US2006287306A1PendingUtilityA1
Compounds to treat alzheimer's disease
Est. expiryMar 23, 2020(expired)· nominal 20-yr term from priority
C07D 261/20C07C 2603/74C07C 2601/14C07K 7/02C07C 271/18C07D 307/52C07D 295/185C07D 417/02C07C 271/22C07D 307/33C07D 307/14C07C 237/22C07K 5/0207C07D 413/02C07D 295/13C07C 271/14C07B 2200/07A61K 38/00C07D 403/02
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Claims
Abstract
The present invention is directed toward substituted hydroxyethylene compounds of formulas (XII) (XIII), and (XIV) useful in treating Alzheimer's disease and other similar diseases.
Claims
exact text as granted — not AI-modified1 . A compound of the formula (XII):
where R 1 is:
(I) C 1 -C 6 alkyl,
(II) C 1 -C 6 alkyl-5-alkyl
(III) C 1 -C 6 alkyl-(C 2 -C 6 alkenyl),
(IV) —(CH 2 ) 0-6 -alkyl —(R 1-aryl ) where R 1-aryl is phenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl, dihydronaphthyl, or tetralinyl and is unsubstituted or substituted with:
(A) C 1 -C 6 alkyl,
(B) —CF 3 ,
(C) —F, Cl, —Br or —I,
(D) C 1 -C 3 alkoxy,
(E) —O—CF 3 ,
(F) —NH 2 ,
(G) —OH, or
(H) —C≡N,
(V) —(CH 2 ) 0-6 -alkyl —(R 1-heteroaryl ) where R 1-heteroaryl is:
(A) pyridinyl,
(B) pyrimidinyl,
(C) quinolinyl,
(D) indenyl,
(E) indanyl,
(F) benzothiophenyl,
(G) indolyl,
(H) indolinyl,
(I) pyridazinyl,
(J) pyrazinyl,
(K) isoindolyl,
(L) isoquinolyl,
(M) quinazolinyl,
(N) quinoxalinyl,
(O) phthalazinyl,
(P) imidazolyl,
(Q) isoxazolyl,
(R) pyrazolyl,
(S) oxazolyl,
(T) thiazolyl,
(U) indolizinyl,
(V) indazolyl,
(W) benzothiazolyl,
(X) benzimidazolyl,
(Y) benzofuranyl,
(Z) furanyl,
(AA) thienyl,
(BB) pyrrolyl,
(CC) oxadiazolyl,
(DD) thiadiazolyl,
(EE) triazolyl,
(FF) tetrazolyl,
(GG) 1,4-benzodioxan
(HH) purinyl,
(II) oxazolopyridinyl,
(JJ) imidazopyridinyl,
(KK) isothiazolyl,
(LL) naphthyridinyl,
(MM) cinnolinyl,
(NN) carbazolyl,
(OO) β-carbolinyl,
(PP) isochromanyl,
(QQ) chromanyl,
(RR) furazanyl,
(SS) tetrahydroisoquinoline,
(TT) isoindolinyl,
(UU) isobenzotetrahydrofuranyl,
(VV) isobenzotetrahydrothienyl,
(WW) isobenzothiophenyl,
(XX) benzoxazolyl, or
(YY) pyridopyridinyl,
where the R 1-heteroaryl group is bonded to -alkyl- by any ring atom of the parent R 1-heteroaryl group substituted by hydrogen such that the new bond to the R 1-heteroaryl group replaces the hydrogen atom and its bond, where R 1-heteroaryl is unsubstituted or substituted with:
(1) C 1 -C 3 alkyl,
(2) —CF 3 ,
(3) —F, Cl, —Br, or I,
(4) C 1 -C 3 alkoxy,
(5) —O—CF 3 ,
(6) —NH 2 ,
(7) —OH, or
(8) —C≡N,
(VI) —(R 1-heteroaryl ) where R 1-heteroaryl is as defined above,
(VII) —C 1 -C 5 alkyl-(R 1-heterocycle ) where R 1-heterocycle is:
(A) morpholinyl,
(B) thiomorpholinyl,
(C) thiomorpholinyl S-oxide,
(D) thiomorpholinyl S,S-dioxide,
(E) piperazinyl,
(F) homopiperazinyl,
(G) pyrrolidinyl,
(H) pyrrolinyl,
(I) tetrahydropyranyl,
(J) piperidinyl,
(K) tetrahydrofuranyl, or
(L) tetrahydrothiophenyl,
where the R 1-heterocycle group is bonded by any atom of the parent R 1-heterocycle group substituted by hydrogen such that the new bond to the R 1-heterocycle group replaces the hydrogen atom and its bond, where R 1-heterocycle is unsubstituted or substituted with:
(1) ═O,
(2) C 1 -C 3 alkyl,
(3) —CF 3 ,
(4) —F, Cl, —Br or —I,
(5) C 1 -C 3 alkoxy,
(6) —O—CF 3 ,
(7) —NH 2 ,
(8) —OH, or
(9) —C≡N, or
(VIII) —R 1-heterocycle , where R 1-heterocycle is as defined above;
where R 2 is:
(I) —H,
(II) alkyl, or
(III) —C 1 -C 5 alkyl-R 2-1 where R 2-1 is cycloalkyl, R 1-aryl or R 1-heteroaryl where R 1-aryl and R 1-heteroaryl are as defined above;
where R N is:
(I) R N-1 —X N — where X N is:
(A) —CO—,
(B) —SO 2 —,
(C) —(CR′R″) 1-6 where R′ and R″ are the same or different and are —H or C 1 -C 4 alkyl,
(D) —CO—(CR′R″) 1-6 —X N-1 where X N-1 is —O—, —S— or —NR′R″— and where R′ and R″ are as defined above, or
(E) a single bond;
where R N-1 is:
(A) R N-aryl where R N-aryl is phenyl, biphenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl, dihydronaphthyl, or tetralinyl and is unsubstituted or substituted with:
(1) C 1 -C 6 alkyl,
(2) —F, —Cl, —Br, or —I,
(3) —OH,
(4) —NO 2 ,
(5) —CO—OH,
(6) —C≡N,
(7) —CO—NR N-2 R N-3 where R N-2 and R N-3 are the same or different and are:
(a) —H,
(b) —C 1 -C 6 alkyl unsubstituted or substituted with
(i) —OH, or
(ii) —NH 2 ,
(c) —C 1 -C 6 alkyl unsubstituted or substituted with —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 1 -C 6 alkenyl with one or two double bonds,
(h) —C 1 -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, or
(k) —R 1-heteroaryl where R 1-heteroaryl is as defined above,
(8) —CO—(C 3 -C 12 alkyl),
(9) —CO—(C 3 -C 6 cycloalkyl),
(10) —CO—R 1-heteroaryl where R 1-heteroaryl is as defined above,
(11) —CO—R 1-heterocycle where R 1-heterocycle is as defined above,
(12) —CO—R N-4 where R N-4 is morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl or pyrrolidinyl where each group is unsubstituted or substituted with C 1 -C 3 alkyl,
(13) —CO—O—R N-5 where R N-5 is:
(a) alkyl, or
(b) —(CH 2 ) 0-2 —(R 1-aryl ) where R 1-aryl is as defined above,
(14) —SO 2 —NR N-2 R N-3 where R N-2 and R N-3 are as defined above,
(15) —SO—(C 1 -C 8 alkyl),
(16) —SO 2 —(C 3 -C 12 alkyl),
(17) —NH—CO—O—R N-5 where R N-5 is as defined above,
(18) —NH—CO—N(C 1 -C 3 alkyl) 2 ,
(19) —N—CS—N(C 1 -C 3 alkyl) 2 ,
(20) —N(C 1 -C 3 alkyl)-CO—R N-5 where R N-5 is as defined above,
(21) —NR N-2 R N-3 where R N-2 and R N-3 can be the same or different and are as defined above,
(22) —R N-4 where R N-4 is as defined above,
(23) —O—CO—(C 1 -C 6 alkyl),
(24) —O—CO—N(C 1 -C 3 alkyl) 2 ,
(25) —O—CS—N(C 1 -C 3 alkyl) 2 ,
(26) —O—(C 1 -C 6 alkyl),
(27) —O—(C 2 -C 5 alkyl)-COOH,
(28) —S—(C 1 -C 6 alkyl),
(29) C 1 -C 6 alkyl unsubstituted or substituted with halo,
(30) —O—(C 1 -C 6 alkyl unsubstituted or substituted with halo), or
(31) —O-phenyl,
(32) (C 1 -C 6 alkyl) substituted with —CO—NH—C(═O)—,
(B) —R N-heteroaryl where R N-heteroaryl is:
(1) pyridinyl,
(2) pyrimidinyl,
(3) quinolinyl,
(4) indenyl,
(5) indanyl,
(6) benzothiophenyl,
(7) indolyl,
(8) indolinyl,
(9) pyridazinyl,
(10) pyrazinyl,
(11) isoindolyl,
(12) isoquinolyl,
(13) quinazolinyl,
(14) quinoxalinyl,
(15) phthalazinyl,
(16) imidazolyl,
(17) isoxazolyl,
(18) pyrazolyl,
(19) oxazolyl,
(20) thiazolyl,
(21) indolizinyl,
(22) indazolyl,
(23) benzothiazolyl,
(24) benzimidazolyl,
(25) benzofuranyl,
(26) furanyl,
(27) thienyl,
(28) pyrrolyl,
(29) oxadiazolyl,
(30) thiadiazolyl,
(31) triazolyl,
(32) tetrazolyl,
(33) 1,4-benzodioxan
(34) purinyl,
(35) oxazolopyridinyl,
(36) imidazopyridinyl,
(37) isothiazolyl,
(38) naphthyridinyl,
(39) cinnolinyl,
(40) carbazolyl,
