US2007299263A1PendingUtilityA1
Hydroxy Alkyl Amines
Assignee: ELAN PHARMACEUTICALS INC AND PPriority: Jun 1, 2001Filed: Dec 6, 2006Published: Dec 27, 2007
Est. expiryJun 1, 2021(expired)· nominal 20-yr term from priority
A61P 43/00C07D 209/08C07C 2601/02C07C 323/60C07C 2601/14C07D 207/12C07D 213/30C07D 277/36C07D 317/30C07C 317/46C07C 2601/08C07D 213/81C07C 317/48C07D 249/08C07D 261/18C07D 307/20C07D 233/74C07D 233/64A61P 25/28C07D 211/96C07D 207/28C07D 207/26A61P 25/16C07D 211/46C07D 231/12C07D 241/24C07C 327/32C07D 233/56C07D 231/14C07D 213/82C07D 319/06C07D 333/48C07D 333/34C07D 233/90C07D 237/04C07D 277/56C07D 333/32C07C 317/50C07D 295/185C07D 309/12
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Claims
Abstract
Disclosed are compounds of formula X, which are useful in treating Alzheimer's disease and other similar diseases. Pharmaceutical compositions comprising compounds of formula X and methods of preparing the compounds of formula X are also disclosed.
Claims
exact text as granted — not AI-modified1 . A compound of the formula:
or a pharmaceutically acceptable salt thereof, wherein
R N is:
wherein
R 4 is selected from the group consisting of H; NH 2 ; —NH—(CH 2 ) n6 —R 4-1 ; —NHR 8 ; —NR 50 C(O)R 5 ; C 1 -C 4 alkyl-NHC(O)R 5 ; —(CH 2 ) 0-4 R 8 ; —O—C 1 -C 4 alkanoyl; OH; C 6 -C 10 aryloxy optionally substituted with 1, 2, or 3 groups that are independently halogen, C 1 -C 4 alkyl, —CO 2 H, —C(O)—C 1 -C 4 alkoxy, or C 1 -C 4 alkoxy; C 1 -C 6 alkoxy; aryl C 1 -C 4 alkoxy; —NR 50 CO 2 R 51 ; —C 1 -C 4 alkyl-NR 50 CO 2 R 51 ; —C≡N; —CF 3 ; —CF 2 —CF 3 ; —C≡CH; —CH 2 —CH═CH 2 ; —(CH 2 ) 1-4 —R 4-1 ; —(CH 2 ) 1-4 —NH—R 4-1 ; —O—(CH 2 ) n6 —R 4-1 ; —S—(CH 2 ) n6 —R 4-1 ; —(CH 2 ) 0-4 —NHC(O)—(CH 2 ) 0-6 —R 52 ; —(CH 2 ) 0-4 —R 53 —(CH 2 ) 0-4 —R 54 ;
wherein
n 6 is 0, 1, 2, or 3;
n 7 is 0, 1, 2, or 3;
R 4-1 is selected from the group consisting of —SO 2 —(C 1 -C 8 alkyl), —SO—(C 1 -C 8 alkyl), —S—(C 1 -C 8 alkyl), —S—CO—(C 1 -C 6 alkyl), —SO 2 —NR 4-2 R 4-3 ; —CO—C 1 -C 2 alkyl; —CO—NR 4-3 R 4-4 ;
R 4-2 and R 4-3 are independently H, C 1 -C 3 alkyl, or C 3 -C 6 cycloalkyl;
R 4-4 is alkyl, arylalkyl, alkanoyl, or arylalkanoyl;
R 4-6 is —H or C 1 -C 6 alkyl;
R 5 is selected from the group consisting of C 3 -C 7 cycloalkyl; C 1 -C 6 alkyl optionally substituted with 1, 2, or 3 groups that are independently halogen, —NR 6 R 7 , C 1 -C 4 alkoxy, C 6 -C 10 aryl, C 3 -C 7 cycloalkyl C 1 -C 4 alkyl, —S—C 1 -C 4 alkyl, —SO 2 —C 1 -C 4 alkyl, —CO 2 H, —CONR 6 R 7 , —CO 2 —C 1 -C 4 alkyl, C 6 -C 10 aryloxy; aryl optionally substituted with 1, 2, 3, or 4 groups that are independently halogen, OH, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or C 1 -C 4 haloalkyl; and —NR 6 R 7 ; wherein
R 6 and R 7 are independently selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkanoyl, phenyl, —SO 2 —C 1 -C 4 alkyl, phenyl C 1 -C 4 alkyl;
R 8 is selected from the group consisting of —SO 2 -aryl, —SO 2 —C 1 -C 10 alkyl, —C(O)NHR 9 , —S—C 1 -C 6 alkyl, —S—C 2 -C 4 alkanoyl, wherein
R 9 is aryl C 1 -C 4 alkyl, C 1 -C 6 alkyl, or H;
R 50 is H or C 1 -C 6 alkyl;
R 51 is selected from the group consisting of aryl C 1 -C 4 alkyl; C 1 -C 6 alkyl optionally substituted with 1, 2, or 3 groups that are independently halogen, cyano, —NR 6 R 7 , —C(O)NR 6 R 7 , C 3 -C 7 cycloalkyl, or —C 1 -C 4 alkoxy; alkenyl; alkynyl; aryl; C 3 -C 8 cycloalkyl; and cycloalkylalkyl; wherein the aryl; C 3 -C 8 cycloalkyl, and cycloalkylalkyl groups are optionally substituted with 1, 2, 3, 4 or 5 groups that are independently halogen, CN, NO 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkanoyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy, C 0 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy C 1 -C 6 alkyl, C 1 -C 6 thioalkoxy, C 1 -C 6 thioalkoxy C 1 -C 6 alkyl, or C 1 -C 6 alkoxy C 1 -C 6 alkoxy;
R 52 is aryl, cycloalkyl, —S(O) 0-2 —C 1 -C 6 alkyl, CO 2 H, —C(O)NH 2 , —C(O)NH(alkyl), —C(O)N(alkyl)(alkyl), —CO 2 -alkyl, —NHS(O) 0-2 —C 1 -C 6 alkyl, —N(alkyl)S(O) 0-2 —C 1 -C 6 alkyl, —S(O) 0-2 -aryl, —NH(arylalkyl), —N(alkyl)(arylalkyl), thioalkoxy, or alkoxy, each of which is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently alkyl, alkoxy, thioalkoxy, halogen, haloalkyl, haloalkoxy, alkanoyl, NO 2 , CN, alkoxycarbonyl, or aminocarbonyl;
R 53 is absent, —O—, —C(O)—, —NH—, —N(alkyl)-, —NH—S(O) 0-2 —, —N(alkyl)-S(O) 0-2 —, —S(O) 0-2 —NH—, —S(O) 0-2 —N(alkyl)-, —NH—C(S)—, or —N(alkyl)-C(S)—;
R 54 is aryl, arylalkyl, CO 2 H, —CO 2 -alkyl, —C(O)NH(alkyl), —C(O)N(alkyl)(alkyl), —C(O)NH 2 , C 1 -C 8 alkyl, OH, aryloxy, alkoxy, arylalkoxy, NH 2 , NH(alkyl), N(alkyl)(alkyl), or —C 1 -C 6 alkyl-CO 2 —C 1 -C 6 alkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently alkyl, alkoxy, CO 2 H, —CO 2 -alkyl, thioalkoxy, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, alkanoyl, NO 2 , CN, alkoxycarbonyl, or aminocarbonyl;
X is selected from the group consisting of —C 1 -C 6 alkylidenyl optionally substituted with 1, 2, or 3 methyl groups; and —NR 4-6 —; or
R 4 and R 4-6 combine to form —(CH 2 ) n10 —, wherein
n 10 is 1, 2, 3, or 4;
Z is selected from the group consisting of a bond; SO 2 ; SO; S; and C(O);
Y is selected from the group consisting of H; C 1 -C 4 haloalkyl; C 5 -C 6 heterocycloalkyl; C 6 -C 10 aryl; OH; —N(Y 1 )(Y 2 ); C 1 -C 10 alkyl optionally substituted with 1 thru 3 substituents which can be the same or different and are selected from the group consisting of halogen, hydroxy, alkoxy, thioalkoxy, and haloalkoxy; C 3 -C 8 cycloalkyl optionally substituted with 1, 2, or 3 groups independently selected from C 1 -C 3 alkyl, and halogen; alkoxy; aryl optionally substituted with halogen, alkyl, alkoxy, CN or NO 2 ; arylalkyl optionally substituted with halogen, alkyl, alkoxy, CN or NO 2 ; wherein
Y 1 and Y 2 are the same or different and are H; C 1 -C 10 alkyl optionally substituted with 1, 2, or 3 substituents selected from the group consisting of halogen, C 1 -C 4 alkoxy, C 3 -C 8 cycloalkyl, and OH; C 2 -C 6 alkenyl; C2-CO alkanoyl; phenyl; —SO 2 —C 1 -C 4 alkyl; phenyl C 1 -C 4 alkyl; or C 3 -C 8 cycloalkyl C 1 -C 4 alkyl; or
Y 1 , Y 2 and the nitrogen to which they are attached form a ring selected from the group consisting of piperazinyl, piperidinyl, morpholinyl, and pyrrolidinyl, wherein each ring is optionally substituted with 1, 2, 3, or 4 groups that are independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxy C 1 -C 6 alkyl, or halogen;
R 20 at each occurrence is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxy C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, C 1 -C 6 alkanoyl, each of which is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from halogen, alkyl, hydroxy, alkoxy, and NH 2 , and —R 26 -R 27 , wherein
R 26 is selected from the group consisting of —C(O)—, —SO 2 —, —CO 2 —, —C(O)NH—, and —C(O)N(C 1 -C 6 alkyl)-;
R 27 is selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, aryl C 1 -C 6 alkyl, heterocycloalkyl, and heteroaryl, wherein each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, haloalkyl, hydroxyalkyl, —C(O)NH 2 , NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —C(O)NH(C 1 -C 6 alkyl), —C(O)N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl);
R 1 is —(CH 2 ) 1-2 —S(O) 0-2 —(C 1 -C 6 alkyl), —CH 2 —CH 2 —S(O) 0-2 —(C 1 -C 6 alkyl), or
