US2006276642A1PendingUtilityA1
Compounds to treat Alzheimer's disease
Est. expiryMar 23, 2020(expired)· nominal 20-yr term from priority
A61P 43/00C07K 7/02C07D 295/185C07D 295/13C07K 5/0207C07B 2200/07C07C 271/18C07C 2601/14A61P 25/28A61P 25/16C07D 307/33A61K 38/00C07C 271/14C07D 307/52C07C 2603/74C07C 271/22C07C 237/22C07D 261/20C07D 307/14
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Claims
Abstract
The present invention is directed toward substituted hydroxyethylene compounds of formula (XII) useful in treating Alzheimer's disease and other similar diseases.
Claims
exact text as granted — not AI-modified1 . A hydroxyethylene compound of the formula
Where R 1 is:
(I) C 1 -C 6 alkyl, unsubstituted or substituted with one, two or three C 1 -C 3 alkyl, —F, —Cl, —Br, —I, —OH, —NH 2 , —C≡N, —CF 3 , or —N 3 ,
(II) —(CH 2 ) 1-2 —S—CH 3 ,
(III) —CH 2 —CH 2 —S—CH 3 ,
(IV) —CH 2 —(C 2 -C 6 alkenyl) unsubstituted or substituted by one —F,
(V) —(CH 2 ) 0-3 —(R 1-aryl ) where R 1-aryl is phenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl, dihydronaphthyl, tetralinyl unsubstituted or substituted on the aryl ring with one or two of the following substituents which can be the same or different:
(A) C 1 -C 3 alkyl,
(B) —CF 3 ,
(C) —F, Cl, —Br and —I,
(D) C 1 -C 3 alkoxy,
(E) —O—CF 3 ,
(F) —NH 2 ,
(G) —OH, or
(H) —C≡N,
(VI) —(CH 2 ) n1-(R 1-heteroaryl ) where n 1 is 0, 1, 2, or 3 and 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 —(CH 2 ) 0-3 — by any ring atom of the parent R N-heteroaryl group substituted by hydrogen such that the new bond to the R 1-heteroaryl group replaces the hydrogen atom and its bond, where heteroaryl is unsubstituted or substituted with one or two:
(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,
with the proviso that when n 1 is zero R 1-heteroaryl is not bonded to the carbon chain by nitrogen, or
(VII) —(CH 2 ) n1 —(R 1-heterocycle ) where n 1 is as defined above and
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-heteroaryl group replaces the hydrogen atom and its bond, where heterocycle is unsubstituted or substituted with one or two:
(1) ═O,
(2) C 1 -C 3 alkyl,
(3) —CF 3 ,
(4) —F, Cl, —Br and —I,
(5) C 1 -C 3 alkoxy,
(6) —O—CF 3 ,
(7) —NH 2 ,
(8) —OH, or
(9) —C≡N,
with the proviso that when n 1 is zero R 1-heterocycle is not bonded to the carbon chain by nitrogen;
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 N is:
(I) R N-1 —X N — where X N is:
(A) —CO—,
(B) —SO 2 —,
(C) —(CR′R″) 1-6 where R 1 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— and —NR′R″— and where R′ and R″ are as defined above,
(E) a single bond;
where R N-1 is:
(A) R N-aryl where R N-aryl is phenyl, 1-naphthyl and 2-naphthyl unsubstituted or substituted with one, two, three or four of the following substituents which can be the same or different and are:
(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 one
(i) —OH, or
(ii) —NH 2 ,
