US2008306136A1PendingUtilityA1
Substituted Ureas and Carbamates
Est. expiryNov 27, 2022(expired)· nominal 20-yr term from priority
A61P 43/00A61P 25/28C07C 311/47C07C 275/24C07C 271/52C07D 407/06C07D 335/06C07D 215/42C07D 311/68C07D 405/04C07D 311/76C07D 317/72C07C 275/28C07C 271/20C07D 277/28C07D 309/14C07D 213/40
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Claims
Abstract
The invention provides compounds of formula I: useful in treating Alzheimer's disease and other similar diseases. These compounds include inhibitors of the beta-secretase enzyme that are useful in the treatment of Alzheimer's disease and other diseases characterized by deposition of A beta peptide in a mammal. The compounds of the invention are useful in pharmaceutical compositions and methods of treatment to reduce A beta peptide formation.
Claims
exact text as granted — not AI-modified1 . A compound of the formula:
or pharmaceutically acceptable salts or esters thereof;
wherein X is —(C═O)—, —(C═S)—, —S(O) n1 — or —(C≡N-Z), wherein Z=R 20 or —OR 20 , and wherein n1 is 0, 1 or 2;
T is absent, NR 20 , or O, with the proviso that when X is —(C═O), T is not absent;
wherein each R 20 is independently H, —CN, C 1-6 alkyl or alkenyl, C 1-6 haloalkyl or C 4-7 cycloalkyl, with the proviso that when Z is R 20 or —OR 20 , R 20 is not —CN;
wherein R 1 is —(CH 2 ) 12 —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, —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, —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, —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 selected from halogen, or
C 3 -C 7 cycloalkyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, —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, —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, —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, C 1 -C 10 alkyl, C 1 -C 10 alkylaryl or C 1 -C 10 alkylheteroaryl;
wherein Rc is
(I) —[—(CH 2 ) (0-8) —(CH) (alkyl 1 ) (alkyl 2 )], where alkyl 1 and alkyl 2 are straight or branched C 2-10 alkanyl, alkenyl or alkynyl, and wherein alkyl 1 and alkyl 2 attach to the same or different methylene carbon with the remaining open methylene valences occupied by hydrogen, thus forming a branched alkyl chain having between 8 and 20 carbon atoms in total;
the alkyl groups, alkyl 1 and alkyl 2 being optionally substituted with one, two or three substituents selected from the group consisting of C 1 -C 3 alkyl, halogen, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, —O-phenyl, —C(O)C 1 -C 3 alkyl, —NR 1-a R 1-b where R 1-a and R 1-b are —H or C 1 -C 6 alkyl, —OC═ONR 1-a R 1-b , —S(═O) 0-2 , —NR 1-a C═ONR 1-a R 1-b ′, —C═ONR 1-a R 1-b , and —S(═O) 2 NR 1-a R 1-b ;
(II) —(C(Rc-x)(Rc-y)) (0-4) -Rc-cycle
wherein each Rc-x and Rc-y is independently chosen from:
H
C 1 -C 6 alkyl
C 1 -C 6 alkoxy
C 2 -C 6 alkenyl or alkynyl
—(CH 2 ) 0-4 -Rc-cycle where Rc-cycle is as defined below and Rc-x and Rc-y may be taken together with the methylene carbon to which they jointly attach to form a spirocyclic ring of 3 to 7 atoms comprising carbon and up to 2 of O, S(O) (0-2) and NR a′ , wherein is R a′ is H or C 1-4 alkyl;
wherein the spirocyclic ring may be fused to another ring to provide a bicyclic ring system comprising carbon and up to 2 of O, S(O) (0-2) and NR a′ . and comprising up to 9 atoms in total including,
Rc-cycle is an aryl, heteroaryl, or cycloalkyl ring or a fused-ring system consisting of no more than three rings where each of the rings is the same or different and is an aryl, heteroaryl, or cycloalkyl ring
wherein Rc-cycle is optionally substituted with up to four substituents independently selected from:
(1) C 1 -C 6 alkyl optionally substituted with one, two or three substituents 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 ,
(2) C 2 -C 6 alkenyl or alkynyl with one or two unsaturated bonds, optionally substituted with one, two or three substituents selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(3) halogen,
(4) C 1 -C 6 alkoxy,
(5) —C 1 -C 6 alkoxy optionally substituted with one, two, or three of —F,
(6) —NR N-6 R N-7 where R N-6 and R N-7 are the same or different and are selected from the group consisting of:
(a) —H,
(b) —C 1 -C 6 alkyl optionally substituted with one substitutent selected from the group consisting of:
(i) —OH, and
(ii) —NH 2 ,
(c) —C 1 -C 6 alkyl optionally substituted with one to three —F, —Cl, —Br, or —I,
(d) —C 3 -C 7 cycloalkyl,
(e) —(C 1 -C 2 alkyl)-(C 3 -C 7 cycloalkyl),