C 1 -C 10 alkyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, —F, —Cl, —Br, —I, OH, ═O, —SH, —C≡N, —CF 3 , —C 1 -C 3 alkoxy, amino, mono- or dialkylamino, —N(R)C(O)R′—, —OC(═O)-amino and —OC(═O)-mono- or dialkylamino, or
C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, each of which is optionally substituted with 1, 2, or 3 groups independently selected from halogen, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, amino, and mono- or dialkylamino, or
aryl, heteroaryl, heterocyclyl, —C 1 -C 6 alkyl-aryl, —C 1 -C 6 alkyl-heteroaryl, or —C 1 -C 6 alkyl-heterocyclyl, where the ring portions of each are optionally substituted with 1, 2, 3, or 4 groups independently selected from halogen, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —NR 105 R′ 105 , —CO 2 R′, —N(R)COR′, or —N(R)SO 2 R′, —C(═O)—(C 1 -C 4 ) alkyl, —SO 2 -amino, —SO 2 -mono or dialkylamino, —C(═O)-amino, —C(═O)-mono or dialkylamino, —SO 2 —(C 1 -C 4 ) alkyl, or
—C 1 -C 6 alkoxy optionally substituted with 1, 2, or 3 groups which are independently a selected from halogen, or
C 3 -C 7 cycloalkyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, amino, —C 1 -C 6 alkyl and mono- or dialkylamino, or
C 1 -C 10 alkyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , —C 1 -C 3 alkoxy, amino, mono- or dialkylamino and —C 1 -C 3 alkyl, or
C 2 -C 10 alkenyl or C 2 -C 10 alkynyl, each of which is optionally substituted with 1, 2, or 3 groups independently selected from halogen, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, amino, C 1 -C 6 alkyl and mono- or dialkylamino; and
the heterocyclyl group is optionally further substituted with oxo;
R and R′ independently are hydrogen or C 1 -C 10 alkyl;
R 2 is selected from the group consisting of H; C 1 -C 6 alkyl, optionally substituted with 1, 2, or 3 substituents that are independently selected from the group consisting of C 1 -C 3 alkyl, halogen, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ; wherein
R 1-a and R 1-b are —H or C 1 -C 6 alkyl;
—(CH 2 ) 0-4 -aryl; —(CH 2 ) 0-4 -heteroaryl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; —CONR N-2 R N-3 ; —SO 2 NR N-2 R N-3 ; —CO 2 H; and —CO 2 —(C 1 -C 4 alkyl);
R 3 is selected from the group consisting of H; C 1 -C 6 alkyl, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of C 1 -C 3 alkyl, halogen, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ; —(CH 2 ) 0-4 -aryl; —(CH 2 ) 0-4 -heteroaryl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; —CO—NR N-2 R N-3 ; —SO 2 —NR N-2 R N-3 ; —CO 2 H; and —CO—O—(C 1 -C 4 alkyl);
or
R 2 , R 3 and the carbon to which they are attached form a carbocycle of three thru seven carbon atoms, wherein one carbon atom is optionally replaced by a group selected from —O—, —S—, —SO 2 —, or —NR N-2 —;
R C is selected from the group consisting of C 1 -C 10 alkyl optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of R 205 , —OC═ONR 235 R 240 , —S(═O) 0-2 (C 1 -C 6 alkyl), —SH, —NR 235 C═ONR 235 R 240 , —C═ONR 235 R 240 , and —S(═O) 2 NR 235 R 240 ; —(CH 2 ) 0-3 —(C 3 -C 8 ) cycloalkyl wherein the cycloalkyl is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of R 205 , —CO 2 H, and —CO 2 —(C 1 -C 4 alkyl); —(CR 245 R 250 ) 0-4 -aryl; —(CR 245 R 250 ) 0-4 -heteroaryl; —(CR 245 R 250 ) 0-4 -heterocycloalkyl; —(CR 245 R 250 ) 0-4 -aryl-heteroaryl; —(CR 245 R 250 ) 0-4 -aryl-heterocycloalkyl; —(CR 245 R 250 ) 0-4 -aryl-aryl; —(CR 245 R 250 ) 0-4 -heteroaryl-aryl; —(CR 245 R 250 ) 0-4 -heteroaryl-heterocycloalkyl; —(CR 245 R 250 ) 0-4 -heteroaryl-heteroaryl; —(CR 245 R 250 ) 0-4 -heterocycloalkyl-heteroaryl; —(CR 245 R 250 ) 0-4 -heterocycloalkyl-heterocycloalkyl; —(CR 245 R 250 ) 0-4 -heterocycloalkyl-aryl; —[C(R 255 )(R 260 )] 1-3 —CO—N—(R 255 ) 2 ; —CH(aryl) 2 ; —CH(heteroaryl) 2 ; —CH(heterocycloalkyl) 2 ; —CH(aryl)(heteroaryl); cyclopentyl, cyclohexyl, or cycloheptyl ring fused to aryl, heteroaryl, or heterocycloalkyl wherein one carbon of the cyclopentyl, cyclohexyl, or cycloheptyl is optionally replaced with NH, NR 215 , O, or S(═O) 0-2 , and wherein the cyclopentyl, cyclohexyl, or cycloheptyl group can be optionally substituted with 1 or 2 groups that are independently R 205 or ═O; —CO—NR 235 R 240 ; —SO 2 —(C 1 -C 4 alkyl); C 2 -C 10 alkenyl optionally substituted with 1, 2, or 3 R 205 groups; C 2 -C 10 alkynyl optionally substituted with 1, 2, or 3 R 205 groups; —(CH 2 )O—, —CH((CH 2 ) 0-6 —OH)—(CH 2 ) 0-1 -aryl; —(CH 2 ) 0-1 —CHR C-6 —(CH 2 ) 0-1 -heteroaryl; —CH(-aryl or -heteroaryl)-CO—O(C 1 -C 4 alkyl); —CH(—CH 2 —OH)—CH(OH)-phenyl-NO 2 ; (C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl)-OH; —CH 2 —NH—CH 2 —CH(—O—CH 2 —CH 3 ) 2 ; —H; and —(CH 2 ) 0-6 —C(═NR 235 )(NR 235 R 240 ); wherein
each aryl is optionally substituted with 1, 2, or 3 R 200 ;
each heteroaryl is optionally substituted with 1, 2, 3, or 4 R 200 ;
each heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 R 210 ;
R 200 at each occurrence is independently selected from the group consisting of C 1 -C 6 alkyl optionally substituted with 1, 2, or 3 R 205 groups; OH; —NO 2 ; halogen; —CO 2 H; C≡N; —(CH 2 ) 0-4 —CO—NR 220 R 225 ; —(CH 2 ) 0-4 —CO—(C 1 -C 12 alkyl); —(CH 2 ) 0-4 —CO—(C 2 -C 12 alkenyl); —(CH 2 ) 0-4 —CO—(C 2 -C 12 alkynyl); —(CH 2 ) 0-4 —CO—(C 3 -C 7 cycloalkyl); —(CH 2 ) 0-4 —CO-aryl; —(CH 2 ) 0-4 —CO-heteroaryl; —(CH 2 ) 0-4 —CO-heterocycloalkyl; —(CH 2 ) 0-4 —CO 2 R 215 ; —(CH 2 ) 0-4 —SO 2 —NR 220 R 225 ; —(CH 2 ) 0-4 —SO—(C 1 -C 8 alkyl); —(CH 2 ) 0-4 —SO 2 —(C 1 -C 12 alkyl); —(CH 2 ) 0-4 —SO 2 —(C 3 -C 7 cycloalkyl); —(CH 2 ) 0-4 —N(H or R 215 )—CO 2 R 215 ; —(CH 2 ) 0-4 —N(H or R 215 )—CO—N(R 215 ) 2 ; —(CH 2 ) 0-4 —N—CS—N(R 215 ) 2 ; —(CH 2 ) 0-4 —N(—H or R 215 )—CO—R 220 ; —(CH 2 ) 0-4 —NR 220 R 225 ; —(CH 2 ) 0-4 —O—CO—(C 1 -C 6 alkyl); —(CH 2 ) 0-4 —O—P(O)—(OR 240 ) 2 ; —(CH 2 ) 0-4 —O—CO—N(R 215 ) 2 ; —(CH 2 ) 0-4 —O—CS—N(R 215 ) 2 ; —(CH 2 ) 0-4 —O—(R 215 ) 2 ; —(CH 2 ) 0-4 —O—(R 215 ) 2 —COOH; —(CH 2 ) 0-4 —S—(R 215 ) 2 ; —(CH 2 ) 0-4 —O—(C 1 -C 6 alkyl optionally substituted with 1, 2, 3, or 5-F); C 3 -C 7 cycloalkyl; C 2 -C 6 alkenyl optionally substituted with 1 or 2 R 205 groups; C 2 -C 6 alkynyl optionally substituted with 1 or 2 R 205 groups; —(CH 2 ) 0-4 —N(H or R 215 )—SO 2 —R 220 ; and —(CH 2 ) 0-4 —C 3 -C 7 cycloalkyl;
wherein each aryl group at each occurrence is optionally substituted with 1, 2, or 3 groups that are independently R 205 , R 210 or C 1 -C 6 alkyl substituted with 1, 2, or 3 groups that are independently R 205 or R 210 ;
wherein each heterocycloalkyl group at each occurrence is optionally substituted with 1, 2, or 3 groups that are independently R 210 ;
wherein each heteroaryl group at each occurrence is optionally substituted with 1, 2, or 3 groups that are independently R 205 , R 210 , or C 1 -C 6 alkyl substituted with 1, 2, or 3 groups that are independently R 205 or R 210 ;
R 205 at each occurrence is independently selected from the group consisting of C 1 -C 6 alkyl, halogen, —OH, —O-phenyl, —SH, —C≡N, —CF 3 , C 1 -C 6 alkoxy, NH 2 , NH(C 1 -C 6 alkyl), and N—(C 1 -C 6 alkyl)(C 1 -C 6 alkyl);
R 210 at each occurrence is independently selected from the group consisting of C 1 -C 6 alkyl optionally substituted with 1, 2, or 3 R 205 groups; C 2 -C 6 alkenyl optionally substituted with 1, 2, or 3 R 205 groups; C 2 -C 6 alkynyl optionally substituted with 1, 2, or 3 R 205 groups; halogen; C 1 -C 6 alkoxy; C 1 -C 6 haloalkoxy; —NR 220 R 225 ; OH; C≡N; C 3 -C 7 cycloalkyl optionally substituted with 1, 2, or 3 R 205 groups; —CO—(C 1 -C 4 alkyl); SO 2 —NR 235 R 240 ; —CO—NR 235 R 240 ; —SO 2 —(C 1 -C 4 alkyl); and ═O; wherein
