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Title:
HETEROCYCLIC ASPARTYL PROTEASE INHIBITORS
Document Type and Number:
WIPO Patent Application WO/2005/058311
Kind Code:
A1
Abstract:
Disclosed are compounds of the formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof. 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.

Inventors:
ZHU ZHAONING (US)
MCKITTRICK BRIAN (US)
SUN ZHONG-YUE (US)
YE YUANZAN C (US)
VOIGT JOHANNES H (US)
STRICKLAND COREY (US)
SMITH ELIZABETH M (US)
STAMFORD ANDREW (US)
GREENLEE WILLIAM J (US)
WU YUSHENG (US)
ISERLOH ULRICH (US)
MAZZOLA ROBERT (US)
CALDWELL JOHN (US)
CUMMING JARED (US)
WANG LINGYAN (US)
GUO TAO (US)
LE THUY X H (US)
SAIONZ KURT W (US)
BABU SURESH D (US)
HUNTER RACHAEL C (US)
Application Number:
PCT/US2004/041700
Publication Date:
June 30, 2005
Filing Date:
December 13, 2004
Export Citation:
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Assignee:
SCHERING CORP (US)
PHARMACOPEIA DRUG DISCOVERY (US)
ZHU ZHAONING (US)
MCKITTRICK BRIAN (US)
SUN ZHONG-YUE (US)
YE YUANZAN C (US)
VOIGT JOHANNES H (US)
STRICKLAND COREY (US)
SMITH ELIZABETH M (US)
STAMFORD ANDREW (US)
GREENLEE WILLIAM J (US)
WU YUSHENG (US)
ISERLOH ULRICH (US)
MAZZOLA ROBERT (US)
CALDWELL JOHN (US)
CUMMING JARED (US)
WANG LINGYAN (US)
GUO TAO (US)
LE THUY X H (US)
SAIONZ KURT W (US)
BABU SURESH D (US)
HUNTER RACHAEL C (US)
International Classes:
C07D233/88; C07D235/02; C07D239/22; C07D271/07; C07D401/04; C07D401/06; C07D401/10; C07D401/12; C07D401/14; C07D403/04; C07D403/06; C07D403/10; C07D403/12; C07D403/14; C07D405/04; C07D405/06; C07D405/10; C07D405/12; C07D405/14; C07D407/14; C07D409/06; C07D409/10; C07D409/14; C07D413/06; C07D413/12; C07D413/14; C07D417/12; C07D271/06; (IPC1-7): A61K31/4168; A61K31/4178; C07D233/88; C07D239/22; C07D271/06; C07D401/04; C07D401/10; C07D401/12; C07D401/14; C07D403/06; C07D403/10; C07D403/14; C07D405/06; C07D405/14; C07D407/14
Domestic Patent References:
WO1990004917A11990-05-17
Foreign References:
Other References:
None
Attorney, Agent or Firm:
Lee, William Y. (Patent Department K-6-1 1990, 2000 Galloping Hill Roa, Kenilworth NJ, US)
Download PDF:
Claims:
We claim :
1. A compound having the structural formula or a stereoisomer, tautomer, or pharmaceutical acceptable salt or solvate thereof, wherein W is a bond, C(=S), S(O), S(O)2, C(=O), O, C(R6)(R7), N(R5) or C(=N(R5)); X isO,N (R5)orC (R6) (R7); provided that when X is O, U is not O, S(O), S(O) 2, C (=O) or C(=NR5); U is a bond,S (O),S (O) 2, C (O),O,P (O) (OR15), C(=NR5), (C(R6)(R7))b or N(R5); wherein b is 1 or 2; provided that when W isS (O),S (O) 2, O, orN (R5), U is notS (O),S (O) 2, O, orN (R5); provided that when X is N(R5) and W isS (O),S (O) 2, O, orN (R5), then U is not a bond; R', R2 and R5 are independently selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, OR15, CN, C(O)R8, C(O)OR9, S(O)R10, S(O)2R10, C(O)N(R11)(R12), S(O)N(R11)(R12), S(O)2N(R11)(R12), NO2, N=C(R8) 2 andN (R 8) 2, provided that R'and R5 are not both selected from NO2, N=C(R8) 2 andN (R°) 2; R3, R4, R6 and R7 are independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, CH2OSi(R9)(R10)(R19), SH, CN, OR9, C(O)R8, C(O)OR9, C(O)N(R11)(R12), SR19, S(O) N (R11)(R12), S(O)2N(R11)(R12), N(R11)(R12), N (R") C (O) R8,N (R") S (O) R10, N(R11)C(O) N (R12)(R13), N(R11) C (O) OR9 and C (=NOH) R8 ; provided that when U is O or N (R5), then R3, R4, R6 and R7 are not halo,SH,OR9,SR'9,S (O) N (R") (R12),S (O) 2N (R") (R12), N(R11)(R12), N(R11) C (O) R8,N (R") S (O) R10, N(R11)C(O) N (R12)(R13), or N(R11)C(O)OR9 ; provided that when W is O or N (R5), then R3 and R4 are not halo, SH,OR9,SR9,S (O) N (R11)(R12), S(O)2N(R11)(R12), N(R11)(R12), N (R") C (O) R8,N (R11) S (O) R10,N (R11) C (O) N (R'2) (R'3), orN (R") C (O) OR9 ; and provided that when X isN (R5), W isC (O) and U is a bond, R3, R4, R6 and R7 are not halo,CN,SH,OR9,SR'9,S (O) N (R11) (R12) orS (O) 2N (R11) (R12) ; or R3, R4, R6 and R7, together with the carbon to which they are attached, form a 37 membered cycloalkyl group optionally substituted by R'4 or a 37 membered cycloalkylether optionally substituted by R'4 or R3 and R4 or R6 and R7 together with the carbon to which they are attached, are combined to form multicyclic groups such as wherein M isCH2, S, N (R19) 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 R3, R4, R6 and R7 form said multicyclic groups then adjacent R3 and R4 or R6 and R7 groups cannot be combined to form said multicyclic groups; Ra is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, OR15, N(R15)(R16), N(R15)C(O)R16, N(R15)S(O)R16, N(R15)S(O)2R16, N(R15)S(O)2N(R16)(R17), N(R15)S(O)N(R16)(R17), N(R15)C(O)N(R16)(R17) and N(R15) C (O) OR ; R9 is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl ; R'° is independently selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl andN (R'5) (R'6) ; R", R12 and R13 are independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,C (O) R8,C (O) OR9,S (O) R10,S (O) 2R1°,C (o) N (R15) (R'6), S(O)N(R15)(R16), S(O)2N(R15)(R16) andCN; R14 is 15 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo,CN,OR C(O)R15, C(O)OR15, C(O)N(R15)(R16), SR15, S(O)N(R15)(R16), S(O)2N(R15)(R16), <BR> <BR> <BR> C(=NOR15)R16, P(O)(OR15)(OR16), N(R15)(R16), N(R15)C(O)R16, N(R15)S(O)R16,<BR> N(R15)S(O)2R16, N(R15)S(O)2N(R16)(R17), N(R15)S(O)N(R16)(R17), N(R15)C(O)N(R16)(R17) and N(R15) C (O) OR16 ; R15, R16 and R17 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, arylheterocycloalkyl, R18alkyl, R18cycloalkyl, R18cycloalkylalkyl, R18heterocycloalkyl, R18heterocycloalkylalkyl, R13aryl, R18arylalkyl, R'8heteroaryl and R18 heteroarylalkyl ; or R", R16 and R17 are wherein R23 numbers 0 to 5 substituents, m is 0 to 6 and n is 1 to 5; R'8 is 15 substituents independently selected from the group consisting of alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, arylalkynyl,N02, halo, heteroaryl, HO alkyoxyalkyl,CF3,CN, alkylCN,C (O) R'9,C (O) OH, C (O) OR'9,C (O) NHR20, C (O) NH2, C (O) NH2C (O) N (alkyl) 2, C (O) N (alkyl) (aryl),C (O) N (alkyl) (heteroaryl), SR'9,S (O) 2R2°,S (O) NH2, S (O) NH (alkyl),S (O) N (alkyl) (alkyl),S (O) NH (aryl), S (0) 2NH2, S (0) 2NHR'9,S (0) 2NH (heterocycloalkyl),S (O) 2N (alkyl) 2, S (0) 2N (alkyl) (aryl),OCF3,OH,OR20,Oheterocycloalkyl,Ocycloalkylalkyl,O heterocycloalkylalkyl,NH2,NHR20,N (alkyl) 2, N (arylalkyl) 2, N (arylalkyl) (heteroarylalkyl),NHC (O) R20,NHC (O) NH2, NHC (O) NH (alkyl), NHC(O) N (alkyl) (alkyl),N (alkyl) C (O) NH (alkyl),N (alkyl) C (O) N (alkyl) (alkyl), NHS (0) 2R2°,NHS (0) 2NH (alkyl),NHS (0) 2N (alkyl) (alkyl),N (alkyl) S (0) 2NH (alkyl) andN (alkyl) S (O) 2N (alkyl) (alkyl) ; or two R18 moieties on adjacent carbons can be linked together to form R'9 is alkyl, cycloalkyl, aryl, arylalkyl or heteroarylalkyl ; R20 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 R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13 and R are independently unsubstituted or substituted by 1 to 5 R21 groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, CN, OR15, C(O)R15, C(O)OR15, C(O) N (R'5) (R'6),SR'5, S(O)N(R15)(R16), CH(R15)(R16), S(O)2N(R15)(R16), C(=NOR15)R16, P(O)(OR15)(OR16), N(R15)(R16), alkylN(R15)(R16), N(R15)C(O)R16, CH2 N(R15)C(O)R16, CH2N(R15)C(O)N(R16(R17), CH2R15; CH2N(R15)(R16), N(R15)S(O)R16, N(R15)S(O)2R16, CH2N(R15)S(O)2R16, N(R15)S(O)2N(R16)(R17), <BR> <BR> <BR> N(R15)S(O)N(R16)(R17), N(R15)C(O)N(R16)(R17), CH2N(R15)C(O)N(R16)(R17),<BR> <BR> <BR> <BR> <BR> <BR> N(R15)C(O)OR16, CH2N(R15)C(O)OR16, S(O)R15, =NOR15, N3, NO2 and S(O)2R15; and wherein each of the alkyl, cycloalkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl groups in R21 are independently unsubstituted or substituted by 1 to 5 R22 groups independently selected from the group consisting of alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, halo,CF3,CN, OR15, C(O)R15, C(O)OR15, alkylC(O)OR15, C(O)N(R15)(R16), SR15, S(O)N(R15)(R16), S(O)2N(R15)(R16), C(=NOR15)R16, P(O)(OR15)(OR16), N(R15)(R16), alkylN(R15)(R16), N(R15)C(O)R16, CH2N(R15)C(O)R16, N(R15)S(O)R16, N(R15)S(O)2R16, CH2N(R15)S(O)2R16, N(R15)S(O)2N(R16)(R17), N(R15)S(O)N(R16)(R17), N(R15)C(O)N(R16)(R17), CH2N(R15)C(O)N(R16)(R17), N(R15)C(O)OR16, CH2N(R15)C(O)OR16, N3, =NOR15, NO2, S(O)R15 and S(O)2R15; or two R21 or two R22 moieties on adjacent carbons can be linked together to form and when R2'or R22 are selected from the group consisting of C(=NOR15)R16, N(R15)C(O)R16, CH2N(R15)C(O)R16, N(R15)S(O)R16, <BR> <BR> <BR> N(R15)S(O)2R16, CH2N(R15)S(O)2R16, N(R15)S(O)20(R16)(R17),<BR> N(R15)S(O)N(R16)(R17), N(R15)C(O)N(R16)(R17), CH2N(R15)C(O)N(R16)(R17), N(R15)C(O)OR16 and CH2N(R15)C(O)OR16, R15 and R16 together can be a C2 to C4 chain wherein, optionally, one, two or three ring carbons can be replaced byC (O) orN (H) and R'5 and R'6, together with the atoms to which they are attached, form a 5 to 7 membered ring, optionally substituted by R23 ; R23 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,OR24, C(O)R24, C(O)OR24, C(O)N(R24)(R25), SR24, S(O)N(R24)(R25), S(O)2N(R24)(R25), C(=NOR24)R25, P(O)(OR24)(OR25), N(R24)(R25), alkylN(R24)(R25), N(R24)C(O)R25, CH2N(R24)C(O)R25, N(R24)S(O)R25, N(R24)S(O)2R25, CH2N(R24)S(O)2R25, N(R24)S(O)2N(R25)(R26), N(R24)S(O)N(R25)(R26), N(R24)C(O)N(R25)(R26), 24 (o) N (R25) (R26),N (R24) C (O) OR25,CH2N (R24) C (O) OR, () S (O) 2R24 ; and wherein each of the alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl groups in R23 are independently unsubstituted or substituted by 1 to 5 R27 groups independently selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo,CF3,CN,OR24,C (O) R24,C (O) OR24, alkylC (O) OR24, C(O)N(R24)(R25), SR24, S(O) N (R24)(R25), S(O)2N(R24)(R25), C(=NOR24)R25, P(O)(OR24)(OR25), N(R24)(R25), alkylN(R24)(R25), N(R24)C(O)R25, CH2N(R24)C(O)R25, N(R24)S(O)R25, N(R24)S(O)2R25, CH2N(R24)S(O)2R25, N(R24)S(O)2N(R25)(R26), N(R24)S(O)N(R25)(R26), N(R24)C(O)N(R25)(R26), CH2N (R24) C (O) N (R250(R26), N(R24) C (O) OR25,CH2N (R24) C (O) OR25, S(O)R24 and S(O)2R24; R24, R25 and R26 are independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, R27alkyl, R27cycloalkyl, R27cycloalkylalkyl, R27heterocycloalkyl, R27heterocycloalkylalkyl, R27aryl, R27arylalkyl, R27heteroaryl and R27heteroarylalkyl ; R27 is 15 substituents independently selected from the group consisting of alkyl, aryl, arylalkyl,N02, halo,CF3,CN, alkylCN,C (O) R28,C (O) OH, C (O) OR C (O) NHR29,C (O) N (alkyl) 2, C (O) N (alkyl) (aryl),C (O) N (alkyl) (heteroaryl),SR S(O)2R29, S(O) NH2, S (O) NH (alkyl),S (O) N (alkyl) (alkyl),S (O) NH (aryl),S (0) 2NH2, S(O)2NHR28, S(O) 2NH (aryl),S (0) 2NH (heterocycloalkyl),S (O) 2N (alkyl) 2, S (0) 2N (alkyl) (aryl),OH,OR29,Oheterocycloalkyl,Ocycloalkylalkyl, Oheterocycloalkylalkyl, NH2, NHR29, N(alkyl) 2, N (arylalkyl) 2, N(arylalkyl)(heteroarylalkyl), NHC(O)R29, NHC(O) NH2, NHC (O) NH (alkyl), NHC(O) N (alkyl) (alkyl),N (alkyl) C (O) NH (alkyl),N (alkyl) C (O) N (alkyl) (alkyl), NHS(O)2R29, NHS(O) 2NH (alkyl),NHS (0) 2N (alkyl) (alkyl),N (alkyl) S (0) 2NH (alkyl) andN (alkyl) S (O) 2N (alkyl) (alkyl) ; R 28 is alkyl, cycloalkyl, arylalkyl or heteroarylalkyl ; and R29 is alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl ; provided that when W isC (O) and U is a bond, R'is not optionally substituted phenyl, and that when U isC (O) and W is a bond, R5 is not optionally substituted phenyl ; provided that neither R'nor R5 isC (O)alkylazetidinone or alkyl disubstituted with (COOR15 orC (O) N (R'5) (R'6)) and (N (R15)(R16), N(R15) C (O) R 16, N(R15)S(O)R16, N(R15)S(O)2R16, N(R15)S(O)2N(R16)(R17), N(R15)S(O)N(R16)(R17), N(R15) C (O) N (R16)(R17), or N(R15) C (O) OR16) ; provided that when R'is methyl, X isN (R5), R2 is H, W isC (O) and U is a bond, (R3, R4) is not (H, H), (phenyl, phenyl), (H, phenyl), (benzyl, H), (benzyl, phenyl), (ibutyl, H), (ibutyl, phenyl), (OHphenyl, phenyl), (halophenyl, phenyl), or (CH3Ophenyl, N02phenyl) ; and when W is a bond and U isC (O), (R3, R4) is not (H, H), (phenyl, phenyl), (H, phenyl), (benzyl, H), (benzyl, phenyl), (ibutyl, H), (ibutyl, phenyl), (OHphenyl, phenyl), (halophenyl, phenyl), or (CH3Ophenyl, N02phenyl) ; provided that when X isN (R5), R'and R5 are each H, W isC (O) and U is a bond, (R3, R4) is not (optionally substituted phenyl, optionally substituted benzyl), (optionally substituted phenyl, heteroarylalkyl) or (heteroaryl, heteroarylalkyl) ; provided that when U is a bond, W isC (O), and R3 and R4 form a ring with the carbon to which they are attached, R'is not 2CF33CNphenyl ; provided that when X isN (R5), U isOand W is a bond orC (R (R7), (R3, R4) is not (H,NHC (O)alkylheteroaryl) or (H, alkylNHC (O)alkylheteroaryl) ; and provided that when X isN (R5), R1 and R5 are not alkylarylarylSO2 N (R15)(R16) wherein R'5 is H and R16 is heteroaryl ; provided that when R1 is R21aryl or R21arylalkyl, wherein R21 is OCF3, S(O) CF3, S (0) 2CF3, S (O) alkyl,S (O) 2alkyl,S (O) 2CHF2, S (O) 2CF2CF3, OCF2CHF2, OCHF2, OCH2CF3, SF5 orS (O) 2NR15R16 ; wherein R'5 and R16 are independently selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, R'8alkyl, R'$cycloalkyl, R'8 heterocycloalkyl, R'8aryl and R18heteroaryl ; U is a bond orCH2; and X isN (R5); then R5 is H; provided that when U is a bond, R3 and R4 are alkyl, where R21 is halo,CN, alkyl, alkoxy, haloalkyl or haloalkoxy, or R3 and R4, together with the carbon to which they are attached, form a 37 membered cycloalkyl group, and R'is where a is 0 to 6 and R22 is alkyl, alkoxy, halo,CN,OH,N02 or haloalkyl ; then R21a is not H,C (O) 2R15, wherein R15 is selected from the group consisting of alkyl, cycloalkyl and alkyl substituted with phenyl, alkyl or alkylR22, wherein R22 is selected from the group consisting of phenyl, phenyl substituted with alkyl, wherein R22 is selected from the group consisting of H, methoxy, nitro, oxo,OH, halo and alkyl,.
2. A compound of claim 1 having the structure IA IB IC ID IE IF IG or IH.
3. A compound of claim 2 wherein in structures IA to IF, U is a bond or C (R6) (R7).
4. A compound of claim 2 wherein in structure IB, U is a bond.
5. A compound of claim 2 of the structure IB wherein U isC (R6) (R7).
6. A compound of claim 1 wherein R2 is H.
7. A compound of claim 1 wherein R3, R4, R6 and R7 are independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo,CH2O Si(R9)(R10)(R19), SH, CN, OR9, C(O)R8, C(O)OR9, C(O)N(R11)(R12), SR19, <BR> <BR> S(O)N(R11)(R12), S(O)2N(R11)(R12), N(R11)(R12), N(R11)C(O)R8, N(R11)S(O)R10,<BR> N(R11)C(O)N(R12)(R13), N(R11)C(O)OR9 and C(=NOH)R8.
8. A compound of claim 1 wherein R3, R4, R6 and R7 are selected from the group consisting of aryl, heteroaryl, heteroarylalkyl, arylalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, alkyl and cycloalkylalkyl.
9. A compound of claim 1 wherein U is a bond orC (O) ; W is a bond orC (O) ; X isN (R5); R'is H, alkyl, R2'alkyl, arylalkyl, R2'arylalkyl, cycloalkylalkyl, R2' cycloalkylalkyl, heterocycloalkyalkyl or R2'heterocycloalkylalkyl, R2 is H; R3 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R2'alkyl, R2' cycloalkylalkyl, R2'cycloalkyl, R2'aryl or R21arylalkyl ; R4 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R21alkyl, R21 cycloalkylalkyl, R21cycloalkyl, R21aryl or R21arylalkyl ; R5 is H, alkyl, R21alkyl, arylalkyl, R21arylalkyl, cycloalkylalkyl, R21 cycloalkylalkyl, heterocycloalkyalkyl or R21heterocycloalkylalkyl ; R6 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R21alkyl, R21 cycloalkylalkyl, R2cycloalkyl, R2'aryl or R21arylalkyl ; R7 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R21alkyl, R21 cycloalkylalkyl, R2'cycloalkyl, R2aryl or R21arylalkyl ; R", R16 and R17 is H, R18alkyl, alkyl or R21 is alkyl, aryl, halo, OR15, NO2, C(O)R15, CH2N(R15) C (O) N (R16)(R17) or CH(R15)(R16) ; n is 1 ; m is 1 ; R18 is OR20 R20 is aryl ; and R23 is alkyl.
10. A compound of claim 9 wherein R3, R4, R6 and R7 are and R'and R5 is H, CH3,.
11. A compound selected from the group consisting of:.
12. A compound of claim 1 wherein U is a bond orC (O) ; W is a bond orC (O) ; X isN (R5) ; R'is H, alkyl, R21alkyl, arylalkyl, R21arylalkyl, cycloalkylalkyl, R21 cycloalkylalkyl, heterocycloalkyalkyl or R21heterocycloalkylalkyl, R2 is H; R3 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R21alkyl, R21 cycloalkylalkyl, R21cycloalkyl, R21aryl, R21arylalkyl, heteroarylalkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl, R21heteroarylalkyl, R21heteroaryl, R21 heterocycloalkyl or R21heterocycloalkylalkyl ; R4 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R21alkyl, R21 cycloalkylalkyl, R21cycloalkyl, R21aryl, R21arylalkyl, heteroarylalkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl, R2'heteroarylalkyl, R21heteroaryl, R2' heterocycloalkyl or R2'heterocycloalkylalkyl ; R5 is H, alkyl, R21alkyl, arylalkyl, R21arylalkyl, cycloalkylalkyl, R21 cycloalkylalkyl, heterocycloalkyalkyl or R21heterocycloalkylalkyl ; R6 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R21alkyl, R21 cycloalkylalkyl, R2'cycloalkyl, R2'aryl, R2'arylalkyl, heteroarylalkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl, R2'heteroarylalkyl, R21heteroaryl, R21 heterocycloalkyl or R21heterocycloalkylalkyl ; R7 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R21alkyl, R21 cycloalkylalkyl, R2'cycloalkyl, R2'aryl, R2'arylalkyl, heteroarylalkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl, R21heteroarylalkyl, R21heteroaryl, R21 heterocycloalkyl or R21heterocycloalkylalkyl ; R15, R16 and R'7 is H, cycloalkyl, cycloalkylalkyl, R'8alkyl, alkyl, aryl, R'8aryl, R18arylalkyl, arylalkyl, n is 1 or 2 ; m is 0 or 1 ; R18 is OR20 or halo ; R20 is aryl or halo substituted aryl ; R21 is alkyl, aryl, heteroaryl, R22alkyl, R22aryl, R22heteroaryl, halo, heterocycloalkyl,N (R15)(R16), OR15, NO2, C(O)R15, N(R15) C (O) R16, N(R15) S (O) 2R,CH2N (R15) C (O) N (R16)(R17), N(R15) C (O) N (R16)(R17) or CH(R15)(R16); R22 isOR'S or halo and R23 is H or alkyl.
13. A compound selected from the group consisting of:.
14. A pharmaceutical composition comprising an effective amount of a compound of claim 1 and a pharmaceutical effective carrier.
15. A method of inhibiting aspartyl protease comprising administering to a patient in need of such treatment an effective amount of a compound of claim 1.
16. A method of treating cardiovascular diseases, cognitive and neurodegenerative diseases, and the methods of inhibiting of Human Immunodeficiency Virus, plasmepins, cathepsin D and protozoal enzymes. comprising administering to a patient in need of such treatment an effective amount of a compound of claim 1.
17. The method of claim 16 wherein a cognitive or neurodegenerative disease is treated.
18. The method of claim 17 wherein Alzheimer's disease is treated.
19. A pharmaceutical composition comprising an effective amount of a compound of claim 1, and an effective amount of a cholinesterase inhibitor or a muscarinic antagonist in a pharmaceutical effective carrier.
20. A method of treating a cognitive or neurodegenerative disease comprising administering to a patient in need of such treatment an effective amount of a compound of claim 1 in combination with an effective amount of a cholinesterase inhibitor.
Description:
HETEROCYCLIC ASPARTYL PROTEASE INHIBITORS 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, etal. N Engl J Med 1974; 291: 381-401/446-57). The octapeptide Angiotensin-11, a potent vasoconstrictor and stimulator for release of adrenal aldosterone, was processed from the precursor decapeptide Angiotensin-l, which in turn was processed from angiotensinogen by the renin enzyme. Angiotensin-) ! 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-)) through antagonism of conversion of angiotensin-l 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-l, 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-if 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'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 ß-amyloid (Aß) plaques and intracellular neurofibrillary tangles comprised of abnormally phosphorylated protein tau. Individuals with AD exhibit characteristic Ap deposits, in brain regions known to be important for memory and cognition. It is believed that Ap is the fundamental causative agent of neuronal cell loss and dysfunction which is associated with cognitive and behavioral decline. Amyloid plaques consist predominantly of Ap 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. Ap peptides result from the cleavage of APP by p-secretase at the position corresponding to the N-terminus of Ap, and at the C- terminus by y-secretase activity. APP is also cleaved by a-secretase activity resulting in the secreted, non-amyloidogenic fragment known as soluble APP.