(41) β-carbolinyl,
(42) isochromanyl,
(43) chromanyl,
(44) furazanyl,
(45) tetrahydroisoquinoline,
(46) isoindolinyl,
(47) isobenzotetrahydrofuranyl,
(48) isobenzotetrahydrothienyl,
(49) isobenzothiophenyl,
(50) benzoxazolyl, or
(51) pyridopyridinyl,
where the R N-heteroaryl group is bonded by any atom of the parent R N-heteroaryl group substituted by hydrogen such that the new bond to the R N-heteroaryl group replaces the hydrogen atom and its bond, where R N-heteroaryl is unsubstituted or substituted with:
(1) C 1 -C 6 alkyl,
(2) —F, —Cl, —Br, or —I,
(3) —OH,
(4) —NO 2 ,
(5) —CO—OH,
(6) —C≡N,
(7) —CO—NR N-2 R N-3 where R N-2 and R N-3 are as defined above,
(8) —CO—(C 3 -C 12 alkyl),
(9) —CO—(C 3 -C 6 cycloalkyl),
(10) —CO—R 1-heteroaryl where R 1-heteroaryl is as defined above,
(11) —CO—R 1-heterocycle where R 1-heterocycle is as defined above,
(12) —CO—R N-4 where R N-4 is as defined above,
(13) —CO—O—R N-5 where R N-5 is as defined above,
(14) —SO 2 —NR N-2 R N-3 where R N-2 and R N-3 are as defined above,
(15) —SO—(C 1 -C 8 alkyl),
(16) —SO 2 —(C 3 -C 12 alkyl),
(17) —NH—CO—O—R N-5 where R N-5 is as defined above,
(18) —NH—CO—N(C 1 -C 3 alkyl) 2 ,
(19) —N—CS—N(C 1 -C 3 alkyl) 2 ,
(20) —N(C 1 -C 3 alkyl)-CO—R N-5 where R N-5 is as defined above,
(21) —NR N-2 R N-3 where R N-2 and R N-3 can be the same or different and are as defined above,
(22) —R N-4 where R N-4 is as defined above,
(23) —O—CO—(C 1 -C 6 alkyl),
(24) —O—CO—N(C 1 -C 3 alkyl) 2 ,
(25) —O—CS—N(C 1 -C 3 alkyl) 2 ,
(26) —O—(C 1 -C 6 alkyl),
(27) —O—(C 2 -C 5 alkyl)-COOH, or
(28) —S—(C 1 -C 6 alkyl),
(29) (C 1 -C 6 alkyl) substituted with —CO—OH and —NH—C(═O)—,
(C) —R N-aryl —R N-aryl where —R N-aryl is as defined above,
(D) —R N-aryl —R N-heteroaryl where —R N-aryl and —R N-heteroaryl are as defined above,
(E) —R N-heteroaryl —R N-aryl where —R N-aryl and —R N-heteroaryl are as defined above,
(F) —R N-heteroaryl —R N-heteroaryl where R N-heteroaryl is as defined above,
(G) —R N-aryl —O—R N-aryl where —R N-aryl is as defined above,
(H) —R N-aryl —S—R N-aryl where —R N-aryl is as defined above,
(I) —R N-heteroaryl —O—R N-heteroaryl where R N-heteroaryl is as defined above,
(J) —R N-heteroaryl —S—R N-heteroaryl where R N-heteroaryl is as defined above,
(K) —R N-aryl —CO—R N-aryl where —R N-aryl is as defined above,
(L) —R N-aryl —CO—R N-heteroaryl where —R N-aryl and R N-heteroaryl are as defined above,
(M) —R N-aryl —SO 2 —R N-aryl where —R N-aryl is as defined above,
(N) —R N-heteroaryl —CO—R N-heteroaryl where R N-heteroaryl is as defined above,
(O) —R N-heteroaryl —SO 2 —R N-heteroaryl where R N-heteroaryl is as defined above,
(P) —R N-aryl —O—(C 1 -C 8 alkyl)-phenyl, where R N-aryl is as defined above,
(Q) —R N-aryl —S—(C 1 -C 8 alkyl)-phenyl, where R N-aryl is as defined above,
(R) —R N-heteroaryl —O—(C 1 -C 8 alkyl)-phenyl, where R N-heteroaryl is as defined above, or
(S) —R N-heteroaryl —S—(C 1 -C 8 alkyl)-phenyl, where R N-heteroaryl is as defined above, or
(II) —CO—(C 1 -C 6 alkyl) where alkyl is unsubstituted or substituted with:
(A) —OH,
(B) —C 1 -C 6 alkoxy,
(C) —C 1 -C 6 thioalkoxy,
(D) —CO—O—R N-8 where R N-8 is —H, C 1 -C 6 alkyl or -phenyl,
(E) —CO—NR N-2 R N-3 where R N-2 and R N-3 are the same or different and are as defined above,
(F) —CO—R N-4 where R N-4 is as defined above,
(G) —SO 2 —(C 1 -C 8 alkyl),
(H) —SO 2 —NR N-2 R N-3 where R N-2 and R N-3 are the same or different and are as defined above,
(I) —NH—CO—(C 1 -C 6 alkyl),
(J) —NH—CO—O—R N-8 where R N-8 is as defined above,
(K) —NR N-2 R N-3 where R N-2 and R N-3 are the same or different and are as defined above,
(L) —R N-4 where R N-4 is as defined above,
(M) —O—CO—(C 1 -C 6 alkyl),
(N) —O—CO—NR N-8 R N-8 where R N-8 are the same or different and are as defined above, or
(O) —O—(C 1 -C 5 alkyl)-COOH;
where B is —O—, —NH—, or —N(C 1 -C 6 alkyl)-; and
where R C is:
(I) C 1 -C 8 alkyl unsubstituted or substituted with —OH, —O-phenyl, halo, or (C 1 -C 6 alkoxy unsubstituted or substituted with halo), or
(II) —C(R C-1 )(R C-2 )—CO—NH—R C-3 where R C-1 and R C-2 are the same or different and are:
(A) —H,
(B) —C 1 -C 6 alkyl,
(C) —(C 1 -C 4 alkyl)-R C′-aryl where R C′-aryl is as defined for R N-aryl ,
(D) —(C 1 -C 4 alkyl)-R C-heteroaryl where R C-heteroaryl is as defined for R N-heteroaryl , and R N-heteroaryl is as defined above,
(E) —(C 1 -C 4 alkyl)-R C-heterocycle where R C-heterocycle is as defined for R N-heterocycle , and R N-heterocycle is as defined above,
(F) —R C-heteroaryl where R C-heteroaryl is as defined above,
(G) —R C-heterocycle where R C-heterocycle is as defined above,
(H) —(CH 2 ) 1-4 —OH,
(I) —(CH 2 ) 1-4 —R C-4 —(CH 2 ) 1-4 —R C′-aryl where R C-4 is —O—, —S—, —NH—, or —NR C-5 — where R C-5 is C 1 -C 6 alkyl, and where R C′-aryl is as defined above,
(J) —(CH 2 ) 1-4 —R C-4 —(CH 2 ) 1-4 —R C-heteroaryl where R C-4 and R C-heteroaryl are as defined above, or
(K) —R C′-aryl where R C′-aryl is as defined above,
and where R C-3 is:
(A) —H,
(B) —C 1 -C 6 alkyl, substituted or unsubstituted with:
(1) —H,
(2) —C 1 -C 6 alkyl,
(3) —(C 1 -C 4 alkyl)-R C′-aryl where R C′-aryl is as defined for R N-aryl ,
(4) —(C 1 -C 4 alkyl)-R C-heteroaryl where R C-heteroaryl is as defined for R N-heteroaryl , and R N-heteroaryl is as defined above,
(5) —(C 1 -C 4 alkyl)-R C-heterocycle where R C-heterocycle is as defined for R N-heterocycle , and R N-heterocycle is as defined above,
(6) —R C-heteroaryl where R C-heteroaryl is as defined above,
(7) —R C-heterocycle where R C-heterocycle is as defined above,
(8) —(CH 2 ) 1-4 —OH,
(9) —(CH 2 ) 1-4 —R C-4 —(CH 2 ) 1-4 —R C′-aryl where R C-4 is —O—, —S—, —NH—, or
—NR C-5 — where R C-5 is C 1 -C 6 alkyl, and where R C′-aryl is as defined above,
(10) —(CH 2 ) 1-4 —R C-4 —(CH 2 ) 1-4 —R C-heteroaryl where R C-4 and R C-heteroaryl are as defined above, or
(11) —R C′-aryl where R C′-aryl is as defined above,
(12) —CO—OH and —NH—C(═O)—,
(C) —R C′-aryl where R C′-aryl is as defined above,
(D) —R C-heteroaryl where R C-heteroaryl is as defined above,
(E) —R C-heterocycle where R C-heterocycle is as defined above,
(F) —(C 1 -C 4 alkyl)-R C′-aryl where R C′-aryl is as defined above,
(G) —(C 1 -C 4 alkyl)-R C-heteroaryl where R C-heteroaryl is as defined above,
(H) —(C 1 -C 4 alkyl)-R C-heterocycle where R C-heterocycle is as defined above, or
(J) —C(R C-5 )(R C-6 )—CO—NH—C(R C-7 )(R C-8 )—COOH, where R C-5 , R C-6 , R C-7 , and R C-8 are the same or different, and are as defined for R C-1 and R C-2 and where R C-1 and R C-2 are as defined above; or pharmaceutically acceptable salts thereof.
