246 
                 247 
               
               
                   
               
               
                 648 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 251 
                 252 
               
               
                   
               
               
                 649 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 267 
                 268 
               
               
                   
               
               
                 650 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 309 
                 310 
               
               
                   
               
               
                 651 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 317 
                 318 
               
               
                   
               
               
                 652 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 319 
                 320 
               
               
                   
               
               
                 653 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 323 
                 324 
               
               
                   
               
               
                 654 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 324 
                 325 
               
               
                   
               
               
                 655 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 329 
                 330 
               
               
                   
               
               
                 656 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 329 
                 330 
               
               
                   
               
               
                 657 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 335 
                 336 
               
               
                   
               
               
                 658 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 335 
                 336 
               
               
                   
               
               
                 659 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 335 
                 336 
               
               
                   
               
               
                 660 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 335 
                 336 
               
               
                   
               
               
                 661 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 335 
                 336 
               
               
                   
               
               
                 662 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 352 
                 353 
               
               
                   
               
               
                 663 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 352 
                 353 
               
               
                   
               
               
                 664 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 377 
                 378 
               
               
                   
               
               
                 665 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 385 
                 386 
               
               
                   
               
               
                 666 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 391 
                 392 
               
               
                   
               
               
                 667 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 420 
                 421 
               
               
                   
               
               
                 668 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 420 
                 421 
               
               
                   
               
             
          
         
       
     
     Method D 
     
       
                 
         
             
             
         
      
     
     Method D, Step 1: 
     A mixture of D1 (R 3 =R 4 =CH 2 C 6 H 5 ) (20 g), potassium cyanide (40 g) and ammonium carbonate (15 g) in ethanol (100 mL) and H 2 O (200 mL) was heated in a sealed flask at 130° C. overnight to yield 25 g of D2 (R 3 =R 4 =CH 2 C 6 H 5 ) after filtration followed by washing with water. 
     Method D, Step 2: 
     A solution of 2 N KOH (3 eq) was added to D2 (R 3 =R 4 =CH 2 C 6 H 5 ) (1 eq) and irradiated via microwave at 185° C. for 3 h followed by addition of concentrated HCl 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 drop wise to a solution of D3 (R 3 =R 4 =CH 2 C 6 H 5 ) (1 eq) in anhydrous CH 3 OH (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 concentrated. The residue was dissolved in a 0.2 N HCl solution (25 mL) and washed with ether (3×). 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 (3×). The organic extracts were combined, dried over Na 2 SO 4 , and concentrated to afford D4 (R 3 =R 4 =CH 2 C 6 H 5 ). 
     The following amino esters were prepared using a similar method. 
     
       
                 
         
             
             
         
      
       
                 
         
             
             
         
       
     
     Method E 
     
       
                 
         
             
             
         
      
     
     Method E, Step 1: 
     Thionyl chloride (0.47, 6.38 mmol) was added drop wise to a solution of E1 (R 3 =CH 2 CH 2 C 6 H 5 ) (2 g, 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 ZnCl 2  (0.18 g, 1.28 mmol) and thionyl chloride (0.1 mL, 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 O. The mixture was stirred occasionally until the ice melted. The aqueous solution was extracted with ether (3×). The combined organic extracts were washed with H 2 O (3×), a sat. aqueous solution of NaHCO 3  (1×), and H 2 O (2×). 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 hexane to yield compound E2 (R 3 =CH 2 CH 2 C 6 H 5 ). 
     Method E, Step 2: 
     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° C. 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° C. for 3 h. The reaction was warmed to −65° C., stirred for 2 h and warmed to rt overnight. The reaction solution was poured into a mixture of sat. NaHCO 3  (aq)/ether/ice. The aqueous layer was extracted with ether (3×). The organic extracts were combined and washed with brine (2×). 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 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 OH) (0.36 mL, 0.36 mmol) was added to compound E3 (R 3 =CH 2 CH 2 C 6 H 5 , R 4 =CH 2 CH(CH 3 ) 2 ). The reaction 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 (1×) and ethyl acetate (1×). The aqueous phase of the filtrate was separated and extracted with ethyl acetate (2×). The organic extracts were combined and washed with a sat. aqueous solution of NaHSO 3  (8×). 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%). 
     Method E, Step 4: 
     To a solution of E4 (R 3 =CH 2 CH 2 C 6 H 5 , R 4 =CH 2 CH(CH 3 ) 2 ) (109 mg, 0.28 mmol) in CH 3 OH (4 mL) was added 1 N HCl (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 CH 3 OH (3×). 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. 
     
       
                 
         
             
             
         
      
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
     
     Method F 
     
       
                 
         
             
             
         
      
     
     A 500 mL methanol solution of 20 g of D5 (R 3 =benzyl, n=1) with 1.5 eq of HCl 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. The combined solution was evaporated to give 20 g of F1 (R 3 =cyclohexylmethyl, n=1) as HCl salt. 
     The following amino esters were examples prepared using similar method. 
     
       
                 
         
             
             
         
      
       
                 
         
             
             
         
       
     
     Method G 
     
       
                 
         
             
             
         
      
     
     Method G, Step 1: 
     To a solution of G1 (R 1 =CH 2 (3-ClC 6 H 4 ) and R 3 =CH 3 ) (400 mg, 1.23 mmol, generated following a procedure similar to Method C, Step 1) in ethanol (5 mL) was added lithium hydroxide monohydrate (100 mg, 2.45 mmol) in H 2 O (0.5 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 O (15 mL) and extracted with ether (2×). A solution of 30% HCl was added to the aqueous phase until its pH=1 to 2. The solution was saturated with NaCl and extracted with ethyl acetate (3×). The organic solution was dried over Na 2 SO 4 , filtered and concentrated to afford G2 (R 1 =CH 2 (3-ClC 6 H 4 ) and R 3 =CH 3 ) (357 mg, 93%). 
     Method G, Step 2: 
     A solution of benzyl amine (1.2 eq) was added to G2 (R 1 =CH 2 (3-ClC 6 H 4 ) and R 3 =CH 3 ) (1 eq), HOBT (1.5 eq) and polystyrene EDC resin (94 mg, 1.53 mmol/g, 3 eq) 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 and the filtrate was concentrated to afford G3 (R 1 =CH 2 (3-ClC 6 H 4 ), R 3 =CH 3 , R 15 =CH 2 C 6 H 5  and R 16 =H). 
     Method G, Step 3: 
     Compound G4 (R 1 =CH 2 (3-ClC 6 H 4 ), R 2 =H, R 3 =CH 3 , R 15 =CH 2 C 6 H 5  and R 15 =H) was prepared from G3 (R 1 =CH 2 (3-ClC 6 H 4 ), R 3 =CH 3 , R 15 =CH 2 C 6 H 5  and R 16 =H) following a procedure similar to Method A, Step 3. 
     The following compounds were prepared using similar methods. 
     
       
         
               
               
               
               
             
           
               
                   
               
               
                   
                   
                   
                 Obs. 
               
               
                 # 
                 Structure 
                 MW 
                 m/e 
               
               
                   
               
             
             
               
                 669 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 322 
                 323 
               
               
                   
               
               
                 670 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 334 
                 335 
               
               
                   
               
               
                 671 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 336 
                 337 
               
               
                   
               
               
                 672 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 348 
                 349 
               
               
                   
               
               
                 673 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 364 
                 365 
               
               
                   
               
               
                 674 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 364 
                 365 
               
               
                   
               
               
                 675 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 376 
                 377 
               
               
                   
               
               
                 676 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 384 
                 385 
               
               
                   
               
               
                 677 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 390 
                 391 
               
               
                   
               
               
                 678 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 393 
                 394 
               
               
                   
               
               
                 679 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 398 
                 399 
               
               
                   
               
               
                 680 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 398 
                 399 
               
               
                   
               
               
                 681 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 406 
                 407 
               
               
                   
               
               
                 682 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 412 
                 413 
               
               
                   
               
               
                 683 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 414 
                 415 
               
               
                   
               
               
                 684 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 414 
                 415 
               
               
                   
               
               
                 685 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 414 
                 415 
               
               
                   
               
               
                 686 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 421 
                 422 
               
               
                   
               
               
                 687 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 428 
                 429 
               
               
                   
               
               
                 688 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 434 
                 435 
               
               
                   
               
               
                 689 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 442 
                 443 
               
               
                   
               
               
                 690 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 449 
                 450 
               
               
                   
               
               
                 691 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 461 
                 462 
               
               
                   
               
               
                 692 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 511 
                 512 
               
               
                   
               
               
                 693 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 511 
                 512 
               
               
                   
               
             
          
         
       
     
     Method H 
     
       
                 
         
             
             
         
      
     
     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 1 —NCS (R 1 =3-chlorobenzyl) (11.5 mL, 78 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 (5×). The organic extracts were combined, washed with water (2×) and dried over Na 2 SO 4 . The solution was filtered and solvent was removed to give a 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 1 =CH 2 (3-ClC 6 H 4 )) (61%). 
     Method H, Step 2: 
     Compound H3 (R 3 =CH 3 , R 1 =CH 2 (3-ClC 6 H 4 )) was synthesized from H2 (R 3 =CH 3 , R 1 =CH 2 (3-ClC 6 H 4 )) following a procedure similar to Method A, Step 3. 
     Method H, Step 3: 
     To a solution of crude H3 (R 3 =CH 3 , R 1 =CH 2 (3-ClC 6 H 4 )) (14 mmol) in a 1:3 mixture of CH 3 OH:THF was added 0.5 M NaHCO 3  in H 2 O (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 (4×). The organic extracts were combined and washed with brine (1×). 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 hexane to afford 1.5 g of H4 (R 1 =CH 2 (3-ClC 6 H 4 ) and R 3 =CH 3 ). 
     Method H, Step 4: 
     A solution of triflic anhydride (128 μL, 0.76 mmol) in CH 2 Cl 2  (5 mL) was added drop wise to a solution of H4 (R 1 =CH 2 (3-ClC 6 H 4 ) and R 3 =CH 3 ) (200 mg, 0.55 mmol) and 2,6-lutidine (176 μL, 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 separated, dried over Na 2 SO 4 , filtered and concentrated to afford 310 mg of H5 (R 1 =CH 2 (3-ClC 6 H 4 ) and R 3 =CH 3 ). 
     Method H, Step 5: 
     A solution of crude H5 (R 1 =CH 2 (3-ClC 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 O gradient with 0.1% formic acid to yield H6 (R 1 =CH 2 (3-ClC 6 H 4 ), R 3 =CH 3 , R 21 =NH 2 ). 
     Method H, Step 6: 
     A solution of 50% trifluoroacetic acid in CH 2 Cl 2  (2 mL) was added to H6 (R 1 =CH 2 (3-ClC 6 H 4 ), R 3 =CH 3 , R 21 =NH 2 ). After 40 min the solvent was evaporated and residue purified by preparative HPLC/LCMS eluting with a CH 3 CN/H 2 O gradient to afford H7 (R 1 =CH 2 (3-ClC 6 H 4 ), R 3 =CH 3 , R 21 =NH2). NMR (CDCl 3 ), δ 7.45, m, 3H; δ 7.35, m, 1H; δ 4.9, m, 2H; δ 3.5, m, 2H; δ 1.65, s, 3H. ES_LCMS (m/e) 267.07. 
     The following compounds were prepared using similar methods. 
     
       
         
               
               
               
               
             
           
               
                   
               
               
                   
                   
                   
                 Obs. 
               
               
                 # 
                 Structure 
                 MW 
                 m/e 
               
               
                   
               
             
             
               
                 694 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 238 
                 239 
               
               
                   
               
               
                 695 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 248 
                 249 
               
               
                   
               
               
                 696 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 257 
                 258 
               
               
                   
               
               
                 697 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 264 
                 265 
               
               
                   
               
               
                 698 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 266 
                 267 
               
               
                   
               
               
                 699 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 292 
                 293 
               
               
                   
               
               
                 700 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 308 
                 309 
               
               
                   
               
               
                 701 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 314 
                 315 
               
               
                   
               
               
                 702 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 320 
                 321 
               
               
                   
               
               
                 703 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 328 
                 329 
               
               
                   
               
               
                 704 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 334 
                 335 
               
               
                   
               
               
                 705 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 342 
                 343 
               
               
                   
               
               
                 706 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 354 
                 355 
               
               
                   
               
               
                 707 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 372 
                 373 
               
               
                   
               
               
                 708 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 418 
                 419 
               
               
                   
               
               
                 709 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 483 
                 484 
               
               
                   
               
             
          
         
       
     
     Method I 
     
       
                 
         
             
             
         
      
     
     Method I, Step 1: 
     Diethylaminomethyl polystyrene resin (5 eq) was added to a solution of the formate salt of I1 (R 1 =CH 2 (3-ClC 6 H 4 ), R 3 =CH 3  and R 16 =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 Cl 2  (4×). The filtrate was concentrated to afford the free base I1 (R 1 =CH 2 (3-ClC 6 H 4 ), R 3 =CH 3  and R 16 =H). 
     A solution of R 15 COOH(R 15 =Phenethyl) (1.3 eq) was added to a mixture of EDC resin (41 mg, 1.53 mmol/g, 3 eq), HOBT (1.5 eq), and the free base of I1 (R 1 =CH 2 (3-ClC 6 H 4 ), R 3 =CH 3  and R 16 =H) (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 concentrated to afford I 2 (R 1 =CH 2 (3-ClC 6 H 4 ), R 3 =CH 3 , R 16 =H and R 15 =CH 2 CH 2 C 6 H 5 ). 
     Method I, Step 2: 
     I3 (R 1 =CH 2 (3-ClC 6 H 4 ), R 3 =CH 3 , R 16 =H and R 15 =CH 2 CH 2 C 6 H 5 ) was prepared from I2 (R 1 =CH 2 (3-ClC 6 H 4 ), R 3 =CH 3 , R 16 =H and R 15 =CH 2 CH 2 C 6 H 5 ) using method similar to method H step 6. 
     The following compounds were prepared using similar method. 
     
       
         
               
               
               
               
             
           
               
                   
               
               
                   
                   
                   
                 Obs. 
               
               
                 # 
                 Structure 
                 MW 
                 m/e 
               
               
                   
               
             
             
               
                 710 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 280 
                 281 
               
               
                   
               
               
                 711 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 308 
                 309 
               
               
                   
               
               
                 712 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 308 
                 309 
               
               
                   
               
               
                 713 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 334 
                 335 
               
               
                   
               
               
                 714 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 342 
                 343 
               
               
                   
               
               
                 715 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 362 
                 363 
               
               
                   
               
               
                 716 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 372 
                 373 
               
               
                   
               
               
                 717 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 376 
                 377 
               
               
                   
               
               
                 718 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 398 
                 399 
               
               
                   
               
               
                 719 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 406 
                 407 
               
               
                   
               
               
                 720 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 410 
                  11 
               
               
                   
               
               
                 721 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 410 
                  11 
               
               
                   
               
               
                 722 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 414 
                  15 
               
               
                   
               
               
                 723 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 420 
                  21 
               
               
                   
               
               
                 724 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 428 
                  29 
               
               
                   
               
               
                 725 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 511 
                  12 
               
               
                   
               
             
          
         
       
     
     Method J 
     
       
                 
         
             
             
         
      
     
     Method J, Step 1: 
     Diethylaminomethyl polystyrene resin (5 eq) was added to a solution of J1 (TFA salt, R 1 =CH 2 (3-ClC 6 H 4 ) and R 3 =CH 3 ) 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 Cl 2  (4×). The filtrate was concentrated to afford the free base. A solution of R 15 NCO(R 15 =butyl) (2 eq) in CH 2 Cl 2  was added to the free base of J1 (R 1 =CH 2 (3-ClC 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 added. The mixture was agitated for 6 h. The suspension was filtered and the filtrate was concentrated to afford J2 (R 1 =CH 2 (3-ClC 6 H 4 ), R 3 =CH 3 , and R 15 =CH 2 CH 2 CH 2 CH 3 ). 
     Method J, Step 2: 
     Compound J3 (R 1 =CH 2 (3-ClC 6 H 4 ), R 3 =CH 3 , and R 15 =CH 2 CH 2 CH 2 CH 3 ) was prepared from J2 (R 1 =CH 2 (3-ClC 6 H 4 ), R 3 =CH 3 , and R 15 =CH 2 CH 2 CH 2 CH 3 ) following the procedure described in Method H, Step 2. 
     The following compounds were prepared using similar method. 
     
       
         
               
               
               
               
             
           
               
                   
               
               
                   
                   
                   
                 Obs. 
               
               
                 # 
                 Structure 
                 MW 
                 m/e 
               
               
                   
               
             
             
               
                 726 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 323 
                 324 
               
               
                   
               
               
                 727 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 337 
                 338 
               
               
                   
               
               
                 728 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   
                 352 
               
               
                   
               
               
                 729 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   
                 358 
               
               
                   
               
               
                 730 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 365 
                 366 
               
               
                   
               
               
                 731 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 377 
                 378 
               
               
                   
               
               
                 732 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 413 
                 414 
               
               
                   
               
               
                 733 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 417 
                 418 
               
               
                   
               
               
                 734 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 421 
                 422 
               
               
                   
               
               
                 735 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 425 
                 426 
               
               
                   
               
             
          
         
       
     
     Method K 
     
       
                 
         
             
             
         
      
     
     Method K, Step 1: 
     A solution of propyl R 15 SO 2 Cl (R 15 =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 K1 prepared using method H(R 1 =CH 2 (3-ClC 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 added. The mixture was agitated for 6 h. The suspension was filtered and the filtrate was concentrated to afford K2 (R 1 =CH 2 (3-ClC 6 H 4 ), R 3 =CH 3 , and R 15 =CH 2 CH 2 CH 3 ). 
     Method K, Step 2: 
     Compound K3 (R 1 =CH 2 (3-ClC 6 H 4 ), R 3 =CH 3 , and R 15 =CH 2 CH 2 CH 3 ) was prepared from K2 (R 1 =CH 2 (3-ClC 6 H 4 ), R 3 =CH 3 , and R 15 =CH 2 CH 2 CH 3 ) following the procedure described in Method H, Step 6. 
     The following compounds were prepared using similar method. 
     
       
         
               
               
               
               
             
           
               
                   
               
               
                   
                   
                   
                 Obs. 
               
               
                 # 
                 Structure 
                 MW 
                 m/e 
               
               
                   
               
             
             
               
                 736 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 316 
                 317 
               
               
                   
               
               
                 737 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 344 
                 345 
               
               
                   
               
               
                 738 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 372 
                 373 
               
               
                   
               
               
                 739 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 378 
                 379 
               
               
                   
               
               
                 740 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 442 
                 443 
               
               
                   
               
               
                 741 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 454 
                 455 
               
               
                   
               
               
                 742 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 492 
                 493 
               
               
                   
               
             
          
         
       
     
     Method L 
     
       
                 
         
             
             
         
      
     
     (In the scheme, —Z—NH—C(O)R 16 — is equivalent to R 1  substituted by R 21 , or R 1  Substituted by alkyl-R 22 , wherein R 21  and R 22  are —N(R 15 )C(O)R 16  and R 15  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, heteroarylene, cycloalkylene or heterocycloalkylene) 
     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 Cl 2  was stirred at rt. The reaction solution was concentrated and purified via flash chromatography. The material was treated with 50% trifluoroacetic acid in CH 2 Cl 2  for 30 min. The solution was concentrated. The residue was dissolved in 1 N HCl (10 mL) and washed with ether (2×). A saturated solution of Na 2 CO 3  in H 2 O was added to the aqueous phase until the solution became basic. The solution was extracted with CH 2 Cl 2  (3×). The CH 2 Cl 2  extracts were combined, dried over Na 2 SO 4 , filtered and 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 )—, R 16 =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 )—, R 1 =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 16 =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. 
     
       
         
               
               
               
               
             
           
               
                   
               
               
                   
                   
                   
                 Obs. 
               
