CONDON, Stephen, M. (3418 Conestoga Road, Glenmoore, Pennsylvania, 19343, US)
| J. CLAIMS
What is claimed is:
1. A compound comprising a homodimer or heterodimer having monomeric units of general formula (1):
(Ro)s (Re)P
R 5
(i) R 1 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; and R 2 is, independently, selected from hydrogen, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, hetereocyclyl, ORn, NR I 5 R I6 , and a moiety of formula (II):
V-
" ' K — R
\ (II) wherein each nx is, independently, 0-6; each R is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl. aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, C(A)Ri 0 , OR t ι, and NR| 5 R !6 ; and each R 6 and R 7 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl; and (ii) any R 1 and R 2 together with a nitrogen atom on which Ri and R 2 are substituted form a heterocyclic or heteroaryl ring; each R 3 , R 4 , and R 5 is, independently, selected from:
-107- (i) Ra and R4 are. independently, selected from hydrogen, lower alkyl, lower alkenyl, alkynyl, lower cycloalkyl, and lower heterocyclyl; and R5 is selected from hydrogen, aikyl, alkenyl, alkynyl, aryl. heteroaryl, cycloalkyl, heterocyclyl and
NR 15 R 16 ; and
(ii) any R 5 and R 3 or R 5 and R 4 together with atoms on which they are substituted form a heterocyclic or heteroaryl ring and remaining R 3 or R 4 is selected as (i); each Rs x is, independently, selected from hydrogen, lower alkyl, lower alkenyϊ, and lower alkynyl; each Rg and R 9 is, independently, selected from:
(i) Rg and R9 are each independently selected from lower alkyl, lower alkenyl, lower alkynyl, aryl, heteroaryl, cycloalkyi, heterocyclyl, C(A)Ri 0 , halo, pseudohalo, OR 1 1 , oxo, thio, S(D) n Ri 2 , NR 15 Ri 6 , N + Rf 5 R 16 R n , =NR 25 , and ^CR 13 R 14 ; (ii) any R 8 and R 9 together with atoms on which they are substituted form a cycloalkyl, aryl, heterocyclic, or heteroaryl ring; and (iii) two R 8 substituents together with carbon atoms to which they are substituted form a cycloalkyl, aryl. heteroaryl, or heterocyclyl ring; each A is, independently, selected from O, S, and NR 25 ; each Rio is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryl ium, cycloalkyl, heterocyclyl, C(A)Ri 6 , halo, pseudohalo, OR2 5 , SR 25 , NR27R28, and SiR 22 R23R24; each Rn is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, C(A)R 2 9, NR30R3!, and SiR 22 R 23 R 24 ; each D is, independently, selected from O and NR 25 ; each n is 0, 1, or 2; with the proviso that when any n is 1 or 2, then Rj 2 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, halo, pseudohalo, OR 25 , SR 25 , and NR32R33; and when n is 0, then R) 2 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, SR 25 , and C(A)R 2 ^; each Ru and R^ is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, C(A)R 2 ?, OR 25 , and NR 32 R 33 ;
-108- each R| 5 , R K , and Rn is, independently, selected from hydrogen, alky!, alkenyl, alkynyl, aryl, heteroaryl, heteroaryiium, cycloalkyl, heterocyclyi, C(λ)R 29 , OR 25 , and NR 32 R 33 ; or any two of Ra, R|6, and R]? together form alkylene, alkenylene, alkynylene, heteroalkylene, and the other is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryiium, cycloalkyi, heterocyclyi, C(A)R 2S i, OR 25 , and NR 32 R 33 ; each R22, R23, and R24 is, independently, selected from:
(i) R22, R23, and R24 are each, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryiium, cycloalkyl, heterocyclyi, OR 25 , and NR 32 R 33 ; or
(ii) any two of R22, R23, and R 2 4 together form alkylene, alkenylene, alkynylene, or heteroalkylene. and the other is selected selected from (i); each R 2 5 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryiium, cycloalkyl, and heterocyclyi; each R29 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryiium, cycloalkyl, heterocyclyi, OR 40 , and NR 32 R 33 ; each R30 and R 3 ] is, independently, selected from hydrogen, alkyϊ, alkenyl, alkynyl, aryl, heteroaryl, heteroaryiium, cycloalkyl, heterocyclyi, and C(A)R 41 , wherein any R 41 is selected from alky ] , alkenyl, alkynyl, aryl, heteroaryl, heteroaryiium, cycloalkyl, heterocyclyl, OR 40 , and NR32R33; or any R3U and R31 together form alkylene, alkenylene, alkynylene, or heteroalkylene; each R 32 and R33 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryiium, cycloalkyl, and heterocyclyi; or R 32 and R 33 together form alkylene, alkenylene, alkynylene, or heteroalkylene; each R, R 5x , and Ri-Ris, R22-R25, and R29-R33 is, independently, unsubstituted or substituted with one or more substitutents, each independently selected from Qj wherein:
Qi is. independently, selected from halo, pseudohalo, hydroxy, oxo, thia, nitrite, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalky], alkenyl containing I to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, heterocyclyi, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyidiarylsϋyl, triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkox year bony 1, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl. aralkoxycarbonyl.
-109- aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy. aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy, aϊkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, gυanidiπe, isothioureido, υreido, N-alkylureido, N-arylυreido, N ' - alkylureido, N',N ' -dialkylureido, N'-alkyl-N'-arylureido, N',N'-diarylureido, N'-arylureido,
N',N'-dialkylureido, N-alkyl-N ' -arylureido, N-aryl-N'-alkylureido, N,N'-diarylureido, N, N ' ,N'- trialkylureido, N,N'-dialkyl-N'~arylureido, N-alkyt-N'.N'-diarylureido, N-aryl-N\N'- dialkylureido, N,N'-diaryl-N'-alkylureido. N,N',N'-triarylureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkyϊarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, aryicarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonyiamino, aryloxycarbonyiamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino, heteroarylthio, azido, -N + R 5 iR5 2 R5 3 ,
P(R 50 )2, P(=O)(R 50 )2, OPC=O)(R 5 O^, -NR 60 C(^O)R 63 , dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl, hydroxyphosphonyl, alkylthio, arylthio, perfϊuoroaJkylthio, hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfmyloxy, alkylsulfcnyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysuifonyioxy, aminosulfonyloxy, alkylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsυlfinyl, alkylsulfonyl, arylsuifinyl, arylsulfonyl, hydroxysulfonylo, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyl, and alkylarylaminosulfonyl; or two Qi groups, which substitute atoms in a 1,2- or 1,3 -arrangement, together form alkylenedioxy, thioalkylenoxy, or alkylenedithioxy; or two Qi groups, which substitute the same atom, together form alkylene; and each Qi is, independently, unsubstituted or substituted with one or more substitutents, each independently selected from Q 2 wherein:
-1 10- QT is, independently, selected from halo, pseudohalo, hydroxy, oxo. thia, nitrile, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalky!, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycioalky], cycioalkylalkyl. heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalky], aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, araikoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy, alkyl aminocarbonyl oxy, dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidine, isothioureido. ureido, N-alkylureido, N-arylureido, W- alkylureido, N',N'-dialkylureido, N'-alkyl-N'-arylureido, N',N'-diarylureido, N'-arylureido, N',N'-dialkylureido, N-alkyl-N'-arylureido, N-aryl-N'-alkylureido, N,N'-diarylureido, N, N',N'- trialkylureido, N.N'-dialkyl-N'-arylureido, N-alkyl-N',N'-diarylureido, N-aryϊ-N\N'- dialkylureido, N,N'-diaryl-N'-alkylureido, N,N',N ' -triarylureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, alkyϊamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamtno, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonyl amino, arylcarbonylaminoalkyi, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxy carbonylamino, alkylsulfonylamino, arylsυlfonylamino, heteroarylsulfonylamino, heterocyclylsiilfonylamino, heteroarylthio, azido, -N + RsjR 52 R 53 , P(R 5 O) 2 , P(=O)(R 50 )2, OP(=O)<R 50 )2, -NR 60 Ct=O)R 63 , dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl, hydroxyphosphonyl, alkylthio. arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsυlfinyloxy, alkylsulfonyioxy, arylsulfinyloxy, arylsuifonyloxy, hydroxysulfonyioxy, alkoxysulfonyloxy, aminosulfonyloxy, alkyiaminosulfonyloxy, alkylaryiaminosuifcnyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfoπyl, hydroxysυlfonylo, alkoxysulfonyl, aminosuifonyJ, alkylaminosulfonyJ,
-1 1 1- dialkylaminosulfonyi, arylaminosulfonyl, diarylaminosulfonyl, and alkylarylaminosulfony]; or two Q 2 groups, which substitute atoms in a 1 ,2- or 1 ,3-arrangement, together form alkylenedioxy, thioalkylenoxy, or aikylenedithioxy; or two Q 2 groups, which substitute the same atom, together form alkylene; each R 50 is, independently, selected from hydroxyl, alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl, and -NR70R7!, wherein any R 70 and R?i is, independently, selected from hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroaralkyl, or heterocyclyl; or any R 70 and R 7 ] together form aikylene, azaalkylene, oxaalkylene, or thiaalkylene; each R 51 , R 52 , and R 53 is, independently, selected from hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroaralkyl, heterocyclyl, and heterocyclylalkyl; each R < 5o is, independently, selected from hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroaralkyl, heterocyclyl, and heterocyclylalkyl; and each Rό3 is, independently, selected from alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl, and -NR70R71, with the proviso that when: a) Y is a seven-membered heterocyclic ring with 1 heteroatom in the ring; b) X is a five-membered heterocyclic ring with 1 heteroatom in the ring; c) R 8 and R 9 together with any atoms on which they are substituted form a phenyl ring; and d) nx is 0; then R, R^, and R 7 are not heterocyclyl or heteroaryl; or a pharmaceutically acceptable salt or hydrate thereof.
2. The compound of claim 1, having the formula (III):
(R 5 )S.
Rsx
R<
M and M' are each, independently, CO, SO, or SO 2 ; Z and Z' are each, independently, CH or N;
-1 12- X, X', Y, and Y' are each, independently, selected from 4-7 membered heterocyclic and heteroaryl rings containing one or two heteroatoms; s and p are each, independently, 0-3; Rι, R| ' , R 2 , and R 2 ' are each, independently, selected from:
(i) R| and RT are each, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloaikyl or heterocycloalkyl; and R 2 and R 2 ' are independently selected from hydrogen, alkenyl, alkynyl, aryl, heteroaryl, cycloaikyl, hetereocyclyl, ORu, NRj 5 Ri S , and a moiety of formula (II):
,Y ,- R 6
R7 (II) where nx is 0-6; each R is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryl ium, cycloaikyl, heterocyclyl, C(A)R !0 , OR11, and NR] 5 R] 6 ; and each R 6 and R 7 is, independently, selected from hydrogen, alkyl, alkenyi, alkynyl, aryl, heteroaryl, cycloaikyl, and heterocyclyl; and (ii) R| and R 2 , either alone or together with Ri ' and R 2 ', together with a nitrogen atom on which they are substituted form a heterocyclic or heteroaryl ring; R3, R3', R4, R4 ' , R5, and R5' are each, independently, selected from:
(i) R3, R 3 ', R 4 , and R 4 ' are each, independently, selected from hydrogen, lower alkyl, lower alkenyl, alkynyl, lower cycloaikyl, lower heterocyclyl; and R 5 , and R 5 ' are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloaikyl, heterocyclyl, and NRi 5 Ri 6 ; and
(ii) R5 and R3, independently or together with R 5 ' and R 3 ", or R 5 and R 4 , independently or together with R 5 ' and R 4 '. together with any atoms on which they are substituted form a heterocyclic or heteroaryl ring and the other Of R 3 , R 3 ', R 4 , or R 4 is selected as (i);
R5X and Rsx' are each, independently, selected from hydrogen, lower alkyl, lower alkenyl, and lower alkynyl;
Rg, Rs', Rg, and R 9 ' are each, independently, selected from:
(i) each Rg, Rs', R 9 , and R 9 ' is, independently, selected from lower alkyl, lower alkenyl, lower alkynyl, aryl, heteroaryl, cycloaikyl, heterocyclyl, C(A)Ri O , halo,
-1 13- pseudohalo, OR n , oxo, thio, S(D) n Rt 2 , NR ! 5 R, 6 , N + Ri 5 Ri 6 Rn, =NR 25 , and -CR 13 Rn;
(ii) any Rg and R 9 independently or together with any Rg' and R 9 ', together with any atoms on which they are substituted form a cycloalkyl, aryl, heterocyclic, or heteroaryl ring; and
(iii) any two Rs substituents, independently or together with any two R«' substitutents, together with carbon atoms to which they are substituted form a cycloalkyl, aryl, heteroaryl, or heterocyclyl ring; each A is, independently, O, S, or NR 25 ; each Rio is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, C(A)Rj 6 , halo, pseudohalo, OR 25 , SR 25 , NR27R28, and SiR 22 R 23 R 24 ; each Rn is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, C(A)R 29 , NR 30 R 31 , and SiR 22 R 2S R 2 ^ each D is, independently, O or NR 25 ; each n is, independently, O, 1, or 2; with the proviso that when any n is 1 or 2, then Ri 2 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, halo, pseudohalo, OR 25 , SR 25 , and NR 32 R 33 ; and when n is 0, then Ri 2 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, SR 25 , and C(A)R 29 ; each R 13 and Rt 4 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, C(A)R 29 , OR 25 , and NR 32 R 33 ; each Ri 5, Rj 6 , and Ri 7 is, independently, selected from:
(a) hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, C(A)R 29 , OR 25 , or NR 32 R 33 ; and
(b) any two of R15, Rt 6 , and Rp together form alkylene, alkenylene, alkynylene, or heteroalkylene, and the other is selected as in (a); each R 22 , R 23 , and R 24 is, independently, selected from:
-1 14- (i) each R22, R23, and R24 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyi, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR 25 , and NRJ2R33; and
(ϋ) any two of R22, R23. and R24 together form alkylene, alkenylene, aikynylene, or heteroalkylene, and the other is selected as in (i); each R2 5 is, independently, selected from hydrogen, alkyl, alkenyl, aikynyl, aryl, heteroaryl, heteroarylium. cycloalkyl, and heterocyclyl; each R 30 and R 3 ] is, independently, selected from hydrogen, alkyl, alkenyl, aikynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl or C(A)R 4 ], where R 41 is alkyl, alkenyl, aikynyl, aryl, heteroaryi, heteroarylium, cycloalkyl, heterocyclyl, OR 40 , and NR 32 R 33 ; or any R 30 and R31 together form alkylene, alkenylene, aikynylene, or heteroalkylene; each R 3 2 and R 33 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyi, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl; or any R 32 and R 33 together form alkylene, alkenylene, aikynylene, or heteroalkylene; each R, R 5x , R 5x ', Ri ', R 2 ', R 3 ', Rλ RS', RS', R<>\ RI-R 18 , R22-R25. and R 29 -R 33 is, independently, unsubstituted or substituted with one or more substitutents, each independently selected from Q] wherein:
Qi is selected from halo, pseudohalo, hydroxy, oxo, thia, nitrile, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyi containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy. alkylaminocarbonyloxy, dJalkylaminocarbonyloxy, aikylarylaminocarbonyloxy, diary laminocarbonyloxy, guanidine, isothioureido, ureido, N-alkylureido, N-arylureido, N'-
-1 15- alkylureido, N',N'-dialkylureido, N'-alkyl-N'-arylureido, N\N'-diarylureido, N'-arylureido, N'.N'-dialkylureido, N-alkyl-N'-arylureido, N-aryl-N'-alkylureido, N,N'-diarylureido, N, N\N'~ tri alkylureido, N.N'-dialkyl-N'-arylureido, N-alkyl-N',N'-diarylureido, N-aryI-N',N'- dialkylureido, N,N'-diaryl-N * -alkylureido, N,N',N"-triarylureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyi, arylaminoalkyl, diarylaniinoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino, haloaikylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, hetcroarylsulfonylamino, heterocyclylsulfonylamino, heteroarylthio, azido, -N -1 R 5 [R 53 R 53 , P(R5o)2, P(=0)(R 5 o)2, OP(=O)(R 50 )2, -NR 60 Ct=O)R^ 3 , dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl, hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysυlfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonylo, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyϊ, and alkylaryiaminosulfonyl; or two Qi groups, which substitute atoms in a 1 ,2- or 1,3-arrangement, together form alkylenedioxy, thioalkylenoxy, or alkylenedithioxy; or two Qi groups, which substitute the same atom, together form alkylene; and each Qi is, independently, unsubstituted or substituted with one or more substitutents, each independently selected from Q 2 wherein:
Q 2 is, independently, selected from halo, pseudohalo, hydroxy, oxo, thia, m ' trile, formyl, mercapto, hydroxycarbonyl, hydroxycarbonyialkyl, alkyl, haioalkyl, polyhaloalky), aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloaikyl, cycloalkyialkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkyisilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl. arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl,
- 1 16- dialkylaminocarbony], arylaminocarbonyl, diary laminocarbony!, arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, aikenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyioxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidine, isothioureido, ureido, N-a!kylureido, N-arylureido, N'- alkylureido, N',N'-dialkylureido, N'-alkyl-N'-arylureido, N\N'-diarylureido, N'-arylureido, N',N'-dialkylureido, N-alkyl-N'-arylureido, N-aryl-N'-alkylureido, N,N'-diarylureido, N, N',N'- trialkylureido, N,N * -dialkyl-N'-arylureido, N-alkyl-N\N'-diarylureido, N-aryl-N',N'~ dialkylureido, N,N'-diaryl-N ' -alkylureido, N,N',N'-triarylureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aryiaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoaikyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino, heteroarylthio, azido, -N + R 5I R 52 Rs 3 , P(R 5 o)2, P(=O)(R 50 )2, OP(=0)(Rso)2, -NR 60 CC=O)R 63 , dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl, hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy, alkylsulfonyloxy, arylsulfmyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, alkylarylaminosuifonyloxy, alkylsulfmyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysuifonylo, alkoxysulfonyl, aminosuifonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyl, and alkylarylaminosulfonyi; or two Q 2 groups, which substitute atoms in a 1 ,2- or 1,3-arrangement, together form alkylenedioxy, thioalkylenoxy, or alkylenedithioxy; or two Q 2 groups, which substitute the same atom, together form alkyiene; each R50 is, independently, selected from hydroxyl, alkoxy, aralkoxy, alkyl. heteroaryl, heterocyclyl, aryl, and -NR70R7!, wherein each R 70 and R 71 is, independently, selected from hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroaralkyl, and heterocyclyl; or R 70 and R 7 ] together form alkyjene, azaalkylene, oxaalkylene, or thiaalkylene;
-1 17- each R 51 , R 52 , and R 53 is, independently, selected from hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroaralkyl, heterocyciyl, and heterocyclylalkyl; each R 6O is, independently, selected from hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroaralkyl, heterocyciyl, and heterocyciylalkyl; and each R63 is, independently, selected from alkoxy, aralkoxy, alkyl, heteroaryl, heterocyciyl, aryl, and -NR 7 OR 7 J , with the proviso that within each monomeric unit when: a) Y or Y 1 is a seven-membered heterocyclic ring with 1 heteroatom in the ring; b) X or X' is a five-membered heterocyclic ring with 1 heteroatom in the ring; c) Rs and R< > or R 8 ' and R 9 ' together with the atoms on which they are substituted form a phenyl ring; and d) nx is 0; then R, R 6 , and R 7 are not heterocyciyl or heteroaryl; and
L is one or more linkers covalently linking one or more of the positions R 2 , R 8 , R 9 with R 2 ', R 8 ', R 9 '; or a pharmaceutically acceptable salt or hydrate thereof.
3. The compound of claim 2, wherein L covalently links two identical monomeric units or L covalently links two non-identical monomeric units.
4. The compound of claim 2, wherein L is selected from alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkylalkylene, aryl, arylalkylene, arylalkylalkylene, and heterocycloalkylene, heterocycloalkyialkylene. heteroaryl, and heteroarylalkylene where one or more carbon atoms are optionally replaced with N, O, or S, optionally-substituted alkylene, alkenylene, alkynylene cycloalkylene, cycloalkylalkylene, heterocycloalkylene, heterocycloalkylalkylene, aryl, arylalkylene, arylalkylalkylene. heteroaryl and heteroarylalkylene where one or more carbon atoms are optionally replaced with N, O, or S, amino, substituted amino, oxygen atom, sulfide, sulfoxide, sulfone, and disulfide.
5. The compound of claim 2, wherein L is selected from -CH 2 CH 2 -, - CH 2 CH 2 CH 2 -, -CH-CH-, 1 ,4-ρhenyl, 2,5-thiophenyI, -CH(OH)CH(OH)-, -CH 2 CH-O-CHCH 2 -, and -CH 2 OCOCCH 2 -.
6. The compound of claim 2, having a formula selected from a compound of formula (IV);
-1 18- R 3 1 R 4 P H {R s χ) χ N N
R 5 ' O
R5
R s
x
R3 R4 O M. ,R2
R1 (IV) wherein:
M, M', R,, R, ', R 2 , R 2 ', R 3 , R 3 ', R 4 , R/, R 5 , R 5 ', R 5 x, R 5 x\ Rs, Rs', Re, R<λ X, X', Y, Y', Z, Z', s, and p are defined as described as in claim 2; and
L 1 and L 2 , independently link any R 9 with any R 9 ' and R 2 with R 2 '; or a pharmaceutically acceptable salt thereof; a compound of formula (V):
R ■ V R; H 9 <%,
R 6 ' O
M, M', R ! ( Ri ', R 2 , R 2 ', R 3 , R 3 ', R 4 , R 4 ' , R 5 , R 5 ', R 5 x, Rsx\ Rs, R 8 '. R 9 , R 9 ', X. X', Y, Y', Z, Z', s, and p are defined as described as in claim 2; and
L i and L 2 , independently, Hnk any R 9 with any R 9 ' and any R 8 with any Rg'; or a pharmaceutically acceptable salt thereof;
-1 19- a compound of formula (VI);
<R s x)
Rr (VI) wherein:
M, M', R 1 , Ri ', R 2 , R 2 ', R 3 , R 3 ' , R 4 , R 4 ' , R 5 , R 5 ', R 5 x, R 5 x\ R 8 , Rs', R 9 , R<λ X, X', Y, Y', Z, Z ' . s, and p are defined as described as in claim 2; and
L links any R< ? with any R 9 '; or a pharmaceutically acceptable salt thereof; a compound of formula (VII):
(R 5 X)' '
R«*
R 1 R
- 120- M, M', Ru Ri ', R 2 , R 2 " , R 3 , R 3 ' , R* RV, R 5 , R 5 " , R 5 x, R s x\ Rs, R 8 ', R 9 , R 9 ', X, X', Y, Y', Z, Z\ s, and p are defined as described as in claim 2; and
L links position R ? with R 2 '; or a pharmaceutically acceptable salt thereof; and a compound of formula (VIIl):
(R 5 X) 1
Ri R,
"i (VIII) wherein:
M 1 M', R 1 , R, ', R 2 , R 2 ', R 3 . R 3 ', R 4 , R^, R 5 , R 5 ', RJX, R 5 X " , RS, Rg', R 9 , R 9 ', X, X', Y, Y', Z, Z', s, and p are defined as described as in claim 2; and
L links position any Rg with any Rs"; or a pharmaceutically acceptable salt thereof.
7 . A compound comprising a homodimer or heterodimer having monomelic units of general formula (IX):
, R 1
, R *
R 8
-
N Rr H
(IX) wherein each M is, independently, CO, SO, or SO 2
-121- each Rt is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroary], cycloalkyl, and heterocycioalkyl; and each R. 2 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, hetereocyclyl, and ORn, NRi 5 R^; or each R 2 is, independently, selected from substituted or unsubstituted aryl, substituted or unsubstituted aralkyl and substituted or unsubstituted cycloalkyl; each Rj, R 4 , and R 5 is, independently, selected from (i) and (ii):
(i) each R 3 and R f is, independently, selected from hydrogen, lower alkyl, lower alkenyl, alkynyi, lower cycloalkyl, lower heterocyclyl; and R 5 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, and NR 15 R 16 ; and
(ii) any R5 and R 3 or any R 5 and R4 together with atoms on which they are substituted form a heterocyclic ring or a heteroaryl ring and any other of R 3 or R 4 is selected as (i); each R 6 is, independently, selected from hydrogen, lower alkyl, lower alkenyl, and lower alkynyl; each R 7 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, C(A)R 29 , heteroaryl, cycloalkyl, and heterocyclyl; each Rg and R9 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl; each A is, independently, O, S, or NR 25 ; each Rn is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, C(A)R 2 ^ NR 30 R 3I , and S1R 22 R 23 R- 24 ; each R|5 and R|6 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl. aryl, heteroaryl, heteroaryjium, cycloalkyl, heterocyclyl, C(A)R 2*? , OR 25 , and NR 32 R 33 ; each R22, R23, and R 24 is, independently, selected from:
(i) R22, R23, and R24 are each, independently, selected from hydrogen, alkyl, alkenyl, atkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR 25 , and NR 32 R 33 ; and
(ii) any two of R22, R23, and R 24 together form alkylene, alkenylene, alkynylene, or heteroalkylene, and the other is selected as in (i);
-122- each R 25 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, and heterocyclyl; each R 26 is, independently, selected from hydrogen, alkyl, alkenyi, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyi, OR 25 , and NR 32 R 33 , wherein each R 34 and R 35 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR 30 , and NR 32 R 33 ; or any R 34 and R 35 together form alkylene, alkenylene, alkynylene, or heteroalkylene, wherein each R 36 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, and heterocyclyl; each R 2 9 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR*o, and NR 32 R 33 ; each R30 and R 31 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, and C(A)R 4J , wherein each R 41 is, independently, selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR40, and NR 32 R 33 ; or any R 3 o and R 31 together form alkylene, alkenylene, alkynylene, or heteroalkylene; each R 32 and R 33 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, and heterocyclyl; or any R 32 and R 33 together form alkylene, alkenylene, alkynylene, or heteroalkylene; each R 1 -R 9 , Rπ-R.25, and R27-R33 is, independently, unsubstituted or substituted with one or more substitutents. each independently selected from Q 1 wherein:
Qi is selected from halo, pseudohalo, hydroxy, oxo, thia, nitrile, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyi, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, heterocyciyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonyialkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonyJalkyl. arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryioxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy,
-123- alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylamiπocarbonyloxy, guanidine, isothioureido, ureido, N-alkylureido, N-arylυreido, N'- alkylureido, N',N'-dialkyIureido, N'-alkyl-N'-arylureido, N',N'-diary!ureido, NT-arylureido, N\N * -diaIkylureido. N-alkyl-N'-arylureido, N-aryl-N'-a!kylureido, N,N'-diarylureido, N, N',N'~ trialkylureido, N,N * -dialkyl-l\T-aryiureido, N-alkyl-N',N'-diarylureido, N-aryl-N',N * - dialkylureido, N,N'-diaryl-N'-alkyIureido, N,N',N"-triarylureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkyiamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsυlfonylamino, heterocyclylsulfonylamino, heteroarylthio, azido, -N + R 5 |R 52 Rs 3 , P(R 5 o)2, P(=0)(Rso)2, OP(=O)(R 50 )2, -NR 60 C(=O)R 63 , dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl, hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy. alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsuϊfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonylo, alkoxysuifonyl, aminosυlfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, aryl amino sulfonyl, diarylaminosulfonyl, and alkylarylaminosulfonyl; or two Qi groups, which substitute atoms in a 1,2- or 1 ,3-arrangement, together form alkylenedioxy, thioalkylenoxy, or alkylenedithioxy; or two Qi groups, which substitute the same atom, together form alkylene; and each Qi is, independently, unsubstituted or substituted with one or more substitutents. each independently selected from Q 2 wherein:
Q 2 is, independently, selected from halo, pseudohalo, hydroxy, oxo, thia, nitrile, formyl, mercapto. hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaJoalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalky], cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyϊ,
-124- aralkynyl, heteroarylalkyl. trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyi, triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryioxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyh aminocarbonyl, alkylaminocarbonyl, dialkylaniinocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, aikenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyioxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylary I aminocarbonyloxy, diarylaminocarbonyloxy, guanidine, isothioureido, ureido, N-alkylureido, N-arylureido, N'- alkylureido, N\N'-dialkylureido, N'-alkyl-N'-arylureido, N',N'-diarylureido, N'-arylureido, N',N'-dialkylureido, N-alkyl-N'-arylureido, N-aryl-N'-aikylureido, N,N'-diarylureido, N, N',N'- tri alky lure ido, N,N'-dialkyl-N'-arylureido, N-alkyl-N',N'-diarylureido, N-aryl-N',N'- dialkylureido, N,N'-diaryl-N'-alkylureido, N,N',N'-triarylureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aryiaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkyiamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonyl amino, heterocyclylsυlfonylamino, heteroarylthio, azido, -N + R 5! R 52 R 53 , P(R 5 O) 2 , P(-0)(Rso)2, OP(=0)(R 5 o)2, -NR 60 C(^O)R 63 , dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl, hydroxyphosphonyl, alkylthio, arylthio, perlluoroalkylthio, hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, aryisulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosullbnyloxy. alkylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl, alkyisulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonylo, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, diaryiaminosulfonyl, and alkylarylaminosulfonyl; or two Q 2 groups, which substitute atoms in a 1,2- or 1 ,3 -arrangement, together form alkylenedioxy, thioalkylenoxy, or alkylenedithioxy; or two Q 2 groups, which substitute the same atom, together form alkylene;
-125- each R 50 is, independently, selected from hydroxyl, alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl. aryl, and NR 70 RvI, wherein each R70 and R71 is, independently, selected from hydrogen, alky!, araikyl. aryl, heteroaryl, heteroaralkyl, and heterocyclyl, or any R 70 and Rj\ together form alkylene, azaalkylene. oxaalkylene, or thiaalkylene; each R 51 , R 52 , and R 53 is, independently, selected from hydrogen, alky], araikyl, aryl, heteroaryl, heteroaralkyl, heterocyclyl, and heterocyclylalkyl; each Rήo is. independently, selected from hydrogen, alkyl, araikyl, aryl, heteroaryl, heteroaralkyl, heterocyclyl, and heterocyclylalkyl; and each R« is, independently, selected from alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl, and -NR70R7]; or a pharmaceutically acceptable salt or hydrate thereof.