(c) —C 1 -C 6 alkyl unsubstituted or 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 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 one or two C 1 -C 3 alkyl,
(13) —CO—O—R N-5 where R N-5 is:
(a) C 1 -C 6 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 1, 2, 3, 4, or 5 —F,
(30) —O—(C 1 -C 6 alkyl unsubstituted or substituted with 1, 2, 3, 4, or 5 —F, or
(31) —O-φ,
(B) —R N-heteroaryl where R N-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 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 heteroaryl is unsubstituted or substituted with one or two:
(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 one
(i) —OH, or
(ii) —NH 2 ,
(c) —C 1 -C 6 alkyl unsubstituted or substituted with 1, 2, or 3 —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 one or two C 1 -C 3 alkyl,
(13) —CO—O—R N-5 where R N-5 is:
(a) C 1 -C 6 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, or
(28) —S—(C 1 -C 6 alkyl),
(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)-φ where R N-aryl is as defined above,
(Q) —R N-aryl —S(C 1 -C 8 alkyl)-φ where R N-aryl is as defined above,
(R) —R N-heteroaryl —O—(C 1 -C 8 alkyl)-φ where R N-heteroaryl is as defined above, or
(S) —R N-heteroaryl —S(C 1 -C 8 alkyl)-φ where R N-heteroaryl is as defined above,
(II) A-X N — where X N is —CO—,
wherein A is
(A) -T-E-(Q) m′ ,
(1) where -T is
where
(a) x=1 when y=1 and x=2 when y=0,
(b) m is 0, 1, 2 or 3,
(c) the values of x and y vary independently on each carbon when m is 2 and 3, and
(d) R′″ varies independently on each carbon and is H, (C 1 -C 2 )alkyl, phenyl, or phenyl(C 1 -C 3 )alkyl;
(2) -E is
(a) C 1 -C 5 alkyl, but only if m′ does not equal 0,
(b) methylthioxy(C 2 -C 4 )alkyl,
(c) an aryl group having 5 to 7 atoms when monocyclic or having 8 to 12 atoms when fused,
(d) a heterocyclic group having 5 to 7 atoms when monocyclic or having 8 to 12 atoms when fused,
(e) a mono or fused ring cycloalkyl group having 5 to 10 carbon atoms,
(f) biphenyl,
(g) diphenyl ether,
(h) diphenylketone,
(i) phenyl(C 1 -C 8 )alkyloxyphenyl, or
(j) C 1 -C 6 alkoxy;
(3) -Q is
(a) C 1 -C 3 alkyl,
(b) C 1 -C 3 alkoxy,
(c) C 1 -C 3 alkylthioxy,
(d) C 1 -C 6 alkylacylamino,
(e) C 1 -C 6 alkylacyloxy,
(f) amido (including primary, C 1 -C 6 alkyl and phenyl secondary and tertiary amino moieties),
(g) C 1 -C 6 alkylamino
(h) phenylamino,
(i) carbamyl (including C 1 -C 6 alkyl and phenyl amides and esters),
(j) carboxyl (including C 1 -C 6 alkyl and phenyl esters),
(k) carboxy(C 2 -C 5 )alkoxy,
(l) carboxy(C 2 -C 5 )alkylthioxy,
(m) heterocyclylacyl,
(n) heteroarylacyl, or
(o) hydroxyl;
(4) m′ is 0, 1, 2 or 3;
(B) -E(Q) m″ wherein E and -Q are as defined as above and m″ is 0, 1, 2, or 3;
(C) -T-E wherein -E and -Q are as defined as above; or
(D) -E wherein -E is as defined as above;
(III) —CO—(C 1 -C 6 alkyl) where alkyl is unsubstituted or substituted with one or two:
(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 -φ,