               
                 # 
                 Structure 
                 MW 
                 m/e 
               
               
                   
               
             
             
               
                 743 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 316 
                 317 
               
               
                   
               
               
                 744 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 316 
                 317 
               
               
                   
               
               
                 745 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 330 
                 331 
               
               
                   
               
               
                 746 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 330 
                 331 
               
               
                   
               
               
                 747 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 344 
                 345 
               
               
                   
               
               
                 748 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 344 
                 345 
               
               
                   
               
               
                 749 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 358 
                 359 
               
               
                   
               
               
                 750 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 358 
                 359 
               
               
                   
               
               
                 751 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 386 
                 387 
               
               
                   
               
               
                 752 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 386 
                 387 
               
               
                   
               
               
                 753 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 386 
                 387 
               
               
                   
               
               
                 754 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 400 
                 401 
               
               
                   
               
               
                 755 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 400 
                 401 
               
               
                   
               
               
                 756 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 420 
                 421 
               
               
                   
               
               
                 757 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 434 
                 435 
               
               
                   
               
               
                 758 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 434 
                 435 
               
               
                   
               
               
                 759 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 436 
                 437 
               
               
                   
               
               
                 760 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 436 
                 437 
               
               
                   
               
               
                 761 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 450 
                 451 
               
               
                   
               
               
                 762 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 450 
                 451 
               
               
                   
               
               
                 763 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 450 
                 451 
               
               
                   
               
               
                 764 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 450 
                 451 
               
               
                   
               
               
                 765 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 464 
                 465 
               
               
                   
               
               
                 766 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 464 
                 465 
               
               
                   
               
               
                 767 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 470 
                 471 
               
               
                   
               
               
                 768 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 478 
                 479 
               
               
                   
               
               
                 769 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 478 
                 479 
               
               
                   
               
               
                 770 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 484 
                 485 
               
               
                   
               
               
                 771 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 484 
                 485 
               
               
                   
               
               
                 772 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 492 
                 493 
               
               
                   
               
               
                 773 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 492 
                 493 
               
               
                   
               
               
                 774 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 519 
                 520 
               
               
                   
               
               
                 775 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 519 
                 520 
               
               
                   
               
               
                 776 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 533 
                 534 
               
               
                   
               
               
                 777 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 533 
                 534 
               
               
                   
               
             
          
         
       
     
     Method M 
     
       
                 
         
             
             
         
      
     
     (In the scheme, —Z—NH—C(O)—NHR 15 — is equivalent to R 1  substituted by R 21 , or R 1  Substituted by alkyl-R 22 , wherein R 21  and R 22  are —N(R 16 )—C(O)—NHR 15  and R 16  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, 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 6 H 4 (CH 2 )—, R 15 =3,4-difluorophenyl) was prepared from M1 (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 J, Step 
     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 )—, R 15 =3,4-difluorophenyl) was prepared from M2 (R 3 =CH 3 , R 4 =CH 2 CH(CH 3 ) 2 , Z=para-(CH 2 )C 6 H 4 (CH 2 )—, R 15 =3,4-difluorophenyl) following the procedure described in Method A, Step 3. NMR (CD 3 OD) δ 7.45, m, 1H; δ 7.26, m, 4H, 7.24, m, 1H; δ 6.96, m, 1H; δ 4.8, m; δ 4.3, s, 2H; δ 1.69, m, 2H; δ 1.44, m, 1H; δ1.37, s, 3H; δ 0.8, m, 3H; δ 0.63, m, 3H. ES_LCMS (m/e) 430.27 
     The following compounds were prepared using similar method. 
     
       
         
               
               
               
               
             
           
               
                   
               
               
                   
                   
                   
                 Obs. 
               
               
                 # 
                 Structure 
                 MW 
                 m/e 
               
               
                   
               
             
             
               
                 778 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 331 
                 332 
               
               
                   
               
               
                 779 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 359 
                 360 
               
               
                   
               
               
                 780 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 359 
                 360 
               
               
                   
               
               
                 781 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 373 
                 374 
               
               
                   
               
               
                 782 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 373 
                 374 
               
               
                   
               
               
                 783 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 373 
                 374 
               
               
                   
               
               
                 784 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 373 
                 374 
               
               
                   
               
               
                 785 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 387 
                 388 
               
               
                   
               
               
                 786 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 387 
                 388 
               
               
                   
               
               
                 787 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 387 
                 388 
               
               
                   
               
               
                 788 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 387 
                 388 
               
               
                   
               
               
                 789 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 401 
                 402 
               
               
                   
               
               
                 790 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 401 
                 402 
               
               
                   
               
               
                 791 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 405 
                 406 
               
               
                   
               
               
                 792 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 407 
                 408 
               
               
                   
               
               
                 793 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 407 
                 408 
               
               
                   
               
               
                 794 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 407 
                 408 
               
               
                   
               
               
                 795 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 413 
                 414 
               
               
                   
               
               
                 796 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 413 
                 414 
               
               
                   
               
               
                 797 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 418 
                 419 
               
               
                   
               
               
                 798 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 418 
                 419 
               
               
                   
               
               
                 799 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 421 
                 422 
               
               
                   
               
               
                 800 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 421 
                 422 
               
               
                   
               
               
                 801 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 421 
                 422 
               
               
                   
               
               
                 802 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 421 
                 422 
               
               
                   
               
               
                 803 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 421 
                 422 
               
               
                   
               
               
                 804 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 421 
                 422 
               
               
                   
               
               
                 805 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 421 
                 422 
               
               
                   
               
               
                 806 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 421 
                 422 
               
               
                   
               
               
                 807 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 423 
                 424 
               
               
                   
               
               
                 808 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 423 
                 424 
               
               
                   
               
               
                 809 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 423 
                 424 
               
               
                   
               
               
                 810 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 423 
                 424 
               
               
                   
               
               
                 811 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 425 
                 426 
               
               
                   
               
               
                 812 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 425 
                 426 
               
               
                   
               
               
                 813 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 427 
                 428 
               
               
                   
               
               
                 814 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 429 
                 430 
               
               
                   
               
               
                 815 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 429 
                 430 
               
               
                   
               
               
                 816 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 429 
                 430 
               
               
                   
               
               
                 817 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 432 
                 433 
               
               
                   
               
               
                 818 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 432 
                 433 
               
               
                   
               
               
                 819 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 432 
                 433 
               
               
                   
               
               
                 820 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 433 
                 434 
               
               
                   
               
               
                 821 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 433 
                 434 
               
               
                   
               
               
                 822 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 435 
                 436 
               
               
                   
               
               
                 823 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 435 
                 436 
               
               
                   
               
               
                 824 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 435 
                 436 
               
               
                   
               
               
                 825 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 435 
                 436 
               
               
                   
               
               
                 826 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 435 
                 436 
               
               
                   
               
               
                 827 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 435 
                 436 
               
               
                   
               
               
                 828 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 435 
                 436 
               
               
                   
               
               
                 829 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 437 
                 438 
               
               
                   
               
               
                 830 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 437 
                 438 
               
               
                   
               
               
                 831 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 437 
                 438 
               
               
                   
               
               
                 832 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 437 
                 438 
               
               
                   
               
               
                 833 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 437 
                 438 
               
               
                   
               
               
                 834 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 437 
                 438 
               
               
                   
               
               
                 835 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 437 
                 438 
               
               
                   
               
               
                 836 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 439 
                 440 
               
               
                   
               
               
                 837 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 439 
                 440 
               
               
                   
               
               
                 838 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 439 
                 440 
               
               
                   
               
               
                 839 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 441 
                 442 
               
               
                   
               
               
                 840 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 441 
                 442 
               
               
                   
               
               
                 841 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 441 
                 442 
               
               
                   
               
               
                 842 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 441 
                 442 
               
               
                   
               
               
                 843 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 443 
                 444 
               
               
                   
               
               
                 844 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 443 
                 444 
               
               
                   
               
               
                 845 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 443 
                 444 
               
               
                   
               
               
                 846 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 447 
                 448 
               
               
                   
               
               
                 847 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 447 
                 448 
               
               
                   
               
               
                 848 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 449 
                 450 
               
               
                   
               
               
                 849 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 450 
                 451 
               
               
                   
               
               
                 850 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 450 
                 451 
               
               
                   
               
               
                 851 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 450 
                 451 
               
               
                   
               
               
                 852 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 451 
                 452 
               
               
                   
               
               
                 853 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 451 
                 452 
               
               
                   
               
               
                 854 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 451 
                 452 
               
               
                   
               
               
                 855 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 452 
                 453 
               
               
                   
               
               
                 856 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 453 
                 454 
               
               
                   
               
               
                 857 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 453 
                 454 
               
               
                   
               
               
                 858 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 455 
                 456 
               
               
                   
               
               
                 859 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 455 
                 456 
               
               
                   
               
               
                 860 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 455 
                 456 
               
               
                   
               
               
                 861 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 457 
                 458 
               
               
                   
               
               
                 862 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 457 
                 458 
               
               
                   
               
               
                 863 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 458 
                 458 
               
               
                   
               
               
                 864 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 458 
                 459 
               
               
                   
               
               
                 865 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 458 
                 459 
               
               
                   
               
               
                 866 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 460 
                 461 
               
               
                   
               
               
                 867 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 461 
                 462 
               
               
                   
               
               
                 868 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 461 
                 462 
               
               
                   
               
               
                 869 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 461 
                 462 
               
               
                   
               
               
                 870 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 461 
                 462 
               
               
                   
               
               
                 871 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 461 
                 462 
               
               
                   
               
               
                 872 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 461 
                 462 
               
               
                   
               
               
                 873 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 461 
                 462 
               
               
                   
               
               
                 874 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 463 
                 464 
               
               
                   
               
               
                 875 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 466 
                 467 
               
               
                   
               
               
                 876 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 466 
                 467 
               
               
                   
               
               
                 877 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 467 
                 468 
               
               
                   
               
               
                 878 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 469 
                 470 
               
               
                   
               
               
                 879 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 469 
                 470 
               
               
                   
               
               
                 880 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 471 
                 472 
               
               
                   
               
               
                 881 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 471 
                 472 
               
               
                   
               
               
                 882 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 472 
                 473 
               
               
                   
               
               
                 883 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 472 
                 473 
               
               
                   
               
               
                 884 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 475 
                 476 
               
               
                   
               
               
                 885 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 475 
                 476 
               
               
                   
               
               
                 886 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 475 
                 476 
               
               
                   
               
               
                 887 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 475 
                 476 
               
               
                   
               
               
                 888 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 475 
                 476 
               
               
                   
               
               
                 889 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 475 
                 476 
               
               
                   
               
               
                 890 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 475 
                 476 
               
               
                   
               
               
                 891 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 475 
                 476 
               
               
                   
               
               
                 892 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 475 
                 476 
               
               
                   
               
               
                 893 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 475 
                 476 
               
               
                   
               
               
                 894 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 475 
                 476 
               
               
                   
               
               
                 895 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 475 
                 476 
               
               
                   
               
               
                 896  
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 477 
                 478 
               
               
                   
               
               
                 897 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 477 
                 478 
               
               
                   
               
               
                 898 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 479 
                 480 
               
               
                   
               
               
                 899 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 479 
                 480 
               
               
                   
               
               
                 900 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 480 
                 481 
               
               
                   
               
               
                 901 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 483 
                 484 
               
               
                   
               
               
                 902 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 483 
                 484 
               
               
                   
               
               
                 903 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 485 
                 486 
               
               
                   
               
               
                 904 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 485 
                 486 
               
               
                   
               
               
                 905 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 485 
                 486 
               
               
                   
               
               
                 906 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 485 
                 486 
               
               
                   
               
               
                 907 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 485 
                 486 
               
               
                   
               
               
                 908 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 489 
                 490 
               
               
                   
               
               
                 909 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 489 
                 490 
               
               
                   
               
               
                 910 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 489 
                 490 
               
               
                   
               
               
                 911 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 491 
                 492 
               
               
                   
               
               
                 912 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 493 
                 494 
               
               
                   
               
               
                 913 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 493 
                 494 
               
               
                   
               
               
                 914 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 493 
                 494 
               
               
                   
               
               
                 915 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 493 
                 494 
               
               
                   
               
               
                 916 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 496 
                 497 
               
               
                   
               
               
                 917 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 496 
                 497 
               
               
                   
               
               
                 918 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 497 
                 498 
               
               
                   
               
               
                 919 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 497 
                 498 
               
               
                   
               
               
                 920 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 499 
                 500 
               
               
                   
               
               
                 921 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 501 
                 502 
               
               
                   
               
               
                 922 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 501 
                 502 
               
               
                   
               
               
                 923 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 502 
                 503 
               
               
                   
               
               
                 924 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 502 
                 503 
               
               
                   
               
               
                 925 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 502 
                 503 
               
               
                   
               
               
                 926 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 502 
                 503 
               
               
                   
               
               
                 927 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 503 
                 504 
               
               
                   
               
               
                 928 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 505 
                 506 
               
               
                   
               
               
                 929 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 507 
                 508 
               
               
                   
               
               
                 930 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 507 
                 508 
               
               
                   
               
               
                 931 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 507 
                 508 
               
               
                   
               
               
                 932 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 509 
                 510 
               
               
                   
               
               
                 933 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 509 
                 510 
               
               
                   
               
               
                 934 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 509 
                 510 
               
               
                   
               
               
                 935 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 510 
                 511 
               
               
                   
               
               
                 936 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 511 
                 512 
               
               
                   
               
               
                 937 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 511 
                 512 
               
               
                   
               
               
                 938 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 514  
                 515 
               
               
                   
               
               
                 939 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 515 
                 516 
               
               
                   
               
               
                 940 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 515 
                 516 
               
               
                   
               
               
                 941 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 519 
                 520 
               
               
                   
               
               
                 942 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 519 
                 520 
               
               
                   
               
               
                 943 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 522 
                 523 
               
               
                   
               
               
                 944 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 523 
                 524 
               
               
                   
               
               
                 945 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 523 
                 524 
               
               
                   
               
               
                 946 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 525 
                 526 
               
               
                   
               
               
                 947 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 527 
                 528 
               
               
                   
               
               
                 948 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 529 
                 530 
               
               
                   
               
               
                 949 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 533 
                 534 
               
               
                   
               
               
                 950 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 537 
                 538 
               
               
                   
               
               
                 951 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 539 
                 540 
               
               
                   
               
               
                 952 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 543 
                 544 
               
               
                   
               
               
                 953 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 545 
                 546 
               
               
                   
               
               
                 954 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 545 
                 546 
               
               
                   
               
               
                 955 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 547 
                 548 
               
               
                   
               
               
                 956 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 549 
                 550 
               
               
                   
               
               
                 957 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 553 
                 554 
               
               
                   
               
               
                 958 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 555 
                 556 
               
               
                   
               
               
                 959 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 559 
                 560 
               
               
                   
               
               
                 960 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 559 
                 560 
               
               
                   
               
               
                 961 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 387 
               
               
                   
               
             
          
         
       
     
     Method N 
     
       
                 
         
             
             
         
      
     
     (In the scheme, —Z—NH—S(O) 2 R 16 — is equivalent to R 1  substituted by R 21 , or R 1  Substituted by alkyl-R 22 , wherein R 21  and R 22  are —N(R 16 )—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-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 )C 6 H 4 (CH 2 )—, 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 )C 6 H 4 (CH 2 )—, R 16 =CH 2 CH(CH 3 ) 2 ) was prepared from N2 (R 3 =CH 3 , R 4 =CH 2 CH(CH 3 ) 2 , Z=para-(CH 2 )C 6 H 4 (CH 2 )—, R 16 =CH 2 CH(CH 3 ) 2 ) following the procedure described in 
     Method A, Step 3. 
     The following compounds were prepared using similar method. 
     
       
         
               
               
               
               
             
           
               
                   
               
               
                   
                   
                   
                 Obs. 
               
               
                 # 
                 Structure 
                 MW 
                 m/e 
               
               
                   
               
             
             
               
                 962 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 380 
                 381 
               
               
                   
               
               
                 963 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 380 
                 381 
               
               
                   
               
               
                 964 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 394 
                 395 
               
               
                   
               
               
                 965 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 394 
                 395 
               
               
                   
               
               
                 966 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 451 
                 452 
               
               
                   
               
               
                 967 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 484 
                 485 
               
               
                   
               
               
                 968 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 484 
                 485 
               
               
                   
               
               
                 969 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 498 
                 499 
               
               
                   
               
               
                 970 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 498 
                 499 
               
               
                   
               
             
          
         
       
     
     Method O 
     
       
                 
         
             
             
         
      
       
                 
         
             
             
         
       
     
     Method O, Step 1: 
     A solution of indole-6-methanol (400 mg, 2.72 mmol), tert-butyldimethysilyl chloride (816 mg, 5.41 mmol) and imidazole (740 mg, 10.9 mmol) in CH 2 Cl 2  was stirred at rt. overnight before the solvent was evaporated and residue chromatographed using ethylacetate/hexane to give product O2. 
     Method O, Step 2: 
     To a solution of O2 (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° C. and p-toluenesulfonyl chloride was added. The solution was warmed to rt and stirred overnight. The reaction was quenched with a saturated aqueous K 2 CO 3  solution, extracted with ethyl acetate and CH 2 Cl 2 . The crude material was purified via flash chromatography using ethylacetate/hexane to afford 360 mg of O3. 
     Method O, Step 3: 
     A solution butyl lithium (1.2 eq) was added to a solution of O3 (340 mg, 0.829 mmol) in THF (20 mL). The reaction mixture was stirred for 15 min at −78° C. then sulfur dioxide was bubbled through the solution for 15 min. Hexane (100 mL) was added to the reaction mixture. The reaction mixture was evaporated to afford O4 which was used in the next step without further purification. 
     Method O, Step 4: 
     To a solution of O4 (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 O5. 
     Method O, Step 5: 
     To a solution of O5 in anhydrous pyridine (3 mL) was added butyl amine (100 μL). The reaction was agitated at rt for 4 d. The reaction mixture was partitioned between 1 N HCl and CH 2 Cl 2 . The organic layer was separated and washed with 1 N HCl (3×). The organic solution was dried over Na 2 SO 4 , filtered and concentrated. The crude material was purified via flash chromatography using ethylacetate/hexane to yield O6. 
     Method O, Step 6: 
     To a solution of O6 (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 O7 (95%). 
     Method O, Step 7: 
     To a solution of O7 (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 O8. 
     Method O, Step 8: 
     To a solution of O8 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 O9 after purification. 
     Method O, Step 9: 
     To a suspension of O9 (70 mg) in CH 3 OH was added 1 eq HCl (aq) and palladium on carbon. The reaction mixture was hydrogenated at 1 atm for 20 min to yield 90 mg of crude product O10. 
     Method O, Step 10: 
     A solution of lithium hydroxide (30 mg) in H 2 O was added to a solution of O10 (40 mg) in CH 3 OH (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 O11. 
     Method P 
     
       
                 
         
             
             
         
      
     
     Method P, Step 1: 
     A 300 mL of THF solution of 100 g of P1 (R 23 =n-Pr) was added to a 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 O, 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 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 O at −10° C. and the mixture was extracted with DCM. After removal of solvent, P2 (R 23 =Pr, 106 g) was obtained. The crude material was used for next step without purification. 
     Method P, Step 2: 
     To a 1.5 L DCM solution of P2 (R 23 =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 H 2 O 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 23 =Pr). 
     Method P, Step 3: 
     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. 
     Method P, Step 4: 
     To a 10 ml DCM solution of P4 at 0° C. (R 23 =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/H2O. After removal of the solvent, the residue was chromatographed using a silica gel column eluted with EtOAc/Hexane to give a white solid which was treated with 2N HCl in dioxane for 2 h. After removal of the solvent, compound P5 (R 23 =Pr) as a white solid was obtained (80 mg). 
     The following compounds were synthesized using similar methods: 
     
       
                 
         
             
             
         
      
     
     Method Q 
     
       
                 
         
             
             
         
      
     
     Method Q, Step 1 
     At room temperature, Q1 (R 3 =Me; R 4 =iBu) (1.00 g) and Q8 (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 silica gel (200 mL) eluted with ethylacetate/hexane to give Q2 (n=1, p=2, m=1, R 3 =Me; R 4 =iBu), a colorless oil (1.59 g). 
     Method Q, Step 2 
     Compound Q3 (n=1, p=2, m=1, R 2 =H, R 3 =Me; R 4 =iBu) was prepared from Q2 (n=1, p=2, m=1, R 3 =Me; R 4 =iBu) using method similar to method A step 3. 
     Method Q, Step 3 
     Compound Q3 (n=1, p=2, m=1, R 2 =H, R 3 =Me; R 4 =iBu) (1.37 g) in anhydrous dichloromethane (25 mL) was treated with di-tert-butyl dicarbonate (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 1N hydrochloric acid. The dried dichloromethane solution was concentrated in vacuo to give a colorless film (1.32 g) which was purified on a column of silica gel (125 mL) and eluted with hexane:ethyl acetate to give compound Q4 (n=1, p=2, m=1, R 2 =H, R 3 =Me; R 4 =i-Bu) as a white foam (0.74 g). 
     Method Q, Step 4 
     Compound Q4 (n=1, p=2, m=1, R 2 =H, R 3 =Me; R 4 = i 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 Q5 (n=1, p=2, m=1, R 2 =H, R 3 =Me; R 4 = i Bu) as a colorless oil (0.35 g). 
     Method Q, Step 5 
     Compound Q5 (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 mmol/g) in a microtiter plate well followed by addition of a 1M dichloroethane solution (40 uL, 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 eq., 1.53 mmol/g) for 18 h before the solution was filtered and the solvent was removed in vacuo to give Q6 (n=1, p=2, m=1, R 2 =H, R 3 =Me; R 4 = i Bu, R 15 =Me). 
     Method Q, Step 6. 
     A dichloromethane solution (1.0 mL) of Q6 (n=1, p=2, m=1, R 2 =H, R 3 =Me; R 4 = i Bu, R 16 =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 purified on a Prep LCMS unit to give Q7 (=1, p=2, m=1, R2=H, R 3 =Me; R 4 =iBu, R 15 =Me). NMR (CDCl 3 ): δ 8.38, br, 2H; δ 4.56, m, 1H; δ 3.79, m, 1H; δ 3.57, m, 2H; δ 2.99, m, 1H; δ 2.48, m, 1H; δ 2.04, s, 3H; δ 1.95, m, 1H; δ 1.5-1.8, m, 5H; δ 1.5, s, 3H, 1.25, m, 2H; δ 0.95, m, 3H; δ 0.85, m, 3H. ES_LCMS (m/e) 309.17. 
     The following compounds were prepared using similar methods: 
     
       
         
               
               
               
               
             
           
               
                   
               
               
                   
                   
                   
                 Obs. 
               