R 215 at each occurrence is independently selected from the group consisting of C 1 -C 6 alkyl, —(CH 2 ) 0-2 -(aryl), C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, and —(CH 2 ) 0-2 -(heteroaryl), —(CH 2 ) 0-2 -(heterocycloalkyl); wherein the aryl group at each occurrence is optionally substituted with 1, 2, or 3 groups that are independently R 205 or R 210 ; wherein the heterocycloalkyl group at each occurrence is optionally substituted with 1, 2, or 3 R 210 ; wherein each heteroaryl group at each occurrence is optionally substituted with 1, 2, or 3 R 210 ;
R 220 and R 225 at each occurrence are independently selected from the group consisting of —H, —C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl; halo C 1 -C 6 alkyl; —C 3 -C 7 cycloalkyl, —(C 1 -C 2 alkyl)-(C 3 -C 7 cycloalkyl), —(C 1 -C 6 alkyl)-O—(C 1 -C 3 alkyl), —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —C 1 -C 6 alkyl chain with one double bond and one triple bond, -aryl, -heteroaryl, and -heterocycloalkyl; wherein the aryl group at each occurrence is optionally substituted with 1, 2, or 3 R 270 groups, wherein
R 270 at each occurrence is independently R 205 , C 1 -C 6 alkyl optionally substituted with 1, 2, or 3 R 205 groups; C 2 -C 6 alkenyl optionally substituted with 1, 2, or 3 R 205 groups; C 2 -C 6 alkynyl optionally substituted with 1, 2, or 3 R 205 groups; halogen; C 1 -C 6 alkoxy; C 1 -C 6 haloalkoxy; NR 235 R 240 ; OH; C≡N; C 3 -C 7 cycloalkyl optionally substituted with 1, 2, or 3 R 205 groups; —CO—(C 1 -C 4 alkyl); SO 2 —NR 235 R 240 ; —CO—NR 235 R 240 ; —SO 2 —(C 1 -C 4 alkyl); and ═O; wherein the heterocycloalkyl group at each occurrence is optionally substituted with 1, 2, or 3 R 205 groups; wherein each heteroaryl group at each occurrence is optionally substituted with 1, 2, or 3 R 205 groups;
R 235 and R 240 at each occurrence are independently H, or C 1 -C 6 alkyl;
R 245 and R 250 at each occurrence are independently selected from the group consisting of H, C 1 -C 4 alkyl, C 1 -C 4 hydroxyalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, —(CH 2 ) 0-4 —C 3 -C 7 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl C 1 -C 4 alkyl, heteroaryl C 1 -C 4 alkyl, and phenyl; or
R 245 and R 250 are taken together with the carbon to which they are attached to form a carbocycle of 3, 4, 5, 6, or 7 carbon atoms, optionally where one carbon atom is replaced by a heteroatom selected from the group consisting of —O—, —S—, —SO 2 —, and —NR 220 —;
R 255 and R 260 at each occurrence are independently selected from the group consisting of H; C 1 -C 6 alkyl optionally substituted with 1, 2, or 3 R 205 groups; C 2 -C 6 alkenyl optionally substituted with 1, 2, or 3 R 205 groups; C 2 -C 6 alkynyl optionally substituted with 1, 2, or 3 R 205 groups; —(CH 2 ) 1-2 —S(O) 0-2 —(C 1 -C 6 alkyl); —(CH 2 ) 0-4 —C 3 -C 7 cycloalkyl optionally substituted with 1, 2, or 3 R 205 groups; —(C 1 -C 4 alkyl)-aryl; —(C 1 -C 4 alkyl)-heteroaryl; —(C 1 -C 4 alkyl)-heterocycloalkyl; -aryl; -heteroaryl; -heterocycloalkyl; (CH 2 ) 1-4 —R 265 —(CH 2 ) 0-4 -aryl; —(CH 2 ) 1-4 —R 265 —(CH 2 ) 0-4 -heteroaryl; and; —(CH 2 ) 1-4 —R 265 —(CH 2 ) 0-4 -heterocycloalkyl; wherein
R 265 at each occurrence is independently —O—, —S— or —N(C 1 -C 6 alkyl)-;
each aryl or phenyl is optionally substituted with 1, 2, or 3 groups that are independently R 205 , R 210 , or C 1 -C 6 alkyl substituted with 1, 2, or 3 groups that are independently R 205 or R 210 ;
each heteroaryl is optionally substituted with 1, 2, 3, or 4 R 200 , each heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 R 210 .
2 . A compound according to claim 1 wherein
R 1 is (CH 2 ) n1 —(R 1-aryl ) where n 1 is zero or one and R 1-aryl is phenyl optionally substituted with 1, 2, 3, or 4 groups independently selected from C 1 -C 6 alkyl optionally substituted with 1, 2, or 3 substituents selected from the group consisting of C 1 -C 3 alkyl, halogen, —OH, —SH, —NR 1-a R 1-b , —C≡N, —CF 3 , and C 1 -C 3 alkoxy; halogen; C 1 -C 6 alkoxy; —NR N-2 R N-3 ; and OH; wherein
R N-2 and R N-3 at each occurrence are independently selected from the group consisting of —C 1 -C 8 alkyl optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of —OH, —NH 2 , phenyl and halogen; —C 3 -C 8 cycloalkyl; —(C 1 -C 2 alkyl)-(C 3 -C 8 cycloalkyl); —(C 1 -C 6 alkyl)-O—(C 1 -C 3 alkyl); —C 2 -C 6 alkenyl; —C 2 -C 6 alkynyl; —C 1 -C 6 alkyl chain with one double bond and one triple bond; aryl; heteroaryl; heterocycloalkyl;
or
R N-2 , R N-3 and the nitrogen to which they are attached form a 5, 6, or 7 membered heterocycloalkyl or heteroaryl group, wherein said heterocycloalkyl or heteroaryl group is optionally fused to a benzene, pyridine, or pyrimidine ring, and said groups are unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that at each occurrence are independently C 0 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, halo C 0 -C 6 alkyl, halo C 0 -C 6 alkoxy, —CN, —NO 2 , —NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —OH, —C(O)NH 2 , —C(O)NH(C 1 -C 6 alkyl), —C(O)N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), C 1 -C 6 alkoxy C 1 -C 6 alkyl, C 1 -C 6 thioalkoxy, and C 1 -C 6 thioalkoxy C 1 -C 6 alkyl.
3 . A compound according to claim 2 , wherein
R N is: wherein R 4 is NH 2 ; —NH—(CH 2 ) n6 —R 4-1 ; —NHR 8 ; —NR 50 C(O)R 5 ; or —NR 50 CO 2 R 51 ;
wherein
n 6 is 0, 1, 2, or 3;
n 7 is 0, 1, 2, or 3;
R 4-1 is selected from the group consisting of —SO 2 —(C 1 -C 8 alkyl), —SO—(C 1 -C 8 alkyl), —S—(C 1 -C 8 alkyl), —S—CO—(C 1 -C 6 alkyl), —SO 2 —NR 4-2 R 4-3 ; —CO—C 1 -C 2 alkyl; —CO—NR 4-3 R 4-4 ;
R 4-2 and R 4-3 are independently H, C, C 3 alkyl, or C 3 -C 6 cycloalkyl;
R 4-4 is alkyl, phenylalkyl, C 2 -C 4 alkanoyl, or phenylalkanoyl;
R 5 is selected from the group consisting of cyclopropyl, cyclopentyl, and cyclohexyl; C 1 -C 6 alkyl optionally substituted with 1, 2, or 3 groups that are independently halogen, —NR 6 R 7 , C 1 -C 4 alkoxy, phenyl, C 3 -C 7 cycloalkyl, —S—C 1 -C 4 alkyl, —SO 2 —C 1 -C 4 alkyl, —CO 2 H, —CONR 6 R 7 , —CO 2 —C 1 -C 4 alkyl, or phenyloxy; phenyl optionally substituted with 1, 2, 3, or 4 groups that are independently halogen, OH, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or C 1 -C 4 haloalkyl; and —NR 6 R 7 ; wherein
R 6 and R 7 are independently selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkanoyl, phenyl, —SO 2 —C 1 -C 4 alkyl, and phenyl C 1 -C 4 alkyl;
R 8 is selected from the group consisting of —SO 2 -aryl, —C(O)NHR 9 , —S—C 2 -C 4 alkanoyl, wherein R 9 is phenyl C 1 -C 4 alkyl, C 1 -C 6 alkyl, or H;
R 50 is H or C 1 -C 6 alkyl;
R 51 is selected from the group consisting of phenyl C 1 -C 4 alkyl; C 1 -C 6 alkyl optionally substituted with 1, 2, or 3 groups that are independently halogen, cyano, —NR 6 R 7 , —C(O)NR 6 R 7 , C 3 -C 7 or —C 1 -C 4 alkoxy; phenyl; C 3 -C 8 cycloalkyl, and cycloalkylalkyl, wherein the phenyl; C 3 -C 8 cycloalkyl, and cycloalkylalkyl groups are optionally substituted with 1, 2, 3, 4 or 5 groups that are independently halogen, CN, NO 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkanoyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy C 1 -C 6 alkyl, C 1 -C 6 thioalkoxy, C 1 -C 6 thioalkoxy C 1 -C 6 alkyl, or C 1 -C 6 alkoxy C 1 -C 6 alkoxy.