(f) —(C 1 -C 6 alkyl)-O—(C 1 -C 3 alkyl),
(g) —C 2 -C 6 alkenyl with one or two double bonds,
(h) —C 2 -C 6 alkynyl with one or two triple bonds,
(i) —C 1 -C 6 alkyl chain with one double bond and one triple bond,
(j) —R 1-aryl where R 1-aryl is as defined above, and
(k) —R 1-heteroaryl where R 1-heteroaryl is as defined above,
(7) —OH,
(8) —C≡N,
(9) C 3 -C 7 cycloalkyl, optionally substituted with one, two or three substituents selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and NR 1-a R 1-b ,
(10) —CO—(C 1 -C 4 alkyl),
(11) —SO 2 —NR 1-a R 1-b ,
(12) —CO—NR 1-a R 1-b ,
(13) —SO 2 —(C 1 -C 4 alkyl),
and when there is a saturated carbon atom in Rc-cycle
(14) oxo,
(15) oxime
(16) ketal rings of 5 to 7 members, and
(17) a spirocyclic ring having from 3 to 7 atoms comprising carbon and when the ring size is 4-7 atoms optionally up to 2 of O, S(O) (0-2) and NR a′ . (IV) —(CR C-x R C-y ) 0-4 -heteroaryl,
(III) —(CR C-x R C-y ) 0-4 -aryl-aryl,
(IV) —(CR C-x R C-y ) 0-4 -aryl-heteroaryl,
(V) —(CR C-x R C-y ) 0-4 -heteroaryl-aryl,
(VI) —(CR C-x R C-y ) 0-4 -heteroaryl-heteroaryl,
(VII) —(CR C-x R C-y ) 0-4 -aryl-heterocycle,
(VIII) —(CR C-x R C-y ) 0-4 -heteroaryl-heterocycle,
(IX) —(CR C-x R C-y ) 0-4 -heterocycle-aryl,
(X) —(CR C-x R C-y ) 0-4 -heterocycle-heteroaryl,
(XI) —(CR C-x R C-y ) 0-4 -heterocycle-heterocycle,
(XII) —[C(R C-1 )(R C-2 )] 1-3 —[CO] 0-1 —N—(R C-3 ) 2 where each R C-1 is the same or different and is selected from the group consisting of: H, C 1-4 alkyl and C 1-4 alkoxy and
where each R C-2 and R C-3 is independently selected from
(A)-C 1 -C 6 alkyl, optionally substituted with one, two or three substituents selected from the group consisting of C 1 -C 3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 6 alkoxy, —O— phenyl, and —NR 1-a R 1-b ,
(B) C 2 -C 6 alkenyl or alkynyl with one or two unsaturated bonds, optionally substituted with one, two or three substituents selected from the group consisting of C 1 -C 3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 6 alkoxy, —O— phenyl, and —NR 1-a R 1-b ,
(C) —(CH 2 ) 1-2 —S(O) 0-2 —(C 1 -C 6 alkyl)
(D) —(CH 2 ) 0-4 —C 3 -C 7 cycloalkyl optionally substituted with one, two or three substituents selected from the group consisting of C 1 -C 3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 6 alkoxy, —O— phenyl, —NR 1-a R 1-b ,
(E) —(CH 2 ) 0-4 -5-7 membered heterocycle optionally substituted with one, two or three substituents selected from the group consisting of C 1 -C 3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 6 alkoxy, —O— phenyl, oxo, NR 1-a R 1-b ,
(XIII) —CH(aryl) 2 where each aryl is the same or different,
(XIV) —CH(heteroaryl) 2 where each heteroaryl is the same or different and are as defined above,
(XVIII) —CH(aryl)(heteroaryl),
wherein R N is R′ 100 , —(CRR′) 16 R′ 100 , —(CRR′) 0-6 R 100 , —(CRR′) 1-6 -β-R′ 100 , —(CRR′) 1-6 —S—R′ 100 , —(CRR′) 1-6 —C(═O)—R 100 , —(CRR′) 1-6 —SO 2 —R 100 , —(CRR′) 1-6 —NR 100 —R′ 100 or —SO 2 R′ 100 , with the proviso that when R N is —SO 2 R′ 100 , X is not —S(═O) n — or —C(═S)—; wherein
R 100 and R′ 100 independently represent aryl, heteroaryl, -aryl-W-aryl, -aryl-W-heteroaryl, -aryl-W-heterocyclyl, -heteroaryl-W-aryl, -heteroaryl-W-heteroaryl, -heteroaryl-W-heterocyclyl, -heterocyclyl-W-aryl, -heterocyclyl-W-heteroaryl, -heterocyclyl-W-heterocyclyl, —CH[(CH 2 ) 0-2 —O—R 150 ]-(CH 2 ) 0-2 -aryl, —CH[(CH 2 ) 0-2 —O—R 10 ]-(CH 2 ) 0-2 -heterocyclyl or —CH[(CH 2 ) 0-2 —O—R 150 ]-(CH 2 ) 0-2 -heteroaryl, where the ring portions of each are optionally substituted with 1, 2, or 3 groups independently selected from
—OR, —NO 2 , halogen, —C≡N, —OCF 3 , —CF 3 , —(CH 2 ) 0-4 —O—P(═O)(OR)(OR′), —(CH 2 ) 0-4 —CO—NR 105 R′ 105 , —(CH 2 ) 0-4 —O—(CH 2 ) 0-4 —CONR 102 R 102 ′, —(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—(CH 2 ) 0-4 (C 3 -C 7 cycloalkyl), —(CH 2 ) 0-4 —R 110 , —(CH 2 ) 0-4 —R 120 , —(CH 2 ) 0-4 —R 130 , —(CH 2 ) 0-4 —CO—R 110 , —(CH 2 ) 0-4 —CO—R 120 , —(CH 2 ) 0-4 —CO—R 130 , —(CH 2 ) 0-4 —CO—R 140 , —(CH 2 ) 0-4 —CO—O—R 150 , —(CH 2 ) 0-4 —SO 2 —NR 105 R′ 105 , —(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 —(CH 2 ) 0-4 —(C 3 -C 7 cycloalkyl), —(CH 2 ) 0-4 —N(R 150 )—CO—O—R 150 , —(CH 2 ) 0-4 —N(R 150 )—CO—N(R 150 ) 2 , —(CH 2 ) 0-4 —N(R 150 )—CS—N(R 150 ) 2 , —(CH 2 ) 0-4 —N(R 150 )—CO—R 105 , —(CH 2 ) 0-4 —NR 105 R′ 105 , —(CH 2 ) 0-4 —R 140 , —(CH 2 ) 0-4 —O—CO—(C 1 -C 6 alkyl), —(CH 2 ) 0-4 —O—P(O)—(O—R 110 ) 2 , —(CH 2 ) 0-4 —O—CO—N(R 150 ) 2 , —(CH 2 ) 0-4 —O—CS—N(R 150 ) 2 , —(CH 2 ) 0-4 —O— (R 150 ), —(CH 2 ) 0-4 —O—R 150 ′-COOH, —(CH 2 ) 0-4 —S—(R 150 ), —(CH 2 ) 0-4 —N(R 150 )—SO 2 —R 105 , —(CH 2 ) 0-4 —C 3 -C 7 cycloalkyl, (C 2 -C 10 )alkenyl, or (C 2 -C 10 )alkynyl, or