               
                 # 
                 Structure 
                 MW 
                 m/e 
               
               
                   
               
             
             
               
                  971 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 308 
                 309 
               
               
                   
               
               
                  972 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 308 
                 309 
               
               
                   
               
               
                  973 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 310 
                 311 
               
               
                   
               
               
                  974 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 322 
                 323 
               
               
                   
               
               
                  975 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 324 
                 325 
               
               
                   
               
               
                  976 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 334 
                 335 
               
               
                   
               
               
                  977 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 336 
                 337 
               
               
                   
               
               
                  978 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 348 
                 349 
               
               
                   
               
               
                  979 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 348 
                 349 
               
               
                   
               
               
                  980 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                  0 
                 351 
               
               
                   
               
               
                  981 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 350 
                 351 
               
               
                   
               
               
                  982 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 350 
                 351 
               
               
                   
               
               
                  983 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 360 
                 361 
               
               
                   
               
               
                  984 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 360 
                 361 
               
               
                   
               
               
                  985 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 362 
                 363 
               
               
                   
               
               
                  986 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 362 
                 363 
               
               
                   
               
               
                  987 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 364 
                 365 
               
               
                   
               
               
                  988 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 364 
                 365 
               
               
                   
               
               
                  989 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 364 
                 365 
               
               
                   
               
               
                  990 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 370 
                 371 
               
               
                   
               
               
                  991 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 370 
                 371 
               
               
                   
               
               
                  992 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 376 
                 377 
               
               
                   
               
               
                  993 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 376 
                 377 
               
               
                   
               
               
                  994 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 376 
                 377 
               
               
                   
               
               
                  995 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 378 
                 379 
               
               
                   
               
               
                  996 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 378 
                 379 
               
               
                   
               
               
                  997 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 378 
                 379 
               
               
                   
               
               
                  998 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 378 
                 379 
               
               
                   
               
               
                  999 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 379 
                 380 
               
               
                   
               
               
                 1000 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 384 
                 385 
               
               
                   
               
               
                 1001 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 384 
                 385 
               
               
                   
               
               
                 1002 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 384 
                 385 
               
               
                   
               
               
                 1003 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 386 
                 387 
               
               
                   
               
               
                 1004 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 388 
                 389 
               
               
                   
               
               
                 1005 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 389 
                 390 
               
               
                   
               
               
                 1006 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 390 
                 391 
               
               
                   
               
               
                 1007 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 390 
                 391 
               
               
                   
               
               
                 1008 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 390 
                 391 
               
               
                   
               
               
                 1009 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 390 
                 391 
               
               
                   
               
               
                 1010 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 390 
                 391 
               
               
                   
               
               
                 1011 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 390 
                 391 
               
               
                   
               
               
                 1012 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 390 
                 391 
               
               
                   
               
               
                 1013 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 390 
                 391 
               
               
                   
               
               
                 1014 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 390 
                 391 
               
               
                   
               
               
                 1015 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 392 
                 393 
               
               
                   
               
               
                 1016 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 392 
                 393 
               
               
                   
               
               
                 1017 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 392 
                 393 
               
               
                   
               
               
                 1018 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 394 
                 395 
               
               
                   
               
               
                 1019 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 398 
                 399 
               
               
                   
               
               
                 1020 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 398 
                 399 
               
               
                   
               
               
                 1021 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 398 
                 399 
               
               
                   
               
               
                 1022 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 398 
                 399 
               
               
                   
               
               
                 1023 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 398 
                 399 
               
               
                   
               
               
                 1024 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 400 
                 401 
               
               
                   
               
               
                 1025 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 400 
                 401 
               
               
                   
               
               
                 1026 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 400 
                 401 
               
               
                   
               
               
                 1027 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 400 
                 401 
               
               
                   
               
               
                 1028 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 400 
                 401 
               
               
                   
               
               
                 1029 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 400 
                 401 
               
               
                   
               
               
                 1030 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 400 
                 401 
               
               
                   
               
               
                 1031 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 400 
                 401 
               
               
                   
               
               
                 1032 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                  02 
                 403 
               
               
                   
               
               
                 1033 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 402 
                 403 
               
               
                   
               
               
                 1034 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 404 
                 405 
               
               
                   
               
               
                 1035 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 404 
                 405 
               
               
                   
               
               
                 1036 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 404 
                 405 
               
               
                   
               
               
                 1037 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 404 
                 405 
               
               
                   
               
               
                 1038 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 404 
                 405 
               
               
                   
               
               
                 1039 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 404 
                 405 
               
               
                   
               
               
                 1040 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 404 
                 405 
               
               
                   
               
               
                 1041 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 404 
                 405 
               
               
                   
               
               
                 1042 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 409 
                 410 
               
               
                   
               
               
                 1043 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 410 
                 411 
               
               
                   
               
               
                 1044 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                  0 
                 411 
               
               
                   
               
               
                 1045 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 410 
                 411 
               
               
                   
               
               
                 1046 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 412 
                 413 
               
               
                   
               
               
                 1047 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 412 
                 413 
               
               
                   
               
               
                 1048 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 412 
                 413 
               
               
                   
               
               
                 1049 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 414 
                 415 
               
               
                   
               
               
                 1050 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 414 
                 415 
               
               
                   
               
               
                 1051 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 414 
                 415 
               
               
                   
               
               
                 1052 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 414 
                 415 
               
               
                   
               
               
                 1053 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 414 
                 415 
               
               
                   
               
               
                 1054 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 414 
                 415 
               
               
                   
               
               
                 1055 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 414 
                 415 
               
               
                   
               
               
                 1056 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 416 
                 417 
               
               
                   
               
               
                 1057 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 416 
                 417 
               
               
                   
               
               
                 1058 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 417 
                 418 
               
               
                   
               
               
                 1059 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 418 
                 419 
               
               
                   
               
               
                 1060 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 418 
                 419 
               
               
                   
               
               
                 1061 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 418 
                 419 
               
               
                   
               
               
                 1062 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 418 
                 419 
               
               
                   
               
               
                 1063 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 418 
                 419 
               
               
                   
               
               
                 1064 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 420 
                 421 
               
               
                   
               
               
                 1065 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 423 
                 424 
               
               
                   
               
               
                 1066 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 424 
                 425 
               
               
                   
               
               
                 1067 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 424 
                 425 
               
               
                   
               
               
                 1068 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 426 
                 427 
               
               
                   
               
               
                 1069 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 426 
                 427 
               
               
                   
               
               
                 1070 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 426 
                 427 
               
               
                   
               
               
                 1071 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 426 
                 427 
               
               
                   
               
               
                 1072 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 426 
                 427 
               
               
                   
               
               
                 1073 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 427 
                 428 
               
               
                   
               
               
                 1074 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 428 
                 429 
               
               
                   
               
               
                 1075 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 428 
                 429 
               
               
                   
               
               
                 1076 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 428 
                 429 
               
               
                   
               
               
                 1077 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 428 
                 429 
               
               
                   
               
               
                 1078 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 428 
                 429 
               
               
                   
               
               
                 1079 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 430 
                 431 
               
               
                   
               
               
                 1080 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 430 
                 431 
               
               
                   
               
               
                 1081 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 430 
                 431 
               
               
                   
               
               
                 1082 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 432 
                 433 
               
               
                   
               
               
                 1083 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 432 
                 433 
               
               
                   
               
               
                 1084 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 432 
                 433 
               
               
                   
               
               
                 1085 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 432 
                 433 
               
               
                   
               
               
                 1086 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 432 
                 433 
               
               
                   
               
               
                 1087 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 432 
                 433 
               
               
                   
               
               
                 1088 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 438 
                 439 
               
               
                   
               
               
                 1089 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 438 
                 439 
               
               
                   
               
               
                 1090 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 438 
                 439 
               
               
                   
               
               
                 1091 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 438 
                 439 
               
               
                   
               
               
                 1092 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 438 
                 439 
               
               
                   
               
               
                 1093 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 440 
                 441 
               
               
                   
               
               
                 1094 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 440 
                 441 
               
               
                   
               
               
                 1095 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 440 
                 441 
               
               
                   
               
               
                 1096  
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 440 
                 441 
               
               
                   
               
               
                 1097 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 442 
                 443 
               
               
                   
               
               
                 1098 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 442 
                 443 
               
               
                   
               
               
                 1099 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 442 
                 443 
               
               
                   
               
               
                 1100 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 442 
                 443 
               
               
                   
               
               
                 1101 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 442 
                 443 
               
               
                   
               
               
                 1102 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 444 
                 445 
               
               
                   
               
               
                 1103 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 444 
                 445 
               
               
                   
               
               
                 1104 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 444 
                 445 
               
               
                   
               
               
                 1105 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 446 
                 447 
               
               
                   
               
               
                 1106 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 446 
                 447 
               
               
                   
               
               
                 1107 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 446 
                 447 
               
               
                   
               
               
                 1108 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 449 
                 450 
               
               
                   
               
               
                 1109 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 451 
                 452 
               
               
                   
               
               
                 1110 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 452 
                 453 
               
               
                   
               
               
                 1111 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 452 
                 453 
               
               
                   
               
               
                 1112 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 452 
                 453 
               
               
                   
               
               
                 1113 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 456 
                 457 
               
               
                   
               
               
                 1114 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 456 
                 457 
               
               
                   
               
               
                 1115 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 456 
                 457 
               
               
                   
               
               
                 1116 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 458 
                 459 
               
               
                   
               
               
                 1117 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 460 
                 461 
               
               
                   
               
               
                 1118 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 460 
                 461 
               
               
                   
               
               
                 1119 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 460 
                 461 
               
               
                   
               
               
                 1120 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 460 
                 461 
               
               
                   
               
               
                 1121 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 462 
                 463 
               
               
                   
               
               
                 1122 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 462 
                 463 
               
               
                   
               
               
                 1123 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 462 
                 463 
               
               
                   
               
               
                 1124 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 462 
                 463 
               
               
                   
               
               
                 1125 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 462 
                 463 
               
               
                   
               
               
                 1126 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 464 
                 465 
               
               
                   
               
               
                 1127 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 466 
                 467 
               
               
                   
               
               
                 1128 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 466 
                 467 
               
               
                   
               
               
                 1129 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 470 
                 471 
               
               
                   
               
               
                 1130 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 472 
                 473 
               
               
                   
               
               
                 1131 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 474 
                 475 
               
               
                   
               
               
                 1132 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 474 
                 475 
               
               
                   
               
               
                 1133 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 476 
                 477 
               
               
                   
               
               
                 1134 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 476 
                 477 
               
               
                   
               
               
                 1135 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 478 
                 479 
               
               
                   
               
               
                 1136 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 482 
                 483 
               
               
                   
               
               
                 1137 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 482 
                 483 
               
               
                   
               
               
                 1138 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 482 
                 483 
               
               
                   
               
               
                 1139 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 488 
                 489 
               
               
                   
               
               
                 1140 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 490 
                 491 
               
               
                   
               
               
                 1141 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 500 
                 501 
               
               
                   
               
               
                 1142 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 502 
                 503 
               
               
                   
               
               
                 1143 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 502 
                 503 
               
               
                   
               
               
                 1144 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 504 
                 505 
               
               
                   
               
               
                 1145 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 504 
                 505 
               
               
                   
               
               
                 1146 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 504 
                 505 
               
               
                   
               
               
                 1147 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 511 
                 512 
               
               
                   
               
               
                 1148 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 512 
                 513 
               
               
                   
               
               
                 1149 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 512 
                 513 
               
               
                   
               
               
                 1150 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 520 
                 521 
               
               
                   
               
               
                 1151 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 520 
                 521 
               
               
                   
               
               
                 1152 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 520 
                 521 
               
               
                   
               
               
                 1153 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 520 
                 521 
               
               
                   
               
               
                 1154 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 522 
                 523 
               
               
                   
               
               
                 1155 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 522 
                 523 
               
               
                   
               
               
                 1156 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 536 
                 537 
               
               
                   
               
               
                 1157 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 536 
                 537 
               
               
                   
               
               
                 1158 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 536 
                 537 
               
               
                   
               
               
                 1159 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 538 
                 539 
               
               
                   
               
               
                 1160 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 538 
                 539 
               
               
                   
               
               
                 1161 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 540 
                 541 
               
               
                   
               
               
                 1162 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 541 
                 542 
               
               
                   
               
               
                 1163 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 542 
                 543 
               
               
                   
               
               
                 1164 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 546 
                 547 
               
               
                   
               
               
                 1165 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 546 
                 547 
               
               
                   
               
               
                 1166 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 550 
                 551 
               
               
                   
               
               
                 1167 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 550 
                 551 
               
               
                   
               
               
                 1168 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 569 
                 570 
               
               
                   
               
               
                 1169 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 582 
                 583 
               
               
                   
               
               
                 1170 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 582 
                 583 
               
               
                   
               
               
                 1171 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 584 
                 585 
               
               
                   
               
               
                 1172 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 584 
                 585 
               
               
                   
               
               
                 1173 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 594 
                 595 
               
               
                   
               
               
                 1174 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 596 
                 597 
               
               
                   
               
               
                 1175 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 596 
                 597 
               
               
                   
               
             
          
         
       
     
     Method R 
     
       
                 
         
             
             
         
      
     
     Method R, Step 1. 
     A solution of R 1  (n=1, p=2, m=1, R 2 =H, R 3 =Me; R 4 = i Bu) (0.010 g) in acetonitrile (0.85 mL) and dichloroethane (0.15 mL) was put into a microtiter 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 (0.5 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 eq., 1.53 mmol/g) and the mixture was 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 = i Bu and R 15 =Ph). 
     Method R, Step 2. 
     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 = i Bu and R 15 =Ph) to R 3  (n=1, p=2, m=1, R 2 =H, R 3 =Me; R 4 = i Bu and R 15 =Ph). 
     The following compounds were prepared using similar methods: 
     
       
         
               
               
               
               
             
           
               
                   
               
               
                   
                   
                   
                 Obs. 
               
               
                 # 
                 Structure 
                 MW 
                 m/e 
               
               
                   
               
             
             
               
                 1176 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 309 
                 310 
               
               
                   
               
               
                 1177 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 309 
                 310 
               
               
                   
               
               
                 1178 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 311 
                 312 
               
               
                   
               
               
                 1179 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 325 
                 326 
               
               
                   
               
               
                 1180 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 337 
                 338 
               
               
                   
               
               
                 1181 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 346 
                 347 
               
               
                   
               
               
                 1182 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 351 
                 352 
               
               
                   
               
               
                 1183 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 351 
                 352 
               
               
                   
               
               
                 1184 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 351 
                 352 
               
               
                   
               
               
                 1185 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 365 
                 366 
               
               
                   
               
               
                 1186 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 365 
                 366 
               
               
                   
               
               
                 1187 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 365 
                 366 
               
               
                   
               
               
                 1188 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 367 
                 368 
               
               
                   
               
               
                 1189 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 377 
                 378 
               
               
                   
               
               
                 1190 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 381 
                 382 
               
               
                   
               
               
                 1191 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 385 
                 386 
               
               
                   
               
               
                 1192 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 391 
                 392 
               
               
                   
               
               
                 1193 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 393 
                 394 
               
               
                   
               
               
                 1194 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 395 
                 396 
               
               
                   
               
               
                 1195 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 399 
                 400 
               
               
                   
               
               
                 1196 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 399 
                 400 
               
               
                   
               
               
                 1197 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 399 
                 400 
               
               
                   
               
               
                 1198 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 399 
                 400 
               
               
                   
               
               
                 1199 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 399 
                 400 
               
               
                   
               
               
                 1200 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 401 
                 402 
               
               
                   
               
               
                 1201 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 403 
                 404 
               
               
                   
               
               
                 1202 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 403 
                 404 
               
               
                   
               
               
                 1203 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 407 
                 408 
               
               
                   
               
               
                 1204 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 407 
                 408 
               
               
                   
               
               
                 1205 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 410 
                 411 
               
               
                   
               
               
                 1206 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 410 
                 411 
               
               
                   
               
               
                 1207 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 413 
                 414 
               
               
                   
               
               
                 1208 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 413 
                 414 
               
               
                   
               
               
                 1209 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 415 
                 416 
               
               
                   
               
               
                 1210 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 415 
                 416 
               
               
                   
               
               
                 1211 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 415 
                 416 
               
               
                   
               
               
                 1212 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 415 
                 416 
               
               
                   
               
               
                 1213 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 417 
                 418 
               
               
                   
               
               
                 1214 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 419 
                 420 
               
               
                   
               
               
                 1215 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 419 
                 420 
               
               
                   
               
               
                 1216 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 419 
                 420 
               
               
                   
               
               
                 1217 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 421 
                 422 
               
               
                   
               
               
                 1218 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 421 
                 422 
               
               
                   
               
               
                 1219 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 425 
                 426 
               
               
                   
               
               
                 1220 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 427 
                 428 
               
               
                   
               
               
                 1221 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 427 
                 428 
               
               
                   
               
               
                 1222 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 429 
                 430 
               
               
                   
               
               
                 1223 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 429 
                 430 
               
               
                   
               
               
                 1224 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 431 
                 432 
               
               
                   
               
               
                 1225 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 431 
                 432 
               
               
                   
               
               
                 1226 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 433 
                 434 
               
               
                   
               
               
                 1227 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 435 
                 436 
               
               
                   
               
               
                 1228 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 441 
                 442 
               
               
                   
               
               
                 1229 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 441 
                 442 
               
               
                   
               
               
                 1230 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 441 
                 442 
               
               
                   
               
               
                 1231 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 445 
                 446 
               
               
                   
               
               
                 1232 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 449 
                 450 
               
               
                   
               
               
                 1233 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 453 
                 454 
               
               
                   
               
               
                 1234 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 453 
                 454 
               
               
                   
               
               
                 1235 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 453 
                 454 
               
               
                   
               
               
                 1236 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 453 
                 454 
               
               
                   
               
               
                 1237 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 453 
                 454 
               
               
                   
               
               
                 1238 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 455 
                 456 
               
               
                   
               
               
                 1239 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 455 
                 456 
               
               
                   
               
               
                 1240 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 457 
                 458 
               
               
                   
               
               
                 1241 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 461 
                 462 
               
               
                   
               
               
                 1242 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 463 
                 464 
               
               
                   
               
               
                 1243 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 467 
                 468 
               
               
                   
               
               
                 1244 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 467 
                 468 
               
               
                   
               
               
                 1245 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 471 
                 472 
               
               
                   
               
               
                 1246 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 475 
                 476 
               
               
                   
               
               
                 1247 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 477 
                 478 
               
               
                   
               
               
                 1248 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 477 
                 478 
               
               
                   
               
               
                 1249 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 487 
                 488 
               
               
                   
               
               
                 1250 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 487 
                 488 
               
               
                   
               
               
                 1251 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 487 
                 488 
               
               
                   
               
               
                 1252 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 491 
                 492 
               
               
                   
               
             
          
         
       
     
     Method S 
     
       
                 
         
             
             
         
      
     
     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 chloride in dioxane (1M, 45 μL, 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 mmol/g) and Isocyanate resin (0.060 g, 3 equiv., 1.53 mmol/g) and shaken for 18 h before the mixture was filtered and the solvent removed to give S2 (n=1, p=2, m=1, R 2 =H, R 3 =Me; R 4 =iBu and R 15 =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, R 2 =H, R 3 =Me; R 4 = i Bu and R 15 =Ph). 
     The following compounds were prepared using similar methods: 
     
       
         
               
               
               
               
             
           
               
                   
               
               
                   
                   
                   
                 Obs. 
               