2 . A compound according to claim 1 , wherein R 1 is C 1 -C 6 alkyl.
3 - 4 . (canceled)
5 . A compound according to claim 1 , wherein R 2 is -alkyl.
6 - 7 . (canceled)
8 . A compound according to claim 1 , wherein R N is:
(I) R N-1 —X N — where X N is:
(A) —CO—,
(B) —SO 2 —,
(C) —(CR′R″) 1-6 where R′ and R″ are the same or different and are —H or C 1 -C 4 alkyl,
(D) —CO—(CR′R″) 1-6 —X N-1 where X N-1 is —O—, —S— or —NR′R″— and where R′ and R″ are as defined above, or
(E) a single bond;
where R N-1 is:
(A) R N-aryl where R N-aryl is phenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl, dihydronaphthyl, or tetralinyl and is unsubstituted or substituted with:
(1) C 1 -C 6 alkyl,
(2) —F, —Cl, —Br, or —I,
(3) —OH,
(4) —NO 2 ,
(5) —CO—OH,
(6) —C≡N,
(7) —CO—NR N-2 R N-3 where R N-2 and R N-3 are the same or different and are:
(a) —H,
(b) —C 1 -C 6 alkyl unsubstituted or substituted with
(i) —OH, or
(ii) —NH 2 ,
(c) —C 1 -C 6 alkyl unsubstituted or substituted with —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 1 -C 6 alkenyl with one or two double bonds,
(h) —C 1 -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, or
(k) —R 1-heteroaryl where R 1-heteroaryl is as defined above,
(8) —CO—(C 3 -C 12 alkyl),
(9) —CO—(C 3 -C 6 cycloalkyl),
(10) —CO—R 1-heteroaryl where R 1-heteroaryl is as defined above,
(11) —CO—R 1-heterocycle where R 1-heterocycle is as defined above,
(12) —CO—R N-4 where R N-4 is morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl or pyrrolidinyl where each group is unsubstituted or substituted with C 1 -C 3 alkyl,
(13) —CO—O—R N-5 where R N-5 is:
(a) alkyl, or
(b) —(CH 2 ) 0-2 —(R 1-aryl ) where R 1-aryl is as defined above,
(14) —SO 2 —NR N-2 R N-3 where R N-2 and R N-3 are as defined above,
(15) —SO—(C 1 -C 8 alkyl),
(16) —SO 2 —(C 3 -C 12 alkyl),
(17) —NH—CO—O—R N-5 where R N-5 is as defined above,
(18) —NH—CO—N(C 1 -C 3 alkyl) 2 ,
(19) —N—CS—N(C 1 -C 3 alkyl) 2 ,
(20) —N(C 1 -C 3 alkyl)-CO—R N-5 where R N-5 is as defined above,
(21) —NR N-2 R N-3 where R N-2 and R N-3 can be the same or different and are as defined above,
(22) —R N-4 where R N-4 is as defined above,
(23) —O—CO—(C 1 -C 6 alkyl),
(24) —O—CO—N(C 1 -C 3 alkyl) 2 ,
(25) —O—CS—N(C 1 -C 3 alkyl) 2 ,
(26) —O—(C 1 -C 6 alkyl),
(27) —O—(C 2 -C 5 alkyl)-COOH,
(28) —S—(C 1 -C 6 alkyl),
(29) C 1 -C 6 alkyl unsubstituted or substituted with halo,
(30) —O—(C 1 -C 6 alkyl unsubstituted or substituted with halo), or
(31) —O-phenyl,
(32) (C 1 -C 6 alkyl) substituted with —CO—NH—C(═O)—,
(B) —R N-heteroaryl where R N-heteroaryl is:
(1) pyridinyl,
(2) pyrimidinyl,
(3) quinolinyl,
(4) indenyl,
(5) indanyl,
(6) benzothiophenyl,
(7) indolyl,
(8) indolinyl,
(9) pyridazinyl,
(10) pyrazinyl,
(11) isoindolyl,
(12) isoquinolyl,
(13) quinazolinyl,
(14) quinoxalinyl,
(15) phthalazinyl,
(16) imidazolyl,
(17) isoxazolyl,
(18) pyrazolyl,
(19) oxazolyl,
(20) thiazolyl,
(21) indolizinyl,
(22) indazolyl,
(23) benzothiazolyl,
(24) benzimidazolyl,
(25) benzofuranyl,
(26) furanyl,
(27) thienyl,
(28) pyrrolyl,
(29) oxadiazolyl,
(30) thiadiazolyl,
(31) triazolyl,
(32) tetrazolyl,
(33) 1,4-benzodioxan
(34) purinyl,
(35) oxazolopyridinyl,
(36) imidazopyridinyl,
(37) isothiazolyl,
(38) naphthyridinyl,
(39) cinnolinyl,
(40) carbazolyl,
(41) β-carbolinyl,
(42) isochromanyl,
(43) chromanyl,
(44) furazanyl,
(45) tetrahydroisoquinoline,
(46) isoindolinyl,
(47) isobenzotetrahydrofuranyl,
(48) isobenzotetrahydrothienyl,
(49) isobenzothiophenyl,
(50) benzoxazolyl, or
(51) pyridopyridinyl,
where the R N-heteroaryl group is bonded by any atom of the parent R N-heteroaryl group substituted by hydrogen such that the new bond to the R N-heteroaryl group replaces the hydrogen atom and its bond, where R N-heteroaryl is unsubstituted or substituted with:
(1) C 1 -C 6 alkyl,
(2) —F, —Cl, —Br, or —I,
(3) —OH,
(4) —NO 2 ,
(5) —CO—OH,
(6) —C≡N,
(7) —CO—NR N-2 R N-3 where R N-2 and R N-3 are as defined above,
(8) —CO—(C 3 -C 12 alkyl),
(9) —CO—(C 3 -C 6 cycloalkyl),
(10) —CO—R 1-heteroaryl where R 1-heteroaryl is as defined above,
(11) —CO—R 1-heterocycle where R 1-heterocycle is as defined above,
(12) —CO—R N-4 where R N-4 is as defined above,
(13) —CO—O—R N-5 where R N-5 is as defined above,
(14) —SO 2 —NR N-2 R N-3 where R N-2 and R N-3 are as defined above,
(15) —SO—(C 1 -C 8 alkyl),
(16) —SO 2 —(C 3 -C 12 alkyl),
(17) —NH—CO—O—R N-5 where R N-5 is as defined above,
(18) —NH—CO—N(C 1 -C 3 alkyl) 2 ,
(19) —N—CS—N(C 1 -C 3 alkyl) 2 ,
(20) —N(C 1 -C 3 alkyl)-CO—R N-5 where R N-5 is as defined above,
(21) —NR N-2 R N-3 where R N-2 and R N-3 can be the same or different and are as defined above,
(22) —R N-4 where R N-4 is as defined above,
(23) —O—CO—(C 1 -C 6 alkyl),
(24) —O—CO—N(C 1 -C 3 alkyl) 2 ,
(25) —O—CS—N(C 1 -C 3 alkyl) 2 ,
(26) —O—(C 1 -C 6 alkyl),
(27) —O—(C 2 -C 5 alkyl)-COOH, or
(28) —S—(C 1 -C 6 alkyl),
(29) (C 1 -C 6 alkyl) substituted with —CO—OH and —NH—C(═O)—,
(C) —R N-aryl —R N-aryl where —R N-aryl is as defined above,
(D) —R N-aryl —R N-heteroaryl where —R N-aryl and —R N-heteroaryl are as defined above,
(E) —R N-heteroaryl —R N-aryl where —R N-aryl and —R N-heteroaryl are as defined above,
(F) —R N-heteroaryl —R N-heteroaryl where R N-heteroaryl is as defined above,
(G) —R N-aryl —O—R N-aryl where —R N-aryl is as defined above,
(H) —R N-aryl —S—R N-aryl where —R N-aryl is as defined above,
(I) —R N-heteroaryl —O—R N-heteroaryl where R N-heteroaryl is as defined above,
(J) —R N-heteroaryl —S—R N-heteroaryl where R N-heteroaryl is as defined above,
(K) —R N-aryl —CO—R N-aryl where —R N-aryl is as defined above,
(L) —R N-aryl —CO—R N-heteroaryl where —R N-aryl and R N-heteroaryl are as defined above,
(M) —R N-aryl —SO 2 —R N-aryl where —R N-aryl is as defined above,
(N) —R N-heteroaryl —CO—R N-heteroaryl where R N-heteroaryl is as defined above,
(O) —R N-heteroaryl —SO 2 —R N-heteroaryl where R N-heteroaryl is as defined above,
(P) —R N-aryl —O—(C 1 -C 8 alkyl)-phenyl, where R N-aryl is as defined above,
(Q) —R N-aryl —S—(C 1 -C 8 alkyl)-phenyl, where R N-aryl is as defined above,
(R) —R N-heteroaryl —O—(C 1 -C 8 alkyl)-phenyl, where R N-heteroaryl is as defined above, or
(S) —R N-heteroaryl —S—(C 1 -C 8 alkyl)-phenyl, where R N-heteroaryl is as defined above.