R 100 is C 1 -C 10 alkyl optionally substituted with 1, 2, or 3 R 115 groups, or
R 100 is —(C 1 -C 6 alkyl)-O—C 1 -C 6 alkyl) or —(C 1 -C 6 alkyl)-S—(C 1 -C 6 alkyl), each of which is optionally substituted with 1, 2, or 3 R 115 groups, or
R 100 is C 3 -C 8 cycloalkyl optionally substituted with 1, 2, or 3 R 115 groups;
W is —(CH 2 ) 0-4 —, —O—, —S(O) 0-2 —, —N(R 135 )—, —CR(OH)— or —C(O)—;
R 102 and R 102 ′ independently are hydrogen, or
C 1 -C 10 alkyl optionally substituted with 1, 2, or 3 groups that are independently halogen, aryl or —R 110 ;
R 105 and R′ 105 independently represent —H, —R 110 , —R 120 , 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, or C 1 -C 6 alkyl chain with one double bond and one triple bond, or
C 1 -C 6 alkyl optionally substituted with —OH or —NH 2 ; or,
C 1 -C 6 alkyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, or
R 105 and R′ 105 together with the atom to which they are attached form a 3 to 7 membered carbocylic ring, where one member is optionally a heteratom selected from —O—, —S(O) 0-2 —, —N(R 135 )—, the ring being optionally substituted with 1, 2 or three R 140 groups;
R 115 at each occurrence is independently halogen, —OH, —CO 2 R 102 , —C 1 -C 6 thioalkoxy, —CO 2 -phenyl, —NR 105 R′ 135 , —SO 2 —(C 1 -C 8 alkyl), —C(═O)R 180 , R 180 , —CONR 105 R′ 105 , —SO 2 NR 105 R′ 105 , —NH—CO—(C 1 -C 6 alkyl), —NH—C(═O)—OH, —NH—C(═O)—OR, —NH—C(═O)—O-phenyl, —O—C(═O)—(C 1 -C 6 alkyl), —O—C(═O)-amino, —O—C(═O)-mono- or dialkylamino, —O—C(═O)-phenyl, —O—(C 1 -C 6 alkyl)-CO 2 H, —NH—SO 2 —(C 1 -C 6 alkyl), C 1 -C 6 alkoxy or C 1 -C 6 haloalkoxy;
R 135 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, —(CH 2 ) 0-2 -(aryl), —(CH 2 ) 0-2 -(heteroaryl), or —(CH 2 ) 0-2 -(heterocyclyl);
R 140 is heterocyclyl optionally substituted with 1, 2, 3, or 4 groups independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, amino(C 1 -C 6 )alkyl, mono(C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, di(C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, and ═O;
R 150 is hydrogen, C 3 -C 7 cycloalkyl, —(C 1 -C 2 alkyl)-(C 3 -C 7 cycloalkyl), C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl with one double bond and one triple bond, —R 110 , —R 120 , or
C 1 -C 6 alkyl optionally substituted with 1, 2, 3, or 4 groups independently selected from —OH, —NH 2 , C 1 -C 3 alkoxy, R 110 , and halogen;
R 150 ′ is C 3 -C 7 cycloalkyl, —(C 1 -C 3 alkyl)-(C 3 -C 7 cycloalkyl), C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl with one double bond and one triple bond, —R 110 , —R 120 , or
C 1 -C 6 alkyl optionally substituted with 1, 2, 3, or 4 groups independently selected from —OH, —NH 2 , C 1 -C 3 alkoxy, R 110 , and halogen;
R 180 is selected from morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl, homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S-oxide, homothiomorpholinyl S,S-dioxide, pyrrolinyl and pyrrolidinyl, each of which is optionally substituted with 1, 2, 3, or 4 groups independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C 1 -C 6 ) alkylamino, di(C 1 -C 6 )alkylamino, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, amino(C 1 -C 6 )alkyl, mono(C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, di(C 1 -C 6 ) alkylamino(C 1 -C 6 )alkyl, and ═O;
R 110 is aryl optionally substituted with 1 or 2 R 125 groups;
R 125 at each occurrence is independently halogen, amino, mono- or dialkylamino, —OH, —C≡N, —SO 2 —NH 2 , —SO 2 —NH—C 1 -C 6 alkyl, —SO 2 —N(C 1 -C 6 alkyl) 2 , —SO 2 —(C 1 -C 4 alkyl), —CO—NH 2 , —CO—NH—C 1 -C 6 alkyl, or —CO—N(C 1 -C 6 alkyl) 2 , or
C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, each of which is optionally substituted with 1, 2, or 3 groups that are independently selected from C 1 -C 3 alkyl, halogen, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, amino, and mono- and dialkylamino, or
C 1 -C 6 alkoxy optionally substituted with one, two or three of halogen;
R 120 is heteroaryl, which is optionally substituted with 1 or 2 R 125 groups; and
R 130 is heterocyclyl optionally substituted with 1 or 2 R 125 groups; and
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);
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 1 -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; 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 —.