8. The compound of claim 7, having the formula (X):
R 1 '
R O M- "
4
RV^ N / < 1 If
X
O RV
(X) wherein:
M and M' are each, independently, CO, SO, or SO 2 ;
Ri and Ri' are each, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl;
R 2 and R2' are each, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, hetereocyclyl, and OR n , NR 15 R 16 ; or
R 2 and R 2 ' are each, independently, selected from substituted or unsubstituted aryl, substituted or unsubstituted araikyl and substituted or unsubstituted cycloalkyl; R 3 , R 3 ', KA, RV, R5, and R 5 ' are each, independently, selected from:
(i) R 3 , R3', R4, and R 4 ' are each, independently, selected from hydrogen, lower alkyl, lower alkenyl, alkynyl, lower cycloalkyl, lower heterocyclyl; and R 5 and Ry are selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, and NRj 5R 16 ; and
-126- (ii) R5 and R 3 , independently or together with R 5 ' and R 3 ', or R 5 and R 4 , either independently or together with R 5 ' and R 4 ', together with atoms on which they are substituted form a heterocyclic or heteroaryl ring and any remaining of R 3 , R 3 ', R 4 , or R 4 ' are selected as (i);
Rn and R^' are each, independently, selected from hydrogen, lower aikyl, lower alkenyl, and lower alkynyl;
R7 and R7' are each, independently, hydrogen, alkyl, alkenyl, alkynyl, aryl, C(A)R 2 ^ heteroaryl, cycloalkyl, and heterocyclyl;
Rg, R 8 ', R9, and R9' are each, independently, selected from hydrogen, alkyl, alkenyl, alkynyi, aryl, heteroaryl, cycloalkyl, and heterocyclyl; each A is, independently, O, S, or NR 25 ; each Rn is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, C(A)R 2 ^ NR 30 R 31 , and SiR 22 R 23 R 24 ;
Ri 5 and R i6 are each, independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, C(A)R 2 ( J , OR 25 , and NR 32 R 33 ; R 22 , R 23 , and R 24 are each, independently, selected from:
(i) R 22 , R2 3 , and R24 are each, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR 25 , and NR32R33; and (ii) any two of R 22 , R23, and R 24 together form alkylene, alkenylene, alkynylene, heteroalkylene, and the other is selected as in (i); each R2 5 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, and heterocyclyl; each R 2 6 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR 25 , and NR 32 R 33 , wherein R 34 and R 35 are each, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR 36 , and NR 32 R 33 , or any R 34 and R 35 together form alkylene, alkenylene, alkynylene, heteroalkylene, wherein each R 36 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, and heterocyclyl;
-127- each R-29 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl. OR4 0 , and NR 32 R 33 ; each R30 and R 3 1 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, and C(A)R 4 I , wherein each R 41 is. independently, selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR40. and NR32R33; or any R 30 and R 31 together form alkylene, alkenylene, alkynylene, or heteroalkylene; each R32 and R33 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl. and heterocyclyl, or any R 32 and R 33 together form alkylene, aikenylene, alkynylene, or heteroalkylene; each Rt', R 2 ', R 3 ', R 4 ', R 5 ', R 8 ', IV, R1-R9, Rπ-Ris, and R27-R33 is, independently, unsubstituted or substituted with one or more substitutents, each, independently, selected from Qi wherein:
Qi is selected from halo, pseudohalo, hydroxy, oxo, thia, nitrile, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalky], alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroaryl carbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalky!, arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidine, isothioureido, ureido, N-alkylureido, N-arylureido, N'- alkylureido, N',N'-dialkylureido, N'-alkyl-N'-ary)ureido, N',N'-diarylureido, N'-arylureido. N',N'-dialkylureido, N-alkyl-N'-arylureido, N-aryl-N'-alkylureido, N,N'-diarylureido, N, N',N'- trialkyiureido. N,N'-dialkyl-N'-arylureido, N-alkyl-N'.N'-diarylureido, N-aryl-N',N'- dialkyl ureido, N, ] SP-diaryl-N'-alkylureido, N,N',N'-triarylureido, amidino, alkylamidino,
-128- arylamidino, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl. dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino, heteroarylthio, azido, -N + R 51 Rs 2 Rs S , P(R 5 O) 2 , P(O)(R 5 O) 2 , OP(O)(R 5 O) 2 , -NR 60 C(O)R 63 , dialkyϊphosphonyl, alkylarylphosphonyl, diarylphosphonyl, hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxy sulfonylo, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyl, and alky I aryl aminosulfonyl; or two Qi groups, which substitute atoms in a 1 ,2- or 1 ,3 -arrangement, together form alkylenedioxy, thioalkylenoxy, or alkylenedithioxy; or two Qi groups, which substitute the same atom, together form alkylene; and each Q] is, independently, unsubstituted or substituted with one or more substitutents, each independently selected from Q 2 wherein:
Q 2 is selected from halo, pseudohalo, hydroxy, oxo, thia, nitrile, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl. alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, araikoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, aikoxy, aryloxy, heteroaryl oxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy. perfluoroaikoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy,
-129- aJkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylarylaminocarbonyioxy, diary laminocarbonyloxy, guanidine, isothioureido, ureido, N-alkylureido, N-arylureido, N'- alkyiureido, N',N'-dialkylureido, N'-alkyl-N'-arylureido, N',N'-diarylureido, N'-arylureido, N',N'-dialkylυreido, N-alkyl-N'-arylureido, N-aryl-N'-alkylureido, N,N'-diarylureido, N, N',N'- trialkylureido, N,N * -dialkyl-N'-arylureido. N-aikyI-N',N'-diarylureido, N-aryl-N\N * - dialkylureido, N,N'-diaryl-N'-aIkylureido, N,N\N'-triarylureido, amidino. alkylamidino, arylamidino, aminothiocarbonyl, alkylaminothiocarbonyi, arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkyiaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonyl amino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyi, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonyiamino, heteroarylsulfonylamino, heterocyclylsulfonylamino, heteroarylthio, azido, ~NT I R 5 |R 52 R 53 , P(R 5 O) 2 , P(=0)(Rso)2, OP(=O)(R 50 )2, -NR 60 CC=O)R 63 , dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl, hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy, aikylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysυlfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonylo, alkoxysυlfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyl, and al ky I aryl aminosulfonyl; or two Q2 groups, which substitute atoms in a 1,2- or 1 ,3-arrangement, together form aikylenedioxy, thioalkylenoxy, or alkylenedithioxy; or two Q 2 groups, which substitute the same atom, together form alkylene; each R50 is, independently, selected from hydroxyl, alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl, and -NR 70 R 71 , wherein each R 70 and R 7 1 is, independently, selected from hydrogen, alkyl, aralkyl, aryl, heteroary], heteroaralkyl, and heterocyclyl; or any R 70 and R 71 together form aikylene, azaalkylene, oxaalkylene, or thiaalkylene; each R 5 1, R 52 , and R 53 is, independently, selected from hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroaralkyl, heterocyclyl, and heterocyclylalkyl; each R< JO is, independently, selected from hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroaralkyl. heterocyclyl, and heterocyclylalkyl;
-130- each R^ is, independently, selected from alkoxy, aralkoxy, alkyi, heteroaryl, heterocyclyi, aryl, and - NR70R71 ; and
L is one or more linkers covalently linking one or more of the positions Ri, R2, R7, Rs, R9 with R, \ R 2 ", R 7 ', R«', R 9 '; or a pharmaceutically acceptable salt or hydrate thereof.
9. The compound of claim 8, wherein L covalently links two identical monomeric units or L covalently links two non-identical monomelic units.
10. The compound of claim 8, wherein L is selected from alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkylalkylene, aryl, arylalkylene, arylalkylalkylene, and heterocycioalkylene, heterocycloalkylalkylene, heteroaryl, and heteroarylalkylene where one or more carbon atoms are optionally replaced with N, O, or S, optionally-substituted alkylene, alkenylene, alkynylene cycloalkylene, cycloalkylalkylene, heterocycioalkylene, heterocycloalkylalkylene, aryl, arylalkylene, arylalkylalkylene, heteroaryl, and heteroarylalkylene where one or more carbon atoms are optionally replaced with N, O, or S, amino, substituted amino, oxygen atom, sulfide, sulfoxide, sulfone, and disulfide.
11. The compound of claim 8, wherein L is selected from -CH 2 CH 2 -, - CH 2 CH 2 CH 2 -, -CH=CH-, 1,4-phenyl, 2,5-thiophenyl, -CH(OH)CH(OH)-, -CH 2 CH-O-CHCH 2 -, and -CH 2 OCOCCH 2 -.
12. The compound of claim 8, having a formula selected from a compound of formula (XI):
R*
R«
R/
«' (XI) wherein:
-131 - M, M', R,, R 1 ', R 2 , R 2 ', R 3 , Rϊ, R 4 , R 4 ', R 5 , R 5 ' , R 6 , R 6 ', R 7 , R 7 ', R 8 , Rs', R 9 , and R 9 ', are defined as in claim 8; and
L] and L 2 , independently, link Rs with Rg' and R 7 with R 7 '; or a pharmaceutically acceptable salt thereof; a compound of formula (XIl):
M, M', R 1 , R 1 ', R 2 , R 2 ', R 3 , R 3 ', R 4 , Rλ R 5 , R 5 ', R 6 , R 6 ', R 7 , R 7 ', R 8 , R 8 ', R 9 , and R 9 ' are defined as in claim 8; and
Lj and L 2 , independently, link Rs with Rg' and R 2 with R 2 '; or a pharmaceutically acceptable salt thereof; a compound of formula (XJU):
R 3 P
Re
RV
-132- M, M', R h R 1 ', R 2 , R 2 ', R 3 , R 3 ', R4, RA', R 5 , R*\ R 6 . R 6 ', RT, R 7 ', RS, RS 1 , R 9 , and R 9 ' are defined as in claim 8; and
L links Rg with Rg"; or a pharmaceutically acceptable salt thereof; a compound of formula (XIV):
Ri
/
R 3
R 7
-
R) Re
R»\ Re
.R? 1
Re '
R;
\ a < (XIV) wherein:
M, M', R 1 , R 1 ' , R 2 , R 2 " , R 3 . R 3 ', R 4 , Rλ R 5 , R 5 ', R 6 , R 6 ', R 7 , R 7 ', R 8 , Rs', R 9 , and R 9 ' are defined as in claim 8; and
L links R 7 with R 7 '; or a pharmaceutically acceptable salt thereof; and a compound of formula (XV):
R<s
A<
-133- M, M', Ri, R 1 ', R 2 , R 2 ', R 3 , R 3 ', ^A, RV, R 5 , R 5 ', R 6 . R*', R?, R?', R 8 , R 8 ', RO, and R 9 ' are defined as in claim 8; and
L links R; with R 2 " ; or a pharmaceutically acceptable salt thereof.
13. λ compounds comprising a homodimer or heterodϊmer having monomelic units of genera! formula (XVI):
R O Il
M IJ
\
(i) each Rj is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryi, cycloalkyl, and heterocycloalkyl; and each R 2 is, independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, hetereocyciyl. ORn, and NR 15 R 16 ; and
(ii) any Rj and R 2 together with atoms on which they are substituted form heterocyclic or heteroaryl; each R 3 , R4, and R 5 is, independently, selected from:
(i) R 3 and R 4 are each, independently, selected from hydrogen, lower alkyl, lower alkenyl, alkynyl. lower cycloalkyl, lower alkyland heterocyclyl; and each R5 is, independently, selected from hydrogen, alkyi, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, and NR 15 R 16 ; and
(ii) any R 5 and R 3 or any Rs and R 4 together with atoms on which they are substituted form a heterocyclic or heteroaryl ring and any remaining R 3 or R 4 is selected as
(i); each Rs x is. independently, selected from hydrogen, lower alkyl, lower alkenyl, and lower alkynyl;
-134- each R^ and R 7 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryi, heteroaryl, cycloalkyl, and heterocyclyl; each R 8 is, independently, selected from:
(i) alkyl, alkenyl, aikynyl, aryl, heteroaryl. cycloalkyl, heterocyclyl, C(A)Ri 0 , halo, pseudohalo, OR n , oxo, thio, S(D) n Ri 2 , NR 55 R 16 , N + R 15 RiURn, ^NR 25 . or =CR I 3 R!4; and (ii) two R 8 S together with atoms on which they are substituted form a cycloalkyl, aryl, heterocyclic, or heteroaryl ring; each A is, independently, O, S, or NR 25 ; each R 1 O is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryl ium, cycloalkyl, heterocyclyl, C(A)R 26 , halo, pseudohalo, OR 2 s, SR 2 S, NR 27 R 28 , and SiR 22 R 23 R 24 ; each Rn is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, C(A)R 2 ^ NR 3 oR 3 i, and SiR 22 R 2 3R24; each D is, independently, O or NR 25 ; each n is, independently, 0,1 , or 2 wherein; when n is 1 or 2, each Rj 2 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, halo, pseudohalo, OR 25 , SR 25 , and NR 32 R 33 ; and when n is 0, each R 12 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryiium, cycloalkyl, heterocyclyl, SR25, and C(A)R 29 ; each R| 3 and Ru is, independently, selected from hydrogen, alkyl. alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, C(A)R 2 ^ OR25, and NR 32 R 33 ; each R 15 , Ri 6 , and Rp is, independently, selected from:
(a) hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, C(A)R 25 , OR 25 , or NR 32 R 3 3; and
(b) any two of R 15 , Rj 6 , and R 17 together form alkylene, alkenylene, alkynylene, or heteroalkylene, and any remaining Rj 5 , R 16 , or R 17 is selected as in (a); each R 22 , R 23 . and R24 is, independently, selected from:
-135- (i) each R22, R23, and R24 is, independently, selected from hydrogen, alky], alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR 25 , and NR 32 R 33 ; and ii) any two of R22, R23, and R 24 together form alkylene, alkenylene, alkynylene, heteroalkylene, and any remaining R 22 . R 23 . and R 24 is selected as in (i); each R25 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryϊ, heteroaryl, heteroarylium, cycloalkyl, and heterocyclyl; each R20 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryi, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR 25 , and NR 32 R 33 , wherein each R 34 and R 35 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl. aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR 36 , and NR 32 R 33 , or any R 34 and R 35 together form alkylene, alkenylene, alkynylene, heteroalkyiene, wherein each R 36 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, and heterocyclyl; each R27 and R 28 is, independently, selected from:
(i) each R 27 and R 28 is, independently, hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl. heteroarylium, cycloalkyl, heterocyclyl, OR 25 , NR 37 R 38 , and C(A)R 39 , wherein each R 37 and R 38 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, or together form alkylene, alkenylene, alkynylene, and heteroalkylene; and each R 39 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR 40 , and NR 32 R 33 , wherein each R 4 O is, independently, selected from alky], alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, and heterocyclyl; and (ii) any R27 and R 2 g together form alkylene, alkenylene, alkynylene, or heteroalkylene; each R 2 9 is, independently, selected from hydrogen, alky], alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR 40 , and NR 32 R 33 ; each R 3 o and R31 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyi, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, and C(A)R 4J , wherein each R 41 is, independently, selected from alkyl, alkenyl. alkynyl, aryl, heteroaryl, heteroarylium, cycloalky].
- 136- heterocyclyl, OR 40 , and NR 32 R 33, or any R 30 and R 3 1 together form alkylene, alkenylene, aikynylene, or heteroalkylene; each R 32 and R 33 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryϊ, heteroaryl, heteroarylium, cycloalkyl, and heterocyclyl, or any R32 and R33 together form alkylene, alkenylene, alkynylene, or heteroalkyiene; each Ri-Rs, Rs x , R 10 -R 17 , and R 22 -R 33 is, independently, unsubstituted or substituted with one or more substitutents, each independently selected from Qi wherein:
Qi is, independently, selected from halo, pseudohalo, hydroxy, oxo, thia, nitrile, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylaikyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroaryl alkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsiiyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyi, alkoxycarbonylaikyl, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy, diary Iaminocarbonyloxy, guanidine, isothioureido, ureido, N-alkylureido, N-arylureido, W- alkylureido, N',N'-diaIkylureido, N '-alkyl -N '-aryl ureido, N',N'-diarylureido, N'-arylureido, N',N'-dialkylureido, N-alkyl-N'-arylureido, N-aryl-N'-alkylureido, N,N'-diarylureido, N, N',N'- trialkylureido, N,N'-dialkyl-N'-arylureido, N-alkyl-N'.N'-diarylureido, N-aryl-N',N'- dialkylureido, N,N'-diaryl-N'-alkylureido, N,N\N'-triarylureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino, haioalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, arylcarbonylaminoaikyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsullbnylamino,
-137- heteroarylsulfonylamiπo, heterocyclylsulfonylamino, heteroarylthio, azido, -N + RsiR52R53, P(Rs O ) 2 , P(^O)(R 50 )I, OP(O)(R 5 O) 2 , -NR 60 Ct=O)R^ 3 , dialkylphosphonyl, alkylaryϊphosphonyl, diarylphosphonyl. hydroxyphosphony!, alkylthio, arylthio, perfluoroaikylthio, hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfmyloxy, alkylsulfonyloxy, arylsulfmyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, alkylarylaminosulfonyloxy, aJkylsυlfinyl, alkylsuifonyl, arylsulfmyl, arylsulfonyl, hydroxysulfonylo, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosυlfonyl, diarylaminosulfonyl, and alkylarylaminosulfonyl; or two Qi groups, which substitute atoms in a 1 ,2- or 1,3 -arrangement, together form alkylenedioxy, thioalkylenoxy, or alkylenedithioxy; or two Q] groups, which substitute the same atom, together form alkylene; and each Qi is, independently, unsubstituted or substituted with one or more substitutents, each independently selected from Q 2 wherein:
Q 2 is, independently, selected from halo, pseudohalo, hydroxy, oxo, thia, nitrile, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, aikenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloaikyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryϊoxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidine, isothioureido, ureido, N-alkylureido, N-arylureido, N'- alkylureido, N',N'-dialkylureido, N η -alkyl-N * -arylureido, N',N'-diarylureido, N ' -arylureido, N',N'-dialkylureido, N-alkyl-N'~arylureido, N-aryi-N ' -alkylureido, N,N'-diaryiureido, N 5 N',N'- trialkylureido, N,N'-dialkyl-N * -arylureido, N-alkyl-N',N'-diarylureido, N-aryl-N',N'- dialkylureido, N.N'-diaryl-N'-alkylureido, N,N',N'-triarylureido, amidino, alkylamidino,
-138- arylamidino, aminothiocarbonyl, alkylaminothiocarbony!, arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkyiaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkyiarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsυlfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino, hetcroarylthio, azido, -N + R 51 R 52 RsS, P(R 5 O) 2 , P(-O){R 50 )2, OP(=0)(R 5 o)2, -NR 60 C(O)R 63 , dialkylphosphonyl, alkylaryiphosphonyl, diarylphosphony], hydroxyphosphonyi, alkylthio, arylthio, perfluoroalkyithio, hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonylo, alkoxysυlfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaniinosulfonyl, diary] aminosulfonyl, and alkylarylaminosulfonyl; or two Q 2 groups, which substitute atoms in a 1,2- or 1,3 -arrangement, together form alkylenedioxy, thioalkylenoxy, or alkylenedithioxy; or two Q 2 groups, which substitute the same atom, together form alkylene; each R 50 is, independently, selected from hydroxyl, alkoxy, aralkoxy, aikyl, heteroaryl, heterocyclyl, aryl, and -NR70R71, wherein each R70 and R71 is, independently, selected from hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroaralkyl, and heterocyclyl; or any R70 and R71 together form alkylene, azaalkylene, oxaalkylene, or thiaalkylene; each R 51 , R«, and R 53 is, independently, selected from hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroaralkyl, heterocyclyl, and heterocyclylalkyl; each R ό o is, independently, selected from hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroaralkyl, heterocyclyl, and heterocyclylalkyl; and each R 63 is, independently, selected from alkoxy, aralkoxy, alkyl, heteroaryl , heterocyciyl, aryl, and -NR7 0 R 71 ; or a pharmaceutically acceptable salt thereof.
14. The compound of claim 13, having the formula (XVII):
-139- O
I
V / yl
H
I N
/ H \
Il / \ "
N '
O
W 2 and W 2 ' are each, independently, an optionally substituted 5-7 member heteroaryl ring containing 1-3 heteroatoms selected from O, S, and N. wherein substitutents, when present, are selected from Rs ;
Ri and R 2 are each, independently, selected from:
(i) Ri and R]' are, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; and eR 2 and R 2 ' are, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, hetereocyclyl, ORn, and NR15R16; and
(ii) Ri and R 2 , together with or independent of RV and R 2 ' together with atoms on which they are substituted form heterocyclic or heteroaryl; R 3 , R 3 ', R 4 , R 4 ', R 5 , and R 5 ' are each, independently, selected from:
(i) R 3 , R 3 ', R 4 , and R 4 ' are each, independently, selected from hydrogen, lower alkyl, lower alkenyl, alkynyl, lower cycloalkyl, and lower heterocyclyl; and R5 and R 5 ' are, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, and NRi 5 R) 6 ; and
(ii) R 5 and R 3 , R 5 and R 4 , R 5 ' and R 3 ' and R 5 ' and R 4 ' each, independently, together with atoms on which they are substituted form a heterocyclic or heteroaryl ring and any remainining Rj, R 4 , R 3 ', or R 4 ' is selected as (i);
R 5x and R^ x ' are each, independently, selected from hydrogen, lower alkyl, lower alkenyl, and lower alkynyl;
R O , R O ', R7, and R 7 ' are each, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl;
Rg and Rs' are each, independently, selected from:
(i) alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, C(A)RiO, halo, pseudohalo, OR n , oxo, thio, S(D) n R 12 , NR 15 Ri 6 , N + R 15 Ri 6 Rn, =NR 25 , or =CR[ 3 R, 4 ; and
-140- (ϋ) two Rg substituents, together with or independent of two Rg' substituents, together with atoms on which they are substituted form a cycloalkyl, aryl, heterocyclic or heteroaryl ring; each λ is, independently, O, S, or NR 25 ; each Rio is, independently, selected from hydrogen, alkyi, alkenyl, alkynyi, aryl, heteroaryl, heteroaryl ium, cycloalkyl, heterocyclyl, CfA)R 26 , halo, pseudohalo, OR25. SR25.
NR 27 R 2 *, and SiR 22 R 23 R 24 ; each Rn is, independently, selected from hydrogen, alkyl, alkenyl, alkynyi, aryl, heteroaryl, heteroaryiium, cycloalkyl, heterocyclyl, C(A)R 2 t > , NR30R31, and S1R22R23R24; each D is, independently, O or NR 25 ; each n is, independently, 0,1, or 2 wherein: when n is 1 or 2, R] 2 is selected from hydrogen, alkyl, alkenyl, alkynyi, aryl, heteroaryl, heteroaryiium, cycloalkyl, heterocyclyl, halo, pseudohalo, OR 25 , SR 2 ;, and NR 3 2R 3 3; and when n is 0, Ri 2 is selected from hydrogen, alkyl, alkenyl, alkynyi, aryl, heteroaryl, heteroaryiium, cycloalkyl , heterocyclyl, SR 25 , and C(A)R 2 ^ each R 13 and Ri 4 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyi, aryl, heteroaryl, heteroaryiium, cycloalkyl, heterocyclyl, C(A)R 2 ?, OR 25 , and NR 32 R 33 ; each R| 5 , Ri 6 , and R 17 is, independently, selected from:
(a) hydrogen, alkyl, alkenyl, alkynyi, aryl, heteroaryl, heteroaryiium, cycloalkyl, heterocyclyl, C(A)R 25 , OR 25 , or NR 32 R 33 ; and
(b) any two of R1 5 , Ri6, and R 17 together form alkylene, alkenylene, alkynylene, or heteroalkylene, and any reaminiind R 15 , Rj 6 , and Ri 7 is selected as in (a); each R 22 , R23, and R 2 4 is, independently, selected from:
(i) R 22 , R 23 , and R 2 4 are each, independently, selected from hydrogen, alkyl, alkenyl, alkynyi, aryl, heteroaryl, heteroaryiium, cycloalkyl. heterocyclyl, OR 25 , and NR 32 R 33 ; and (ϋ) any two of R 22 , R 23 , and R 24 together form alkylene, alkenylene. alkynylene, heteroalkylene, and any remaining R 22 , R 2 . 3 , and R24 is selected as in (i); each R25 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyi, aryl, heteroaryl, heteroaryiium, cycloalkyl, and heterocyclyl;
-141- each R 26 is, independently, selected from hydrogen, alkyl. alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR 25 , and NR32R33, wherein R34 and R35 are each, independently, selected from hydrogen, alkyl. alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR 36 , and NR 32 R 33 , or any R34 and R35 together form alkylene, alkenylene, alkynylene, or heteroalkylene, wherein each R 36 is, independently, selected from hydrogen, alkyl, alkenyi, alkynyl, aryl, heteroaryl. heteroaryiium, cycloalkyi, and heterocyclyl; each R 27 and R 28 is, independently, selected from:
(i) R 27 and R 28 are each, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR 25 , NR 37 R 38 , and C{A)R 39 , wherein R 37 and R 3 g are each, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloaikyl, andheterocyclyl, or any R 37 and R^ together form alkylene, alkenylene, alkynylene, or heteroalkylene; and each R 39 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR40, and NR 32 R 33 , wherein each R4 0 is, independently, selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, and heterocyclyl; and (ii) any R 2 7 and R 2 g together form alkylene, alkenylene, alkynylene, or heteroalkylene; each R 29 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR 40 , and NR 32 R 33 ; each R 30 and R 31 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, and C(A)Rj 1 , wherein each Rj 1 is, independently, selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR4 0 , and NR 32 R 33 ; or any R 30 and R 3 1 together form alkylene, alkenylene, alkynylene, or heteroalkylene; each R 32 and R 33 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, and heterocyclyl; or any R 32 and R 33 together form alkylene, alkenylene, alkynylene, or heteroalkylene;
-142- each IW, Ri ', R 2 ', R 3 ', Rλ R 5 ', RV, R 7 ' R 8 '- Ri-R 8 , R 5 χ, Rio-Rt?. and R 22 -R 33 is, independently, unsubstituted or substituted with one or more substitutents, each independently selected from Qi wherein:
Qi is, independently, selected from halo, pseudohalo, hydroxy, oxo, thia, nitrile, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyi, cycioalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, di alky lam inocarbonyl, aryl aminocarbonyl, diarylaminocarbonyl. arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyioxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidine, isothioureϊdo, ureido, N-alkylureido, N-arylureido, N'- alkylureido, N'.N ' -dialkylureido, N'-alkyl-N ' -arylureido, N',N'-diarylureido, N'-arylureido, N\N'-dialkylureido, N-alkyl-N'-ary] ureido, N-aryl-N' -alkyl ureido, N,N'-diarylureido, N, N',N'- trialkylureido, N,N'-dialkyl-N'-arylureido, N-alkyl-N',N'-diarylureido, N-aryl-N',N'- dialkylureido, N,N'-diaryl-N'-alkylureido, N,N',N'-triarylureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl, aikylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl, alkyiaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diary laminoalkyl, alkylarylaminoaikyl, alkylamino, dialkylamino. haloalkylamino, arylamino, diarylamino, alkylaryiamino, alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, aikylsulfonylamino, arylsuifonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino, heteroarylthio, azido, -N + R 5 |R 52 Rs 3 , P(R 50 ):, P(=O)(R 50 )2, OP(=0)(R 5 o) 2 , -NR 60 Ci=O)Rt,), dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl. hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonyialkylthio, thiocyano, isothiocyano, alkylsulfinyloxy, aikylsulfonyloxy,
-143- arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosυlfonyloxy, alkylammosulfonyloxy, alkylarylaminosulfonyloxy, alkylsuifinyl, alkylsulfonyl, arylsulfinyl, aryisulfonyl, hydroxysulfonylo, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfony!, diarylaminosulfonyl, and alkylarylaminosulfonyl; or two Qi groups, which substitute atoms in a 1,2- or 1 ,3 -arrangement, together form alkylenedioxy, thioalkylenoxy, or alkylenedithioxy; or two Qi groups, which substitute the same atom, together form alkylene; and each Q] is, independently, unsubstituted or substituted with one or more substitutents, each independently selected from Q 2 wherein:
Q 2 is, independently, selected from halo, pseudohalo, hydroxy, oxo, thia, nitrile, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, aikyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroaryl alky 1, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, aikynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidine, isothioureido, ureido, N-alkylureido, N-arylureido, W- alkylurejdo, N',N'-diaikylureido, N'-alkyi-N'-arylureido, N',N'-diarylureido, N'-arylureido, N\N'-dialkylureido, N-alkyl-N r -arylureido, N-aryl-N'-alkylureido, N,N'-diarylureido, N, N',N'- trialkylureido, N,N'-dialkyl-N'-arylureido, N-aIkyl-N',N'-diarylureido, N-aryl-N',N'- dialkylureido, N,N * -diaryl-N'-alkylureido, N,N',N'-triarylureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyi, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoaikyl, arylaminoalkyl, diarylaminoalkyl, alkylaryiaminoalkyl, alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino,
-144- arylcarbonyiamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryioxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino, heteroarylthio, azido, -N + R5iR52Rs3 > P(R 5 O) 2 , P(=0)(Rso)2, OP(=O)(R 50 )2. -NR 60 C(O)R 63 , dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl, hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsullbnyl, arylsuifinyl, arylsulfonyl, hydroxysulfonylo, alkoxysulfonyl, aminosulfonyl, alkylaminosuifonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyl, and alkylarylaminosulfonyl; or two Q 2 groups, which substitute atoms in a 1 ,2- or 1,3-arrangement, together form alkylenedioxy, thioalkylenoxy, or alkylenedithioxy; or two Q 2 groups, which substitute the same atom, together form alkylene; each R 50 is, independently, selected from hydroxy!, alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl, and -NR 70 R 71 , wherein each R70 and R71 is, independently, selected from hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroaralkyl, and heterocyclyl; or any R70 and R71 together form alkylene, azaalkylene, oxaalkylene or thiaaikylene; each R 5 ], R 52 , and R 53 is, independently, selected from hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroaralkyl, heterocyclyl, and heterocyclylalkyl; each R^o is, independently, selected from hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroaraikyl, heterocyclyl, and heterocyclylalkyl; each R f , 3 is, independently, selected from alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl, and -NR70R71; and
L is one or more linkers covalently linking one or more of the positions R 2 , R O , and W 2 with R 2 ', R 6 ', and W 2 '; or a pharmaceutically acceptable salt thereof.
15. The compound of claim 14, wherein L covalently links two identical monomelic units or L covalently links two non-identical monomelic units.
16. The compound of claim 14, wherein L is selected from alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkylalkylene, aryl, arylalkylene, arylalkylalkylene, heterocycloalkylene, heterocycloalkylalkylene, heteroaryl, and heteroarylalkylene where one or
-145- more carbon atoms are optionally replaced with N, O, or S, optionally-substituted alkylene, alkenylene, alkynyiene cycloalkylene, cycloalkylalkylene, heterocycloalkylene, heterocycloalkylalkylene, aryl, arylalkylene, arylalkylalkylene, heteroaryl, and heteroarylalkylene where one or more carbon atoms are optionally replaced with N, O, or S, amino, substituted amino, oxygen atom, sulfide, sulfoxide, sulfone, and disulfide.
17. The compound of claim 14, wherein L is selected from -CH 2 CH 2 -, - CH 2 CH 2 CH 2 -, -CH=CH-, 1 ,4-phenyl, 2,5-thiophenyl, -CH(OH)CH(OH)-, -CH 2 CH-O-CHCH 2 -, and -CϊI 2 C≡CC≡CCH 2 -.