               
                 # 
                 Structure 
                 MW 
                 m/e 
               
               
                   
               
             
             
               
                 1253 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 344 
                 345 
               
               
                   
               
               
                 1254 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 344 
                 345 
               
               
                   
               
               
                 1255 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 358 
                 359 
               
               
                   
               
               
                 1256 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 358 
                 359 
               
               
                   
               
               
                 1257 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 360 
                 361 
               
               
                   
               
               
                 1258 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 372 
                 373 
               
               
                   
               
               
                 1259 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 372 
                 373 
               
               
                   
               
               
                 1260 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 386 
                 387 
               
               
                   
               
               
                 1261 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 406 
                 407 
               
               
                   
               
               
                 1262 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 406 
                 407 
               
               
                   
               
               
                 1263 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 406 
                 407 
               
               
                   
               
               
                 1264 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 412 
                 413 
               
               
                   
               
               
                 1265 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 416 
                 417 
               
               
                   
               
               
                 1266 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 420 
                 421 
               
               
                   
               
               
                 1267 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 420 
                 421 
               
               
                   
               
               
                 1268 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 420 
                 421 
               
               
                   
               
               
                 1269 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 420 
                 421 
               
               
                   
               
               
                 1270 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 420 
                 421 
               
               
                   
               
               
                 1271 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 420 
                 421 
               
               
                   
               
               
                 1272 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 424 
                 425 
               
               
                   
               
               
                 1273 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 424 
                 425 
               
               
                   
               
               
                 1274 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 424 
                 425 
               
               
                   
               
               
                 1275 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 431 
                 432 
               
               
                   
               
               
                 1276 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 432 
                 433 
               
               
                   
               
               
                 1277 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 434 
                 435 
               
               
                   
               
               
                 1278 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 434 
                 435 
               
               
                   
               
               
                 1279 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 436 
                 437 
               
               
                   
               
               
                 1280 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 436 
                 437 
               
               
                   
               
               
                 1281 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 438 
                 439 
               
               
                   
               
               
                 1282 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 440 
                 441 
               
               
                   
               
               
                 1283 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 440 
                 441 
               
               
                   
               
               
                 1284 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 440 
                 441 
               
               
                   
               
               
                 1285 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 442 
                 443 
               
               
                   
               
               
                 1286 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 442 
                 443 
               
               
                   
               
               
                 1287 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 442 
                 443 
               
               
                   
               
               
                 1288 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 442 
                 443 
               
               
                   
               
               
                 1289 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 442 
                 443 
               
               
                   
               
               
                 1290 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 446 
                 447 
               
               
                   
               
               
                 1291 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 448 
                 449 
               
               
                   
               
               
                 1292 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 448 
                 449 
               
               
                   
               
               
                 1293 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 448 
                 449 
               
               
                   
               
               
                 1294 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 454 
                 455 
               
               
                   
               
               
                 1295 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 456 
                 457 
               
               
                   
               
               
                 1296 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 456 
                 457 
               
               
                   
               
               
                 1297 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 458 
                 459 
               
               
                   
               
               
                 1298 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 458 
                 459 
               
               
                   
               
               
                 1299 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 458 
                 459 
               
               
                   
               
               
                 1300 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 462 
                 463 
               
               
                   
               
               
                 1301 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 464 
                 465 
               
               
                   
               
               
                 1302 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 466 
                 467 
               
               
                   
               
               
                 1303 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 466 
                 467 
               
               
                   
               
               
                 1304 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 466 
                 467 
               
               
                   
               
               
                 1305 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 466 
                 467 
               
               
                   
               
               
                 1306 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 470 
                 471 
               
               
                   
               
               
                 1307 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 474 
                 475 
               
               
                   
               
               
                 1308 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 474 
                 475 
               
               
                   
               
               
                 1309 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 474 
                 475 
               
               
                   
               
               
                 1310 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 474 
                 475 
               
               
                   
               
               
                 1311 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 474 
                 475 
               
               
                   
               
               
                 1312 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 474 
                 475 
               
               
                   
               
               
                 1313 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 474 
                 475 
               
               
                   
               
               
                 1314 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 474 
                 475 
               
               
                   
               
               
                 1315 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 474 
                 475 
               
               
                   
               
               
                 1316 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 474 
                 475 
               
               
                   
               
               
                 1317 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 476 
                 477 
               
               
                   
               
               
                 1318 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 480 
                 481 
               
               
                   
               
               
                 1319 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 482 
                 483 
               
               
                   
               
               
                 1320 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 484 
                 485 
               
               
                   
               
               
                 1321 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 484 
                 485 
               
               
                   
               
               
                 1322 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 488 
                 489 
               
               
                   
               
               
                 1323 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 490 
                 491 
               
               
                   
               
               
                 1324 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 490 
                 491 
               
               
                   
               
               
                 1325 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 492 
                 493 
               
               
                   
               
               
                 1326 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 498 
                 499 
               
               
                   
               
               
                 1327 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 508 
                 509 
               
               
                   
               
               
                 1328 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 508 
                 509 
               
               
                   
               
               
                 1329 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 508 
                 509 
               
               
                   
               
               
                 1330 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 508 
                 509 
               
               
                   
               
               
                 1331 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 542 
                 543 
               
               
                   
               
               
                 1332 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 557 
                 558 
               
               
                   
               
             
          
         
       
     
     Method T 
     
       
                 
         
             
             
         
      
     
     Method T, Step 1. 
     To a microtiter plate well containing 1 ml solution of T1 (n=1, p=2, m=1, R 2 =H, R 3 =Me; R 4 =iBu) in DCM (0.010 g) and R 15 C(O)R 16  (5 equiv, R 15 =H, R 16 =Ph) was added Sodium cyanoborohydride in dichloroethane (14.3 mg/mL, 2 equiv.). The well was capped and shaken for 20 h 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 was filtered and the resin washed with dichloroethane (1 mL) (3×), then MeOH (1 mL) (2×). The resin was treated with 7N ammonia in MeOH (1 mL) for 30 min (2×) followed by filtration and evaporation of solvent to give T2 (n=1, p=2, m=1, R 2 =H, R 3 =Me; R 4 = i Bu and R 15 =Ph and R 16 =H). 
     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 15 =Ph and R 16 =H) to T3 (n=1, p=2, m=1, R 2 =H, R 3 =Me; R 4 = i Bu and R 15 =Ph and R 16 =H). 
     The following compounds were prepared using similar methods: 
     
       
         
               
               
               
               
             
           
               
                   
               
               
                   
                   
                   
                 Obs. 
               
               
                 # 
                 Structure 
                 MW 
                 m/e 
               
               
                   
               
             
             
               
                 1333 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 348 
                 349 
               
               
                   
               
               
                 1334 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 350 
                 351 
               
               
                   
               
               
                 1335 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 350 
                 351 
               
               
                   
               
               
                 1336 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 356 
                 357 
               
               
                   
               
               
                 1337 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 362 
                 363 
               
               
                   
               
               
                 1338 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 370 
                 371 
               
               
                   
               
               
                 1339 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 384 
                 385 
               
               
                   
               
               
                 1340 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 384 
                 385 
               
               
                   
               
               
                 1341 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 400 
                 401 
               
               
                   
               
               
                 1342 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 446 
                 447 
               
               
                   
               
               
                 1343 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 448 
                 449 
               
               
                   
               
             
          
         
       
     
     Method U 
     
       
                 
         
             
             
         
      
     
     In a microwave vial was charged U1 (R 2 =H; R 3 =i-Bu, R 4 =Me) (0.025 g) in toluene (4 mL), potassium carbonate (0.035 g), Pd(dppf)Cl 2  (0.020 g). water (0.02 mL) and R 21 B(OH) 2  (R 21 =m-Methoxyphenyl) (3 eq.) were placed. The vial was placed in a microwave for 10 min. at 150° C. The reaction mixture was diluted with dichloromethane and extracted with 2.5N NaOH. The dried (MgSO 4 ) dichloromethane solution was concentrated in vacuo to give a brown residue which was purified via a RP Prep LCMS system to give product U2 (R 2 =H; R 3 = i Bu: R 4 =Me; R 21 =m-methoxyphenyl). 
     The following compounds were prepared using similar methods: 
     
       
         
               
               
               
               
             
           
               
                   
               
               
                   
                   
                   
                 Obs. 
               
               
                 # 
                 Structure 
                 MW 
                 m/e 
               
               
                   
               
             
             
               
                 1344 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 279 
                 280 
               
               
                   
               
               
                 1345 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 285 
                 286 
               
               
                   
               
               
                 1346 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 293 
                 294 
               
               
                   
               
               
                 1347 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 299 
                 300 
               
               
                   
               
               
                 1348 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 299 
                 300 
               
               
                   
               
               
                 1349 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 304 
                 305 
               
               
                   
               
               
                 1350 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 309 
                 310 
               
               
                   
               
               
                 1351 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 313 
                 314 
               
               
                   
               
               
                 1352 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 318 
                 319 
               
               
                   
               
               
                 1353 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 323 
                 324 
               
               
                   
               
               
                 1354 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 323 
                 324 
               
               
                   
               
               
                 1355 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 323 
                 324 
               
               
                   
               
               
                 1356 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 329 
                 330 
               
               
                   
               
               
                 1357 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 335 
                 336 
               
               
                   
               
               
                 1358 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 335 
                 336 
               
               
                   
               
               
                 1359 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 337 
                 338 
               
               
                   
               
               
                 1360 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 343 
                 344 
               
               
                   
               
               
                 1361 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 347 
                 348 
               
               
                   
               
               
                 1362 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 347 
                 348 
               
               
                   
               
               
                 1363 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 347 
                 348 
               
               
                   
               
               
                 1364 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 347 
                 348 
               
               
                   
               
               
                 1365 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 347 
                 348 
               
               
                   
               
               
                 1366 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 349 
                 350 
               
               
                   
               
               
                 1367 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 349 
                 350 
               
               
                   
               
               
                 1368 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 350 
                 351 
               
               
                   
               
               
                 1369 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 351 
                 352 
               
               
                   
               
               
                 1370 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 352 
                 353 
               
               
                   
               
               
                 1371 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 357 
                 358 
               
               
                   
               
               
                 1372 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 359 
                 360 
               
               
                   
               
               
                 1373 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 360 
                 361 
               
               
                   
               
               
                 1374 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 360 
                 361 
               
               
                   
               
               
                 1375 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 360 
                 361 
               
               
                   
               
               
                 1376 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 360 
                 361 
               
               
                   
               
               
                 1377 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 360 
                 361 
               
               
                   
               
               
                 1378 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 360 
                 361 
               
               
                   
               
               
                 1379 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 365 
                 366 
               
               
                   
               
               
                 1380 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 365 
                 366 
               
               
                   
               
               
                 1381 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 365 
                 366 
               
               
                   
               
               
                 1382 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 365 
                 366 
               
               
                   
               
               
                 1383 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 366 
                 367 
               
               
                   
               
               
                 1384 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 371 
                 372 
               
               
                   
               
               
                 1385 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 371 
                 372 
               
               
                   
               
               
                 1386 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 371 
                 372 
               
               
                   
               
               
                 1387 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 372 
                 373 
               
               
                   
               
               
                 1388 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 372 
                 373 
               
               
                   
               
               
                 1389 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 375 
                 376 
               
               
                   
               
               
                 1390 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 377 
                 378 
               
               
                   
               
               
                 1391 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 377 
                 378 
               
               
                   
               
               
                 1392 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 377 
                 378 
               
               
                   
               
               
                 1393 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 377 
                 378 
               
               
                   
               
               
                 1394 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 379 
                 380 
               
               
                   
               
               
                 1395 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 379 
                 380 
               
               
                   
               
               
                 1396 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 380 
                 381 
               
               
                   
               
               
                 1397 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 381 
                 382 
               
               
                   
               
               
                 1398 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 383 
                 384 
               
               
                   
               
               
                 1399 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 384 
                 385 
               
               
                   
               
               
                 1400 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 385 
                 386 
               
               
                   
               
               
                 1401 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 385 
                 386 
               
               
                   
               
               
                 1402 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 386 
                 387 
               
               
                   
               
               
                 1403 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 387 
                 388 
               
               
                   
               
               
                 1404 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 389 
                 390 
               
               
                   
               
               
                 1405 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 389 
                 390 
               
               
                   
               
               
                 1406 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 392 
                 393 
               
               
                   
               
               
                 1407 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 395 
                 396 
               
               
                   
               
               
                 1408 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 403 
                 404 
               
               
                   
               
               
                 1409 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 403 
                 404 
               
               
                   
               
               
                 1410 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 405 
                 406 
               
               
                   
               
               
                 1411 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 406 
                 407 
               
               
                   
               
               
                 1412 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 413 
                 414 
               
               
                   
               
               
                 1413 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 419 
                 420 
               
               
                   
               
               
                 1414 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 497 
                 498 
               
               
                   
               
               
                 1415 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 398 
                 TBD 
               
               
                   
               
               
                 1416 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 399 
                 TBD 
               
               
                   
               
             
          
         
       
     
     Method V 
     
       
                 
         
             
             
         
      
     
     Method V, Step 1: 
     Compound V1 (R 3 =R 4 =Me) (14.76 mmole), EDCl (14.76 mmole), HOAt (14.76 mmole), and DIEA (14.76 mmole) were mixed with 36 ml DCM. This mixture was stirred at RT for 15 min before 3-chlorobenzylamine was added. After the reaction solution was stirred at RT overnight, it was washed with sodium carbonate (3×), water, 1N HCl (4×), 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 1 =3-chlorobenzyl; R 3 =R 4 =Me). 
     Method V, step 2 
     Compound V2 (R 1 =3-chlorobenzyl; R 3 =R 4 =Me) (8.33 mmole) was dissolved in 35 ml anhydrous DCM, and cooled to 0-5° C. Thiophosgene (9.16 mmole) in 10 ml DCM was added dropwise under N 2  followed by addition of DIEA (11.96 mmole). The solution was stirred in ice bath for 0.5 h before the reaction mixture was washed with saturated sodium bicarbonate (3×), brine, 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 1 =3-chlorobenzyl; R 3 =R 4 =Me). 
     Method V, step 3: 
     The thiohydantoin V3 (R 1 =3-chlorobenzyl; R 3 =R 4 =Me) was treated with t-butyl hydroperoxide and ammonium hydroxide in MeOH at RT for 48 h to give compound V4 (R 1 =3-chlorobenzyl; R 2 =H; R 3 =R 4 =Me). 
     The following compounds were prepared using similar method. 
     
       
         
               
               
               
               
               
             
           
               
                   
                   
               
               
                   
                   
                   
                   
                 Obs. 
               
               
                   
                 # 
                 Structure 
                 MW 
                 m/e 
               
               
                   
                   
               
             
             
               
                   
                 1417 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 251 
                 252 
               
               
                   
                   
               
               
                   
                 1418 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 265 
                 266 
               
               
                   
                   
               
               
                   
                 1419 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 293 
                 294 
               
               
                   
                   
               
               
                   
                 1420 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 307 
                 308 
               
               
                   
                   
               
               
                   
                 1421 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 357 
                 358 
               
               
                   
                   
               
               
                   
                 1422 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 371 
                 372 
               
               
                   
                   
               
             
          
         
       
     
     Method W 
     
       
                 
         
             
             
         
      
     
     Compound W1 obtained using method A (n=1, R 2 =m-Cl—Bn, R 3 =Me) was 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. 
               
               
                 # 
                 Structure 
                 MW 
                 m/e 
               
               
                   
               
             
             
               
                 1423 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 295 
                 296 
               
               
                   
               
               
                 1424 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 311 
                 312 
               
               
                   
               
               
                 1425 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 325 
                 326 
               
               
                   
               
               
                 1426 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 411 
                 412 
               
               
                   
               
               
                 1427 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 425 
                 426 
               
               
                   
               
             
          
         
       
     
     Method X 
     
       
                 
         
             
             
         
      
     
     (In the scheme, —Z—NH—C(O)—N(R 16 )(R 17 )— is equivalent to R 1  substituted by R 21 , or R 1  Substituted by alkyl-R 22 , wherein R 21  and R 22  are —NH—C(O)—N(R 16 )(R 17 ) and R 15  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, heteroarylene, cycloalkylene or heterocycloalkylene) 
     Method X, Step 1: 
     To a mixture of the amine X1 obtained using method L (R 3 =Me; R 4 = i -Bu; Z=para-(CH 2 )C 6 H 4 (CH 2 )—) (10 mg) in DCM and sat. NaHCO 3  (1:1 by 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 )—). 
     Method X, Step 2: 
     Compound X3 (R 15 =H; R 16 =cyclopropylmethyl; R 3 =Me; R 4 = i Bu; Z=para-(CH 2 )C 6 H 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. 
     Method X, Step 3: 
     Compound X4 (R 16 =H; R 17 =cyclopropylmethyl; R 2 =H; R 3 =Me; R 4 = i Bu; Z=para-(CH 2 )C 6 H 4 (CH 2 )—) was prepared from X3 (R 16 =H; R 17 =cyclopropylmethyl; R 2 =H; R 3 =Me; R 4 = i Bu; Z=para-(CH 2 )C 6 H 4 (CH 2 )—) using method similar to method A Step 3. NMR (CD 3 OD): δ 7.25, s, 4H; δ 4.8, m, 2H; δ 4.25, s, 2H; δ 2.9, m, 2H; δ 1.68, m, 2H; δ 1.44, m, 1H; δ 1.36, s, 3H; δ 0.9, m, 1H; δ 0.82, m, 3H; δ 0.66, m, 3H; δ 0.4, m, 2H; δ 0.12, m, 2H. ES_LCMS (m/e) 386.1. 
     The following compounds were prepared using a similar method. 
     
       
         
               
               
               
               
             
           
               
                   
               
               
                   
                   
                   
                 Obs. 
               
               
                 # 
                 Structure 
                 MW 
                 m/e 
               
               
                   
               
             
             
               
                 1428 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 385 
                 386 
               
               
                   
               
               
                 1429 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 401 
                 402 
               
               
                   
               
               
                 1430 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 401 
                 402 
               
               
                   
               
               
                 1431 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 415 
                 416 
               
               
                   
               
               
                 1432 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 427 
                 428 
               
               
                   
               
               
                 1433 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 435 
                 436 
               
               
                   
               
               
                 1434 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 435 
                 436 
               
               
                   
               
               
                 1435 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 443 
                 444 
               
               
                   
               
               
                 1436 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 449 
                 450 
               
               
                   
               
               
                 1437 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 463 
                 464 
               
               
                   
               
               
                 1438 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 471 
                 472 
               
               
                   
               
               
                 1439 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 485 
                 486 
               
               
                   
               
               
                 1440 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 496 
                 497 
               
               
                   
               
               
                 1441 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 504 
                 505 
               
               
                   
               
               
                 1442 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 513 
                 514 
               
               
                   
               
               
                 1443 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 518 
                 519 
               
               
                   
               
               
                 1444 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 518 
                 519 
               
               
                   
               
               
                 1445 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 524 
                 525 
               
               
                   
               
               
                 1446 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 524 
                 525 
               
               
                   
               
               
                 1447 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 526 
                 527 
               
               
                   
               
               
                 1448 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 532 
                 533 
               
               
                   
               
               
                 1449 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 533 
                 534 
               
               
                   
               
               
                 1450 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 537 
                 538 
               
               
                   
               
               
                 1451 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 537 
                 538 
               
               
                   
               
               
                 1452 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 545 
                 546 
               
               
                   
               
               
                 1453 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 559 
                 560 
               
               
                   
               
               
                 1454 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 570 
                 571 
               
               
                   
               
               
                 1455 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 572 
                 573 
               
               
                   
               
               
                 1456 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 598 
                 599 
               
               
                   
               
             
          
         
       
     
     Method Y 
     
       
                 
         
             
             
         
      
     
     (In the scheme, 
                                
is equivalent to R 1  substituted by R 21 , or R 1  Substituted by alkyl-R 22 , wherein R 21  and R 22  are —N(R 15 )—C(O)—N(R 16 )(R 17 ) and R 15  and R 16  form a ring as defined above, 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, heteroarylene, cycloalkylene or heterocycloalkylene)
 
     Method Y, Step 1: 
     The reaction mixture of compound Y1 obtained from Method L (R 3 =Me; R 4 =i-Bu; Z=para-(CH 2 )C 6 H 4 (CH 2 )—) (0.1639 mmole), Y2 (R 23 =H; R 23 =Pr) (0.1967 mmole), PS-EDC resin (0.4917 mmole) and HOBT (0.2459 mmole) 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 6 hrs 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 (CH 2 )—, R 23 =H; R 23 =Pr). 
     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 )—, R 23 =H; R 23 =Pr) (0.030 mmole), carbonyl diimidazole (0.032 mmole), and DIEA (0.09 mmole) in 0.5 ml DCM was shaken overweekend at RT. The crude was then purified on reverse column to give the thiohydantoin product which was converted into Y4 (R 2 =H; R 3 =Me; R 4 = i Bu; Z=para-(CH 2 )C 6 H 4 (CH 2 )—, R 23 =H; R 23 =Pr). 
     The following compounds were prepared using similar method. 
     
       
         
               
               
               
               
             
           
               
                   
               
               
                   
                   
                   
                 Obs. 
               