(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 the R N-8 is the same or different and are as defined above, or
(O) —O—(C 1 -C 5 alkyl)-COOH,
(IV) —CO—(C 1 -C 3 alkyl)-O—(C 1 -C 3 alkyl) where alkyl is unsubstituted or substituted with one or two
(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 -φ,—(P,
(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 the R N-8 are the same or different and are as defined above, or
(O) —O—(C 1 -C 5 alkyl)-COOH,
(V) —CO—(C 1 -C 3 alkyl)-S—(C 1 -C 3 alkyl) where alkyl is unsubstituted or substituted with one or two
(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 -φ,—(P,
(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 the R N-8 are the same or different and are as defined above, or
(O) —O—(C 1 -C 5 alkyl)-COOH,
(VI) —CO—CH(—(CH 2 ) 0-2 —O—R N-0 )—(CH 2 ) 0-2 —R N-aryl /R N-heteroaryl ) where R N-aryl and R N-heteroaryl are as defined above, where R N-10 is:
(A) —H,
(B) C 1 -C 6 alkyl,
(C) C 3 -C 7 cycloalkyl,
(D) C 2 -C 6 alkenyl with one double bond,
(E) C 2 -C 6 alkynyl with one triple bond,
(F) R 1-aryl where R 1-aryl is as defined above, or
(G) R N-heteroaryl where R N-heteroaryl is as defined above;
where B is —O—, —NH—, or —N(C 1 -C 6 alkyl)-;
where R C is:
(I) —(C 1 -C 10 )alkyl-K 1-3 in which:
(A) the alkyl chain is unsubstituted or substituted with one —OH,
(B) the alkyl chain is unsubstituted or substituted with one C 1 -C 6 alkoxy unsubstituted or substituted with 1-5 —F,
(C) the alkyl chain is unsubstituted or substituted with one —O-φ
(D) the alkyl chain is unsubstituted or substituted with 1-5 —F,
(E) the alkyl chain is unsubstituted or substituted with a combination of up to three atoms of oxygen and sulfur each such atom replacing one carbon,
(F) each K is:
(1) H,
(2) C 1 -C 3 alkyl,
(3) C 1 -C 3 alkoxy,
(4) C 1 -C 3 alkylthioxy,
(5) C 1 -C 6 alkylacylamino,
(6) C 1 -C 6 alkylacyloxy,
(7) amido
(8) C 1 -C 6 alkylamino
(9) phenylamino,
(10) carbamyl
(11) carboxyl
(12) carboxy(C 2 -C 5 )alkoxy,
(13) carboxy(C 2 -C 5 )alkylthioxy,
(14) heterocyclylacyl,
(15) heteroarylacyl,
(16) amino unsubstituted or substituted with C 1 -C 6 alkyl,
(17) hydroxyl, or
(18) carboxylmethyl ester;
(II) —(CH 2 ) 0-3 -J-[(—(CH 2 ) 0-3 —K] 1-3 where K is as defined above and J is:
(A) a 5 to 7 atom monocyclic aryl group,
(B) a 8 to 12 atom multicyclic aryl group,
(C) a 5 to 7 atom heterocyclic group,
(D) a 8 to 12 atom multicyclic heterocyclic group, or
(E) a 5 to 10 atom monocyclic or multicyclic cycloalkyl group;
(III) —(CH 2 ) 0-3 —(C 3 -C 7 )cycloalkyl where cycloalkyl can be unsubstituted or substituted with one, two or three
(A) C 1 -C 3 alkyl unsubstituted or substituted with 1, 2, 3, or 4 —F,
—Cl, —Br, or —I,
(B) —CO—OH,
(C) —CO—O—(C 1 -C 4 alkyl),
(D) —OH, or
(E) C 1 -C 6 alkoxy,
(IV) —(CH 2 ) 2-6 —OH,
(V) —(CR C-x R C-y ) 0-4 —R C-aryl where R C-x and R C-y are —H, C 1 -C 4 alkyl and φ- and R C-aryl is the same as R N-aryl ,