2 . A compound of the formula:
or a pharmaceutically acceptable salt or ester thereof; wherein X, T, R 20 , R 1 , R 2 , R 3 and R C are as defined in claim 1 and 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 ; —C(H 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 1 -C 6 heterocycloalkyl, C 1 -C 6 heteroaryl, 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; heteroaryl 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; heterocycloalkyl optionally substituted with 1, 2, or 3 groups that are independently C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, or C 2 -C 4 alkanoyl; 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 -heteroaryl, —SO 2 -aryl, —SO 2 -heterocycloalkyl, —SO 2 —C 1 -C 10 alkyl, —C(O)NHR 9 , heterocycloalkyl, —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, heteroaryl, —NR 6 R 7 , —C(O)NR 6 R 7 , C 3 -C 7 cycloalkyl, or —C 1 -C 4 alkoxy; heterocycloalkyl optionally substituted with 1 or 2 groups that are independently C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, C 2 -C 4 alkanoyl, aryl C 1 -C 4 alkyl, and —SO 2 C 1 -C 4 alkyl; alkenyl; alkynyl; heteroaryl optionally substituted with 1, 2, or 3 groups that are independently OH, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, NH 2 , NH(C 1 -C 6 alkyl) or N(C 1 -C 6 alkyl) (C 1 -C 6 alkyl); heteroarylalkyl optionally substituted with 1, 2, or 3 groups that are independently C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, NH 2 , NH(C 1 -C 6 alkyl) or N(C 1 -C 6 alkyl) (C 1 -C 6 alkyl); aryl; heterocycloalkyl; C 3 -C 8 cycloalkyl; and cycloalkylalkyl; wherein the aryl; heterocycloalkyl, 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 52 is heterocycloalkyl, heteroaryl, 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 -heteroaryl, —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 heteroaryl, aryl, arylalkyl, heterocycloalkyl, 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; 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
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.
3 . A compound according to claim 1 of the formula
or a pharmaceutically acceptable salt or ester thereof wherein
R C is selected from —(CH 2 ) 0-3 —(C 3 -C 8 )cycloalkyl wherein the cycloalkyl is optionally substituted with 1, 2, or 3 groups independently selected from —R 205 ; 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; —CHR 245 —CHR 250 -aryl; —(CR 245 R 250 ) 0-4 -heterocycloalkyl-heteroaryl; —(CR 245 R 250 ) 0-4 -heterocycloalkyl-heterocycloalkyl; —(CR 245 R 250 ) 0-4 -heterocycloalkyl-aryl; a monocyclic or bicyclic ring of 5, 6, 7 8, 9, or 10 carbons fused to 1 or 2 aryl, heteroaryl, or heterocycloalkyl groups;
wherein 1, 2 or 3 carbons of the monocyclic or bicyclic ring are optionally replaced with —NH—, —N(CO) 0-1 R 215 —, —N(CO) 0-1 R 220 —, —O—, or —S(═O) 0-2 —, and wherein the monocyclic or bicyclic ring is optionally substituted with 1, 2 or 3 groups that are independently —R 205 , —R 245 , —R 250 or ═O;
and —C 2 -C 6 alkenyl optionally substituted with 1, 2, or 3 R 205 groups;
wherein each aryl or heteroaryl group attached directly or indirectly to the —(CR 245 R 250 ) 0-4 group is optionally substituted with 1, 2, 3 or 4 R 200 groups;
wherein each heterocycloalkyl attached directly or indirectly to the —(CR 245 R 250 ) 0-4 group is optionally substituted with 1, 2, 3, or 4 R 210 ;
R 200 at each occurrence is independently selected from —C 1 -C 6 alkyl optionally substituted with 1, 2, or 3 R 205 groups; —OH; —NO 2 ; -halogen; —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—(C 2 -C 8 alkenyl); —(CH 2 ) 0-4 —CO—(C 2 -C 8 alkynyl); —(CH 2 ) 0-4 —CO—(C 3 -C 7 cycloalkyl); —(CH 2 ) 0-4 —(CO) 0-1 -aryl; —(CH 2 ) 0-4 —(CO) 0-1 -heteroaryl; —(CH 2 ) 0-4 —(CO) 0-1 -heterocycloalkyl; —(CH 2 ) 0-4 —CO 2 R 215 ; —(CH 2 ) 0-4 —SO 2 —NR 220 R 225 ; —(CH 2 ) 0-4 —S(O) 0-2 —(C 1 -C 8 alkyl); —(CH 2 ) 0-4 —S(O) 0-2 —(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 )—SO 2 —R 220 ; —(CH 2 ) 0-4 —N(H or R 215 )—CO—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— (R 215 ); —(CH 2 ) 0-4 —S—(R 215 ); —(CH 2 ) 0-4 —O—(C 1 -C 6 alkyl optionally substituted with 1, 2, 3, or 5-F); —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; adamantly, and (CH 2 ) 0-4 —C 3 -C 7 cycloalkyl;