An aspartyl protease known as BACE-1 has been identified as the p-secretase activity responsible for cleavage of APP at the position corresponding to the N- terminus of Ap peptides.

Accumulated biochemical and genetic evidence supports a central role of Ap in the etiology of AD. For example, Ap 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 AD and are considered causative of AD.

Since AD peptides are formed as a result ß-secretase activity, inhibition of BACE-1 should inhibit formation of AD peptides. Thus inhibition of BACE-1 is a therapeutic approach to the treatment of AD and other cognitive and neurodegenerative diseases caused by AD 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 55th Southeast Regional Meeting of the American Chemical Society, Atlanta, GA, US November 16-19,2003 (2003), 1073. CODEN; 69EUCH Conference, AN 2004: 137641 CAPLUS.

Plasmepsins are essential aspartyl protease enzymes of the malarial parasite.

Compounds for the inhibition of aspartyl proteases plasmepsins, particularly l, ll, 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 1

or a stereoisomer, tautomer, or pharmaceutical acceptable salt or solvate thereof, wherein W is a bond, -C (=S)-,-S (O)-,-S (O) 2-, -C (=O)-,-O-,-C (R (R7)-, -N(R5)- or -C (=N (R5))-; X is-O-,-N (R5)-or-C (R6) (R7)-; provided that when X is -O-, U is not -O-, -S(O)-, -S(O) 2-, -C (=O)- or -C(=NR5)-; U is a bond,-S (O)-,-S (O) 2-, -C (O)-,-O-,-P (O) (OR15)-, -C(=NR5)-, -(C(R6)(R7))b- or -N(R5)-; wherein b is 1 or 2; provided that when W is-S (O)-,-S (O) 2-, -O-, or-N (R5)-, U is not-S (O)-,-S (O) 2-, -O-, or-N (R5)-; provided that when X is- N (R5)-and W is-S (O)-,-S (O) 2-, -O-, or-N (R5)-, then U is not a bond; R', R2 and R5 are independently selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, -OR15, -CN, -C(O)R8, -C(O)OR9, -S(O)R10, -S(O)2R10, -C(O)N(R11)(R12), -S(O)N(R11)(R12), -S(O)2N(R11)(R12), -NO2, -N=C(R8)2 and -N(R8) 2, provided that R'and R5 are not both selected from - N02,-N=C (R8) 2 and-N (R8) 2; R3, R4, R6 and R7 are independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, -CH2-O-Si(R9)(R10)(R19), -SH, -CN, -OR9, -C(O)R8, -C(O)OR9, -C(O)N(R11)(R12), -SR19, -S(O) N (R11)(R12), -S(O)2N(R11)(R12), -N(R11)(R12), -N(R11) C (O) R8, -N (R11) S (O) R10, -N (R") C (O) N (R12)(R13), -N(R11) C (O) OR9 and - C (=NOH) R8 ; provided that when U is -O- or -N (R5)-, then R3, R4, R6 and R7 are not halo,-SH,-OR9,-SR'9,-S (O) N (R11)(R12), -S(O)2N(R11)(R12), -N(R11)(R12), -N(R11)C(O)R8, -N(R11)S(O)R10, -N(R11) C (O) N (R12)(R13), or -N(R11) C (O) OR9 ; provided that when W is -O- or -N (R5)-, then R3 and R4 are not halo, -SH, -OR9, -SR19, -S(O) N (R11)(R12), -S(O)2N(R11)(R12), -N(R11)(R12), - N (R") C (O) R8,-N (R") S (O) R'°,-N (R") C (O) N (R12)(R13), or-N (R") C (O) OR9 ;

and provided that when X is-N (R5)-, W is-C (O)- and U is a bond, R3, R4, R5 and R7 are not halo,-CN,-SH,-OR9,-SR'9,-S (O) N (R") (R12) or-S (O) 2N (R") (R12) ; or R3 R4, R6 and R7, together with the carbon to which they are attached, form a 3-7 membered cycloalkyl group optionally substituted by R'4 or a 3-7 membered cycloalkylether optionally substituted by R14 ; or R3and R4or R6and R7together with the carbon to which they are attached, are combined to form multicyclic groups such as wherein M is-CH2-, S,-N (R19)- 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 R3, R4, R6 and R7 form said multicyclic groups then adjacent R3 and R4 or R6 and R7 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, arylalyl, heteroaryl, heteroarylalkyl, -OR15, -N(R15)(R16), -N(R15)C(O)R16, -N(R15)S(O)R16, -N(R15)S(O)2R16, -N(R15)S(O)2N(R16)(R17), -N(R15)S(O)N(R16)(R17), -N(R15)C(O)N(R16)(R17) and -N(R15)C(O)OR16; R9 is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl ;

Rlo is independently selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl and-N (R15) (Rl6) ; R", R12 and R13 are independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -C(O)R8, -C(O)OR9, -S(O)R10, -S(O)2R10, -C(O) N (R15)(R16), - S (O) N (R15) (Rl6)-S (O) 2N (R15)(R16) and-CN; R14 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 -C(O)R15, -C(O)OR15, -C(O)N(R15)(R16), -SR15, -S(O)N(R15)(R16), -S(O)2N(R15)(R16), -C(=NOR15)R16, -P(O)(OR15)(OR16), -N(R15)(R16), -N(R15)C(O)R16, -N(R15)S(O)R16, <BR> <BR> <BR> <BR> <BR> <BR> <BR> -N(R15)S(O)2R16, -N(R15)S(O)2N(R16)(R17), -N(R15)S(O)N(R16)(R17),<BR> -N(R15)C(O)N(R16)(R17) and -N(R15)C(O)OR16; R15, R16 and R17 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, arylheterocycloalkyl, R18-alkyl, R18-cycloalkyl, R18-cycloalkylalkyl, R18-heterocycloalkyl, R18-heterocycloalkylalkyl, R18-aryl, R18-arylalkyl, R18-heteroaryl and R'8- heteroarylalkyl ; or R15, R16 and R17 are wherein R23 numbers 0 to 5 substituents, m is 0 to 6 and n is 1 to 5; R'8 is 1-5 substituents independently selected from the group consisting of alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, arylalkynyl,-N02, halo, heteroaryl, HO- alkyoxyalkyl,-CF3,-CN, alkyl-CN,-C (O) R'9,-C (O) OH, -C (O) OR19, -C (O) NHR20, -C(O) NH2, -C (O) NH2-C (O) N (alkyl) 2, -C (O) N (alkyl) (aryl),-C (O) N (alkyl) (heteroaryl), - SR'9,-S (O) 2R2°,-S (O) NH2, -S (O) NH (alkyl),-S (O) N (alkyl) (alkyl),-S (O) NH (aryl), -S(O) 2NH2, -S (0) 2NHR'9,-S (0) 2NH (heterocycloalkyl),-S (O) 2N (alkyl) 2, - S (0) 2N (alkyl) (aryl),-OCF3,-OH,-OR20,-O-heterocycloalkyl,-O-cycloalkylalky l,-O-

heterocycloalkylalkyl,-NH2,-NHR20,-N (alkyl) 2, -N (arylalkyl) 2, -N (arylalkyl)- (heteroarylalkyl),-NHC (O) R20,-NHC (O) NH2, -NHC (O) NH (alkyl), -NHC(O) N (alkyl) (alkyl),-N (alkyl) C (O) NH (alkyl),-N (alkyl) C (O) N (alkyl) (alkyl), -NHS (0) 2R2°,-NHS (0) 2NH (alkyl),-NHS (0) 2N (alkyl) (alkyl),-N (alkyl) S (0) 2NH (alkyl) and-N (alkyl) S (O) 2N (alkyl) (alkyl) ; or two R18 moieties on adjacent carbons can be linked together to form R'9 is alkyl, cycloalkyl, aryl, arylalkyl or heteroarylalkyl ; R20 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', R, R, R, R5, R, R, R8, R9, R10 R", R R13 and R14 independently unsubstituted or substituted by 1 to 5 R21 groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, -CN, -OR15, -C(O)R15, -C(O)OR15, -C(O) N (R15) (R16),-SR15 -S(O)N(R15)(R16), -CH(R15)(R16), -S(O)2N(R15)(R16), -C(=NOR15)R16, - P(O)(OR15)(OR16), -N(R15)(R16), -alkyl-N(R15)(R16), -N(R15)C(O)R16, -CH2- N(R15)C(O)R16, -CH2-N(R15)C(O)N(R16)(R17), -CH2-R15; -CH2N(R15)(R16), -N(R15)S(O)R16, -N(R15)S(O)2R16, -CH2-N(R15)S(O)2R16, -N(R15)S(O)2N(R16)(R17), -N(R15)S(O)N(R16)(R17), -N(R15)C(O)N(R16)(R17), -CH2-N(R15)C(O)N(R16)(R17), -N(R15)C(O)OR16, -CH2-N(R15)C(O)OR16, -S(O)R15, =NOR15, -N3, -NO2 and-S (O) 2R15 ; and wherein each of the alkyl, cycloalkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl groups in R21 are independently unsubstituted or substituted by 1 to 5 R22 groups independently selected from the group consisting of alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, halo,-CF3,-CN, -OR15, -C(O)R15, -C(O)OR15, -alkyl-C(O)OR15, C(O)N(R15)(R16), -SR15, -S(O)N(R15)(R16), -S(O)2N(R15)(R16), -C(=NOR15)R16, -P(O)(OR15)(OR16), <BR> <BR> <BR> -N(R15)(R16), -alkyl-N(R15)(R16), -N(R15)C(O)R16, -CH2-N(R15)C(O)R16, -N(R15)S(O)R16,<BR> -N(R15)S(O)2R16, -CH2-N(R15)S(O)2R16, -N(R15)S(O)2N(R16)(R17),

-N(R15)S(O0N(R16)(R17), -N(R15)C(O)N(R16)(R17), -CH2-N(R15)C(O)N(R16)(R17), <BR> <BR> -N(R15)C(O)OR16, -CH2-N(R15)C(O)OR16, -N3, =NOR15, -NO2, -S(O)R15 and -S(O)2R15; or two R21 or two R22 moieties on adjacent carbons can be linked together to form and when R21 or R22 are selected from the group consisting of -C(=NOR15)R16, -N(R15)C(O)R16, -CH2-N(R15)C(O)R16, -N(R15)S(O)R16, -N(R15)S(O)2R16, -CH2-N(R15)S(O)2R16, -N(R15)S(O)2N(R16)(R17), -N(R15)S(O)N(R16)(R17), -N(R15)C(O)N(R16)(R17), -CH2-N(R15)C(O)N(R16)(R17), -N(R15)C(O)OR16 and -CH2-N(R15) C (O) oR16 R15 and R16 together can be a C2 to C4 chain wherein, optionally, one, two or three ring carbons can be replaced by-C (O)- or-N (H)- and R and R, together with the atoms to which they are attached, form a 5 to 7 membered ring, optionally substituted by R23 ; R23 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,-OR24, -C(O)R24, -C(O)OR25, -C(O)N(R25)(R25), -SR24, -S(O)N(R24)(R25), -S(O)2N(R24)(R25), -C(=NOR24)R25, -P(O)(OR24)(OR25), -N(R24)(R25), -alkyl-N(R24)(R25), -N(R24)C(O)R25, -CH2-N(R24)C(O)R25, -H(R24)S(O)R25, -N(R24)S(O)2R25, -CH2-N(R24)S(O)2R25, <BR> <BR> <BR> <BR> <BR> <BR> -N(R24)S(O)2N(R25)(R26), -N(R24)S(O)N(R25)(R26), -N(R24)C(O)N(R25)(R26),<BR> -CH2-N(R24)C(O)N(R25)(R26), -N(R24)C(O)OR25, -CH2-N(R24)C(O)OR25, -S(O)R24 and -S(O)2R24; and wherein each of the alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl groups in R23 are independently unsubstituted or substituted by 1 to 5 R27 groups independently selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo,-CF3,-CN,-OR24,-C (O) R24,-C (O) OR24, alkyl-C (O) OR24, C(O)N(R24)(R25), -SR24, -S(O)N(R24)(R25), -S(O)2N(R24)(R25), -C(=NOR24)R25, -P(O)(OR24)(OR25), -N(R24)(R25), -alkyl-N(R24)(R25), -N(R24)C(O)R25, -CH2-N(R24)C(O)R25, -N(R24)S(O)R25, -N(R24)S(O)2R25, -CH2-N(R24)S(O)2R25, <BR> <BR> <BR> <BR> <BR> <BR> -N(R24)S(O)2N(R25)(R26), -N(R24)S(O)N(R25)(R26), -N(R24)C(O)N(R25)(R26),<BR> -CH2-N(R24)C(O)N(R25)(R26), -N(R24)C(O)OR25, -CH2-N(R24)C(O)OR25, -S(O)R24 and -S(O)2R24;