4 . A compound according to claim 3 , wherein
X is C 1 -C 4 alkylidenyl optionally substituted with 1, 2, or 3 methyl groups; or —NR 4-6 —; or
R 4 and R 4-6 combine to form —(CH 2 ) n10 —, wherein
n 10 is 1, 2, 3, or 4;
Z is selected from a bond; SO 2 ; SO; S; and C(O);
Y is selected from H; C 1 -C 4 haloalkyl; C 5 -C 6 heterocycloalkyl containing at least one N, O, or S; phenyl; OH; —N(Y 1 )(Y 2 ); C 1 -C 10 alkyl optionally substituted with 1 thru 3 substituents which can be the same or different and are selected from halogen, hydroxy, alkoxy, thioalkoxy, and haloalkoxy; C 3 -C 8 cycloalkyl optionally substituted with 1, 2, or 3 groups independently selected from C 1 -C 3 alkyl, and halogen; alkoxy; phenyl optionally substituted with halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, CN or NO 2 ; phenyl C 1 -C 4 alkyl optionally substituted with halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, CN or NO 2 ; wherein
Y 1 and Y 2 are the same or different and are H; C 1 -C 10 alkyl optionally substituted with 1, 2, or 3 substituents selected from the group consisting of halogen, C 1 -C 4 alkoxy, C 3 -C 8 cycloalkyl, and OH; C 2 -C 6 alkenyl; C 2 -C 6 alkanoyl; phenyl; —SO 2 —C 1 -C 4 alkyl; phenyl C 1 -C 4 alkyl; and C 3 -C 8 cycloalkyl C 1 -C 4 alkyl; or
—N(Y 1 )(Y 2 ) forms a ring selected from piperazinyl, piperidinyl, morpholinyl, and pyrrolidinyl, wherein each ring is optionally substituted with 1, 2, 3, or 4 groups that are independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxy C 1 -C 6 alkyl, or halogen;
R 20 at each occurrence is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, C 1 -C 6 alkanoyl, each of which is unsubstituted or substituted with 1, or 2 groups independently selected from halogen, C 1 -C 6 alkyl, hydroxy, C 1 -C 6 alkoxy, NH 2 , and —R 26 -R 27 , wherein
R 26 is selected from —C(O)—, —SO 2 —, —CO 2 —, —C(O)NH—, and —C(O)N(C 1 -C 6 alkyl)-;
R 27 is selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, aryl C 1 -C 6 alkyl, heterocycloalkyl, and heteroaryl, wherein each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, halo C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, —C(O)NH 2 , NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —C(O)NH(C 1 -C 6 alkyl), or —C(O)N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl).
5 . A compound according to claim 4 , wherein
R 1 is benzyl which is optionally substituted with 1, 2, 3, or 4 groups independently selected from halogen, C 1 -C 4 alkoxy, hydroxy, and C 1 -C 4 alkyl optionally substituted with 1, 2, or 3 substituents halogen, OH, SH, NH 2 , NH(C 1 -C 6 alkyl), N—(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), C≡N, CF 3 ; R 2 and R 3 are independently selected from H or C 1 -C 4 alkyl optionally substituted with 1 substituent selected from halogen, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, NH 2 , NH(C 1 -C 6 alkyl), and NH(C 1 -C 6 alkyl)(C 1 -C 6 alkyl); R 20 at each occurrence is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 2 alkoxy C 1 -C 4 alkyl, halo C 1 -C 4 alkyl, C 2 -C 6 alkanoyl, each of which is unsubstituted or substituted with 1 or 2 groups independently selected from halogen, hydroxy, and NH 2 ; R C is C 1 -C 8 alkyl optionally substituted with 1, 2, or 3 groups independently selected from R 205 , —SH, —C═ONR 235 R 240 , and —S(═O) 2 NR 235 R 240 ; —(CH 2 ) 0-3 —(C 3 -C 6 ) cycloalkyl wherein the cycloalkyl is optionally substituted with 1, 2, or 3 groups independently selected from R 205 , —CO 2 H, and —CO 2 —(C 1 -C 4 alkyl); —(CR 245 R 250 ) 0-4 -phenyl optionally substituted with 1, 2, or 3 R 200 ; —(CR 245 R 250 ) 0-3 -pyridyl; —(CR 245 R 250 ) 0-3 -pyridazinyl; —(CR 245 R 250 ) 0-3 -pyrimidinyl; —(CR 245 R 250 ) 0-3 -pyrazinyl; —(CR 245 R 250 ) 0-3 -furyl; —(CR 245 R 250 ) 0-3 -indolyl; —(CR 245 R 250 ) 0-3 -thienyl; —(CR 245 R 250 ) 0-3 -pyrrolyl; —(CR 245 R 250 ) 0-3 -pyrazolyl; (CR 245 R 250 ) 0-3 -benzoxazolyl; —(CR 245 R 250 ) 0-3 -imidazolyl; each of the above heteroaryl groups is optionally substituted with 1, 2, 3, or 4 R 200 ; —(CR 245 R 250 ) 0-3 -imidazolidinyl; (CR 245 R 250 ) 0-3 -tetrahydrofuryl; (CR 245 R 250 ) 0-3 -tetrahydropyranyl; (CR 245 R 250 ) 0-3 -piperazinyl; (CR 245 R 250 ) 0-3 -pyrrolidinyl; (CR 245 R 250 ) 0-3 -piperidinyl; (CR 245 R 250 ) 0-3 -indolinyl; each of the above heterocycloalkyl groups is optionally substituted with 1, 2, 3, or 4 R 210 ; (CH 2 ) 0-1 —CH((CH 2 ) 0-4 —OH)—(CH 2 ) 0-1 -phenyl; —(CH 2 ) 0-1 —CH(C 1 -C 4 hydroxyalkyl)-(CH 2 ) 0-1 -pyridyl;
R 200 at each occurrence is independently C 1 -C 6 alkyl optionally substituted with 1, 2, or 3 R 205 groups; OH; —NO 2 ; halogen; —CO 2 H; C≡N; —(CH 2 ) 0-4 —CO—NR 220 R 225 ; —(CH 2 ) 0-4 —CO—(C 1 -C 8 alkyl); —(CH 2 ) 0-4 —CO 2 R 215 ; and —(CH 2 ) 0-4 —O—(C 1 -C 6 alkyl optionally substituted with 1, 2, 3, or 5-F);
R 205 at each occurrence is independently C 1 -C 6 alkyl, halogen, —OH, —O-phenyl, —SH, —C≡N, —CF 3 , C 1 -C 6 alkoxy, NH 2 , NH(C 1 -C 6 alkyl), and N—(C 1 -C 6 alkyl)(C 1 -C 6 alkyl);
R 210 at each occurrence is independently C 1 -C 6 alkyl optionally substituted with 1 or 2 R 205 groups; halogen; C 1 -C 4 alkoxy; C 1 -C 4 haloalkoxy; —NR 220 R 225 ; OH; C≡N; C 3 -C 7 cycloalkyl optionally substituted with 1 or 2 R 205 groups; —CO—(C 1 -C 4 alkyl); —SO 2 —NR 235 R 240 ; —CO—NR 235 R 240 ; —SO 2 —(C 1 -C 4 alkyl); and ═O; wherein
R 215 at each occurrence is independently C 1 -C 6 alkyl, —(CH 2 ) 0-2 -(phenyl), C 3 -C 6 cycloalkyl, —(CH 2 ) 0-2 -(pyridyl), —(CH 2 ) 0-2 -(pyrrolyl), —(CH 2 ) 0-2 -(imidazolyl), —(CH 2 ) 0-2 -(pyrimidyl), —(CH 2 ) 0-2 -(pyrrolidinyl), —(CH 2 ) 0-2 -(imidazolidinyl)-(CH 2 ) 0-2 -(piperazinyl), —(CH 2 ) 0-2 -(piperidinyl), and —(CH 2 ) 0-2 -(morpholinyl); wherein the phenyl group at each occurrence is optionally substituted with 1 or 2 groups that are independently R 205 or R 210 ; wherein each heterocycloalkyl group at each occurrence is optionally substituted with 1 or 2 R 210 ; wherein each heteroaryl group at each occurrence is optionally substituted with 1 or 2 R 210 ;
R 220 and R 225 at each occurrence are independently —H, —C 1 -C 4 alkyl, hydroxy C 1 -C 4 alkyl, halo C 1 -C 4 alkyl; —C 3 -C 6 cycloalkyl, and —(C 1 -C 4 alkyl)-O—(C 1 -C 2 alkyl);
R 235 and R 240 at each occurrence are independently H, or C 1 -C 6 alkyl;
R 245 and R 250 at each occurrence are independently H, C 1 -C 4 alkyl, C 1 -C 4 hydroxyalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, or
R 245 and R 250 are taken together with the carbon to which they are attached to form a carbocycle of 3, 5, or 6 carbon atoms.
6 . A compound according to claim 5 , wherein
X is —C 1 -C 3 alkylidenyl optionally substituted with 1 methyl group; Z is SO 2 ; SO; S; or C(O); Y is OH; —N(Y 1 )(Y 2 );
—N(Y 1 )(Y 2 ) forms a ring selected from piperazinyl, piperidinyl, morpholinyl, and pyrrolidinyl, wherein each ring is optionally substituted with 1 or 2 groups that are independently C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or halogen;
R 1 is benzyl which is optionally substituted with 1, 2, or 3 groups independently selected from methyl, ethyl, n-propyl, isopropyl, hydroxymethyl, monohalomethyl, dihalomethyl, trihalomethyl, —CH 2 CF 3 , methoxymethyl, halogen, methoxy, ethoxy, n-propyloxy, isopropyloxy, and OH; R 2 and R 3 are independently H or C 1 -C 4 alkyl; R 20 at each occurrence is independently hydrogen, C 1 -C 4 alkyl, or C 2 -C 4 alkanoyl; R C is C 1 -C 6 alkyl optionally substituted with 1, 2, or 3 R 205 groups; cyclopropyl, cyclopropylmethyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cyclohexylmethyl; —(CR 245 R 250 ) 0-3 -phenyl optionally substituted with 1 or 2 R 200 groups; —(CR 245 R 250 ) 0-3 -pyridyl optionally substituted with 1 or 2 R 200 ; —(CR 245 R 250 ) 0-3 -piperazinyl; or (CR 245 R 250 ) 0-3 -pyrrolidinyl; —(CR 245 R 250 ) 0-3 -piperidinyl; each of the above heterocycloalkyl groups is optionally substituted with 1 or 2 R 210 groups;
R 200 at each occurrence is independently selected from C 1 -C 4 alkyl optionally substituted with 1 or 2 R 205 groups; OH; and halogen;
R 205 at each occurrence is independently selected from C 1 -C 4 alkyl, halogen, —OH, —SH, —C≡N, —CF 3 , and C 1 -C 4 alkoxy;
R 210 at each occurrence is independently selected from C 1 -C 4 alkyl optionally substituted with 1 or 2 R 205 groups; halogen; C 1 -C 4 alkoxy; OCF 3 ; NH 2 , NH(C 1 -C 6 alkyl); N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl); OH; and —CO—(C 1 -C 4 alkyl); wherein
R 245 and R 250 at each occurrence are independently selected from H, C 1 -C 4 hydroxyalkyl, C 1 -C 4 alkoxy, or
R 245 and R 250 are taken together with the carbon to which they are attached to form a carbocycle of 3, 5, or 6 carbon atoms.