each aryl and heteroaryl group included within R 200 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 heterocycloalkyl group included within R 200 is optionally substituted with 1, 2, or 3 groups that are independently R 210 ;
R 205 at each occurrence is independently selected from —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —C 1 -C 6 haloalkoxy, —(CH 2 ) 0-3 (C 3 -C 7 cycloalkyl), -halogen, —(CH 2 ) 0-6 —OH, —O-phenyl, OH, SH, —(CH 2 ) 0-6 —C≡N, —(CH 2 ) 0-6 —C(═O)NR 235 R 240 , —CF 3 , —C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl, and —NR 235 R 240 ;
R 210 at each occurrence is independently selected from —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 1 -C 6 alkanoyl; —SO 2 —(C 1 -C 6 alkyl); —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;
R 215 at each occurrence is independently selected from —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, —(CH 2 ) 0-2 -(heteroaryl), and —(CH 2 ) 0-2 -(heterocycloalkyl); wherein the aryl group included within R 215 is optionally substituted with 1, 2, or 3 groups that are independently —R 205 or —R 210 ; wherein the heterocycloalkyl and heteroaryl groups included within R 215 are optionally substituted with 1, 2, or 3 R 210 ;
R 220 at each occurrence is independently H, —C 1 -C 6 alkyl, —CHO, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkoxycarbonyl, -amino C 1 -C 6 alkyl, —SO 2 —C 1 -C 6 alkyl, C 1 -C 6 alkanoyl optionally substituted with up to three halogens, —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), -halo C 1 -C 6 alkyl, —(CH 2 ) 0-2 —(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, -aryl, -heteroaryl, or -heterocycloalkyl; wherein the aryl, heteroaryl and heterocycloalkyl groups included within R 220 and R 225 is optionally substituted with 1, 2, or 3 R 270 groups,
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; -phenyl; -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;
R 235 and R 240 at each occurrence are independently —H, —C 1 -C 6 alkyl, C 2 -C 6 alkanoyl, —SO 2 —(C 1 -C 6 alkyl), or -phenyl;
R 245 and R 250 at each occurrence are independently selected from H, —(CH 2 ) 0-4 CO 2 C 1 -C 4 alkyl, —(CH 2 ) 0-4 C(═O)C 1 -C 4 alkyl, —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, —(CH 2 ) 0-4 aryl, —(CH 2 ) 0-4 heteroaryl, and —(CH 2 ) 0-4 heterocycloalkyl, or
R 245 and R 250 are taken together with the carbon to which they are attached to form a monocycle or bicycle of 3, 4, 5, 6, 7 or 8 carbon atoms, where 1, 2, or 3 carbon atoms are optionally replaced by 1, 2, or 3 groups that are independently —O—, —S—, —SO 2 —, —C(O)—, —NR 220 —, or —NR 220 R 220 — wherein both R 220 groups are alkyl; and wherein the ring is optionally substituted with 1, 2, 3, 4, 5, or 6 groups that are independently C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxyl, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —NH—C(O)C 1 -C 5 alkyl, —NH—SO 2 —(C 1 -C 6 alkyl), or halogen;
wherein the aryl, heteroaryl or heterocycloalkyl groups included within R 245 and R 250 are optionally substituted with 1, 2, or 3 groups that are independently halogen, C 1-6 alkyl, CN or OH.
4 . A compound according to claim 3 , wherein
R 1 is C 1 -C 10 alkyl optionally substituted with 1 or 2 groups independently selected from halogen, —OH, ═O, —CN, —CF 3 , —OCF 3 , —C 3 -C 7 cycloalkyl, —C 1 -C 4 alkoxy, amino, mono-dialkylamino, aryl, heteroaryl or heterocycloalkyl, wherein the aryl group is optionally substituted with 1 or 2 R 50 groups;
R 50 is halogen, OH, CN, —CO—(C 1 -C 4 alkyl), —NR 7 R 8 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, and C 3 -C 8 cycloalkyl;
R 7 and R 8 are selected from H; —C 1 -C 4 alkyl optionally substituted with 1, 2, or 3 groups selected from —OH, —NH 2 and halogen; —C 3 -C 6 cycloalkyl; —(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl); —C 2 -C 4 alkenyl; and —C 2 -C 4 alkynyl;
R C is selected from —(CR 245 R 250 ) 0-4 -aryl; —(CR 245 R 250 ) 0-4 -heteroaryl; —(CR 245 R 250 ) 0-4 -heterocycloalkyl; where the aryl and heteroaryl groups attached to the —(CR 245 R 250 ) 0-4 — group are optionally substituted with 1, 2, 3 or 4 R 200 groups; where the heterocycloalkyl group attached to the —(CR 245 R 250 ) 0-4 group is optionally substituted with 1, 2, 3, or 4 R 210 groups; and R 245 R 250 , R 200 , and R 210 are as defined above.