9 . A compound according to claim 8 , wherein X N is —CO—.
10 . A compound according to claim 9 , wherein R N-1 is substituted or unsubstituted R N-aryl .
11 . A compound according to claim 10 , wherein R N-aryl is substituted or unsubstituted phenyl.
12 . (canceled)
13 . A compound according to claim 1 , wherein R N is
14 - 15 . (canceled)
16 . A compound according to claim 1 , wherein R N is:
17 - 47 . (canceled)
48 . A compound according to claim 1 of the formula (XIII)
wherein R 1 is:
(I) C 1 -C 6 alkyl,
(II) C 1 -C 6 alkyl-5-alkyl
(III) C 1 -C 6 alkyl-(C 2 -C 6 alkenyl),
(IV) —(CH 2 ) 0-6 -alkyl —(R 1-aryl ) where R 1-aryl is phenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl, dihydronaphthyl, or tetralinyl and is unsubstituted or substituted with:
(A) C 1 -C 6 alkyl,
(B) —CF 3 ,
(C) —F, Cl, —Br or —I,
(D) C 1 -C 3 alkoxy,
(E) —O—CF 3 ,
(F) —NH 2 ,
(G) —OH, or
(H) —C≡N,
(V) —(CH 2 ) 0-6 -alkyl —(R 1-heteroaryl ) where R 1-heteroaryl is:
(A) pyridinyl,
(B) pyrimidinyl,
(C) quinolinyl,
(D) indenyl,
(E) indanyl,
(F) benzothiophenyl,
(G) indolyl,
(H) indolinyl,
(I) pyridazinyl,
(J) pyrazinyl,
(K) isoindolyl,
(L) isoquinolyl,
(M) quinazolinyl,
(N) quinoxalinyl,
(O) phthalazinyl,
(P) imidazolyl,
(Q) isoxazolyl,
(R) pyrazolyl,
(S) oxazolyl,
(T) thiazolyl,
(U) indolizinyl,
(V) indazolyl,
(W) benzothiazolyl,
(X) benzimidazolyl,
(Y) benzofuranyl,
(Z) furanyl,
(AA) thienyl,
(BB) pyrrolyl,
(CC) oxadiazolyl,
(DD) thiadiazolyl,
(EE) triazolyl,
(FF) tetrazolyl,
(GG) 1,4-benzodioxan
(HH) purinyl,
(II) oxazolopyridinyl,
(JJ) imidazopyridinyl,
(KK) isothiazolyl,
(LL) naphthyridinyl,
(MM) cinnolinyl,
(NN) carbazolyl,
(OO) β-carbolinyl,
(PP) isochromanyl,
(QQ) chromanyl,
(RR) furazanyl,
(SS) tetrahydroisoquinoline,
(TT) isoindolinyl,
(UU) isobenzotetrahydrofuranyl,
(VV) isobenzotetrahydrothienyl,
(WW) isobenzothiophenyl,
(XX) benzoxazolyl, or
(YY) pyridopyridinyl,
where the R 1-heteroaryl group is bonded to -alkyl- by any ring atom of the parent R 1-heteroaryl group substituted by hydrogen such that the new bond to the R 1-heteroaryl group replaces the hydrogen atom and its bond, where R 1-heteroaryl is unsubstituted or substituted with:
(1) C 1 -C 3 alkyl,
(2) —CF 3 ,
(3) —F, Cl, —Br, or I,
(4) C 1 -C 3 alkoxy,
(5) —O—CF 3 ,
(6) —NH 2 ,
(7) —OH, or
(8) —C≡N,
(VI) —(R 1-heteroaryl ) where R 1-heteroaryl is as defined above,
(VII) —C 1 -C 5 alkyl-(R 1-heterocycle ) where R 1-heterocycle is:
(A) morpholinyl,
(B) thiomorpholinyl,
(C) thiomorpholinyl S-oxide,
(D) thiomorpholinyl S,S-dioxide,
(E) piperazinyl,
(F) homopiperazinyl,
(G) pyrrolidinyl,
(H) pyrrolinyl,
(I) tetrahydropyranyl,
(J) piperidinyl,
(K) tetrahydrofuranyl, or
(L) tetrahydrothiophenyl,
where the R 1-heterocycle group is bonded by any atom of the parent R 1-heterocycle group substituted by hydrogen such that the new bond to the R 1-heterocycle group replaces the hydrogen atom and its bond, where R 1-heterocycle is unsubstituted or substituted with:
(1) ═O,
(2) C 1 -C 3 alkyl,
(3) —CF 3 ,
(4) —F, Cl, —Br or —I,
(5) C 1 -C 3 alkoxy,
(6) —O—CF 3 ,
(7) —NH 2 ,
(8) —OH, or
(9) —C≡N, or
(VIII) —R 1-heterocycle , where R 1-heterocycle is as defined above;
where R 2 is:
(I) —H,
(II) C 1 -C 6 alkyl, or
(III) —(CH 2 ) 0-4 —R 2-1 where R 2-1 is (C 3 -C 6 )cycloalkyl, R 1-aryl or R 1-heteroaryl where R 1-aryl and R 1-heteroaryl are as defined above;
where R 3 , R 4 , R 5 , R 6 , and R 7 , are each independently —H, —CH 3 , —CH(CH 3 ) 2 , —CH 2 CH(CH 3 ) 2 , —CH(CH)CH 2 CH 3 , —CH 2 CH 2 .CH 2 , wherein the .CH 2 is bonded to the adjancent NH to form a five membered heterocycle, —CH 2 -phenyl, —CH 2 (phenol), —CH 2 -(3-indole), —CH 2 SH, —CH 2 CH 2 SCH 3 , —CH 2 OH, —CH(OH)CH 3 , —CH 2 CH 2 CH 2 CH 2 NH 3 + , —CH 2 CH 2 CH 2 (NH)C(═NH 2 + )NH 2 , —CH 2 -(5-(3H-imidazol-1-ium)), —CH 2 COO − , —CH 2 CH 2 COO − , CH 2 CONH 2 , or —CH 2 CH 2 CONH 2 ;
where x is 1 or 0;
where y is 1 or 0; and
where Prot is t-butoxycarbonyl, benzyloxycarbonyl, formyl, trityl, acetyl, trichloroacetyl, dichloroacetyl, chloroacetyl, trifluoroacetyl, difluoroacetyl, fluoroacetyl, 4-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl, 4-ethoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-cyanobenzyloxycarbonyl, 2-(4-xenyl)isopropoxycarbonyl, 1,1-diphenyleth-1-yloxycarbonyl, 1,1-diphenylprop-1-yloxycarbonyl, 2-phenylprop-2-yloxycarbonyl, 2-(p-toluyl)prop-2-yloxycarbonyl, cyclopentanyloxycarbonyl, 1-methylcyclopentanyloxycarbonyl, cyclohexanyloxycarbonyl, 1-methylcyclohexanyloxycabonyl, 2-methylcyclohexanyloxycarbonyl, 2-(4-toluylsulfonyl)ethoxycarbonyl, 2-(methylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphino)ethoxycarbonyl, fluorenylmethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl, 1-(trimethylsilylmethyl)prop-1-enyloxycarbonyl, 5-benzisoxalylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl, cyclopropylmethoxycarbonyl, 4-(decyloxyl)benzyloxycarbonyl, isobornyloxycarbonyl and 1-piperidyloxycarbonyl, 9-fluorenylmethyl carbonate, —CH—CH═CH 2 , or phenyl-C(═N—)—H, or pharmaceutically acceptable salts thereof.