7 . (canceled)
8 . A compound according to claim 3 wherein
R N is: n 7 is 0, 1, 2, or 3; R 50 is H or C 1 -C 6 alkyl; R 51 is phenyl C 1 -C 4 alkyl; C 1 -C 6 alkyl optionally substituted with 1, 2, or 3 groups that are independently halogen, cyano, —NR 6 R 7 , —C(O)NR 6 R 7 , or —C 1 -C 4 alkoxy; alkenyl; alkynyl; phenyl; C 3 -C 8 cycloalkyl; or cycloalkylalkyl; wherein the phenyl, C 3 -C 8 cycloalkyl, and cycloalkylalkyl groups are optionally substituted with 1, 2, 3, 4 or 5 groups that are independently halogen, CN, NO 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkanoyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy C 1 -C 6 alkyl, C 1 -C 6 thioalkoxy, C 1 -C 6 thioalkoxy C 1 -C 6 alkyl, or C 1 -C 6 alkoxy C 1 -C 6 alkoxy;
R 6 and R 7 are independently H, C 1 -C 6 alkyl, C 2 -C 6 alkanoyl, phenyl, —SO 2 —C 1 -C 4 alkyl, or phenyl C 1 -C 4 alkyl;
X is C 1 -C 4 alkylidenyl optionally substituted with 1, 2, or 3 methyl groups; or —NR 4-6 —; or R 4 and R 4-6 combine to form —(CH 2 ) n10 —, wherein
n 10 is 1, 2, 3, or 4;
Z is a bond; SO 2 ; SO; S; or C(O); Y is H; C 1 -C 4 haloalkyl; C 5 -C 6 heterocycloalkyl containing at least one N, O, or S; phenyl; OH; —N(Y 1 )(Y 2 ); C 1 -C 10 alkyl optionally substituted with 1 thru 3 substituents which can be the same or different and are selected from halogen, hydroxy, alkoxy, thioalkoxy, and haloalkoxy; C 3 -C 8 cycloalkyl optionally substituted with 1, 2, or 3 groups independently selected from C 1 -C 3 alkyl, and halogen; alkoxy; phenyl optionally substituted with halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, CN or NO 2 ; or phenyl C 1 -C 4 alkyl optionally substituted with halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, CN or NO 2 ; wherein
Y 1 and Y 2 are the same or different and are H; C 1 -C 10 alkyl optionally substituted with 1, 2, or 3 substituents selected from halogen, C 1 -C 4 alkoxy, C 3 -C 8 cycloalkyl, and OH; C 2 -C 6 alkenyl; C 2 -C 6 alkanoyl; phenyl; —SO 2 —C 1 -C 4 alkyl; phenyl C 1 -C 4 alkyl; or C 3 -C 8 cycloalkyl C 1 -C 4 alkyl; or
—N(Y 1 )(Y 2 ) forms a ring selected from piperazinyl, piperidinyl, morpholinyl, and pyrrolidinyl, wherein each ring is optionally substituted with 1, 2, 3, or 4 groups that are independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxy C 1 -C 6 alkyl, or halogen;
R 20 at each occurrence is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, or C 1 -C 6 alkanoyl, each of which is unsubstituted or substituted with 1, or 2 groups independently selected from halogen, C 1 -C 6 alkyl, hydroxy, C 1 -C 6 alkoxy, NH 2 , and —R 26 -R 27 , wherein
R 26 is —C(O)—, —SO 2 —, —CO 2 —, —C(O)NH—, or —C(O)N(C 1 -C 6 alkyl)-;
R 27 is C 1 -C 6 alkyl, C 1 -C 6 alkoxy, aryl C 1 -C 6 alkyl, heterocycloalkyl, or heteroaryl, wherein each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, halo C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, —C(O)NH 2 , NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —C(O)NH(C 1 -C 6 alkyl), or —C(O)N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl).
9 . A compound according to claim 8 , wherein
X is —C 1 -C 3 alkylidenyl; Z is SO 2 ; SO; S; or C(O); Y is OH; —N(Y 1 )(Y 2 );
where
—N(Y 1 )(Y 2 ) forms a ring selected from piperazinyl, piperidinyl, morpholinyl, and pyrrolidinyl, wherein each ring is optionally substituted with 1 or 2 groups that are independently C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or halogen;
R 1 is benzyl which is optionally substituted with 1, 2, or 3 groups independently selected from methyl, ethyl, n-propyl, isopropyl, hydroxymethyl, monohalomethyl, dihalomethyl, trihalomethyl, —CH 2 CF 3 , methoxymethyl, halogen, methoxy, ethoxy, n-propyloxy, isopropyloxy, and OH; R 2 and R 3 are independently H or C 1 -C 4 alkyl; R 20 at each occurrence is independently hydrogen, C 1 -C 4 alkyl, or C 2 -C 4 alkanoyl; R C is C 1 -C 6 alkyl optionally substituted with 1, 2, or 3 R 205 groups; cyclopropyl, cyclopropylmethyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cyclohexylmethyl; —(CR 245 R 250 ) 0-3 -phenyl optionally substituted with 1 or 2 R 200 groups; or —(CR 245 R 250 ) 0-3 -pyridyl optionally substituted with 1 or 2 R 200 ;
R 200 at each occurrence is independently C 1 -C 4 alkyl optionally substituted with 1 or 2 R 205 groups; OH; or halogen;
R 205 at each occurrence is independently C 1 -C 4 alkyl, halogen, —OH, —SH, —C≡N, —CF 3 , or C 1 -C 4 alkoxy;
R 245 and R 250 at each occurrence are independently H, C 1 -C 4 hydroxyalkyl, or C 1 -C 4 alkoxy, or
R 245 and R 250 are taken together with the carbon to which they are attached to form a carbocycle of 3 carbon atoms.
10 . (canceled)
11 . (canceled)
12 . A compound according to claim 8 , wherein
R C is C 3 -C 8 alkyl, cyclopropyl, cyclopentyl, cyclohexyl, or —(C 1 -C 4 )alkyl-cyclopropyl.
13 . (canceled)
14 . A compound according to claim 8 that is selected from
3-(butylsulfinyl)-N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N˜2˜-[(methoxy)carbonyl]-D-alaninamide; S-butyl-N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N˜2˜-[(methoxy)carbonyl]-D-cysteinamide; N˜2˜-[(benzyloxy)carbonyl]-N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(4,4,4-trifluorobutyl)sulfonyl]-D-alaninamide; N˜2˜-[(benzyloxy)carbonyl]-N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(4,4,4-trifluorobutyl)sulfinyl]-D-alaninamide; N˜2˜-[(benzyloxy)carbonyl]-N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-S-(4,4,4-trifluorobutyl)-D-cysteinamide; 3-(butylsulfonyl)-N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N˜2˜-[(methoxy)carbonyl]-D-alaninamide; 3-(butylsulfonyl)-N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N˜2˜-[(2,2,2-trifluoroethoxy)carbonyl]-D-alaninamide; N˜2˜-[(2-cyanoethoxy)carbonyl]-N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-(butylsulfonyl)-D-alaninamide; 3-(butylsulfonyl)-N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N˜2˜-{[(3R)-pyrrolidin-3-yl]carbonyl}-D,L-alaninamide; 3-(butylsulfonyl)-N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N˜2˜-[(3S)-tetrahydrofuran-3-yloxy]carbonyl)-D-alaninamide; N˜2˜-{[2-(acetylamino)ethoxy]carbonyl}-3-(butylsulfonyl)-N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-D-alaninamide; 3-(butylsulfonyl)-N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N˜2˜-{[[(pyridin-3-yl)methyl]oxy]carbonyl}-D-alaninamide; 3-(butylsulfonyl)-N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N˜2˜-{[[(pyridin-4-yl)methyl]oxy]carbonyl}-D-alaninamide; 3-(butylsulfonyl)-N˜2˜-[(methoxy)carbonyl]-N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-(cyclopropylamino)-2-hydroxypropyl}-D-alaninamide; 3-(butylsulfonyl)-N˜2˜-[(2-cyanoethoxy)carbonyl]-N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-(cyclopropylamino)-2-hydroxypropyl}-D-alaninamide; N˜2˜-[(benzyloxy)carbonyl]-3-(butylsulfonyl)-N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-methylbutyl)amino]-2-hydroxypropyl})-D-alaninamide; 3-(butylsulfonyl)-N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-methylbutyl)amino]-2-hydroxypropyl}-N˜2˜-[(methyloxy)carbonyl]-D-alaninamide; N˜2˜-[(2-cyanoethoxy)carbonyl]-N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-(cyclopropylamino)-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-D-alaninamide; N˜2˜-{[2-(acetylamino)ethoxy]carbonyl}-N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-(cyclopropylamino)-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-D-alaninamide; N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-methylbutyl)amino]-2-hydroxypropyl}-N˜2˜-[(methyloxy)carbonyl]-3-[(1-propylbutyl)sulfonyl]-D-alaninamide; N˜2˜-[(benzyloxy)carbonyl]-N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-methylbutyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-D-alaninamide; N˜2˜-{[2-(diethylamino)-2-oxoethoxy]carbonyl}-N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-D-alaninamide; N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N˜2˜-[(methoxy)carbonyl]-3-[(1-propylbutyl)sulfonyl]-D-alaninamide; N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N˜2˜-[(isopropoxy)carbonyl]-3-[(1-propylbutyl)sulfonyl]-D-alaninamide; N˜2˜-[(cyclopropylmethoxy)carbonyl]-N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-D-alaninamide; N˜2˜-[(allyloxy)carbonyl]-N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-D-alaninamide; N˜2˜-[(2-cyanoethoxy)carbonyl]-N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-D-alaninamide; N˜2˜-{[2-(acetylamino)ethoxy]carbonyl}-N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethyl benzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-D-alaninamide; N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-N˜2˜-{[[(pyridin-3-yl)methyl]oxy]carbonyl}-D-alaninamide; N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-N˜2˜-{[[(pyridin-4-yl)methyl]oxy]carbonyl}-D-alaninamide; benzyl (1R)-1-[({(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}amino)carbonyl]-3-(methylsulfonyl)propylcarbamate; N˜2˜-[(benzyloxy)carbonyl]-3-(butylsulfonyl)-N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-D-alaninamide trifluoroacetate; N˜2˜-[(benzyloxy)carbonyl]-3-(butylsulfonyl)-N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-L-alaninamide trifluoroacetate; N˜2˜-[(benzyloxy)carbonyl]-N˜1˜-((1S,2S)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{([(1R)-2-hydroxy-1-phenylethyl]amino}propyl)-3-[(1-propylbutyl)sulfonyl]-D-alaninamide; N˜2˜-[(benzyloxy)carbonyl]-N˜1˜-((1S,2S)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(1R)-2-methoxy-1-phenylethyl]amino}propyl)-3-[(1-propylbutyl)sulfonyl]-D-alaninamide; N˜2˜-[(benzyloxy)carbonyl]-N˜1˜-((1S,2S)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(1S)-2-methoxy-1-phenylethyl]amino}propyl)-3-[(1-propylbutyl)sulfonyl]-D-alaninamide; N˜2˜-[(benzyloxy)carbonyl]-N˜1-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-ethylphenyl)cyclopropyl]amino}-2-hydroxypropyl)-3-[(1-propylbutyl)sulfonyl]-D-alaninamide; N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-N˜2˜-{[(prop-2-ynyl)oxy]carbonyl}-D-alaninamide; N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N˜2˜-(2-methoxyethylcarbonyl)-3-[(1-propylbutyl)sulfonyl]-D-alaninamide; N˜2˜-{[(3R)-1-acetylpyrrolidin-3-yl]carbonyl}-N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-D-alaninamide; N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N˜2˜-{[(3S)-tetrahydrofuran-3-yloxy]carbonyl}-3-[(1-propylbutyl)sulfonyl]-D-alaninamide; N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N˜2˜-{[(3S)-tetrahydrofuran-3-yloxy]carbonyl}-3-[(1-propylbutyl)sulfonyl]-L-alaninamide; N˜2˜-[(benzyloxy)carbonyl]-N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-D-alaninamide; N˜2˜-[(benzyloxy)carbonyl]-N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-L-alaninamide; N˜2˜-[(benzyloxy)carbonyl]-N˜1˜-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-ethylphenyl)cyclopropyl]amino}-2-hydroxypropyl)-3-[(1-propylbutyl)sulfonyl]-D, L-alaninamide; N˜2˜-[(benzyloxy)carbonyl]-N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-D, L-alaninamide; N˜2˜-[(benzyloxy)carbonyl]-N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-methylbutyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-D, L-alaninamide; N˜2˜-[(benzyloxy)carbonyl]-N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-(cyclopropylamino)-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-D,L-alaninamide; N˜2˜-[(benzyloxy)carbonyl]-N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(cyclopropylmethyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-D, L-alaninamide; N˜2˜-[(benzyloxy)carbonyl]-N˜1˜-{(1S,2S)-1-(3,5-difluorobenzyl)-3-[(3-ethylphenyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-D, L-alaninamide; N˜2˜-[(benzyloxy)carbonyl]-N˜1˜-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({2-[3-(trifluoromethyl)phenyl]ethyl}amino)propyl]-3-[(1-propylbutyl)sulfonyl]-D, L-alaninamide; N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-N˜2˜-{[[(pyridin-3-yl)methyl]oxy]carbonyl}-D, L-alaninamide; N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N˜2˜-{[(3S)-tetrahydrofuran-3-yloxy]carbonyl}-3-[(1-propylbutyl)sulfonyl]-D,L-alaninamide; N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}—N˜2˜-{[(3R)-tetrahydrofuran-3-yloxy]carbonyl}-3-[(1-propylbutyl)sulfonyl]-D, L-alaninamide; N˜1˜-{(1S,2R)-1-benzyl-3-[(3-methoxybenzyl)amino]-2-hydroxypropyl}-N˜2˜-{[(3S)-tetrahydrofuran-3-yloxy]carbonyl}-3-[(1-propylbutyl)sulfonyl]-D, L-alaninamide; N˜2˜-{[(3R)-1-acetylpyrrolidin-3-yl]carbonyl}-N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-D, L-alaninamide; N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-N˜2˜-{[(3R)-pyrrolidin-3-yl]carbonyl}-D,L-alaninamide; N˜2˜-{[(3R)-1-benzylpyrrolidin-3-yl]carbonyl}-N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-D, L-alaninamide; N˜1˜-{(1S,2R)-1-(3,5difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N˜2˜-{[(3S)-1,1-dioxidotetrahydrothien-3-yloxy]carbonyl}-3-[(1-propylbutyl)sulfonyl]-D, L-alaninamide; N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N˜2˜-{[(3S)-tetrahydrothiophen-3-yloxy]carbonyl}-3-[(1-propylbutyl)sulfonyl]-D, L-alaninamide; N˜2˜-(cyclopentylcarbonyl)-N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-D, L-alaninamide; N˜2˜-(cyclohexylcarbonyl)-N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-D, L-alaninamide; N˜1˜-[(1S,2R)-3-(cyclopropylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-3-[(1-propylbutyl)sulfonyl]-N˜2˜-{[tetrahydropyran-4-yloxy]carbonyl}-D, L-alaninamide; N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-N˜2˜-{[tetrahydropyran-4-yloxy]carbonyl}-D, L-alaninamide; N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N˜2˜-{[1-(methylsulfonyl)piperidin-4-yloxy]carbonyl}-3-[(1-propylbutyl)sulfonyl]-D, L-alaninamide; N˜2˜-{[1-acetylpiperidin-4-yloxy]carbonyl}-N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-D, L-alaninamide; N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N˜2˜-{[[[(3S)-5-oxopyrrolidin-3-yl]methyl]oxy]carbonyl}-3-[(1-propylbutyl)sulfonyl]-D, L-alaninamide; N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N˜2˜-{[[[(3R)-5-oxopyrrolidin-3-yl]methyl]oxy]carbonyl}-3-[(1-propylbutyl)sulfonyl]-D, L-alaninamide; N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N˜2˜-{[[2-methoxyethyl]oxy]carbonyl}-3-[(1-propylbutyl)sulfonyl]-D, L-alaninamide; N˜2˜-[(benzyloxy)carbonyl]-3-(butylsulfonyl)-N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-D, L-alaninamide; N˜1˜-{(1S,2R)-1-benzyl-3-[(3-methoxybenzyl)amino]-2-hydroxypropyl}-N˜2˜-[(benzyloxy)carbonyl]-3-[(1-propylbutyl)sulfonyl]-D, L-alaninamide; N˜2˜-[(benzyloxy)carbonyl]-N˜1˜-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[2-(3-methoxyphenyl)ethyl]amino}propyl)-3-[(1-propylbutyl)sulfonyl]-D,L-alaninamide; N˜2˜-[(benzyloxy)carbonyl]-N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N˜5˜,N˜5˜-dipropyl-L-glutamamide; and N˜2˜-[(benzyloxy)carbonyl]-N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N˜5˜,N˜5˜-dipropyl-D-glutamamide; methyl (1R)-1-[({(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}amino)carbonyl]-3-oxoheptylcarbamate; 4-butyl-N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N˜2˜-(methoxycarbonyl)-D-homoserinamide; 3-(2-butyl-1,3-dioxolan-2-yl)-N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N˜2˜-(methoxycarbonyl)-D-alaninamide; 3-(2-butyl-1,3-dioxan-2-yl)-N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N˜2˜-(methoxycarbonyl)-D-alaninamide; methyl (1R)-1-[({(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}amino)carbonyl]-3,3-difluoroheptylcarbamate; methyl (1R)-1-[({(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}amino)carbonyl]-3-fluoroheptylcarbamate; methyl (1R)-1-[({(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}amino)carbonyl]-4-oxooctylcarbamate; methyl (1R)-1-[({(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}amino)carbonyl]-4-hydroxyoctylcarbamate; methyl (1R)-3-(2-butyl-1,3-dioxolan-2-yl)-1-[({(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}amino)carbonyl]propylcarbamate; methyl (1R)-3-(2-butyl-1,3-dioxan-2-yl)-1-[({(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}amino)carbonyl]propylcarbamate; methyl (1R)-1-[({(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}amino)carbonyl]-4-fluorooctylcarbamate; methyl (1R)-1-[({(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}amino)carbonyl]-4,4-difluorooctylcarbamate; 3-(butylsulfonyl)-N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethynylbenzyl)amino]-2-hydroxypropyl}-N˜2˜-(methoxycarbonyl)-D-alaninamide; 3-(butylsulfonyl)-N˜1˜-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(trifluoromethyl)benzyl]amino}propyl)-N˜2˜-(methoxycarbonyl)-D-alaninamide; 3-(butylsulfonyl)-N˜1˜-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-ethylphenyl)cyclopropyl]amino}-2-hydroxypropyl)-N˜2˜-(methoxycarbonyl)-D-alaninamide; 3-(butylsulfonyl)-N˜1˜-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-ethynylphenyl)cyclopropyl]amino}-2-hydroxypropyl)-N˜2˜-(methoxycarbonyl)-D-alaninamide; and 3-(butylsulfonyl)-N˜1˜-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)propyl]-N˜2˜-(methoxycarbonyl)-D-alaninamide.