(VI) —(CH 2 ) 0-4 —R C-heteroaryl where R C-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) isoxazolyl,
(Q) pyrazolyl,
(R) indolizinyl,
(S) indazolyl,
(T) benzothiazolyl,
(U) benzimidazolyl,
(V) benzofuranyl,
(W) furanyl,
(X) thienyl,
(Y) pyrrolyl,
(Z) oxadiazolyl,
(AA) thiadiazolyl,
(BB) triazolyl,
(CC) tetrazolyl,
(DD) 1,4-benzodioxan
(EE) purinyl,
(FF) oxazolopyridinyl,
(GG) imidazopyridinyl,
(HH) isothiazolyl,
(II) naphthyridinyl,
(JJ) cinnolinyl,
(KK) carbazolyl,
(LL) β-carbolinyl,
(MM) isochromanyl,
(NN) chromanyl,
(OO) furazanyl,
(PP) tetrahydroisoquinoline,
(QQ) isoindolinyl,
(RR) isobenzotetrahydrofuranyl,
(SS) isobenzotetrahydrothienyl,
(TT) isobenzothiophenyl,
(UU) benzoxazolyl, or
(VV) pyridopyridinyl,
(VII) —(CH 2 ) 0-4 —R C-heterocycle where R C-heterocycle is the same as R 1-heterocycle ,
(VIII) —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 above for
R 1-aryl i
(D) —(C 1 -C 4 alkyl)-R C-heteroaryl where R C-heteroaryl is as defined above,
(E) —(C 1 -C 4 alkyl)-R C-heterocycle where R C-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
—NHR 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,
(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, or
(H) —(C 1 -C 4 alkyl)-R C-heterocycle where R C-heterocycle is as defined above,
(IX) —CH(φ) 2 ,
(X) -cyclopentyl or -cyclohexyl ring fused to a phenyl or heteroaryl ring where heteroaryl is as defined above and phenyl and heteroaryl are unsubstituted or substituted with one, two or three:
(A) C 1 -C 3 alkyl,
(B) —CF 3 ,
(C) —F, Cl, —Br and —I,
(D) C 1 -C 3 alkoxy,
(E) —OCF 3 ,
(F) —NH 2 ,
(G) —OH, or
(H) —C≡N,
(XI) —CH 2 —C≡CH;
(XII) —(CH 2 ) 0-1 —CHR C-5 —(CH 2 ) 0-1 -φ where R C-5 is:
(A) —OH, or
(B) —CH 2 —OH;
(XIII) —CH(-φ) —CO—O(C 1 -C 3 alkyl);
(XIV) —CH(—CH 2 —OH)—CH(—OH)-φ-NO 2 ;
(XV) —(CH 2 ) 2 —O—(CH 2 ) 2 —OH;
(XVI) —CH 2 —NH—CH 2 —CH(—O—CH 2 —CH 3 ) 2;
(XVII) —(C 2 -C 8 )alkynyl; or
(XVIII) —H; or a pharmaceutically acceptable salt thereof.
2 - 29 . (canceled)
30 . A compound of the formula
where R 1 is:
(V) —CH 2 -phenyl, where phenyl is substituted with two —F in the 3- and 5-positions giving 3,5-difluorophenyl, or
(VI) —(CH 2 ) n1 —(R 1-heteroaryl ), where n1 and R 1-heteroaryl are as defined above; and
PROTECTING GROUP is t-butoxycarbonyl, benzyloxycarbonyl, formyl, trityl, phthalimido, trichloroacetyl, chloroacetyl, bromoacetyl, iodoacetyl, 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-methylcycoopentanyloxycarbonyl, cyclohexanyloxycarbonyl, 1-methylcyclohexanyloxycarbonyl, 2-methylcyclohexanyloxycarbonyl, 2-(4-toluylsulfonyl)ethoxycarbonyl, 2-(methylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphino)ethoxycarbonyl, fluorenylmethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl, 1-(trimethylsilylmethyl)prop-1-enyloxycarbonyl, 5-benzisoxazoylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl, cyclopropylmethoxycarbonyl, 4-(decyloxyl)benzyloxycarbonyl, isobornyloxycarbonyl, -phenyl-C(═N)—H, or 1-piperidyloxycarbonyl.