18. The compound of claim 14, having a formula selected from a compound of formula (XVIII):
R* R
(R 5
X)' X H Y w, R 1
R 5 -- R V a (XVIII) wherein:
Ri, R 1 ', R 2 , R 2 ', R 3 , R 3 ', RA, R 4 ', R 5 , R 5 ', R 5 X, R 5 X', R 6 , R 6 ', R 7 , R 7 ', W 2 , and W 2 ' are defined as in claim 14; and
Li and L 2 independently link R 6 with R 6 ' and R 2 with R 2 '; or a pharmaceutically acceptable salt thereof; a compound of formula (XIX):
R j R 4
R 5 X , .W, M λ
R 5
O K R7 7 R«
R .,\ *V\ Re
(R 5
") w, R 1
R 3
RV
(XIX)
-146- wherein:
R 1 , R, ', R 2 , R 2 ' , R 3 , R 3 ', R 4 , R 4 ', R 5 , Rs', R 5 X- R s x\ R*. R 6 ', R?, R 7 ' , W 2 , and W 2 ' are defined as in claim 14; and
L f and L 2 independently link R 6 with R 6 ' and W 2 with W 2 ' ; or a pharmaceutically acceptable salt thereof; a compound of formula (XX):
RsX - ,W,
Rs
RT \ RG * .Ry
(R 6
X)' W, 1
R 1 1
R3' R « O (XX) wherein:
Ri, R 1 ' , R 2 , R 3 ', R 3 , R 3 ', R 4 , R 4 ', Rs, Rs', R5X, RSX\ Re, Re', R?, R 7 ' , W 2 , and W 2 ' are defined as in claim 14; and
L links Re with R<,'; or a pharmaceutically acceptable salt thereof; a compound of formula (XXI):
R 5 X . ,W,
f*
R?\ JV
(R 5 X)1 ' x H Tf W;1 Ri'
"> ' R - o (XXI) wherein:
Ri, R, ', R 2 , R 2 ' , R 3 , R 3 \ R 4 , R 4 ', R 5 , Rs', Rs*, Rsx\ FU, R 6 " , R 7 , R 7 ', W 2 , and W 2 ' are defined as in claim 14; and
L links position R 2 with R 2 '; or a pharmaceutically acceptable salt thereof; and
-147- a compound of formula (XXII):
R.
( R 5
X)
Ri, Ri ', R 2 . R 2 ', R 3 , R 3 ', R 4 , RV, R 5 , R 5 ', R 5 *, R 5 x\ R*, RO', R?, R?', W 2 , and W 2 ' are defined as in claim 14; and
L links position W 2 with W 2 '; or a pharmaceutically acceptable salt thereof.
19. The compositions of any one of claims 1-18, further comprising a pharmaceutically acceptable excipient.
20. The composition of claim 19, further comprising a second therapeutic agent selected from chemotherapeutic agents, radiation, immunotherapeutic agents, photodynamic therapy agents, and combinations thereof.
-148- |
A. Title:
DIMERIC IAP INHIBITORS
B. Cross-Reference to Related Applications:
JOOOlJ This application claims priority to and benefit of U.S. Provisional Application No. 60/820, 163 entitled "Dimeric IAP Inhibitors" filed on July 24, 2006; the entire contents of which is hereby incorporated by reference in its entirety.
C. Government Interests: Not applicable
D. Parties to a Joint Research Agreement: Not applicable
E. Incorporation by Reference of Material submitted on a Compact Disc: Not applicable
F. Background
1. Field of Invention:
[0002J The invention presented herein provides compositions and methods for modulation of apoptotic signaling pathways,
2. Description of Related Art:
[0003] Apoptosis plays a central role in the development and homeostasis of all multicellular organisms. Alterations in apoptotic pathways have been implicated in many types of human pathologies, including developmental disorders, cancer, autoimmune diseases, and neurodegenerative disorders. One mode of action of chemotherapeutic drugs is cell death via apoptosis.
[0004] Apoptosis is conserved across species and executed primarily by activated caspases, a family of cysteine proteases that cleave their substrates specifically at aspartate residues. Caspases are produced in cells as catalytically inactive zymogens (procaspases) that are activated by proteolytic processing during the intitation of apoptosis. Once activated, effector caspases proteolytically activate a broad spectrum of cellular targets ultimately leading to cell death.
[0005] In mammalian cells activation of the caspases is achieved through at least two independent mechanisms which are initiated by distinct caspases, but result in the activation of common executioner (effector) caspases. The 'intrinsic pathway' is activated by cytochrome c which is released from mitochondria within the cell when apoptosis is initiated. The 'extrinsic pathway' is intiated via activation of a death receptor located on the cell membrane. During extrinsic activation, death receptors, such as, Fas (CD-95/Apol ) and TNF-Rl , as well as other
members of the TNF group of cytokine receptors, are activated by their corresponding iigands, Fas ligand (FasL/CD-95L) and TNF-alpha or Apo2 Hgand/TNF-related apoptosis inducing Hgand (Apo2L/TRAlL), respectfully. Binding of procaspase-8 to an activated death receptor induces cleavage and removal of inhibitory domain of procaspase- 8 releasing it from the receptor and allowing it to activate effector caspases-3, -6, and -7. The result is the proteolytic cleavage of cellular targets by the effector caspases and the induction of apoptosis.
[0006J In normal cells that have not received an apoptotic stimulus, most caspases remain inactive. Aberrantly activatation of caspases is inhibited by a family of evolutionarily conserved proteins called IAPs (inhibitors of apoptosis proteins). IAPs have been described in organisms ranging from Drosophila to Humans. All mammalian IAPs identified to date, including, for example, XIAP, cIAP-1 , cIAP-2, ML-IAP, NAIP, Bruce, and survivin exhibit anti- apoptotic activity in cell culture.
[0007] IAPs were originally discovered in Baculovirus by their ability to substitute for P35, an anti-apoptotic protein. Generally, IAPs are made up of one to three Baculovirus IAP repeat (BIR) domains, and must also possess a carboxyl-terminal RING finger motif. The BIR domain itself includes a zinc binding domain of about 70 residues made up of 4 alpha-heiices and 3 beta strands. The BIR domain itself is believed to inhibit apoptosis by interacting with the procaspase and inhibiting proteolytic activation of the procaspase. IAPs are also known to be overexpressed in many human cancers. For example, XIAP is ubiquitously expressed in most adult and fetal tissues. However, overexpression of XlAP in tumor cells has been demonstrated to confer protection against a variety of apoptotic stimuli and promote resistance to chemotherapy. Consistent with this, a strong correlation between XIAP protein levels and survival of patients with acute myelogenous leukemia has been demonstrated. Down-regulation of XIAP expression by antisense oligonucleotides has been shown to sensitize tumor cells to a wide range of pro-apoptotic agents, both in vitro and in vivo.
J0008] Smac/DIABLO-derived peptides have also been demonstrated to sensitize tumor cell lines to pro-apoptotic drugs. In non-tumorigenic cells signaled to undergo apoptosis, IAP- mediated inhibition of apoptosis must be eliminated, which is accomplished, at least in part, by Smac (second mitochondrial activator of caspases). Smac, or DIABLO, is synthesized in the cytoplasm as a 239 amino acid precursor protein, of which the N-terminal 55 residues serve as the mitochondria targeting sequence that is removed after import to the mitochondria. Mature
-2-
Smac, containing 184 amino acids, accumulates in the inter-membrane space of the mitochondria where it has been shown to behave as an oligomer. When apoptosis is induced, Smac is released from the mitochondria into the cytosol together with cytochrome c where it binds to IAPs eliminating the inhibitory effect of IAPs on proteaiysis of procaspases and enabling caspase activation. At the same time, cytochrome c induces multimerization of Apaf-1 to activate procaspase-9 and procaspase-3.
[θ009j Smac interacts with essentially all IAPs identified to date including XIAP, c- IAPl , c-1 AP2, ML-IAP, Bruce and survivin and may be a master regulator of apoptosis in mammals. X-ray crystallography has shown that the first four amino acids (AVPI) of mature Smac bind to a portion of IAPs and this binding is thought to be essential for blocking the anti- apoptotic effects of IAPs. Therefore, Smac and various fragments of Smac, including AVPI peptides, have been proposed for use as targets for identification of therapeutic agents.
[0010] The basic biology of IAP antagonists, such as Smac, suggests that these proteins may complement or synergize other chemotherapeutic/anti-neoplastic agents and/or radiation. Chemotherapeutic/anti-neoplastic agents and radiation would be expected to induce apoptosis as a result of DNA damage and/or the disruption of cellular metabolism. G. Brief summary of the invention:
[0011] Various embodimentd of the invention include a compound including a homodimer or heterodimer having monomelic units of general formula (I):
(R 9 )S x ^- ^ ^, ^ (Rj)P
R 5
R 3 R,
-3-
(i) Ri is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryJ, heteroaryl, cycloalkyl, and heterocycloalkyl; and R 2 is, independently, selected from hydrogen, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, hetereocyclyl, ORn, NR I 5 R J 6 , and a moiety of formula (II):
V-- / ■
R
R ' (H) wherein each nx is, independently, 0-6; each R is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, C(A)R[ O , ORn, and NR J 5 -R K ,; and each R^ and R 7 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl; and (ii) any R] and R 2 together with a nitrogen atom on which R t and R 2 are substituted form a heterocyclic or heteroaryl ring; each R 3 , R 4 , and R 5 is, independently, selected from:
(i) R 3 and R 4 are, independently, selected from hydrogen, lower alkyl, lower alkenyl, alkyny], lower cycloalkyi, and lower heterocyclyl; and R 5 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl and
NR 15 Ri 6 ; and
(ii) any R 5 and R 3 or R 5 and R 4 together with atoms on which they are substituted form a heterocyclic or heteroaryl ring and remaining R 3 or R 4 is selected as (i); each R 5x is, independently, selected from hydrogen, lower alkyl, lower aikenyl, and lower alkynyl; each Rs and Ry is, independently, selected from:
(i) Rg and R 9 are each independently selected from lower alkyl, lower alkenyl, lower alkynyl, aryi, heteroaryl, cycloalkyl, heterocyclyl, C(A)Ri O , halo, pseudohalo, OR 1 1 , oxo, thio, S(D) n R 12 , NR i S Ri6, N + R 15 Ri 6 Rn, =NR 25 , and =CR 13 R !4 ; (ii) any Rg and R 9 together with atoms on which they are substituted form a cycloalkyl, aryl, heterocyclic, or heteroaryl ring; and (iii) two R 8 substituents together with carbon atoms to which they are substituted form a cycloalkyl, aryl, heteroaryl, or heterocyclyl ring; each A is, independently, selected from O, S, and NR 25 ;
.4.
each R io is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyi, heterocyclyl, C(A)Rj 6 , halo, pseudohalo, OR2 5 , SR2 5 , NR 27 R 28 , and SiR 22 R 23 R 24 ; each Rn is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyi, heterocyclyl, C(A)R 2 9, NR30R31, and SiR 2 2R23R24; each D is, independently, selected from O and NR 25 ; each n is 0, 1 , or 2; with the proviso that when any n is 1 or 2, then R 12 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyi, heterocyclyl, halo, pseudohalo, OR 15 , SR 25 , and NR 32 R 33 ; and when n is 0, then Rj 2 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyi, heterocyclyl, SR 25 , and C(A)R 2 ?; each Ru and R H is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyi, heterocyclyl, C(A)R 2 (J, OR 25 , and NR 32 R 33 ; each Rj 5 , R] 6 , and Ri 7 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyi, heterocyclyl, C(A)R 2 ^ OR25, and NR32R33; or any two of Rj 5 , Riβ, and R1 7 together form alkylene, alkenylene, alkynylene, heteroalkylene, and the other is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyi, heterocyclyl, C(A)R 2 Ct. OR25, and NR 32 R 33 ϊ each R 22 , R 23 , and R 24 is, independently, selected from:
(i) R 22 , R2 3 , and R 24 are each, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyi, heterocyclyl, OR 25 , and NR 32 R 33 ; or
(ii) any two of R 22 . R23, and R 24 together form alkylene, alkenylene, alkynylene, or heteroalkylene, and the other is selected selected from (i); each R2 5 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryi. heteroarylium, cycloalkyi, and heterocyclyl; each R 29 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyi, heterocyclyl, OR 40 , and NR 32 R 33 ; each R 3 0 and R 3 1 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyi, heterocyclyl, and C(A)R 4 I , wherein any R 41 is selected
.5.
from alkyi, alkenyϊ, aikynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR 4 O, and NR 32 R 33 ; or any R 3C and R 31 together form alkylene, alkenylene, alkynylene, or heteroalkylene; each R 32 and R 33 is, independently, selected from hydrogen, alkyi, alkenyl, aikynyl, aryl, heteroaryi, heteroarylium, cycloalkyl, and heterocyclyl; or R 32 and R 33 together form alkylene, alkenylene, alkynylene, or heteroalkylene; each R, Rs x , and R|-Rig, R22-R25, and R29-R33 is, independently, unsubstituted or substituted with one or more substitutents, each independently selected from Qs wherein:
Qi is, independently, selected from halo, pseudohalo, hydroxy, oxo, thia, nitrile, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyi, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, aikynyl containing 1 to 2 triple bonds, cycloalkyl. cycloalkylalkyl, heterocyclyl, heterocycϊyϊalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyi, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidϊne, isothioureido, ureido, N-alkylureido, N-arylureido, N'- alkylureido, N',N"-dialkylureido. N'-alkyl-N'-arylureido, N',N'-diaryIureido, N'-arylureido, N\N'-dialkylureido, N-alkyl-N'-arylureido, N-aryl-N ' -alkylureido, N,N'-diarylureido, N, N',N * - tri alky lure i do, N,N'-dialkyi-N'-arylureido, N-alkyI-N',N'-diarylureido, N-aryl-N',N'- dialkylureido, N,N'-diary!-N'-alkyiureido, N,N',N'-triarylureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino,
-6-
heteroarylsulfonylamino, heterocyclyisulfonylamino, heteroarylthio, azido, -N + R5iR5 2 R53, P(R 5O ) 2 , P(=0)(Rso)2. OP(O)(R 5 O) 2 , -NR 6 CCi=O)R 63 , dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl, hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyano. isothiocyano, alkylsulfinyloxy, alkyisulfonyloxy, arylsulfmyloxy, aryisulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, amϊnosuifonyloxy, alkylaminosulfonyloxy, alkylarylaminosujfcnyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonylo, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosυlfonyl, arylaminosulfonyl. diarylaminosulfonyl, and alkylarylaminosulfonyl; or two Qi groups, which substitute atoms in a 1,2- or 1,3-arrangement. together form alkylenedioxy, thioalkylenoxy, or alkylenedithioxy; or two Qi groups, which substitute the same atom, together form alkylene; and each Qi is, independently, unsubstituted or substituted with one or more substitutents, each independently selected from Q 2 wherein:
Q 2 is, independently, selected from halo, pseudohalo, hydroxy, oxo, thia, nitrile, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyi containing 1 to 2 double bonds, alkynyi containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyi, trialkyϊsilyl, dialkylarylsiiyl, alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, ar alkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl. alkylaminocarbonyl, dialkylaminocarbony], arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, aikoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylarninocarbonyloxy, guanidine, isothioureido, ureido. N-alkylureido, N-arylureido, N'- alkylureido, N',N'-dialkylureido, N'-a!kyl-N'-arylureido, N',N'-diarylureido, N'-arylureido, N',N'-dialkylureido, N-alkyl-N'-arylureido, N-aryl-N'-alkylureido, N,N'-diarylureido, N, N'.N'- trialkylureido, N,N'-dialkyl-N'-arylureido, N-a!kyI-N',N'-diarylureido, N-ary!-N',N'- dialkylureido, N,N'-diaryl-N'-alkylureido, N,N',N * -triarylureido, amidino, alkyiamidino,
-7-
arylamidino, aminothiocarbonyl, alkylaminothiocarbonyl. arylaminothiocarbonyl, amino, aminoaikyl, aikylaminoalkyl, dialkylaminoalkyi, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylaryiamino, alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino. heteroarylsulfoπy) amino, heterocyclylsulfonylamino, heteroarylthio, azido, -N + R 5 I R 52 Rs S , P(Rso)2, P(=O)(R 50 )2, OP(=O)(R 50 } 2 , -NR 60 Ct=O)FU 3 , dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl. hydroxyphosphonyl, alkylthio, aryithio, perfluoroalkylthio. hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysυlfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl. aJkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonylo, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyl, and alkylarylaminosulfonyl; or two Q 2 groups, which substitute atoms in a 1 ,2- or 1,3 -arrangement, together form alkylenedioxy, thioalkylenoxy, or alkylenedithioxy; or two Q 2 groups, which substitute the same atom, together form alkylene; each R50 is, independently, selected from hydroxyl, alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl, and -NR70R7 ! , wherein any R 7 ø and R 71 is, independently, selected from hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroaralkyl, or heterocyclyl; or any R 70 and R 71 together form alkylene, azaalkylene, oxaalkylene, or thiaalkylene; each R 51 , R 53 , and R5 3 is, independently, selected from hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroaralkyl, heterocyclyl, and heterocyclylalkyl; each Rήo is, independently, selected from hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroaralkyl, heterocyclyl, and heterocyclylalkyl; and each R^ 3 is, independently, selected from alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl, and -NR 7 oR7j, with the proviso that when: aj Y is a seven-membered heterocyclic ring with 1 heteroatom in the ring; b) X is a five-membered heterocyclic ring with 1 heteroatom in the ring;
-8-
c) Rg and R9 together with any atoms on which they are substituted form a phenyl ring; and d) nx is 0; then R, R^, and R 7 are not heterocyclyl or heteroaryl; or a pharmaceutically acceptable salt or hydrate thereof.
[0012J In some embodiments, the compounds of the invention may have the formula (III):
M and NT are each, independently, CO, SO, or SO 2 ;
Z and Z' are each, independently, CH or N;
X, X', Y, and Y' are each, independently, selected from 4-7 membered heterocyclic and heteroaryl rings containing one or two heteroatoms; s and p are each, independently, 0-3;
Rι, R| ', R2, and R 2 ' are each, independently, selected from:
(i) R| and Ri ' are each, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl; and R 2 and R 2 ' are independently selected from hydrogen, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, hetereocyclyl, ORj 1 , NR 15 R 16 , and a moiety of formula (II):
^
• ^
«7 (II) where nx is 0-6; each R is, independently, selected from hydrogen, alky], alkenyl, alkyny], aryi, heteroaryl, heteroaryl ium, cycloalkyl, heterocyclyl, C(A)R] 0 , ORi 1, and NRj 5 R] 6 ; and each R 6 and R 7 is, independently, selected from hydrogen, alkyl, alkenyl, alkyny!, aryl, heteroaryl, cycloalkyl, and heterocyclyl; and
-9-
(ii) R] and R 2 , either aione or together with R) ' and R 2 ', together with a nitrogen atom on which they are substituted form a heterocyclic or heteroaryl ring; R 3 , R 3 ', R 4 , R 4 ', R 5 , and R 5 ' are each, independently, selected from:
(i) R 3 , R 3 ', R 4 , and R 4 ' are each, independently, selected from hydrogen, lower alkyl, lower alkenyl, alkynyl, lower cycloalkyl, lower heterocyclyl; and Rs 1 and R 5 ' are independently selected from hydrogen, alkyl, alkenyi, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, and NR 15 Ri 6 ; and
(ii) R 5 and R 3 , independently or together with R 5 ' and R 3 ', or R 5 and R 4 , independently or together with R 5 ' and R 4 ', together with any atoms on which they are substituted form a heterocyclic or heteroaryl ring and the other Of R 3 , R 3 ', R 4 , or R 4 is selected as (i);
R 5 X and R 5 x' are each, independently, selected from hydrogen, lower alkyl, lower alkenyl, and lower alkynyl;
Rg, Rs', R(), and R 9 ' are each, independently, selected from:
(i) each R 8 , Rg " , R 9 , and R 9 ' is, independently, selected from lower alkyl, lower alkenyl, lower alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, C(A)Ri O , halo, pseudohalo, ORn, oxo, thio, S(D) n R, 2 , NR| 5 R, 6 , N + R 15 R 16 Ri 7 , =NR 25 , and =CRBR[ 4 ;
(ii) any Rg and R9 independently or together with any Rs' and R 9 ', together with any atoms on which they are substituted form a cycloalkyl, aryl, heterocyclic, or heteroaryl ring; and
(iii) any two Rg substituents, independently or together with any two Rg' substitutents, together with carbon atoms to which they are substituted form a cycloalkyl, aryl, heteroaryl, or heterocyclyl ring; each A is, independently, O, S, or NR 25 ; each R 10 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, C(A)Ri 6 , halo, pseudohalo, OR 25 , SR 25 , NR 27 R 28 , and SiR 32 R 23 R 24 ; each Rn is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryfium, cycloalkyl, heterocyclyl, C(A)R 29 , NR 30 R 31 , and SiR 22 R 2J R 24 ; each D is, independently, O or NR 25 ;
-10-
each n is, independently, 0, 1 , or 2; with the proviso that when any n is 1 or 2, then R] 2 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, halo, pseudohalo, OR 25 , SR 25 , and NR 32 R 33 ; and when n is 0, then R] 2 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, SR 2S , and C(A)R 2 ^; each Ru and Ru is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, C(A)R 29 , OR25. and NR 32 R 33 ; each R] 5, Rι&, and Ri 7 is, independently, selected from:
(a) hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, C(A)R 29 , OR 25 , or NR 32 R 33 ; and
(b) any two of R 15 , Ri 6 , and R) 7 together form alkylene, alkenylene, alkynylene, or heteroalkylene, and the other is selected as in (a); each R22, R23, and R 24 is, independently, selected from:
(i) each R 22 , R2 3 , and R 2 4 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR 25 , and NR 32 R 33 ; and (ii) any two of R 22 , R 23 , and R 24 together form alkylene, alkenylene, alkynylene, or heteroalkylene, and the other is selected as in (i); each R25 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, and heterocyclyl; each R 3 o and R 31 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl. heteroarylium, cycloalkyl, heterocyclyl or C(A)R 4J , where R 4 ] is alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyi, heterocyclyl, OR 40 , and NR 32 R 33 ; or any R 30 and R 3 s together form alkylene, alkenylene, alkynylene, or heteroalkylene; each R32 and R33 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl; or any R 32 and R 33 together form alkylene, alkenylene, alkynylene. or heteroalkylene; each R, R 5x , R 5 , 1 , R 1 ', R 2 ', R 3 ', R 4 ', R 5 " , R 8 ', R 9 ', R 1 -R 18 , R 22 -R 25 , and R 29 -R 33 is, independently, unsubstituted or substituted with one or more substitutents, each independently selected from Qi wherein:
-1 1-
Qi is selected from halo, pseudohalo, hydroxy, oxo, thia, nitrile, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylaikyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing I to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloaikyl, cycioalkylalkyl, heterocyclyl, heterocyclylalky], aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyi, dialkylarylsilyl, alkyldiarylsilyl, trtarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyi, heteroarylcarbony], alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonyialkyl, araikoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyi, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidine, isothioureido, ureido, N-alkylureido, N-arylureido, N'- alkylureido, N',N'-dialkylureido, N'-alkyi-N'-arylureido, N ',N '-di aryl ureido, N'-arylureido, N',N'-dialkylureido, N-alkyl-N'-arylureido, N-aryl-N'-alkylureido, N,N'-diarylureido, N, N',N'- trialkylureido, N,N'-dialkyl-N'-arylureido, N-alkyl-N',N'-diaryiureido, N-aryl-N',N'- dialkylureido, N,N'-diaryl-N'-alkylureido, N,N\N'-triarylureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl. alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dϊalkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, diaikylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryioxycarbonylamino, alkylsulfonyiamino, arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino, heteroarylthio, azido, -N + R 5I R 52 Rs 3 , P(R 5 o)2, P(=O)(R 5ϋ ) 2 , OP(=O)(R 50 )2, -NR 60 C(O)R 63 , dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl, hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy, alkylsulfoπyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkyisulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonylo, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl,
-12-
dialkylaminosυlfonyl, arylaminosulfonyl, diarylaminosulfonyl, and alkylarylaminosulfonyl; or two Qi groups, which substitute atoms in a 1 ,2- or 1,3 -arrangement, together form alkyleπedjoxy, thioalkylenoxy, or alkylenedithioxy; or two Q 1 groups, which substitute the same atom, together form alkylene; and each Qi is, independently, unsubstituted or substituted with one or more substitutents, each independently selected from Q 2 wherein:
Q2 is, independently, selected from halo, pseudohalo, hydroxy, oxo, thia, nitrile, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alky], haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, heterocycly], heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbony], heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl. aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl. aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, aryl alkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy. aryl oxycar bony loxy, aralkoxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidine, isothioureϊdo, ureido, N-alkylureido, N-arylureido, N'- alkylureido, N',N'-dialkyIureido, N'-alkyl-N'-arylureido, N \N '-diary I ureido, N '-aryl ureido, N',N'-diaJkylureido, N-alkyl-N'-arylureido, N-aryl-N'-alkylureido, N,N ' -diarylureido, N. N',N'- trialkylureido, N,N ' -dialkyl-N'-arylureido, N~alkyl-N',l\P-diarylureido, N-aryl-N\N'- dialkylureido, N,N * -diaryl-N'-alkylureido, N,N',N'-triarylureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl, aikylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl, diaJkylaminoalkyl, aryl aminoalkyl. diarylaminoalkyl, alkylaryiaminoalkyl, alkylamino, dialkylamino, haloalkylamino, arylamino, diaryϊamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, aryicarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonyiamino, aryioxycarbonylamino, aikylsulfonylamino, arylsulfonylammo, heteroarylsulfonylamino, heterocyclylsulfonylamino, heteroarylthio, azido, -N 4 R 5t R 52 R 53 ,
-13-
P(Rw) 2 , P(K ) )(R 5 Oh, OP(=0)(R 5 o)2, -NR 60 CC=O)R 63 , dialkylphosphonyl, aikylarylphosphonyl, diary Iphosphonyl, hydroxyphosphonyl, alkylthio, aryithio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfmyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosuffonyloxy, alkylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfony], hydroxysulfonylo, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, aryϊaminosulfonyl, diarylaminosulfonyl, and alkylarylaminosulfonyl; or two Q2 groups, which substitute atoms in a 1 ,2- or 1,3 -arrangement, together form alkylenedioxy, thioalkyienoxy, or alkylenedithioxy; or two Q 2 groups, which substitute the same atom, together form alkylene; each R JO is, independently, selected from hydroxyl, alkoxy, araikoxy, alkyl, heteroaryl, heterocyclyl, aryl, and -NR 7 oR 7 j, wherein each R 70 and R ? t is, independently, selected from hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroaralkyl, and heterocyclyl; or R 70 and R 71 together form alkylene, azaalkylene, oxaalkylene, or thiaalkylene; each R 51 , R 52 , and R 53 is, independently, selected from hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroaralkyl, heterocyclyl, and heterocyclylalkyl; each R^o is, independently, selected from hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroaralkyl, heterocyclyl, and heterocyclylalkyi; and each Rό3 is, independently, selected from alkoxy, araikoxy, alkyl, heteroaryl, heterocyclyl, aryl, and -NR 7O R 7I , with the proviso that within each monomelic unit when: a) Y or Y' is a seven-membered heterocyclic ring with 1 heteroatom in the ring; b) X or X' is a five-membered heterocyclic ring with 1 heteroatom in the ring; c) Rs and R9 or R$ * and R9' together with the atoms on which they are substituted form a phenyl ring; and d) nx is 0; then R, R^. and R 7 are not heterocyclyl or heteroaryl; and
L is one or more linkers covalently linking one or more of the positions R 2 , Rs, R 9 with R 2 ', R 8 ', R 9 '; or a pharmaceutically acceptable salt or hydrate thereof.
-14-
[0013] In some embodiments, L may covalently link two identical monomelic units or L covalently links two non-identical monomelic units. In other embodiments, L may be selected from alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkylalkylene, aryi, arylalkylene, arylalkylalkylene, and heterocycloalkylene, heterocycloalkylalkylene, heteroaryl, and heteroarylalkylene where one or more carbon atoms are optionally replaced with N, O, or S. optionally-substituted alkylene, alkenylene, alkynylene cycloalkylene, cycloalkylalkylene, heterocycloalkylene, heterocycloalkylalkylene, aryl, arylalkylene, arylalkylalkylene, heteroaryl and heteroarylalkylene where one or more carbon atoms are optionally replaced with N, O, or S, amino, substituted amino, oxygen atom, sulfide, sulfoxide, sulfone. and disulfide, and in still other embodiments, L may be selected from -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH-CH-, 1,4-phenyl, 2,5-thiophenyl, -CH(OH)CH(OH)-, -CH 2 CH-O-CHCH 2 -, and -CH 2 C≡CO≡CCH 2 -.
In certain embodiments, the compounds of the invention may have a formula selected from a compound of formula (IV):
FV
(R 5 X)'
R c x
M, M\ R 1 , R 1 \ R 2 , R 2 1 , R 3 . R 3 ', R 4 , R 4 '. R 5 , Rs', R 5 X. R 5 X ', R 8 , Rs'. R 9 , R 9 ', X, X'. Y, Y', Z, Z', s, and p are defined as described as in claim 2; and
Li and L 2 , independently link any Rg with any R ? ' and R 2 with R 2 '; or a pharmaceutically acceptable salt thereof; a compound of formula (V):
-15-
(R 5 X) V N P^
R1 (V) wherein:
M, M\ R 1 , R,\ R 2 , R 2 ', R 3 , R 3 ', R 4 , R 4 ', R 5 , R 5 ', R 5 x, R 5 x\ R 8 , R 8 ', R 9 , R 9 ", X, X', Y, Y', Z, Z', s, and p are defined as described as in claim 2; and
Li and L 2 , independently, link any R 9 with any R 9 ' and any Rg with any R 8 1 ; or a pharmaceutically acceptable salt thereof; a compound of formula (VI):
(R^x) 1 -
R i (VI) wherein:
M, M', R 1 , Ri ', R 2 , R 3 -, R 3 , R 3 ', R 4 , R 4 ', R 5 , R 5 ', Rs*, R S x\ Rs- Rg', Ro, R<λ X, X', Y, Y', Z, Z\ s, and p are defined as described as in claim 2; and
L links any Rt) with any R 9 '; or
-36-
a pharmaceutically acceptable salt thereof; a compound of formula (VII):
(R 5 Xf-X x
(FV)S (R« J )P
(R 9 )S. (R 1 )P
!
R 5
X
R 5
R 4
M^ ^R 2
*> (VII) wherein:
M, M', Ri, R, ', R 2 , R 2 ', R 3 , R 3 ', R 4 , R 4 ', R 5 , R 5 ', R s x, Rsx\ Rs, Rs', R 9 , R 9 " , X, X', Y, Y', Z, Z', s, and p are defined as described as in claim 2; and
L links position R? with R 2 "; or a pharmaceutically acceptable salt thereof; and a compound of formula (VIII):
(Rs*> ' \
K. (VIII) wherein:
-17-
M, M', R 1 , Rj\ R 2 - R 2 ' , R 3 , R 3 ' , R4, R 4 ', R 5 , Rs 1 , R 5 X, R 5 x\ Re, Rs " , R 9 , Re', X, X', Y,
Y', Z, Z', s, and p are defined as described as in claim 2; and
L links position any Rg with any R 8 '; or a pharmaceutically acceptable salt thereof,
[0014] Various other embodiments of the invention include a compound including a homodimer or heterodimer having monomelic units of general formula (IX):
,R 1
/
,N V
R 3
R.