15 . A compound according to claim 3 , wherein
R N is: wherein n 7 is 0, 1, 2, or 3; R 50 is H or C 1 -C 6 alkyl; R 5 is selected from the group consisting of cyclopropyl; cyclopentyl; cyclohexyl; C 1 -C 6 alkyl optionally substituted with 1, 2, or 3 groups that are independently halogen, —NR 6 R 7 , C 1 -C 4 alkoxy, phenyl, C 3 -C 7 cycloalkyl, —S—C 1 -C 4 alkyl, —SO 2 —C 1 -C 4 alkyl, —CO 2 H, —CONR 6 R 7 , —CO 2 —C 1 -C 4 alkyl, or phenyloxy; phenyl optionally substituted with 1, 2, 3, or 4 groups that are independently halogen, OH, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or C 1 -C 4 haloalkyl; and —NR 6 R 7 ; wherein
R 6 and R 7 are independently selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkanoyl, phenyl, —SO 2 —C 1 -C 4 alkyl, and phenyl C 1 -C 4 alkyl;
X is C 1 -C 4 alkylidenyl optionally substituted with 1, 2, or 3 methyl groups; or —NR 4-6 —; or R 4 and R 4-6 combine to form —(CH 2 ) n10 —, wherein
n 10 is 1, 2, 3, or 4;
Z is a bond; SO 2 ; SO; S; or C(O); Y is C 5 -C 6 heterocycloalkyl containing at least one N, O, or S; —N(Y 1 )(Y 2 ); wherein
—N(Y 1 )(Y 2 ) forms a ring selected from piperazinyl, piperidinyl, morpholinyl, and pyrrolidinyl, wherein each ring is optionally substituted with 1, 2, 3, or 4 groups that are independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxy C 1 -C 6 alkyl, or halogen; and
R 20 at each occurrence is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, or C 1 -C 6 alkanoyl, each of which is unsubstituted or substituted with 1, or 2 groups independently selected from halogen, C 1 -C 6 alkyl, hydroxy, C 1 -C 6 alkoxy, NH 2 , and —R 26 -R 27 , wherein
R 26 is —C(O)—, —SO 2 —, —CO 2 —, —C(O)NH—, or —C(O)N(C 1 -C 6 alkyl)-;
R 27 is C 1 -C 6 alkyl, C 1 -C 6 alkoxy, aryl C 1 -C 6 alkyl, heterocycloalkyl, or heteroaryl, wherein each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, halo C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, —C(O)NH 2 , NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —C(O)NH(C 1 -C 6 alkyl), or —C(O)N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl).
16 . A compound according to claim 15 , wherein
R 1 is benzyl which is optionally substituted with 1, 2, 3, or 4 groups independently selected from C 1 -C 4 alkyl optionally substituted with 1, or 2 substituents selected from halogen, —OH, —SH, NH 2 , NH(C 1 -C 6 alkyl), N—(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —C≡N, —CF 3 , and C 1 -C 3 alkoxy; halogen; C 1 -C 4 alkoxy; and OH.
17 . A compound according to claim 16 , wherein
X is C 1 -C 3 alkylidenyl optionally substituted with 1 or 2 methyl groups; Z is SO 2 ; SO; S; or C(O); Y is pyrrolidinyl; piperidinyl; imidazolidinyl; piperazinyl; —N(Y 1 )(Y 2 ); wherein
—N(Y 1 )(Y 2 ) forms a ring selected from piperazinyl, piperidinyl, morpholinyl, and pyrrolidinyl, wherein each ring is optionally substituted with 1, 2, or 3 groups that are independently C 0 -C 4 alkyl, C 0 -C 4 alkoxy, C 1 -C 4 alkoxy C 1 -C 4 alkyl, or halogen; and
R 2 and R 3 are independently H or C 1 -C 4 alkyl
18 . (canceled)
19 . A compound according to claim 18 , of the formula:
wherein
R C is C 3 -C 8 alkyl, cyclopropyl, cyclopentyl, cyclohexyl, or —(C 1 -C 4 )alkyl-cyclopropyl;
A 3 and A 4 are independently H, F, Cl, Br, or I;
R 5 is selected from cyclopropyl; cyclopentyl; or cyclohexyl; each of which is optionally substituted with 1, 2, or 3 groups that are independently C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, C 1 -C 4 haloalkyl, or OH; phenyl optionally substituted with 1, 2, 3, or 4 groups that are independently halogen, OH, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or C 1 -C 2 haloalkyl.
20 . A compound according to claim 18 , wherein
wherein
A 1 is H, C 1 -C 4 alkyl or C 1 -C 4 alkoxy;
A 2 is H, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 haloalkyl or OH;
A 3 and A4 are independently H, F, Cl, Br, or I;
R 5 is selected from cyclopropyl; cyclopentyl; or cyclohexyl; each of which is optionally substituted with 1, 2, or 3 groups that are independently C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, C 1 -C 4 haloalkyl, or OH; phenyl optionally substituted with 1, 2, 3, or 4 groups that are independently halogen, OH, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or C 1 -C 2 haloalkyl.
21 . A compound according to claim 15 selected from
3-(butylsulfonyl)-N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N˜2˜-(pyridin-3-ylcarbonyl)-D-alaninamide; 3-(butylsulfonyl)-N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N˜2˜-[(2,4-dimethyl-1,3-thiazol-5-yl)carbonyl]-D-alaninamide; 3-(butylsulfonyl)-N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N˜2˜-{[3-(trifluoromethyl)-1H-pyrazol-4-yl]carbonyl}-D-alaninamide; 3-(butylsulfonyl)-N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N˜2˜-[(3-methyl-1H-pyrazol-5-yl)carbonyl]-D-alaninamide; 3-(butylsulfonyl)-N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N˜2˜-(1H-imidazol-4-ylacetyl)-D-alaninamide; 3-(butylsulfonyl)-N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N˜2˜-(pyrazin-2-ylcarbonyl)-D-alaninamide; 3-(butylsulfonyl)-N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N˜2˜-[(6-hydroxypyridin-3-yl)carbonyl]-D-alaninamide; N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-(cyclopropylamino)-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-N˜2˜-(pyridin-4-ylcarbonyl)-D-alaninamide; N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-N˜2˜-(pyridin-4-ylcarbonyl)-D-alaninamide; N˜2˜-[(5-bromoopyridin-3-yl)carbonyl]-N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-D-alaninamide; N˜2˜-[(5-chloropyridin-3-yl)carbonyl]-N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-D-alaninamide; N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N˜2˜-[(5-methylpyridin-3-yl)carbonyl]-3-[(1-propylbutyl)sulfonyl]-D-alaninamide; N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-N˜2˜-{[3-(trifluoromethyl)-1H-pyrazol-4-yl]carbonyl}-D-alaninamide; N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N˜2˜-[(3-methyl-1H-pyrazol-5-yl)carbonyl]-3-[(1-propylbutyl)sulfonyl]-D-alaninamide; N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-N˜2˜-(1,3-thiazol-4-ylcarbonyl)-D-alaninamide; N˜1˜-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-ethylphenyl)cyclopropyl]amino}-2-hydroxypropyl)-3-[(1-propylbutyl)sulfonyl]-N˜2˜-[(pyridin-3-yl)carbonyl]-D-alaninamide trifluoracetate; N˜1˜-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-ethylphenyl)cyclopropyl]amino}-2-hydroxypropyl)-3-[(1-propylbutyl)sulfonyl]-N-alaninamide; trifluoracetate; N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N˜2-propionyl-3-[(1-propylbutyl)sulfonyl]-D-alaninamide; 3-[butylsulfonyl]-N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N˜2˜-[(pyridin-3-yl)carbonyl]-D, L-alaninamide; N˜1˜-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-ethylphenyl)cyclopropyl]amino}-2-hydroxypropyl)-N˜2˜-(3-hydroxybenzoyl}-3-[(1-propylbutyl)sulfonyl]-D,L-alaninamide trifluoracete; N˜1˜-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-ethylphenyl)cyclopropyl]amino}-2-hydroxypropyl)-3-[(1-propylbutyl)sulfonyl]-N˜2˜-[(pyridin-4-yl)carbonyl]-D-alaninamide trifluoracetate; N˜1˜-{(1S,2S)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N˜2˜-[(6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)carbonyl]-3-[(1-propylbutyl)sulfonyl]alaninamide hydrochloride; 5-oxo-D-prolyl-N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]alaninamide; 5-oxo-L-prolyl-N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]alaninamide; N˜1˜-{(1S,2S)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N˜2˜-[3-(4-oxo-2-thioxo-1,3-thiazolidin-3-yl)propanoyl]-3-[(1-propylbutyl)sulfonyl]alaninamide; N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N˜2˜-[(piperidin-4-yl)carbonyl]-3-[(1-propylbutyl)sulfonyl]-D, L-alaninamide; N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N˜2˜-[(2,4-dimethyl-1,3-thiazol-5-yl)carbonyl]-3-[(1-propylbutyl)sulfonyl]-D,L-alaninamide; N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N˜2˜-[(2-methyl-4-(trifluoromethyl)-1,3-thiazol-5-yl)carbonyl]-3-[(1-propylbutyl)sulfonyl]-D, L-alaninamide; N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N˜2˜-[(3,5-dimethylisoxazol-4-yl)carbonyl]-3-[(1-propylbutyl)sulfonyl]-D, L-alaninamide; N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N˜2˜-[(3-methyl-1H-pyrazol-5-yl)carbonyl]-3-[(1-propylbutyl)sulfonyl]-D, L-alaninamide trifluoroacetate; N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N˜2˜-[(1H-pyrazol-4-yl)carbonyl]-3-[(1-propylbutyl)sulfonyl]-D, L-alaninamide; N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N˜2˜-[(1H-imidazol-5-yl)carbonyl]-3-[(1-propylbutyl)sulfonyl]-D,L-alaninamide; N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N˜2˜-(1H-imidazol-4-ylacetyl)-3-[(1-propylbutyl)sulfonyl]-D, L-alaninamide; N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-N˜2˜-[(pyrazin-2-yl)carbonyl]-D, L-alaninamide; N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N˜2˜-[(3,5-dihydroxypyridin-4-yl)carbonyl]—3-[(1-propylbutyl)sulfonyl]-D, L-alaninamide; N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N˜2˜-[(6-hydroxypyridin-3-yl)carbonyl]-3-[(1-propylbutyl)sulfonyl]-D, L-alaninamide; N˜2˜-[(6-chloropyridin-3-yl)carbonyl]-N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-D, L-alaninamide; N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-N˜2˜-[(pyridin-4-yl)carbonyl]-D, L-alaninamide; N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N˜2˜-[(pyridin-3-yl)carbonyl]-3-[(1-propylbutyl)sulfonyl]-D,L-alaninamide; N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-N˜2˜-[(pyridin-2-yl)carbonyl]-D, L-alaninamide; N˜1˜-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N˜2˜-[1H-indole-6-carbonyl]-3-[(1-propylbutyl)sulfonyl]-D, L-alaninamide; N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-(2S)-2-[(4-methoxy-4-oxobutanoyl)amino]-5-oxo-5-piperidin-1-ylpentanamide; (2R)-2-{[(benzyloxy)carbonyl]amino}-N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-oxo-5-piperidin-1-ylpentanamide; N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-(2R)-2-[(3-ethoxy-3-oxopropanoyl)amino]-5-oxo-5-piperidin-1-ylpentanamide; N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-(2R)-2-[(4-methoxy-4-oxobutanoyl)amino]-5-oxo-5-piperidin-1-ylpentanamide; and N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-(2R)-2-[(5-methoxy-5-oxopentanoyl)amino]-5-oxo-5-piperidin-1-ylpentanamide.