49 - 59 . (canceled)
60 . A compound according to claim 1 of formula (XIV)
wherein R N is:
(I) R N-1 —X N — where X N is:
(A) —CO—,
(C) —(CR′R″) 1-6 where R′ and R″ are the same or different and are —H or C 1 -C 4 alkyl,
(D) —CO—(CR′R″) 1-6 —X N-1 where X N-1 is —O—, —S— or —NR′R″— and where R′ and R″ are as defined above,
where R N-1 is:
(A) R N-aryl where R N-aryl is phenyl, biphenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl, dihydronaphthyl, or tetralinyl and is unsubstituted or substituted with:
(1) C 1 -C 6 alkyl,
(2) —F, —Cl, —Br, or —I,
(3) —OH,
(4) —NO 2 ,
(5) —CO—OH,
(6) —C≡N,
(7) —CO—NR N-2 R N-3 where R N-2 and R N-3 are the same or different and are:
(a) —H,
(b) —C 1 -C 6 alkyl unsubstituted or substituted with
(i) —OH, or
(ii) —NH 2 ,
(c) —C 1 -C 6 alkyl unsubstituted or substituted with —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 1 -C 6 alkenyl with one or two double bonds,
(h) —C 1 -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, or
(k) —R 1-heteroaryl where R 1-heteroaryl is as defined above,
(8) —CO—(C 3 -C 12 alkyl),
(9) —CO—(C 3 -C 6 cycloalkyl),
(10) —CO—R 1-heteroaryl where R 1-heteroaryl is as defined above,
(11) —CO—R 1-heterocycle where R 1-heterocycle is as defined above,
(12) —CO—R N-4 where R N-4 is morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl or pyrrolidinyl where each group is unsubstituted or substituted with C 1 -C 3 alkyl,
(13) —CO—O—R N-5 where R N-5 is:
(a) alkyl, or
(b) —(CH 2 ) 0-2 —(R 1-aryl ) where R 1-aryl is as defined above,
(14) —SO 2 —NR N-2 R N-3 where R N-2 and R N-3 are as defined above,
(15) —SO—(C 1 -C 8 alkyl),
(16) —SO 2 —(C 3 -C 12 alkyl),
(17) —NH—CO—O—R N-5 where R N-5 is as defined above,
(18) —NH—CO—N(C 1 -C 3 alkyl) 2 ,
(19) —N—CS—N(C 1 -C 3 alkyl) 2 ,
(20) —N(C 1 -C 3 alkyl)-CO—R N-5 where R N-5 is as defined above,
(21) —NR N-2 R N-3 where R N-2 and R N-3 can be the same or different and are as defined above,
(22) —R N-4 where R N-4 is as defined above,
(23) —O—CO—(C 1 -C 6 alkyl),
(24) —O—CO—N(C 1 -C 3 alkyl) 2 ,
(25) —O—CS—N(C 1 -C 3 alkyl) 2 ,
(26) —O—(C 1 -C 6 alkyl),
(27) —O—(C 2 -C 5 alkyl)-COOH,
(28) —S—(C 1 -C 6 alkyl),
(29) C 1 -C 6 alkyl unsubstituted or substituted with halo,
(30) —O—(C 1 -C 6 alkyl unsubstituted or substituted with halo), or
(31) —O-phenyl,
(32) (C 1 -C 6 alkyl) substituted with —CO—NH—C(═O)—,
(B) —R N-heteroaryl where R N-heteroaryl is:
(1) pyridinyl,
(2) pyrimidinyl,
(3) quinolinyl,
(4) indenyl,
(5) indanyl,
(6) benzothiophenyl,
(7) indolyl,
(8) indolinyl,
(9) pyridazinyl,
(10) pyrazinyl,
(11) isoindolyl,
(12) isoquinolyl,
(13) quinazolinyl,
(14) quinoxalinyl,
(15) phthalazinyl,
(16) imidazolyl,
(17) isoxazolyl,
(18) pyrazolyl,
(19) oxazolyl,
(20) thiazolyl,
(21) indolizinyl,
(22) indazolyl,
(23) benzothiazolyl,
(24) benzimidazolyl,
(25) benzofuranyl,
(26) furanyl,
(27) thienyl,
(28) pyrrolyl,
(29) oxadiazolyl,
(30) thiadiazolyl,
(31) triazolyl,
(32) tetrazolyl,
(33) 1,4-benzodioxan
(34) purinyl,
(35) oxazolopyridinyl,
(36) imidazopyridinyl,
(37) isothiazolyl,
(38) naphthyridinyl,
(39) cinnolinyl,
(40) carbazolyl,
(41) β-carbolinyl,
(42) isochromanyl,
(43) chromanyl,
(44) furazanyl,
(45) tetrahydroisoquinoline,
(46) isoindolinyl,
(47) isobenzotetrahydrofuranyl,
(48) isobenzotetrahydrothienyl,
(49) isobenzothiophenyl,
(50) benzoxazolyl, or
(51) pyridopyridinyl,
where the R N-heteroaryl group is bonded by any atom of the parent R N-heteroaryl group substituted by hydrogen such that the new bond to the R N-heteroaryl group replaces the hydrogen atom and its bond, where R N-heteroaryl is unsubstituted or substituted with:
(1) C 1 -C 6 alkyl,
(2) —F, —Cl, —Br, or —I,
(3) —OH,
(4) —NO 2 ,
(5) —CO—OH,
(6) —C≡N,
(7) —CO—NR N-2 R N-3 where R N-2 and R N-3 are as defined above,
(8) —CO—(C 3 -C 12 alkyl),
(9) —CO—(C 3 -C 6 cycloalkyl),
(10) —CO—R 1-heteroaryl where R 1-heteroaryl is as defined above,
(11) —CO—R 1-heterocycle where R 1-heterocycle is as defined above,
(12) —CO—R N-4 where R N-4 is as defined above,
(13) —CO—O—R N-5 where R N-5 is as defined above,
(14) —SO 2 —NR N-2 R N-3 where R N-2 and R N-3 are as defined above,
(15) —SO—(C 1 -C 8 alkyl),
(16) —SO 2 —(C 3 -C 12 alkyl),
(17) —NH—CO—O—R N-5 where R N-5 is as defined above,
(18) —NH—CO—N(C 1 -C 3 alkyl) 2 ,
(19) —N—CS—N(C 1 -C 3 alkyl) 2 ,
(20) —N(C 1 -C 3 alkyl)-CO—R N-5 where R N-5 is as defined above,
(21) —NR N-2 R N-3 where R N-2 and R N-3 can be the same or different and are as defined above,
(22) —R N-4 where R N-4 is as defined above,
(23) —O—CO—(C 1 -C 6 alkyl),
(24) —O—CO—N(C 1 -C 3 alkyl) 2 ,
(25) —O—CS—N(C 1 -C 3 alkyl) 2 ,
(26) —O—(C 1 -C 6 alkyl),
(27) —O—(C 2 -C 5 alkyl)-COOH, or