R24, R25 and R26 are independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, R27-alkyl, R27-cycloalkyl, R27-cycloalkylalkyl, R27-heterocycloalkyl, R27-heterocycloalkylalkyl, R27-aryl, R27-arylalkyl, R27-heteroaryl and R27-heteroarylalkyl ; R27 is 1-5 substituents independently selected from the group consisting of alkyl, aryl, arylalkyl,-N02, halo,-CF3,-CN, alkyl-CN,-C (O) R28,-C (O) OH, -C (O) OR -C (O) NHR29,-C (O) N (alkyl) 2, -C (O) N (alkyl) (aryl),-C (O) N (alkyl) (heteroaryl),-SR28, -S(O)2R29, -S(O) NH2, -S (O) NH (alkyl),-S (O) N (alkyl) (alkyl),-S (O) NH (aryl),-S (O) 2NH2, -S(O)2NHR28, -S(O) 2NH (aryl),-S (0) 2NH (heterocycloalkyl),-S (O) 2N (alkyl) 2, - S (0) 2N (alkyl) (aryl),-OH,-OR29,-O-heterocycloalkyl,-O-cycloalkylalkyl, -O-heterocycloalkylalkyl, -NH2, -NHR29, -N(alkyl) 2, -N (arylalkyl) 2, -N(arylalkyl)(heteroarylalkyl), -NHC(O)R29, -NHC(O) NH2, -NHC (O) NH (alkyl), -NHC(O) N (alkyl) (alkyl),-N (alkyl) C (O) NH (alkyl),-N (alkyl) C (O) N (alkyl) (alkyl), -NHS(O)2R29, -NHS(O) 2NH (alkyl),-NHS (0) 2N (alkyl) (alkyl),-N (alkyl) S (0) 2NH (alkyl) and-N (alkyl) S (O) 2N (alkyl) (alkyl) ; R28 is alkyl, cycloalkyl, arylalkyl or heteroarylalkyl ; and R29 is alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl ; provided that when W is-C (O)- and U is a bond, R'is not optionally substituted phenyl, and that when U is-C (O)- and W is a bond, R5 is not optionally substituted phenyl ; provided that neither R'nor R5 is-C (O)-alkyl-azetidinone or alkyl di-substituted with (-COOR15 or-C (O) N (R15) (R16)) and (-N (R15) (R16), -N(R15) C (O) R 16, -N(R15)S(O)R16, -N(R15)S(O)2R16, -N(R15)S(O)2N(R16)(R17), -N(R15)S(O)N(R16)(R17), -N(R15) C (O) N (R16)(R17), or -N(R15) C (O) OR16) ; provided that when R'is methyl, X is-N (R5)-, R2 is H, W is-C (O)- and U is a bond, (R3, R4) 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 (CH3O-phenyl, N02-phenyl) ; and when W is a bond and U is-C (O)-, (R3, R4) 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 (CH3O-phenyl, N02-phenyl) ; provided that when X is-N (R5)-, R'and R5 are each H, W is-C (O)- and U is a bond, (R3, R4) 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 R3 and R4 form a ring with the carbon to which they are attached, R'is not 2-CF3-3-CN-phenyl ; provided that when X is-N (R5)-, U is-O-and W is a bond or-C (R6) (R7)-, (R3,R4) is not (H,-NHC (O)-alkyl-heteroaryl) or (H, alkyl-NHC (O)-alkyl-heteroaryl) ; and provided that when X is-N (R5)-, R'and R5 are not-alkylaryl-aryl-S02- N (R15)(R16) wherein R15 is H and R16 is heteroaryl ; provided that when R1 is R21-aryl or R21-arylalkyl, wherein R21 is -OCF3, -S(O) CF3, -S (0) 2CF3,-S (O) alkyl,-S (O) 2alkyl,-S (0) 2CHF2, -S (0) 2CF2CF3, -OCF2CHF2, -OCHF2, -OCH2CF3, -SF5 or-S (O) 2NR15R16 ; wherein R15 and R16 are independently selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, R18-alkyl, R18-cycloalkyl, R18- heterocycloalkyl, R18-aryl and R18-heteroaryl ; U is a bond or-CH2; and X is-N (R5)-; then R5 is H; provided that when U is a bond, R3 and R4 are alkyl, where R is halo,-CN, alkyl, alkoxy, haloalkyl or haloalkoxy, or R3 and R4, together with the carbon to which they are attached, form a 3-7 membered cycloalkyl group, and R'is where a is 0 to 6 and R22 is alkyl, alkoxy, halo,-CN,-OH,-N02 or haloalkyl ;

then R is not H,-C (O) 2R, wherein R is selected from the group consisting of alkyl, cycloalkyl and alkyl substituted with phenyl, alkyl or alkyl-R22, wherein R22 is selected from the group consisting of phenyl, phenyl substituted with alkyl, wherein R22 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 pharmaceutical 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's Disease;

the method of inhibiting plasmepins and)) for treatment of malaria ; the method of inhibiting Cathepsin D for the treatment of Alzheimer's Disease, breast cancer, and ovarian cancer; and the method of inhibiting protozoal enzymes, for example inhibition of plasmodium falciparnum, for the treatment of fungal infections. Said method of treatment comprise administering at least one compound of formula I to a patient in need of such treatment. In particular, the invention comprises the method of treating Alzheimer's disease comprising administering at least one compound of formula I to a patient in need of such treatment.

In another aspect, the invention comprises the method of treating Alzheimer's 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 pharmaceutical acceptable carrier and a second container comprises a cholinesterase inhibitor or a muscarinic antagonist in a pharmaceutical acceptable carrier, the combined quantities being an effective amount to treat a cognitive disease or neurodegenerative disease such as Alzheimer's disease.

DETAILED DESCRIPTION : Compounds of formula I wherein X, W and U are as defined above include the following independently preferred structures: IA IB IC ID

IE IF IG IH In compounds of formulas IA to IF, U is preferably a bond or-C (R6) (R7)-. In compounds of formula IG and IH, U is preferably-C (O)-.

It will be understood that since the definition of R'is the same as the definition of R5, when X is-N (R5)-, compounds of formula I wherein W is a bond and U is a <BR> <BR> <BR> bond, -S (O)-,-S (O) 2-, -C (O)-,-O-,-C (R (R7)- or -N(R5)- are equivalent to compounds<BR> <BR> <BR> <BR> <BR> of formula I wherein U is a bond and W is a bond,-S (O)-,-S (O) 2-, -C (O)-,-O-, -C(R6)(R7)- or -N(R5)-.

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 (R7)-.

Another group of preferred compounds of formula I is that wherein R2 is H.

R3, R4, R6 and R7 are preferably selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, -CH2-O-Si(R9)(R10)(R19), -SH, -CN, -OR9, -C(O)R8, -C(O)OR9, -C(O)N(R11)(R12), -SR19, -S(O)N(R11)(R12), -S(O)2N(R11)(R12), -N(R11)(R12), -N(R11)C(O)R8, -N(R11)S(O)R10, -N(R11)C(O)N(R12)(R13), -N(R11)C(O)OR9 and -C(=NOH)R8.

R3, R4, R6 and R7 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 (R5)- ; R'is H, alkyl, R21-alkyl, arylalkyl, R21-arylalkyl, cycloalkylalkyl, R21- cycloalkylalkyl, heterocycloalkyalkyl or R21-heterocycloalkylalkyl, R2 is H; R3 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R21-alkyl, R21- cycloalkylalkyl, R21-cycloalkyl, R21-aryl or R21-arylalkyl ; R4 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R21-alkyl, R21- cycloalkylalkyl, R21-cycloalkyl, R21-aryl or R21-arylalkyl ; R5 is H, alkyl, R21-alkyl, arylalkyl, R21-arylalkyl, cycloalkylalkyl, R21- cycloalkylalkyl, heterocycloalkyalkyl or R21-heterocycloalkylalkyl ; R6 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R21-alkyl, R21- cycloalkylalkyl, R21-cycloalkyl, R21-aryl or R21-arylalkyl ; R7is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R21-alkyl, R21- cycloalkylalkyl, R21-cycloalkyl, R21-aryl or R21-arylalkyl ;

R15, R16 and R17 si H, R18-alkyl, alkyl or R21 is alkyl, aryl, halo, -OR15, -NO2, -C(O)R15, -CH2-N(R15) C (O) N (R16)(R17) or -CH(R15)(R16); n is 1 ; m is 1 ; R18 is -OR20 R20 is aryl ; and R23 is alkyl.

In a group of preferred compounds R3 R4 R6and R7are and R'and R5 is H, CH3, In an additional group of preferred compounds; U is a bond or-C (O)- ; W is a bond or-C (O)- ; X is-N (R5)- ;

R'is H, alkyl, R2'-alkyl, arylalkyl, R2'-arylalkyl, cycloalkylalkyl, R2'- cycloalkylalkyl, heterocycloalkyalkyl or R2'-heterocycloalkylalkyl, R2 is H; R3 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R2'-alkyl, R21- cycloalkylalkyl, R21-cycloalkyl, R21-aryl, R21-arylalkyl, heteroarylalkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl, R2'-heteroarylalkyl, R2'-heteroaryl, R21- heterocycloalkyl or R21-heterocycloalkylalkyl ; R4 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R2'-alkyl, R21- cycloalkylalkyl, R21-cycloalkyl, R21-aryl, R21-arylalkyl, heteroarylalkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl, R2'-heteroarylalkyl, R2'-heteroaryl, R2'- heterocycloalkyl or R2'-heterocycloalkylalkyl ; R5 is H, alkyl, R2'-alkyl, arylalkyl, R21-arylalkyl, cycloalkylalkyl, R21- cycloalkylalkyl, heterocycloalkyalkyl or R21-heterocycloalkylalkyl ; R6 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R2'-alkyl, R21_ cycloalkylalkyl, R21-cycloalkyl, R21-aryl, R21-arylalkyl, heteroarylalkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl, R21-heteroarylalkyl, R21-heteroaryl, R21- heterocycloalkyl or R21-heterocycloalkylalkyl ; R7 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R21-alkyl, R21- cycloalkylalkyl, R21-cycloalkyl, R21-aryl, R21-arylalkyl, heteroarylalkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl, R21-heteroarylalkyl, R21-heteroaryl, R21- heterocycloalkyl or R21-heterocycloalkylalkyl ; R"5, R16 and R17 is H, cycloalkyl, cycloalkylalkyl, R18-alkyl, alkyl, aryl, R18-aryl, R18-arylalkyl, arylalkyl, n is 1 or 2 ; m is 0 or 1 ; R18 is-OR20 or halo ; R20 is aryl or halo substituted aryl ; R21 is alkyl, aryl, heteroaryl, R22-alkyl, R22-aryl, R22-heteroaryl, halo, heterocycloalkyl,-N (R (R16), -OR15, -NO2, -C(O)R15, -N(R15) C (0) R16,

-N(R15)S(O)2R16, -CH2-N(R15)C(O)N(R16)(R17), -N(R15)C(O)N(R16)(R17) or -CH(R15)(R16); R22 is -OR15 or halo and R23 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. R32-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., R13, R2' R22, etc. ) which may be the same or different, and are as defined herein or two substituents on adjacent carbons can be linked together to form 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 R2'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 R21 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 R21 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.

"Heterocyclyi" (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 R21 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 aralkyl 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 R21 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 R21 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"heterocycloa lkylalkyl"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 aryiatkeny) can be optionally substituted by one or more R27 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 R27 substituents. The bond to the parent moiety is through a non-aromatic carbon atom.

The suffix"ene"on alkyl, aryl, hetercycloalkyl, etc. indicates a divalent moiety, e. g.,-CH2CH2-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., R3 in-N (R8) 2, or a variable appears more than once in the structure of formula 1, e. g., Ruz may appear in both R'and R3, 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 :

represents

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 (R5)- and R'and R5 are each H can be represented by any of the following structures: When R21 and R22, are, for example,-N (R15) C (O) N (R'6) (R") and R15 and R16 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 H20.

"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. Pharmaceutical 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 pharmaceutical 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 & 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'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 arginin, 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 1, and of the salts, solvates and prodrugs of the compounds of formula 1, 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 1 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: W saturated: sat.; anhydrous: anhyd.

1-hydroxybenzotriazole : HOBt 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride : EDCI 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: Et20; 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 (Rt); molecular weight (MW); milliliter (mL); gram (g). milligram (mg); equivalent (eq); day (d); microwave (, uW) ; microliter (, uL) ; 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 A1 A2 A3 A4 Method A, Step 1: To a solution of A1 (R3 = CH3 & R4 = CH2CH (CH3) 2) (10 mmol, 1 eq) in 30ml of anhyd. CH2CI2 was added thiocarbonyl dipyridone (1.2 eq). After stirring

overnight the solution was diluted with CH2C12, washed with 1 N HCI, H20 (2x), and a saturated aqueous NaCI solution (2x). The organic solution was dried over Na2SO4, filtered and concentrated. The crude material was purified via flash chromatography to afford A2 (R3 = CH3 & R4 = CH2CH (CH3) 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 (R3 = CH3 & R4 = CH2CH (CH3) 2) (0.1 mmol, 1 eq) in anhydrous CH2CI2 (1 mL). The reaction mixture was refluxed overnight.

The reaction solution was added to MP-TsOH resin (2-3 eq) and diluted with CH3CN. The suspension was agitated overnight. The mixture was filtered and the filtrate was concentrated to afford A3 (R' =3, 5-difluorobenzyl, R3 = CH3, & R4 = CH2CH (CH3) 2).

Method A, Step 3: To a solution of A3 (R1 = 3, 5-difluorobenzyl, R3 = CH3, & R4= CH2CH (CH3) 2) (10 mg) in CH30H (1 mL) was added NH40H (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 CH30H (1.2 mL) and was treated with sulfonic acid resin. The suspension was agitated overnight and the resin was washed with CH30H (4 x 10 min) before it was treated with 2 N NH3 in CH30H 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 CH3CN/H20 gradient to afford A4 (R1 = 3, 5-difluorobenzyl, R2 = H, R3 = CH3, & R4 = CH2CH (CH3) 2). NMR (CD30D) : 86. 9, m, 3H; 54. 8-4.9, m; #1. 75, d, 2H; 81. 5, m, 1 H ; 81. 42, s, 3H; 80. 85, d, 3H; 80. 65, d, 3H. ES_LCMS (m/e) 296. 1.

The following compounds were synthesized using similar methods: Obs. Obs.

&num Structure MW &num Structure MW m/e m/e

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 (HCI salt, R'= 3-chlorophenethyl) (1.1 g, 5.73 mmol) in anhydrous CH30H (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 (R3=Me, R4='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 (R3 = CH3, R4 = CH2CH (CH3) 2, and R'= 3-Chlorophenethyl).

Method B, Step 2: A solution of 40% concentrated HCI in CH3CH20H was added to B2 (R3 = CH3, R4 = CH2CH (CH3) 2, and R'=3-Chlorophenethyl) and the solution was heated in a microwave at 160 °C for 30 min. The solution was concentrated and purified via reverse phase preparative HPLC eluting with a CH3CN/H20 (with 0. 1% formic acid) gradient to afford B3 (R3= CH3, R4 = CH2CH (CH3) 2, and R1 = 3-Chlorophenethyl).

Method B, Step 3: Compound B4 (R2 = H, R3 = CH3, R4 = CH2CH (CH3) 2, and R'=3- Chlorophenethyl) was prepared from B3 (R3 = CH3, R4 = CH2CH (CH3) 2, and R' =3-Chlorophenethyl) following a procedure similar to Method A, Step 3.

NMR (CD30D): 8 8.1, br, 1 H ; 8 7.35, s, 1 H ; 8 7.25, m, 3H; 8 3.6, m, 1 H ; 8 3.4, m, 1 H; # 3. 0, m, 1H; # 2. 8, m, 1 H; # 1. 75, m, 1H ; 81. 6, m, 1H ; # 1. 35, m, 1H; # 1. 2 s, 3H; 8 0.8, m, 6H. ES_LCMS (m/e): 308.1 The following compounds were prepared using similar methods Obs. Obs.

&num Structure MW &num Structure MW m/e m/e Method C

ci C2 C3 Method C, Step 1: A solution of C1 (R3 = R4 = CH2CH2CH2CH3) (50 mg, 0.25 mmol) and C4 (R'=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 CH2Cl2 (3x) and CH30H (3x). The filtrate was concentrated to afford C2 (R1 = 3- Cl-C6H4, R3 = R4= CH2CH2CH2CH3) (60 mg, 68%).

Method C, Step 2: Compound C3 (R'= 3-CI-C6H4, R2 = H, R3 = R4 = CH2CH2CH2CH3) was prepared from C2 (R1 = 3-Cl-C6H4, R3 = R4 = CH2CH2CH2CH3) following a procedure similar to Method A, Step 3. NMR (CDC13) : S 7.4, m, 2H; 8 7.2, m, 2H; 8 5.0, s, 2H; 8 1.7, m, 4H; 8 1.1, m, 8H; 8 0.7 ; m, 6H. ES-LCMS (m/e): 336.1.

The following compounds were prepared using similar method.

Obs. Obs.

&num Structure MW &num Structure MW m/e m/e Method D

D1 D2 D3 D4 Method D, Step 1: A mixture of D1 (R3 = R4 = CH2C6H5) (20 g), potassium cyanide (40 g) and ammonium carbonate (15 g) in ethanol (100 mL) and H20 (200 mL) was heated in a sealed flask at 130 °C overnight to yield 25 g of D2 (R3= R4 CH2C6H5) after filtration followed by washing with water.