               
                 # 
                 Structure 
                 MW 
                 m/e 
               
               
                   
               
             
             
               
                 1457 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 413 
                 414 
               
               
                   
               
               
                 1458 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 413 
                 414 
               
               
                   
               
               
                 1459 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 427 
                 428 
               
               
                   
               
             
          
         
       
     
     Method Z 
     
       
                 
         
             
             
         
      
     
     (In the scheme, —Z—NH—C(O)—N(R 16 )(R 17 )— is equivalent to R 1  substituted by R 21 , or R 1  Substituted by alkyl-R 22 , wherein R 21  and R 22  are —N(R 15 )—C(O)—N(R 16 )(R 17 ) and R 15  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, heteroarylene, cycloalkylene or heterocycloalkylene) 
     Method Z, Step 1: 
     To the solution of the Phoxime™ resin (1.23 mmol/g) in DCM was added the amine Z1 obtained from method L (R 3 =Me; R 4 = i 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 (×2), dried in vacuum to get resin Z2 (R 3 =Me; R 4 = i Bu; Z=para-(CH 2 )C 6 H 4 (CH 2 )—). 
     Method Z, Step 2: 
     To the resin Z2 (R 3 =Me; R 4 = i Bu; Z=para-(CH 2 )C 6 H 4 (CH 2 )—), swelled in DCM, in toluene was added N-methylbenzylamine (4 eq). The mixture was heated at 80-90° 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 concentrated in vacuo to get Z3 (R 3 =Me; R 4 = i Bu; Z=para-(CH 2 )C 6 H 4 (CH 2 )—; R 16 =Me; R 17 =Bn). 
     Method Z, Step 3: 
     Compound Z4 (R 3 =Me; R 4 = i Bu; Z=para-(CH 2 )C 6 H 4 (CH 2 )—; R 16 =Me; R 17 =Bn) was generated from Z3 (R 3 =Me; R 4 = i Bu; Z=para-(CH 2 )C 6 H 4 (CH 2 )—; R 16 =Me; R 17 =Bn) using method similar to Method A step 3. 
     The following compounds were prepared using similar method. 
     
       
         
               
               
               
               
             
           
               
                   
               
               
                   
                   
                   
                 Obs. 
               
               
                 # 
                 Structure 
                 MW 
                 m/e 
               
               
                   
               
             
             
               
                 1460 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 457 
                 458 
               
               
                   
               
               
                 1461 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 469 
                 470 
               
               
                   
               
               
                 1462 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 471 
                 472 
               
               
                   
               
               
                 1463 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 471 
                 472 
               
               
                   
               
               
                 1464 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 483 
                 484 
               
               
                   
               
               
                 1465 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 485 
                 486 
               
               
                   
               
               
                 1466 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 485 
                 486 
               
               
                   
               
               
                 1467 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 495 
                 496 
               
               
                   
               
               
                 1468 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 499 
                 500 
               
               
                   
               
               
                 1469 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 501 
                 502 
               
               
                   
               
               
                 1470 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 507 
                 508 
               
               
                   
               
               
                 1471 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 509 
                 510 
               
               
                   
               
               
                 1472 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 517 
                 518 
               
               
                   
               
               
                 1473 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 517 
                 518 
               
               
                   
               
               
                 1474 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 531 
                 532 
               
               
                   
               
               
                 1475 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 533 
                 534 
               
               
                   
               
               
                 1476 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 533 
                 534 
               
               
                   
               
               
                 1477 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 538 
                 539 
               
               
                   
               
               
                 1478 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 545 
                 546 
               
               
                   
               
               
                 1479 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 547 
                 548 
               
               
                   
               
               
                 1480 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 547 
                 548 
               
               
                   
               
               
                 1481 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 547 
                 548 
               
               
                   
               
               
                 1482 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 551 
                 552 
               
               
                   
               
               
                 1483 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 568 
                 569 
               
               
                   
               
               
                 1484 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 571 
                 572 
               
               
                   
               
               
                 1485 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 593 
                 594 
               
               
                   
               
               
                 1486 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 596 
                 597 
               
               
                   
               
               
                 1487 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 607 
                 608 
               
               
                   
               
               
                 1488 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 364 
                 365 
               
               
                   
               
               
                 1489 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 377 
                 377 
               
               
                   
               
               
                 1490 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 513 
                 514 
               
               
                   
               
             
          
         
       
     
     Method AA 
     
       
                 
         
             
             
         
      
     
     8,11-Dichloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (AA2) (18 mg) was reacted with AA1, obtained from method Q, 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 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. 
               
               
                 # 
                 Structure 
                 MW 
                 m/e 
               
               
                   
               
             
             
               
                 187 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 491 
                 492 
               
               
                   
               
               
                 188 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 493 
                 494 
               
               
                   
               
             
          
         
       
     
     The following compounds were prepared using similar method. 
     Method AB 
     
       
                 
         
             
             
         
      
     
     Method AB, Step 1: 
     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, 1.1 eq) 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 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 (2×20 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-phenylpentylidene)propane-2-sulfinamide.  1 HNMR (CDCl 3 , 300 MHz): δ 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 t R =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), 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 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 Cl (10 eq) was added and the suspension was warmed to room temperature. The mixture was diluted with H 2 O (50 mL) and stirred for 10 min. The mixture was then partitioned between H 2 O (50 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (3×50 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.  1 HNMR (CDCl 3 , 300 MHz): δ 7.15-7.07 (m, 5H), 3.35 (s, 1H), 3.19 (dd, J=16, 5.6 Hz, 1H), 3.01 (dd, J=15.8, 5.5 Hz, 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 t R =7.50, 7.6 min (E/Z=1.5:1) 
     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 HCl/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 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): δ 9.01 (br s, 2H), 7.37-7.12 (m, 5H), 3.64 (m, 1H), 3.54 (s, 3H), 3.31 (m, 1H), 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 t R =4.72 min. 
     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, R 4 =n-butyl, R 1 =Me).  1 HNMR (CDCl 3 , 300 MHz): δ 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 t R =5.09 min. 
     The following compounds were synthesized using similar methods: 
     
       
         
               
               
               
               
             
           
               
                   
               
               
                   
                   
                   
                 Obs. 
               
               
                 # 
                 Structure 
                 MW 
                 m/e 
               
               
                   
               
             
             
               
                 189 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 239 
                 240 
               
               
                   
               
               
                 190 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 253 
                 254 
               
               
                   
               
               
                 191 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 259 
                 260 
               
               
                   
               
               
                 192 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 333 
                 334 
               
               
                   
               
               
                 193 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 333 
                 334 
               
               
                   
               
               
                 194 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 349 
                 350 
               
               
                   
               
               
                 195 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 443 
                 444 
               
               
                   
               
               
                 196 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 463 
                 464 
               
               
                   
               
               
                 197 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 537 
                 538 
               
               
                   
               
               
                 198 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 537 
                 538 
               
               
                   
               
               
                 199 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 295 
                 296 
               
               
                   
               
               
                 200 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 295 
                 296 
               
               
                   
               
             
          
         
       
     
     Method AC 
     
       
                 
         
             
             
         
      
     
     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 AC1 (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 volatiles were removed in vacuo and the residue was partitioned between ether and H 2 O. 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 OH/CH 2 Cl 2  as eluent followed by reverse phase preparative HPLC to give 0.15 g (8.0%) of AC3 (R 1 =benzyl, R 4 =Me and R 3 =Me) as a white solid.  1 H NMR (CH 3 OH, 300 MHz): δ 7.35-7.33 (m, 5H), 4.71 (s, 2H), 1.46 (s, 6H);  13 C NMR (CDCl 3 , 75 MHz) δ 157.8, 135.6, 129.1, 128.5, 127.9, 104.2, 59.6, 28.8. MS (ESI) m/e 206.1 (M+H) + . 
     
       
         
               
               
               
               
               
             
           
               
                   
                   
               
               
                   
                   
                   
                   
                 Obs. 
               
               
                   
                 # 
                 Structure 
                 MW 
                 m/e 
               
               
                   
                   
               
             
             
               
                   
                 201 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 205 
                 206 
               
               
                   
                   
               
             
          
         
       
     
     Method AD 
     
       
                 
         
             
             
         
      
     
     Method AD, Step 1: 
     AD2 (R 3 =Ph, R 4 = t Butyl) was prepared from AD1 using method similar to Method AB, step 2. 
     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 CCl 4  (25 mL) was added N-bromosuccinimide (0.49 g, 2.7 mmol). The mixture was irradiated with a 200 watt 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.  1 H NMR (CDCl 3 , 300 MHz): δ 7.63-7.61 (m, 2H), 7.37-7.26 (m, 3H), 1.17 (s, 9H);  13 C NMR (CDCl 3 , 75 MHz): δ 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-(1-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 vacuo. The residue was purified by column chromatography using CH 3 OH/CH 2 Cl 2  as eluent to give 0.050 g (42%) of AD3 (R 3 =Ph, R 4 =tert-Butyl) as a glassy solid.  1 H NMR (CDCl 3 , 300 MHz): δ 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: 
     To a solution of AD3 (R 3 =Ph, R 4 =tert-Butyl) (0.065 g, 0.26 mmol) in CH 3 OH (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 AD4 (R 3 =Ph, R 4 =tert-Butyl) as a colorless oil.  1 H NMR (CDCl 3 , 300 MHz) δ 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. 
               
               
                   
                 # 
                 Structure 
                 MW 
                 m/e 
               
               
                   
                   
               
             
             
               
                   
                 202 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 213 
                 214 
               
               
                   
                   
               
               
                   
                 203 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 233 
                 234 
               
               
                   
                   
               
               
                   
                 204 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 309 
                 310 
               
               
                   
                   
               
             
          
         
       
     
     Method AE 
     
       
                 
         
             
             
         
      
     
     Method AE, Step 1: 
     TBDMS-Cl (5.3 g, 35.19 mmole) and imidazole (2.4 g, 35.19 mmole) were added to a suspension of H2 (R 1 =Me, R 3 =cyclohexylmethyl) (8.2 g, 31.99 mmole) in 220 ml DCM. The reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered, and the filtrate was diluted with 1200 ml EtOAc. The organic phase was washed with saturated NaHCO 3  3× and brine 3×, and dried over anhydrous Na 2 SO 4  to give 12 g of AE2 (R 1 =Me, R 3 =cyclohexylmethyl), which was used for next step without further purification. 
     Method AE, Step 2: 
     AE2 (R 1 =Me, R 3 =cyclohexylmethyl; 12 grams crude) was converted to iminohydantoin using conditions similar to Method A Step 3, which was subsequently treated with 75% TFA in DCM at room temperature for 24 hrs. The solvent was evaporated in vacuo to give 13.6 g of a product that was reacted with Boc anhydride to give 5.8 g AE3 (R 1 =Me, R 3 =cyclohexylmethyl) after column purification. 
     Method AE, Step 3: 
     AE4 (R 1 =Me, R 3 =cyclohexylmethyl)(8.2 g) was obtained from AE3 (5.8 g) according to the step 4 of the method H. 
     Method AE, Step 4: 
     To a solution of AE4 (R 1 =Me, R 3 =cyclohexylmethyl) ((3.95 g, 8.38 mmol) in anhydrous THF (98 mL) was added diisopropylethylamine (7 mL, 40 mmol). 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 1 =Me, R 3 =cyclohexylmethyl) (2.48 g, 92%). 
     Method AE, Step 4: 
     To a solution of R 15 OH(R 15 =cyclobutyl) (10 μl) and HBF 4  (1 equiv) in anhydrous methylene chloride (0.5 mL) was added a solution of AE5 (R 1 =Me, R 3 =cyclohexylmethyl) (20 mg, 0.062 mmol) in methylene chloride (0.5 mL). The 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 O with 0.1% formic acid to afford AE5 (R 1 =Me, R 3 =cyclohexylmethyl, R 15 =cyclobutyl). 
     The following compounds were synthesized using similar method: 
     
       
         
               
               
               
               
             
           
               
                   
               
               
                   
                   
                   
                 Obs. 
               
               
                 # 
                 Structure 
                 MW 
                 m/e 
               
               
                   
               
             
             
               
                 205 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 267 
                 268 
               
               
                   
               
               
                 206 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 293 
                 294 
               
               
                   
               
               
                 207 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 295 
                 296 
               
               
                   
               
               
                 208 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 295 
                 296 
               
               
                   
               
               
                 209 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 295 
                 296 
               
               
                   
               
               
                 210 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 295 
                 296 
               
               
                   
               
               
                 211 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 305 
                 306 
               
               
                   
               
               
                 212 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 307 
                 308 
               
               
                   
               
               
                 213 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 307 
                 308 
               
               
                   
               
               
                 214 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 309 
                 310 
               
               
                   
               
               
                 215 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 309 
                 310 
               
               
                   
               
               
                 216 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 309 
                 310 
               
               
                   
               
               
                 217 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 309 
                 310 
               
               
                   
               
               
                 218 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 321 
                 322 
               
               
                   
               
               
                 219 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 321 
                 322 
               
               
                   
               
               
                 220 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 321 
                 322 
               
               
                   
               
               
                 221 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 322 
                 323 
               
               
                   
               
               
                 222 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 329 
                 330 
               
               
                   
               
               
                 223 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 333 
                 334 
               
               
                   
               
               
                 224 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 335 
                 336 
               
               
                   
               
               
                 225 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 335 
                 336 
               
               
                   
               
               
                 226 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 335 
                 336 
               
               
                   
               
               
                 227 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 335 
                 336 
               
               
                   
               
               
                 228 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 335 
                 336 
               
               
                   
               
               
                 229 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 335 
                 336 
               
               
                   
               
               
                 230 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 335 
                 336 
               
               
                   
               
               
                 231 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 335 
                 336 
               
               
                   
               
               
                 232 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 335 
                 336 
               
               
                   
               
               
                 233 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 337 
                 338 
               
               
                   
               
               
                 234 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 337 
                 338 
               
               
                   
               
               
                 235 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 349 
                 350 
               
               
                   
               
               
                 236 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 349 
                 350 
               
               
                   
               
               
                 237 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 349 
                 350 
               
               
                   
               
               
                 238 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 349 
                 350 
               
               
                   
               
               
                 239 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 353 
                 354 
               
               
                   
               
               
                 240 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 361 
                 362 
               
               
                   
               
               
                 241 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 363 
                 364 
               
               
                   
               
               
                 242 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 363 
                 364 
               
               
                   
               
               
                 243 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 363 
                 364 
               
               
                   
               
               
                 244 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 389 
                 390 
               
               
                   
               
               
                 245 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 321 
                 NA 
               
               
                   
               
             
          
         
       
     
     Method AF 
     
       
                 
         
             
             
         
      
     
     To a solution of tBuOK (9.5 mg, 0.0848 mmole) in 0.5 ml anhydrous THF was added ArOH (Ar=m-Chlorophenyl)(13 μl, 0.1273 mmole) in 0.5 ml anhydrous THF followed by addition of AE4 (R 1 =Me, R 3 =cyclohexylmethyl) (20 mg, 0.0424 mmole) in 0.5 ml anhydrous THF. The reaction mixture was stirred at room temperature for 2 days before it was diluted with 1 ml MeCN, treated with 100 mg MP-TsOH resin and 100 mg Amberlyst A26 resin. The resin was 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 2 ml MeCN, and treated with 100 mg 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 1 =Me, R 3 =cyclohexylmethyl and R 15 =3-chlorophenyl). 
     The following compounds were synthesized using similar method: 
     
       
         
               
               
               
               
             
           
               
                   
               
               
                   
                   
                   
                 Obs. 
               
               
                 # 
                 Structure 
                 MW 
                 m/e 
               
               
                   
               
             
             
               
                 246 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 316 
                 317 
               
               
                   
               
               
                 247 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 316 
                 317 
               
               
                   
               
               
                 248 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 316 
                 317 
               
               
                   
               
               
                 249 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 329 
                 330 
               
               
                   
               
               
                 250 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 329 
                 330 
               
               
                   
               
               
                 251 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 329 
                 330 
               
               
                   
               
               
                 252 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 330 
                 331 
               
               
                   
               
               
                 253 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 331 
                 332 
               
               
                   
               
               
                 254 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 331 
                 332 
               
               
                   
               
               
                 255 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 333 
                 334 
               
               
                   
               
               
                 256 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 333 
                 334 
               
               
                   
               
               
                 257 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 333 
                 334 
               
               
                   
               
               
                 258 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 333 
                 334 
               
               
                   
               
               
                 259 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 333 
                 334 
               
               
                   
               
               
                 260 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 340 
                 341 
               
               
                   
               
               
                 261 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 340 
                 341 
               
               
                   
               
               
                 262 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 340 
                 341 
               
               
                   
               
               
                 263 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 343 
                 344 
               
               
                   
               
               
                 264 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 343 
                 344 
               
               
                   
               
               
                 265 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 343 
                 344 
               
               
                   
               
               
                 266 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 343 
                 344 
               
               
                   
               
               
                 267 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 344 
                 345 
               
               
                   
               
               
                 268 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 344 
                 345 
               
               
                   
               
               
                 269 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 345 
                 346 
               
               
                   
               
               
                 270 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 345 
                 346 
               
               
                   
               
               
                 271 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 345 
                 346 
               
               
                   
               
               
                 272 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 345 
                 346 
               
               
                   
               
               
                 273 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 347 
                 348 
               
               
                   
               
               
                 274 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 347 
                 348 
               
               
                   
               
               
                 275 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 349 
                 350 
               
               
                   
               
               
                 276 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 349 
                 350 
               
               
                   
               
               
                 277 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 349 
                 350 
               
               
                   
               
               
                 278 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 349 
                 350 
               
               
                   
               
               
                 279 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 351 
                 352 
               
               
                   
               
               
                 280 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 351 
                 352 
               
               
                   
               
               
                 281 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 351 
                 352 
               
               
                   
               
               
                 282 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 351 
                 352 
               
               
                   
               
               
                 283 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 351 
                 352 
               
               
                   
               
               
                 284 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 351 
                 352 
               
               
                   
               
               
                 285 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 351 
                 352 
               
               
                   
               
               
                 286 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 351 
                 352 
               
               
                   
               
               
                 287 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 355 
                 356 
               
               
                   
               
               
                 288 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 355 
                 356 
               
               
                   
               
               
                 289 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 357 
                 358 
               
               
                   
               
               
                 290 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 357 
                 358 
               
               
                   
               
               
                 291 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 357 
                 358 
               
               
                   
               
               
                 292 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 357 
                 358 
               
               
                   
               
               
                 293 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 358 
                 359 
               
               
                   
               
               
                 294 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 358 
                 359 
               
               
                   
               
               
                 295 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 358 
                 359 
               
               
                   
               
               
                 296 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 358 
                 359 
               
               
                   
               
               
                 297 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 359 
                 360 
               
               
                   
               
               
                 298 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 359 
                 360 
               
               
                   
               
               
                 299 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 359 
                 360 
               
               
                   
               
               
                 300 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 359 
                 360 
               
               
                   
               
               
                 301 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 359 
                 360 
               
               
                   
               
               
                 302 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 360 
                 361 
               
               
                   
               
               
                 303 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 360 
                 361 
               
               
                   
               
               
                 304 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 360 
                 361 
               
               
                   
               
               
                 305 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 363 
                 364 
               
               
                   
               
               
                 306 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 363 
                 364 
               
               
                   
               
               
                 307 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 363 
                 364 
               
               
                   
               
               
                 308 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 363 
                 364 
               
               
                   
               
               
                 309 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 365 
                 366 
               
               
                   
               
               
                 310 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 365 
                 366 
               
               
                   
               
               
                 311 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 366 
                 367 
               
               
                   
               
               
                 312 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 366 
                 367 
               
               
                   
               
               
                 313 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 366 
                 367 
               
               
                   
               
               
                 314 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 366 
                 367 
               
               
                   
               
               
                 315 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 366 
                 367 
               
               
                   
               
               
                 316 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 366 
                 367 
               
               
                   
               
               
                 317 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 366 
                 367 
               
               
                   
               
               
                 318 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 367 
                 368 
               
               
                   
               
               
                 319 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 367 
                 368 
               
               
                   
               
               
                 320 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 367 
                 368 
               
               
                   
               
               
                 321 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 369 
                 370 
               
               
                   
               
               
                 322 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 371 
                 372 
               
               
                   
               
               
                 323 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 371 
                 372 
               
               
                   
               
               
                 324 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 371 
                 372 
               
               
                   
               
               
                 325 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 372 
                 373 
               
               
                   
               
               
                 326 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 372  
                 373 
               
               
                   
               
               
                 327 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 372 
                 373 
               
               
                   
               
               
                 328 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 372 
                 373 
               
               
                   
               
               
                 329 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 373 
                 374 
               
               
                   
               
               
                 330 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 373 
                 374 
               
               
                   
               
               
                 331 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 375 
                 376 
               
               
                   
               
               
                 332 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 375 
                 376 
               
               
                   
               
               
                 333 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 375 
                 376 
               
               
                   
               
               
                 334 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 377 
                 378 
               
               
                   
               
               
                 335 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 377 
                 378 
               
               
                   
               
               
                 336 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 377 
                 378 
               
               
                   
               
               
                 337 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 383 
                 384 
               
               
                   
               
               
                 338 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 383 
                 384 
               
               
                   
               
               
                 339 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 383 
                 384 
               
               
                   
               
               
                 340 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 383 
                 384 
               
               
                   
               
               
                 341 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 383 
                 384 
               
               
                   
               
               
                 342 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 383 
                 384 
               
               
                   
               
               
                 343 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 383 
                 384 
               
               
                   
               
               
                 344 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 383 
                 384 
               
               
                   
               
               
                 345 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 383 
                 384 
               
               
                   
               
               
                 346 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 383 
                 384 
               
               
                   
               
               
                 347 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 385 
                 386 
               
               
                   
               
               
                 348 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 385 
                 386 
               
               
                   
               
               
                 349 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 386 
                 387 
               
               
                   
               
               
                 350 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 387 
                 388 
               
               
                   
               
               
                 351 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 387 
                 388 
               
               
                   
               
               
                 352 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 393 
                 394 
               
               
                   
               
               
                 353 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 393 
                 394 
               
               
                   
               
               
                 354 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 393 
                 394 
               
               
                   
               
               
                 355 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 393 
                 394 
               
               
                   
               
               
                 356 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 399 
                 400 
               
               
                   
               
               
                 357 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 399 
                 400 
               
               
                   
               
               
                 358 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 400 
                 401 
               
               
                   
               
               
                 359 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 400 
                 401 
               
               
                   
               
               
                 360 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 400 
                 401 
               
               
                   
               
               
                 361 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 401 
                 402 
               
               
                   
               
               
                 362 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 401 
                 402 
               
               
                   
               
               
                 363 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 401 
                 402 
               
               
                   
               
               
                 364 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 405 
                 406 
               
               
                   
               
               
                 365 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 411 
                 412 
               
               
                   
               
               
                 366 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 414 
                 415 
               
               
                   
               
               
                 367 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 417 
                 418 
               
               
                   
               
               
                 368 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 417 
                 418 
               
               
                   
               
               
                 369 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 421 
                 422 
               
               
                   
               
               
                 370 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 434 
                 435 
               
               
                   
               
               
                 371 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 451 
                 452 
               
               
                   
               
             
          
         
       
     
     Method AG 
     
       
                 
         
             
             
         
      
     
     Method AG, Step 1: 
     R 21 —H(R 21 =PhS—) (33 μl, 0.318 mmole) was treated with NaH (10.2 mg, 60% in mineral oil) in 0.5 ml anhydrous THF. A solution of AE4 (R 1 =Me, R 3 =Cyclohexylmethyl) (20 mg, 0.0424 mmol) in 0.5 ml anhydrous THF was added. 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 AG1 (R 21 =PhS-, R 1 =Me, R 3 =cyclohexylmethyl) (49.2% yield). 
     Method AG, Step 2: 
     AG1 (R 21 =PhS—, R 1 =Me, R 3 =cyclohexylmethyl) was treated with 50% TFA according to the Step 6 of the method H to give AG2 (R 21 =PhS—, R 1 =Me, R 3 =cyclohexylmethyl). 
     The following compounds were synthesized using similar method: 
     
       
         
               
               
               
               
               
             
           
               
                   
               
               
                   
                   
                   
                   
                 Obs. 
               