31 - 34 . (canceled)
35 . An epoxide compound of the formula
where R 1 is:
(A) —CH 2 -φ where -φ is substituted with two —F,
(B) —(CH 2 ) n1 —R 1-heteroaryl where n 1 is 0, 1, 2, or 3 and 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,
(C) —(CH 2 ) n1 —R 1-heterocycle where n, is 0, 1, 2, or 3 and 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, and
PROTECTING GROUP is t-butoxycarbonyl, benzyloxycarbonyl, formyl, trityl, phthalimido, trichloroacetyl, chloroacetyl, bromoacetyl, iodoacetyl, 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-methylcycoopentanyloxycarbonyl, cyclohexanyloxycarbonyl, 1-methylcyclohexanyloxycarbonyl, 2-methylcyclohexanyloxycarbonyl, 2-(4-toluylsulfonyl)ethoxycarbonyl, 2-(methylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphino)ethoxycarbonyl, fluorenylmethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl, 1-(trimethylsilylmethyl)prop-1-enyloxycarbonyl, 5-benzisoxazoylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl, cyclopropylmethoxycarbonyl, 4-(decyloxyl)benzyloxycarbonyl, isobornyloxycarbonyl, -phenyl-C(═N)—H, or 1-piperidyloxycarbonyl.
36 - 43 . (canceled)
44 . A compound of formula
where R 1 is:
(V) —CH 2 -phenyl, where phenyl is substituted with two —F in the 3- and 5-positions giving 3,5-difluorophenyl, or
(VI) —(CH 2 ) n1 —(R 1-heteroaryl ), where n1 and R 1-heteroaryl are as defined above;
where R 2 is as defined in claim 1; and
PROTECTING GROUP is t-butoxycarbonyl, benzyloxycarbonyl, formyl, trityl, phthalimido, trichloroacetyl, chloroacetyl, bromoacetyl, iodoacetyl, 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-methylcycoopentanyloxycarbonyl, cyclohexanyloxycarbonyl, 1-methylcyclohexanyloxycarbonyl, 2-methylcyclohexanyloxycarbonyl, 2-(4-toluylsulfonyl)ethoxycarbonyl, 2-(methylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphino)ethoxycarbonyl, fluorenylmethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl, 1-(trimethylsilylmethyl)prop-1-enyloxycarbonyl, 5-benzisoxazoylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl, cyclopropylmethoxycarbonyl, 4-(decyloxyl)benzyloxycarbonyl, isobornyloxycarbonyl, -phenyl-C(═N)—H, or 1-piperidyloxycarbonyl.
45 - 50 . (canceled)
51 . A compound of formula
where R 1 is:
(V) —CH 2 -phenyl, where phenyl is substituted with two —F in the 3- and 5-positions giving 3,5-difluorophenyl, or
(VI) —(CH 2 ) n1 —(R 1-heteroaryl ), where n1 and R 1-heteroaryl are as defined above; and
where R 2 is as defined in claim 1 .
52 - 57 . (canceled)
58 . A compound of formula
where R 1 , R 2 and R N are as defined in claim 1 .
59 - 72 . (canceled)
73 . A method of treating or preventing a disease or condition selected from Alzheimer's disease, mild cognitive impairment, Down's syndrome, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, cerebral amyloid angiopathy, degenerative dementia, diffuse Lewy body type of Alzheimer's disease or central or preipheral amyloid diseases in a patient who is in need of such treatment which comprises administration to said patient a therapeutically effective amount of a hydroxyethylene compound of the formula
where R 1 is:
(I) C 1 -C 6 alkyl, unsubstituted or substituted with one, two or three C 1 -C 3 alkyl, —F, —Cl, —Br, —I, —OH, —NH 2 , —C≡N, —CF 3 , or —N 3 ,