Method D, Step 2: A solution of 2 N KOH (3eq) was added to D2 (R3 = R4 = CH2C6H5) (1 eq) and irradiated via microwave at 185 °C for 3h followed by addition of concentrated HCI to the solution until a pH = 2-3 was obtained. The solid was filtered and washed with water to afford D3 (R3 = R4 = CH2C6H5).

Method D, Step 3: A solution of trimethylsilyldiazomethane in hexane (2 N) (2 eq) was added drop wise to a solution of D3 (R3 = R4 = CH2C6H5) (1 eq) in anhydrous CH30H (30 mL). After 1 h, an additional 2 eq of trimethylsilyldiazomethane in hexane (2 N) was added and the reaction was stirred for 20 minutes before it was was concentrated. The residue was dissolved in a 0.2 N HCI solution (25 mL) and

washed with ether (3x). A saturated solution of Na2CO3 was added to the aqueous phase until the pH of the solution was basic. The solution was extracted with ethyl acetate (3x). The organic extracts were combined, dried over Na2SO4, and concentrated to afford D4 (R3 = R4 = CH2C6H5).

The following amino esters were prepared using a similar method.

D5 D6 D7 D8 D9 D10 Dll D12 D13 10 D14 Method E CBZ'H 0 R4X 0 0 Ph B T UH \/-------*-).- CBZ OH >' R3 SOOz g)-N HMPA RbBZ ZINC12 THF/Hexane THF E1 E2 E3

E4 E5 Method E, Step 1: Thionyl chloride (0.47, 6.38 mmol) was added drop wise to a solution of E1 (R3 = CH2CH2C6H5) (2g, 6.38 mmol) and benzaldehyde dimethyl acetal (0.96 mL, 6.38 mmol) in anhydrous THF at 0°C under N2. After 5 min, ZnCl2 (0.87 g, 6.38 mmol) was added and the reaction mixture was stirred at 0 °C. After 3 h, an additional amount of ZnCI2 (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/H20. The mixture was stirred occasionally until the ice melted. The aqueous solution was extracted with ether (3x). The combined organic extracts were washed with H20 (3x), a sat. aqueous solution of NaHCO3 (1x), and H20 (2x). The organic solution was dried over Na2SO4, filtered and concentrated. The crude material was purified via flash chromatography eluting with ethyl acetate in hexane to yield compound E2 (R3 = CH2CH2C6H5).

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 (R3 = CH2CH2C6H5) (600 mg, 1.49 mmol) and HMPA (0.85 mL) in THF (6.5 mL) cooled at-78 °C under N2.

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. NaHCO3 (aq) /ether/ice. The aqueous layer was extracted with ether (3x). The organic extracts were combined and washed with brine (2x).

The organic solution was dried over Na2SO4, filtered and concentrated. The crude material was purified via flash chromatography eluting with ethyl acetate in hexane to yield compound E3 (R3 = CH2CH2C6H5, R = CH2CH (CH3) 2).

Method E, Step 3: A solution of lithium methoxide (1 N in CH30H) (0.36 mL, 0.36 mmol) was added to compound E3 (R3 = CH2CH2C6H5, R4 = CH2CH (CH3) 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 NaHSO3 (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 NaHSO3 (1x) and ethyl acetate (1x). The aqueous phase of the filtrate was separated and extracted with ethyl acetate (2x). The organic extracts were combined and washed with a sat. aqueous solution of NaHSO3 (8x). The organic solution was dried over Na2SO4, filtered and concentrated to afford E4 (R3 = CH2CH2C6H5, R4 = CH2CH (CH3) 2) (109 mg, 87%).

Method E, Step 4 : To a solution of E4 (R3 = CH2CH2C6H5, R4 = CH2CH (CH3) 2) (109 mg, 0.28 mmol) in CH30H (4 mL) was added 1 N HCI (0.28 mL, 0.28 mmol) and 20% palladium hydroxide on carbon (22 mg). The reaction mixture was hydrogenated at 40 psi. After 2.5 h, the reaction was filtered and the catalyst was washed with CH30H (3x). The filtrate was concentrated to afford E5 (R3 = CH2CH2C6H5, R4 = CH2CH (CH3) 2) (78 mg, 96%).

The following aminoesters were prepared using similar method.

E14 E15 E16 E17

Method F D5 F1 A 500 mL methanol solution of 20 g of D5 (R3 = benzyl, n = 1) with 1.5 eq of HCI was hydrogenated with 1 g of Rh/C (5% w/w) and 2 g of Pt/C (5% w/w) at 60 psi for 2 days. The solid was filtered and washed with excessive methanol.

The combined solution was evaporated to give 20 g of F1 (R3 = cyclohexylmethyl, n = 1) as HCI salt.

The following amino esters were examples prepared using similar method.

F2 F3 F4 F5 F6 F7 F8 F9 F10 Method G G1 G2

G3 G4 Method G, Step 1: To a solution of G1 (R' = CH2 (3-CIC6H4) and R3 = CH3) (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 H20 (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 H20 (15 mL) and extracted with ether (2x). A solution of 30% HCI was added to the aqueous phase until its pH = 1 to 2. The solution was saturated with NaCI and extracted with ethyl acetate (3x). The organic solution was dried over Na2SO4, filtered and concentrated to afford G2 (R1 = CH2 (3-CIC6H4) and R3 = CH3) (357 mg, 93%).

Method G, Step 2: A solution of benzyl amine (1.2 eq) was added to G2 (R1 = CH2 (3-CIC6H4) and R3 = CH3) (1 eq), HOBT (1.5 eq) and polystyrene EDC resin (94 mg, 1.53 mmol/g, 3eq) in 1: 1 THF : CH3CN (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 (R1 = CH2 (3-CIC6H4), R3= CH3, R15 = CH2C6H5 and R = H).

Method G, Step 3: Compound G4 (R1 = CH2 (3-CIC6H4), R2 = H, R3 = CH3, R'5 = CH2C6H5 and R15 = H) was prepared from G3 (R1 = CH2 (3-CIC6H4), R3 = CH3, R 15 = CH2C6H5 and R16 = H) following a procedure similar to Method A, Step 3.

The following compounds were prepared using similar methods.

Obs. Obs.

&num Structure MW &num Structure MW m/e m/e Method H 3 3 Tf2O R3 o R2l_H at o TFA R21< /v-/v 2, 6-Lutidine HNYN'R CH2CI2 HNYN-R1 CH2CI2 HN"N-Rt CHZCIy "" N. N NH Boc Boc

H5 H6 H7 Method H, Step 1: To a solution of H1 (R3 = CH3) (5 g, 39 mmol) in a 1: 1 mixture of 0.5 M NaHCO3 : CH3CH20H was added R'-NCS (R'=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 (5x). The organic extracts were combined, washed with water (2x) and dried over Na2SO4. 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 (R3= CH3, R'= CH2 (3-CIC6H4)) (61 %).

Method H, Step 2: Compound H3 (R3 = CH3, R'= CH2 (3-CIC6H4)) was synthesized from H2 (R3 = CH3, R'= CH2 (3-CIC6H4)) following a procedure similar to Method A, Step 3.

Method H, Step 3: To a solution of crude H3 (R3 = CH3, R'= CH2 (3-CIC6H4)) (14 mmol) in a 1: 3 mixture of CH30H : THF was added 0.5 M NaHCO3 in H20 (28 mL, 14 mmol) and di-tert-butyl dicarbonate (3.69 g, 16.9 mmol). The reaction was stirred at rt for 2. 5 h and then stored at-10 °C overnight. The reaction was diluted with brine and extracted with ethyl acetate (4x). The organic extracts were combined and washed with brine (1x). The organic solution was dried over Na2SO4, filtered and concentrated. The crude material was purified via flash chromatography eluting with ethyl acetate in hexane to afford 1.5 g of H4 (R1 = CH2 (3-CIC6H4) and R3 = CH3).

Method H, Step 4: A solution of triflic anhydride (128 µL, 0.76 mmol) in CH2CI2 (5 mL) was added drop wise to a solution of H4 (R'= CH2 (3-CIC6H4) and R3= CH3) (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 Na2SO4, filtered and concentrated to afford 310 mg of H5 (R1 = CH2 (3-CIC6H4) and R3= CH3).

Method H, Step 5:

A solution of crude H5 (R'= CH2 (3-CIC6H4) and R3 = CH3) (0.11 MMOI) and 7N ammonia in Methanol (R21-H = NH2-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 CH3CN/H20 gradient with 0. 1% formic acid to yield H6 (R'= CH2 (3-ClC6H4), R3 = CH3, R21 = NH2).

Method H, Step 6: A solution of 50% trifluoroacetic acid in CH2CI2 (2 mL) was added to H6 (R1 = CH2 (3-ClC6H4), R3 = CH3, R21 = NH2). After 40 min the solvent was evaporated and residue purified by preparative HPLC/LCMS eluting with a CH3CN/H2O gradient to afford H7 (R1 = CH2 (3-ClC6H4), R3 = CH3, R21 = NH2).

NMR (CDC13), 8 7.45, m, 3H; 8 7.35, m, 1 H; 8 4.9, m, 2H; 8 3.5, m, 2H; # 1.65, s, 3H. ES_LCMS (m/e) 267.07.

The following compounds were prepared using similar methods.

Obs. Obs.

&num Structure MW &num Structure MW m/e m/e Method I

11 12 13 Method 1, Step 1: Diethylaminomethyl polystyrene resin (5 eq) was added to a solution of the formate salt of 11 (R'= CH2 (3-CIC6H4), R3 = CH3 and R16=H) in CH2CI2 and the suspension was agitated. After 15 min, the mixture was filtered and the resin was washed with CH2CI2 (4x). The filtrate was concentrated to afford the free base 11 (R1 = CH2 (3-CIC6H4), R3 = CH3 and R'6=H).

A solution of R'5COOH (R'5=Phenethyl) (1.3 eq) was added to a mixture of EDC resin (41 mg, 1.53 mmol/g, 3eq), HOBT (1.5 eq), and the free base of 11 (R1 = CH2 (3-CIC6H4), R3 = CH3 and R16=H) (0.021 mmol) in 1: 1 CH3CN: 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 CH3CN : THF (0.5 mL) was added. The mixture was agitated for 6 h. The suspension was filtered and the filtrate was concentrated to afford 12 (R'= CH2 (3-CIC6H4), R3 = CH3, R'6=H and R'5 = CH2CH2C6H5).

Method I, Step 2: 13 (R'= CH2 (3-ClC6H4), R3 = CH3, R16=H and R15 = CH2CH2C6H5) was prepared from 12 (R1 = CH2 (3-CIC6H4), R3 = CH3, R16=H and R15 = CH2CH2C6H5) using method similar to method H step 6.

The following compounds were prepared using similar method.

M Obs. Obs.

&num Structure &num Structure MW W m/e m/e Method J

J1 J2 J3 Method J, Step 1: Diethylaminomethyl polystyrene resin (5 eq) was added to a solution of J1 (TFA salt, R'= CH2 (3-CIC6H4) and R3 = CH3) in CH2CI2 and the suspension was agitated. After 15 min, the mixture was filtered and the resin was washed with CH2Cl2 (4x). The filtrate was concentrated to afford the free base. A solution of R15NCO (R'5= butyl) (2 eq) in CH2Cl2 was added to the free base of J1 (R'= CH2 (3-CIC6H4) and R3 = CH3) (0.021 mmol) in 1: 1 CH3CN : 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 CH3CN: 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'= CH2 (3-CIC6H4), R3= CH3, and R'5 = CH2CH2CH2CH3).

Method J, Step 2:

Compound J3 (R1 = CH2 (3-ClC6H4), R3 = CH3, and R15 = CH2CH2CH2CH3) was prepared from J2 (R1 = CH2 (3-CIC6H4), R3 = CH3, and R15 = CH2CH2CH2CH3) following the procedure described in Method H, Step 2.

The following compounds were prepared using similar method.

Obs. Obs.

&num Structure MW &num Structure MW m/e m/e Method K

15 R S02CI R3 0 R'5S02CI 0,/o R3 0 0 0 R3 0 HNXN-R1 HN) N-R1 H HN) f N-R1 N, Boc N, Boc NH K1 K2 K3 Method K, Step 1: A solution of propyl R15SO2Cl (R15=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 (R1 = CH2 (3-CIC6H4) and R3= CH3) (0.021 mmol) in 1: 1 CH3CN : 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 CH3CN : 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 (R1 = CH2 (3-ClC6H4), R3 = CH3, and R'5 =CH2CH2CH3).

Method K, Step 2: Compound K3 (R1 = CH2 (3-ClC6H4), R3 = CH3, and R'5 = CH2CH2CH3) was prepared from K2 (R1 = CH2 (3-CIC6H4), R3 = CH3, and R'5 = CH2CH2CH3) following the procedure described in Method H, Step 6.

The following compounds were prepared using similar method.

Obs. Obs.

&num Structure MW &num Structure MW m/e m/e Method L

L3 L4 (In the scheme,-Z-NH-C (O) R'6-is equivalent to R'substituted by R21, or R1 Substituted by alkyl-R22, wherein R2'and R22 are-N (R15) C (O) Rr6 and R'5 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 (R3 = CH3 and R4 = CH2CH(CH3) 2) (1 eq) and Z =-para- methylene-benzyl) (1.05 eq) in CH2CI2 was stirred at rt. The reaction solution was concentrated and purified via flash chromatography. The material was treated with 50% trifluoroacetic acid in CH2CI2 for 30 min. The solution was concentrated. The residue was dissolved in 1 N HCI (lOmL) and washed with ether (2x). A saturated solution of Na2CO3 in H20 was added to the aqueous phase until the solution became basic. The solution was extracted with CH2CI2 (3x). The CH2Cl2 extracts were combined, dried over Na2SO4, filtered and concentrated to yield L2 (R3 = CH3, R4 = CH2CH (CH3) 2, Z = para- (CH2) C6H4 (CH2)-).

Method L, Step 2: Compound L3 (R3 = CH3, R4 = CH2CH (CH3) 2, Z = para- (CH2) C6H4 (CH2)-, R16 = CH2CH2CH2CH3) was prepared from L2 (R3 = CH3, R4 = CH2CH (CH3) 2, Z = para- (CH2) C6H4 (CH2) -) following the procedure described in Method I, Step 1.

Method L, Step 3: Compound L4 (R3 = CH3, R4 = CH2CH (CH3) 2, Z = para- (CH2) C6H4 (CH2)-, R'= CH2CH2CH2CH3) was prepared from (R3 = CH3, R4 = CH2CH (CH3) 2, Z = para- (CH2) C6H4 (CH2) -, R = CH2CH2CH2CH3) following the procedure described in Method A, Step 3.

The following compounds were prepared using similar method.

Obs. Obs.

&num Structure MW &num Structure MW m/e m/e

Method M M1 M2 M3 (In the scheme,-Z-NH-C (O)-NHR15 - is equivalent to R'substituted by R2', or R'Subsitituted by alkyl-R22, wherein R21 and R22 are-N (R16)-C(O)-NHR15 and R16 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 (R3 = CH3, R4= CH2CH (CH3) 2, Z = para- (CH2) C6H4 (CH2) -, R15 = 3, 4-difluorophenyl) was prepared from M1 (R3 = CH3, R4 = CH2CH (CH3) 2, Z = para- (CH2) C6H4 (CH2) -) following the procedure described in Method J, Step 1.

Method M, Step 2: Compound M3 (R3 = CH3, R4 = CH2CH (CH3) 2, Z = para-(CH2)C6H4 (CH2) -, R15 = 3, 4-difluorophenyl) was prepared from M2 (R3 = CH3, R4 = CH2CH (CH3) 2, Z = para- (CH2) C6H4 (CH2)-, R15 = 3, 4-difluorophenyl) following the procedure described in Method A, Step 3. NMR (CD30D) 8 7.45, m, 1 H; 8 7.26, m, 4H; 7.24, m, 1 H ; 8 6. 96, m, 1 H ; 8 4. 8, m; 8 4. 3, s, 2H; 8 1.69, m, 2H; 8 1. 44, m, 1 H ; # 1,37, s, 3H; 8 0.8, m, 3H; 8 0.63, m, 3H. ES_LCMS (m/e) 430.27 The following compounds were prepared using similar method.

Obs. Obs.

&num Structure MW &num Structure MW m/e m/e Method N

N1 N2 N3 (In the scheme,-Z-NH-S (O) 2R16 - is equivalent to R'substituted by R21, or R'Subsitituted by alkyl-R22, wherein R21 and R22 are-N (R16)-C(O)-NHR15 and R'6is 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 (R3 = CH3, R4 = CH2CH (CH3) 2, Z = para- (CH2) C6H4 (CH2)-, R16 = CH2CH (CH3) 2) was prepared from N1 (R3 = CH3, R4 = CH2CH (CH3) 2, Z = para- (CH2) C6H4 (CH2) -) following the procedure described in Method K, Step 1.

Method N, Step 2: Compound N3 (R3 = CH3, R4 = CH2CH (CH3) 2, Z = para- (CH2) C6H4 (CH2)-, R'6 = CH2CH (CH3) 2) was prepared from N2 (R3 = CH3, R4 = CH2CH (CH3) 2, Z = para-(CH2)C6H4 (CH2) -, R16 = CH2CH (CH3) 2) following the procedure described in Method A, Step 3.

The following compounds were prepared using similar method.

Obs. Obs.

&num Structure MW &num Structure MW m/e m/e Method O TBSCI \ \ BuLi \N I \ N Ho m lmidazole TBS., TBSO I/N N tuf - 78 °C S, O 01 02 03 top 04 05 06 07 08 09

010 o11 Method O, Step 1: A solution of indole-6-methanol (400 mg, 2.72 mmol), tert- butyldimethysilyl choride (816 mg, 5.41 mmol) and imidazole (740 mg, 10.9 mmol) in CH2CI2 was stirred at rt. overnight before the solvent was evaporated and residue chromatographed using ethylacetate/hexane to give product 02.

Method O, Step 2: To a solution of 02 (200 mg, 0.77 mmol) in THF (10 mL) at-78 °C was added butyl lithium (1.2 eq). The solution was stirred at-78 °C for 5 min and then warmed to rt. The reaction mixture was cooled to-78 °C and p- toluenesulfonyl chloride was added. The solution was warmed to rt and stirred overnight. The reaction was quenched with a saturated aqueous K2CO3 solution, extracted with ethyl acetate and CH2CI2. The crude material was purified via flash chromatography using ethylacetate/hexane to afford 360 mg of 03.

Method O, Step 3: A solution butyl lithium (1.2 eq) was added to a solution of 03 (340 mg, 0.829 mmol) in THF (20 mL). The reaction mixture was stirred for 15 min at-78 °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 04 which was used in the next step without further purification.