(i) each R 3 and R 4 is, independently, selected from hydrogen, lower alkyl, lower alkenyl, alkynyl, lower cycloalkyl, lower heterocyclyl; and R 5 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, and NR 15 R 16 ; and
(ii) any R5 and R 3 or any R 5 and R4 together with atoms on which they are substituted form a heterocyclic ring or a heteroaryl ring and any other of R 3 or R 4 is selected as (i); each Rf, is, independently, selected from hydrogen, lower alkyl, lower alkenyl, and lower alkynyl; each R 7 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, C(A)R 2? , heteroaryl, cycloalkyl, and heterocyclyl;
-18-
each Rs and R 9 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycioalkyl, and heterocyclyl; each A is, independently, O. S, or NR 25 ; each R] [ is, independently, selected from hydrogen, alkyl, alkenyl. alkynyl, aryl, heteroaryl, heteroaryiium, cycloalkyi, heterocyclyl, C(A)R^, NR30R31, and S1R22R23R24; each R| 5 and R K , is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryiium, cycloaikyl, heterocyclyl, C(A)R 2 ^ OR 2 S, and NR32R33; each R22, R23, and R 24 is, independently, selected from:
(i) R 22 , R 23 , and R 24 are each, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryiium, cycloaikyl, heterocyclyl, OR 25 , and NR 3 2R3 3 ; and
(ii) any two of R 22 , R 23 , and R 24 together form alkylene, alkenylene, alkynylene, or heteroalkylene, and the other is selected as in (i); each R 25 is, independently, selected from hydrogen, alkyl, alkenyl. alkynyl, aryl, heteroaryl, heteroaryiium, cycioalkyl, and heterocyclyl; each R 26 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryiium, cycloalkyl, heterocyclyl, OR2 5 , and NR32R33, wherein each R34 and R 35 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryiium. cycloalkyl, heterocyclyl, OR 36 , and NR32R33; or any R34 and R35 together form alkylene, alkenylene, alkynylene, or heteroalkylene, wherein each R 36 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryiium, cycloalkyl, and heterocyclyl; each R 29 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryiium, cycloalkyl, heterocyclyl, OR 40 , and NR 32 R 33 ; each R 30 and R 31 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryiium, cycloalkyl, heterocyclyl, and C(A)R 4 I , wherein each R 41 is, independently, selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryiium, cycloalkyl, heterocyclyl, OR4 0 , and NR 3 2R 3 3; or any R 30 and R 31 together form alkylene, alkenylene, alkynylene, or heteroalkylene;
-19-
each R 32 and R 33 is, independently, selected from hydrogen, alky], alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, and heterocyciyl; or any R 32 and R 33 together form alkylene, alkenylene, alkynylene, or heteroalkylene; each R 1 -R9, Ri rR25- and R27-R 33 is, independently, unsubstituted or substituted with one or more substitutents, each independently selected from Q t wherein:
Qi is selected from halo, pseudohalo, hydroxy, oxo, thia, nitrile, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaioalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkyialkyl, heterocyciyl, heterocyclylalkyl, aryl, heteroaryi, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsily], dialkylaryisilyl, alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonyialkyl, araikoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, di aryl aminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidine, isothioureido, ureido, N-alkylureido, N-arylureido, N'- alkylureido, N\N'-dialkylureido, N'-alkyl-Nλarylureido, N',N'-diarylureido. N'-arylureido, N',N'-diaIkylureido, N-alkyl-N' -aryl ureido, N-aryl-N'-alkylureido, N,N'-diarylureido, N, N',N'- tri alkyl ureido, N,N'-dialkyl-N'-arylureido, N-alkyl-N',N'-diarylureido, N-aryl-N',N'- di alkyl ureido, N,N ' -diaryl-N'-alkylureido, N,N',N"-triarylureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyi, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, aikylarylaminoalkyl, alkylamino, diaikylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonyiamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, aryisulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino, heteroaryithio, azido, -N 1 R 5 ]R 52 R 5S , P(R 5 O) 2 , P(-O)(R 50 )2, OP(=O)(R 50 )2, -NR 60 C(^O)R 63 , dialkylphosphonyl, alkylarylphosphonyl.
-20-
diarylphosphonyl, hydroxyphosphonyL alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonyialkylthio, thiocyano, isothiocyano, alkylsulfinyloxy, alkylsuifonyloxy, arylsυlfinyloxy, arylsulfonyloxy, hydroxysulfonyfoxy, alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonylo, alkoxysulfonyl, aminosυlfonyl, alkylaminosulfonyl, diaikylaminosulfonyl, arylaminosulfonyl. diarylaminosulfonyl, and alkylarylaminosulfonyl; or two Qi groups, which substitute atoms in a 1,2- or 1,3-arrangement, together form alkylenedioxy, thioalkylenoxy, or alkylenedithioxy; or two Qi groups, which substitute the same atom, together form alkylene; and each Qi is, independently, unsubstituted or substituted with one or more substitutents, each independently selected from Q 2 wherein:
Q 2 is, independently, selected from halo, pseudohalo, hydroxy, oxo, thia, nitrile, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, aikyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene. alkylcarbonyl, arylcarbonyh heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl, alkyl aminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diary laminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy. aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy, alkylamjnocarbonyloxy, dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidine, isothioureido, ureido, N-alkylureido, N-arylureido, N'- alkylureido, N',N'-dialkylureido, N'-alkyl-N'-arylureido, N ', N "-di aryl ureido, N'-arylureido, N',N'-dialkylureido, N-alkyl-N'-arylureido, N-aryl-N'-alkylureido, N,N'-diarylureido, N, N',N'- tri alky I ureido, N,N'-dialkyl-N'-arylureido, N-alkyl-N',N'-diarylureido, N-aryl-N',N'- diaikylureido, N,N'-diaryl-N * -alkyiureido, N,N\N'-triarylureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyi, diarylaminoalkyl.
-21-
alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, aikylarylamino, alkylcarboπylamino, alkoxycarbonylamino, aralkoxycarbonylamino, aryicarbonyiamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonyiamino, heteroarylsulfonylamino, heterocyclylsulfonylamino, heteroarylthio, azido, -N + R S iR 52 Rs 3 , P(R 5 Oh, P(=0)(R 5 o)2, OP(=0)(R 5 o) 2 , -NR 60 C(^O)R 63 , dialkylphosphonyl, alkylarylphosphonyl. diarylphosphonyl, hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyioxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsuifonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonylo, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyl, and alkylarylaminosulfonyl; or two Q 2 groups, which substitute atoms in a 1,2- or 1,3 -arrangement, together form alkylenedioxy, thioalkylenoxy, or alkylenedithioxy; or two Q 2 groups, which substitute the same atom, together form aikylene; each R 50 is, independently, selected from hydroxyl, alkoxy, aralkoxy, alkyi, heteroaryl, heterocyclyl, aryl, and -NR70R7!, wherein each R70 and Rγi is, independently, selected from hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroaralkyl, and heterocyclyl, or any R 70 and R 7 ] together form aikylene, azaalkylene, oxaalkylene, or thiaalkylene; each R 5 [, R 52 , and R 53 is, independently, selected from hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroaralkyl, heterocyclyl, and heterocyclylalkyi; each R 6O is, independently, selected from hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroaralkyl, heterocyclyl, and heterocyclylalkyl; and each R^ 3 is, independently, selected from alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl, and -NR 7 oR7i ; or a pharmaceutically acceptable salt or hydrate thereof.
[0015] In some embodiments, the compounds of the invention may have the formula (X):
-22-
/• ■
O M' "
R λ
\ Il
<
N X -N '
/ H JL
R 5
(X) wherein:
M and M' are each, independently, CO, SO, or SOj;
Rj and Rf are each, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryf, cycloalkyl, and heterocycioalkyl;
R 2 and R 2 ' are each, independently, selected from hydrogen, alky], alkenyl, alkynyl, ary], heteroaryl, cycloalkyl, hetereocyclyl, and ORn, NR1 5 R16; or
R 2 and R 2 ' are each, independently, selected from substituted or unsubstituted aryl, substituted or unsubstituted aralkyl and substituted or unsubstituted cycloalkyl; R 3 , R 3 ', R4, R4', Rs, and R 5 ' are each, independently, selected from:
(i) R 3 , R 3 ', R 4 , and R 4 ' are each, independently, selected from hydrogen, lower alkyl, lower alkenyl, alkynyl, lower cycloalkyl, lower heterocyclyl; and R 5 and Rs- are selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycioalkyl, heterocyclyl, and NR 15 R 16 ; and
(ii) R 5 and R 3 , independently or together with R 5 ' and R 3 ', or R 5 and R 4 , either independently or together with R 5 ' and R 4 ', together with atoms on which they are substituted form a heterocyclic or heteroaryl ring and any remaining of R 3 , R 3 ', R4, or R4' are selected as (i);
R^ and R O ' are each, independently, selected from hydrogen, lower alkyl, lower alkenyl, and lower alkynyl;
R 7 and R 7 ' are each, independently, hydrogen, alky], alkenyl, alkynyl, aryl, C(A)R 29 , heteroaryl, cycioalkyl, and heterocyclyl;
Rg, Rg 1 , R9, and R9' are each, independently, selected from hydrogen, alkyl, alkenyL alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl; each A is, independently, O, S, or NR 25 ; each R] [ is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, C(A)R29, NR30R31, and S1R22R23R-24;
-23-
R. I 5 and R( 6 are each, independently selected from hydrogen, alky], alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, C(A)R 2 Ct, OR25, and NR32R33;
R22, R23, and R24 are each, independently, selected from:
(i) R 2 2, R 23ϊ and & 2 4 are each, independently, selected from hydrogen, alkyl, alkenyl, alkynyi, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR 25 , and NR 32 R 33 ; and
(ii) any two of R 22 , R 23> and R 2 4 together form alkylene, alkenylene, alkynylene, heteroalkylene, and the other is selected as in (i); each R 25 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, and heterocyclyl; each R 20 is, independently, selected from hydrogen, alkyl. alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR2 5 , and NR 3 2R 33 , wherein R34 and R 3 5 are each, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR 36 , and NR 32 R 33 , or any R 34 and R 35 together form alkylene, alkenylene, alkynylene, heteroalkylene, wherein each R 36 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, and heterocyclyl; each R 29 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR40, and NR 3 2R 3 3; each R 30 and R 31 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, and C(A)Rn, wherein each R 41 is, independently, selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR40, and NR 3 2R 33 ; or any R 3 0 and R31 together form alkylene, alkenylene, alkynylene, or heteroalkylene; each R 32 and R 33 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, and heterocyclyl, or any R 32 and R 33 together form alkylene, alkenylene, alkynylene, or heteroalkylene; each Ri \ R 2 '. R 3 ', R 4 ', Rs', Rs', R<λ R1-R9, Rn-R 2 S, and R27-R33 is, independently, unsubstituted or substituted with one or more substitutents, each, independently, selected from Qi wherein:
-24-
Qi is selected from halo, pseudohalo, hydroxy, oxo, thia, nitrile, formyl, mercapto, hydroxycarbonyj, hydroxycarbonylalkyl, alkyi, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycioalkylalkyl, hetcrocyclyl, heterocyclyialkyi, aryl, hetcroaryl, aralkyl, aralkenyl, aralkyny], heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene, arylaikylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyi, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, araikoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyioxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidine, isothioureido, ureido, N-alkylureido, N-arylureido, N'- alkylureido, N'.N'-dialkylureido, N'-alkyl-N'-arylureido, N',N'-diarylureido, N'-arylureido, N',N'-diaIkylureido, N-alkyl-N'-arylureido, N-aryl-N'-alkylureido. N,N'-diaryIureido, N, N',N'- trialkylureido, N,N'-dialkyl-N ' -arylureido, N-alkyl-N', N '-diary! ureido, N-aryl-N',N'- di alky I ureido, N,N'-diaryl-N'-alkylureido, N,N',N'-triaryIureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl, alkylaminothiocarbonyl, aryϊaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, araikoxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonyiamino, heterocyclylsulfonylamino, heteroarylthio, azido, -N + R 5 ] R 52 R 53 , P(R 5 O) 2 , P(O)(R 5 O) 2 , OP(=O)(R 50 )2, -NR 60 CC=O)R 63 , dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl, hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy, alkylsulfonyloxy, arylsυlfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, alkylaryiaminosulfonyloxy, alkylsulfinyi, alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonylo, alkoxysulfonyl, aminosuifonyi, alkylaminosuifonyl,
-25-
dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyl, and alkylarylaminosulfonyl; or two Qi groups, which substitute atoms in a 1 ,2- or 1 , 3 -arrangement, together form alkylenedioxy, thioalkylenoxy, or alkylenedithioxy; or two Q t groups, which substitute the same atom, together form alkylene; and each Qi is, independently, unsubstiruted or substituted with one or more substitutents, each independently selected from Q 2 wherein:
Q 2 is selected from halo, pseudohalo, hydroxy, oxo, thia, nitrile, formyl, mercapto, hydroxycarbonyl. hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing i to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalky], arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, aryl alkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidine, isothioureido, ureido, N-aikylureido, N-arylureido, N'- alkylureido, N',N'-dialkylureido, N'-alkyl-N'-arylureido, N',N'-diaryIureido, N'-aryiureido, N',N " -dialkylureido, N-alkyl-N'-arylureido, N-aryl-N'-alkylureido, N,N'-diarylureido, N, N',N'~ tri alkyl ureido, N,N'-dialkyl-N'-arylureido, N-alkyl-N',N'-diarylureido, N-aryI-N',N'- dialkylureido, N,N'-diaryl-N'-alkylureido, N,N',N'-triarylureido, amidino, alkylamidino, aryiamidino, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkyiaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, afkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroaryisulfonylamino, heterocyclylsuifonylamino, heteroarylthio, azido, -N + R S iRs 2 Rs 3 ,
-26-
P(Rso)2. P(=0)(Rso)2, OP{=0)(R 5 o)2, -NR 60 CX=O)R 63 . dialkylphosphonyl, alkylarylphosphonyϊ, diarylphosphonyl, hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyano, isothiocyaπo, alkylsulfinyloxy, alkylsulfonyloxy, aryisuifinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy. alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonylo. alkoxysulfonyl, aminosulfonyl, alkyianiinosuifonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyl, and alkylarylaminosulfonyl; or two Q 2 groups, which substitute atoms in a 1,2- or 1 ,3-arrangement, together form alkylenedioxy, thioalkylenoxy, or alkylenedithioxy; or two Ch groups, which substitute the same atom, together form alkylene; each R 50 is, independently, selected from hydroxyl, alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl, and -NR 70 R7 1 , wherein each R 70 and R 71 is, independently, selected from hydrogen, alkyi, aralkyl, aryl, heteroaryl, heteroaralkyl, and heterocyclyl; or any R70 and R71 together form alkylene, azaalkylene, oxaalkylene, or thiaalkylene; each R 51 , R 52 , and R 53 is, independently, selected from hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroaralkyl, heterocyclyl, and heterocyclylalkyl; each R^o is. independently, selected from hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroaralkyl, heterocyclyl, and heterocyclylalkyl; each R ό3 is, independently, selected from alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl, and -NR70R71; and
L is one or more linkers covalently linking one or more of the positions Rj, R2. R7, R«, R9 with Ri', R 2 ', R 7 ', R 8 ', R 9 '; or a pharmaceutically acceptable salt or hydrate thereof.
[0016] In some other embodiments, L may covalently link two identical monomeric units or L covalently links two non-identical monomeric units. In various other embodiments. L may be selected from alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkylalkylene, aryl, arylalkylene, arylalkylalkylene, and heterocycloalkylene, heterocycloalkylalkylene, heteroaryl, and heteroarylalkylene where one or more carbon atoms are optionally replaced with N, O, or S, optionally-substituted alkylene, alkenylene, alkynylene cycloalkylene, cycloaikylalkylene, heterocycloalkylene, heterocycloalkylalkylene, aryl, arylalkylene, arylalkylalkylene, heteroaryl, and heteroarylalkylene where one or more carbon atoms are optionally replaced with N, O, or S,
-27-
amino, substituted amino, oxygen atom, sulfide, sulfoxide, sulfone, and disulfide, and in certain embodiments, L may be selected from -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH=CH-, 1,4-ρhenyl, 2,5- thiophenyl, -CH(OH)CH(OH)-, -CH 2 CH-O-CHCH 2 -, and -CI I 2 OCC≡CCH 2 -.
[0017] in particular embodiments, the compounds of the invention may be of a formula selected from a compound of formula (XI):
/
R 3 P
R 8
.
N
R 5
N^ ,,R 7 1
Rd"
R 3 1 RV
R i (XI) wherein:
M, M', R 1 , R, ', R 2 , R 2 ', R 3 , R 3 1 , R 4 , R 4 '. R 5 , R 5 ', R 6 , R 6 ', R 7 , R 7 ', R 8 , Rs', R 9 , and R 9 ', are defined as in claim 8; and
Li and L 2 , independently, link RR with Rs' and R 7 with R 7 '; or a pharmaceutically acceptable salt thereof; a compound of formula (XII):
R j R +
R 5
-28-
M, M', R 1 , R, \ R 2 , R 2 ', R 3 , R 3 ', R^, RT, Rs, Rs', R*, Re', R?, R 7 ', Re, Rs'. R* and R 9 ' are defined as in claim 8; and
Lj and L 2 , independently, link Rg with R«' and R 2 with R 2 ': or a pharmaceutically acceptable salt thereof; a compound of formula (XIII):
««
" X R i ' - (XIII) wherein:
M, M\ R 1 , R 1 ', R 2 , R 2 '. R 3 , R 3 ', RA, R 4 ', RS, RV, R 6 , R 6 ', R 7 , RT' , R 8 . RS' , R 9 , and R 9 ' are defined as in claim 8; and
L links Rg with Rg'; or a pharmaceutically acceptable salt thereof; a compound of formula (XIV):
R 6
.
N
R 0 R 9
Rβ\ Re
FV
R, R 4
O M "\ / R 2
\
(XIV) wherein:
-29-
M, M\ Ru Ri', R 2 , R 2 " , R 3 , R 3 ', R 4 , R 4 ', R 5 , Rs', R 6 , R«\ R?, R 7 ', R 8 , R 8 " , R 9 . and R 9 ' are defined as in claim 8; and
L links R 7 with R 7 '; or a pharmaceutically acceptable salt thereof; and a compound of formula (XV):
, R <
R«
^ (XV) wherein:
M, M', R 1 , Ri ', R 2 , R 2 ', R 3 , R3% FU, Rλ Rs Rs', Re, Re', R?, R 7 ', R 8 , Rs'- R 9 , and R 9 ' are defined as in claim 8; and
L links R 2 with R 2 ' ; or a pharmaceutically acceptable salt thereof.
[0018] Further embodiments of the invention include a compound including a homodimer or heterodϊmer having monomeric units of general formula (XVI):
R, R 4 j?
H I!
\
(i) each R] is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyclσalkyl, and heterocycloalkyl; and each R 2 is, independently
-30-
selected from hydrogen, alkyl, alkeny!, alkynyl, ary!, heteroaryl, cycloalkyi, hetereocyclyl, ORn, and NR^R^; and (ii) any R] and R 2 together with atoms on which they are substituted form heterocyclic or heteroary!; each R3, R4. and R5 is, independently, selected from:
(i) R 3 and R4 are each, independently, selected from hydrogen, lower alkyl, lower alkenyl, alkynyl, lower cycloalkyi, lower alkyland heterocyclyl; and each R 5 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyi, aryl, heteroaryl, cycloalkyi, heterocyclyl, and NRi 5 R 16 ; and (ii) any R 5 and R 3 or any R 5 and R 4 together with atoms on which they are substituted form a heterocyclic or heteroaryl ring and any remaining R 3 or R 4 is selected as
0); each Rs x is, independently, selected from hydrogen, lower alkyl, lower alkenyl, and lower alkynyl; each R« and R 7 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, ary], heteroaryl, cycloalkyL and heterocyclyl; each Rs is, independently, selected from:
(i) alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, C(A)R[Q, halo, pseudohaϊo, OR n , oxo, thio, S(D) n R, 2 , NR i5 R]6, N + Ri 5 Ri 6 Ri?, =NR 25 , or ^CR B R J4 ; and (ii) two R^s together with atoms on which they are substituted form a cycloalkyi, aryl, heterocyclic, or heteroaryl ring; each A is, independently, O, S, or NR 2? ; each Rio is, independently, selected from hydrogen, alkyi, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyi, heterocyclyl, C(A)R 26 , halo, pseudohalo, OR 25 , SR 25 , NR 27 R 28 , and SiR 22 R 23 R 24 ; each Rn is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, C(A)R 29 , NR 3 0R 3 1, and S1R 22 R 23 R 24 ; each D is, independently, O or NR 25 ; each n is, independently, 0, 1, or 2 wherein:
-31-
when n is 1 or 2, each R 12 is, independently, selected from hydrogen, alkyl. alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, halo, pseudohalo, OR 25 , SR 25 , and NR32R33; and when n is 0, each Rj 2 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl. aryi, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, SR 25 , and C(A)R 2 ^; each R| 3 and R 1 4 is, independently, selected from hydrogen, alkyi, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, C(A)R 2 Q, OR 25 , and NR 32 R 33 ; each R| 5 , Ri 6 , and R t7 is, independently, selected from:
(a) hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, C(A)R 25 , OR 25 , or NR32R33; and
(b) any two of Ri 5 , Rj 6 , and Rp together form alkylene, alkenylene, alkynylene, or heteroalkylene, and any remaining R 15 , R H» or Ri 7 is selected as in (a); each R22, R23, and R24 is, independently, selected from:
(i) each R22, R23, and R 2 4 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryϊium, cycloalkyl, heterocyclyl, OR 25 , and NR32R33; and ii) any two of R 22 , R 23 . and R 2 4 together form alkylene, alkenylene, alkynylene, heteroalkylene, and any remaining R22, R23, and R24 is selected as in (i); each R 25 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, and heterocyclyl ; each R 26 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR 25 , and NR 32 R 33 , wherein each R 34 and R 35 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR 36 , and NR 32 R 33 , or any R 34 and R 35 together form alkylene, alkenylene, alkynylene, heteroalkylene, wherein each R 36 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, and heterocyclyl; each R 27 and R 2 ^ is, independently, selected from:
(i) each R27 and R 2 g is, independently, hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR 25 , NR 37 R 3S , and C(A)R 39 , wherein each R 3 7 and R 3 g is, independently, selected from hydrogen, alkyl,
-32-
aikenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycioalkyl, heterocyclyl, or together form alkylene, alkeπylene, alkynylene, and heteroalkylene; and each R 3 y is, independently, selected from hydrogen, alkyl, aikenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyi, OR 40 , and NR 32 R 33 , wherein each R 40 is, independently, selected from alkyl, aikenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, and heterocyclyl; and (ii) any R 2 7 and R 28 together form alkylene, alkenylene, alkynylene, or heteroalkylene; each R29 is, independently, selected from hydrogen, alkyl, aikenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR40, and NR32R33; each R 3 0 and R 3 ] is, independently, selected from hydrogen, alkyl, aikenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, and C(A)R 4 I , wherein each R 4 I is, independently, selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR 4 Q, and NR32R3 3 , or any R 30 and R 31 together form alkylene, alkenylene, alkynylene, or heteroalkylene; each R 32 and R 33 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, and heterocyclyl, or any R 32 and R 33 together form alkylene, alkenylene, alkynylene, or heteroalkylene; each Ri-Rg, Rs^, R10-R17, and R22-R33 is, independently, unsubstituted or substituted with one or more substitutents, each independently selected from Qi wherein:
Qi is, independently, selected from halo, pseudohalo, hydroxy, oxo, thia, nitrile, formyl, mercapto, hydroxycarbonyl, hydroxycarbonyialkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing I to 2 double bonds, aJkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsiiyl, triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroaryl carbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyi, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, aryialkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy,
-33-
alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, diaikylaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidine, isothioureido, ureido, N-alkylureido, N-arylureido, N'- alkyiureido, N\N * -dialkylureido, N'-alkyl-N'-arylureido, N'.N'-diarylureido, N'-arylureido, N\N'-dialkylureido, N-alkyl-N'-arylureido, N-aryl-N * -alkylureido, N,N'-diarylureido, N, N',N'- trialkylureido, N>T-dialkyl-NT-arylureido, N-alkyl-N',N λ -diarylureido, N-aryl-N',N * - dialkylureido, N,N'-diaryl-N'-alkylυreido, N,N',N'-triarylureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl, aϊkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diary laminoalky I 5 alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonyiamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino, heteroarylthio, azido, "N + RS I R S2 R S3 , P(R 5 O) 2 , P(O)(R 5 O) 2 . OP(=O)(R 50 )2, -NR 60 Ct=O)R 63 , dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl, hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsυlfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysuifonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonyio, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyl, and alkylarylaminosulfonyl; or two Qj groups, which substitute atoms in a 1 ,2- or 1,3 -arrangement, together form alkyienedioxy, thioaϊkylenoxy, or alkylenedithioxy; or two Qi groups, which substitute the same atom, together form alkylene; and each Qi is, independently, unsubstituted or substituted with one or more substitutents, each independently selected from Q 2 wherein:
Q? is. independently, selected from halo, pseudohaio, hydroxy, oxo, thia, nitriie, formyl, mercapto, hydroxycarbonyl. hydroxycarbonylalkyl, alkyl, haioalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing I to 2 double bonds, alkynyi containing I to 2 triple bonds, cycloalkyl, cycloalkyialkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene,
-34-
arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkylj aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarboπylalkyl, arylcarbonylalkyl, aminocarbonyl, alkylamiπocarbonyl, dialkylaminocarbonyl, ary I aminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloaikoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyioxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyioxy, diaikylaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidine, isothioureido, ureido, N-alkyϊureido, N-arylureido, N'- alkylureido, N\N'-dialkylureido, N'-alkyl-N'-arylureido, N',N'-diarylureido, N'-arylureido, N',N * -dialkylureido, N-alkyl-N'-arylureido, N-ary]-N'-alky!ureido, N,N'-diarylureido, N, N',N'- trialkylureido, N,N'-dialkyl-N'-arylureido, N-aIkyl-N',N'-diarylureido, N-aryl-N',N"- diaikylureido, N,N'-diaryl-N'-alkylureido, N,N',N'-triarylureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl, alkylaminothiocarbony], arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkyiaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino, heteroarylthio, azido, -N + R S iRs 2 Rs 3 , P(R 5 O) 2 , P(=O)(R 50 )2, OP(-0)(Rso>2, -NR 60 C(^O)R 63 , dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyϊ, hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosuUbnyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsυlfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonylo, alkoxysulfonyl, aminosυlfonyl, alkylaminosulfonyl, dialkylaminosulfony], aryiaminosulfonyl, d i ary 1 aminosυlfonyl, and alkylarylaminosulfonyl; or two Q 2 groups, which substitute atoms in a 1,2- or 1 ,3 -arrangement, together form alkylenedioxy, thioalkylenoxy, or alkylenedithioxy; or two Q 2 groups, which substitute the same atom, together form alkylene;
-35-
each R 50 is, independently, selected from hydroxy!, alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl, and -NR 70 R 71 , wherein each R 70 and R 7 ] is, independently, selected from hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroaralkyl, and heterocyclyl; or any R 70 and R 71 together form alkylene, azaalkylene, oxaalkylene, or thiaalkylene; each R 5 1, R 52 , and R 53 is, independently, selected from hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroaralkyl, heterocyclyl, and heterocyclylalkyl; each R 60 is, independently, selected from hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroaralkyl, heterocyclyl, and heterocyclylalkyl; and each R« is, independently, selected from alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl, and -NR70R7]; or a pharmaceutically acceptable salt thereof.
[0019] In still further embodiments, the compounds may have the formula (XVII):
R O
4
H
> y i I!