(II) —(CH 2 ) 1-2 —S—CH 3 ,
(III) —CH 2 —CH 2 —S—CH 3 ,
(IV) —CH 2 —(C 2 -C 6 alkenyl) unsubstituted or substituted by one —F,
(V) —(CH 2 ) 0-3 —(R 1-aryl ) where R 1-aryl is phenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl, dihydronaphthyl, tetralinyl unsubstituted or substituted on the aryl ring with one or two of the following substituents which can be the same or different:
(A) C 1 -C 3 alkyl,
(B) —CF 3 ,
(C) —F, Cl, —Br and —I,
(D) C 1 -C 3 alkoxy,
(E) —O—CF 3 ,
(F) —NH 2 ,
(G) —OH, or
(H) —C≡N,
(VI) —(CH 2 ) n1 —(R 1-heteroaryl ) where n 1 is 0, 1, 2, or 3 and 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 —(CH 2 ) 0-3 — by any ring atom of the parent R N-heteroaryl group substituted by hydrogen such that the new bond to the R 1-heteroaryl group replaces the hydrogen atom and its bond, where heteroaryl is unsubstituted or substituted with one or two:
(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,
with the proviso that when n 1 is zero R 1-heteroaryl is not bonded to the carbon chain by nitrogen, or
(VII) —(CH 2 ) n1 —(R 1-heterocycle ) where n 1 is as defined above and
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-heteroaryl group replaces the hydrogen atom and its bond, where heterocycle is unsubstituted or substituted with one or two:
(1) ═O,
(2) C 1 -C 3 alkyl,
(3) —CF 3 ,
(4) —F, Cl, —Br and —I,
(5) C 1 -C 3 alkoxy,
(6) —O—CF 3 ,
(7) —NH 2 ,
(8) —OH, or
(9) —C≡N,
with the proviso that when n 1 is zero R 1-heterocycle is not bonded to the carbon chain by nitrogen;
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 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— and —NR′R″— and where R′ and R″ are as defined above,
(E) a single bond;
where R N- 1 is:
(A) R N-aryl where R N-aryl is phenyl, 1-naphthyl and 2-naphthyl unsubstituted or substituted with one, two, three or four of the following substituents which can be the same or different and are:
(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 one
(i) —OH, or
(ii) —NH 2 ,
(c) —C 1 -C 6 alkyl unsubstituted or 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 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 one or two C 1 -C 3 alkyl,
(13) —CO—O—R N-5 where R N-5 is:
(a) C 1 -C 6 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 1, 2, 3, 4, or 5 —F,
(30) —O—(C 1 -C 6 alkyl unsubstituted or substituted with 1, 2, 3, 4, or 5 —F, or
(31) —O-T,
(B) —R N-heteroaryl where R N-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 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 heteroaryl is unsubstituted or substituted with one or two:
(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 one
(i) —OH, or
(ii) —NH 2 ,
(c) —C 1 -C 6 alkyl unsubstituted or substituted with 1, 2, or 3 —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 one or two C 1 -C 3 alkyl,
(13) —CO—O—R N-5 where R N-5 is:
(a) C 1 -C 6 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, or
(28) —S—(C 1 -C 6 alkyl),
(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)-φ where R N-aryl is as defined above,
(Q) —R N-aryl —S—(C 1 -C 8 alkyl)-φ where R N-aryl is as defined above,
(R) —R N-heteroaryl —O(C 1 -C 8 alkyl)-φ where R N-heteroaryl is as defined above, or