Method O, Step 4: To a solution of 04 (0.829 mmol) in CH2CI2 cooled to 0 °C was added N- chlorosuccinimide (220 mg, 1.66 mmol). After 2 h of stirring, the solution was filtered through a Celite plug. The filtrate was concentrated to afford 05.

Method O, Step 5: To a solution of 05 in anhydrous pyridine (3 mL) was added butyl amine (100 uL). The reaction was agitated at rt for 4 d. The reaction mixture was partitioned between 1 N HCI and CH2CI2. The organic layer was separated and washed with 1 N HCI (3x). The organic solution was dried over Na2SO4, filtered and concentrated. The crude material was purified via flash chromatography using ethylacetate/hexane to yield 06.

Method O, Step 6:

To a solution of 06 (70 mg) in THF was added TBAF. The reaction was stirred at rt. before the reaction mixture was chromatographed using ethylacetate/hexane to afforded 50 mg of 07 (95%).

Method O, Step 7: To a solution of 07 (50 mg) in CH2CI2 (5 mL) was added thionyl chloride (1 mL) the reaction was stirred for 5 min and then evaporated to afford 08.

Method O, Step 8: To a solution of 08 in CH30H (5 mL) was added sodium azide (50 mg).

The solution was stirred at rt overnight and solvent evaporated. The residue was chromatographed using ethylacetate/hexane to afforded 09 after purification.

Method O, Step 9: To a suspension of 09 (70 mg) in CH30H was added 1 eq HCI (aq) and palladium on carbon. The reaction mixture was hydrogenated at 1 atm for 20 min to yield 90 mg of crude product 010.

Method O, Step 10: A solution of lithium hydroxide (30 mg) in H20 was added to a solution of 010 (40 mg) in CH30H (3 mL). The reaction was stirred at rt for 2 h and an additional portion of LiOH (40 mg) was added and solution was stirred for 2 more hours. The solvent was evaporated and residue chromatographed using ethylacetate/hexane to afforded 011.

Method P

Method P, Step 1: A 300 mL of THF solution of 100 g of P1 (R23=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 mi of H20, 90 MI of 15% NaOH was added at 0 °C. The mixture was stirred at r. t. for one hour before Na2SO4 (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 H20 at-10 °C and the mixture was extracted with DCM. After removal of solvent, P2 (R23=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 (R23=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 H20 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 (R23=Pr).

Method P, Step 3: A 10 ml MeOH solution of P3 (R23=Pr, 110 mg) was hydrogenated using Pd/C (5%, 11 mg) at 1 atm of hydrogen to give product P4 (R23=Pr) after removal of solvent and catalyst.

Method P, Step 4: To a 10 ml DCM solution of P4 at 0 °C (R23=Pr) was added triphosgene ( 1.2 eq) and triethylamine (2.4 eq) and the solution was stirred at 0 C for 2 h before the reaction was extracted with DCM/H20. After removal of the solvent, the residue was chromatographed using a silica gel column eluted with EtOAc/Hexane to give a white solid which was treated with 2N HCI in dioxane for 2 h. After removal of the solvent, compound P5 (R23=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 (R3=Me ; R4= 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, R3=Me ; R4= iBu), a colorless oil (1.59 g).

Method Q, Step 2 Compound Q3 (n=1, p=2, m=1, R2=H, R3=Me ; R4= iBu) was prepared from Q2 (n=1, p=2, m=1, R3=Me ; R4= iBu) using method similar to method A step 3.

Method Q, Step 3 Compound Q3 (n=1, p=2, m=1, R2=H, R3=Me ; R4= 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 1 N 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, R2=H, R3=Me ; R4= i-Bu) as a white foam (0.74 g).

Method Q, Step 4 Compound Q4 (n=1, p=2, m=1, R2=H, R3=Me ; R4=iBu) (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, R2=H, R3=Me ; R4= iBu) as a colorless oil (0.35 g).

Method Q, Step 5 Compound Q5 (n=1, p=2, m=1, R2=H, R3=Me ; R4= 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 1 M dichloroethane solution (40uL, 1.25 eq. ). After the well was capped and shaken for 18 h, the mixture was filtered and the resin washed with acetonitrile (0.5 mL). The combined solution was treated with Trisamine resin (0.050 g, 6 eq. , 4.23 mmol/g) and Isocyanate resin (0.067 g, 3 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, R2=H, R3=Me ; R4= Bu, R'5 = Me).

Method Q, Step 6.

A dichloromethane solution (1.0 mL) of Q6 (n=1, p=2, m=1, R2=H, R3=Me ; R 4='Bu, R16 =Me) was mixed with trifluoroacetic acid (1.0 mL) and the solution was shaken for 2 h before it was concentrated. Diethyl ether (0.5 mL) was added and then concentrated in vacuo to give a residue, which was was purified on a Prep LCMS unit to give Q7 (=1, p=2, m=1, R2=H, R3=Me ; R4= iBu, Ri5 = Me). NMR (CDC13) : 8 8.38, br, 2H; 8 4.56, m, 1 H; 8 3.79, m, 1 H; 8 3.57, m, 2H; 8 2. 99, m, 1 H ; 8 2. 48, m, 1 H ; 8 2. 04, s, 3H; 8 1. 95, m, 1 H ; 8 1. 5-1.8, m, 5H; 8 1.5, s, 3H; 1.25, m, 2H; 8 0.95, m, 3H; 8 0.85, m, 3H. ES_LCMS (m/e) 309.17.

The following compounds were prepared using similar methods: Obs. Obs.

&num Structure MW &num Structure MW<BR> <BR> <BR> m/e m/e 1084 Method R

R1 R2 R3 Method R, Step 1.

A solution of R' (n=1, p=2, m=1, R2=H, R3=Me ; R4='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. 5moi). 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, R2=H, R3=Me ; R4='Bu and R15=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, R2=H, R3=Me ; R4='Bu and R15=Ph) to R3 (n=1, p=2, m=1, R2=H, R3=Me ; R4='Bu and R15=Ph).

The following compounds were prepared using similar methods: Obs. Obs.

&num Structure MW &num Structure MW m/e m/e Method S

S1 S2 S3 Method S, Step 1.

A solution of S1 (n=1, p=2, m=1, R2=H, R3=Me ; R4= 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, R2=H, R3=Me ; R4= Bu and R'5=Ph).

Method S, Step 2.

Procedure similar to Method Q, step 6 was used for the transformation of S2 to S3 (n=1, p=2, m=1, R2=H, R3=Me ; R4='Bu and R15=Ph).

The following compounds were prepared using similar methods: Obs. Obs.

&num Structure MW &num Structure MW m/e mie Method T

T1 T2 T3 Method T, Step 1.

To a microtiter plate well containing 1 mi solution of T1 (n=1, p=2, m=1, R2=H, R3=Me; R4= iBu) in DCM (0. 010 g) and R'5C (O) R'6 (5 equiv, R15=H, R'6=Ph) was added Sodium cyanoborohydride in dichloroethane (14.3 mg/mL, 2 equiv. ). The well was capped and shaken for 20h before MP-TsOH Resin (100 mg, 1.29 mmol/g) was added to the well followed by additional MP-TsOH resin (50 mg) after 2 h. After the mixture was shaken for another 1 h, the mixture was filtered and the resin washed with dichloroethane (1 mL) (3 X), then MeOH (1 mL) (2 X). The resin was treated with 7N ammonia in MeOH (1 mL) for 30 min (2X) followed by filtration and evaporation of solvent to give T2 (n=1, p=2, m=1, R2=H, R3=Me ; R4='Bu and R15=Ph and R'6=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, R2=H, R3=Me ; R4=iBu and R15=Ph and R'6=H) to T3 (n=1, p=2, m=1, R2=H, R3=Me ; R4='Bu and R15=Ph and R16=H).

The following compounds were prepared using similar methods: Obs. Obs.

&num Structure MW &num Structure MW m/e m/e Method U 2 2 N S R2 R B (OH) 2 N S R2 Pd (dppf) CI2 HN N toluene, HO N N N R<O U Br K2CO3 R<O (U microwave

U1 U2 In a microwave vial was charged U1 (R2= H; R3= i-Bu, R4 = Me) (0.025 g) in toluene (4 mL), potassium carbonate (0.035 g), Pd (dppf) C12 (0.020 g). water (0.02 mL) and R2'B (OH) 2 (R2'= 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 (MgSO4) dichloromethane solution was concentrated in vacuo to give a brown residue which was purified via a RP Prep LCMS system to give product U2 (R2= H; R3= 'Bu : R4 = Me ; R2'= m-methoxyphenyl).

The following compounds were prepared using similar methods: Obs. Obs.

&num Structure MW &num Structure MW m/e m/e Method V

V1 V2 V3 V4 Method V, Step 1: Compound V1 (R3 = R4 = Me) (14. 76mmole), EDCI (14. 76mmole), HOAt (14. 76mmole), and DIEA (14. 76mmole) were mixed with 36 ml DCM. This mixture was stirred at RT for 15min before 3-chlorobenzylamine was added.

After the reaction solution was stirred at RT overnight, it was washed with sodium carbonate (3X), water, 1 N HCI (4 X), and aq sodium bicarbonate and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified on flash column to give the amide product V2 (R'= 3- chlorobenzyl ; R3 = R4 = Me).

Method V, step 2 Compound V2 (R'= 3-chlorobenzyl ; R3 = R4 = Me) (8. 33mmole) was dissolved in 35 ml anhydrous DCM, and cooled to 0-5°C. Thiophosgene (9. 16mmole) in 10ml DCM was added dropwise under N2 followed by addition of DIEA (11. 96mmole). The solution was stirred in ice bath for 0.5 h before the reaction mixture was washed with saturated sodium bicarbonate (3 X), brine,

and dried over anhydrous sodium sulfate. The solvent was evaporated and residue purified on flash column using ethylacetate/hexane to give the thiohydantoin V3 (R'= 3-chlorobenzyl ; R3= R4 = Me).

Method V, step 3: The thiohydantoin V3 (R'= 3-chlorobenzyl ; R3= R4 = Me) was treated with t-butyl hydroperoxide and ammonium hydroxide in MeOH at RT for 48 h to give compound V4 (R'= 3-chlorobenzyl ; R2 = H; R3 = R4 = Me).

The following compounds were prepared using similar method.

Obs. Obs.

&num Structure MW &num Structure MW m/e m/e Method W

Compound W1 obtained using method A (n=1, R2=m-CI-Bn, R3=Me) was hydrolyzed to W2 (n=1, R2=m-CI-Bn, R3=Me) using two equivalent of LiOH in MeOH.

The following compounds were synthesized in similar fashion: Obs. Obs.

&num Structure MW &num Structure MW m/e m/e Method X

xi X2 X3 X4 (In the scheme,-Z-NH-C (O)-N (R16)(R17) - is equivalent to R'substituted by R2', or R'Subsitituted by alkyl-R22, wherein R21 and R22 are-NH-C (O)- N (R16)(R17) and R'5 is H, and wherein Z is optionally substituted alkylen- 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, Step1 : To a mixture of the amine X1 obtained using method L (R3 = Me ; R' Bu; Z = para- (CH2) C6H4 (CH2) -) (10 mg) in DCM and sat. NaHCO3 (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 Na2SO4. The organic solution was evaporated to give compound X2 (R3 = Me ; R4 = i-Bu ; Z = para- (CH2) C6H4 (CH2) -).

Method X, Step2: Compound X3 (R15 = H; R16 = cyclopropylmethyl ; R3 = Me ; R4='Bu ; Z = para- (CH2) C6H4 (CH2) -) was prepared from X2 (R3 = Me; R4 = i-Bu ; Z = para- (CH2) C6H4 (CH2) -) using method similar to method M, step 1.

Method X, Step3: Compound X4 (R16 = H; R17 = cyclopropylmethyl ; R2 = H; R3 = Me; R4= 'Bu ; Z= para-(CH2)C6H4(CH2)-) was prepared from X3 (R16 = H ; R cyclopropylmethyl ; R2 = H; R3 = Me; R4 = iBu ; Z = para-(CH2)C6H4 (CH2) -) using method similar to method A Step 3. NMR (CD30D) : 8 7.25, s, 4H; # 4.8, m, 2H; S 4. 25, s, 2H; 8 2. 9, m, 2H; 8 1.68, m, 2H; 8 1. 44, m, 1 H ; 8 1.36, s, 3H; 8 0. 9, m,

0.82, m, 3H; 8 0.66, m, 3H; 8 0.4, m, 2H; # 0.12, m, 2H. ES_LCMS (m/e) The following compounds were prepared using a similar method.

Obs. Obs.

Structure MW # Structure MW m/e m/e Method Y

Y1 Y2 Y3 Y4 (In the scheme, equivalent to R'substituted by R2', or R'

Substituted by alkyl-R22, wherein R21 and R22 are -N(R15)-C(O)-N(R16)(R17) and R'5 and R16 form a ring as defined above, and wherein Z is optionally substituted <BR> <BR> <BR> 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 (R3 = Me; R4 = i-Bu ; Z = para- (CH2) C6H4 (CH2)-) (0. 1639mmole), Y2 (R23 = H; R23 = Pr) (0. 1967mmole), PS-EDC resin (0. 4917mmole) and HOBT (0. 2459mmole) in 3.5 ml of mixture of THF, MeCN and DMF (1: 1: 0.3) was shaken overnight at RT before 6 eq of PS-trisamine resin 3 eq of PS-isocyanate resin were added. After 6hrs the reaction mixture was filtered and the resin was washed with THF, DCM and MeOH. The combined filtrate was evaporated and the crude was treated with 40% TFA in DCM for 40 min before the solvent was evaporated and residue purified on RP HPLC system to give product Y3 (R3 = Me; R4 = i-Bu; Z = para- (CH2) C6H4 (CH2)-, R23= H ; R23= Pr) Method Y, Step 2: The reaction solution of Y3 (R3 = Me ; R4 = i-Bu ; Z = para- (CH2) C6H4 (CH2)- , 23 = H; R23 = Pr) (0. 030mmole), carbonyl diimidazole (0. 032mmole), and DIEA (0. 09mmole) 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 (R2 = H; R3 = Me; R4 = iBu ; Z = para-(CH2)C6H4(CH2)-, R23 = H; R23= Pr) The following compounds were prepared using similar method.

M Obs. Obs.

&num Structure &num Structure MW W m/e m/e

Method Z II 1'. R I1 'Z H2 S HN RN R6 S HNN_Rs HZ N. Ris HN N- Phoxime.'k HN N_z Ri7 Rs'\ Rs' R 4 R O Ra Ra R O Z1 Z2 Z3 Z4 Z1 Z2 Z3

(In the scheme,-Z-NH-C (O)-N (R16) (R")-is equivalent to R'substituted by R2', or R'Subsitituted by alkyl-R22, wherein R21 and R22 are-N (R'S)-C (O)- N (R16)(R17) and R'5 is H, and wherein Z is optionally substituted alkylen- 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 PhoximeT resin (1.23 mmol/g) in DCM was added the amine Z1 obtained from method L (R3 = Me; R4 = iBu ; Z = para- (CH2) C6H4 (CH2) -) (2 eq). The mixture was shaken overnight before the resin was filtered and washed with DCM, MeOH, THF (3 cycles), then DCM (x2), dried in vacuum to get resin Z2 (R3 = Me; R4 = iBu ; Z = para- (CH2) C6H4 (CH2)-).

Method Z, Step 2: To the resin Z2 (R3 = Me ; R4 = iBu ; Z = para-(CH2)C6H4 (CH2) -), 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 (R3 = Me; R4 = iBu ; Z = para- (CH2) C6H4 (CH2)- ; R16 = Me; R17 = Bn).

Method Z, Step 3: Compound Z4 (R3 = Me; R4 = iBu ; Z = para-(CH2) C6H4 (CH2)-; R16 = Me; R 17 = Bn) was generated from Z3 (R3 = Me; R4 = iBu ; Z = para-(CH2)C6H4(CH2)-; R16 = Me; R 17 = Bn) using method similar to Method A step 3.

The following compounds were prepared using similar method.

Obs. Obs.

&num Structure MW &num Structure MW m/e m/e 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. Obs &num Structure MW &num Structure MW m/e m/e

The following compounds were prepared using similar method.

Method AB AB4 AB5 Method AB, Step 1:

To a solution of (R)- (+)-2-methyl-2-propane sulfonamide (1.0 g, 8.3 mmol, 1 eq) and AB1 (R3=Ph, R4= 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 x 20 mL). The filtrate was washed with brine (30 mL), dried (Na2SO4), and concentrated in vacuo. The residue was chromatographed on silica by eluting with hexane/Et2O (5: 1) to give 1.9 g (85%) of (R)-2-methyl-N- (1- phenylpentylidene) propane-2-sulfinamide.'HNMR (CDC13, 300 MHz): 8 7. 91 (m, 2H), 7.52-7. 37 (m, 3H), 3.27 (m, 1 H), 3.15 (m, 1 H), 1.73-1. 61 (m, 2H), 1.47-1. 38 (m, 2H), 1.31 (s, 9H), 0.95 (m, 3H). MS (ESI) : MH+ = 265.9. HPLC tR =7.24, 7.58 min (E/Z = 5.5 : 1).

To a solution of methyl acetate (0.6 mL, 6.9 mmol, 2 eq) in THF (5 mL), 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 C ! Ti (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 NH4CI (10 eq) was added and the suspension was warmed to room temperature. The mixture was diluted with H20 (50 mL) and stirred for 10 min. The mixture was then partitioned between H20 (50 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried (MgS04) 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. 1HNMR (CDCI3, 300 MHz): 8 7.15-7. 07 (m, 5H), 3.35 (s, 1 H), 3.19 (dd, J=16, 5.6Hz, 1H), 3.01 (dd, J=15. 8,5. 5Hz, 1H), 2.07 (m, 2H), 1.71 (m, 2H), 1.35-1. 26 (m, 4H), 1.17 (s, 9H), 0.89 (m, 3H). MS (ESI) : MH+ = 339.9. HPLC tR = 7.50, 7. 6min (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 HCI/dioxane. After stirring for 30 min, the volatiles were removed in vacuo. The residue was re-dissolved in MeOH (6 mL), stirred for 5 min, and evaporated again to afford 0.30 g (97%) of AB2 (R3=Ph, R4= n-Bu) as a yellow solid.

'HNMR (CDCI3, 300 MHz): # 9. 01 (br s, 2H), 7.37-7. 12 (m, 5H), 3.64 (m, 1H), 3.54 (s, 3H), 3.31 (m, 1 H), 2.09 (m, 2H), 1.8 (m, 2H), 1.1 (m, 4H), 1.07 (s, 9H), 0.7 (m, 3H). MS (ESI) : MH+ = 235.9. HPLC tR = 4.72 min.