               
                   
                 # 
                 Structure 
                 MW 
                 m/e 
               
               
                   
               
             
             
               
                   
                 372 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 315 
                 316 
               
               
                   
               
               
                   
                 373 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 331 
                 332 
               
               
                   
               
               
                   
                 374 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 337 
                 338 
               
               
                   
               
             
          
         
       
     
     Method AH 
     
       
                 
         
             
             
         
      
     
     Method AH, Step 1: 
     Benzophenone imine (3.27 g, 18.04 mmole) was added to a suspension of AH1 (R 3 =cyclohexylmethyl) (4 g, 18.04 mmole) in 65 ml 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 2× and dried over anhydrous MgSO 4 . The crude was purified on flash column to give 5.08 g (80.57% yield) of AH2 (R 3 =cyclohexylmethyl). 
     Method AH, Step 2: 
     A solution of AH2 (R 3 =cyclohexylmethyl) (1 g, 2.86 mmole) in 12 ml anhydrous THF was added to a suspension of 18-crown-6 (0.76 g, 2.86 mmole) and 30% KH in mineral oil (1.16 g, 8.58 mmole) in 4 ml 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 for 30 min and at room temperature for 2 more hrs before the reaction was quenched with 2 ml of HOAc/THF/H 2 O (0.25:0.75:1). The mixture was diluted with 40 ml EtOAc/H 2 O (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 0.44 g (35.14% yield) of product which was treated with 1N HCl (2.2 ml, 2.22 mmole) in 3 ml 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 0.22 g (66% yield) of AH3 (R 4 =3-pyridylmethyl; R 3 =cyclohexylmethyl). 
     Method AI 
     
       
                 
         
             
             
         
      
     
     To a solution of compound AI1 (R 1 =Me, R 3 =n-Bu) (34 mg, 0.105 mmol) in methanol (1 ml) was added 10% Pd/C (5 mg). 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 AI2 (R 1 =Me, R 3 =n-Bu) (25 mg, 100%). Observed MW (M+H) 246.1; exact mass 245.15.  1 H NMR (400 MHz, CD 3 OD): δ=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=7.2 Hz). 
     The following compounds were synthesized using similar method: 
     
       
         
               
               
               
               
             
           
               
                   
               
               
                   
                   
                   
                 Obs. 
               
               
                 # 
                 Structure 
                 MW 
                 m/e 
               
               
                   
               
             
             
               
                 375 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 283 
                 284 
               
               
                   
               
               
                 376 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 285 
                 286 
               
               
                   
               
               
                 377 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 299 
                 300 
               
               
                   
               
               
                 378 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 450 
                 451 
               
               
                   
               
               
                 379 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 462 
                 463 
               
               
                   
               
               
                 380 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 463 
                 464 
               
               
                   
               
               
                 381 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 487 
                 488 
               
               
                   
               
               
                 382 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 489 
                 490 
               
               
                   
               
               
                 383 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 503 
                 504 
               
               
                   
               
               
                 384 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 516 
                 517 
               
               
                   
               
             
          
         
       
     
     Method AJ 
     
       
                 
         
             
             
         
      
     
     To a mixture of compound AJ1 (R 1 =Me, R 3 =n-Bu) (70 mg, 0.165 mmol) and butylzincbromide (1.32 ml, 0.6 mmol) was added Pd(dppf)Cl 2 . The mixture was degassed, sealed and heated at 55° C. for 1 day. The mixture was diluted with CH 2 Cl 2  and NH 3 /H 2 O. The organic layer was separated, dried, concentrated, and purified by RP HPLC to get product which was then treated with 4N HCl/dioxane for 30 min to give compound AJ2(R 1 =Me, R 3 =n-Bu) (12 mg, 25%). Observed MW (M+H) 302.1;  1 H NMR (400 MHz, CD 3 OD): δ=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. 
               
               
                 # 
                 Structure 
                 MW 
                 m/e 
               
               
                   
               
             
             
               
                 386 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 518 
                 519 
               
               
                   
               
               
                 385 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 301 
                 302 
               
               
                   
               
             
          
         
       
     
     Method AK 
     
       
                 
         
             
             
         
      
     
     To a solution of AK1 (R 1 =Me, R 3 =n-Butyl, R 21 =n-Bu) (9 mg, 0.03 mmol) in methanol (1 ml) was added 5% Pt/C (5 mg), Rh/C (5 mg) and conc. HCl (0.05 ml). 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 1 =Me, R 3 =n-butyl, R 21 =n-Bu) Observed MW (M+H) 308.1.  1 H NMR (CD 3 OD): δ=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. 
               
               
                 # 
                 Structure 
                 MW 
                 m/e 
               
               
                   
               
             
             
               
                 387 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 277 
                 278 
               
               
                   
               
               
                 388 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 291 
                 292 
               
               
                   
               
               
                 389 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 305 
                 306 
               
               
                   
               
               
                 390 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 307 
                 308 
               
               
                   
               
               
                 391 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 391 
                 392 
               
               
                   
               
               
                 392 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 391 
                 392 
               
               
                   
               
               
                 393 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 468 
                 469 
               
               
                   
               
             
          
         
       
     
     Method AL 
     
       
                 
         
             
             
         
      
     
     Method AL, Step 1: 
     To a solution of compound AL1 (R 3 =n-Bu) (418 mg, 1.39 mmol) in methanol (8 ml) was added PtO 2  (40 mg) and conc. HCl (0.4 ml). The mixture was hydrogenated (50 psi) 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 mixture was extracted with ethyl acetate. The organic layer was separated, dried and concentrated to get compound AL2 (R 3 =n-Bu) (316 mg, 100%). 
     Method AL, Step 2: 
     To a solution of compound AL2 (R 3 =n-Bu) (300 mg, 1.32 mmol) in dichloromethane (6 ml) was added (BOC) 2 O (316 mg, 1.45 mmol). The mixture was stirred at RT for 1.5 hr. It was diluted with water and dichloromethane. The organic layer was separated, dried and concentrated to get compound AL3 (R 3 =n-Bu) (464 mg, 100%). 
     Method AM 
     
       
                 
         
             
             
         
      
     
     Method AM, Step 1: 
     Compound AM1 (R 1 =Me, R 3 =n-Butyl) was treated with 4N HCl in dioxane for 2 hr. The mixture was concentrated to get compound AM2 as an HCl salt (R 1 =Me, R 3 =n-Butyl). Observed MW (M+H) 470.1;  1 H NMR (CD 3 OD): δ=7.28 (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). 
     Method AM, Step 2: 
     To a solution of compound AM2 (R 1 =Me, R 3 =n-Butyl) (32 mg, 0.068 mmol) in dichloromethane (1 ml) was added acetyl chloride (5 ul, 0.072 mmol). 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 get compound AM3 (R 1 =Me, R 3 =n-Butyl and R 15 =Me) Observed MW (M+H) 512.3;  1 H NMR (400 MHz, CDCl 3 ): δ=7.27 (m, 2H), 6.98 (m, 1H), 6.92 (m, 2H), 4.65 (s, 2H), 4.50 (m, 2H), 3.98 (m, 1H), 3.70 (m, 1H), 3.41 (m, 2H), 2.98 (m, 2H), 2.62 (m, 1H), 2.50 (m, 1H), 2.47 (m, 1H), 2.02 (m, 5H), 1.75 (m, 6H), 1.26 (m, 7H), 0.84 (m, 3H). 
     The following compounds were synthesized using similar method: 
     
       
         
               
               
               
               
             
           
               
                   
               
               
                   
                   
                   
                 Obs. 
               
               
                 # 
                 Structure 
                 MW 
                 m/e 
               
               
                   
               
             
             
               
                 394 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 252 
                 253 
               
               
                   
               
               
                 395 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 252 
                 253 
               
               
                   
               
               
                 396 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 456 
                 457 
               
               
                   
               
               
                 397 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 469 
                 470 
               
               
                   
               
               
                 398 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 498 
                 499 
               
               
                   
               
               
                 399 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 511 
                 512 
               
               
                   
               
             
          
         
       
     
     Method AN 
     
       
                 
         
             
             
         
      
     
     To a solution of compound AN2 (R 1 =4-N-(α-phenoxyacetyl)piperidinylmethyl, R3=n-Butyl) (28 mg, 0.06 mmol) in dichloroethane (2 ml) was added butyraldehyde (5.3 ul, 0.06 mmol), triethylamine (8.4 ul, 0.06 mmol) and NaBH(OAc) 3  (18 mg, 0.084 mmol). 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 1 =4-N-(a-phenoxyacetyl)piperidinylmethyl, R 3 =n-Butyl, R 15 =propyl and R 16 =H) (5.4 mg, 17%). Observed MW (M+H) 526.1; exact mass 525.37.  1 H NMR (CD 3 OD): δ=7.28 (m, 2H), 6.96 (m, 3H), 4.76 (m, 2H), 4.55 (m, 1H), 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). 
     The following compound was synthesized using similar method: 
     
       
         
               
               
               
               
             
           
               
                   
               
               
                   
                   
                   
                 Obs. 
               
               
                 # 
                 Structure 
                 MW 
                 m/e 
               
               
                   
               
             
             
               
                 400 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 308 
                 309 
               
               
                   
               
               
                 401 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 308 
                 309 
               
               
                   
               
               
                 402 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 525 
                 526 
               
               
                   
               
             
          
         
       
     
     Method AO 
     
       
                 
         
             
             
         
      
     
     A mixture of copper chloride (2.06 g, 20.8 mmol) and lithium chloride (1.76 g, 41.6 mmol) in 100 ml of THF was cooled down to −78° C. To this mixture, a 2.0M solution of AO1 (R 3 =n-butyl) (10 ml, 20 mmol) was added gradually. The reaction was warmed up to −60° C., and AO2 (R 4 =m-Br—Ph) (2.9 ml, 22 mmol) 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 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 AO3 (R 4 =m-BrPh, R 3 =n-Bu) (3.93 g, 82%). Observed MW (M+H) 241.1; exact mass 240.01.  1 H NMR (400 MHz, CDCl 3 ): δ=8.07 (m, 1H), 7.88 (m, 1H), 7.64 (m, 1H), 7.34 (m, 1H), 2.94 (t, 3H, J=7.2 Hz), 1.71 (m, 2H), 1.40 (m, 2H), 0.95 (t, 3H, J=7.6 Hz). 
     The following ketones were made according to Method 9: 
     
       
         
               
               
               
               
             
           
               
                   
               
               
                   
                   
                 Observed MW 
                   
               
               
                   
                 Structure 
                 (M + H) 
                 Exact mass 
               
               
                   
               
             
             
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 242.1 
                 241.01 
               
               
                   
               
             
          
         
       
     
     Method AP 
     
       
                 
         
             
             
         
      
     
     Method AP, Step 1: 
     To a solution of AP1 (R 4 =3-Bromophenyl) (5 g, 25 mmol) in dichloromethane (10 ml) were added N,O-dimethylhydroxylamine hydrochloride (2.56 g, 26.25 mmol) and 4-methylmorpholine (2.95 ml, 26.25 mmol). EDCl (5.04 g, 26.25 mmol) was then added portionwise. The reaction mixture was stirred at RT overnight and was then quenched with 1N HCl (60 ml). The mixture was extracted with dichloromethane. The organic layer was washed with 1N HCl and brine, dried over Na 2 SO 4 , and concentrated to give the Weinreb amide AP2 (R 4 =m-Bromophenyl) (5.96 g, 98%). Observed MW (M+H) 244.1; exact mass 243.99.  1 H NMR (CDCl 3 ): δ=7.78 (m, 1H), 7.58 (m, 2H), 7.24 (m, 1H), 3.51 (s, 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 (1.19 g, 48.8 mmol) in 30 ml of THF was added dropwise a solution of R 3 Br (R 3 =cyclohexylethyl) (5.73 ml, 36.6 mmol) in 24 ml of THF. After addition of half of the solution of bromide, 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) (5.96 g, 24.4 mmol) was added. The mixture was stirred at RT for 3 hr and then quenched with 1N HCl until no 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) (8.06 g, 100%). Observed MW (M+H) 295.2; exact mass 294.06.  1 H NMR (400 MHz, CDCl 3 ): δ=8.18 (m, 1H), 7.85 (m, 1H), 7.64 (m, 1H), 7.33 (m, 1H), 2.94 (t, 3H, J=7.2 Hz), 1.70 (m, 9H), 1.63 (m, 4H). 
     Method AQ 
     
       
                 
         
             
             
         
      
     
     To a −78° C. solution of AQ1 (R 4 =cyclopropyl) (2.55 g, 38.0 mmol) in diethyl ether (100 ml) was added AQ2 (R 3 =n-BuLi) (38 ml, 1.5 M in hexanes, 57 mmol). After 45 min, the cooling bath was removed. After 3 h at RT, the reaction 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 (2×). 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 Cl 2 /hexanes) to provide the desired ketone AQ4 (R 4 =cyclopropyl, R 3 =n-Butyl) (2.57 g, 20.4 mmol, 54%).  1 H NMR (CDCl 3 ) δ 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 
     
       
                 
         
             
             
         
      
     
     Method AR: 
     Compound B2 (R 1 =m-Cl-Phenethyl, R 3 =Me, R 4 =i-butyl and R 5 =benzyl) was converted into AR2 (R 1 =m-Cl-Phenethyl, R 3 =Me, R 4 =i-butyl and R 5 =benzyl) using method A step 3. 
     The following compounds were synthesized using similar methods: 
     
       
         
               
               
               
               
             
           
               
                   
               
               
                   
                   
                   
                 Obs. 
               
               
                 # 
                 Structure 
                 MW 
                 m/e 
               
               
                   
               
             
             
               
                 403 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 396 
                 397 
               
               
                   
               
               
                 404 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 354 
                 NA 
               
               
                   
               
               
                 405 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 477 
                 NA 
               
               
                   
               
               
                 406 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 460 
                 NA 
               
               
                   
               
               
                 407 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 340 
                 NA 
               
               
                   
               
               
                 408 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 382 
                 NA 
               
               
                   
               
               
                 409 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 446 
                 NA 
               
               
                   
               
             
          
         
       
     
     Method AS 
     
       
                 
         
             
             
         
      
     
     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 HCl 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 CH 2 Cl 2 , solid sodium bicarbonate added, filtered and then the CH 2 Cl 2  solution was concentrated in vacuo to give AS2 (R 3 =Ph). 
     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 h. The reaction mixture was concentrated and partitioned between H 2 O and Et 2 O. The dried Et 2 O solution was concentrated in vacuo to give a yellow residue which was placed on preparative silica gel plates and eluted with CH 2 Cl 2  to give AS3 (R 3 =Ph, R 4 =p-CIPh). (Miyashita, A., Matsuda, H., Hiagaskino, T., Chem. Pharm. Bull., 1992, 40 (10), 2627-2631). 
     Method AS, Step 3: 
     Hydrochloric acid (1N, 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 CH 2 Cl 2  and H 2 O. The dried CH 2 Cl 2  was concentrated in vacuo to give a residue which was placed on preparative silica gel plates and eluted with CH 2 Cl 2 :hexane 1:1 to afford AS4 (R 3 =Ph, R 4 =p-CIPh). 
     Method AS, Step 4: 
     AS4 (R 3 =Ph, R 4 =p-CIPh) (0.12 g) and methylguanidine, HCl (AS6, R 1 =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 CH 2 Cl 2  and H 2 O. The dried CH 2 Cl 2  was concentrated in vacuo to give a residue which was placed on preparative silica gel plates and eluted with CH 2 Cl 2 :MeOH 9:1 to afford AS5 (R 3 =Ph, R 4 =p-CIPh and R 1 =Me). 
     The following compounds were synthesized using similar methods: 
     
       
         
               
               
               
               
             
           
               
                   
               
               
                   
                   
                   
                 Obs. 
               
               
                 # 
                 Structure 
                 MW 
                 m/e 
               
               
                   
               
             
             
               
                 411 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 265 
                 266 
               
               
                   
               
               
                 412 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 265 
                 266 
               
               
                   
               
               
                 413 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 271 
                 272 
               
               
                   
               
               
                 414 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 271 
                 272 
               
               
                   
               
               
                 415 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 279 
                 280 
               
               
                   
               
               
                 416 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 295 
                 296 
               
               
                   
               
               
                 417 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 295 
                 296 
               
               
                   
               
               
                 418 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 299 
                 300 
               
               
                   
               
               
                 419 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 299 
                 300 
               
               
                   
               
               
                 420 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 309 
                 310 
               
               
                   
               
               
                 421 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 325 
                 326 
               
               
                   
               
               
                 422 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 343 
                 344 
               
               
                   
               
               
                 423 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 343 
                 344 
               
               
                   
               
               
                 424 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 421 
                 422 
               
               
                   
               
               
                 425 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 482 
                 483 
               
               
                   
               
               
                 426 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 512 
                 513 
               
               
                   
               
               
                 427 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 560 
                 561 
               
               
                   
               
             
          
         
       
     
     Method AT 
     
       
                 
         
             
             
         
      
     
     Method AT, Step 1: 
     AT1, prepared using a method similar to Method H, Step 1, 2 and 3, (n=4, R 3 =R 4 =n-Bu) (0.146 g) in MeOH (3 ml) and 1N NaOH (0.727 ml) were stirred overnight at rt. The mixture was concentrated and then partitioned in water (pH ˜3, adjusted using conc. HCl) 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: 
     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 (R 15 =H, R 16 =n-butyl) (0.007 ml). The reaction was carried out overnight at rt. before Argonaut PS—NCO resin (0.150 g), PS-polyamine resin (0.120 g) and THF (2 ml) were added and the mixture shaken for 4 h. The 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 1N HCl 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). 
     The following compounds were synthesized using similar method: 
     
       
         
               
               
               
               
             
               
               
               
               
             
           
               
                   
               
               
                   
                   
                   
                 Obs. 
               