(S) —R N-heteroaryl —S—(C 1 -C 8 alkyl)-φ where R N-heteroaryl is as defined above,
(II) A-X N — where X N is —CO—,
wherein A is
(A) -T-E-(Q) m′ ,
(1) where -T is
where
(a) x=1 when y=1 and x=2 when y=0,
(b) m is 0, 1, 2 or 3,
(c) the values of x and y vary independently on each carbon when m is 2 and 3, and
(d) R′″ varies independently on each carbon and is H, (C 1 -C 2 )alkyl, phenyl, or phenyl(C 1 -C 3 )alkyl;
(2) -E is
(a) C 1 -C 5 alkyl, but only if m′ does not equal 0,
(b) methylthioxy(C 2 -C 4 )alkyl,
(c) an aryl group having 5 to 7 atoms when monocyclic or having 8 to 12 atoms when fused,
(d) a heterocyclic group having 5 to 7 atoms when monocyclic or having 8 to 12 atoms when fused,
(e) a mono or fused ring cycloalkyl group having 5 to 10 carbon atoms,
(f) biphenyl,
(g) diphenyl ether,
(h) diphenylketone,
(i) phenyl(C 1 -C 8 )alkyloxyphenyl, or
(j) C 1 -C 6 alkoxy;
(3) -Q is
(a) C 1 -C 3 alkyl,
(b) C 1 -C 3 alkoxy,
(c) C 1 -C 3 alkylthioxy,
(d) C 1 -C 6 alkylacylamino,
(e) C 1 -C 6 alkylacyloxy,
(f) amido (including primary, C 1 -C 6 alkyl and phenyl secondary and tertiary amino moieties),
(g) C 1 -C 6 alkylamino
(h) phenylamino,
(i) carbamyl (including C 1 -C 6 alkyl and phenyl amides and esters),
(j) carboxyl (including C 1 -C 6 alkyl and phenyl esters),
(k) carboxy(C 2 -C 5 )alkoxy,
(l) carboxy(C 2 -C 5 )alkylthioxy,
(m) heterocyclylacyl,
(n) heteroarylacyl, or
(o) hydroxyl;
(4) m′ is 0, 1, 2 or 3;
(B) -E(Q) m″ wherein E and -Q are as defined as above and m″ is 0, 1, 2, or 3;
(C) -T-E wherein -E and -Q are as defined as above; or
(D) -E wherein -E is as defined as above;
(III) —CO—(C 1 -C 6 alkyl) where alkyl is unsubstituted or substituted with one or two:
(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 -φ,
(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)I
(N) —O—CO—NR N-8 R N-8 where the R N-8 is the same or different and are as defined above, or
(O) —O—(C 1 -C 5 alkyl)-COOH,
(IV) —CO—(C 1 -C 3 alkyl)-O—(C 1 -C 3 alkyl) where alkyl is unsubstituted or substituted with one or two
(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 -φ,—(P,
(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 the R N-8 are the same or different and are as defined above, or
(O) —O—(C 1 -C 5 alkyl)-COOH,
(V) —CO—(C 1 -C 3 alkyl)-S—(C 1 -C 3 alkyl) where alkyl is unsubstituted or substituted with one or two
(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 -φ,
(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 the R N-8 are the same or different and are as defined above, or
(O) —O—(C 1 -C 5 alkyl)-COOH,
(VI) —CO—CH(—(CH 2 ) 0-2 —O—R N-0 )—(CH 2 ) 0-2 —R N-aryl /R N-heteroaryl ) where R N-aryl and R N-heteroaryl are as defined above, where R N-10 is:
(A) —H,
(B) C 1 -C 6 alkyl,
(C) C 3 -C 7 cycloalkyl,
(D) C 2 -C 6 alkenyl with one double bond,
(E) C 2 -C 6 alkynyl with one triple bond,
(F) R 1-aryl where R 1-aryl is as defined above, or
(G) R N-heteroaryl where R N-heteroaryl is as defined above;
where B is —O—, —NH—, or —N(C 1 -C 6 alkyl)-;
where R C is:
(I) —(C 1 -C 10 )alkyl-K 1-3 in which:
(A) the alkyl chain is unsubstituted or substituted with one —OH,
(B) the alkyl chain is unsubstituted or substituted with one C 1 -C 6 alkoxy unsubstituted or substituted with 1-5 —F,