Method AB, Step 2: Treatment of compound AB2 (R3=Ph, R4=n-butyl) with thiophosgene in CH2CI2 in the presence of aqueous NaHCO3 at 0 °C generates isothiocyanate AB3 (R3=Ph, R4=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 (R3=Ph, R4=n-butyl, R'=Me)..'HNMR (CDC13, 300 MHz): 8 10.4 (br s, 1 H), 7.25-7. 11 (m, 5H), 3.23 (dd, J = 16,5. 6 Hz, 1 H), 3.03 (s, 3H), 2.8 (dd, J = 15.8, 5.5 Hz, 1 H), 2.49 (s, 1 H), 1.78 (m, 2H), 1.1-1. 0 (m, 4H), 0.99 (m, 3H). MS (ESI) : MH+ = 260.2.

HPLC tR = 5.09 min.

The following compounds were synthesized using similar methods: Obs. Obs &num Structure MW &num Structure MW m/e m/e 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'=Benzyl) (0.72 g, 5.9 mmol) in AC1 (R4=Me, R3=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 H2O. The organic layer was dried over Na2SO4, filtered and the volatiles were removed in vacuo. The residue was purified by column chromatography using 5-10% CH30H/CH2CI2 as eluent followed by reverse phase preparative HPLC to give 0.15 g (8.0%) of AC3 (R=benzyl, R4=Me and R3=Me) as a white solid.'H NMR (CH30H, 300 MHz): 87. 35-7.33 (m, 5H), 4.71 (s, 2H), 1.46 (s, 6H) ; 13C NMR (CDCl3, 75 MHz) 8 157.8, 135.6, 129.1, 128.5, 127.9, 104.2, 59.6, 28.8. MS (ESI) m/e 206.1 (M+H) +.

&num Structure MW Obs. m/e Method AD Method AD, Step 1: AD2 (R3=Ph, R4='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 (R3=Ph, R4=tert- Butyl) (0.56 g, 2.7 mmol) and boiling chips in CCl4 (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.'H NMR (CD3, 300 MHz): 8 7.63- 7.61 (m, 2H), 7.37-7. 26 (m, 3H), 1.17 (s, 9H) ; 13C NMR (CD3, 75 MHz): 8 139.1, 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 CH3OH/CH2CI2 as eluent to give 0.050 g (42%) of AD3 (R3=Ph, R4=tert-Butyl) as

a glassy solid.'H NMR (CDCI3, 300 MHz): 8 7.35-7. 26 (m, 5H), 3.38 (s, 3H), 1.0 (s, 9H); MS (ESI) m/e 251.1 (M+H) +.

Method AD, Step 2: To a solution of AD3 (R3=Ph, R4=tert-Butyl) (0.065 g, 0.26 mmol) in CH30H (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 (R3=Ph, R4=tert-Butyl) as a colorless oil.'H NMR (CDC13, 300 MHz) 8 7.47- 7.43 (m, 2H), 7.39-7. 35 (m, 3H), 3.23 (s, 3H), 1.0 (s, 9H); MS (ESI) m/e 234.2 (M+H) +.

The following compounds were synthesized using similar methods: Obs. Obs.

&num Structure MW &num Structure MW m/e m/e Method AE s s NBoc NBOC N TBS-CI tNA 1) tBUOOH tNA 2 6-lutidine N NH Imidazole NH NH3/MeOH NH-'' NH 2) TFA/DCM 3 OH OTBS 3) BOC20 H Tf H2 AE2 AE3 AE4 | DIEA/THF I //NH//NBoc RsN RsN N) t « 1) R'50H/HBF4 N 2) TFA/DCM R3 _R5

AE5 AE5 Method AE, Step 1: TBDMS-CI (5.3g, 35. 19mmole) and imidazole (2.4g, 35. 19mmole) were added to a suspension of H2 (R'=Me, R3=cyclohexylmethyl) (8.2g, 31. 99mmole) in 220 ml DCM. The reaction mixture was stirred at room temperature overnight.

The reaction mixture was filtered, and the filtrate was diluted with 1200moi EtOAc.

The organic phase was washed with saturated NaHCO3 3X and brine 3X, and dried over anhydrous Na2SO4 to give 12g of AE2 (R'=Me, R3=cyclohexylmethyl), which was used for next step without further purification.

Method AE, Step 2: AE2 (R'=Me, R3=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. 6g of a product that was reacted with Boc anhydride to give 5.8g AE3 (R'=Me, R3=cyclohexylmethyl) after column purification.

Method AE, Step 3: AE4 (R'=Me, R3=cyclohexylmethyl) (8.2 g) was obtained from AE3 (5.8g) according to the step 4 of the method H.

Method AE, Step 4 : To a solution of AE4 (R'=Me, R3=cyclohexylmethyl) ((3. 95 g, 8.38 mmol) in anhydrous THF (98 mL) was added diisopropylethylamine (7 mL, 40 mmol).

The reaction was stirred under N2 (gas) at room temperature. After 5.5 h, the reaction was concentrated and the crude material was purified via flash chromatography eluting with a gradient of 0 to 75% ethyl acetate in hexane to afford AE5 (R'=Me, R3=cyclohexylmethyl) (2.48 g, 92%).

Method AE, Step 4: To a solution of R'50H (R'5=cyclobutyl) (10 1AI) and HBF4 (1 equiv) in anhydrous methylene chloride (0.5 mL) was added a solution of AE5 (R'=Me, R3=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% CH3CN in H20 with 0. 1% formic acid to afford AE5 (R'=Me, R3=cyclohexylmethyl, R'5 = cyclobutyl).

The following compounds were synthesized using similar method: Obs. Obs.

&num Structure MW &num Structure MW m/e m/e Method AF

To a solution of tBuOK (9.5mg, 0. 0848mmole) in 0. 5ml anhydrous THF was added ArOH (Ar=m-Chlorophenyl)(13µl, 0. 1273mmole) in 0. 5ml anhydrous

THF followed by addition of AE4 (R'=Me, R3=cyclohexylmethyl) (20mg, 0. 0424mmole) in 0. 5ml anhydrous THF. The reaction mixture was stirred at room temperature for 2 days before it was diluted with 1 ml MeCN, treated with 100mg MP-TsOH resin and 100mg Amberlyst A26 resin. The resin was removed by filtration and the filtrate was evaporated down to give a product that was treated with 50% TFA for 1 hr. After evaporation of TFA in vacuo, the residue was dissolved in 2ml MeCN, and treated with 100mg MP-TsOH resin.

The resin was washed thoroughly with THF, MeCN and MeOH, and then treated with 2M NH3 in MeoH to give AF2 (R'=Me, R3=cyclohexylmethyl and R'S=3- chlorophenyl).

The following compounds were synthesized using similar method: Obs. Obs.

&num Structure MW &num Structure MW m/e m/e Method AG

NBoc < NBoe NH I R"I R, R2-H/NaH NH 50% TFA/DCM NH THF O'3 O R R R OTf R2 AE4 AG1 AG2 Method AG, Step 1: R21-H (R21 =PhS-) (33µl, 0. 318mmole) was treated with NaH (10. 2mg, 60% in mineral oil) in 0. 5ml anhydrous THF. A solution of AE4 (R'=Me, R3=Cyclohexylmethyl) (20mg, 0. 0424mmol) in 0. 5mi anhydrous THF was added.

The reaction mixture was stirred at room temperature overnight before it was partitioned between ether and saturated NaHCO3 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 NaS04. The crude was purified on flash column with EtOAc/hexane to give 9 mg of AG1 (R2'=PhS-, R1=Me, R3=cyclohexylmethyl) (49.2 % yield).

Method AG, Step 2: AG1 (R2'=PhS-, R'=Me, R3=cyclohexylmethyl) was treated with 50% TFA according to the Step 6 of the method H to give AG2 (R2'=PhS-, R'=Me, R3=cyclohexylmethyl).

The following compounds were synthesized using similar method: Obs. Obs.

&num Structure MW &num Structure MW m/e m/e Method AH

zu HCI Ph-/Ph 1) R4Br/KH NN2 N 18-Crown-6 NH2 HCI 3 DCM O'1 2) 1N HCl "R3"

AH1 AH2 AH3 Method AH, Step 1: Benzophenone imine (3.27g, 18. 04mmole) was added to a suspension of AH1 (R3=cyclohexylmethyl) (4g, 18. 04mmole) in 65ml DCM. The reaction mixture was stirred at room temperature overnight under N2 before the solid was filtered, and the solvent was evaporated. The residue was dissolved in 100 ml ether, washed with water 2X and dried over anhydrous MgS04. The crude was

purified on flash column to give 5.08 g (80. 57% yield) of AH2 (R3=cyclohexylmethyl).

Method AH, Step 2: A solution of AH2 (R3=cyclohexylmethyl) (1 g, 2. 86mmole) in 12 ml anhydrous THF was added to a suspension of 18-crown-6 (0.76g, 2. 86mmole) and 30% KH in mineral oil (1. 16g, 8. 58mmole) in 4ml anhydrous THF under N2.

The mixture was cooled in ice-bath and R4Br (R4=3-pyridylmethyl, as a hydrobromide salt) was then added. The reaction mixture was stirred in ice-bath for 30min and at room temperature for 2 more hrs before the reaction was quenched with 2ml of HOAc/THF/H20 (0.25 : 0.75 : 1). The mixture was diluted with 40ml EtOAc/H2O (1: 1). The aqueous phase was extracted with EtOAc 3 times. The combined organic phase was washed with brine 3 times and dried over anhydrous MgS04. The crude was purified on flash column to give 0. 44g (35.14% yield) of product which was treated with1 N HCI (2. 2ml, 2. 22mmole) in 3ml ether in ice-bath followed by stirred at r. t. overnight. The aqueous phase was evaporated and purified on C-18 reverse phase column to give 0.22g (66% yield) of AH3 (R4=3-pyridylmethyl ; R3=cyclohexylmethyl).

Method Al All A12 To a solution of compound Al1 (R'=Me, R3=n-Bu) (34mg, 0. 105mmol) in methanol (1 ml) was added 10% Pd/C (5mg). The mixture was kept under an H2 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 (R1=Me, R3=n-Bu) (25mg, 100%). Observed MW (M+H) 246.1 ; exact mass 245. 15. 1H NMR (400 MHz, CD3OD) : 5 = 7.59 (m, 2H), 7.36 (m, 3H), 3.17 (s, 3H), 2.17 (m, 2H), 1.27 (m, 4H), 0.86 (t, 3H, J=7. 2Hz).

The following compounds were synthesized using similar method: Obs. Obs.

&num Structure MW &num Structure MW m/e m/e Method AJ \ NHBoc R\ N- N-- 0 N 0 NH 3 1) BuZnBr, Pd (dppf) C ! 2/o THF, 55° C Br w 2) 4N HCU dioxane <

AJ1 AJ2 To a mixture of compound AJ1 (R'=Me, R3=n-Bu) (70mg, 0. 165mmol) and butylzincbromide (1. 32ml, 0. 6mmol) was added Pd (dppf) C12. The mixture

was degassed, sealed and heated at 55 °C for 1 day. The mixture was diluted with CH2CI2 and NH3/H20. The organic layer was separated, dried, concentrated, and purified by RP HPLC to get product which was then treated with 4N HCI/dioxane for 30min to give compound AJ2 (R'=Me, R3=n-Bu) (12mg, 25%). Observed MW (M+H) 302.1 ;'H NMR (400 MHz, CD30D) : 5 = 7.32 (m, 3H), 7.22 (m, 1H), 3.19 (s, 3H), 2.65 (m, 2H), 2.20 (m, 2H), 1.60 (m, 2H), 1.38 (m, 4H), 1.24 (m, 2H), 0.92 (m, 6H).

The following compound was synthesized in a similar fashion: Obs. Obs.

&num Structure MW &num Structure MW m/e m/e

Method AK

AK1 AK2 To a solution of AK1 (R'=Me, R3=n-Butyl, R2'=n-Bu) (9mg, 0. 03mmol) in methanol (1 ml) was added 5% Pt/C (5mg), Rh/C (5mg) and conc. HCI (0. 05ml).

The mixture was kept under H2 (50 psi) for 2 days. After the filtration of the catalyst, the filtrate was concentrated to get compound AK2 (R'=Me, R3=n-butyl, R21=n-Bu) Observed MW (M+H) 308. 1.'H NMR (CD30D) : 5 = 3. 16 (s, 3H), 1.80 (m, 6H), 1.26 (m, 16H), 0.88 (m, 6H).

The following compounds were synthesized using similar method: Obs. Obs.

&num Structure MW &num Structure MW m/e m/e Method AL

AL1 AL2 AL3 Method AL, Step 1: To a solution of compound AL1 (R3=n-Bu) (418mg, 1. 39mmol) in methanol (8ml) was added Pt02 (40mg) and conc. HCI (0. 4mi). The mixture was hydrogenated (50psi) for 1 day. After filtration of the catalyst, the filtrate was concentrated. The crude residue was basified to pH=11-12 by 1 N NaOH. This mixture was extracted with ethyl acetate. The organic layer was separated, dried and concentrated to get compound AL2 (R3=n-Bu) (316mg, 100%).

Method AL, Step 2: To a solution of compound AL2 (R3=n-Bu) (300mg, 1. 32mmol) in dichloromethane (6ml) was added (BOC) 20 (316mg, 1. 45mmol). The mixture was stirred at RT for 1. 5hr. It was diluted with water and dichloromethane. The organic layer was separated, dried and concentrated to get compound AL3 (R3=n-Bu) (464mg, 100%).

Method AM nu Nu NH NH NH RL1 NH V X °t dioxane t CH2Ci2 N N N R1540 Boy AM1 AM2 AM3 Method AM, Step 1: Compound AM1 (R'=Me, R3=n-Butyl) was treated with 4N HCI in dioxane for 2 hr. The mixture was concentrated to get compound AM2 as an HCI salt (R'=Me, R3=n-Butyl). Observed MW (M+H) 470.1 ;'H NMR (CD30D) : 5 = 7.28

(m, 2H), 6.96 (m, 3H), 4.80 (m, 2H), 4.56 (m, 1 H), 4.00 (m, 1 H), 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'=Me, R3=n-Butyl) (32mg, 0. 068mmol) in dichloromethane (1 ml) was added acetyl chloride (5ul, 0. 072mol). The mixture was stirred for 2 hr. It was then diluted with CH2CI2 and water. The organic layer was separated, dried, concentrated and purified by RP HPLC to get compound AM3 (R'=Me, R3=n-Butyl and R'5=Me) Observed MW (M+H) 512.3 ;'H NMR (400 MHz, CDCI3) : o = 7.27 (m, 2H), 6.98 (m, 1H), 6.92 (m, 2H), 4.65 (s, 2H), 4.50 (m, 2H), 3.98 (m, 1 H), 3.70 (m, 1 H), 3.41 (m, 2H), 2.98 (m, 2H), 2.62 (m, 1 H), 2.50 (m, 1 H), 2.47 (m, 1 H), 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. Obs.

&num Structure MW &num Structure MW m/e m/e Method AN

AN2 AN3 To a solution of compound AN2 (R1=4-N-(α- phenoxyacetyl) piperidinylmethyl, R3=n-Butyl) (28mg, 0. 06mmol) in dichloroethane (2ml) was added butyraldehyde (5. 3ul, 0. 06mmol), triethylamine

(8. 4ul, 0. 06mmol) and NaBH (OAc) 3 (18mg, 0. 084mmol). The mixture was stirred overnight. It was then diluted with dichloromethane and water. The organic layer was separated, dried, concentrated and purified by RP HPLC to get AN2 (R'=4- N- (a-phenoxyacetyl) piperidinylmethyl, R3=n-Butyl, R'5=propyl and R'6=H) (5.4mg, 17%). Observed MW (M+H) 526.1 ; exact mass 525. 37.'H NMR (CD30D) : 5 = 7.28 (m, 2H), 6.96 (m, 3H), 4.76 (m, 2H), 4.55 (m, 1 H), 4.05 (m, 1H), 3.77 (m, 1H), 3.61 (m, 3H), 3.50 (m, 1H), 3.11 (m, 4H), 2.85 (m, 1H), 2.68 (m, 1 H), 2.38 (m, 1 H), 2.05 (m, 2H), 1.95 (m, 2H), 1.73 (m, 5H), 1.39 (m, 8H), 1.10 (m, 1 H), 0.99 (m, 3H), 0.92 (m, 3H).

The following compound was synthesized using similar method: Obs. Obs.

&num Structure MW &num Structure MW m/e m/e

Method AO

A mixture of copper chloride (2. 06g, 20. 8mmol) and lithium chloride (1. 76g, 41. 6mmol) in 100ml of THF was cooled down to-78 °C. To this mixture, a 2. 0M solution of A01 (R3=n-butyl) (l0ml, 20mmol) was added gradually. The reaction was warmed up to-60 °C, and A02 (R4=m-Br-Ph) (2. 9moi, 22mmol) was injected. The mixture was stirred at-60 °C for 15 minutes and then quickly warmed up to RT by removing the dry-ice bath. The reaction was quenched with water and sat. NaHCO3. 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 A03 (R4=m-BrPh, R3=n-Bu) (3. 93g, 82%). Observed MW (M+H) 241.1 ; exact mass 240. 01. 1H NMR (400 MHz, CDCb) : 5 = 8.07 (m, 1 H), 7.88 (m, 1 H), 7.64 (m, 1 H), 7.34 (m, 1 H), 2.94 (t, 3H, J=7.2Hz), 1.71 (m, 2H), 1.40 (m, 2H), 0.95 (t, 3H, J=7.6Hz).

The following ketones were made according to Method 9: Structure Observed MW Exact mass (M+H) Method AP Method AP, Step 1:

To a solution of AP1 (R4=3-Bromophenyl) (5g, 25mmol) in dichloromethane (10ml) were added N, O-dimethylhydroxylamine hydrochloride (2.56g, 26. 25mmol) and 4-methylmorpholine (2. 95ml, 26. 25mol). EDCI (5. 04g, 26. 25mmol) was then added portionwise. The reaction mixture was stirred at RT overnight and was then quenched with 1 N HCI (60moi). The mixture was extracted with dichloromethane. The organic layer was washed with 1 N HCI and brine, dried over Na2SO4, and concentrated to give the Weinreb amide AP2 (R4=m-BromoPhenyl) (5. 96g, 98%). Observed MW (M+H) 244. 1 ; exact mass 243. 99.'H NMR (CD3) : 5 = 7.78 (m, 1 H), 7.58 (m, 2H), 7.24 (m, 1 H), 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. 19g, 48. 8mmol) in 30ml of THF was added dropwise a solution of R3Br (R3=cyclohexylethyl) (5. 73ml, 36. 6mmol) in 24ml 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 (R4=m-BromoPhenyl) (5. 96g, 24. 4mmol) was added. The mixture was stirred at RT for 3 hr and then quenched with 1 N HCI until no 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 (R4=m-BromoPhenyl, R3=Cyclohexylethyl) (8. 06g, 100%). Observed MW (M+H) 295.2 ; exact mass 294. 06.'H NMR (400 MHz, CDCI3) : # = 8. 18 (m, 1 H), 7.85 (m, 1H), 7.64 (m, 1H), 7.33 (m, 1H), 2.94 (t, 3H, J=7.2Hz), 1.70 (m, 9H), 1.63 (m, 4H).