/
^R 1
-L—
Rs
O Rf
Wi and WY are each, independently, an optionally substituted 5-7 member heteroaryl ring containing I -3 heteroatoms selected from O, S, and N, wherein substitutents, when present, are selected from Rg;
Rι and R 2 are each, independently, selected from:
(i) Ri and Rf are, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; and eR 2 and Ri' are, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, hetereocyclyl, ORn , and NRi 5 R^: and
(ii) Ri and R 2 , together with or independent of Rj ' and R 2 " together with atoms on which they are substituted form heterocyclic or heteroaryl; R 3 , R3', R4, R 4 ', R 5 , and R 5 ' are each, independently, selected from:
(i) R 3 , R 3 1 , R 4 , and R4' are each, independently, selected from hydrogen, lower alkyl, lower alkenyl, alkynyl, lower cycloalkyl, and lower heterocyclyl; and R 5 and R 5 '
-36-
are, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycioalkyl, heterocyclyl, and NR. t 5 R. 10 ; and
(U) R 5 and R- 3 , R 5 and R 4 , R 5 ' and R 3 ' and R 5 ' and R 4 ' each, independently, together with atoms on which they are substituted form a heterocyclic or heteroaryl ring and any remainining R 3 , R 4 , R 3 ', or R 4 ' is selected as (i);
Rs x and Rs x ' are each, independently, selected from hydrogen, lower alkyl, lower alkenyl, and lower alkynyS;
R&, Rό\ R-7, and R 7 ' are each, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyi, and heterocyclyl;
Re and Rg' are each, independently, selected from:
(i) alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyi, heterocyclyl, C(A)Ri O , halo, pseudohalo, OR n , oxo, thio, S(D) n R 12 , NR 15 Ri 6 , N + Ri 5 Ri 6 Ri?, ^NR 25 , or =CRι 3 R I4 ; and
(ii) two Rs substituents, together with or independent of two Rg' substituents, together with atoms on which they are substituted form a cycloalkyi, aryl, heterocyclic or heteroaryl ring; each A is, independently, O, S, or NR 25 ; each Rio is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryl ium, cycloalkyi, heterocyclyl, C(A)R 26 , halo, pseudohalo. OR 25 , SR 25 , NR 27 R 28 , and SiR 22 R 23 R 24 ; each Rn is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyi, heterocyclyl, C(A)R 2 ^ NR30R31, and SiR 22 R 23 R 2 *; each D is, independently, O or NR 25 ; each n is, independently, 0, 1 , or 2 wherein: when n is 1 or 2, R t2 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium. cycloalkyi, heterocyclyl, halo, pseudohalo, OR 25 , SR25, and NR 32 R 33 ; and when n is 0, R 12 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyi, heterocyclyi, SR 25 , and C(A)R 2 - ? ; each Rn and R| 4 is, independently, selected from hydrogen, aikyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyi, heterocyclyl, C(A)R 2 ^ OR 25 , and NR 32 R 33 ; each Rj 5 , Rj 6 , and R ] 7 is, independently, selected from:
-37-
(a) hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycioalkyl, heterocyclyl, C(A)R 25 , OR 25 , or NR 32 R 33 ; and
(b) any two of R 15 , R| 6 , and Rj 7 together form aikylene, alkenylene, aJkynyiene, or heteroalkylene, and any reaminiind R 15 , Rj 6 , and Rp is selected as in (a); each R22, R23, and R 24 is, independently, selected from:
(i) R22, R23, and R 24 are each, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycioalkyl, heterocyclyl, OR 2J , and NR 32 R 33 ; and (ii) any two of R 22 , R 23 , and R 2 4 together form alkylene, alkenylene, alkynylene, heteroalkylene, and any remaining R 22 , R 23 , and R 24 is selected as in (i); each R 25 is, independently, selected from hydrogen, alkyl, alkenyl, aikynyl, aryl, heteroaryl, heteroarylium, cycioalkyl, and heterocyclyl; each R 26 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycioalkyl, heterocyclyl, OR 25 , and NR 32 R 33 , wherein R 34 and R 35 are each, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycioalkyl, heterocyclyl, OR 36 , and NR 32 R 33 , or any R 34 and R 35 together form alkylene, alkenylene, alkynylene, or heteroalkylene, wherein each R 36 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycioalkyl, and heterocyclyl; each R 2 7 and R 2 s is, independently, selected from:
(i) R 27 and R 2 « are each, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycioalkyl, heterocyclyl, OR 25 , NR 37 R 3S , and C(A)R 3 (J, wherein R 37 and R 3 s are each, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryi, heteroarylium, cycioalkyl, andheterocyclyl, or any R 3 7 and R 3 s together form alkylene, alkenylene, alkynylene, or heteroalkylene; and each R 39 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycioalkyl, heterocyclyl, OR40, and NR 32 R 33 , wherein each R40 is, independently, selected from alkyl, alkenyl. alkynyl, aryl, heteroaryl. heteroarylium, cycioalkyl, and heterocyclyl; and
-38-
(ii) any R 2 ? and R 28 together form alkylene, alkenylene, alkynylene, or heteroalkylene; each R29 is, independently, selected from hydrogen, alkyl, alkeny!, alkynyl, aryi, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR4 0 , and NR 32 R 33 ; each R 3 0 and R 3 1 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, and C(A)Rj], wherein each R 41 is, independently, selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR40, and NR 3 2R 33 ; or any R 30 and R 31 together form alkylene, aikenylene, alkynylene, or heteroalkylene; each R 32 and R 33 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, and heterocyclyl; or any R 32 and R 33 together form alkylene, alkenylene, alkynylene, or heteroalkylene; each R 5x ' , R, ' , R 3 ', R 3 " , R 4 ', R 5 ', R 6 " , R 7 ' Rβ\ RrRs, R 5x , R 10 -Rn, and R 22 -R 33 is, independently, unsubstituted or substituted with one or more substitutents, each independently selected from Qi wherein:
Qi is, independently, selected from halo, pseudohalo, hydroxy, oxo, thia, nitrile, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloaikylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroaryl carbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkcnyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyioxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidine, isothioureido, ureido, N-alkylureido, N-arylureido, N'- alkylureido, N',N'-dialkylureido, N'-alkyl-N'-arylureido, N',N'-diarylureido, N'-arylureido, N'.N'-dialkylureido, N-alkyl-NT-arylureido, N-aryl-N'-alkylureido, N,N'-diarylureido, N, N\N'-
-39-
trialkylureido, N,N'-dialkyl-N'-arylureido, N-a]kyl-N\N'-diarylureido, N-aryl-N',N'- dialkylureido, N,N'-diaryl-N'~alkylureido, N,N\N'-triarylureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalky], alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, aϊkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, aikylsulfonylamino, aryisulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino, heteroarylthio, azido, -N + R S iRs 2 Rs 3 , P(R 50 ) 2 , P(=O)(R 50 ) 2 , OPC-O)(R 5 O) 2 , -NR 60 C(O)R 63 , dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl, hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, aikoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, alkyiarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, aryfsulfinyl, arylsuifonyl, hydroxysulfonylo, alkoxysulfonyl. aminosulfonyl, alkylaminosulfonyi, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosuifonyl, and alkylarylaminosulfonyl; or two Qi groups, which substitute atoms in a 1,2- or 1 ,3 -arrangement, together form alkylenedioxy, thioalkylenoxy, or alkylenedithioxy; or two Q t groups, which substitute the same atom, together form alkylene; and each Qi is, independently, unsubstituted or substituted with one or more substitutents, each independently selected from Q 2 wherein:
Q 2 is, independently, selected from halo, pseudohalo. hydroxy, oxo, thia, nitrile, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloaikyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalky], cycloalkylalkyl, heterocyclyi, heterocyclylalkyl, aryl heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroaryialkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonyl alkyl, aralkoxycarbonyl, araJkoxycarbonyialkyi, arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyi, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryioxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy,
-40-
alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkyicarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy, aikylaminocarbonyloxy, dialkylaminocarbonyloxy, aikylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidine, isothioureido, ureido, N-alkylureido, N-arylυreido, N'- alkylureido, N',N'-dialkylureido, N'-alkyl-N'-arylureido, N',N'-diarylureido, N'-arylureido, N\N * -dialkylureido, N-aikyl-N'-arylureido, N-aryl-N'-alkylureido, N,N'-diarylureido, N, N\N'- trialkylureido, N,N'-dialkyl-N'-arylureido, N-alkyl-N\N'-diaryiureido, N-aryl-N',N'- dialkylureido, N,N'-diaryl-N'-alkylureido, N,N',N'-triary!ureido, amidino, alkyiamidino, arylamidino, arαinothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl. alkylaminoaikyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino, haioalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, arylcarbonylaminoaikyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, heterocycly Isulfonylamino, heteroarylthio, azido, -N f Rs I R 52 R S3 , P(R 5 O) 2 , P(=0)(Rso)2, OP(=O)(R 50 ) 2 , -NR 60 CC=O)R 63 , dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl, hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyano, isothiocyano, aikylsulfinyloxy, alkylsulfonyloxy, arylsullinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfcnyloxy, alkylaminosulfonyloxy, alkylarylaminosuifonyloxy, alkylsulfinyi, alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonylo, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosuifonyl, diarylaminosulfonyl, and alkylarylaminosulfonyl; or two Q 2 groups, which substitute atoms in a 1 ,2- or 1 ,3-arrangement, together form alkylenedioxy, thioalkylenoxy, or alkylenedithioxy; or two Q 2 groups, which substitute the same atom, together form alkylene; each R 50 is, independently, selected from hydroxy!, alkoxy, aralkoxy, alkyl, heteroaryl, heterocycly], aryl, and -NR70R 7 1, wherein each R 70 and R 7 ] is, independently, selected from hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroaralkyl, and heterocyclyl; or any R 70 and R 71 together form alkylene, azaalkylene, oxaalkylene or thiaalkylene; each Rs:, R 52 , and R 53 is, independently, selected from hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroaralkyl, heterocyclyl, and heterocycly IaI kyl;
-41 -
each R^o is, independently, selected from hydrogen, alkyl aralkyl, aryl, heteroaryl, heteroaralkyl, heterocyclyl, and heterocyclylalkyl; each R^ 3 is, independently, selected from alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl, and -NR 70 R 71 ; and
L is one or more linkers covalently linking one or more of the positions R 2 , R 6 , and W 2 with R 2 ', R 6 ', and W 2 ' ; or a pharmaceutically acceptable salt thereof.
[0020] In some embodiments, L may covalently links two identical monomeric units or L covalently links two non-identical monomeric units. In some other embodiments, L may be selected from alkylene, alkenylene, alkynylene, cycloaikylene, cycloalkylalkylene, aryl, arylalkylene, arylalkylalkylene, heterocycloalkylene, heterocycloalkylalkylene, heteroaryl, and heteroarylalkylene where one or more carbon atoms are optionally replaced with N, O, or S, optionally-substituted alkylene, alkenylene, alkynylene cycloaikylene, cycloalkylalkylene, heterocycloalkylene, heterocycloalkylalkylene, aryl, arylalkylene, arylalkylalkylene, heteroaryl, and heteroarylalkylene where one or more carbon atoms are optionally replaced with N, O, or S, amino, substituted amino, oxygen atom, sulfide, sulfoxide, sulfone, and disulfide, and in still other embodiments, L may be selected from -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH=CH-, 1 ,4-phenyl, 2,5-thiophenyl, -CH(OH)CH(OH)-, -CH 2 CH-O-CHCH 2 -, and -CH 2 C≡CC≡CCH 2 -.
[0021] In particular embodiments, the compounds of the invention may be of a formula selected from a compound of formula (XVIII):
Rs
R.x
(
R 5
" )
' X fj ¥ W
2 R
i '
R > ' R * ' o (XVIlI) wherein:
R 1 , R, \ R 2 , R 2 1 , R 3 , R 3 ' , R 4 , R 4 ', R 5 , R 5 ' , R 5 x, R 5 x\ Re, IV, Rv, R 7 ', W 2 , and W 2 ' are defined as in claim 14; and
L [ and L 2 independently link R 6 with R^' and R 2 with R 2 '; or
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a pharmaceutically acceptable salt thereof; a compound of formula (XIX):
RJ R
R.x
(R 6
X)
R * ' R < o (XIX) wherein:
R 1 , Rf, R 2 , R 2 ', R 3 , R 3 ' , R 4 , R 4 ', R 5 , R 5 ', R S X, R S X\ Re, R 6 ', R 7 , R 7 ', W 2 , and W 2 ' are defined as in claim 14; and
Li and L 2 independently link R^ with R*,' and W 2 with W 2 '; or a pharmaceutically acceptable salt thereof; a compound of formula (XX):
R > " R « " B (XX) wherein:
R 1 . R, 1 , R 2 , R 2 ', R 3 , R 3 ', R 4 , R 4 ', R 5 , R 5 ' , R5X, Rsx'. R 6 , R 6 '. R 7 , R?', W 2 . and W 2 ' are defined as in claim 14; and
L links R^ with R 6 '; or a pharmaceutically acceptable salt thereof; a compound of formula (XXI):
-43-
RJ
R«x .
R 7 R 4 R 2 '
RTV
(R 5
X)'
R > ' R < ' 8 (XXI) wherein:
Ri, R 1 ', R 2 , R 2 ', R 3 , R 3 ', R 4 , R 4 ', R 5 , R 5 ', R 5 X, R 5 X', R 6 , R 6 ', R 7 , RT' , W 2 , and W 2 ' are defined as in claim 14; and
L links position R 2 with R 2 " ; or a pharmaceutically acceptable salt thereof; and a compound of formula (XXII):
R 3
(R 5
If)'
R 1 , R, ', R 2 , R 2 ', R 3 , R 3 ', R 4 , R 4 ', R 5 , R 5 ', R 5 X, R 5 x\ R 6 , R 6 ', R 7 , R 7 ', W 2 , and W 2 ' are defined as in claim 14; and
L links position W 2 with W 2 '; or a pharmaceutically acceptable salt thereof.
(0022) The compounds of the invention may further include a pharmaceutically acceptable excipient, and in several embodiments, the compounds may further include a second therapeutic agent selected from chemotherapeutic agents, radiation, immunotherapeutic agents, photodynamic therapy agents, and combinations thereof. H. Description of Drawings: Not Applicable. I. Detailed Description:
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[0023] It must be noted that, as used herein, and in the appended claims, the singular forms "a", "an" and "the" include plural reference unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein, have the same meanings as commonly understood by one of ordinary skill in the art. Although any methods similar or equivalent to those described herein can be used in the practice or testing of embodiments of the present invention, the preferred methods are now described. Ail publications and references mentioned herein are incorporated by reference. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.
(0024) As used herein, the term "about" means plus or minus 10% of the numerical value of the number with which it is being used. Therefore, about 50% means in the range of 45%-55%.
[0025J The terms "mimetic", "peptide mimetic" and "peptidomimetic" are used interchangeably herein, and generally refer to a peptide, partial peptide or non-peptide molecule that mimics the tertiary binding structure or activity of a selected native peptide or protein functional domain (e.g., binding motif or active site). These peptide mimetics include recombinantiy or chemically produced peptides, recombinantly or chemically modified peptides, as well as non-peptide agents, such as small molecule drug mimetics, as further described below.
[0026] As used herein, the terms "pharmaceutically acceptable", "physiologically tolerable" and grammatical variations thereof, as they refer to compositions, carriers, diluents and reagents, are used interchangeably and represent that the materials are capable of administration upon a mammal without the production of undesirable physiological effects such as nausea, dizziness, rash, or gastric upset.
{0027] "Providing" when used in conjunction with a therapeutic means to administer a therapeutic directly into or onto a target tissue, or to administer a therapeutic to a patient whereby the therapeutic positively impacts the tissue to which it is targeted.
[0028] As used herein, "subject", "patient" or "individual" refers to an animal or mammal including, but not limited to, a human, dog, cat, horse, cow. pig, sheep, goat, chicken, monkey, rabbit, rat, or mouse, etc.
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|0029] As used herein, the term "therapeutic" means an agent utilized to treat, combat, ameliorate, prevent or improve an unwanted condition or disease of a patient. Embodiments of the present invention are directed to promote apoptosis and, thus, cell death.
[0030] The terms "therapeutically effective amount" or "effective amount," as used herein, may be used interchangeably and refer to an amount of a therapeutic compound component of the present invention. For example, a therapeutically effective amount of a therapeutic compound is a predetermined amount calculated to achieve the desired effect, i.e., to effectively promote apoptosis, preferably by eliminating IAP inhibition of apoptosis, more preferably by inhibiting an IAP binding to a caspase.
[0031] The terms "mimetics" or "peptidomimetics" are interchangeable and refer to synthetic compounds having a three-dimensional structure (i.e. a "core peptide motif) based upon the three-dimensional structure of a selected peptide. The peptide motif provides the mimetic compound with the desired biological activity, i.e., binding to IAP, wherein the binding activity of the mimetic compound is not substantially reduced, and is often the same as or greater than the binding affinity of the native peptide on which the mimetic is modeled. For example, in the mimetics of the present invention, we have found that portions of compounds based on peptides can be non-peptide like. Peptidomimetic compounds can have additional characteristics that enhance their therapeutic application, such as increased cell permeability, greater affinity and/or avidity, and prolonged biological half-life.
[0032] "Optional" or "optionally" may be taken to mean that the subsequently described structure, event or circumstance may or may not occur, and that the description includes instances where the events occurs and instances where it does not.
{0033] "Alkyl" or "alkylene" unless otherwise specified, means a branched or unbranched, saturated aliphatic hydrocarbon group, having up to 12 carbon atoms. When used as part of another term, for example, "alkylamino," the alkyl portion may be a saturated hydrocarbon chain. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n- butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyi, n-hexyl, 2- methylpentyl, 2,2-dimethylbutyl, n-heptyl, 3-heptyl, 2-methy]hexyL and the like. The terms "lower alkyl", "Ci-C 4 alkyl", and "alkyl of 1 to 4 carbon atoms" are synonymous and used interchangeably to mean methyl, ethyl, 1 -propyl, isopropyl, cyclopropyl, 1 -butyl, sec-butyl or t-
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butyl. Unless specified, substituted aikyl groups may contain one, two, three or four substituents which may be the same or different,
[0034] "Substituent" or "substituents" as used herein refer to a molecular group that replaces a hydrogen at any methyl group on a hydrocarbon, Substituents include, for example, halo, pseudohalo, hydroxy, protected hydroxy, trityloxy, carboxy, carbonyl, cyano, nitro, acyi, acyloxy, acetyl, acetoxy, carbamoyl, carbamoyloxy, allyl, allyloxy, oxo, thia, nitrile, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyi, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloaikyl, cycloalkylalkyl, cycloalkyloxy, heterocyclyl, heterocyclylalkyl, aryl, aryloxy, arylalkyl, aralkenyl, aralkynyl, heteroaryl, heteroaryloxy, heteroaryl alkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl. triarylsilyl, alkylidene, arylalkylidene, alkyl carbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyh aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, heterocyclylsulfonyl, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkyiaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino, isothioureido, ureido, N-alkylureido, N-arylureido, N'-alkylureido, N',N'-dialkyIureido, N'- alkyl-N'-arylureido, N',N'-diarylureido, N'-arylureido, N',N'-dialkylureido, N-alkyl-N'- arylureido, N-aryl-N'-alkylureido, N,N'-diarylureido, N, N',N'-triaIkylureido, N,N'-dialkyl-N'- arylureido, N-alkyl-N',N'-diarylureido, N-aryl-N\N'-dialkylureido, N,N'-diaryI-N'-alkylureido, N,N\N'-triarylureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl. amino, protected amino, aminoalkyl, aminothio, acylamino, aminosulfinyl, aminosulfonyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino, aryiamiπo, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, arylcarbonylaminoaikyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonyl ami no, alkylsulfonylamino, arylsulfonyiamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,
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heteroarylthio, azido, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl, hydroxyphosphonyl, aikylthio, arylthio, perfluoroalkylthio, hydroxycarbonyialkylthio, thiocyano, isothiocyano, alkylsυlfinyi, alkylsulfinyloxy, alkylsulfonyl. aikylsulfonyloxy, arylsulflnyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyl alkylaminosulfonyloxy, aikyiarylaminosulfonyloxy, alkylsulfonyl, arylsulfinyl, alkyisulfonylamino. arylsυlfonyi, hydroxysulfonylo, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl. dialkylaminosulfony], arylaminosulfonyl, diarylaminosulfonyl, and alkylarylaminosulfonyl, alkyloxycarbony (amino, aliyloxycarbonyl, allyloxycarbonylamino, and the like. For example, particular substituted alkyls are substituted methyls, e.g., a methyl group substituted by the same substituents as the "substituted C n -C n , alkyl" group. "Substituted alkyl" may include alkyloxymethyl, such as, methoxymethyl, ethoxymethyl, and t-butoxymethyl; haϊomethyl, such as, chloromethyl, bromomethyl, iodomethyl, and trifluoromethyl; hydroxymethyl; protected hydroxymethyl, such as, tetrahydropyranyloxymethyl; trityloxymethyl; cyanomethyl; nitromethyl; aminomethyl; carboxy methyl; alkyloxycarbonylmethyl; acetoxymethyl, carbamoyloxymethyl; ailyloxycarbonylaminomethyl; propionyloxymethyl; acetoxymethyl; 6-hydroxyhexyl; 2,4-dichioro(n-butyl); 2-amino(iso- propyl); 2-carbamoyloxyethyl; carbocycle group, such as, for example, cyciopropylmethyl, cyclobutylmethyl, cyclopentyimethyl, and cyclohexylmethyl groups, as well as the corresponding-ethyl, -propyl, -butyl, -pentyl, -hexyl groups, etc.
[0035) "Alkenyl" or "alkenylene" as used herein refers to an unsaturated, branched or unbranched, aiphatic hydrocarbon having one or more double bond (-C=C-), and "alkynyl" or "alkynylene" as used herein refers to an unsaturated, branched or unbranched, aiphatic hydrocarbon containing one or more triple bond (-C≡C-). Unsaturated hydrocarbons may have up to 12 carbon atoms and may be substituted by one or more of any of the substituents described hereinabove. When used as part of another term, for example, "alkenylamino" and "alkynylamino" the alkyl portion may be an unsaturated hydrocarbon chain.
[0036] "Amino" denotes primary (i.e. -NII 2 ), secondary (i.e. -NRH), and tertiary (i.e. - NRR) amines. Particular secondary and tertiary amines include, but are not limited to, alkylamine, dialkylamine, arylamine, diary lamine, arylalkylamine and diary lalkylamine including, for example, methylamine, ethylamine, propylamine, isopropylamine, phenylamine, benzylamine, dimethylamine, diethylamine, dipropylamine and disopropylamine.
-48-
(0037] "Aryl", when used alone or as part of another term, means a fused or unfused carbocyclic aromatic group having a designated number of carbon atoms, or if no number is designated, up to 14 carbon atoms. Particular aryl groups include phenyl, naphthyl, biphenyl, phsnanthrenyl, naphthacenyl, and the like (see, Lang's Handbook of Chemistry 13 th ed. (Dean, J, A., ed.) Table 7-2 [1985]). Substituted phenyl or substituted aryl denotes a phenyl or aryl group substituted with one, two, three, four or five substituents chosen from those described above, for example, halogen (F, Cl, Br, I), hydroxy, protected hydroxy, cyano, nitro, alkyl (such as Q-Cn alkyl), alkoxy (such as, Q-Q, alkoxy), benzyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxy methyl, aminomethyl, protected aminomethyl, trifluoromethyl, alkylsulfonylamino, arylsulfonylamino, heterocyclylsulfonylamino, heterocyclyl, or aryl, and one or more methyne (CH) and/or methylene (CH 2 ) groups in these substituents may be substituted with a group similar to those described above. Examples of "substituted phenyls" that may be utilized in embodiments of the invention include, but are not limited to, mono- or di-halo-phenyl, such as, 2-chlorophenyl, 2- bromophenyl, 4-chlorophenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 3- chlorophenyl, 3-bromophenyl, 4-bromophenyl, 3,4-dibromophenyl, 3-chloro-4-fluorophenyl, 2- fluorophenyl, and the like; mono- or di-hydroxyphenyl, such as, 4-hydroxyphenyl, 3- hydroxyphenyl, 2,4-dihydroxyphenyl, protected-hydroxy derivatives thereof, and the like; nitrophenyl, such as, 3- or 4-nitrophenyl; cyanophenyl, for example, 4-cyanophenyl; mono- or di-lower alkyl-phenyl group, such as, 4-methylphenyl, 2,4-dimethylphenyl, 2-methylphenyl, 4- (iso-propyl)phenyl, 4-ethylphenyl, 3-(n-propyl)phenyl, and the like; a mono- or di-alkoxy-phenyl group, for example, 3,4-dimethoxyphenyl, 3-methoxy-4-benzyIoxyphenyl, 3-methoxy-4-(l- chloromethyl) benzyloxy-phenyl, 3-ethoxyphenyl, 4-(isopropoxy)phenyl, 4~(t-butoxy)phenyl, 3- ethoxy-4-methoxyphenyl and the like; 3- or 4-trifluoromethylphenyl; mono- or di-carboxyphenyl or protected carboxy phenyl, such as, 4-carboxyphenyl; mono- or di-hydroxymethyl-phenyl or protected hydroxymethyl phenyl, such as 3-(prσtected hydroxymethyl) phenyl or 3,4- di(hydroxymethyl)phenyl; mono- or di-(aminomethyl) phenyl or protected aminomethyl phenyl, such as 2-(aminomethyi)phenyl or 2.4-(protected aminomethyl) phenyl; or mono- or di-(N- (methyJsulfonylamino)) phenyl, such as. 3-(N-methyIsulfony!amino) phenyl. In addition, "substituted phenyl" may represent di-substituted phenyl groups where the substituents are different, such as, for example, 3-methyl-4-hydroxyphenyl, 3-chloro-4-hydroxyphenyl, 2-
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methoxy-4-bromophenyi, 4-ethyI-2-hydroxyphenyl, 3-hydroxy-4-nitrophenyI, 2-hydroxy-4- chlorophenyl, and the like, as well as tri-substituted phenyl groups where the substituents are different, such as, for example, 3~methoxy-4-benzy!oxy-6-methyl sulfonylamino, 3-methoxy-4- benzyloxy-6-phenyl sulfonylamino and the like and tetra-substituted phenyl groups where the substituents are different, such as, for example, 3-methoxy-4-benzyJoxy-5-methyl-6-phenyϊ sulfonylamino. Particular substituted phenyl groups include 2-ch!orophenyl, 2-aminophenyl, 2- bromophenyl, 3 -methoxy phenyl, 3-ethoxy-phenyl, 4-benzyloxyphenyl, 4-methoxyphenyI, 3- ethoxy-4-benzyloxyphenyl, 3,4-diethoxyphenyl, 3-methoxy-4-benzyloxyphenyl, 3-methoxy-4- (1 -chloromethyl) benzyloxy-phenyl, 3-methoxy-4-(l-chloromethyl), and benzyloxy-6-methyl sulfonyi aminophenyl groups. Fused aryl rings may also be substituted with one or more of any of the substituents specified herein, for example, fused aryl groups may contain 1 , 2 or 3 substituents in the same manner as substituted alkyl groups.
|0038] "Heterocyclic group", "heterocyclic", "heterocycle", "heterocyclyl", or "heterocyclo" alone, and when used as a moiety in a complex group such as a heterocycloalkyl group, are used interchangeably and refer to any mono-, bi-, or tri-cyclic, saturated or unsaturated, aromatic (heteroaryl) or non-aromatic ring having the number of atoms designated, generally from 5 to about 14 ring atoms, where the ring atoms are carbon and at least one heteroatom (nitrogen, sulfur or oxygen). In a particular embodiment, the group incorporates 1 to 4 heteroatoms. Typically, a 5- member ring has 0 to 2 double bonds and a 6- or 7-member ring has 0 to 3 double bonds; and the nitrogen or sulfur heteroatoms may optionally be oxidized (e.g. SO, SO 2 ), and any nitrogen heteroatom may optionally be quaternized. Particular non-aromatic heterocycles include morpholinyl (morpholino), pyrrolidinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, 2,3-dihydrofuranyl, 2H-pyranyl, tetrahydropyranyl, thiiranyl, thietanyl, tetrahydrothietanyl. aziridinyh azetidinyl, 1 -methyl -2-pyrrolyl, piperazinyl, and piperidinyl. λ "heterocycloaikyl" group is a heterocycle group as defined above, covalently bonded to an alkyl group as defined above. Particular 5-membered heterocycles containing a sulfur or oxygen atom and one to three nitrogen atoms include thiazolyl, such as thiazol-2-yl and thiazol-2-yl N-oxide, thiadiazolyl, such as l,3,4-thiadiazol-5-yl and l,2,4-thiadiazoϊ-5-yi, oxazolyl, such as, oxazol-2- yl, and oxadiazolyl, such as l,3,4-σxadiazol-5-yl, and l,2,4-oxadiazol~5-yl. Particular 5- membered ring heterocycles containing 2 to 4 nitrogen atoms include imidazolyl, such as imidazol-2-yl; triazolyl, such as i ,3,4-triazol-5-yl, l,2,3-triazol-5-yl, and l ,2,4-triazol-5-yI, and
-50-
tetrazolyl such as lH-tetrazoi-5-yl. Particular benzo-fused 5-membered heterocycles are benzoxazoi-2-yi, benzthiazol-2-yl, and benzimidazol-2-yl. Particular 6-membered heterocycles contain one to three nitrogen atoms and, optionally, a sulfur or oxygen atom, for example pyridyl, such as, pyrid-2-yl, pyrid-3-yl, and pyrid-4-yl; pyrimidyl, such as, pyrimid-2-yl and pyrimid-4-yi; triazinyl, such as, l,3.4-triazin-2-yl and l ,3,5-triazin-4-yl; pyridazinyl, such as, pyridazin-3-yl, and pyrazinyi. Substituents for optionally substituted heterocycles, and further examples of the 5- and 6-membered ring systems discussed above, can be found in U. S. Patent No. 4,278, 793 to W. Druckheimer et al,
[0039] "Heteroaryl" alone and when used as a moiety in a complex group such as a heteroarylalkyl group, refers to any mono-, bi-, or tri-cyclic aromatic ring system having the number of atoms designated where at least one ring is a 5-, 6- or 7-membered ring containing from one to four heteroatoms selected from the group nitrogen, oxygen, and sulfur (see Lang's Handbook of Chemistry, supra). Included in the definition are any bicyclic groups where any of the above heteroaryl rings are fused to a benzene ring. The following ring systems are examples of the heteroaryl (whether substituted or unsubstituted) group denoted by the term "heteroaryl": thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, pyrazinyi, pyridazinyl, thiazinyl, oxazinyl, triazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl, tetrazinyl, thtatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl, dihydropyrimidyl, tetrahydropyrimidyl, tetrazolo[l ,5-b]pyridazinyl and purinyl, as well as benzo-fused derivatives, for example, benzoxazolyl, benzofuryl, benzothiazoiyl, benzothiadiazolyl. benzotriazoiyl, benzoimidazolyl, and indolyl. Particular "heteroaryls" include: l,3-thiazol-2-yl, 4-(carboxymethyl)-5-methyl, l ,3-thiazol-2-yl, 4-(carboxymethyl)-5- methy!-l ,3-thiazol-2-yl sodium salt, I ,2,4-thiadiazol-5-yl, 3-methyl-l ,2,4-thiadiazol-5-yl, 1,3,4- triazol-5-yl, 2-methyl-l ,3,4-triazol-5-yl, 2-hydroxy-l,3,4-triazol-5-yl, 2~carboxy-4-methyl-l,3,4- triazoI-5-y ] sodium salt, 2-carboxy-4-methyl-I ,3,4-triazol-5-yl, l,3-oxazoi-2-yl, 1 ,3,4-oxadiazol- 5-y ] , 2-methyl- l,3,4-oxadiazol-5-yl, 2-(hydroxymethyl)-l,3.4-oxadiazol-5-yl, 1 ,2,4-oxadiazoI-5- yl, l ,3,4-thiadiazol-5-yl, 2-thio]-l ,3,4-thiadiazol-5-yl, 2-(mcthylthio)-l ,3,4-thiadiazol-5-yl, 2- amino- l,3,4-thiadiazol-5-yl, 1 H-tctrazol-5-yl, 1 -methyl- l H-tetrazol-5-yl, 1-(1-
(dimethy lamino)eth-2-yl)- 1 H-tetrazol-5-yl, 1 -(carboxymethyl)- 1 H-tetrazol-5-y I, I-
(carboxymethy!)-IH-tetrazol-5-yl sodium salt, l-(methylsulfonic acid)-!H-tetrazol-5-yl ? 1-
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(methylsuϊfonic acid)-IH-tetrazol-5-yl sodium salt, 2-methyl-lH-tetrazoI-5-yi, l,2,3-triazol-5-yI, 1 -methyl- 1, 2, 3-triazoI-5-yl. 2-methyl-l,2,3-triazol-5-yl, 4-methyl-l ,2,3-triazol-5-yI, pyrid-2-yl N-oxide, 6-methoxy-2-(n-oxide)-pyridaz-3-yl, 6-hydroxypyridaz-3-yl, l-methylpyrid-2-yl, 1- methylpyrid-4-yl, 2-hydroxypyrimid-4-yl, l,4,5,6-tetrahydro-5, 6-dioxo-4-methyl-as-triazin-3-yl, 1 ,4,5,6-tetrahydro-4-(formylmethyl)-5, 6-dioxo-as-triazin-3-yl, 2,5-dihydro-5-oxo-6-hydroxy- astriazin-3-yl, 2,5-dihydro-5-oxo-6-hydroxy-as-triazin-3-yl sodium salt, 2,5-dihydro-5-oxo-6- hydroxy-2-methyl-astriazin-3-yl sodium salt, 2,5-dihydro-5-oxo-6-hydroxy-2-methyl-as-triazin- 3-yl, 2,5-dihydro-5-oxo~6-methoxy-2-methyI-as-triazin-3-yl, 2,5-dihydro-5-oxo-as-triazin-3-yl, 2,5-dihydro-5-oxo-2-methy]-as-triazin-3-yf, 2,5-dihydro-5-oxo-2, 6-dimethyi-as-triazin-3-yl, tetrazolo[l,5-b]pyridazin-6-yl and 8-aminotetrazolo[l,5-bJ-pyridazin-6-yl. An alternative group of "heteroaryl" includes: 4-(carboxymethyl)-5-methyl~I , 3-thiazol-2-yl, 4-(carboxymethyl)-5- methyl-l,3-thiazol-2-yl sodium salt, l ,3,4-triazoI-5-yl, 2-methyl-l,3,4-triazoi-5-yl, lH-tetrazol- 5-yl, 1 -methyl- l H-tetrazol-5-yl. l-(Hdimethylamino)eth-2-yl)-lH-tetrazol-5-yl, 1- (carboxymethyl)-l H-tetrazol-5-yl, l -(carboxymethyl)-lH-tetra2ol-5-yl sodium salt, 1- (methyl sulfonic acid)-lH- tetrazol-5-yl, l-(methylsulfonic acid)-lH-tetrazol-5-yl sodium salt, 1 ,2,3-triazol-5-yl, 1 ,4,5,6-tetrahydro-5,6-dioxo-4-methyl-as-triazin-3-yl, 1 ,4,5, 6-tetrahydro-4-(2- formylmethyl)-5, 6-dioxo-as-triazin-3-yi, 2,5-dihydro-5-oxo-6-hydroxy-2-methyl-as-triazin-3-yl sodium salt, 2,5-dihydro~5-oxo-ό-hydroxy-2-methyl-as-triazin-3-yl, tetrazolo[ l ,5-bJpyridazin-6- yl, and 8-aminotetrazolo[ l,5-b]pyridazin-6-yl.