               
                 # 
                 Structure 
                 MW 
                 m/e 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 428 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 324 
                 325 
               
               
                   
               
               
                 429 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 325 
                 326 
               
               
                   
               
               
                 430 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 338 
                 339 
               
               
                   
               
               
                 431 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 339 
                 340 
               
               
                   
               
               
                 432 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 366 
                 367 
               
               
                   
               
               
                 433 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 368 
                 369 
               
               
                   
               
               
                 434 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 380 
                 381 
               
               
                   
               
               
                 435 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 382 
                 383 
               
               
                   
               
               
                 436 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 400 
                 401 
               
               
                   
               
               
                 437 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 406 
                 07 
               
               
                   
               
               
                 438 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 414 
                 15 
               
               
                   
               
               
                 439 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 414 
                 15 
               
               
                   
               
               
                 440 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 420 
                 21 
               
               
                   
               
               
                 441 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 428 
                 29 
               
               
                   
               
               
                 442 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 444 
                 45 
               
               
                   
               
               
                 443 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 458 
                 59 
               
               
                   
               
             
          
         
       
     
     Method AU 
     
       
                 
         
             
             
         
      
     
     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 15 =H, R 16 =H) (0.300 g), prepared according to procedure described by Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G.; Tatchell, A. R., ( Vogel&#39;s Textbook of Practical Organic Chemistry.  5 th  ed. Longman: new York, 1989; pp 1034-1035), AU2 (HCl salt, R 1 =Me) (0.237 g), 50% KOH (0.305 ml), 30% H 2 O 2  (0.115 ml) and EtOH (4.6 ml) were heated in a sealed tube for 2 h. Reaction mixture was concentrated and extracted with CH 2 Cl 2 . The dried organic solution was concentrated in vacuo to give a residue which was placed on preparative silica gel plates eluting with CH 2 Cl 2 :MeOH 9:1 to afford AU3 (R 15 =H, R 16 =H, R 1 =Me). 
     The following compounds were synthesized using similar method: 
     
       
         
               
               
               
               
             
           
               
                   
               
               
                   
                   
                   
                 Obs. 
               
               
                 # 
                 Structure 
                 MW 
                 m/e 
               
               
                   
               
             
             
               
                 444 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 265 
                 266 
               
               
                   
               
               
                 446 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 280 
                 281 
               
               
                   
               
               
                 447 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 285 
                 286 
               
               
                   
               
               
                 448 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 285 
                 286 
               
               
                   
               
               
                 449 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 309 
                 310 
               
               
                   
               
               
                 450 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 309 
                 310 
               
               
                   
               
             
          
         
       
     
     Method AV 
     
       
                 
         
             
             
         
      
     
     Method AV, Step 1: 
     In a microwave tube, AV1 (R 3 =Me, R 4 =Bu-i) (0.0012 g) and AV2 (R 22 =OPh) (0.0059 ml) in isopropanol (2 ml) was placed in a microwave at 125° C. for 5 min. The reaction mixture was concentrated in vacuo to give AV3 (R 3 =Me, R 4 =i-Bu, R 22 =OPh). 
     Method AV, Step 2: 
     AV3 (R 3 =Me, R 4 =i-Bu, R 22 =OPh) in CH 2 Cl 2  (1 ml) and TFA (1 ml) was shaken for 2 h and the concentrated in vacuo and purified on Prep LCMS to afford AV4 (R 3 =Me, R 4 =i-Bu, R 22 =OPh). 
     The following compounds were synthesized in a similar fashion. 
     
       
         
               
               
               
               
             
           
               
                   
               
               
                   
                   
                   
                 Obs. 
               
               
                 # 
                 Structure 
                 MW 
                 m/e 
               
               
                   
               
             
             
               
                 451 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 378 
                 379 
               
               
                   
               
               
                 452 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 396 
                 397 
               
               
                   
               
               
                 453 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 416 
                 417 
               
               
                   
               
             
          
         
       
     
     Method AW 
     
       
                 
         
             
             
         
      
     
     Method similar to Method U was used for this transformation. The following compounds were generated using similar methods. 
     The following compounds were synthesized in a similar fashion: 
     
       
         
               
               
               
               
             
           
               
                   
               
               
                   
                   
                   
                 Obs. 
               
               
                 # 
                 Structure 
                 MW 
                 m/e 
               
               
                   
               
             
             
               
                 454 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 341 
                 342 
               
               
                   
               
               
                 455 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 341 
                 342 
               
               
                   
               
               
                 456 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 342 
                 343 
               
               
                   
               
               
                 457 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 342 
                 343 
               
               
                   
               
               
                 458 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 347 
                 348 
               
               
                   
               
               
                 459 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 359 
                 360 
               
               
                   
               
               
                 460 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 323 
                 324 
               
               
                   
               
               
                 461 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 294 
                 295 
               
               
                   
               
             
          
         
       
     
     Method AX 
     
       
                 
         
             
             
         
      
     
     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 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). 
     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 mixture of AX3 (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, R 4 =phenethyl) as the first fraction and 2.2 g of AX4 (n=1, R 4 =phenethyl) as the second fraction. 
     Method AX, Step 3. 
     A 100 ml methanolic solution of AX4 (n=1, R 4 =phenethyl) (2.2 g) and 1,1′-bis(di-1-propylphosphino)ferrocene (1,5-cyclooctadiene)rhodium (I) 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 chromatography to yield AX6 (n=1, R 4 =phenethyl) (1.7 g). 
     The following compounds were generated using similar method. 
     
       
                 
         
             
             
         
      
     
     Method AY 
     
       
                 
         
             
             
         
      
     
     A solution of AY1 (n=1; 1.5 g, 3.4 mmol), 5% Rh/C (1.5 g), 5% Pd/C (0.5 g) 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 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. 
     
       
                 
         
             
             
         
      
     
     Method AZ 
     
       
                 
         
             
             
         
      
     
     Method AZ, Step 1 
     To a solution of AZ1 (n=1, R 1 =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 O and diluted with EtOAc. After removal of the organic phase, the aqueous layer was extracted with EtOAc (3×). The combined organics were dried (Na 2 SO 4 ), filtered, and concentrated. The residue was purified by silica gel chromatography (0-100% EtOAc/hexanes) to yield AZ2 (n=1, R 1 =Me, R 3 =2-cyclohexylethyl) (0.408 g, 0.94 mmol, 93% yield). MS m/e: 434.1 (M+H). 
     Method AZ Step 2: 
     To a solution of AZ2 (n=1, R 1 =Me, R 3 =2-cyclohexylethyl) (0.011 g, 0.025 mmol) and AZ5 (R 15 =H and R 16 =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 (0.095 g, 2.42 mmol/g). The reaction was agitated for 40 hours at room temperature. The reaction was treated with 7N NH 3 /MeOH, and solution was filtered. After concentration, the residue was purified by silica gel HPLC (0-4% [(5% 7N NH 3 /MeOH)/MeOH]/(50% DCM/hexanes) to furnish fraction 1 and fraction 2 which, after removal of solvent, were treated with 20% TFA in DCM for 3 h at r.t. to give AZ4 (n=1, R 1 =Me, R 3 =2-cyclohexylethyl, R 15 =H and R 16 =m-pyridylmethyl) (0.005 g, 0.009 mmol) and the AZ3 (n=1, R 1 =Me, R 3 =2-cyclohexylethyl, R 15 =H and R 16 =m-pyridylmethyl) (0.012 g, 0.022 mmol) respectively. 
     The following compounds were generated using similar methods: 
     
       
         
               
               
               
               
             
           
               
                   
               
               
                   
                   
                   
                 Obs. 
               
               
                 # 
                 Structure 
                 MW 
                 m/e 
               
               
                   
               
             
             
               
                 462 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 333 
                 334 
               
               
                   
               
               
                 463 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 348 
                 349 
               
               
                   
               
               
                 464 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 374 
                 375 
               
               
                   
               
               
                 465 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 374 
                 375 
               
               
                   
               
               
                 466 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 374 
                 375 
               
               
                   
               
               
                 467 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 374 
                 375 
               
               
                   
               
               
                 468 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 376 
                 377 
               
               
                   
               
               
                 469 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 376 
                 377 
               
               
                   
               
               
                 470 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 376 
                 377 
               
               
                   
               
               
                 471 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 376 
                 377 
               
               
                   
               
               
                 472 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 377 
                 378 
               
               
                   
               
               
                 473 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 377 
                 378 
               
               
                   
               
               
                 474 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 378 
                 379 
               
               
                   
               
               
                 475 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 378 
                 379 
               
               
                   
               
               
                 476 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 388 
                 389 
               
               
                   
               
               
                 477 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 388 
                 389 
               
               
                   
               
               
                 478 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 388 
                 389 
               
               
                   
               
               
                 479 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 388 
                 389 
               
               
                   
               
               
                 480 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 388 
                 389 
               
               
                   
               
               
                 481 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 388 
                 389 
               
               
                   
               
               
                 482 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 388 
                 389 
               
               
                   
               
               
                 483 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 388 
                 389 
               
               
                   
               
               
                 484 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 390 
                 391 
               
               
                   
               
               
                 485 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 390 
                 391 
               
               
                   
               
               
                 486 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 390 
                 391 
               
               
                   
               
               
                 487 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 390 
                 391 
               
               
                   
               
               
                 488 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 391 
                 392 
               
               
                   
               
               
                 489 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 391 
                 392 
               
               
                   
               
               
                 490 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 391 
                 392 
               
               
                   
               
               
                 491 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 391 
                 392 
               
               
                   
               
               
                 492 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 392 
                 393 
               
               
                   
               
               
                 493 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 392 
                 393 
               
               
                   
               
               
                 494 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 392 
                 393 
               
               
                   
               
               
                 495 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 392 
                 393 
               
               
                   
               
               
                 496 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 402 
                 403 
               
               
                   
               
               
                 497 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 402 
                 403 
               
               
                   
               
               
                 498 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 402 
                 403 
               
               
                   
               
               
                 499 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 405 
                 406 
               
               
                   
               
               
                 500 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 406 
                 407 
               
               
                   
               
               
                 501 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 406 
                 407 
               
               
                   
               
               
                 502 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 406 
                 407 
               
               
                   
               
               
                 503 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 406 
                 407 
               
               
                   
               
               
                 504 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 406 
                 407 
               
               
                   
               
               
                 505 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 410 
                 411 
               
               
                   
               
               
                 506 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 410 
                 411 
               
               
                   
               
               
                 507 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 410 
                 411 
               
               
                   
               
               
                 508 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 411 
                 412 
               
               
                   
               
               
                 509 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 411 
                 412 
               
               
                   
               
               
                 510 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 411 
                 412 
               
               
                   
               
               
                 511 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 416 
                 417 
               
               
                   
               
               
                 512 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 416 
                 417 
               
               
                   
               
               
                 513 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 416 
                 417 
               
               
                   
               
               
                 514 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 416 
                 417 
               
               
                   
               
               
                 515 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 417 
                 418 
               
               
                   
               
               
                 516 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 417 
                 418 
               
               
                   
               
               
                 517 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 424 
                 425 
               
               
                   
               
               
                 518 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 424 
                 425 
               
               
                   
               
               
                 519 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 424 
                 425 
               
               
                   
               
               
                 520 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 424 
                 425 
               
               
                   
               
               
                 521 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 425 
                 426 
               
               
                   
               
               
                 522 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 425 
                 426 
               
               
                   
               
               
                 523 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 425 
                 426 
               
               
                   
               
               
                 524 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 425 
                 426 
               
               
                   
               
               
                 525 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 425 
                 426 
               
               
                   
               
               
                 526 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 425 
                 426 
               
               
                   
               
               
                 527 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 425 
                 426 
               
               
                   
               
               
                 528 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 425 
                 426 
               
               
                   
               
               
                 529 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 425 
                 426 
               
               
                   
               
               
                 530 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 425 
                 426 
               
               
                   
               
               
                 531 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 425 
                 426 
               
               
                   
               
               
                 532 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 425 
                 426 
               
               
                   
               
               
                 533 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 428 
                 429 
               
               
                   
               
               
                 534 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 428 
                 429 
               
               
                   
               
               
                 535 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 439 
                 440 
               
               
                   
               
               
                 536 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 439 
                 440 
               
               
                   
               
               
                 537 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 442 
                 443 
               
               
                   
               
               
                 538 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 442 
                 443 
               
               
                   
               
               
                 539 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 442 
                 443 
               
               
                   
               
               
                 540 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 442 
                 443 
               
               
                   
               
               
                 541 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 444 
                 445 
               
               
                   
               
               
                 542 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 445 
                 446 
               
               
                   
               
               
                 543 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 459 
                 460 
               
               
                   
               
               
                 544 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 459 
                 460 
               
               
                   
               
             
          
         
       
     
     Method BA 
     
       
                 
         
             
             
         
      
     
     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; 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). 
     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).  1 H NMR (CDCl 3 ) 1.43 (s, 9H), 3.98 (s, 2H), 4.11 (d, 4H), 5.78 (d, 1H). 
     Method BB 
     
       
                 
         
             
             
         
      
     
     Method BB, Step 1; 
     Compound BB1 (n=1, R 1 =Me, R 3 =cyclohexylethyl) was converted to BB2 (n=1, R 1 =Me, R 3 =cyclohexylethyl) and BB3 (n=1, R 1 =Me, R 3 =cyclohexylethyl) which were separated via a silica gel column eluted with EtOAc in Hexane (0-15%). 
     Method BB, Step 2; 
     Compound BB4 (n=1, R 1 =Me, R 3 =cyclohexylethyl) was generated from BB2 (n=1, R 1 =Me, R 3 =cyclohexylethyl) using 20% TFA in DCM. 
     The following compounds were generated using similar method: 
     
       
                 
         
             
             
         
      
     
     Method BC 
     
       
                 
         
             
             
         
      
     
     Method BC, Step 1; 
     Compound BC2 (n=1, R 1 =Me, R 3 =cyclohexylethyl and R 15 =m-Pyridyl) was obtained from BC1 (n=1, R 2 =Me, R 3 =cyclohexylethyl) using method L step 2. 
     Method BC, Step 2; 
     Compound BC3 (n=1, R 1 =Me, R 3 =cyclohexylethyl and R 15 =m-Pyridyl) was obtained from BC2 (n=1, R 1 =Me, R 3 =cyclohexylethyl and R 15 =m-Pyridyl) using method L step 3. 
     The following compounds were generated using a similar method: 
     
       
         
               
               
               
               
             
           
               
                   
               
               
                   
                   
                   
                 Obs. 
               
               
                 # 
                 Structure 
                 MW 
                 m/e 
               
               
                   
               
             
             
               
                 552 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 374 
                 375 
               
               
                   
               
               
                 553 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 388 
                 389 
               
               
                   
               
               
                 554 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 388 
                 389 
               
               
                   
               
               
                 555 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 388 
                 389 
               
               
                   
               
               
                 556 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 388 
                 389 
               
               
                   
               
               
                 557 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 390 
                 391 
               
               
                   
               
               
                 558 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 390 
                 391 
               
               
                   
               
               
                 559 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 402 
                 403 
               
               
                   
               
               
                 560 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 402 
                 403 
               
               
                   
               
               
                 561 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 402 
                 403 
               
               
                   
               
               
                 562 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 402 
                 403 
               
               
                   
               
               
                 563 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 404 
                 405 
               
               
                   
               
               
                 564 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 404 
                 405 
               
               
                   
               
               
                 565 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 404 
                 405 
               
               
                   
               
               
                 566 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 404 
                 405 
               
               
                   
               
               
                 567 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 410 
                 411 
               
               
                   
               
               
                 568 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 410 
                 411 
               
               
                   
               
               
                 569 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 411 
                 412 
               
               
                   
               
               
                 570 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 411 
                 412 
               
               
                   
               
               
                 571 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 411 
                 412 
               
               
                   
               
               
                 572 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 411 
                 412 
               
               
                   
               
               
                 573 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 411 
                 412 
               
               
                   
               
               
                 574 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 411 
                 412 
               
               
                   
               
               
                 575 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 416 
                 417 
               
               
                   
               
               
                 576 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 416 
                 417 
               
               
                   
               
               
                 577 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 416 
                 417 
               
               
                   
               
               
                 578 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 416 
                 417 
               
               
                   
               
               
                 579 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 424 
                 425 
               
               
                   
               
               
                 580 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 424 
                 425 
               
               
                   
               
               
                 581 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 424 
                 425 
               
               
                   
               
               
                 582 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 424 
                 425 
               
               
                   
               
               
                 583 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 425 
                 426 
               
               
                   
               
               
                 584 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 425 
                 426 
               
               
                   
               
               
                 585 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 425 
                 426 
               
               
                   
               
               
                 586 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 425 
                 426 
               
               
                   
               
               
                 587 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 425 
                 426 
               
               
                   
               
               
                 588 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 425 
                 426 
               
               
                   
               
               
                 589 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 425 
                 426 
               
               
                   
               
               
                 590 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 430 
                 431 
               
               
                   
               
               
                 591 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 430 
                 431 
               
               
                   
               
               
                 592 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 438 
                 439 
               
               
                   
               
               
                 593 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 438 
                 439 
               
               
                   
               
               
                 594 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 439 
                 440 
               
               
                   
               
             
          
         
       
     
     Method BD 
     
       
                 
         
             
             
         
      
     
     Method BD, Step 1; 
     Compound BD2 (n=1, R 1 =Me, R 3 =cyclohexylethyl and R 15 =Ph) was obtained from BD1 (n=1, R 2 =Me, R 3 =cyclohexylethyl) using Method N, Step 1. 
     Method BD, Step 2; 
     Compound BD3 (n=1, R 1 =Me, R 3 =cyclohexylethyl and R 15 =Ph) was obtained from BD2 (n=1, R 1 =Me, R 3 =cyclohexylethyl and R 15 =m-Pyridyl) using Method N, Step 2. 
     The following compounds were generated using a similar method: 
     
       
         
               
               
               
               
             
           
               
                   
               
               
                   
                   
                   
                 Obs. 
               
               
                 # 
                 Structure 
                 MW 
                 m/e 
               
               
                   
               
             
             
               
                 595 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 440 
                 441 
               
               
                   
               
               
                 596 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 460 
                 461 
               
               
                   
               
             
          
         
       
     
     Method BE 
     
       
                 
         
             
             
         
      
     
     Method similar to Method M was adapted for these transformations. The following compounds were generated similar methods. 
     
       
         
               
               
               
               
             
           
               
                   
               
               
                   
                   
                   
                 Obs. 
               
               
                 # 
                 Structure 
                 MW 
                 m/e 
               
               
                   
               
             
             
               
                 597 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 405 
                 406 
               
               
                   
               
               
                 598 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 439 
                 440 
               
               
                   
               
             
          
         
       
     
     Method BF 
     
       
                 
         
             
             
         
      
     
     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 16 =n-propyl). 
     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. 
               
               
                 # 
                 Structure 
                 MW 
                 m/e 
               
               
                   
               
             
             
               
                 599 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 376 
                 377 
               
               
                   
               
               
                 600 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 390 
                 391 
               
               
                   
               
               
                 601 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 390 
                 391 
               
               
                   
               
               
                 602 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 390 
                 391 
               
               
                   
               
               
                 603 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 397 
                 398 
               
               
                   
               
               
                 604 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 397 
                 398 
               
               
                   
               
               
                 605 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 397 
                 398 
               
               
                   
               
               
                 606 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 397 
                 398 
               
               
                   
               
               
                 607 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 411 
                 412 
               
               
                   
               
             
          
         
       
     
     Method BG 
     
       
                 
         
             
             
         
      
     
     Method BG: 
     To a solution of BG1 (n=1, R 3 =cyclohexylethyl) (0.136 g, 0.31 mmol) in CH 2 Cl 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 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 15 =n-butyl) (0.124 g, 0.25 mmol, 80% yield). MS m/e: 426.1 (M-OBu). 
     The following compound was prepared using similar method: 
     
       
                 
         
             
             
         
      
     
     Method BH 
     
       
                 
         
             
             
         
      
     
     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 product mixture BH2 (n=1, R 3 =cyclohexylethyl and R 15 =n-butyl) was carried on to the next step without purification. 
     Method BH, Step 2. 
     A solution of BH2 (n=1, R 3 =cyclohexylethyl and R 15 =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 15 =n-butyl) (0.032 g, 0.078 mmol, 56% yield) and BH3 (n=1, R 2 =Me, R 3 =cyclohexylethyl and R 15 =n-butyl) (0.008 g, 0.020 mmol, 14% yield). For BH4 (n=1, R 2 =Me, R 3 =cyclohexylethyl and R 15 =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). 
     Method BH, Step 3. 
     Compound BH4 (n=1, R 2 =Me, R 3 =cyclohexylethyl and R 15 =n-butyl) (0.032 g, 0.078 mmol) was converted to BH5 (n=1, R 2 =Me, R 3 =cyclohexylethyl and R 15 =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). 
     The following compound was generated using a similar method: 
     
       
         
               
               
               
               
               
             
           
               
                   
                   
               
               
                   
                   
                   
                   
                 Obs. 
               