Method AQ

To a-78 °C solution of AQ1 (R4= cyclopropyl) (2.55 g, 38.0 mmol) in diethyl ether (100 ml) was added AQ2 (R3=n-BuLi) (38 ml, 1.5 M in hexanes, 57 mmol). After 45 min, the cooling bath was removed. After 3h at RT, the reaction was quenched by dropwise addition of water and then diluted further with EtOAc and water. The phases were separated and the aqueous layer was extracted with EtOAc (2X). The organic portions were combined, washed with brine, dried over MgSO4, and concentrated. This crude residue was subjected to column chromatography (silica gel, O%#100% CH2Cl2/hexanes) to provide the desired ketone AQ4 (R4=cyclopropyl, R3=n-Butyl) (2.57 g, 20.4 mmol, 54%).'H NMR (CDCI3) 8 2.52 (t, J = 7.2 Hz, 2 H), 1.90 (m, 1 H), 1.57 (m, 2 H), 1.30 (m, 2 H), 0.98 (m, 2 H), 0.89 (t, J = 7.6 Hz, 3 H), 0.83 (m, 2 H).

Method AR B2 AR2 Method AR: Compound B2 (R1=m-CI-Phenethyl, R3=Me, R4=i-butyl and R5=benzyl) was converted into AR2 (R1=m-Cl-Phenethyl, R3=Me, R4=i-butyl and R5=benzyl) using method A step 3.

The following compounds were synthesized using similar methods: Obs. Obs.

&num Structure MW &num Structure MW m/e m/e Method AS 0 -p4 AS5 SOC12 I NaH, THF ArR . tr. N R \=/-, 1 AS1 AS2 AS3 AS4 H2N NEt,, N Et3, NsR1 | abs. EtOH A AS6 R4 o R40 Ruz HNrNR1 NH

AS5 Method AS, Step 1: To a mixture of AS1 (R3=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 HCI evolution ceased). The reaction mixture was kept overnight at rt before it was concentrated in vacuo. Toluene (10 ml) was added and the mixture was concentrated in vacuo again. The reaction mixture was dissolved in CH2CI2, solid sodium bicarbonate added, filtered and then the CH2CI2 solution was concentrated in vacuo to give AS2 (R3=Ph).

Method AS, Step 2: To AS2 (R3=Ph) (0.645 g) and AS5 (R4=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 H20 and Et20. The dried Et20 solution was concentrated in vacuo to give a yellow residue which was placed on preparative silica gel plates and eluted with CH2CI2 to give AS3 (R3=Ph, R4=p-CIPh). (Miyashita, A. , Matsuda, H. , Hiagaskino, T. , Chem.

Pharm. Bull., 1992,40 (10), 2627-2631).

Method AS, Step 3: Hydrochloric acid (1 N, 1.5 ml) was added to AS3 (R3=Ph, R4=p-CIPh) in THF (10 ml) and the resulting solution was stirred at rt for 20 h. The reaction mixture was concentrated in vacuo and then partitioned between CH2CI2 and H20. The dried CH2CI2 was concentrated in vacuo to give a residue which was

placed on preparative silica gel plates and eluted with CH2CI2 : hexane 1: 1 to afford AS4 (R3=Ph, R4=p-CIPh).

Method AS, Step 4: AS4 (R3=Ph, R4=p-CIPh) (0.12 g) and methylguanidine, HCI (AS6, R'= Me) (0.055 g) were mixed in absolute EtOH (5 ml) with triethylamine (0.2 ml) and then heated under reflux for 20 h. The resulting mixture was concentrated and then partitioned between CH2CI2 and H20. The dried CH2CI2 was concentrated in vacuo to give a residue which was placed on preparative silica gel plates and eluted with CH2CI2 : MeOH 9: 1 to afford AS5 (R3=Ph, R4=p-CIPh and R'=Me).

The following compounds were synthesized using similar methods: Obs. Obs.

&num Structure MW &num Structure MW m/e m/e Method AT I R'5 Boc, N 0 0 Boc, 0 OH 1) R'5. NH Boc, o-'I NaON/MeOH Rs j Rs NC Jn Jw HN N) n EDC resin HN N) n HN N N'l n 2 2) TFA/DCM R4 40 4 44

AT1 AT2 AT3 Method AT, Step1 : AT1, prepared using a method similar to Method H, Step1, 2 and 3, (n=4, R3=R4=n-Bu) (0.146 g) in MeOH (3 ml) and 1 N NaOH (0.727 ml) were stirred overnight at rt. The mixture was concentrated and then partitioned in water (pH -3, adjusted using conc. HCI) and EtOAc. The dried EtOAc layer was concentrated in vacuo to afford AT2 (n=4, R3=R4=n-Bu).

Method AT, Step 2: Compound AT2 (n=4, R3=R4=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 (R15=H, R16=n-butyl) (0.007 ml). The reaction was carried out overnight at rt. before Argonaut PS-NCO resin (0.150 g), PS-polyamine resin (0. 120g) and THF (2 ml) were added and the mixture shaken for 4 h. The reaction mixture was filtered and resin washed with THF (2 ml). The combined organic phase was concentrated in vacuo before the residue was treated with 1 N HCI in MeOH (1 ml) for 4 h followed by evaporation of solvent to give AT3 (n=4, R3=R4=n-Bu, R15=H and R16=n-Butyi) The following compounds were synthesized using similar method: Obs. Obs.

&num Structure MW &num Structure MW m/e m/e Method AU

AU1 AU2 AU3 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 (R15=H, R16=H) (0.300 g), prepared according to procedure described by Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G.; Tatchell, A. R.,

(Vogel's Textbook of Practical Organic Chemistry. 5t ed. Longman: new York, 1989; pp1034-1035), AU2 (HCI salt, R'=Me) (0.237 g), 50% KOH (0.305 ml), 30% H202 (0.115 ml) and EtOH (4.6 ml) were heated in a sealed tube for 2 h.

Reaction mixture was concentrated and extracted with CH2CI2. The dried organic solution was concentrated in vacuo to give a residue which was placed on preparative silica gel plates eluting with CH2CI2 : MeOH 9: 1 to afford AU3 (R15=H, R'6=H, R'= Me).

The following compounds were synthesized using similar method: Obs. Obs.

&num Structure MW &num Structure MW m/e m/e

Method AV

Boc, N Boc, N HN H 4N---0 HN TF. A H'4N-"*'a OH E>-, 3 OH 2, DCM R3 22 Ru p AV1 AV2 AV3 AV4 Method AV, Step 1: In a microwave tube, AV1 (R3=Me, R4=Bu-i) (0.0012 g) and AV2 (R22=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 (R3=Me, R4=i-Bu, R22=OPh).

Method AV, Step 2: AV3 (R3=Me, R4=i-Bu, R22=OPh) in CH2CI2 (1 ml) and TFA (1 ml) was shaken for 2h and the concentrated in vacuo and purified on Prep LCMS to afford AV4 (R3=Me, R4=i-Bu, R22=OPh).

The following compounds were synthesized in a simlar fashion.

M Obs. M Obs.

&num Structure &num Structure W m/e W m/e Method AW R2 HN Pd (dppf) C) 2 HN"N" HN N R Pd (dPPf) Cl2 HN N Ru toluene. H20 \/n O K2COs nO microwave

AW1 AW2 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. Obs.

&num Structure MW &num Structure MW m/e m/e Method AX H O H 0 H 0 H 0 n Cbz'N p PC Cbi N O 1) NaBH4 Cbz'N O Cbz'N O K2C03 _ Ra 2) AS R4 + rua t-BuOOH ChiralPak \ w O n OH n OH AX1 AX2 AX3 AX4 Rh-Catalysi Rh-Catalys H2 H2 i H 0 H 0 Cbz 40 Cbz 40 "47"4) H % H n OH n"OH AX5 AX6

Method AX, Step 1.

A literature procedure was adapted. (J-Q Yu and E. J. Corey, Organic Letters, 2002,4, 2727-2730).

To a 400 ml DCM solution of AX1 (n=1, R4=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, R4=phenethyl).

Method AX, Step 2.

A solution of AX2 (4.5 g, n=1, R4=phenethyl) in MeOH (50 ml) was treated with 0.4 g of Sodium borohydride and the reaction was stirred for 30 min before the solvent was removed and residue chromatographed to give a mixtrue of AX3 (n=1, R4=phenethyl) and AX4 (n=1, R4=phenethyl) which was separated using an AS chiralpak column eluted with 8% IPA in Hexane (0. 05% DEA) to give 2.1 g of AX3 (n=1, R4=phenethyl) as the first fraction and 2.2 g of AX4 (n=1, R4=phenethyl) as the second fraction.

Method AX, Step 3.

A 100 mi methanolic solution of AX4 (n=1, R4=phenethyl) (2.2 g) and 1,1'-bis (di-i-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, R4=phenethyl) (1.7g).

The following compounds were generated using similar method.

Method AY

AY1 AY2 A solution of AY1 (n = 1; 1.5g, 3.4 mmol), 5% Rh/C (1.5g), 5% Pd/C (0.5g) in AcOH (30 mL) was shaken in a Parr apparatus at 55 psi for 18 hours.

The vessel was flushed with N2, 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.

AY3 Method AZ AZ1 AZ2 AZ3 AZ4 Method AZ, Step 1 To a solution of AZ1 (n=1, R'=Me, R3=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 H20 and diluted with EtOAc. After removal of the organic phase, the aqueous layer was extracted with EtOAc (3x). The combined organics were dried (Na2SO4), filtered,

and concentrated. The residue was purified by silica gel chromatography (0- 100% EtOAc/hexanes) to yield AZ2 (n=1, R'=Me, R3=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'=Me, R3=2-cyclohexylethyl) (0.011 g, 0.025 mmol) and AZ5 (R'5=H and R16=m-pyridylmethyl) (0.0067 mL, 0.066 mmol) in DCE (1.8 mL) and MeOH (0.2 mL) was added AcOH (4 drops) and MP- cycanoborohydride resin (. 095 g, 2.42 mmol/g). The reaction was agitated for 40 hours at room temperature. The reaction was treated with 7N NH3/MeOH, and solution was filtered. After concentration, the residue was purified by silica gel HPLC (0-4% [ (5% 7N NH3/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 3h at r. t. to give AZ4 (n=1, R'=Me, R3=2-cyclohexylethyl, R'S=H and R'6=m-pyridylmethyl) (0.005 g, 0.009 mmol) and the AZ3 (n=1, R'=Me, R3=2-cyclohexylethyl, R'S=H and R'6=m-pyridylmethyl) (0.012 g, 0.022 mmol) respectively.

The following compounds were generated using similar methods: Obs. Obs.

&num Structure MW &num Structure MW m/e m/e Method BA

BA1 BA2 BA3 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, 1 ;

Crapnell, K. M; Fernandez, J-C; Moseley J. D. and Rabot, R. (Joumal of Organic Chemistry, 67 (17), 2002,6185-6187).

'H NMR (CDC) s) for BA2: 1.42 (s, 9H), 4.06 (d, 4H), 4.09 (s, 1 H), 4.18 (s, 2H), 5.62 (d, 1 H).

Method BA, Step 2: BA3 was generated from BA2 using a literature procedure described by Winkler J. D.; Axten J.; Hammach A. H.; Kwak, Y-S; Lengweiler, U.; Lucero, M.

J.; Houk, K. N. (Tetrahedron, 54 1998,7045-7056). Analytical data for compound BA3: MS m/e: 262.1, 264.1 (M+H).'H NMR (CDCl3) 1.43 (s, 9H), 3.98 (s, 2H), 4.11 (d, 4H), 5.78 (d, 1 H).

Method BB

BB4 BB5 Method BB, Step 1; Compound BB1 (n=1, R'=Me, R3=cyclohexylethyl) was converted to BB2 (n=1, R'=Me, R3=cyclohexylethyl) and BB3 (n=1, R'=Me, R3=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'=Me, R3=cyclohexylethyl) was generated from BB2 (n=1, R'=Me, R3=cyclohexylethyl) using 20% TFA in DCM.

The following compounds were generated using similar method: BB5 BB6 BB7 Method BC

BC1 BC2 BC3 Method BC, Step 1; Compound BC2 (n=1, R'=Me, R3=cyclohexylethyl and R'S=m-Pyridyl) was obtained from BC1 (n=1, R2=Me, R3=cyclohexylethyl) using method L step 2.

Method BC, Step 2; Compound BC3 (n=1, R'=Me, R3=cyclohexylethyl and Rr5=m-Pyridyl) was obtained from BC2 (n=1, R'=Me, R3=cyclohexylethyl and Rr5=m-Pyridyl) using method L step 3.

The following compounds were generated using a similar method: Obs. Obs.

&num Structure MW &num Structure MW m/e m/e Method BD

BD1 BD2 BD3 Method BD, Step 1; Compound BD2 (n=1, R'=Me, R3=cyclohexylethyl and R'5=Ph) was obtained from BD1 (n=1, R2=Me, R3=cyclohexylethyl) using Method N, Step 1.

Method BD, Step 2; Compound BD3 (n=1, R1=Me, R3=cyclohexylethyl and R'5=Ph) was obtained from BD2 (n=1, R'=Me, R3=cyclohexylethyl and R'S=m-Pyridyl) using Method N, Step 2.

The following compounds were generated using a similar method: Obs. Obs.

&num Structure MW &num Structure MW m/e m/e Method BE

BE1 BE2 BE3 Method similar to Method M was adapted for these transformations. The following compounds were generated similar methods.

Obs. Obs.

&num Structure MW &num Structure MW m/e m/e

Method BF BF1 BF2 BF3 Method BF, Step 1: Method similar to Method T, Step 1 was used for the synthesis of BF2 (n =1, R'=Me and R3=phenethyl, R'5=H and R'5=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. Obs.

&num Structure MW &num Structure MW m/e m/e

Method BG \ \ J H J H ON-Z ON-Z R3 R3 Rs -' 0. () \n A/n

BG1 BG 2 Method BG: To a solution of BG1 (n=1, R3=cyclohexylethyl) (0.136 g, 0.31 mmol) in CH2CI2 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, R3=cyclohexylethyl, R'S=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 \ \ H ) n) n R3 R3 R5 Rv5 O O n n BH1 BH2 Step2 i OH OH OH NH R2NS R2N¢S 0<, NH 0=<_NH 0<, NH > Step 3 \ R3 + o R3 5 R 15 R'-, H R15 H R\-H n n n BH5 BH4 BH3

Method BH, Step 1.

Compound BH1 (n=1, R3=cyclohexylethyl and R'5=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 H2 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, R3=cyclohexylethyl and R'S=n-butyl) was carried on to the next step without purification.

Method BH, Step 2.

A solution of BH2 (n=1, R3=cyclohexylethyl and R15=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, R2=Me, R3=cyclohexylethyl and R15=n-butyl) (0.032 g, 0.078 mmol, 56% yield) and BH3 (n=1, R2=Me, R3=cyclohexylethyl and R15=n-butyl) (0.008 g, 0.020 mmol, 14% yield). For BH4 (n=1, R2=Me, R3=cyclohexylethyl and R15=n-butyl), MS m/e: 409.1 M+H). For BH3 (n=1, R2=Me, R3=cyclohexylethyl and R15=n-butyl), MS m/e: 409.1 (M+H).

Method BH, Step 3.

Compound BH4 (n=1, R2=Me, R3=cyclohexylethyl and R'S=n-butyl) (0.032 g, 0.078 mmol) was converted to BH5 (n=1, R2=Me, R3=cyclohexylethyl and R'S=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. Obs.

&num Structure MW &num Structure MW m/e m/e Method Bl

A solution of Bl1 (0.020 g, 0.040 mmol) in DCM (1 mL) was degassed using freeze/pump/thaw (4x) method. At the end of the fourth cycle Crabtree's catalyst was added and the system was evacuated. While thawing, the system was charged with hydrogen gas, and the reaction was stirred at room temperature for 16 hours under an H2 atmosphere. The reaction was concentrated, and the brown oil was purified by reverse phase HPLC to furnish B12 (0.011 g, 0.022 mmol, 55% yield). MS m/e: 368.2 (M+H).

Method BJ BJ1 BJ2 BJ3 Method BJ, Step 1 A mixture of 2 ml dioxane solution of BJ1 (R'=Me, R3=Me) (140 mg, 0.5 mmol) generated using Method BK Steps 1 & 2, indole (1.2 eq), potassium t- Butoxide (1.4 eq), Pd2 (dba) 3 (0.02 eq) and 2-di-t-butylphospinobiphenyl (0.04 eq) in a sealed tube was irradiated in a microwave oven at 120 °C for 10 min and the mixture was separated via a silica gel column to give BJ2 (R'=Me, R3=Me) (0.73 mg).

Method BJ, Step 2 BJ2 (R'=Me, R3=Me) was converted to BJ3 (R'=Me, R3=Me) using Method BK, Steps 3 & 4. Obs. Mass for BJ3 (R'=Me, R3=Me) : 319.2.

Obs.

&num Structure MW m/e Method BK OMe OMe (NH,), CO4 OMe rL-agAnt Rg R4 KCN '4 O 3'4 R3 R4 R3 R4 BK1 BK2 BK3 XS \NXS MeOH \ XNH. HCI N N' MeOH N NH +,, NH NH R3 Ra R3 Ra R3 R4

BK4 BK5 BK6 Method BK, Step 1: Hydantoin BK2 (R3=N-benzyl-3-piperidyl, R4=n-Bu) was prepared according to Method D, Step 1 from the corresponding ketone BK1 (R3=N- benzyl-3-piperidyl, R4=n-Bu). Analytical data for BK2 (R3=N-benzyl-3-piperidyl, R4=n-Bu) : (M+H) = 330.1.

Method BK, Step 2: To a suspension of hydantoin BK2 (R3=N-benzyl-3-piperidyl, R4=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 16h and then cooled to RT and concentrated under vacuum. This crude residue was purified by column chromatography (MeOH/DCM) to give

product BK3 (R3=N-benzyl-3-piperidyl, R4=n-Bu) (140 mg, 0.408 mmol, 97%), (M+H) = 344. 1.