[004Oj A "linker" is a bond or linking group whereby two chemical moieties, such as, monomers of an active compound, are directly covalently linked to one another or are indirectly linked via a third chemical moiety to form a homo- or heterodimer. The compounds set forth herein may include a single linker linking the two chemical moieties, or more than one linker linking the two chemical moieties at one or more position independently on each of the two chemical moieties. A "linker" (L, L \ or L 2 ) may be a single or double covalent bond or a branched or unbranched, substituted or unsubstituted, hydrocarbon chain of 1 to about 100 atoms, typically, 1 to about 20 atoms, having a molecular weight up to about 500 MW. For example, a linker can be a bond, alkylene, aikenylene, alkynylene, cycloalkylene, cycloalkylalkylene, heterocycloalkylene, heterocycioalkylalkylene, aryl, arylalkylene, arylalkylalkylene, heteroaryl, or heteroarylalkylene, or an optionally-substituted alkylene, aikenyiene, alkynylene cycloalkylene, cycloalkylalkylene, heterocycloalkylene,
-52-
heterocycloalkylalkylene, aryl, arylalkylene, arylalkylalkylene, heteroaryi, or heteroarylalkylene, of 2 to 12 atoms where one or more carbon atoms can be replaced with N, O. or S or an amino, substituted amino, oxygen atom, sulfide (-S-), sulfoxide (-SO-), sulfone (-SO 2 -), or disulfide (- SS-) group. Illustrative linkers and linking groups are described in U.S. Patent Publication No. 20050197403, as well as in U.S. Patent Application Serial Number 1 1/363,387, filed February 27, 2006, both of which are incorporated herein by reference as though fully set forth. For example, particular "linkers" include, but are not limited to, -CFI 2 CH 2 -, -CFbCH 2 CH 2 -, - CH=CH-, 1 ,4-phenyl, 2,5-thiophenyI, -CH(OH)CH(OH)-, -CH 2 CH-O-CHCH 2 -, and - CH 2 C≡CC≡CCH 2 -.
[0041] The term "homodimer" as used herein refers to a compound composed of two covalently bound monomeric units of a chemical moiety wherein the monomeric units are identical.
[0042] The term "heterodimer" as used herein refers to a compound composed of two covalently bound monomeric units of a chemical moiety wherein the monomeric units are different. For example, one monomeric unit of a heterodimer may include a substituent that is different from the other monomeric unit at one or more position.
[0043] "Inhibitor" means a compound which reduces or prevents a particular interaction or reaction. For example, the binding of IAP proteins to caspase proteins reduces or prevents the inhibition of apoptosis by an IAP protein.
[0044] "Pharmaceutically acceptable salts" include both acid and base addition salts. "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and the like. Organic acids may be selected from aliphatic, cycloaliphatic, aromatic, arylaliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids, such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, maloneic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanes ulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicyclic acid, and the like.
-53-
J0045] The present invention is generally directed to Smac peptidomimetics (herein referred to as "Smac mimetics" or "a Smac mimetic' * ) and the uses of Smac mimetics. One embodiment of the invention is a therapeutic composition including a Smac mimetic. In another embodiment, Smac mimetics act as chemopotentiating or chemotherapeutic agents. The term "chemopotentiating agent" as used herein refers to an agent that acts to increase the sensitivity of an organism, tissue, or cell to a chemical compound, or treatment namely "chemotherapeutic agents" or "chemo drugs" or radiation treatment. Therefore, a further embodiment of the invention is the therapeutic composition of a Smac mimetic, which acts as a chemopotentiating agent, and a biological agent, chemotherapeutic agent or radiation. Another embodiment of the invention is a method of inhibiting tumor growth in vivo by administering a Smac mimetic. Yet another embodiment is a method of inhibiting tumor growth in vivo by administering a Smac mimetic and a biologic agent, chemotherapeutic agent or radiation. Still another embodiment of the invention is a method of treating an individual, such as, for example, patient with cancer, by administering Smac mimetics of the present invention alone, or in combination with, a biological agent, chemotherapeutic agent or radiation.
[0046] In various embodiments of the invention, in situ cells or pathogenic cells, in an individual, may be treated with a Smac mimetic or a Smac mimietic in combination with a secondary agent, such as, a biological agent, chemotherapeutic agent or radiation. In such embodiments, the contacting step is affected by administering a pharmaceutical composition including a therapeutically effective amount of the Smac mimetic, wherein the individual may be subject to concurrent or antecedent radiation or chemotherapy for treatment of a neoproliferative pathology. Pathogenic cells may be of a tumor such as, but not limited to, bladder cancer, breast cancer, prostate cancer, lung cancer, pancreatic cancer, gastric cancer, colon cancer, ovarian cancer, renal cancer, hepatoma, melanoma, lymphoma, sarcoma, and combinations thereof.
[0047] In addition to apoptosis defects found in tumors, defects in the ability to eliminate self-reactive cells of the immune system due to apoptosis resistance may be considered to play a key role in the pathogenesis of autoimmune diseases. Autoimmune diseases are characterized in that the cells of the immune system produce antibodies against its own organs and molecules or directly attack tissues resulting in the destruction of these tissues. Failure of these self-reactive cells to undergo apoptosis leads to the manifestation of the disease. Defects in
-54-
apoptosis regulation have been identified in autoimmune diseases such as systemic lupus erthematosus, or rheumatoid arthritis.
[0048) In some embodiments of the invention, pathogenic cells may be those cells effected by an autoimmune disease or any disease whose symptoms include production of cells that are resistant to apoptosis. In at least one embodiment, affected cells are resistant to apoptosis due to the expression or overexpression of members of the BcI-2 family of caspases. Examples of such autoimmune diseases include, but are not limited to, collagen diseases, such as, rheumatoid arthritis, systemic lupus erythematosus, Sharp's syndrome. CREST syndrome, calcinosis, Raynaud's syndrome, esophageal dysmotility, telangiectasia, dermatomyositis, vasculitis (Morbus Wegener's), and Sjogren's syndrome; renal diseases, such as, Goodpasture's syndrome, rapidly-progressing glomerulonephritis, and membrano-proliferative glomerulonephritis type II; endocrine diseases, such as, type-ϊ diabetes, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), autoimmune parathyroidism, pernicious anemia, gonad insufficiency, idiopathic Morbus Addison's, hyperthyreosis, Hashimoto's thyroiditis, and primary myxedema; skin diseases, such as, pemphigus vulgaris, bullous pemphigoid, herpes gestationis, epidermolysis bullosa, and erythema multiforme major; liver diseases, such as, primary biliary cirrhosis, autoimmune cholangitis, autoimmune hepatitis type-1, autoimmune hepatitis type-2, primary sclerosing cholangitis; neuronal diseases, such as, multiple sclerosis, myasthenia gravis, myasthenic Lambert-Eaton syndrome, acquired neuromyotony, ϋuillain-Barre syndrome (Mϋlier-Fischer syndrome), stiff-man syndrome, cerebellar degeneration, ataxia, opsoklonus, sensoric neuropathy, and achalasia; blood diseases, such as, autoimmune hemolytic anemia and idiopathic thrombocytopenic purpura (Morbus Werlhof); and infectious diseases with associated autoimmune reactions, such as, AIDS, Malaria, and Chagas disease.
[0049] It has been demonstrated in accordance with the present invention that the IAP- binding peptides or mimetics, thereof, are capable of potentiating apoptosis of cells. The mimetics described herein are suitably small, and since structural features in relation to the IAP binding groove are well-characterized, a wide variety of mimetic compounds may be synthesized. Mimetics of the core iAP-binding portions are preferred. Added advantages of compounds of this size include improved solubility in aqueous solution and ease of delivery to selected targets in vivo.
-55-
[0050] The following compounds are illustrative of IAP-binding compounds that may be prepared as dimers and dimers of these IAP-binding compounds. Thus, various embodiments of the invention include these dimers. Such dimers can be prepared using any synthetic technique available to persons of ordinary skill in the art, such as, for example, the dimeric Smac peptidomimetics disclosed in U.S. Patent Application Serial Number 1 1/363.387, filed 2/27/2006, which provides guidance on preparation of the dimers of the instant invention.
[0051] Various embodiments of the invention include homodimers and heterodimer of compounds having monomelic units of general formula (I):
(Ro)S.^ — -^ s- - s i^*
R 5
(I) wherein: each M is, independently, CO, SO, or SO 2 ; each Z is, independently, CH or N; each X and Y is, independently, selected from 4-7 member heterocyclic and heteroaryl rings having one or two heteroatoms; each s and p is, independently, 0-3; each R] and R 2 is, independently, selected from:
(i) Rt is, independently, selected from hydrogen, alky], alkenyi, alkynyi, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; and R 2 is, independently, selected from hydrogen, alkenyi, alkynyi, aryl, heteroaryl, cycloalkyl, hetereocycϊyl, ORn, NRi 5 Ri 6 , and a moiety of formula (II):
V-- " ' KJ. — R
(H) wherein each nx is, independently, 0-6; each R is, independently, selected from hydrogen, alkyl, alkenyi, alkynyl, aryl, heteroaryl, heteroaryl ium, cycloalkyl, heterocyclyl, C(A)R]O, ORn. and NR ^R I6 ; and each R 6 and R 7 is, independently,
-56-
selected from hydrogen, alkyl, alkenyl, alkynyi, aryl, heteroaryl, cycloalkyl, and heterocyclyl; and (ii) any R| and R 2 together with a nitrogen atom on which Ri and R 2 are substituted form a heterocyclic or heteroaryl ring; each R 3 , R 4 , and R 5 is, independently, selected from:
(i) R 3 and R 4 are, independently, selected from hydrogen, lower alkyl, lower alkenyl, alkynyi, lower cycloalkyl, and lower heterocyclyl; and R 5 is selected from hydrogen, alkyl, alkenyl, alkynyi, aryl, heteroaryl, cycloalkyl, heterocyclyl and
NR 15 Ri 6 : and
(ii) any Rs and R 3 or R 5 and R 4 together with atoms on which they are substituted form a heterocyclic or heteroaryl ring and remaining R 3 or R 4 is selected as (i); each R 5x is, independently, selected from hydrogen, lower alkyl, lower alkenyl, and lower alkynyi; each Rs and R 9 is, independently, selected from:
(i) Rs and R9 are each independently selected from lower alkyl, lower alkenyl, lower alkynyi, aryl, heteroaryl, cycloalkyl, heterocyclyl, C(A)R f 0 , halo, pseudohalo, OR n , oxo, thio, S(D) n Ri 2 , NR 15 R 16 , N + R 15 Ri 6 Ri 7 , =NR 25 , and =CR 13 R !4 ; (ϋ) any Rs and R9 together with atoms on which they are substituted form a cycloalkyl, aryl, heterocyclic, or heteroaryl ring; and (iii) two Rg substituents together with carbon atoms to which they are substituted form a cycloalkyl, aryl, heteroaryl, or heterocyclyl ring; each A is, independently, selected from O, S, and NR 25 ; each Rio is, independently, selected from hydrogen, alkyl, alkenyl, alkynyi, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, C(A)R] 6 , halo, pseudohalo, OR 25 , SR 25 , NR 27 R 28 , and SiR 22 R 23 R 2 ^ each Rn is, independently, selected from hydrogen, alkyl, alkenyl, aikynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, C(A)R 2 *?, NR 30 R 3 I, and SiR 22 R 23 R 24 ; each D is, independently, selected from O and NR 25 ; each n is 0, 1 , or 2;
-57-
with the proviso that when any n is 1 or 2, then Rj 2 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, halo, pseudohalo, OR 25 , SR 25 , and NR32R33; and when n is 0, then R12 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, SR25, and C(A)R 2 ^ each Ru and R^ is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, C(A)R 29 , OR 25 , and NR 32 R 33 ; each Ri 5 , R| 6η and R [7 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, C(A)R 2 ς>, OR 25 , and NR 32 R 33 ; or any two of R15, R\β, and R17 together form alkylene, alkenylene, alkynylene, heteroalkylene, and the other is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, C(A)R 2? , OR 25 , and NR 32 R 33 ; each R 22 , R 23 , and R 24 is, independently, selected from:
(i) R22, R 23 , and R24 are each, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR 25 , and NR32R33; or (ii) any two of R22, R23, and R2 4 together form alkylene, alkenylene, alkynylene, or heteroalkylene, and the other is selected selected from (i); each R25 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, and heterocyclyl; each R 2 7 and R 28 is, independently, selected from:
(i) R27 and R 2 g are each, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloaikyl, heterocyclyl, C(A)R 3 ^, OR 25 , and NR 37 R 38 , wherein any R 37 and R 3 g are each, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, and heterocyclyl; or any R 37 and R38 together form alkylene, alkenylene, aikynylene, or heteroalkylene; and any R 3 9 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR 40 , and NR 32 R 33 , wherein any R 40 is selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, and heterocyclyl; or
-58-
<ii) R27 and R 2 8 together form alkylene, alkenylene, aikynylene, heteroalkylene, OR 40 , or NR 32 R 3 ^; each R29 is, independently, selected from hydrogen, alky], alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR 4O , and NR 32 R 33 ; each Rrø and R31 is, independently, selected from hydrogen, alky!, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, and C(A)R 4 ], wherein any R 41 is selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR 40 , and NR32R33: or any R30 and R31 together form alkylene, alkenylene, aikynylene, or heteroalkylene; each R 32 and R 33 is, independently, selected from hydrogen, alkyl, aikenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, and heterocyclyl; or R 32 and R 33 together form alkylene, alkenylene, aikynylene, or heteroalkylene; each R, R 5x , and Ri-Rig, R22-R25, and R27-R33 is, independently, unsubstituted or substituted with one or more substitutents, each independently selected from Qi wherein: each Q] is, independently, selected from halo, pseudohalo, hydroxy, oxo, thia, nitrile, formyl, mercapto, hydroxycarbonyi, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aJkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl. alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyioxy, aralkoxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidine, isothioureido, ureido, N-alkylureido, N-arylureido, N'- alkylureido, N',N'-dialkyIureido, N'-alkyl-N'-arylureido, N\N'-diarylureido, N'-aryϊureido, N',N'-dialkylureido, N-alkyl-N'-arylureido, N-aryl-N'-aikylureido, N,N'-diarylureido, N, N'.N'- trialkylureido, N,N'-dialkyl-N^arylureido, N-alkyl-N',N η -diarylureido, N-aryl-N',N'- dialkylureido, N,N'-diaryI-N'-alkylureido. N,N',N'-triarylureido, amidino, alkylamidino,
-59-
arylamidino. aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl, aikylaminoalkyl, dialkylaminoalkyk arylaminoalkyl, diarylarninoalkyl, alkylarylaminoalkyl, aikylamino, diaikylamino, haloalkylamino, aryiamino, diarylamino, alkylarylamino, alkylcarbonylamino, aikoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyi, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino, heteroarylthio, azido. -N + R 5 iR . <i 2 R 53 , P(R 5 O) 2 , P(O)(R 5 O) 2 , OP(=OJ(R 50 )2. -NR 6 OCt=O)R 63 , dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl, hydroxyphosphonyl, alkylthio, aryithio, perfluoroalkylthio, hydroxycarbonylalkylthio, thtocyano, isothiocyano, alkylsulfinyioxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonylo, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyl, and alkylarylaminosulfonyl; or two Qi groups, which substitute atoms in a 1 ,2- or 1 ,3-arrangement, together form alkylenedioxy, thioalkylenoxy, or alkylenedithioxy; or two Qi groups, which substitute the same atom, together form alkylene; and each Qt is, independently, unsubstituted or substituted with one or more substitutents, each independently selected from Q 2 wherein:
Q2 is, independently, selected from halo, pseudohalo, hydroxy, oxo, thia, nitrile, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclyialky], aryl, heteroaryl, araikyl, aralkenyl, aralkynyl, heteroarylalkyl, triaikylsilyl, dialkylarylsilyl, alkyldiarylsilyi, triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl. alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy. heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy,
-60-
alkylaminocarbonyioxy, dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidine, isothioureido, ureido, N-alkylureido, TN-arylureido, N'- alkyiureido, N',N'-dialkylureido, N'-alkyl-N'-arylureido, N',N'-diarylureido, N'-arylureido, N',ϊ\T-dialkylureido, N-alkyl-N'-arylureido, N-aryl-N'-alkylureido, N,N λ -diarylureido, N, N',N'- trialkylureido, T^N'-dialkyl-N'-arylureido, N-alkyl-N',N'-diarylureido, N-aryl-N',N'- diaikylureido, N,lsT-diaryl-N * -alkyiureido, N,N\N'-triarylureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, alkyϊamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino. alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, arylcarbonylaminoaikyl, aryloxycarbonylaminoaJkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonyiamino, arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino, heteroarytthio, azido, -N + R 5I R 52 Rs 3 , P(R 50 )I, P(=0)(R 5 o)2, OP(=O)(R 50 )2, -NR 60 C(^O)R 63 , dialkylphosphonyl, alkylarylphosphonyl, diaiylphosphonyl, hydroxyphosphonyl, alkylthio, arylthio, perlluoroalkylthio, hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy, alkyisulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, aikoxysulfonyloxy, aminosulfonyloxy, alkylaminosυlfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfmyl, arylsulfonyl, hydroxysulfonylo, alkoxysulfonyl, aminosulfony], alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyl, and alkylarylaminosυlfonyl; or two Q 2 groups, which substitute atoms in a 1,2- or 1,3-arrangement, together form alkylenedioxy, thioalkylenoxy, or alkylenedithioxy; or two Q 2 groups, which substitute the same atom, together form alkylene; each R50 is, independently, selected from hydro xyl s alkoxy, aralkoxy, alkyl, hetcroaryl, heterocyclyl, aryl, and -NR70R71, wherein any R 70 and R 7! is, independently, selected from hydrogen, aikyl, aralkyl, aryi, heteroaryl, heteroaralkyl, or heterocyclyl; or any R 70 and R 71 together form alkylene, azaalkylene, oxaalkylene, or thiaalkylene; each R 5 ), R52, and R 53 is, independently, selected from hydrogen, alkyl, araikyl, aryl, heteroaryl, heteroaralkyl, heterocyclyl, and heterocyclylalkyl; each Rόo is, independently, selected from hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroaralkyl, heterocyclyl, and heterocyclylalkyl; and
-61 -
each R <53 is, independently, selected from alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyi, aryl, and -NR70R7I, with the proviso that when: a) Y is a seven-membered heterocyclic ring with 1 heteroatom in the ring; b) X is a five-membered heterocyclic ring with 1 heteroatom in the ring; c) Rg and Rg together with any atoms on which they are substituted form a phenyl ring; and d) nx is 0; then R, R O , and R 7 are not heterocyclyi or heteroaryl; and pharmaceutically acceptable salts and hydrates thereof.
[0052J Other embodiments of the invention include compounds of general formula (III):
(R 9 )S, .(R 8 )P
R 5
*'
λ
R,
M and M ' are each, independently, CO, SO, or SO 2 ; Z and Z' are each, independently, CH or N;
X, X', Y, and Y' are each, independently, selected from 4-7 membered heterocyclic and heteroaryl rings containing one or two heteroatoms; s and p are each, independently, 0-3; Ri, Rj', R 2 , and R 2 ' are each, independently, selected from:
(i) R] and Ri' are each, independently, selected from hydrogen, alky], alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or heterocycioalkyl; and R 2 and R 2 ' are independently selected from hydrogen, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, hetereocyclyl, ORn, NR] S R 16 , and a moiety of formula (II):
"X -R
^ (II)
-62-
where nx is 0-6; each R is, independently, selected from hydrogen, alkyl, alkenyi, aikynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyciyi, C(A)R J O , ORH , and NRi 5 R^; and each R^ and R 7 is, independently, selected from hydrogen, alkyl, alkenyi, aikynyl, aryl, heteroaryl, cycloalkyl, and heterocyciyi; and (ii) Ri and R 2 , either alone or together with Ri ' and R 2 ', together with a nitrogen atom on which they are substituted form a heterocyclic or heteroaryl ring; R3, R^, R4, R 4 * , R5, and R 5 ' are each, independently, selected from:
(i) R3, R 3 ', R4, and R 4 ' are each, independently, selected from hydrogen, lower alkyl, lower alkenyi, aikynyl, lower cycloalkyl, lower heterocyciyi; and Rs 1 and R 5 ' are independently selected from hydrogen, alkyl, alkenyi, aikynyl, aryl, heteroaryl, cycloalkyl, heterocyciyi, and NRi 5 R 16 ; and
(ii) R 5 and R 3 , independently or together with R 5 ' and R 3 ', or R 5 and R 4 , independently or together with R 5 ' and R 4 ', together with any atoms on which they are substituted form a heterocyclic or heteroaryl ring and the other of R 3 , R 3 ', R4, or R4 is selected as (i);
R5X and R5X' are each, independently, selected from hydrogen, lower alkyl, lower alkenyi, and lower alkynyl;
Rs, R«\ R9, and R9' are each, independently, selected from:
(i) each R R , Rg', R9, and R9' is, independently, selected from lower alkyl, lower alkenyi, lower alkynyl, aryl, heteroaryl, cycloalkyl. heterocyciyi, C(A)R 10 , halo, pseudohalo, OR n , oxo, thio, S(D) n Rj 2 , NR 15 R 16 , N + Ri 5 R] 6 R)?, =NR 25 , and ^CRi 3 Rf 4 ;
(ii) any Rg and R 9 independently or together with any Rs' and Rg', together with any atoms on which they are substituted form a cycloalkyl, aryl, heterocyclic, or heteroaryl ring; and
(iii) any two Rg substituents, independently or together with any two Rs' substitutents, together with carbon atoms to which they are substituted form a cycloalkyl, aryl, heteroaryl, or heterocyciyi ring; each A is, independently, O, S, or NR 25 ;
-63-
each Rio is, independently, selected from hydrogen, alkyl, alkenyL alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, C(A)R^,, halo, pseudohalo, OR 25 , SR 25 , NR 27 R 2 S, and SiR 22 R 23 R 24 ; each Rn is, independently, selected from hydrogen, alkyl, alkenyl. alkynyl, ary], heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, C(A)R 29 , NR 30 R 3 N and SiR 22 R 23 R 24 ; each D is, independently. O or NR 25 ; each n is, independently, 0, 1, or 2; with the proviso that when any n is 1 or 2, then Ri 2 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, halo, pseudohalo, OR 25 , SR 25 , and NR 32 R 33 ; and when n is O 1 then R12 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, SR 25 , and C(A)R 2S ; each R13 and R14 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, C(A)R 2 ^ OR25, and NR 32 R 33 ; each R[5, R|6, and R1 7 is, independently, selected from:
(a) hydrogen, alkyl, alkenyl. alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, C(A)R 29 , OR 25 , or NR 32 R 33 ; and
(b) any two of R15, Rj 6 , and R] 7 together form alkylene, alkenylene, alkynylene, or heteroalkylene, and the other is selected as in (a); each R 22 , R2 3 , and R 24 is, independently, selected from:
(i) each R22, R 23 , and R 24 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR 25 , and NR 32 R 33 ; and (ii) any two of R22, R23, and R 24 together form alkylene, alkenylene, alkynylene, or heteroalkylene, and the other is selected as in (i); each R 25 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, and heterocyclyl; each R 2 7 and R 28 is, independently, selected from:
(i) each R 27 and R 2 s is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl. heterocyclyl, C(A)R^, OR 25 , or NR 37 R 3 S, where R37 and R 3 s are each, independently, hydrogen, alkyl, alkenyl,
, 64-
alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, or together form alkylene, alkenylene, alkynylene, heteroalkylene; and R 39 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR 40 , or NR^R^i, where R40 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, and heterocyclyl; and (ii) any R 27 and R 2 g together form alkylene, alkenylene, alkynylene. heteroalkylene,
OR 40 , or NR 32 R 33 ; each R 30 and R 3 1 is, independently, selected from hydrogen, alkyl, alkenyl , alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl or C(A)R 4 I , where R4 1 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR4 0 , and NR 32 R 33 ; or any R 30 and R 31 together form alkylene, alkenylene, alkynylene, or heteroalkylene; each R 32 and R 33 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl; or any R 32 and R 33 together form alkylene, alkenylene, alkynylene, or heteroalkylene;
R, R 5 ,, R 5x ', Rf, R 2 ', R 3 ', R 4 ', RS', RS', R9', and each R 1 -Ri 8 , R22-R25, and R 27 -R 33 are each, independently, unsubstituted or substituted with one or more substitυtents, each independently selected from Qi wherein:
Q] is selected from halo, pseudohalo, hydroxy, oxo, thia, nitrile, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryl oxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, aikynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, aikoxycarbonyloxy, aryloxycarbonyioxy, aralkoxycarbonytoxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidine, isothioureido, ureido, N-alkylureido, N-arylureido, N'-
-65-
alkylureido, N\N'-dialkyIureido, N'-alkyl-N'-arylureido, N',N'-diarylureido, N'-arylureido. N',N'-dialkylureido, N-alkyi-N ' -arylureido, N-aryl-N'-alkylureido, N,N'-diarylureido, N, N\N'- trialkylureido, N,N'-dialkyl-N'-arylureido, N~alkyl-N\N'-diarylureido, N-aryl-N\N'- dialkylureido, N,N'-diaryl-N'-alkylureido. N,N',N'-triarylureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl. alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoaiky], dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, aikylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsυlfonylamino, arylsulfonylamino, heteroarylsulfonyl amino, heterocyclylsulfonyiamϊno, heteroarylthio, azido, -N + R5iR 52 R 535 P(R 5 O) 2 . P(^O)(R 50 )2, OP(=O)(R 50 )2, -NR 60 C(O)R 63 , dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl, hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonylo, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyl, and alkylarylaminosulfonyi; or two Qi groups, which substitute atoms in a 1 ,2- or 1 ,3 -arrangement, together form alkylenedioxy, thioalkylenoxy, or alkylenedithioxy; or two Qi groups, which substitute the same atom, together form alkylene; and each Qi is, independently, unsubstituted or substituted with one or more substitutents, each independently selected from Q 2 wherein:
Q 2 is, independently, selected from halo, pseudohalo, hydroxy, oxo, thia, nitrile, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyi, alkenyl containing ! to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyi, cycloaikyialkyl, heterocyclyl, heterocyclylaikyl, aryl, heteroaryl, aralkyl, aralkenyl. aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiaryisilyl, triarylsilyl, alkylidene, arylalkylideπe, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl. alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyi, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl. aminocarbonyl, alkyl am inocarbonyl,
-66-
dialkylaminocarbonyl, arylaminocarbonyl, diaryϊaminocarbonyl, arylalkylaniinocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, araikoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyioxy, aralkoxycarbonyloxy. aminocarbonyloxy, alkyiaminocarbonyioxy, dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidine, isothioureido, ureido, N-alkylureido, N-arylureido, N'- alkylureido, N",N'-dialkylureido, N'-alkyl-N'-arylureido, N\N'-diarylureido, N '-aryl ureido, N',N'-dialkylureido, N-alkyl-N'-arylureido, N-aryl-N'-alkylureido, N,N'-diaryIureido, N, N',N'- tri alky lure ido, N,N'-dialkyi-N'-arylureido, N-alkyl-N',N'-diarylureido, N-aryl-N',N'- dialkylureido, N,N'-diaryl-N'-alkylureido, N,N',N'-triarylureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, aikylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, aikylsulfonylamino, arylsulfonylamino, heteroaryisulfonylamino, heterocyclylsulfonylamino, heteroarylthio, azido, -N + R S iRs 2 Rs 3 , P(R 5 O) 2 , P(=O)(R S α)2, OP(=O)(R 50 ) 2 , -NR^ 0 C(=O)FU 3 , dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl, hydroxyphosphony], alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfmyloxy, alkylsuifonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosυlfonyloxy, alkylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyi, alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonylo, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyi, diarylaminosulfonyl, and alkylarylaminosulfonyl; or two Qz groups, which substitute atoms in a 3 ,2- or 1,3-arrangement, together form alkylenedioxy, thioalkylenoxy, or alkylenedithioxy; or two Q 2 groups, which substitute the same atom, together form alkyϊene; each R50 is, independently, selected from hydroxyl, alkoxy, araikoxy, alkyl, heteroaryl, heterocyclyi, aryl, and -NR70R71, wherein each R70 and R 7] is, independently, selected from hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroaraikyl, and heterocyclyi; or R 70 and R 71 together form alkylene, azaalkylene, oxaalkylene, or thiaalkylene;
-67-
each R 51 , R 52 , and R 53 is, independently, selected from hydrogen, alky], aralkyl, aryl, heteroaryl, heteroaralkyl, heterocyclyl, and heterocyclylalkyl; each R ύ o is, independently, selected from hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroaralkyl, heterocyclyl, and heterocyclylalkyl; and each R^ 3 is, independently, selected from alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl, and -NR 7 oR7 t , with the proviso that within each monomeric unit when: a) Y or Y' is a seven-membered heterocyclic ring with 1 heteroatom in the ring; b) X or X' is a five-membered heterocyclic ring with 1 heteroatom in the ring; c) Rs and Rg or R 8 1 and Rg ' together with the atoms on which they are substituted form a phenyl ring; and d) nx is 0; then R, R^, and R 7 are not heterocyclyl or heteroaryl; and
L is one or more linkers covalently linking one or more of the positions R 2 , Rs, R9 with R 3 ', R 8 ', IV; or pharmaceutically acceptable salts and hydrates thereof.