(28) —S—(C 1 -C 6 alkyl),
(29) (C 1 -C 6 alkyl) substituted with —CO—OH and —NH—C(═O)—,
(C) —R N-aryl —R N-aryl where —R N-aryl is as defined above,
(D) —R N-aryl —R N-heteroaryl where —R N-aryl and —R N-heteroaryl are as defined above,
(E) —R N-heteroaryl —R N-aryl where —R N-aryl and —R N-heteroaryl are as defined above,
(F) —R N-heteroaryl —R N-heteroaryl where R N-heteroaryl is as defined above,
(II) —CO—(C 1 -C 6 alkyl) where alkyl is unsubstituted or substituted with:
(A) —OH,
(B) —C 1 -C 6 alkoxy,
(C) —C 1 -C 6 thioalkoxy,
(D) —CO—O—R N-8 where R N-8 is —H, C 1 -C 6 alkyl or -phenyl,
(E) —CO—NR N-2 R N-3 where R N-2 and R N-3 are the same or different and are as defined above,
(F) —CO—R N-4 where R N-4 is as defined above,
(G) —SO 2 —(C 1 -C 8 alkyl),
(H) —SO 2 —NR N-2 R N-3 where R N-2 and R N-3 are the same or different and are as defined above,
(I) —NH—CO—(C 1 -C 6 alkyl),
(J) —NH—CO—O—R N-8 where R N-8 is as defined above,
(K) —NR N-2 R N-3 where R N-2 and R N-3 are the same or different and are as defined above,
(L) —R N-4 where R N-4 is as defined above,
(M) —O—CO—(C 1 -C 6 alkyl),
(N) —O—CO—NR N-8 R N-8 where R N-8 are the same or different and are as defined above, or
(O) —O—(C 1 -C 5 alkyl)-COOH;
wherein R 1 is:
(I) C 1 -C 6 alkyl,
(II) C 1 -C 6 alkyl-5-alkyl
(III) C 1 -C 6 alkyl-(C 2 -C 6 alkenyl),
(IV) —(CH 2 ) 0-6 -alkyl —(R 1-aryl ) where R 1-aryl is phenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl, dihydronaphthyl, or tetralinyl and is unsubstituted or substituted with:
(A) C 1 -C 6 alkyl,
(B) —CF 3 ,
(C) —F, Cl, —Br or —I,
(D) C 1 -C 3 alkoxy,
(E) —O—CF 3 ,
(F) —NH 2 ,
(G) —OH, or
(H) —C≡N,
(V) —(CH 2 ) 0-6 -alkyl —(R 1-heteroaryl ) where R 1-heteroaryl is:
(A) pyridinyl,
(B) pyrimidinyl,
(C) quinolinyl,
(D) indenyl,
(E) indanyl,
(F) benzothiophenyl,
(G) indolyl,
(H) indolinyl,
(I) pyridazinyl,
(J) pyrazinyl,
(K) isoindolyl,
(L) isoquinolyl,
(M) quinazolinyl,
(N) quinoxalinyl,
(O) phthalazinyl,
(P) imidazolyl,
(Q) isoxazolyl,
(R) pyrazolyl,
(S) oxazolyl,
(T) thiazolyl,
(U) indolizinyl,
(V) indazolyl,
(W) benzothiazolyl,
(X) benzimidazolyl,
(Y) benzofuranyl,
(Z) furanyl,
(AA) thienyl,
(BB) pyrrolyl,
(CC) oxadiazolyl,
(DD) thiadiazolyl,
(EE) triazolyl,
(FF) tetrazolyl,
(GG) 1,4-benzodioxan
(HH) purinyl,
(II) oxazolopyridinyl,
(JJ) imidazopyridinyl,
(KK) isothiazolyl,
(LL) naphthyridinyl,
(MM) cinnolinyl,
(NN) carbazolyl,
(OO) β-carbolinyl,
(PP) isochromanyl,
(QQ) chromanyl,
(RR) furazanyl,
(SS) tetrahydroisoquinoline,
(TT) isoindolinyl,
(UU) isobenzotetrahydrofuranyl,
(VV) isobenzotetrahydrothienyl,
(WW) isobenzothiophenyl,
(XX) benzoxazolyl, or
(YY) pyridopyridinyl,
where the R 1-heteroaryl group is bonded to -alkyl- by any ring atom of the parent R 1-heteroaryl group substituted by hydrogen such that the new bond to the R 1-heteroaryl group replaces the hydrogen atom and its bond, where R 1-heteroaryl is unsubstituted or substituted with:
(1) C 1 -C 3 alkyl,
(2) —CF 3 ,
(3) —F, Cl, —Br, or I,
(4) C 1 -C 3 alkoxy,
(5) —O—CF 3 ,
(6) —NH 2 ,
(7) —OH, or
(8) —C≡N,
(VI) —(R 1-heteroaryl ) where R 1-heteroaryl is as defined above,
(VII) —C 5 -C 5 alkyl-(R 1-heterocycle ) where R 1-heterocycle is:
(A) morpholinyl,
(B) thiomorpholinyl,
(C) thiomorpholinyl S-oxide,
(D) thiomorpholinyl S,S-dioxide,
(E) piperazinyl,
(F) homopiperazinyl,
(G) pyrrolidinyl,
(H) pyrrolinyl,
(I) tetrahydropyranyl,
(J) piperidinyl,
(K) tetrahydrofuranyl, or
(L) tetrahydrothiophenyl,
where the R 1-heterocycle group is bonded by any atom of the parent R 1-heterocycle group substituted by hydrogen such that the new bond to the R 1-heterocycle group replaces the hydrogen atom and its bond, where R 1-heterocycle is unsubstituted or substituted with:
(1) ═O,
(2) C 1 -C 3 alkyl,
(3) —CF 3 ,
(4) —F, Cl, —Br or —I,
(5) C 1 -C 3 alkoxy,
(6) —O—CF 3 ,
(7) —NH 2 ,
(8) —OH, or
(9) —C≡N, or
(VIII) —R 1-heterocycle , where R 1-heterocycle is as defined above;
where R 2 is:
(I) —H,
(II) C 1 -C 6 alkyl, or
(III) —(CH 2 ) 0-4 —R 2-1 where R 2-1 is (C 3 -C 6 )cycloalkyl, R 1-aryl or R 1-heteroaryl where R 1-aryl and R 1-heteroaryl are as defined above;
where R 3 , R 4 , and R 5 , are each independently —H, —CH 3 , —CH(CH 3 ) 2 , —CH 2 CH(CH 3 ) 2 , —CH(CH)CH 2 CH 3 , —CH 2 CH 2 .CH 2 , wherein the .CH 2 is bonded to the adjancent NH to form a five membered heterocycle, —CH 2 -phenyl, —CH 2 (phenol), —CH 2 -(3-indole), —CH 2 SH, —CH 2 CH 2 SCH 3 , —CH 2 OH, —CH(OH)CH 3 , —CH 2 CH 2 CH 2 CH 2 NH 3 + , —CH 2 CH 2 CH 2 (NH)C(═NH 2 + )NH 2 , —CH 2 -(5-(3H-imidazol-1-ium)), —CH 2 COO − , —CH 2 CH 2 COO − , CH 2 CONH 2 , or —CH 2 CH 2 CONH 2 ;
where x is 1 or 0; and
where y is 1 or 0, or pharmaceutically acceptable salts thereof.