5 . A compound according to claim 4 , wherein
R C is —(CR 245 R 250 ) 0-4 -heterocycloalkyl; where the heterocycloalkyl group attached to the —(CR 245 R 250 ) 0-4 — group is optionally substituted with 1, 2, 3, or 4 R 210 groups, wherein R 245 , R 250 , and R 210 are as defined above.
6 . A compound according to claim 5 , wherein
R 1 is C 1 -C 10 alkyl substituted with one aryl group, where the aryl group is optionally substituted with 1 or 2 R 50 groups; R c is —(CR 245 R 250 ) 1-4 -aryl or —(CR 245 R 250 ) 1-4 -heteroaryl,
R 245 and R 250 are independently selected from H, —(CH 2 ) 0-4 CO 2 C 1 -C 4 alkyl, —(CH 2 ) 0-4 CO 2 H, —C 1 -C 4 alkyl, —(C 1 -C 4 alkyl)OH, or
R 245 , R 250 and the carbon to which they are attached form a monocycle or bicycle of 3, 4, 5, 6, 7 or 8 carbon atoms, where 1 or 2 carbon atoms are optionally replaced by —O—, —S—, —SO 2 —, or —NR 220 —, where R 220 is as defined above; and
wherein the aryl and heteroaryl groups attached to the —(CR 245 R 250 ) 1-4 — groups are optionally substituted with 1 or 2 R 200 groups.
7 . A compound according to claim 3 , wherein
R c is (CR 245 R 250 ) 1 -aryl, where the aryl is optionally substituted with 1, 2, or 3 R 200 groups; and R 245 is H and R 250 is H or C 1 -C 6 alkyl; or R 245 and R 250 are independently C 1 -C 3 alkyl; or CR 245 R 250 represents a C 3 -C 7 cycloalkyl group.
8 . A compound according to claim 7 , wherein
the (CR 245 R 250 ) 1 -aryl is (CR 245 R 250 ) 1 -phenyl where the phenyl is optionally substituted with 1, 2, or 3 R 200 groups.
9 . A compound according to claim 8 , wherein the phenyl in (CR 245 R 250 ) 1 -phenyl is substituted with
1-3 independently selected R 200 groups, or 1 or 2 independently selected R 200 groups, and 1 heteroaryl group optionally substituted with 1 R 200 group or 1 phenyl group optionally substituted with 1 R 200 group.
10 . A compound according to claim 8 , wherein R 245 is hydrogen and R 250 is C 1 -C 3 alkyl.
11 . A compound according to claim 8 , wherein R 245 and R 250 are both hydrogen.
12 . A compound according to claim 8 , wherein the phenyl in (CR 245 R 250 ) 1 -phenyl is substituted with
(a) 1 R 200 group and 1 heteroaryl group optionally substituted with 1 R 200 group; or (b) 1 R 200 group and 1 phenyl group optionally substituted with 1 R 200 group; or (c) 1 R 200 group, and 1 heterocycloalkyl which is optionally substituted with one R 200 or ═O.
13 . A compound according to claim 12 , wherein CR 245 R 250 represents a C 3 -C 7 cycloalkyl group.
14 . A compound according to claim 12 , wherein CR 245 R 250 represents a C 5 -C 7 cycloalkyl group.
15 . A compound according to claim 12 , wherein CR 245 R 250 represents a C 3 -C 6 cycloalkyl group.