[0053] In other embodiments, the invention includes compounds of formulae (IV), (V), (VI), (VII) and (VIII):
R 6 ' O
M, M ' , Ri, R 1 * , R 2 , R 2 1 . R 3 , R 3 ', R* IV, Rs, RV, Rsx, R 5 χ \ Rs- R 8 " , Ro, R9 1 , X, X', Y, Y', Z, Z\ s, and p are defined as described above; and
-68-
L i and Lj, independently link any R 9 with any R9 1 and Ro with R 2 ' ; and pharmaceutically acceptable salts thereof;
(R 5 X)'
R5 0 ( Y f x J
R3 R4 H 0 Wk .R2
! R1 (V) wherein:
M, M', R 1 , R, \ R 2 , R 2 ', R 3 , R 3 ', R 4 , R 4 ', R 5 - R 5 ; R 5 X, R S X\ RS, R 8 ', RO, R 9 ', X X\ Y > Y', Z, Z', s, and p are defined as described in claim 2; and
Li and L 2 , independently, link any R 9 with any R 9 1 and any Rg with any R 8 '; and pharmaceutically acceptable salts thereof;
(R 5 X) 1 -^
R,
R . (VI) wherein:
M, M\ Ri, R, ', R 2 , R 2 ' , R 3 , R 3 ' , R 4 , Rλ R 5 , Rs', Rsx, Rsx', Rs, R 8 '. R9, R9 ' , X, X', Y, Y', Z, Z', s, and p are defined as described in claim 2; and
-69-
L links any Rg with any R<T; and pharmaceutically acceptable salts thereof;
(R 5 Xt''
R,x
R, R
R i (VII) wherein:
M, M', R 1 . R 1 ' , R 2 , R 2 ', R 3 . R 3 '. R 4 , R 4 ', R 5 , R 5 " , R s χ , R s χ \ R 8 , Rs', R 9 , R 9 ', X, X', Y, Y', Z, Z\ s, and p are defined as described in claim 2; and
L links position R 2 with R 2 '; and pharmaceutically acceptable salts thereof; and
(R5*}'\
FU*
R.
-70-
M, M', R 1 , R 1 ', R 2 , R 2 ' , R 3 , R 3 \ R 4 , RV, Rs, R 5 \ R 5 χ , Rsx\ Rs, R 8 '. R 9 , R?', X, X ' , Y, Y\ Z, Z\ s, and p are defined as described in claim 2; and
L links position any Rg with any R 8 '; and pharmaceutically acceptable salts thereof.
[0054] Other embodiments of the invention include homodimers and heterodimers of general formula (IX):
R 3 R, O M R,
F
W λ λ
υ X
Ri o R . R » (IX) wherein each M is, independently, CO, SO, or SOi; each Ri is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; and each R2 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, hetereocyclyl, and ORn, NR^R^; or each R 2 is, independently, selected from substituted or unsubstituted aryl, substituted or unsubstituted aralkyl and substituted or unsubstituted cycloalkyl; each R 3 , R 4 , and R 5 is, independently, selected from (i) and (ϋ):
(i) each R3 and R 4 is, independently, selected from hydrogen, lower alkyl, lower alkenyl, alkynyl, lower cycloaikyl, lower heterocyclyl; and R 5 is selected from hydrogen, alkyl. alkenyl , alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, and NRi 5 R 16 ; and
(ii) any R5 and R3 or any R5 and R4 together with atoms on which they are substituted form a heterocyclic ring or a heteroaryl ring and any other of R 3 or R 4 is selected as (i); each Rn is, independently, selected from hydrogen, lower alkyl, lower alkenyl, and lower alkynyl; each R7 is. independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, C(A)R 2 ^ heteroaryl, cycloalkyl, and heterocyclyl;
-71-
each Rs and Rg is, independently, selected from hydrogen, alkyi, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl; each A is, independently, O, S, or NR 25 ; each Rn is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl. aryl, heteroaryl, heteroaryl ium, cycloalkyl, heterocyclyl, C(A)R 2 ?, NR30R31. and SiR2 2 R 23 R 2 4; each R[ J and R i6 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, C(A)R 29 , OR 2 S, and NR 32 R 33 ; each R22, R23 > and R24 is, independently, selected from:
(i) R22, R2 3 , and R 24 are each, independently, selected from hydrogen, alky], aJkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR 25 , and NR32R33; and
(ii) any two of R 22 , R2 3 , and R 24 together form alkylene, alkenylene, alkynylene, or heteroalkyiene, and the other is selected as in (i); each R25 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, and heterocyclyl; each R29 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR 40 , and NR 32 R 33 ; each R30 and R31 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, and C(A)R 4J , wherein each R 4 f is, independently, selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR40, and NR32R 33 ; or any R 30 and R 31 together form alkylene, alkenylene, alkynylene, or heteroalkyiene; each R32 and R33 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, and heterocyclyl; or any R 32 and R 33 together form alkylene, alkenylene, alkynylene, or heteroalkyiene; each R1-R9, Rπ-Riϊ, and R29-R 3 3 is, independently, unsubstituted or substituted with one or more substitutents, each independently selected from Qj wherein:
Qi is selected from halo, pseudohalo, hydroxy, oxo, thia, nitriie, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylaJkyl, alkyl, haloalkyl, polyhaloaikyl, aminoalkyi, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, araikyl, aralkenyl,
-72-
aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonyialkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aryiaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, aikynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyioxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidine, isothioureido, ureido, N-alkylureido, N-aryluretdo, N'- alkylureido, N'.N'-dialkylureido, N'-alkyl-N'-arylureido, N',N'-diarylureido, N'-arylureido, N ' ,N'-dialkylureido, N -alkyl -N'-arylureido, N-aryl-N'-alkylureido, N,N'-diarylureido, N, N',N'- trialkylureido, N,N'-dialkyl-N'-aryiureido, N-alkyl-N\N'~diarylureido, N-aryI-N',N'- dialkylureido, N,N'~diaryl-N'-alkylureido, N,N',N'-triary)ureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino, heteroarylthio, azido, -N + R S iRs 2 Rs 3 , P(R 5 O) 2 , P(O)(R 5 O) 2 . OP(=O)(R 50 )2, -NR 60 C(O)R 63 , dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl, hydroxyphosphonyl, alkyithio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy, aikylsulfonyloxy, arylsulfinyloxy. arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, aikylarylaminosulfonyloxy, alkyisulfinyl, alkyl sulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonylo, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfony!, arylaminosυlfonyl, diarylaminosulfonyl, and alkylarylaminosulfonyl; or two Qi groups, which substitute atoms in a 1 ,2- or 1 ,3 -arrangement, together form alkylenedioxy, thioalkylenoxy, or alkylenedithioxy; or two Q s groups, which substitute the same atom, together form alkylene; and
-73-
each Q] is, independently, unsubstituted or substituted with one or more substitutents, each independently selected from Q 2 wherein:
Q2 is, independently, selected from halo, pseudohalo, hydroxy, oxo, thia, nitrile, formyl, mercapto. hydroxycarbonyl, hydroxycarbonylalkyl, alky], haioalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl. heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl, diaikylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkyϋdene, arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylaikylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alky I aryl aminocarbonyloxy, diarylaminocarbonyloxy, guanidine, isothioureido, ureido, N-alkylureido, N-arylureido, W- alkylureido, N\N " -dialkylureido, N'-alkyl-N'-arylureido, N\N'-diarylureido, N'-arylureido, N',N ' -dialkylureido, N-alkyl-N'-arylureido, N-aryl-N'-alkylureido, N,N'-diarylureido. N, N',N'- trialkylureido, N,N'-dialkyl-N'-arylureido, N-alkyl-N\N'-diarylureido, N-aryl-N',N'- dialkylureido, N,N'-diary]-N'-alkylureido, N,N',N'-triaryIureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino. aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino. heteroarylsulfonylamino, heterocyclylsulfonylamino, heteroarylthio, azido, -N f R 5t Rs 2 R 53 , P(R 5 o)2, P(-O)(R 50 )2, OP(=O)(R 50 )2, -NR n OCt=O)R 63 , dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl, hydroxyphosphonyl, alkylthio. arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyano, isothiocyano, aikylsulfinyloxy, alkyisulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxy sulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy,
-74-
alkylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsυlfonyl, arylsulfinyl, arylsulfony], hydroxysulfonylo, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosuifonyl, and alkylarylaminosυlfonyl; or two Q 2 groups, which substitute atoms in a 1 ,2- or 1,3-arrangement, together form alkylenedioxy, thioalkylenoxy, or alkylenedithioxy; or two Q 2 groups, which substitute the same atom, together form alkylene; each R 50 is, independently, selected from hydroxyl, alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl, and -NR 7 oR 7t , wherein each R7 0 and R 71 is, independently, selected from hydrogen, alkyl, aralkyl. aryl, heteroaryl, heteroaralkyl, and heterocyclyl, or any R 70 and R 71 together form alkylene, azaalkylene, oxaalkylene, or thiaalkylene; each R51, R 5 2, and R 53 is, independently, selected from hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroaralkyl, heterocyclyl, and heterocyclylalkyl; each R^o is, independently, selected from hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroaralkyl, heterocyclyl, and heterocyclylalkyl; and each R^ 3 is, independently, selected from alkoxy, aralkoxy, alkyl, heteroaryl, heterocycly], aryl, and -NR 70 R7S; and pharmaceutically acceptable salts and hydrates thereof.
[0055] Some embodiments of the invention include compounds of general formula (X):
R O /"
A
\
<
N
/ i I l
O R
(X) wherein:
M and M' are each, independently, CO, SO, or SO 2 ;
Rι and Rf are each, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl;
R2 and Rj" are each, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, hetereocyclyl, and ORu, NR t sR^; or
R 2 and R2 1 are each, independently, selected from substituted or unsubstituted aryl, substituted or unsubstituted aralkyl and substituted or unsubstituted cycloalkyl;
-75-
R 3 , R 3 -, R 4 , R-r, Rs, and R5 are each, independently, selected from:
(i) R3, Ry, R4, and RJ γ are each, independently, selected from hydrogen, lower alkyl, lower alkenyl, alkynyl, lower cycloalkyl, lower heterocyclyl; and R 5 and Ry are selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, and NR^R^; and
(ii) R5 and R 3 , independently or together with Ry and R 3 ', or R 5 and R 4 , either independently or together with Rs- and R 4 -, together with atoms on which they are substituted form a heterocyclic or heteroaryl ring and any remaining of R 3 , R 3 ', R 4 , or R 4 - are selected as (i);
R 6 and R 6 ' are each, independently, selected from hydrogen, lower alkyl, lower alkenyl, and lower alkynyl;
R 7 and R 7 ' are each, independently, hydrogen, alkyl, alkenyl, alkynyl, aryl, C(A)R 29 , heteroaryl, cycloalkyl, and heterocyclyl;
Rg, R$', R9, and R^ are each, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl; each A is, independently, O, S, or NR 25 ; each Rn is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, C(A}R 29 , NR 30 R 31 , and SiR 22 R 23 R 2* *;
Ri5 and R16 are each, independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, C(A)R 2? , OR 25 , and NR 32 R 33 ; R22, R23, and R 24 are each, independently, selected from:
(i) R22, R 2 3 > and R24 are each, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR 25 , and NR 32 R 33 ; and (ii) any two of R 22 , R 23 , and R 24 together form alkylene, alkenylene, alkynylene, heteroalkylene, and the other is selected as in (i); each R25 is, independently, selected from hydrogen, atkyl, alkenyl, alkynyi, aryl, heteroaryl, heteroarylium, cycloalkyl, and heterocyclyl; each R29 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR 40 , and NR 32 R 33 ;
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each R 30 and R 3 s is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, and C(A)R 4 I , wherein each R 4 I is, independently, selected from alkyl, alkenyi, alkynyl, aryl, heteroary], heteroarylium, cycloalkyl, heterocyclyl, OR 4 O, and NR 32 R 33 ; or any R 30 and R 3 1 together form alkylene, alkenylene, alkynylene, or heteroalkylene; each R32 and R 33 is, independently, selected from hydrogen, alkyL alkenyl, alkynyi, aryl, heteroaryl, heteroarylium, cycloalkyi, and heterocyclyl, or any R 32 and R 33 together form alkylene, alkenylene, alkynylene, or heteroalkylene; each Ri 1 , R 2 1 , R 3 ', RV, Rs', Rs', IV R1-R9, R11-R25, and R29-R33 is, independently, unsubstituted or substituted with one or more sυbstitutcnts, each, independently, selected from Qi wherein:
Qi is selected from halo, pseudohalo, hydroxy, oxo, thia, nitrile, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylaikyl, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkyiaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy. guanidine, isothioureido, ureido, N-alkyiureido, N-arylureido, N'- alkylureido, N',N'-dialkylureido, N'-alkyϊ-N'-arylureido, N\N * -diarylureido, N'-arylureido, N\N'-dialkylureido, N-alky!-N'~arylureido, N-aryl-N'-alkylureido, N,N'-diaryIureido, N, N',N'- tri a ikyl ureido, N.N'-dialkyl-N'-arylureido, N-alkyI-N',N'-diarylureido, N-aryl-N' 5 N'- dialkylureido, N,N'-diaryI-N'-alkylureido, N,N\N'-triaryIureido, amidino, aikylamidino, arylamidino, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl,
-77-
alkyiarylaminoalkyl, alkylamino, dialkylamino, haloalkyiamino, arylamino, diarylamino. alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamiπo, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino. aryloxycarbonylamino, alkylsulfonylamino, arylsuifonylamino, heteroarylsulfonylamino, heterocyclylsυlfonylamino, heteroarylthio, azido, -N + R5iRs2R53, P(R 5 O) 2 , P(=O)(R 50 )2, OP(O)(R 5 U) 2 , -NR 60 C(O)R 63 , dialkylphosphonyl, alkylarylphosphonyl, diarylphosphony], hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio. thiocyano, isothiocyaπo, alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyioxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfiny], arylsulfonyl, hydroxysulfonylo, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyl, and alkylarylaminosulfonyl; or two Qi groups, which substitute atoms in a 1 ,2- or 1 ,3 -arrangement, together form alkylenedioxy, thioalkylenoxy, or alkylenedithioxy; or two Qi groups, which substitute the same atom, together form alkylene; and each Qi is, independently, unsubstituted or substituted with one or more substitutents, each independently selected from Q 2 wherein:
Q 2 is selected from halo, pseudohalo, hydroxy, oxo, thia, nitrile, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloaikyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyi, araikenyl, aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl. arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalky!, aryloxycarbonyl, aryloxycarbonylalkyl, araikoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl, alkyl aminocarbonyl, djaikylaminocarbonyl, aryiaminocarbonyl. diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy. heterocyclyloxy. cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkyl carbonyloxy, arylcarbonyloxy, aralkylcarbonyioxy, alkoxycarbonyloxy, aryloxycarbonyfoxy, aralkoxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarboπyioxy, alkylaryiaminocarbonyloxy, diarylaminocarbonyloxy, guanidine, isothioureido, ureido, N-alkylureido, N-arylureido, N'-
-78-
alkylureido, N',N'-dialkylureido, N'-alkyl-N'-arylureido, N",N * -diaryϊureido, N'-arylureido, N',N'-dialkylureido, N-alkyl-N'-arylureido, N-aryl-NT -alkylureido, N,N'-diarylureido, N, N',N'- trialkyiureido, N,N'-dialkyl-N'-arylureido, N-aIkyl-N',N'-diarylureido, N-aryl-N',N'- dialkylureido, N.N'-diaryl-NT -alkylureido, N,N\N'-triarylureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl, alkylaminothiocarbonyi, arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkyiarylaminoalkyl, alkylamino, dialkyiamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsυllbnylamino, heteroarylthio, azido, -N + R5f R52Rs3, P(Rso)2, P(=0)(Rso)2, OP(=O)(R 50 )2, -NR 60 CC=O)R 63 , dialkylphosphonyl, aikylarylphosphonyl, diarylphosphonyl, hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, alkyiarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonylo, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyl, and alkylaryiaminosυlfonyl; or two Q 2 groups, which substitute atoms in a 1 ,2- or 1,3 -arrangement, together form alkylenedioxy, thioalkylenoxy, or alkylenedithioxy; or two Q 2 groups, which substitute the same atom, together form alkylene; each R 50 is, independently, selected from hydroxyl, alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl, and -NR 7 oR ? i, wherein each R 70 and R 7ϊ is. independently, selected from hydrogen, alkyl, aralky], ary], heteroaryϊ, heteroaralkyl, and heterocyclyl; or any R 70 and R 71 together form alkylene. azaalkylene, oxaalkylene, or thiaalkylene; each R 5 j, R 52 , and R 53 is, independently, selected from hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroaralkyl. heterocyciyl, and heterocyclylalkyi; each R 6O is, independently, selected from hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroaralkyl, heterocyclyl, and heterocyciylalkyl; each R 63 is, independently, selected from alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl, and -NR 7 0R71 ; and
-79-
L is one or more linkers covalentiy linking one or more of the positions Ri, R 2 , R 7 , Rs, R 9 with Rf, R 2 ', R 7 ', R 8 '. R 9 ': or a pharmaceutically acceptable salt or hydrate thereof.
[0056] Still other embodiments of the invention include compounds of formulae (Xl), (XlI), (XIlI), (XIV) AND (XV):
R 3
Rt
R 3
' R 4
'
M, M', R 1 , R, ', R 2 , R 2 " , R 3 , R 3 ', R 4 , RV, Rs, Rs', R 6 , R 6 ', R 7 , R 7 ', R 8 , R 8 ', R* and R 9 ', are defined as described above; and
Li and L 2 , independently, link R 8 with R/ and R 7 with R 7 '; and pharmaceutically acceptable salts thereof;
R 3 R
R 6
M, M', R 1 , Rf, R 2 , R 2 ', R 3 , R 3 ', RA, RV, R 5 . R 5 ', R 6 , R 6 ', R 7 , R 7 ', R*, R 8 ', R 9 , and R 9 ' are defined as described above; and
-80-
L 1 and L 2 , independently, link Rs with Ri and R 2 with R 2 * ; and pharmaceutically acceptable salts thereof; a,
/
R 3 R M R, i V
N
Rs\
KU ,R 7 '
Re' '
R 3 1
R 4
'
0 M' \ / R ' '
V (XIII) wherein:
M, M\ Ri, R, ', R 2 , R 2 ', R 3 , R 3 ', R 4 , IV, R 5 , Rs', R 6 , R 6 ', Rv, R 7 ', Rs, Rs', R 9 , and R 9 ' are defined as described above; and L links R 8 with Rs'; and pharmaceutically acceptable salts thereof;
/ R1
Rj R 4
R, \
N
R 5
R 8 R 9
H S \ RJV RJ'
R 3
' R 4 1
0 M' \. ^ H ^
N
Rf (XIV) wherein:
M, M', R 1 , R 1 ', R 3 , R 2 ', R 3^ RJ \ R4, R 4 ' , Rs Rs', Ro, R*\ Rv, R?', Rs, R*\ R 9 , and R 9 ' are defined as described above; and L links R 7 with R 7 * ; and pharmaceutically acceptable salts thereof; and
-81 -
«3
Rt
R 3
M, M 7 , Ru R, \ R 2 , R 2 ' , R 3 , R 3 ', R 4 , Rλ R 5 , R 5 ' , Re, R*\ R?, R 7 ', Rs, Rs', R 9 , and R 9 ' are defined as described above; and L links R 2 with R 2 1 ; and pharmaceutically acceptable salts thereof.
[0057] Embodiments of the invention further include homodimers and heterodimes of compounds of general formula (XVI):
(i) each Ri is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; and each R 2 is, independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, hetereocyclyl, OR U , and NRisRioi and
(ii) any R] and R 2 together with atoms on which they are substituted form heterocyclic or heteroaryl; each R 3 , R 4 , and R 5 is, independently, selected from:
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(i) R 3 and R 4 are each, independently, selected from hydrogen, lower alkyl, lower alkenyl, alkynyl, lower cycloalkyl, lower aikyland heterocyclyl; and each R5 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryi, heteroaryl, cycloalkyl, heterocyclyl, and NR 15 R 16 ; and
(ii) any R 5 and R 3 or any R 5 and R 4 together with atoms on which they are substituted form a heterocyclic or heteroaryl ring and any remaining R3 or R 4 is selected as
(i): each R 5v; is, independently, selected from hydrogen, lower alkyl, lower alkenyl, and lower alkynyl; each R^ and R 7 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl; each R 8 is, independently, selected from:
(i) alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycioalkyl, heterocyclyl, C(A)RiO, halo, pseudohalo, ORu, oxo, thio, S(D) n Rj 2 , NRi 5 R 16 , N + Ri 5 Ri 6 Ri 7 , = NR 2 5, or =CR| 3 Ri4; and (ii) two RgS together with atoms on which they are substituted form a cycloalkyl, aryl, heterocyclic, or heteroaryl ring; each A is, independently, O, S, or NR 25 ; each Rio is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, C(A)R 26 , halo, pseudohalo, OR 25 , SR 25 , NR 27 R 28 , and SiR 22 R 23 IUt; each Rn is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, C(A)R 2 ^ NR30R3], and SiR 22 R 2 JR^; each D is, independently, O or NR25; each n is, independently, 0,1, or 2 wherein: when n is 1 or 2, each R t2 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, halo, pseudohalo, OR25, SR 2 5, and NR32R33; and when n is 0, each R1 2 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, SR 25 , and C(A)R 2 ?;
-83-
each R| 3 and R] 4 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloaikyl, heterocycly!, C(A)R29, OR25, and NR32R33; each R| 5 , R 16 , and R (7 is, independently, selected from:
(a) hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloaikyl, heterocyclyl, C(A)R 25 , OR 25 , or NR32R33; and
(b) any two of R t $, Ri 6 , and R 17 together form alkylene, alkenylene, alkynylene, or hetcroalkylene, and any remaining Ru, Ri 6 , or R n is selected as in (a); each R 22 , R 23 , and R 24 is, independently, selected from:
(ϊ) each R 22 , R 23 , and R 24 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloaikyl, heterocyclyl, OR25, and NR32R33; and ii) any two of R 22 , R 23 , and R 24 together form alkylene, alkenylene, alkynylene, heteroalkylene, and any remaining R22, R23, and R 24 is selected as in (i); each R 25 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, and heterocyclyl; each R 26 is, independently, selected from hydrogen, alkyl, alkenyi, alkynyl, aryl, heteroaryl, heteroarylium, cycloaikyl, heterocyclyl, OR 25 , and NR 3 2R 3 3, wherein each R34 and R 35 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloaikyl, heterocyclyl, OR36. and NR32R33, or any R 3 4 and R 35 together form alkylene, alkenylene, alkynylene, heteroalkylene, wherein each R 36 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, and heterocyclyl; each R 27 and R 28 is, independently, selected from:
(i) each R 2 7 and R 2 g is, independently, hydrogen, alky!, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR 2J , NR 37 R 38 , and C(A)R 39 , wherein each R 37 and R 3 g is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium. cycloaikyl, heterocyclyl, or together form alkylene, alkenylene, alkynylene, and heteroalkylene; and each R 3 ^ is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR 40 , and NR 32 R 33 , wherein
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each R 40 is, independently, selected from alkyl. alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, and heterocyclyl; and
(ii) any R 27 and R 28 together form alkylene, alkenylene, alkynylene, or heteroalkylene; each R 29 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryiium, cycloalkyl, heterocyclyl, OR 4 O, and NR32R33; each R 30 and R 31 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalky], heterocyclyl. and C(A)R 4 ], wherein each R41 is, independently, selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR 40 , and NR 32 R 33 , or any R30 and R31 together form alkylene, alkenylene, alkynylene, or heteroalkylene; each R 32 and R 33 is. independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, and heterocyclyl, or any R32 and R 33 together form alkylene, alkenylene, alkynylene, or heteroalkylene; each Ri-Rs, R 5\ , Rio-Rπ, and R 22 -R3 3 is, independently, unsubstituted or substituted with one or more substitutents, each independently selected from Q 1 wherein:
Qi is, independently, selected from halo, pseudohalo, hydroxy, oxo, thia, nitrile, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl. heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsϋyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy. heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyioxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyioxy, dialkyiaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidine, isothioureido, ureido, N-alkylureido, N-arylureido, N'- alkylureido. N\N'-dialkylureido, N'-alkyl-N'-arylureido, N',N'-diarylureido, N'-arylureido,
-85-
N\N'-dialkylureido, N-alkyl-N'-arylυreido, N-aryl-N'-alkylureido, N,N'-diarylureido, N, N',N'- trialkylureido, N,N'-dialkyl-N'-aryiureido, N-alkyl-N',N'-diary!ureido, N-aryl-N\N'- dialkylureido, N,N'-diaryl-N'-alkylureido, N,N\N'-triarylureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylaryjaminoalkyl. alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonyiamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonyiamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino, heteroarylthio, azido, -N + R 5 IRs 2 Rs 3 , P(R 5 O) 2 , POO)(R 5 Oh, OP(O)(R 5 O) 2 , -NR 60 C(O)R 63 , dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl, hydroxyphosphonyl, alkyithio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonylo, alkoxysulfonyl, aminosuifonyl, alkylaminosulfonyl, dialkylaminosυlfonyl, arylaminosulfonyl, diarylaminosulfonyl, and alkylarylaminosulfonyl; or two Q J groups, which substitute atoms in a 1 ,2- or 1,3 -arrangement, together form alkylenedioxy, thioalkylenoxy, or alkylenedithioxy; or two Qj groups, which substitute the same atom, together form alkylene; and each Qi is, independently, unsubstituted or substituted with one or more substitutents, each independently selected from Q 2 wherein:
Q 2 is, independently, selected from halo, pseudohalo, hydroxy, oxo, thia, nitrile, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalky], cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyi, aryicarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyi, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyi, arylcarbonylalkyl, aminocarbonyl, aikylaminocarbonyl, dialkyiaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl,
-86-
alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidine, isothioureido, ureido, N-alkylureido, N-arylureido, N ' - alkylureido, N ', N '-di alkyl ureido, N'-alkyl-N'-arylureido, N\N'-diarylureido, N '-aryl ureido, N\ϊsT-dialkylureido, N-alkyl-N'-arylureido, N-aryl-N'-alkylureido, N,N'-diarylureido, N, N\N'- trialkylureido, N,N'-dialkyl-NT-arylureido, N-alkyl-N',N'-diarylureido, N-aryl-N',N'- dialkylureido, N,N'-diaryl-N'-alkylureido, N,N\N'-triarylureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl, diaikylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, aikylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, aikylarylamino, alkylcarbonylamino. alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonyl amino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino, heteroarylthio, azido, -N + RSiR 52 Rj 3 , P(R 5O ^, P(=0)(Rso)2, OP(=O)(R 5fl ) 2 , -NR 60 CX=O)R 63 , dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl, hydroxyphosphonyl. alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonylo, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyl, and alkylarylaminosulfonyl; or two Q j groups, which substitute atoms in a 1,2- or 1,3-arrangement, together form alkylenedioxy, thioaikylenoxy, or alkylenedithioxy; or two Q 2 groups, which substitute the same atom, together form alkyiene; each R 50 is, independently, selected from hydroxyl, alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl, and -NR 70 R71, wherein each R7 0 and R71 is, independently, selected from hydrogen, alkyl, aralkyl, aryl. heteroaryl, heteroaralkyl, and heterocyclyl; or any R70 and R 71 together form alkyiene. azaalkylene, oxaalkylene, or thiaalkylene;
-87-
each R 51 , R 52 , and R 53 is, independently, selected from hydrogen, alky!, aralkyl, aryl, heteroaryl, heteroaralkyl, heterocyclyl, and heterocyclylalkyl; each Rήo is, independently, selected from hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroaralkyl, heterocyclyl, and heterocyciylalky!; and each R 63 is, independently, selected from alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl, and -NR 7 OR 7 I ; or a pharmaceutically acceptable salt thereof,
[0θ58] Other embodiments of the invention include compounds of general formula (XVIl):
R O / A I
\ / H
^ y Ul
N N
/ / / H \
Rs' I il \
(XVII) wherein:
W 2 and Wy are each, independently, an optionally substituted 5-7 member heteroaryl ring containing 1-3 heteroatoms selected from O, S, and N, wherein substitutents, when present, are selected from R^;
Ri and R 2 are each, independently, selected from:
(1) Ri and Rf are, independently, selected from hydrogen, alkyl, alkenyl, alkynyi, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; and eR 2 and R 2 1 are, independently, selected from hydrogen, alkyl, alkenyl, alkynyi, aryl, heteroaryl, cycloalkyl, hetereocyclyl, ORn, and NRi 5 Ri 6 ; and
(ii) R] and R 2 , together with or independent of Ri ' and R 2 ' together with atoms on which they are substituted form heterocyclic or heteroaryl; R 3 , R 3 ", R 4 , R 4 '. R 5 , and Rj " are each, independently, selected from:
(i) R 3 , R 3 ', R 4 , and R 4 ' are each, independently, selected from hydrogen, lower alkyl, lower alkenyl, alkynyi, lower cycloalkyl, and lower heterocyclyl; and R 5 and R 5 ' are, independently, selected from hydrogen, alkyl, alkenyl, alkynyi, aryl, heteroaryl, cycloalkyl, heterocyclyl, and NR t5 Ri O ; and
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(ii) R 5 and R 3 , R 5 and R 4 , R 5 ' and R 3 ' and R 5 * and R 4 ' each, independently, together with atoms on which they are substituted form a heterocyclic or heteroaryl ring and any remainining Rj, R 4 , Rj " , or R 4 1 is selected as (i);
R 5x and R 5x ' are each, independently, selected from hydrogen, lower alkyl, lower alkenyi, and lower alkynyl;
Rj,, RV, R 7 , and R 7 ' are each, independently, selected from hydrogen, alkyl, alkenyi, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl;
Rg and Rs' are each, independently, selected from:
(i) alkyl, alkenyi, alkynyl, aryl, heteroaryl, cycioalkyl, heterocyclyl, C(A)Ri O , halo, pseudohalo, OR n , oxo, thio, S(D) n R 12 , NR) 5 Ri 6 , N + Ri 5 Ri 6 Ri?- ^NR 25 , or ^CRi 3 Ri 4 ; and
(ii) two Rg substituents, together with or independent of two Rg' substituents, together with atoms on which they are substituted form a cycloalkyl, aryl, heterocyclic or heteroaryl ring; each A is, independently, O, S, or NR 25 ; each Rj 0 is. independently, selected from hydrogen, alkyl, alkenyi, alkynyl, aryi, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, C(A)R 26 , halo, pseudohalo, OR 25 , SR 25 , NR 27 R 28 , and SiR 22 R 23 R 24 ; each Rn is, independently, selected from hydrogen, alkyl, alkenyi, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, C(A)R 2 ^, NR 30 R 3 I, and SiR 22 R 23 R 24 ; each D is, independently, O or NR 25 ; each n is, independently, 0, 1, or 2 wherein: when n is 1 or 2, R t2 is selected from hydrogen, alkyi, alkenyi, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, halo, pseudohalo, OR 25 , SR 25 , and NR 32 R 33 ; and when n is 0, Rj 2 is selected from hydrogen, alkyl, alkenyi, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, SR 25 , and C(A)R 2 ^ each Ri 3 and R 1 4 is, independently, selected from hydrogen, alkyl, alkenyi, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, C(A)R 29 , OR 25 , and NR 32 R 33 ; each R[ 5 , Ri 6 , and Rj 7 is, independently, selected from:
(a) hydrogen, alkyl, alkenyi, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, C(A)R 25 , OR 25 , or NR 32 R 33 ; and
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(b) any two of Ris, Ri 6 , and Ri 7 together form alkylene, alkenylene, alkynylene, or heteroalkylene, and any reaminiind R ) 5 , R|ή, and R] 7 is selected as in fa); each R22, R23. and R24 is, independently, selected from:
(i) R 22 , R 23 , and R 24 are each, independently, selected from hydrogen, alkyl, alkenyl, alkynyl. aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR 25 , and NR 32 R 33 ; and (ii) any two of R 22 , R 23 , and R 2 4 together form alkylene, alkenylene, alkynylene, heteroalkylene, and any remaining R2 2 , R 23 , and R 2 4 is selected as in (i); each R 25 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, and heterocyclyl; each R 26 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR2 5 , and NR 32 R 33 , wherein R34 and R35 are each, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR 36 , and NR 32 R 33 , or any R 34 and R35 together form alkyiene, alkenylene, alkynylene, or heteroalkylene, wherein each R 36 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, and heterocyclyl; each R 29 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR 40 , and NR32R33; each R 30 and R 31 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, and C(A)R 4 ], wherein each R41 is, independently, selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR40, and NR 32 R 33 ; or any R 30 and R 3 1 together form alkylene, alkenylene, alkynylene, or heteroalkylene; each R 32 and R 33 is, independently, selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, and heterocyclyl; or any R 32 and R 33 together form alkylene, alkenylene, alkynylene, or heteroalkylene; each R 5x , IV, Ri '. R2', Rs\ Rλ R 5 ', Re', R 7 ' Rs', Ri-R 8 , R 5 X, R10-R17, and R 22 -R 33 is, independently, unsubstituted or substituted with one or more substitutents, each independently selected from Qi wherein:
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Qi is, independently, selected from halo, pseudohalo, hydroxy, oxo, thia, nitrile, formyl, mercapto, hydroxycarbonyi, hydroxycarbonylalkyl, aikyl, haloalkyl, polyhaloalkyl, aminoalky ] , diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloaikylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroaryl aikyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsϋyl, triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyi, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl. aryiaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyi, alkoxy. aryloxy, heteroaryl oxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, peril uoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyioxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyioxy, guanidine, isothioureido, ureido, N-alkylureido, N-arylureido, N'- alkylureido, N\N'-dialkyl ureido, N'-alkyl-N'-arylureido, N',N'-diaryIureido, N'-arylureido, N',N'-dialkylureido, N-alkyl-N'-arylureido, N-aryl-N'-alkylureido, N,N'-diarylureido, N, N',N'- trialkylureido, N,N'-dialkyJ-N'~arylureido, N-alkyl-N',N'-diarylureido, N-aryl-N\N'- dialkylureido, N,N'-diaryl-N'-alkylureido, N,N',N'-triarylureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylaryiamino. alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, aryisulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino, heteroarylthio, azido, -N R5iR5 2 Rs3, P(Rso)2, P(O)(R 5 O) 2 , OP(=0)(R 5 o)2, -NR 60 C(O)R 63 , dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl, hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyioxy, hydroxysulfonyloxy. alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy. alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyi, arylsulfinyl, arylsulfonyi, hydroxy sulfonylo, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl,
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dialkylaminosulfonyl, arylaminosυlfonyl, diaryfaminosulfonyl, and alkylarylaminosulfonyl; or two Qi groups, which substitute atoms in a 1 ,2- or 1,3 -arrangement, together form alkylenedioxy, thioalkylenoxy, or alkylenedithioxy; or two Qi groups, which substitute the same atom, together form alkylene; and each Qi is, independently, unsubstituted or substituted with one or more substitutents, each independently selected from Q 2 wherein:
Q 2 is, independently, selected from halo, pseudohalo, hydroxy, oxo, thia, nitrile, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylaikyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkyiarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidine, isothioureido, ureido, N-alkylureido, N-arylureido, N'- alkylureido, N\N'-dialkylureido, N'-alkyl-N'-arylureido, N',]\T-diarylureido, N'-arylureido, N',N'-dialkylureido, N-alkyl-N'-arylureido, N-aryl-N'-alkylureido, N,N'-diarylureido, N, N',N'- trialkylureido, N,N'-dialkyl-N'-arylureido, N-aikyl-N',N'-diarylureido, N-aryl-N',N'- dialkylureido, N,N'-diaryl-N'-alkylureido, N,N',N'-triarylureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl. amino, aminoalkyl, alkylaminoalkyl, dialkyiaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, diaikylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino. arylcarbonylaminoalkyl, aryloxycarbonylaminoaJkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino, heteroarylthio, azido, -N + RsiR52R53,
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P{Rso)2, P(--O)(R 5O )2, OP(0)(RSO)2, -NR 60 C(^O)R 63 , diaJkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl, hydroxyphosphonyl, alkylthio, arylthio, perflυoroalkylthio, hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfmyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonylo, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfony], arylaminosulfonyl, diarylaminosulfonyl, and alkylarylaminosulfonyl; or two Q 2 groups, which substitute atoms in a 1 ,2- or 1 ,3 -arrangement, together form alkylenedioxy, thioalkylenoxy, or alkylenedithioxy; or two Q 2 groups, which substitute the same atom, together form alkylene; each R 50 is, independently, selected from hydroxyl, alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl, and -NR 70 R 71 , wherein each R 70 and R7 1 is, independently, selected from hydrogen, aikyl, aralkyl, aryl, heteroaryl, heteroaralkyl, and heterocyclyl; or any R70 and R 7 ] together form alkylene, azaalkylene, oxaalkylene or thiaalkylene; each Rsi, R 52 , and R 53 is, independently, selected from hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroaralkyl, heterocyclyl, and heterocyclylalkyl; each R 6O is, independently, selected from hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroaralkyl, heterocyclyl, and heterocyclylalkyl; each R 63 is, independently, selected from alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl, and -NR70R71; and
L is one or more linkers covalently linking one or more of the positions R 2 , R & , and W 2 with R 2 ', R 6 ', and W 2 '; or a pharmaceutically acceptable salt thereof.