61 - 84 . (canceled)
85 . 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 disubstituted amine of formula (XII)
where R 1 is:
(I) C 1 -C 6 alkyl,
(II) C 1 -C 6 alkyl-5-alkyl
(III) C 1 -C 6 alkyl-(C 2 -C 6 alkenyl),
(IV) —(CH 2 ) 0-6 -alkyl —(R 1-aryl ) where R 1-aryl is phenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl, dihydronaphthyl, or tetralinyl and is unsubstituted or substituted with:
(A) C 1 -C 6 alkyl,
(B) —CF 3 ,
(C) —F, Cl, —Br or —I,
(D) C 1 -C 3 alkoxy,
(E) —O—CF 3 ,
(F) —NH 2 ,
(G) —OH, or
(H) —C≡N,
(V) —(CH 2 ) 0-6 -alkyl —(R 1-heteroaryl ) where R 1-heteroaryl is:
(A) pyridinyl,
(B) pyrimidinyl,
(C) quinolinyl,
(D) indenyl,
(E) indanyl,
(F) benzothiophenyl,
(G) indolyl,
(H) indolinyl,
(I) pyridazinyl,
(J) pyrazinyl,
(K) isoindolyl,
(L) isoquinolyl,
(M) quinazolinyl,
(N) quinoxalinyl,
(O) phthalazinyl,
(P) imidazolyl,
(Q) isoxazolyl,
(R) pyrazolyl,
(S) oxazolyl,
(T) thiazolyl,
(U) indolizinyl,
(V) indazolyl,
(W) benzothiazolyl,
(X) benzimidazolyl,
(Y) benzofuranyl,
(Z) furanyl,
(AA) thienyl,
(BB) pyrrolyl,
(CC) oxadiazolyl,
(DD) thiadiazolyl,
(EE) triazolyl,
(FF) tetrazolyl,
(GG) 1,4-benzodioxan
(HH) purinyl,
(II) oxazolopyridinyl,
(JJ) imidazopyridinyl,
(KK) isothiazolyl,
(LL) naphthyridinyl,
(MM) cinnolinyl,
(NN) carbazolyl,
(OO) β-carbolinyl,
(PP) isochromanyl,
(QQ) chromanyl,
(RR) furazanyl,
(SS) tetrahydroisoquinoline,
(TT) isoindolinyl,
(UU) isobenzotetrahydrofuranyl,
(VV) isobenzotetrahydrothienyl,
(WW) isobenzothiophenyl,
(XX) benzoxazolyl, or
(YY) pyridopyridinyl,
where the R 1-heteroaryl group is bonded to -alkyl- by any ring atom of the parent R 1-heteroaryl group substituted by hydrogen such that the new bond to the R 1-heteroaryl group replaces the hydrogen atom and its bond, where R 1-heteroaryl is unsubstituted or substituted with:
(1) C 1 -C 3 alkyl,
(2) —CF 3 ,
(3) —F, Cl, —Br, or I,
(4) C 1 -C 3 alkoxy,
(5) —O—CF 3 ,
(6) —NH 2 ,
(7) —OH, or
(8) —C≡N,
(VI) —(R 1-heteroaryl ) where R 1-heteroaryl is as defined above,
(VII) —C 1 -C 5 alkyl-(R 1-heterocycle ) where R 1-heterocycle is:
(A) morpholinyl,
(B) thiomorpholinyl,
(C) thiomorpholinyl S-oxide,
(D) thiomorpholinyl S,S-dioxide,
(E) piperazinyl,
(F) homopiperazinyl,
(G) pyrrolidinyl,
(H) pyrrolinyl,
(I) tetrahydropyranyl,
(J) piperidinyl,
(K) tetrahydrofuranyl, or
(L) tetrahydrothiophenyl,
where the R 1-heterocycle group is bonded by any atom of the parent R 1-heterocycle group substituted by hydrogen such that the new bond to the R 1-heterocycle group replaces the hydrogen atom and its bond, where R 1-heterocycle is unsubstituted or substituted with:
(1) ═O,
(2) C 1 -C 3 alkyl,
(3) —CF 3 ,
(4) —F, Cl, —Br or —I,
(5) C 1 -C 3 alkoxy,
(6) —O—CF 3 ,
(7) —NH 2 ,
(8) —OH, or
(9) —C≡N, or
(VIII) —R 1-heterocycle , where R 1-heterocycle is as defined above;
where R 2 is:
(I) —H,
(II) alkyl, or
(III) —C 1 -C 5 alkyl-R 2-1 where R 2-1 is cycloalkyl, R 1-aryl or R 1-heteroaryl where R 1-aryl and R 1-heteroaryl are as defined above;
where R N is:
(I) R N-1 —X N — where X N is:
(A) —CO—,
(B) —SO 2 —,
(C) —(CR′R″) 1-6 where R′ and R″ are the same or different and are —H or C 1 -C 4 alkyl,
(D) —CO—(CR′R″) 1-6 —X N-1 where X N-1 is —O—, —S— or —NR′R″— and where R′ and R″ are as defined above, or
(E) a single bond;
where R N-1 is:
(A) R N-aryl where R N-aryl is phenyl, biphenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl, dihydronaphthyl, or tetralinyl and is unsubstituted or substituted with:
(1) C 1 -C 6 alkyl,
(2) —F, —Cl, —Br, or —I,
(3) —OH,
(4) —NO 2 ,
(5) —CO—OH,
(6) —C≡N,
(7) —CO—NR N-2 R N-3 where R N-2 and R N-3 are the same or different and are:
(a) —H,
(b) —C 1 -C 6 alkyl unsubstituted or substituted with
(i) —OH, or
(ii) —NH 2 ,
(c) —C 1 -C 6 alkyl unsubstituted or substituted with —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 1 -C 6 alkenyl with one or two double bonds,
(h) —C 1 -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, or
(k) —R 1-heteroaryl where R 1-heteroaryl is as defined above,
(8) —CO—(C 3 -C 12 alkyl),
(9) —CO—(C 3 -C 6 cycloalkyl),
(10) —CO—R 1-heteroaryl where R 1-heteroaryl is as defined above,
(11) —CO—R 1-heterocycle where R 1-heterocycle is as defined above,
(12) —CO—R N-4 where R N-4 is morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl or pyrrolidinyl where each group is unsubstituted or substituted with C 1 -C 3 alkyl,
(13) —CO—O—R N-5 where R N-5 is:
(a) alkyl, or
(b) —(CH 2 ) 0-2 —(R 1-aryl ) where R 1-aryl is as defined above,
(14) —SO 2 —NR N-2 R N-3 where R N-2 and R N-3 are as defined above,
(15) —SO—(C 1 -C 8 alkyl),
(16) —SO 2 —(C 3 -C 12 alkyl),
(17) —NH—CO—O—R N-5 where R N-5 is as defined above,
(18) —NH—CO—N(C 1 -C 3 alkyl) 2 ,
(19) —N—CS—N(C 1 -C 3 alkyl) 2 ,
(20) —N(C 1 -C 3 alkyl)-CO—R N-5 where R N-5 is as defined above,
(21) —NR N-2 R N-3 where R N-2 and R N-3 can be the same or different and are as defined above,
(22) —R N-4 where R N-4 is as defined above,
(23) —O—CO—(C 1 -C 6 alkyl),
(24) —O—CO—N(C 1 -C 3 alkyl) 2 ,
(25) —O—CS—N(C 1 -C 3 alkyl) 2 ,
(26) —O—(C 1 -C 6 alkyl),
(27) —O—(C 2 -C 5 alkyl)-COOH,
(28) —S—(C 1 -C 6 alkyl),
(29) C 1 -C 6 alkyl unsubstituted or substituted with halo,
(30) —O—(C 1 -C 6 alkyl unsubstituted or substituted with halo), or
(31) —O-phenyl,
(32) (C 1 -C 6 alkyl) substituted with —CO—NH—C(═O)—,
(B) —R N-heteroaryl where R N-heteroaryl is:
(1) pyridinyl,
(2) pyrimidinyl,
(3) quinolinyl,
(4) indenyl,
(5) indanyl,
(6) benzothiophenyl,
(7) indolyl,
(8) indolinyl,
(9) pyridazinyl,
(10) pyrazinyl,
(11) isoindolyl,
(12) isoquinolyl,
(13) quinazolinyl,
(14) quinoxalinyl,
(15) phthalazinyl,
(16) imidazolyl,
(17) isoxazolyl,
(18) pyrazolyl,
(19) oxazolyl,
(20) thiazolyl,
(21) indolizinyl,
(22) indazolyl,
(23) benzothiazolyl,
(24) benzimidazolyl,
(25) benzofuranyl,
(26) furanyl,
(27) thienyl,
(28) pyrrolyl,
(29) oxadiazolyl,
(30) thiadiazolyl,
(31) triazolyl,
(32) tetrazolyl,
(33) 1,4-benzodioxan
(34) purinyl,
(35) oxazolopyridinyl,
(36) imidazopyridinyl,
(37) isothiazolyl,
(38) naphthyridinyl,
(39) cinnolinyl,
(40) carbazolyl,
(41) β-carbolinyl,
(42) isochromanyl,
(43) chromanyl,
(44) furazanyl,
(45) tetrahydroisoquinoline,
(46) isoindolinyl,
(47) isobenzotetrahydrofuranyl,
(48) isobenzotetrahydrothienyl,
(49) isobenzothiophenyl,
(50) benzoxazolyl, or
(51) pyridopyridinyl,
where the R N-heteroaryl group is bonded by any atom of the parent R N-heteroaryl group substituted by hydrogen such that the new bond to the R N-heteroaryl group replaces the hydrogen atom and its bond, where R N-heteroaryl is unsubstituted or substituted with:
(1) C 1 -C 6 alkyl,
(2) —F, —Cl, —Br, or —I,
(3) —OH,
(4) —NO 2 ,
(5) —CO—OH,
(6) —C≡N,
(7) —CO—NR N-2 R N-3 where R N-2 and R N-3 are as defined above,
(8) —CO—(C 3 -C 12 alkyl),
(9) —CO—(C 3 -C 6 cycloalkyl),
(10) —CO—R 1-heteroaryl where R 1-heteroaryl is as defined above,
(11) —CO—R 1-heterocycle where R 1-heterocycle is as defined above,
(12) —CO—R N-4 where R N-4 is as defined above,
(13) —CO—O—R N-5 where R N-5 is as defined above,
(14) —SO 2 —NR N-2 R N-3 where R N-2 and R N-3 are as defined above,