Method BK, Step 3: To a solution of a portion of BK3 (R3=N-benzyl-3-piperidyl, R4=n-Bu) (70 mg, 0.20 mmol) in toluene (1 ml) was added Lawesson's reagent (107 mg, 0.26 mmol). The resulting mixture was placed in an oil bath at 60 °C for 16h and then at 100 °C for 24h. After cooling to RT, the reaction was quenched by addition of several drops of 1 N HCI and then diluted with EtOAc and 1 N KOH. The phases were separated and the aqueous layer extracted with EtOAc (2X). The organic portions were combined, washed with brine, dried over MgS04, filtered, and concentrated. This crude residue was purified by preparative TLC (1000 um silica, 15% EtOAc/DCM) to give two separated diastereomers BK4 (R3=N- benzyl-3-piperidyl, R4=n-Bu) (24 mg, 0.067 mmol, 33%, MS: (M+H) = 360.2) and BK5 (R3=N-benzyl-m-piperidyl, R4=n-Bu) (22 mg, 0.062 mmol, 31%, MS: (M+H) = 360. 2).

Method BK, Step 4: Diastereomer BK5 (R3=N-benzyl-3-piperidyl, R4=n-Bu) was treated with NH40H (2 ml) and t-butyl hydrogen peroxide (70% aqueous, 2 ml) in MeOH (4 ml) for 24 h. After concentration, the crude sample was purified by preparative TLC (1000 mm silica, 7.5% 7N NH3/MeOH in DCM). The resulting sample was dissolved in DCM (1 ml), treated with 4N HCI in dioxane for 5 min, and finally concentrated to give diastereomeric products BK7 (R3=N-benzyl-3- piperidyl, R4=n-Bu) (12 mg, 0.029 mmol, 43%).'H NMR (CD30D) 8 7.60 (m, 2 H), 7.49 (m, 3 H), 4.39 (ABq, JAB = 12.8 Hz, AVAB = 42.1 Hz, 2 H), 3.69 (m, 1 H), 3.39 (brd, J= 13.6 Hz, 1 H), 3.20 (s, 3 H), 2.96 (m, 2 H), 2.45 (m, 1 H), 1.99 (m, 1 H), 1.92-1. 78 (m, 3 H), 1.68 (br d, J = 12.4 Hz, 1 H), 1.50 (dq, Jd = 3.6 Hz, Jq = 12.8 Hz, 1 H), 1.36-1. 22 (m, 4 H), 1.03 (m, 1 H), 0.90 (t, J= 7.2 Hz, 3 H). LCMS: tR (doubly protonated) = 0.52 min, (singly protonated) = 2.79 min; (M+H) for both peaks = 343.2.

The following compounds were synthesized using similar methods: M Obs.

&num Structure W m/e Method BL

BL1 BL2 To a 2ml Methanolic solution of BL1 (n=1, R3=cyclohexylethyl, R'=Me) (10 mg) was added BL3 (HCI salt, R'S=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, R3=cyclohexylethyl, R'= Me and R15 = H).

The following compounds were synthesized using similar methods.

Obs. Obs.

&num Structure MW &num Structure MW m/e m/e Method BM

BM4 BM5 Method BM, Step 1: To a toulene solution (3ml) of BM1 (n=1, R3=cyclohexylethyl, R2=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, R3=cyclohexylethyl, R2=Me) after reverse phase purification.

Method BM Step 2: To a DCM solution of BM2 (n=1, R3=cyclohexylethyl, R2=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, R3=cyclohexylethyl, R2=Me).

Compound BM4 (n=1, R3=cyclohexylethyl, R2=Me) and BM5 (n=1, R3=cyclohexylethyl, R2=Me) were generated from BM2 (n=1, R3=cyclohexylethyl, R2=Me) and BM3 (n=1, R3=cyclohexylethyl, R2=Me) through Boc-deprotection.

The following compounds were synthesized using similar method: Obs. Obs.

&num Structure MW &num Structure MW m/e m/e Method BN

BN1 BN2 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. Obs.

&num Structure MW &num Structure MW m/e m/e Method BP

Method BP, Step 1 To a solution of BP1 (n=1, R'=Me, R2=H, R3= cyclohexylethyl) (0.012 g, 0.028 mmol) in CH2CI2 (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'=Me, R2=H, R3= cyclohexylethyl) (0.010 g, 0.019 mmol). MS m/e: 526.1 (M+H).

Method BP, Step 2 BP3 (n=1, R'=Me, R2=H, R3 = cyclohexylethyl) was prepared from BP2 (n=1, R'=Me, R2=H, R3 = cyclohexylethyl) using 30% TFA/DCM. MS m/e: 426.1 (M+H).

M Obs.

&num Structure W m/e

Method BQ BOC BOC R2 N_ z R N 11 N_R2 N Il R J. N N- ( ON O= « N O+ NH Step 1 p R3 Step 2 HN N HN non Me0/ Me0 \1 B01 B02 BQ3 OMe OMe

Method BQ Step 1: BQ1 was prepared according to Method AZ.

To a solution of BQ1 (n=1, R'=Me, R2=H, R3 = cyclohexylethyl) (0.004 g, 0.007 mmol) in CH2CI2 (0.3 mL) was added DIEA (0.007 mL, 0.040 mmol), acetic acid (0.001 mL, 0.017 mmol), HOBt (0.003 g, 0.019 mmol), and EDCI (0.003 g, 0.016 mmol). The reaction was stirred at room temperature for 16 hours. The reaction was concentrated and purified by reverse phase HPLC to provide BQ2 (n=1, R'=Me, R2=H, R3 = cyclohexylethyl) (0.003 g, 0.005 mmol).

MS m/e: 627.1 (M+H).

Method BQ Step 2: BQ2 (n=1, R'=Me, R2=H, R3 = cyclohexylethyl) (0.003 g, 0.005 mmol) was treated with 20% TFA/CH2CI2 (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'=Me, R2=H, R3 = cyclohexylethyl) (0.002 g, 0.005 mmol). MS m/e: 377.2 (M+H).

&num Structure MW Obs. m/e Method BR BOC BOC 2 -Y-"'W N OH R3 R3 3 Step 1 O=S O R Step 2 R HN N--- O=S O non MeO MeO BR1 BR2 BR3 OMe OMe

Method BR, Step 1: To a solution of BR1 (n=1, R'=Me, R2=H, R3= cyclohexylethyl) (0.004 g, 0.007 mmol) in pyridine (0.2 ml) was added DMAP (a few crystals) and methylsulfonyl chloride (3 drops). The reaction was stirred at room temperature for 6 days. The reaction was quenched with water and diluted with CH2CI2. The organic layer was removed, and the aqueous phase was extracted with CH2CI2 (3x). After concentration, the brown residue was purified by reverse phase HPLC to yield BR2 (n=1, R'=Me, R2=H, R3 = cyclohexylethyl) (0.003 g, 0.004 mmol). MS m/e: 663.2 (M+H).

Method BR, Step 2: BR3 (n=1, R'=Me, R2=H, R3 = cyclohexylethyl) was prepared from BR2 (n=1, R1=Me, R2=H, R3= cyclohexylethyl) following a procedure similar to Method BQ Step 2. MS m/e: 413.1 (M+H).

Obs.

&num Structure MW m/e Method BS

Method BS Step 1: To a solution of BS1 (n=1, R'=Me, R2=H, R3 = cyclohexylethyl) (0.003 g, 0.006 mmol) in CH2Cl2 (0.3 mL) was added phenyl isocyanate (2 drops). The reaction was stirred at room temperature for 16 hours. The reaction was concentrated and purified by reverse phase HPLC to provide BS2 (n=1, R'=Me, R2=H, R3 = cyclohexylethyl) (0.002 g, 0.002 mmol). MS m/e: 823.5 (M+H).

Method BS Step 2: Compound BS2 (n=1, R'=Me, R2=H, R3 = 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'=Me, R2=H, R3 = cyclohexylethyl) (0. 0012 g, 0.002 mmol). MS m/e: 454.1 (M+H).

Obs.

&num Structure MW m/e Method BT

BT1 BT2 Method BT: To a round bottom flask were added compound BT1 (R'=Me, R3=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 N2 for 2 minutes before NaO-t-Bu (61 mg, 0.638 mmol) and Pd2 (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 CH2CI2. The combined organic layer was then dried over Na2SO4. After the filtration, the concentrated residue was separated by TLC (CH30H : CH2CI2=1 : 10) and reverse phase HPLC (10%-100% acetonitrile in water w/0. 1 % formic acid) to produce the desired compound BT2 (R1=Me, R3=Me and R2'= m-pyridyl) as a formate salt (23.6 mg, white solid, 20%).'HNMR (CDC13) 8 7.50-6. 90 (m, 13 H), 3.14 (s, 3H) MS m/e 358 (M+H).

Obs. Obs.

&num Structure MW &num Structure MW m/e m/e Method BU

Method BU, Step 1, To a round bottmed flask containing BU1 (m =1, n = 1, R'=Me, R3=Cyclohexylethyl) (99 mg, 0.307 mmol) of the trifluroacetic acid salt of pyrollidine derivative in 5 ml of DCM was added (86 L, 0.614 mmol) of triethylamine followed by addition of (76 mg, 0.307 mmol) N-(benzyyloxycarbonyloxy) succinimide. Stir at room temperature for 18h. Dilute the mixture with DCM and extract with sat'd NaHCO3 soln, then water. Collect the organic portion and dry over Na2SO4, 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'=Me, R3=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'=Me, R3=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 NH40H. Seal the vial and shake at room temperature for 72h. The mixture was concentrated in vacuo. The mixture was diluted with 1 ml of MeOH and a mixture 30 mg of NaHCO3 and Boc20 (87 mg, 0.398 mmol) were added. The solution mixture was stirred at room temperature for 18h before it was concentrated and the residue purified by silica gel chromatography using EtOAc/hexanes to yield the BU3 (m =1, n = 1, R'=Me, R3=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'=Me, R3=Cyclohexylethyl) (90mg, 0.167 mmol) in 5 ml of MeOH was hydrogenated using100 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'=Me, R3=Cyclohexylethyl) (47 mg 0.116 mmol, 70% yield). MS m/e: 407.1 (M+H).

Method BU, Step 4, To a vial containing 10 mg of powdered 4 4 molecular sieves was added 3- methoxyphenyl boronic acid (60 mg, 0.395 mmol) then 3 ml of anhydrous MeOH. To this mixture was added pyridine (100 ml, 0.650 mmol), Cu (OAc) 2 (7 mg, 0.038 mmol), and BU4 (m =1, n = 1, R'=Me, R3=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 5ml of 40% of TFA in DCM for 5 h. After removal of the volatiles, the residue was purified using a reverse phase HPLC system to furnish BU5 (m =1, n = 1, R'=Me, R3=Cyclohexylethyl and R2'=m-MeOPh) as the formic acid salt (0.7 mg, 0.0015 mmol, 30. 1% yield). MS m/e: 413.1 (M+H).

Obs. Obs. <BR> <BR> m/e<BR> &num Structure MW &num Structure MW<BR> maze 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 (R4= phenyl) (2.0 g, 10 mmol) in THF (47 mL). After 60 minutes at-78 C, a solution of BV1 (R3 = 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 CH2CI2 (2 x), dried over MgS04 and concentrated under vacuum. The resulting oil was subjected to silica gel chromatography using 4-10% EtOAc/Hexanes to give a white solid BX3 (fuzz 3- bromo-4-fluorophenyl and R4= phenyl) (1.69 g, 4.23 mmol, 42%).'H NMR (CDCI3) 8 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 (R3 = 3-bromo-4-fluorophenyl and R4 = 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 Na2S03. After diluting with CH2Cl2, the layers were separated, and the organic layer washed with water (2x), brine (1 x) and dried over MgS04. Concentration under vacuum afforded an oil which was subjected to silica gel chromatography using 5% EtOAc/Hexanes to give a solid BV4 (R3= 3-bromo-4-fluorophenyl and R4= phenyl) (690 mg, 2.24 mmol, 53%).'H NMR (CD3) 6 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 (R3= 3-bromo-4-fluorophenyl and R4 = phenyl and R'=Me and R2 = H) was prepared from BV4 (R3= 3-bromo-4-fluorophenyl and R4= phenyl) using Method AS, Step 4.

Obs. Obs m/e<BR> &num Structure MW &num Structure MW<BR> m/e Human Catheosin D 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'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 consisitent with Yasuda et al.

The assay is run in a 30ul final volume using a 384 well Nunc black plate. 8 concentrationsof compound are pre-incubated with enzyme for 30mins at 37C followed by addition of substrate with continued incubation at 37C for 45 mins. The rate of increase in fluorescence is linear for over 1 h and is measured at the end of the incubation period using a Molecular Devices FLEX station plate reader. Kis are interpolated from the IC50s using a Km value of 4uM and the substrate concentration of 2.5uM.

Reagents Na-Acetate pH 5 1% Brij-35 from 10% stock (Calbiochem) DMSO Purified (>95%) human liver Cathepsin D (Athens Research & Technology Cat&num 16-12- 030104) Peptide substrate (Km=4uM) Bachem Cat # M-2455 Pepstatin is used as a control inhibitor (Ki-0. 5nM) and is available from Sigma.

Nunc 384 well black plates Final Assay buffer conditions 100mM Na Acetate pH 5.0 0.02% Brij-35 1% DMSO Compound is diluted to 3x final concentration in assay buffer containing 3% DMSO.

10ul of compound is added to 10ul of 2.25nM enzyme (3x) diluted in assay buffer without DMSO, mixed briefly, spun, and incubated at 37C for 30mins. 3x substrate (7.5uM) is prepared in 1 x assay buffer without DMSO. 10ul of substrate is added to each well mixed and spun briefly to initiate the reaction. Assay plates are incubated

at 37 C for 45mins and read on 384 compatible fluorescence plate reader using a 328nm Ex and 393nm Em.

Compounds of the present invention exhibit hCathD Ki data ranges from about 0.1 to about 500 nM, preferably about 0.1 to about 100 nM more preferably about 0.1 to about 75 nM.

The following are examples of compounds that exhibit hCathD Ki data under 75 nM. structure structure The following compound

has a hCath D Ki value of 0.45 nM.

BACE-1 CloninQ, 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, CA). A Hindlil/Pmel fragment from pCDNA4-sBACE1 myc/His was blunt ended using Klenow and subcloned into the Stu I site of pFASTBACI (A) (Invitrogen). A sBACE1mycHis recombinant bacmid was generated by transposition in DHlOBac cells (GIBCO/BRL). Subsequently, the sBACE1mycHis bacmid construct was transfected into sf9 cells using CellFectin (Invitrogen, San Diego, CA) in order to generate recombinant baculovirus. Sf9 cells were grown in SF 900-il medium (Invitrogen) supplemented with 3% heat inactivated

FBS and 0.5X penicillin/streptomycin solution (Invitrogen). Five milliliters of high titer plaque purified sBACEmyc/His virus was used to infect 1 L of logarithmically growing sf9 cells for 72 hours. Intact cells were pelleted by centrifugation at 3000xg for 15 minutes. The supernatant, containing secreted sBACEI, 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 NaCI).

Proteins, were eluted from the Q-sepharose column with Buffer B (20 mM HEPES, pH 8.0, 500 mM NaCI). The protein peaks from the Q-sepharose column were pooled and loaded onto a Ni-NTA agarose column. The Ni-NTA column was then washed with Buffer C (20 mM HEPES, pH 8.0, 500 mM NaCI). Bound proteins were then eluted with Buffer D (Buffer C+250 mM imidazole). Peak protein fractions as determined by the Bradford Assay (Biorad, CA) were concentrated using a Centricon 30 concentrator (Millipore). sBACE1 purity was estimated to be-90% as 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 Hydrolvsis Assav.

The inhibitor, 25 nM EuK-biotin labeled APPsw substrate (EuK- KTEEISEVNLDAEFRHDKC-biotin ; CIS-Bio International, France), 5 FM unlabeled APPsw peptide (KTEEISEVNLDAEFRHDK ; American Peptide Company, Sunnyvale, CA), 7 nM sproBACE1, 20 mM PIPES pH 5.0, 0. 1% Brij-35 (protein grade, Calbiochem, San Diego, CA), and 10% glycerol were preincubated for 30 min at 30°C. Reactions were initiated by addition of substrate in a 5 11 aliquot resulting in a total volume of 25 gl. After 3 hr at 30° C reactions were terminated by addition of an equal volume of 2x stop buffer containing 50 mM Tris-HCI pH 8.0, 0.5 M KF, 0.001 % Brij-35,20 Zg/ml SA-XL665 (cross-linked allophycocyanin protein coupled to streptavidin; CIS-Bio International, France) (0. 5 ug/well). Plates were shaken briefly and spun at 1200xg 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 lis delay and simultaneous measurements of both 620 nm and 665 nm emissions for 400 lis.

IC50 determinations for inhibitors, (0, 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/ 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 1, Y is the percent change in ratio and Y starts at bottom and goes to top with a sigmoid shape.

Compounds of the present invention have an IC50 range from about 0.1 to about 500 ßM, preferably about 0.1 to about 100 FM, more preferably about 0.1 to about 20 µM. The last compound in Table M has an In50 value of 0. 35 µM.

Examples of compounds under 1 FM 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 V5-6His sequence into pCDNA3.1. pCNDA3.1-Renin-V5- 6His was stably expressed in HEK293 cells and purified to >80% using standard Ni- Affinity chromatography. The prodomain of the recombinant human renin-V5-6His was removed by limited proteolysis using immobilized TPCK-trypsin to give mature- human renin. Renin enzymatic activity was monitored using a commercially available fluorescence resonance energy transfer (FRET) peptide substrate, RS-1 (Molecular Probes, Eugene, OR) in 50mM Tris-HCI pH 8.0, 1 OOmM NaCI, 0. 1% Brij-35 and 5% DMSO buffer for 40mins at 30 degrees celsius in the presence or absence of different concentrations of test compounds. Mature human Renin was present at approximately 200nM. Inhibitory activity was defined as the percent decrease in renin induced fluorescence at the end of the 40min incubation compared to vehicle controls and samples lacking enzyme.

1% of hRenin at 1001lM Compound

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, mi or m2 antagonists can be used. Examples of m, antagonists are known in the art. Examples of m2 antagonists are also known in the art; in particular, m2 antagonists are disclosed in US patents 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 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, pharmaceutical 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's Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co. , Easton, Pennsylvania.

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 pharmaceutical 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 pharmaceutical 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 pharmaceutical 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 pharmaceutical acceptable carrier, and a separate container comprising a cholinesterase inhibitor in a pharmaceutical acceptable carrier, with the compound of formula I and the cholinesterase inhibitor being present in amounts such that the combination is therapeutical 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.