16 - 18 . (canceled)
19 . A compound selected from the group consisting of:
phenyl((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(1S)-7-ethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-hydroxypropyl)carbamate;
methyl (3S)-3-{[(2R,3S)-3-[(anilinocarbonyl)amino]-4-(3,5-difluorophenyl)-2-hydroxybutyl]amino}-3-(3-bromophenyl)propanoate;
N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[4-(3-ethylphenyl)tetrahydro-2H-pyran-4-yl]amino}-2-hydroxypropyl)-N′-phenylurea;
N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(4R)-6-ethyl-2,2-dioxido-3,4-dihydro-1H-isothiochromen-4-yl]amino}-2-hydroxypropyl)methanesulfonamide;
N-benzyl-N′-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(4R)-6-ethyl-2,2-dioxido-3,4-dihydro-1H-isothiochromen-4-yl]amino}-2-hydroxypropyl)urea;
N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(4R)-6-ethyl-2,2-dioxido-3,4-dihydro-1H-isothiochromen-4-yl]amino}-2-hydroxypropyl)-N-phenylurea;
N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(4R)-6-ethyl-2,2-dioxido-3,4-dihydro-1H-isothiochromen-4-yl]amino}-2-hydroxypropyl)-N′-propylurea;
N-(sec-butyl)-N′-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(4R)-6-ethyl-2,2-dioxido-3,4-dihydro-1H-isothiochromen-4-yl]amino}-2-hydroxypropyl)urea;
phenyl((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(4R)-6-ethyl-2,2-dioxido-3,4-dihydro-1H-isothiochromen-4-yl]amino}-2-hydroxypropyl)carbamate;
ethyl((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(4R)-6-ethyl-2,2-dioxido-3,4-dihydro-1H-isothiochromen-4-yl]amino}-2-hydroxypropyl)carbamate;
N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(6-ethyl-3,4-dihydro-2H-chromen-4-yl)amino]-2-hydroxypropyl}-N′-phenylurea;
N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(6-isopropyl-3,4-dihydro-2H-chromen-4-yl)amino]propyl}-N′-phenylurea;
N-[(1S,2R)-1-(3,5-difluorobenzyl)-3-({6-[(dimethylamino)methyl]-3,4-dihydro-2H-chromen-4-yl}amino)-2-hydroxypropyl]-N′-phenylurea;
phenyl {(1S,2R)-1-(3,5-difluorobenzyl)-3-[(6-ethyl-3,4-dihydro-2H-chromen-4-yl)amino]-2-hydroxypropyl}carbamate;
phenyl {(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(6-isopropyl-3,4-dihydro-2H-chromen-4-yl)amino]propyl}carbamate;
phenyl[(1S,2R)-1-(3,5-difluorobenzyl)-3-({6-[(dimethylamino)methyl]-3,4-dihydro-2H-chromen-4-yl}amino)-2-hydroxypropyl]carbamate;
N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(6-ethyl-3,4-dihydro-1H-isochromen-4-yl)amino]-2-hydroxypropyl}-N′-phenylurea;
N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(6-isopropyl-3,4-dihydro-1H-isochromen-4-yl)amino]propyl}-N′-phenylurea;
N-[(1S,2R)-1-(3,5-difluorobenzyl)-3-({6-[(dimethylamino)methyl]-3,4-dihydro-1H-isochromen-4-yl}amino)-2-hydroxypropyl]-N-phenylurea;
phenyl {(1S,2R)-1-(3,5-difluorobenzyl)-3-[(6-ethyl-3,4-dihydro-1H-isochromen-4-yl)amino]-2-hydroxypropyl}carbamate;
phenyl {(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(6-isopropyl-3,4-dihydro-1H-isochromen-4-yl)amino]propyl}carbamate;
phenyl[(1S,2R)-1-(3,5-difluorobenzyl)-3-({6-[(dimethylamino)methyl]-3,4-dihydro-1H-isochromen-4-yl}amino)-2-hydroxypropyl]carbamate;
N 3 -[({(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}amino)carbonyl]-N 1 ,N 1 -dipropyl-b-alaninamide; and
2-{[({(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}amino)carbonyl]amino}-N,N-dipropylethanesulfonamide.
20 . A compound of the formula:
wherein
R C is selected from —(CH 2 ) 0-3 —(C 3 -C 8 )cycloalkyl wherein the cycloalkyl is optionally substituted with 1, 2, or 3 groups independently selected from —R 205 ; 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 ) 04-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; —CHR 245 —CHR 250 -aryl; —(CR 245 R 250 ) 0-4 -heterocycloalkyl-heteroaryl; —(CR 245 R 250 ) 0-4 -heterocycloalkyl-heterocycloalkyl; —(CR 245 R 250 ) 0-4 -heterocycloalkyl-aryl; a monocyclic or bicyclic ring of 5, 6, 7 8, 9, or 10 carbons fused to 1 or 2 aryl, heteroaryl, or heterocycloalkyl groups;
wherein 1, 2 or 3 carbons of the monocyclic or bicyclic ring are optionally replaced with —NH—, —N(Co) 0-1 R 215 —, —N(CO) 0-1 R 220 —, —O—, or —S(═O) 0-2 —, and wherein the monocyclic or bicyclic ring is optionally substituted with 1, 2 or 3 groups that are independently —R 205 , —R 245 , —R 250 or ═O;
and —C 2 -C 6 alkenyl optionally substituted with 1, 2, or 3 R 205 groups;
wherein each aryl or heteroaryl group attached directly or indirectly to the —(CR 245 R 250 ) 0-4 group is optionally substituted with 1, 2, 3 or 4 R 200 groups;
wherein each heterocycloalkyl attached directly or indirectly to the —(CR 245 R 250 ) 0-4 group is optionally substituted with 1, 2, 3, or 4 R 210 ;
R 200 at each occurrence is independently selected from —C 1 -C 6 alkyl optionally substituted with 1, 2, or 3 R 205 groups; —OH; —NO 2 ; -halogen; —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—(C 2 -C 8 alkenyl); —(CH 2 ) 0-4 —CO—(C 2 -C 8 alkynyl); —(CH 2 ) 0-4 —CO—(C 3 -C 7 cycloalkyl); —(CH 2 ) 0-4 —(CO) 0-1 -aryl; —(CH 2 ) 0-4 —(CO) 0-1 -heteroaryl; —(CH 2 ) 0-4 —(CO) 0-1 -heterocycloalkyl; —(CH 2 ) 0-4 —CO 2 R 215 ; —(CH 2 ) 0-4 —SO 2 —NR 220 R 225 ; —(CH 2 ) 0-4 —S(O) 0-2 —(C 1 -C 8 alkyl); —(CH 2 ) 0-4 —S(O) 0-2 —(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 )—SO 2 —R 220 ; —(CH 2 ) 0-4 —N(H or R 215 )—CO—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— (R 215 ); —(CH 2 ) 0-4 —S—(R 215 ); —(CH 2 ) 0-4 —O—(C 1 -C 6 alkyl optionally substituted with 1, 2, 3, or 5-F); —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; adamantly, and —(CH 2 ) 0-4 —C 3 -C 7 cycloalkyl;