22 . A compound according to claim 3 , wherein
R N is of the formula: wherein n 7 is 0, 1, or 2; R 4 is —NHR 8 or NH(CH 2 ) n6 —R 4-1 ; wherein
N 6 is 0, 1, 2, or 3;
R 4-1 is selected from the group consisting of —SO 2 —(C 1 -C 8 alkyl), —SO—(C 1 -C 8 alkyl), —S—(C 1 -C 8 alkyl), —S—CO—(C 1 -C 6 alkyl), —SO 2 —NR 4-2 R 4-3 ; —CO—C 1 -C 2 alkyl; —CO—NR 4-3 R 4-4 ; R 4-2 and R 4-3 are independently H, C 1 -C 3 alkyl, or C 3 -C 6 cycloalkyl; R 4-4 is C 1 -C 4 alkyl, phenyl C 1 -C 4 alkyl, C 2 -C 4 alkanoyl, or phenyl C 1 -C 4 alkanoyl;
R 8 is selected from the group consisting of —SO 2 -phenyl; —C(O)NHR 9 ; —S—C 2 -C 4 alkanoyl; wherein
R 9 is phenyl C 1 -C 4 alkyl, C 1 -C 6 alkyl, or H;
X is C 1 -C 4 alkylidenyl optionally substituted with 1, 2, or 3 methyl groups; or —NR 4-6 —; or R 4 and R 4-6 combine to form —(CH 2 ) n10 —, wherein
n 10 is 1, 2, 3, or 4;
Z is SO 2 ; SO; S; or C(O); Y is C 5 -C 6 heterocycloalkyl containing at least one N, O, or S; —N(Y 1 )(Y 2 ); wherein
—N(Y 1 )(Y 2 ) forms a ring selected from piperazinyl, piperidinyl, morpholinyl, and pyrrolidinyl, wherein each ring is optionally substituted with 1, 2, 3, or 4 groups that are independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxy C 1 -C 6 alkyl, or halogen; and
R 20 at each occurrence is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, or C 1 -C 6 alkanoyl, each of which is unsubstituted or substituted with 1, or 2 groups independently selected from halogen, C 1 -C 6 alkyl, hydroxy, C 1 -C 6 alkoxy, NH 2 , and —R 26 -R 27 , wherein
R 26 is —C(O)—, —SO 2 —, —CO 2 —, —C(O)NH—, or —C(O)N(C 1 -C 6 alkyl)-;
R 27 is C 1 -C 6 alkyl, C 1 -C 6 alkoxy, aryl C 1 -C 6 alkyl, heterocycloalkyl, or heteroaryl, wherein each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, halo C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, —C(O)NH 2 , NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —C(O)NH(C 1 -C 6 alkyl), or —C(O)N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl).
23 . (canceled)
24 . A compound according to claim 1 , wherein
R 4 is H; C 1 -C 4 alkyl-NHC(O)R 5 ; —(CH 2 ) 0-4 R 8 ; —O—C 1 -C 4 alkanoyl; OH; C 6 -C 10 aryloxy optionally substituted with 1, 2, or 3 groups that are independently halogen, C 1 -C 4 alkyl, CO 2 H, —C(O)—C 1 -C 4 alkoxy, or C 1 -C 4 alkoxy; C 1 -C 6 alkoxy; aryl C 1 -C 4 alkoxy; —C 1 -C 4 alkyl-NR 50 CO 2 R 51 ; —C≡N; —CF 3 ; —CF 2 —CF 3 ; —C≡CH; —CH 2 —CH═CH 2 ; —(CH 2 ) 1-4 —R 4-1 ; —(CH 2 ) 1-4 —NH—R 4-1 ; —O—(CH 2 ) n6 —R 4-1 ; —S—(CH 2 ) n6 —R 4-1 ; (CH 2 ) 0-4 —NHC(O)—(CH 2 ) 0-6 —R 52 ; or —(CH 2 ) 0-4 —R 53 —(CH 2 ) 0-4 —R 54 .
25 . A compound according to claim 24 , wherein
R 1 is (CH 2 ) n1 —(R 1-aryl ) where n 1 is zero or one and R 1-aryl is phenyl optionally substituted with 1, 2, 3, or 4 groups independently selected from C 1 -C 6 alkyl optionally substituted with 1, 2, or 3 substituents selected from the group consisting of C 1 -C 3 alkyl, halogen, —OH, —SH, —NR 1-a R 1-b , —C≡N, —CF 3 , and C 1 -C 3 alkoxy; halogen; C 1 -C 6 alkoxy; —NR N-2 R N-3 ; and OH; wherein
R N-2 and R N-3 at each occurrence are independently selected from the group consisting of —C 1 -C 8 alkyl optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of —OH, —NH 2 , phenyl and halogen; —C 3 -C 8 cycloalkyl; —(C 1 -C 2 alkyl)-(C 3 -C 8 cycloalkyl); —(C 1 -C 6 alkyl)-O—(C 1 -C 3 alkyl); —C 2 -C 6 alkenyl; —C 2 -C 6 alkynyl; —C 1 -C 6 alkyl chain with one double bond and one triple bond; aryl; heteroaryl; heterocycloalkyl;
or
R N-2 , R N-3 and the nitrogen to which they are attached form a 5, 6, or 7 membered heterocycloalkyl or heteroaryl group, wherein said heterocycloalkyl or heteroaryl group is optionally fused to a benzene, pyridine, or pyrimidine ring, and said groups are unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that at each occurrence are independently C 0 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, halo C 1 -C 6 alkyl, halo C 1 -C 6 alkoxy, —CN, —NO 2 , —NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —OH, —C(O)NH 2 , —C(O)NH(C 1 -C 6 alkyl), —C(O)N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), C 1 -C 6 alkoxy C 1 -C 6 alkyl, C 1 -C 6 thioalkoxy, and C 1 -C 6 thioalkoxy C 1 -C 6 alkyl.
26 . A compound according to claim 25 , wherein
R 20 at each occurrence is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 4 alkoxy C 1 -C 4 alkyl, halo C 1 -C 6 alkyl, C 2 -C 4 alkanoyl, each of which is unsubstituted or substituted with 1, or 2 groups independently selected from halogen, C 1 -C 6 alkyl, hydroxy, C 1 -C 6 alkoxy, NH 2 , and —R 26 -R 27 , wherein
R 26 is selected from —C(O)—, —SO 2 —, —CO 2 —;
R 27 is selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, aryl C 1 -C 6 alkyl, piperidyl, pyrrolyl, and pyridyl, wherein each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, halo C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, —C(O)NH 2 , NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —C(O)NH(C 1 -C 6 alkyl), or —C(O)N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl).
27 . A compound according to claim 26 , wherein
R 4 is H; C 1 -C 4 alkyl-NHC(O)R 5 ; —(CH 2 ) 0-4 R 8 ; —C 1 -C 4 alkyl-NR 50 CO 2 R 51 ; —C≡N; —CF 3 ; —CF 2 —CF 3 ; —C≡CH; —CH 2 —CH═CH 2 ; —(CH 2 ) 1-4 —R 4-1 ; —(CH 2 ) 1-4 —NH—R 4-1 ; (CH 2 ) 0-4 —NHC(O)—(CH 2 ) 0-6 —R 52 ; or —(CH 2 ) 0-4 —R 53 —(CH 2 ) 0-4 —R 54 .
28 . A compound according to claim 27 , wherein
X is C 1 -C 4 alkylidenyl optionally substituted with 1, 2, or 3 methyl groups; or —NR 4-6 —; or R 4 and R 4-6 combine to form —(CH 2 ) n10 —, wherein
n 10 is 1, 2, 3, or 4;
Z is selected from a bond; SO 2 ; SO; S; and C(O); Y is C 5 -C 6 heterocycloalkyl containing at least one N, O, or S; or —N(Y 1 )(Y 2 ); wherein
—N(Y 1 )(Y 2 ) forms a ring selected from piperazinyl, piperidinyl, morpholinyl, and pyrrolidinyl, wherein each ring is optionally substituted with 1, 2, 3, or 4 groups that are independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxy C 1 -C 6 alkyl, or halogen.
29 . (canceled)
30 . (canceled)
31 . A compound according to claim 28 of the formula:
wherein
A 1 is H, C 1 -C 4 alkyl or C 1 -C 4 alkoxy;
A 2 is H, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 haloalkyl or OH;
A 3 and A 4 are independently C 1 -C 4 alkyl, halogen, or H.
32 . A compound according to claim 28 of the formula:
wherein
R C is C 3 -C 8 alkyl, cyclopropyl, cyclopentyl, cyclohexyl, or —(C 1 -C 4 )alkyl-(C 3 -C 6 ) cycloalkyl; and
A 3 and A 4 are independently C 1 -C 4 alkyl, halogen, or H.
33 . (canceled)
34 . (canceled)
35 . (canceled)
36 . (canceled)
37 . (canceled)Cited by (0)
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