[0059} In some embodiments, the invention includes compounds of formulae (XVlII), (XlX), (XX), (XXI) and (XXII):
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Rj P<
H 5 X - ^W^ ^R,
/ H \
R 5
Li
Rs 1 N
H /
(R 5 X) 1 X N ϊf Wj 1 R 1 ' ft ^ s v B (XVIII) wherein:
Ri, Ri ', Ri, R 2 ', R 3 , R 3 ', R 4 , R 4 ' , Rs, Rs', R 5 x, R 5 x\ Re, RO' , R 7 , R?', W 2 , and W 2 ' are defined as described above; and
L i and L 2 independently link R 6 with R^' and Ri with R 2 '; and pharmaceutically acceptable salts thereof;
(R 5 X)
/ \ h
Il
R 1 , Rf, R 2 , R 2 ', R 3 , R 3 ', R 4 , R 4 ' , R 5 , Rs', R 5 x, R s x\ R 6 , R 6 ', R?, Ry', W 2 , and W 2 ' are defined as described above; and
L i and L 2 independently link R<, with RV and W 2 with W 2 '; and pharmaceutically acceptable salts thereof;
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R 3 R
(Re*) 1
SV Ri 1
R 1 , R 1 ', R 2 , R 2 ', R 3 , R 3 ', R 4 , R 4 ', Rs, Rs', R 5 x, R s x'. R 6 , R 6 ', R 7 , R 7 ', W 2 , and W 2 ' are defined as described above; and L links R 6 with R 6 '; and pharmaceutically acceptable salts thereof;
R 3 R 4 o
R 5 X^
N N
H
Rs
O R J Rβ
Rλ R 7 '. R R 2 "
H /
(R 5
* )1
X "
H TT W R
i'
R V R , o (XXl) wherein:
R 1 , Rt', R 2 , R 2 ', R 3 , R 3 ', R 4 , R 4 ' , R 5 , Rs', R 5 x, R 5 x\ R 6 , R 6 ', R 7 , R 7 ', W 2 , and W 2 ' are defined as described above; and
L links position R 2 with R 2 '; and pharmaceutically acceptable salts thereof; and
R 6 X- ^W, ^R,
/
R 6
O κ R~r> R«
R 5 1
(R 5
")' WV R, 1
R 3
R/
(XXII)
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wherein:
Ri, R 1 " , R 2 , R 2 ', R 3 , R 3 " . R 4 , R*', R 5 , R 5 ', R 5 X, R 5 x\ R 6 , Rβ\ R 7 . Rv'. W 2 , and W 2 * are defined as described above; and
L links position W 2 with W 2 '; and pharmaceutically acceptable salts thereof.
{0060] Mimetic, specifically, peptidomimetic design strategies are readily available in the art and can be easily adapted for use in the present invention (see, e.g., Ripka & Rich, Curr. Op. Chem. Biol. 2, 441-452, 1998; Hruby et al., Curr. Op. Chem. Biol. 1 , 1 14-1 19, 1997; Hruby & Balse, Curr. Med. Chem. 9, 945-970, 2000). One class of mimetic mimics a backbone that is partially or completely non-peptide, but mimics the peptide backbone atom-for-atom and comprises side groups that likewise mimic the functionality of the side groups of the native amino acid residues. Several types of chemical bonds, e.g. ester, thioester, thioamide, retroamide, reduced carbonyl, dimethylene, and ketomethylene bonds, are known in the art to be generally useful substitutes for peptide bonds in the construction of protease-resistant ' peptidomimetics. Another class of peptidomimetics comprises a small non-peptide molecule that binds to another peptide or protein, but which is not necessarily a structural mimetic of the native peptide. Yet another class of peptidomimetics has arisen from combinatorial chemistry and the generation of massive chemical libraries. These generally comprise novel templates which, though structurally unrelated to the native peptide, possess necessary functional groups positioned on a non-peptide scaffold to serve as "topographical" mimetics of the original peptide (Ripka & Rich, 1998, supra).
[0061) In one embodiment, the Smac mimetics of the invention are modified to produce peptide mimetics by replacement of one or more naturally occurring side chains of the 20 genetically encoded amino acids, or D-amino acids, with other side chains, for instance with groups, such as, alkyl, lower alkyl, cyclic 4-, 5-, 6-, to 7-membered alkyl, amide, amide lower alkyl, amide di-(lower alkyl), lower alkoxy, hydroxy, carboxy, and the lower ester derivatives thereof, and with 4-, 5-, 6-, to 7-membered heterocycles. For example, proline analogs can be made in which the ring size of the proline residue is changed from 5 members to 4, 6, or 7 members. Cyclic groups can be saturated or unsaturated, and if unsaturated, can be aromatic or non-aromatic. Heterocyclic groups can contain one or more nitrogen, oxygen, and/or sulphur heteroatoms. Examples of such groups include furazanyi, imidazolidinyl, imidazolyl,
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imidazolinyl, isothiazolyl, isoxazolyl, morpholinyl (e.g. morpholino), oxazolyl, piperazinyl (e.g. l-piperazinyl), piperidyl (e.g. 1-piperidyl, piperidino), pyranyl, pyrazinyl, pyrazolidinyl, pyrazolmyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl (e.g. 1-pyrrolidinyJ), pyrrolinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, thiomorpholinyi (e.g. thiomorpholino), and triazolyl. These heterocyclic groups can be substituted or unsubstituted. Where a group is substituted, the substituent can be alky), alkoxy, halogen, oxygen, or substituted or unsubstituted phenyl. Peptidomimetics may also have amino acid residues that have been chemically modified by phosphorylation, sulfonation, biotinylation, or the addition or removal of other moieties.
[0062] Pharmaceutical compositions The subject compositions encompass pharmaceutical compositions including a therapeutically effective amount of a Smac mimetic in dosage form and a pharmaceutically acceptable carrier, wherein the Smac mimetic inhibits the activity of an Inhibitor of Apoptosis protein (IAP), thus promoting apoptosis. In another embodiment, the compositions include a therapeutically effective amount of a Smac mimetic in dosage form and a pharmaceutically acceptable carrier in combination with a chemotherapeutic and/or radiotherapy, wherein the Smac mimetic inhibits the activity of an IAP, thus promoting apoptosis and enhancing the effectiveness of the chemotherapeutic and/or radiotherapy.
[0063] In an embodiment of the invention, a therapeutic composition for promoting apoptosis can be a therapeutically effective amount of a Smac mimetic which binds to at least one IAP. In one embodiment, the IAP can be XIAP. In another embodiment, the IAP can be ML-IAP, and in yet another embodiment, the IAP can be clAP-1 or cIAP-2. In further embodiments, the IAP can be multiple IAPs.
[0064] Embodiments of the invention also include methods for treating a patient having a condition characterized by inhibited apoptosis, wherein administration of a therapeutically effective amount of a Smac mimetic is delivered to the patient, and the Smac mimetic binds to at least one IAP. In one embodiment, the IAP can be XIAP. In another embodiment the IAP can be ML-IAP, and in still another embodiment, the IAP can be cIAP-1 or cIAP-2. In further embodiments, the IAP can be multiple IAPs.
[0065] In one embodiment of the invention, an additional chemotherapeutic agent (infra) or radiation may be administered prior to, along with, or following administration of the Smac mimetic. Exemplary chemotherapeutic agent, include, but are not limited to, alkylating agents, antimetabolites, anti-tumor antibiotics, taxanes, hormonal agents, monoclonal antibodies,
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glucocorticoids, mitotic inhibitors, topoisomerase ϊ inhibitors, topoisomerase II inhibitors, immunomodulating agents, cellular growth factors, cytokines, and nonsteroidal antiinflammatory compounds.
[0θ66J In various embodiments, the Smac mimetics of the invention may be combined with a pharmaceutically acceptable carrier or excipient, and in some embodiments, the Smac mimetics of the invention may be combined with an additional chemotherapeutic agent and a pharmaceutically acceptable carrier or excipient. The term "pharmaceutically-acceptable carrier" as used herein means one or more compatible solid or liquid fillers, diluents or encapsulating substances which are suitable for administration into a human. The term "carrier" or "excipient" denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application. The components of the pharmaceutical compositions are also capable of being co-mingled with the molecules of the present invention, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficacy.
[0067] The delivery systems of the invention are designed to include time-released, delayed release or sustained release delivery systems such that the delivering of the Smac mimetic occurs prior to, and with sufficient time, to cause sensitization of the site to be treated. A Smac mimetic may be used in conjunction with radiation and/or additional anti-cancer chemical agents (infra). Such systems can avoid repeated administrations of the Smac mimetic compound, increasing convenience to the subject and the physician, and may be particularly suitable for certain compositions of the present invention.
[0068] Many types of release delivery systems are available and known to those of ordinary skill in the art. They include, but are not limited to, polymer base systems, such as, poly(lactide-glycolide), copo Iy oxalates, polycaprolactones. polyesteramides, polyorthoesters, polyhydroxybutyric acid, and polyanhydrides. Microcapsules of the foregoing polymers containing drugs are described in, for example, U.S. Pat. No. 5,075, 109. Delivery systems also include non-polymer systems including: lipids including sterols, such as cholesterol, cholesterol esters and fatty acids or neutral fats, such as mono-, di- and tri-glycerides; hydrogel release systems; sylastic systems; peptide based systems; wax coatings; compressed tablets using conventional binders and excipients; partially fused implants; and the like. Specific examples include, but are not limited to: (a) erosional systems in which the active compound is contained
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in a form within a matrix such as those described in U.S. Pat. Nos. 4,452,775, 4,667,014, 4,748,034, and 5,239,660 and (b) diffusional systems in which an active component permeates at a controlled rate from a polymer, such as described in U.S. Pat, Nos. 3,832,253, and 3,854,480. In addition, pump-based hardware delivery systems can be used, some of which are adapted for implantation.
[0069] Use of a long-term sustained release implant may be desirable. Long-term release is used herein, and means that the implant is constructed and arranged to deliver therapeutic levels of the active ingredient for at least about 30 days, and preferably about 60 days. Long-term sustained release implants are well-known to those of ordinary skill in the art and include some of the release systems described above.
[0070] The pharmaceutical compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active agent into association with a carrier that constitutes one or more accessory ingredients. In general, the compositions may be prepared by uniformly and intimately bringing the active compound into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product.
[0071 ] Compositions suitable for parenteral administration conveniently include a sterile aqueous preparation of a Smac mimetic which is preferably isotonic with the blood of the recipient. This aqueous preparation may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1 ,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. In addition, fatty acids, such as oleic acid, may be used in the preparation of injectables. Carrier formulation suitable for oral, subcutaneous, intravenous, intramuscular, etc. administrations can be found, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA which is incorporated herein in its entirety by reference thereto.
[0072] Administration of Smac peptidomimetics The Smac peptidomimetics of the invention may be administered in effective amounts. An effective amount is that amount of a
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preparation that alone, or together with further doses, produces the desired response. This may involve only slowing the progression of the disease temporarily, although it may involve halting the progression of the disease permanently or delaying the onset of or preventing the disease or condition from occurring. This can be monitored by routine methods known and practiced in the art. Generally, doses of active compounds may be from about 0.01 mg/kg per day to about 1000 mg/kg per day, and in some embodiments, the dosage may be from 50-500 mg/kg. In various embodiments, the compounds of the invention may be administered intravenously, intramuscularly, or intradermally, and in one or several administrations per day. The administration of the Smac peptidomimetic can occur simultaneous with, subsequent to, or prior to chemotherapy or radiation.
[0073} In general, clinical trials will determine specific ranges for optimal therapeutic effect for each therapeutic agent and each administrative protocol, and administration to specific patients will be adjusted to within effective and safe ranges depending on the patient condition and responsiveness to initial administrations. However, the ultimate administration protocol will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient, the potency of the Smac mimetic administered, the duration of the treatment and the severity of the disease being treated. For example, a dosage regimen of the Smac mimetic to reduce tumor growth can be oral administration of from about 1 mg to about 2000 mg/day, preferably about 1 to about 1000 mg/day. more preferably about 50 to about 600 mg/day, in two to four divided doses. Intermittent therapy (e.g., one week out of three weeks or three out of four weeks) may also be used.
[0074] In the event that a response in a subject is insufficient at the initial doses applied, higher doses (or effectively higher doses by a different, more localized delivery route) may be employed to the extent that the patient's tolerance permits. Multiple doses per day are contemplated to achieve appropriate systemic levels of compounds. Generally, a maximum dose is used, that is, the highest safe dose according to sound medical judgment. Those of ordinary skill in the art will understand, however, that a patient may insist upon a lower dose or tolerable dose for medical reasons, psychological reasons or for virtually any other reason.
[0075] Embodiments of the invention also include a method of treating a patient with cancer or an autoimmune disease by promoting apoptosis wherein administration of a therapeutically effective amount of a Smac mimetic and the Smac mimetic binds to at least one
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IAP, In one embodiment, the IAP can be XIAP. In another embodiment, the IAP can be ML- IAP, and in still another embodiment, the IAP can be cIAP-1 or cIAP-2. In further embodiments, the IAP can be multiple IAPs. The method may further include concurrent administration of a chemotherapeutic agent including, but not limited to, alkylating agents, antimetabolites, anti-tumor antibiotics, taxanes, hormonal agents, monoclonal antibodies, glucocorticoids, mitotic inhibitors, topoisomerase I inhibitors, topoisomerase II inhibitors, immunomodulating agents, cellular growth factors, cytokines, and nonsteroidal antiinflammatory compounds.
[0076] A variety of administration routes are available. The particular mode selected will depend, of course, upon the particular chemotherapeutic drug selected, the severity of the condition being treated, and the dosage required for therapeutic efficacy. The methods of the invention may be practiced using any mode of administration that is medically acceptable, meaning any mode that produces effective levels of active compounds without causing clinically unacceptable adverse effects. Such modes of administration include, but are not limited to, oral, rectal, topical, nasal, intradermal, inhalation, intra-peritoneal, or parenteral routes. The term "parenteral" includes subcutaneous, intravenous, intramuscular, or infusion. Intravenous or intramuscular routes are particularly suitable for purposes of the present invention.
[0077) In one aspect of the invention, a Smac mimetic as described herein, with or without additional biological or chemotherapeutic agents or radiotherapy, does not adversely affect normal tissues, while sensitizing tumor cells to the additional chemotherapeutic/radiation protocols. While not wishing to be bound by theory, because the induced apoptosis is tumor specific, marked and adverse side effects such as inappropriate vasodilation or shock may be minimized. Preferably, the composition or method may be designed to allow sensitization of the cell or tumor to the chemotherapeutic or radiation therapy by administering at least a portion of the Smac mimetic prior to chemotherapeutic or radiation therapy. The radiation therapy, and/or inclusion of chemotherapeutic agents, may be included as part of the therapeutic regimen to further potentiate the tumor cell killing by the Smac mimetic.
(0078) Combination Therapy A combination of a Smac mimetic and a chemotherapeutic/anti-neoplastic agent and/or radiation therapy of any type may be used in embodiments of the invention and may provide a more effective approach to destroying tumor cells. Smac mimetics generally interact with IAPs, such as XlAP, cIAP-1 , cIAP-2, ML-IAP,
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etc., and block the IAP mediated inhibition of apoptosis while chemotherapeutics/anti neoplastic agents and/or radiation therapy kills actively dividing cells by activating the intrinsic apoptotic pathway leading to apoptosis and cell death. As is described in more detail below, embodiments of the invention provide combinations of a Smac mimetic and chemotherapeutic/anti-neoplastic agents and/or radiation that may provide synergistic action against unwanted cell proliferation. This synergistic action between a Smac mimetic and a chemotherapeutic/anti-neoplastic agent and/or radiation therapy can improve the efficiency of the chemotherapeutic/anti-neoplastic agent and/or radiation therapy. This may allow for an increase in the effectiveness of current chemotherapeutic/anti-neoplastic agents or radiation treatment allowing the dose of the chemotherapeutic/anti-neoplastic agent to be lowered, thereby providing both a more effective dosing schedule, as well as a more tolerable dose of chemotherapeutic/anti-neoplastic agent and/or radiation therapy.
[0079] Additional chemolherapeutic agents Suitable chemotherapeutic agents include, but are not limited to the chemotherapeutic agents described in "Modern Pharmacology with Clinical Applications," Sixth Edition, Craig & Stitzel, Chpt. 56, pgs. 639-656 (2004), hereby incorporated by reference. This reference describes chemotherapeutic drugs including alkylating agents, antimetabolites, anti-tumor antibiotics, plant-derived products such as taxanes, enzymes, hormonal agents such as glucocorticoids, miscellaneous agents such as cisplatin, monoclonal antibodies, immunomodulating agents such as interferons, and cellular growth factors. Other suitable classifications for chemotherapeutic agents include mitotic inhibitors and nonsteroidal anti-estrogenic analogs. Other suitable chemotherapeutic agents include toposiomerase I and II inhibitors and kinase inhibitors.
|0080] Specific examples of suitable biological and chemotherapeutic agents include, but are not limited to, cisplatin. carmustine (BCNU), 5-flourouracil (5-FU), cytarabine (Ara-C), gemcitabine, methotrexate, daunorubicin, doxorubicin, dexamethasone, topotecan, etoposide, paclitaxel, vincristine, tamoxifen, TNF-alpha, TRAIL, interferon (in both its alpha and beta forms), thalidomide, and melphalan. Other specific examples of suitable chemotherapeutic agents include nitrogen mustards such as cyclophosphamide, alkyl sulfonates, nitrosoureas, ethytenimines, triazenes, folate antagonists, purine analogs, pyrimidine analogs, anthracyciines, bleomycins, mitomycins, dactinomycins, plicamycin, vinca alkaloids, epipodophyllotoxins, taxanes, glucocorticoids, L- asparaginase, estrogens, androgens, progestins, luteinizing hormones,
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octreotide actetate, hydroxyurea, procarbazine, mitotane, hexamethylmelamine, carboplatin, mitoxantrone, monoclonal antibodies, levamisole, interferons, interleυkins, filgrastim, and sargramostim. Chemotherapeutic compositions also comprise other members, i.e., other than TRAIL of the TNF superfamily of compounds.
[0081] For example, in one embodiment of the invention, the therapeutic compounds of the present invention may be administered with TRAIL or other chemical or biological agents which bind to and activate the TRAIL receptor(s). Many cancer cell types are sensitive to TRAIL-induced apoptosis, while most normal cells appear to be resistant to TRAIL-induced apoptosis. TRAIL-resistant cells may arise by a variety of different mechanisms including loss of the receptor, presence of decoy receptors, or overexpression of FLIP which competes for zymogen caspase-8 binding during DISC formation. Smac mimetics appear to increase tumor cell sensitivity to TRAIL leading to enhanced apoptosis, the clinical correlations of which are expected to be increased apoptotic activity in TRAIL resistant tumors, improved clinical response, increased response duration, and ultimately, enhanced patient survival rate. In support of this, reduction in XIAP levels by in vitro antisense treatment has been shown to cause sensitization of resistant melanoma cells and renal carcinoma cells to TRAIL (Chawla-Sarkar, et al., 2004). The Smac mimetics disclosed herein may bind to IAPs and inhibit their interaction with caspases, therein potentiating TRAIL-induced apoptosis.
[0082] Another embodiment of the invention provides Smac mimetics that act synergistically with a topoismerase inhibitor to potentiate their apoptotic inducing effect. Topoisomerase inhibitors inhibit DNA replication and promote DNA damage by inhibiting the enzymes that are required in the DNA repair process thereby promoting apoptosis. Therefore, export of Smac from the mitochondria into the cell cytosol is provoked by the DNA damage caused by topoisomerase inhibitors. Topoisomerase inhibitors, such as those of the Type I class, including camptothecin, topotecan, SN-38 (irinotecan active metabolite), and those of the Type Il class including etoposide, show potent synergy with the Smac mimetics of the invention in a multi-resistant glioblastoma cell line (T98G), breast cancer line (MDA-MB-231), and ovarian cancer line (OVCAR-3) among others. Exemplary topoisomerase inhibiting agents that may be used in embodiments of the invention include, but are not limited to irinotecan, topotecan, etoposide, amsacrine, exatecan, gimatecan, aclacinomycin A, camptothecin, daunorubicin, doxorubicin, ellipticine, epirubicin, and mitaxantrone.
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(00831 m S *M another embodiment of the invention, a platinum containing compound may be used as chemotherapeutic/anti-neoplastic agent in combination with a Smac mimetic. Exemplary platinum containing compounds that may synergize with a Smac mimetic include, but are not limited to, cisplatin, carboplatin, and oxaliplatin.
(0084] In yet another embodiment of the invention, taxanes may be used as the chemotherapeutic /anti-neoplastic agent that synergizes with a compound according to the invention. Taxanes may act as, for example, anti-mitotic, mitotic inhibitors or microtubule polymerization agents and include, but are not limited to, docetaxel and paclitaxel. Taxanes are characterized as compounds that promote assembly of microtubules by inhibiting tubulin depolymerization, thereby blocking cell cycle progression. Microtubules are highly dynamic cellular polymers made of alpha-beta-tubulin and associated proteins that play key roles during mitosis by participating in the organization and function of the spindle, assuring the integrity of the segregated DNA. Therefore, microtubules represent an effective target for cancer therapy, and taxanes may effectively attack this target by causing, for example, centrosomal impairment, induction of abnormal spindles, and suppression of spindle microtubule dynamics.
[0085] Another class of agents that may be utilized in embodiments of the invention includes microtubule poisons which, in contrast to taxanes, inhibit tubulin polymerization. These compounds include, but are not limited to vinca alkaloids, colchicine, and crypt ophycines.
|0086] In a further embodiment, any agent that activates the intrinsic apoptotic pathway and/or causes the release of Smac or cytochrome c from the mitochondria has the potential to act synergistically with a Smac mimetic and may be used in combination with the compounds of embodiments of the invention.
|0087] Radiotherapy protocols Additionally, in several embodiments of the invention, Smac mimetic therapy may be used in connection with chemo-radiation or other radiation treatment protocols used to inhibit tumor cell growth.
[0088] Radiation therapy (or radiotherapy) is the medical use of ionizing radiation as part of cancer treatment to control malignant cells and is suitable for use in embodiments of the present invention. Although radiotherapy is often used as part of curative, primary, therapy, it is occasionally used as a palliative treatment where cure is not possible and the aim is for symptomatic relief. Radiotherapy is commonly used for the treatment of tumors, and it is common to combine radiotherapy with surgery and/or chemotherapy. The most common tumors
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treated with radiotherapy are breast cancer, prostate cancer, rectal cancer, head and neck cancers, gynecological tumors, bladder cancer, and lymphoma. Radiation therapy is commonly applied just to the localized area involved with the tumor. Often the radiation fields include the draining lymph nodes. It is possible, but uncommon, to give radiotherapy to the whole body or entire skin surface. Radiation therapy is usually given daily for up to 35-38 fractions {a daily dose is a fraction). These small frequent doses allow healthy cells time to grow back, repairing damage inflicted by the radiation. Three main divisions of radiotherapy are external beam radiotherapy, or teletherapy, brachytherapy or sealed source radiotherapy and unsealed source radiotherapy, which are all suitable examples of treatment protocol in the present invention. The differences relate to the position of the radiation source: external is outside the body, while sealed and unsealed source radiotherapy has radioactive material delivered internally. Brachytherapy sealed sources are usually extracted later, while unsealed sources are injected into the body. Administration of a Smac mimetic may occur prior to and/or concurrently with the treatment protocol.
EXAMPLE
[0089] Annexin V/Prυpidium Iodide Staining Annexin V-fluorescein isothiocyanate staining shows the ability of dimeric Smac mimetics to induce apoptosis. Cells are briefly exposed to various concentrations of dimeric Smac mimetics for 18-24 hours and removed from the assay plate by trypsinization. Cells are pelleted and resuspended in assay buffer (supplied by manufacturer). Annexin V and propidium iodide are added to the cell preparations and incubated for 1 hour in the dark at room temperature. Following the incubation, additional buffer (200 μl) is added to each tube, and the samples are analyzed by flow cytometry. In the presence of Smac mimetics apoptosis is strongly promoted as assessed by Annexin V/PI staining and analyzed by flow cytometry. The amplification in the number of apoptotic cells by IAP antagonists as compared to control was dose dependent and due to the induction of apoptosis and not via increasing the proportion of necrotic cells.
[0090| Biological and chemotherapcutics/anti-neoplastic agents and radiation induce apoptosis by activating the extrinsic or intrinsic apoptotic pathways. Since Smac mimetics relieve inhibitors of apoptotic proteins (IAPs) and thus, remove the block in apoptosis, the combination of chemotherapeutics/anti-neoplastic agents and radiation with Smac mimetics should work synergistically to facilitate apoptosis.
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{0091 j The relevance of this potent synergy is that it makes possible the use of the tumeric Smac mimetics, which are IAP antagonists, to improve the efficacy of conventional chemotherapeutic agents, such as, marketed platinum containing compounds (cisplatin and carboplatin). This may be accomplished by lowering the required dose of the poorly tolerated platinum containing compounds anαVor by improving the response rate at the marketed dose.
|0092J The present invention is not limited to the embodiments described and exemplified above, but is capable of variation and modification within the scope of the appended claims,
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