each aryl and heteroaryl group included within R 200 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 heterocycloalkyl group included within R 200 is optionally substituted with 1, 2, or 3 groups that are independently R 210 ;
R 205 at each occurrence is independently selected from —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —C 1 -C 6 haloalkoxy, —(CH 2 ) 0-3 (C 3 -C 7 cycloalkyl), -halogen, —(CH 2 ) O 6 —OH, —O-phenyl, OH, SH, —(CH 2 ) 0-6 —C≡N, —(CH 2 ) 0-6 —C(═O)NR 235 R 240 , —CF 3 , —C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl, and —NR 235 R 240 ;
R 210 at each occurrence is independently selected from —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 1 -C 6 alkanoyl; —SO 2 —(C 1 -C 6 alkyl); —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;
R 215 at each occurrence is independently selected from —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, —(CH 2 ) 0-2 -(heteroaryl), and —(CH 2 ) 0-2 -(heterocycloalkyl); wherein the aryl group included within R 215 is optionally substituted with 1, 2, or 3 groups that are independently —R 205 or —R 210 ; wherein the heterocycloalkyl and heteroaryl groups included within R 215 are optionally substituted with 1, 2, or 3 R 210 ;
R 220 at each occurrence is independently H, —C 1 -C 6 alkyl, —CHO, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkoxycarbonyl, -amino C 1 -C 6 alkyl, —SO 2 —C 1 -C 6 alkyl, C 1 -C 6 alkanoyl optionally substituted with up to three halogens, —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), -halo C 1 -C 6 alkyl, —(CH 2 ) 0-2 —(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, -aryl, -heteroaryl, or -heterocycloalkyl; wherein the aryl, heteroaryl and heterocycloalkyl groups included within R 220 and R 225 is optionally substituted with 1, 2, or 3 R 270 groups,
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; -phenyl; -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;
R 235 and R 240 at each occurrence are independently —H, —C 1 -C 6 alkyl, C 2 -C 6 alkanoyl, —SO 2 —(C 1 -C 6 alkyl), or -phenyl;
R 245 and R 250 at each occurrence are independently selected from H, —(CH 2 ) 0-4 CO 2 C 1 -C 4 alkyl, —(CH 2 ) 0-4 C(═O)C 1 -C 4 alkyl, —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, —(CH 2 ) 0-4 aryl, —(CH 2 ) 0-4 heteroaryl, and —(CH 2 ) 0-4 heterocycloalkyl, or
R 245 and R 250 are taken together with the carbon to which they are attached to form a monocycle or bicycle of 3, 4, 5, 6, 7 or 8 carbon atoms, where 1, 2, or 3 carbon atoms are optionally replaced by 1, 2, or 3 groups that are independently —O—, —S—, —SO 2 —, —C(O)—, —NR 220 —, or —NR 220 R 220 — wherein both R 220 groups are alkyl; and wherein the ring is optionally substituted with 1, 2, 3, 4, 5, or 6 groups that are independently C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxyl, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —NH—C(O)C 1 -C 5 alkyl, —NH—SO 2 —(C 1 -C 6 alkyl), or halogen;
wherein the aryl, heteroaryl or heterocycloalkyl groups included within R 245 and R 250 are optionally substituted with 1, 2, or 3 groups that are independently halogen, C 1-6 alkyl, CN or OH.
21 . A compound which has the formula:
or a pharmaceutically acceptable salt thereof.
22 . A method of treating a patient who has, or in preventing a patient from getting, a disease or condition selected from the group consisting of Alzheimer's disease, for helping prevent or delay the onset of Alzheimer's disease, for treating patients with mild cognitive impairment (MCI) and preventing or delaying the onset of Alzheimer's disease in those who would progress from MCI to AD, for treating Down's syndrome, for treating humans who have Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, for treating cerebral amyloid angiopathy and preventing its potential consequences, i.e. single and recurrent lobar hemorrhages, for treating other degenerative dementias, including dementias of mixed vascular and degenerative origin, dementia associated with Parkinson's disease, dementia associated with progressive supranuclear palsy, dementia associated with cortical basal degeneration, diffuse Lewy body type of Alzheimer's disease and who is in need of such treatment which comprises administration of a therapeutically effective amount of a compound selected from the group consisting of a substituted aminoalcohol of the formula (I), or a pharmaceutically acceptable salt or ester thereof, wherein X, T, R 20 , R 1 , R 2 , R 3 , R N and R C are as defined in claim 1 .
23 . A method for making a compound of formula I
or a pharmaceutically acceptable salt or ester thereof, wherein X, T, R 20 , R 1 , R 2 , R 3 , R N and R C are as defined in claim 1 .Join the waitlist — get patent alerts
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