(15) —SO—(C 1 -C 8 alkyl),
(16) —SO 2 —(C 3 -C 12 alkyl),
(17) —NH—CO—O—R N-5 where R N-5 is as defined above,
(18) —NH—CO—N(C 1 -C 3 alkyl) 2 ,
(19) —N—CS—N(C 1 -C 3 alkyl) 2 ,
(20) —N(C 1 -C 3 alkyl)-CO—R N-5 where R N-5 is as defined above,
(21) —NR N-2 R N-3 where R N-2 and R N-3 can be the same or different and are as defined above,
(22) —R N-4 where R N-4 is as defined above,
(23) —O—CO—(C 1 -C 6 alkyl),
(24) —O—CO—N(C 1 -C 3 alkyl) 2 ,
(25) —O—CS—N(C 1 -C 3 alkyl) 2 ,
(26) —O—(C 1 -C 6 alkyl),
(27) —O—(C 2 -C 5 alkyl)-COOH, or
(28) —S—(C 1 -C 6 alkyl),
(29) (C 1 -C 6 alkyl) substituted with —CO—OH and —NH—C(═O)—,
(C) —R N-aryl —R N-aryl where —R N-aryl is as defined above,
(D) —R N-aryl —R N-heteroaryl where —R N-aryl and —R N-heteroaryl are as defined above,
(E) —R N-heteroaryl —R N-aryl where —R N-aryl and —R N-heteroaryl are as defined above,
(F) —R N-heteroaryl —R N-heteroaryl where R N-heteroaryl is as defined above,
(G) —R N-aryl —O—R N-aryl where —R N-aryl is as defined above,
(H) —R N-aryl —S—R N-aryl where —R N-aryl is as defined above,
(I) —R N-heteroaryl —O—R N-heteroaryl where R N-heteroaryl is as defined above,
(J) —R N-heteroaryl —S—R N-heteroaryl where R N-heteroaryl is as defined above,
(K) —R N-aryl —CO—R N-aryl where —R N-aryl is as defined above,
(L) —R N-aryl —CO—R N-heteroaryl where —R N-aryl and R N-heteroaryl are as defined above,
(M) —R N-aryl —SO 2 —R N-aryl where —R N-aryl is as defined above,
(N) —R N-heteroaryl —CO—R N-heteroaryl where R N-heteroaryl is as defined above,
(O) —R N-heteroaryl —SO 2 —R N-heteroaryl where R N-heteroaryl is as defined above,
(P) —R N-aryl —O—(C 1 -C 8 alkyl)-phenyl, where R N-aryl is as defined above,
(Q) —R N-aryl —S—(C 1 -C 8 alkyl)-phenyl, where R N-aryl is as defined above,
(R) —R N-heteroaryl —O—(C 1 -C 8 alkyl)-phenyl, where R N-heteroaryl is as defined above, or
(S) —R N-heteroaryl —S—(C 1 -C 8 alkyl)-phenyl, where R N-heteroaryl is as defined above, or
(II) —CO—(C 1 -C 6 alkyl) where alkyl is unsubstituted or substituted with:
(A) —OH,
(B) —C 1 -C 6 alkoxy,
(C) —C 1 -C 6 thioalkoxy,
(D) —CO—O—R N-8 where R N-8 is —H, C 1 -C 6 alkyl or -phenyl,
(E) —CO—NR N-2 R N-3 where R N-2 and R N-3 are the same or different and are as defined above,
(F) —CO—R N-4 where R N-4 is as defined above,
(G) —SO 2 —(C 1 -C 8 alkyl),
(H) —SO 2 —NR N-2 R N-3 where R N-2 and R N-3 are the same or different and are as defined above,
(I) —NH—CO—(C 1 -C 6 alkyl),
(J) —NH—CO—O—R N-8 where R N-8 is as defined above,
(K) —NR N-2 R N-3 where R N-2 and R N-3 are the same or different and are as defined above,
(L) —R N-4 where R N-4 is as defined above,
(M) —O—CO—(C 1 -C 6 alkyl),
(N) —O—CO—NR N-8 R N-8 where R N-8 are the same or different and are as defined above, or
(O) —O—(C 1 -C 5 alkyl)-COOH;
where B is —O—, —NH—, or —N(C 1 -C 6 alkyl)-; and
where R C is:
(I) C 1 -C 8 alkyl unsubstituted or substituted with —OH, —O-phenyl, halo, or (C 1 -C 6 alkoxy unsubstituted or substituted with halo), or
(II) —C(R C-1 )(R C-2 )—CO—NH—R C-3 where R C-1 and R C-2 are the same or different and are:
(A) —H,
(B) —C 1 -C 6 alkyl,
(C) —(C 1 -C 4 alkyl)-R C′-aryl where R C′-aryl is as defined for R N-aryl ,
(D) —(C 1 -C 4 alkyl)-R C-heteroaryl where R C-heteroaryl is as defined for R N-heteroaryl , and R N-heteroaryl is as defined above,
(E) —(C 1 -C 4 alkyl)-R C-heterocycle where R C-heterocycle is as defined for R N-heterocycle , and R N-heterocycle is as defined above,
(F) —R C-heteroaryl where R C-heteroaryl is as defined above,
(G) —R C-heterocycle where R C-heterocycle is as defined above,
(H) —(CH 2 ) 1-4 —OH,
(I) —(CH 2 ) 1-4 —R C-4 —(CH 2 ) 1-4 —R C′-aryl where R C-4 is —O—, —S—, —NH—, or —NR C-5 — where R C-5 is C 1 -C 6 alkyl, and where R C′-aryl is as defined above,
(J) —(CH 2 ) 1-4 —R C-4 —(CH 2 ) 1-4 —R C-heteroaryl where R C-4 and R C-heteroaryl are as defined above, or
(K) —R C′-aryl where R C′-aryl is as defined above,
and where R C-3 is:
(A) —H,
(B) —C 1 -C 6 alkyl, substituted or unsubstituted with:
(1) —H,
(2) —C 1 -C 6 alkyl,
(3) —(C 1 -C 4 alkyl)-R C′-aryl where R C′-aryl is as defined for R N-aryl ,
(4) —(C 1 -C 4 alkyl)-R C-heteroaryl where R C-heteroaryl is as defined for R N-heteroaryl , and R N-heteroaryl is as defined above,
(5) —(C 1 -C 4 alkyl)-R C-heterocycle where R C-heterocycle is as defined for R N-heterocycle , and R N-heterocycle is as defined above,
(6) —R C-heteroaryl where R C-heteroaryl is as defined above,
(7) —R C-heterocycle where R C-heterocycle is as defined above,
(8) —(CH 2 ) 1-4 —OH,
(9) —(CH 2 ) 1-4 —R C-4 —(CH 2 ) 1-4 —R C′-aryl where R C-4 is —O—, —S—, —NH—, or
—NR C-5 — where R C-5 is C 1 -C 6 alkyl, and where R C′-aryl is as defined above,
(10) —(CH 2 ) 1-4 R C-4 —(CH 2 ) 1-4 —R C-heteroaryl where R C-4 and R C-heteroaryl are as defined above, or
(11) —R C′-aryl where R C-aryl is as defined above,
(12) —CO—OH and —NH—C(═O)—,
(C) —R C′-aryl where R C′-aryl is as defined above,
(D) —R C-heteroaryl where R C-heteroaryl is as defined above,
(E) —R C-heterocycle where R C-heterocycle is as defined above,
(F) —(C 1 -C 4 alkyl)-R C′-aryl where R C′-aryl is as defined above,
(G) —(C 1 -C 4 alkyl)-R C-heteroaryl where R C-heteroaryl is as defined above,
(H) —(C 1 -C 4 alkyl)-R C-heterocycle where R C-heterocycle is as defined above, or
(J) —C(R C-5 )(R C-6 )—CO—NH—C(R C-7 )(R C-8 )—COOH, where R C-5 , R C-6 , R C-7 , and R C-8 are the same or different, and are as defined for R C-1 and R C-2 and where R C-1 and R C-2 are as defined above;
or pharmaceutically acceptable salts thereof.
86 - 87 . (canceled)
88 . A method of treatment according to claim 85 , wherein the disease is Alzheimer's disease.
89 - 100 . (canceled)
101 . A method of treatment according to claim 85 , wherein the compound is:
102 - 120 . (canceled)
121 . A method for inhibiting beta-secretase activity, comprising exposing said beta-secretase to an effective inhibitory amount of a compound according to claim 1 .
122 - 125 . (canceled)
126 . The method of claim 121 , wherein the compound is selected from:
127 - 132 . (canceled)
133 - 144 . (canceled)
145 . A method for inhibiting production of amyloid beta peptide (A beta) in a cell, comprising administering to said cell an effective inhibitory amount of a compound according to claim 1 .
146 - 150 . (canceled)
151 . A method for inhibiting the production of beta-amyloid plaque in an animal, comprising administering to said animal an effective inhibitory amount of a compound according to claim 1 .
152 - 154 . (canceled)
155 . A method for treating or preventing a disease characterized by beta-amyloid deposits in the brain comprising administering to a patient an effective therapeutic amount of a compound according to claim 1 .
156 - 169 . (canceled)
170 - 172 . (canceled)
173 . A kit comprising component parts capable of being assembled, wherein at least one component part comprises a compound according to claim 1 , enclosed in a container.
174 - 187 . (canceled)Cited by (0)
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