               
                   
                 # 
                 Structure 
                 MW 
                 m/e 
               
               
                   
                   
               
             
             
               
                   
                 608 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 391 
                 392 
               
               
                   
                   
               
               
                   
                 609 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 391 
                 392 
               
               
                   
                   
               
               
                   
                 610 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 391 
                 392 
               
               
                   
                   
               
             
          
         
       
     
     Method BI 
     
       
                 
         
             
             
         
      
     
     A solution of BI1(0.020 g, 0.040 mmol) in DCM (1 mL) was degassed using freeze/pump/thaw (4×) method. At the end of the fourth cycle Crabtree&#39;s catalyst was added and the system was evacuated. While thawing, the system 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 BI2 (0.011 g, 0.022 mmol, 55% yield). MS m/e: 368.2 (M+H). 
     Method BJ 
     
       
                 
         
             
             
         
      
     
     Method BJ, Step 1 
     A mixture of 2 ml dioxane solution of BJ1 (R 1 =Me, R 3 =Me) (140 mg, 0.5 mmol) generated using Method BK Steps 1 &amp; 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 1 =Me, R 3 =Me) (0.73 mg). 
     Method BJ, Step 2 
     BJ2(R 1 =Me, R 3 =Me) was converted to BJ3 (R 1 =Me, R 3 =Me) using Method BK, Steps 3 &amp; 4. Obs. Mass for BJ3 (R 1 =Me, R 3 =Me): 319.2. 
     
       
         
               
               
               
               
               
             
           
               
                   
                   
               
               
                   
                   
                   
                   
                 Obs. 
               
               
                   
                 # 
                 Structure 
                 MW 
                 m/e 
               
               
                   
                   
               
             
             
               
                   
                 614 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 318 
                 319 
               
               
                   
                   
               
             
          
         
       
     
     Method BK 
     
       
                 
         
             
             
         
      
     
     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. 
     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° C. oil bath for 16 h and then cooled to RT and concentrated under vacuum. This crude residue was purified by column chromatography (MeOH/DCM) to give 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: 
     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&#39;s reagent (107 mg, 0.26 mmol). The resulting mixture was placed in an oil bath at 60° C. for 16 h and then at 100° C. for 24 h. After cooling to RT, the reaction was quenched by addition of several drops of 1 N HCl and then diluted with EtOAc and 1 N KOH. The phases were separated and the aqueous layer extracted with EtOAc (2×). The organic portions were combined, washed with brine, dried over MgSO 4 , filtered, and concentrated. This crude residue was purified by preparative TLC (1000 μm 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 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 with NH 4 OH (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 NH 3 /MeOH in DCM). The resulting sample was dissolved in DCM (1 ml), treated with 4N HCl in dioxane for 5 min, and finally concentrated to give diastereomeric products BK7 (R 3 =N-benzyl-3-piperidyl, R 4 =n-Bu) (12 mg, 0.029 mmol, 43%).  1 H NMR (CD 3 OD) δ 7.60 (m, 2 H), 7.49 (m, 3 H), 4.39 (ABq, J AB =12.8 Hz, Δv AB =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, J d =3.6 Hz, J q =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: t R  (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: 
     
       
         
               
               
               
               
               
             
           
               
                   
                   
               
               
                   
                   
                   
                   
                 Obs. 
               
               
                   
                 # 
                 Structure 
                 MW 
                 m/e 
               
               
                   
                   
               
             
             
               
                   
                 615 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 281 
                 282 
               
               
                   
                   
               
             
          
         
       
     
     Method BL 
     
       
                 
         
             
             
         
      
     
     To a 2 ml Methanolic solution of BL1 (n=1, R 3 =cyclohexylethyl, R 1 =Me) (10 mg) was added BL3 (HCl salt, R 15 =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 1 =Me and R 15 =H). 
     The following compounds were synthesized using similar methods. 
     
       
         
               
               
               
               
             
           
               
                   
               
               
                   
                   
                   
                 Obs. 
               
               
                 # 
                 Structure 
                 MW 
                 m/e 
               
               
                   
               
             
             
               
                 616 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 348 
                 349 
               
               
                   
               
               
                 617 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 388 
                 389 
               
               
                   
               
             
          
         
       
     
     Method BM 
     
       
                 
         
             
             
         
      
     
     Method BM, Step 1: 
     To a toulene solution (3 ml) 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 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 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, 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. 
     The following compounds were synthesized using similar method: 
     
       
         
               
               
               
               
             
           
               
                   
               
               
                   
                   
                   
                 Obs. 
               
               
                 # 
                 Structure 
                 MW 
                 m/e 
               
               
                   
               
             
             
               
                 618 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 332 
                 333 
               
               
                   
               
               
                 619 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 468 
                 469 
               
               
                   
               
             
          
         
       
     
     Method BN 
     
       
                 
         
             
             
         
      
     
     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. 
     Method BO 
     The following compounds were generated through boc-deprotection of the corresponding starting material using 50% TFA in DCM, rt 30 min. 
     
       
         
               
               
               
               
               
             
           
               
                   
                   
               
               
                   
                   
                   
                   
                 Obs. 
               
               
                   
                 # 
                 Structure 
                 MW 
                 m/e 
               
               
                   
                   
               
             
             
               
                   
                 620 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 266 
                 267 
               
               
                   
                   
               
               
                   
                 621 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 266 
                 267 
               
               
                   
                   
               
               
                   
                 622 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 274 
                 275 
               
               
                   
                   
               
               
                   
                 623 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 274 
                 275 
               
               
                   
                   
               
               
                   
                 624 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 288 
                 289 
               
               
                   
                   
               
               
                   
                 625 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 320 
                 321 
               
               
                   
                   
               
               
                   
                 626 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 320 
                 321 
               
               
                   
                   
               
             
          
         
       
     
     Method BP 
     
       
                 
         
             
             
         
      
     
     Method BP, Step 1 
     To a solution of BP1 (n=1, R 1 =Me, R 2 =H, R 3 =cyclohexylethyl) (0.012 g, 0.028 mmol) in CH 2 Cl 2  (0.5 mL) was added 2,6-lutidine (0.010 mL, 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 1 =Me, R 2 =H, R 3 =cyclohexylethyl) (0.010 g, 0.019 mmol). MS m/e: 526.1 (M+H). 
     Method BP, Step 2 
     BP3 (n=1, R 1 =Me, R 2 =H, R 3 =cyclohexylethyl) was prepared from BP2 (n=1, R 1 =Me, R 2 =H, R 3 =cyclohexylethyl) using 30% TFA/DCM. MS m/e: 426.1 (M+H). 
     
       
         
               
               
               
               
             
           
               
                   
               
               
                   
                   
                   
                 Obs. 
               
               
                 # 
                 Structure 
                 MW 
                 m/e 
               
               
                   
               
             
             
               
                 627 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 425 
                 426 
               
               
                   
               
             
          
         
       
     
     Method BQ 
     
       
                 
         
             
             
         
      
     
     Method BQ Step 1: 
     BQ1 was prepared according to Method AZ. 
     To a solution of BQ1 (n=1, R 1 =Me, R 2 =H, R 3 =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 EDCl (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 to provide BQ2 (n=1, R 1 =Me, R 2 =H, R 3 =cyclohexylethyl) (0.003 g, 0.005 mmol). MS m/e: 627.1 (M+H). 
     Method BQ Step 2: 
     BQ2 (n=1, R 1 =Me, R 2 =H, R 3 =cyclohexylethyl) (0.003 g, 0.005 mmol) was treated with 20% TFA/CH 2 Cl 2  (1 mL) in the presence of PS-thiophenol resin (0.030 g, 1.42 mmol/g) for 3 hours. The solution was filtered and concentrated to produce BQ3 (n=1, R 1 =Me, R 2 =H, R 3 =cyclohexylethyl) (0.002 g, 0.005 mmol). MS m/e: 377.2 (M+H). 
     
       
         
               
               
               
               
             
           
               
                   
               
               
                   
                   
                   
                 Obs. 
               
               
                 # 
                 Structure 
                 MW 
                 m/e 
               
               
                   
               
             
             
               
                 628 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 376 
                 377 
               
               
                   
               
             
          
         
       
     
     Method BR 
     
       
                 
         
             
             
         
      
     
     Method BR, Step 1: 
     To a solution of BR1 (n=1, R 1 =Me, R 2 =H, R 3 =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 Cl 2 . The organic layer was removed, and the aqueous phase was extracted with CH 2 Cl 2  (3×). After concentration, the brown residue was purified by reverse phase HPLC to yield BR 2  (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: 
     BR3 (n=1, R 1 =Me, R 2 =H, R 3 =cyclohexylethyl) was prepared from BR2 (n=1, R 1 =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 
                 m/e 
               
               
                   
               
             
             
               
                 629 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 412 
                 413 
               
               
                   
               
             
          
         
       
     
     Method BS 
     
       
                 
         
             
             
         
      
     
     Method BS Step 1: 
     To a solution of BS1 (n=1, R 1 =Me, R 2 =H, R 3 =cyclohexylethyl) (0.003 g, 0.006 mmol) in CH 2 Cl 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 1 =Me, R 2 =H, R 3 =cyclohexylethyl) (0.002 g, 0.002 mmol). MS m/e: 823.5 (M+H). 
     Method BS Step 2: 
     Compound BS2 (n=1, R 1 =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 reaction was concentrated, and the residue was purified by reverse phase HPLC to furnish BS3 (n=1, R 1 =Me, R 2 =H, R 3 =cyclohexylethyl) (0.0012 g, 0.002 mmol). MS m/e: 454.1 (M+H). 
     
       
         
               
               
               
               
             
           
               
                   
               
               
                   
                   
                   
                 Obs. 
               
               
                 # 
                 Structure 
                 MW 
                 m/e 
               
               
                   
               
             
             
               
                 630 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 453 
                 454 
               
               
                   
               
             
          
         
       
     
     Method BT 
     
       
                 
         
             
             
         
      
     
     Method BT: 
     To a round bottom flask were added compound BT1 (R 1 =Me, R 3 =Me) (100 mg, 0.29 mmol), anhydrous toluene (2 ml), 3-aminopyridine (55 mg, 0.58 mmol) 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 Cl 2 . The combined organic layer was then dried over Na 2 SO 4 . After the filtration, the concentrated residue was separated by TLC (CH 3 OH:CH 2 Cl 2 =1:10) and reverse phase HPLC (10%-100% acetonitrile in water w/0.1% formic acid) to produce the desired compound BT2 (R 1 =Me, R 3 =Me and R 21 =m-pyridyl) as a formate salt (23.6 mg, white solid, 20%).  1  HNMR (CDCl 3 ) δ 7.50-6.90 (m, 13 H), 3.14 (s, 3H) MS m/e 358 (M+H). 
     
       
         
               
               
               
               
             
           
               
                   
               
               
                   
                   
                   
                 Obs. 
               
               
                 # 
                 Structure 
                 MW 
                 m/e 
               
               
                   
               
             
             
               
                 631 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 347 
                 348 
               
               
                   
               
               
                 632 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 156 
                 357 
               
               
                   
               
               
                 633 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 357 
                 358 
               
               
                   
               
               
                 634 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 357 
                 358 
               
               
                   
               
               
                 635 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 357 
                 358 
               
               
                   
               
               
                 636 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 358 
                 359 
               
               
                   
               
             
          
         
       
     
     Method BU 
     
       
                 
         
             
             
         
      
     
     Method BU, Step 1, 
     To a round bottomed flask containing BU1 (m=1, n=1, R 1 =Me, R 3 =Cyclohexylethyl) (99 mg, 0.307 mmol) of the trifluoroacetic acid salt of pyrollidine derivative in 5 ml of DCM was added (86 μL, 0.614 mmol) of triethylamine followed by addition of (76 mg, 0.307 mmol) N-(benzyyloxycarbonyloxy)succinimide. Stir at room temperature for 18 h. Dilute the mixture with DCM and extract with sat&#39;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% EtOAc/hexanes) to yield BU2 (m=1, n=1, R 1 =Me, R 3 =Cyclohexylethyl) (130 mg, 0.284 mmol, 93% yield). MS m/e: 458.1 (M+H). 
     Method BU, Step 2, 
     To a solution of BU2 (m=1, n=1, R 1 =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 OH. Seal the vial and shake at room temperature for 72 h. 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 O (87 mg, 0.398 mmol) were added. The solution mixture was stirred at room temperature for 18 h before it was concentrated and the residue purified by silica gel chromatography using EtOAc/hexanes to yield the BU3 (m=1, n=1, R 1 =Me, R 3 =Cyclohexylethyl) (90 mg, 0.167 mmol, 58% yield). MS m/e: 541.1, 441.1 (M+H). 
     Method BU, Step 3, 
     A solution of BU3 (m=1, n=1, R 1 =Me, R 3 =Cyclohexylethyl) (90 mg, 0.167 mmol) in 5 ml of MeOH was hydrogenated using 100 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 in vacuo yielded BU4 (m=1, n=1, R 1 =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 4Å molecular sieves was added 3-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 1 =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 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 5 ml 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 1 =Me, 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. 
               
               
                 # 
                 Structure 
                 MW 
                 m/e 
               
               
                   
               
             
             
               
                 637 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 258 
                 259 
               
               
                   
               
               
                 638 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 412 
                 413 
               
               
                   
               
             
          
         
       
     
     Method BV 
     
       
                 
         
             
             
         
      
     
     Method BV Step 1: 
     The method was adapted from a literature procedure (Page et al.,  Tetrahedron  1992, 35, 7265-7274) 
     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×), dried over 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%).  1 H NMR (CDCl 3 ) δ □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). 
     Method BV Step 2: 
     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% aqueous Na 2 SO 3 . After diluting with CH 2 Cl 2 , the layers were separated, and the organic layer washed with water (2×), brine (1×) 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 ) δ□8.19 (m, 1 H), 7.93 (m, 3 H), 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 1 =Me and R 2 =H) was prepared from BV4 (R 3 =3-bromo-4-fluorophenyl and R 4 =phenyl) using Method AS, Step 4. 
     
       
         
               
               
               
               
               
             
           
               
                   
                   
               
               
                   
                   
                   
                   
                 Obs. 
               
               
                   
                 # 
                 Structure 
                 MW 
                 m/e 
               
               
                   
                   
               
             
             
               
                   
                 639 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 261 
                 362 
               
               
                   
                   
               
               
                   
                 640 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 261 
                 N/A 
               
               
                   
                   
               
             
          
         
       
     
     Human Cathepsin D FRET Assay 
     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&#39;s disease. Cathespin D knockout mice die within weeks after birth due to multiple GI, immune and CNS defects.
 
The substrate used below has been described (Y. Yasuda et al.,  J. Biochem.,  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 consistent with Yasuda et al.
 
The assay is run in a 30 ul final volume using a 384 well Nunc black plate. 8 concentrations of compound are pre-incubated with enzyme for 30 mins at 37 C. followed by addition of substrate with continued incubation at 37 C. for 45 mins. The rate of increase in fluorescence is linear for over 1 h and is measured at the end of the incubation period using a Molecular Devices FLEX station plate reader. K is are interpolated from the IC50s using a Km value of 4 uM and the substrate concentration of 2.5 uM.
 
Reagents
     Na-Acetate pH 5   1% Brij-35 from 10% stock (Calbiochem)   DMSO   Purified (&gt;95%) human liver Cathepsin D (Athens Research &amp; Technology Cat#16-12-030104)   Peptide substrate (Km=4 uM) Bachem Cat # M-2455   Pepstatin is used as a control inhibitor (Ki-0.5 nM) and is available from Sigma.   Nunc 384 well black plates
 
Final Assay Buffer Conditions
   100 mM Na Acetate pH 5.0   0.02% Brij-35   1% DMSO
 
Compound is diluted to 3× final concentration in assay buffer containing 3% DMSO. 10 ul of compound is added to 10 ul of 2.25 nM enzyme (3×) diluted in assay buffer without DMSO, mixed briefly, spun, and incubated at 37 C. for 30 mins. 3× substrate (7.5 uM) is prepared in 1× assay buffer without DMSO. 10 ul of substrate is added to each well mixed and spun briefly to initiate the reaction. Assay plates are incubated at 37 C. for 45 mins and read on 384 compatible fluorescence plate reader using a 328 nm Ex and 393 nm 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 to about 75 nM. 
     The following are examples of compounds that exhibit hCathD Ki data under 75 nM. 
                             structure                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
The following compound
 
                                
has a hCath D Ki value of 0.45 nM.
 
     BACE-1 Cloning, Protein Expression 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 BACE1 cDNA in pcDNA4/mycHisA construct; University of Toronto) by PCR using the advantage-GC cDNA PCR kit (Clontech, Palo Alto, Calif.). A HindIII/PmeI fragment from pcDNA4-sBACE1 myc/H is was blunt ended using Klenow and subcloned into the Stu I site of pFASTBACI(A) (Invitrogen). A sBACE1 mycHis recombinant bacmid was generated by transposition in DH10Bac cells (GIBCO/BRL). Subsequently, the sBACE1 mycHis bacmid construct was transfected into sf9 cells using CellFectin (Invitrogen, San Diego, Calif.) in order to generate recombinant baculovirus. Sf9 cells were grown in SF 900-II medium (Invitrogen) supplemented with 3% heat inactivated FBS and 0.5× 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 3000×g for 15 minutes. The supernatant, containing secreted sBACE1, was collected and diluted 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 NaCl). 
     Proteins, were eluted from the Q-sepharose column with Buffer B (20 mM HEPES, pH 8.0, 500 mM NaCl). The protein peaks from the Q-sepharose column 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 NaCl). 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 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-KTEEISEVNLDAEFRHDKC-biotin (SEQ ID NO: 1); CIS-Bio International, France), 5 μM unlabeled APPsw peptide (KTEEISEVNLDAEFRHDK (SEQ ID NO: 2); American Peptide Company, Sunnyvale, Calif.), 7 nM sproBACE1, 20 mM PIPES pH 5.0, 0.1% Brij-35 (protein grade, Calbiochem, San Diego, Calif.), and 10% glycerol were preincubated for 30 min at 30° C. Reactions were initiated by addition of substrate in a 5 μl aliquot resulting in a total volume of 25 μl. After 3 hr at 30° C. reactions were terminated by addition of an equal volume of 2× stop buffer containing 50 mM Tris-HCl pH 8.0, 0.5 M KF, 0.001% Brij-35, 20 μg/mISA-XL665 (cross-linked allophycocyanin protein coupled to streptavidin; CIS-Bio International, France) (0.5 μg/well). Plates were shaken briefly and spun at 1200×g for 10 seconds to pellet all liquid to the bottom of the plate before 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 μs delay and simultaneous measurements of both 620 nm and 665 nm emissions for 400 μs. 
     IC 50  determinations for inhibitors, (I), 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 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+10^((LogEC50−X)*Hill Slope)); X is the logarithm of concentration of I, 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 IC 50  range from about 0.1 to about 500 μM, preferably about 0.1 to about 100 μM, more preferably about 0.1 to about 20 μM. The last compound in Table M has an IC 50  value of 0.35 μM. 
     Examples of compounds under 1 μM are listed below: 
                                                                                                                                                                                                                                                                          
Human Mature Renin Enzyme Assay:
 
Human Renin was cloned from a human kidney cDNA library and C-terminally epitope-tagged with the V5-6H is sequence into pcDNA3.1. pCNDA3.1-Renin-V5-6His was stably expressed in HEK293 cells and purified to &gt;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 Probes, Eugene, Oreg.) in 50 mM Tris-HCl pH 8.0, 100 mM NaCl, 0.1% Brij-35 and 5% DMSO buffer for 40 mins at 30 degrees celsius in the presence or absence of different concentrations of test compounds. Mature human Renin was present at approximately 200 nM. Inhibitory activity was defined as the percent decrease in renin induced fluorescence at the end of the 40 min incubation compared to vehicle controls and samples lacking enzyme.
 
     
       
         
               
               
             
           
               
                   
               
               
                   
                 I % of 
               
               
                   
                 hRenin 
               
               
                   
                 at 
               
               
                   
                 100 
               
               
                 Compound 
                 μM 
               
               
                   
               
             
             
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 68.8 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 75.3 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 76.9 
               
               
                   
               
             
          
         
       
     
     In the aspect of the invention relating to a combination of a compound of formula I with a cholinesterase inhibitor, acetyl- and/or butyrylchlolinesterase inhibitors can be used. Examples of cholinesterase inhibitors are tacrine, donepezil, rivastigmine, galantamine, pyridostigmine and neostigmine, with tacrine, donepezil, 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 U.S. Pat. Nos. 5,883,096; 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 U.S. Pat. No. 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. 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 administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington&#39;s Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pa. 
     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 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, 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 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 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. 
     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. 
     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 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-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, 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 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 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, modifications and variations are intended to fall within the spirit and scope of the present invention.