(C) the alkyl chain is unsubstituted or substituted with one —O-φ,
(D) the alkyl chain is unsubstituted or substituted with 1-5 —F,
(E) the alkyl chain is unsubstituted or substituted with a combination of up to three atoms of oxygen and sulfur each such atom replacing one carbon,
(F) each K is:
(1) H,
(2) C 1 -C 3 alkyl,
(3) C 1 -C 3 alkoxy,
(4) C 1 -C 3 alkylthioxy,
(5) C 1 -C 6 alkylacylamino,
(6) C 1 -C 6 alkylacyloxy,
(7) amido
(8) C 1 -C 6 alkylamino
(9) phenylamino,
(10) carbamyl
(11) carboxyl
(12) carboxy(C 2 -C 5 )alkoxy,
(13) carboxy(C 2 -C 5 )alkylthioxy,
(14) heterocyclylacyl,
(15) heteroarylacyl,
(16) amino unsubstituted or substituted with C 1 -C 6 alkyl,
(17) hydroxyl, or
(18) carboxylmethyl ester;
(II) —(CH 2 ) 0-3 -J-[(—(CH 2 ) 0-3 —K] 1-3 where K is as defined above and J is:
(A) a 5 to 7 atom monocyclic aryl group,
(B) a 8 to 12 atom multicyclic aryl group,
(C) a 5 to 7 atom heterocyclic group,
(D) a 8 to 12 atom multicyclic heterocyclic group, or
(E) a 5 to 10 atom monocyclic or multicyclic cycloalkyl group;
(III) —(CH 2 ) 0-3 —(C 3 -C 7 )cycloalkyl where cycloalkyl can be unsubstituted or substituted with one, two or three
(A) C 1 -C 3 alkyl unsubstituted or substituted with 1, 2, 3, or 4 —F,
—Cl, —Br, or —I,
(B) —CO—OH,
(C) —CO—O—(C 1 -C 4 alkyl),
(D) —OH, or
(E) C 1 -C 6 alkoxy,
(IV) —(CH 2 ) 2-6 —OH,
(V) —(CR C-x R C-y ) 0-4 —R C-aryl where R C-1 and R C-y are —H, C 1 -C 4 alkyl and φ- and R C-aryl is the same as R N-aryl ,
(VI) —(CH 2 ) 0-4 —R C-heteroaryl where R C-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) isoxazolyl,
(Q) pyrazolyl,
(R) indolizinyl,
(S) indazolyl,
(T) benzothiazolyl,
(U) benzimidazolyl,
(V) benzofuranyl,
(W) furanyl,
(X) thienyl,
(Y) pyrrolyl,
(Z) oxadiazolyl,
(AA) thiadiazolyl,
(BB) triazolyl,
(CC) tetrazolyl,
(DD) 1,4-benzodioxan
(EE) purinyl,
(FF) oxazolopyridinyl,
(GG) imidazopyridinyl,
(HH) isothiazolyl,
(II) naphthyridinyl,
(JJ) cinnolinyl,
(KK) carbazolyl,
(LL) β-carbolinyl,
(MM) isochromanyl,
(NN) chromanyl,
(OO) furazanyl,
(PP) tetrahydroisoquinoline,
(QQ) isoindolinyl,
(RR) isobenzotetrahydrofuranyl,
(SS) isobenzotetrahydrothienyl,
(TT) isobenzothiophenyl,
(UU) benzoxazolyl, or
(VV) pyridopyridinyl,
(VII) —(CH 2 ) 0-4 —R C-heterocycle where R C-heterocycle is the same as R 1-heterocycle ,
(VIII) —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 above for R 1-aryl ,
(D) —(C 1 -C 4 alkyl)-R C-heteroaryl where R C-heteroaryl is as defined above,
(E) —(C 1 -C 4 alkyl)-R C-heterocycle where R C-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
—NHR 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,
(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, or
(H) —(C 1 -C 4 alkyl)-R C-heterocycle where R C-heterocycle is as defined above,
(IX) —CH(φ) 2 ,
(X) -cyclopentyl or -cyclohexyl ring fused to a phenyl or heteroaryl ring where heteroaryl is as defined above and phenyl and heteroaryl are unsubstituted or substituted with one, two or three:
(A) C 1 -C 3 alkyl,
(B) —CF 3 ,
(C) —F, Cl, —Br and —I,
(D) C 1 -C 3 alkoxy,
(E) —OCF 3 ,
(F) —NH 2 ,
(G) —OH, or
(H) —C≡N,
(XI) —CH 2 —C≡CH;
(XII) —(CH 2 ) 0-1 —CHR C-5 —(CH 2 ) 0-1 -φ where R C-5 is:
(A) —OH, or
(B) —CH 2 —OH;
(XIII) —CH(-φ)-CO—O(C 1 -C 3 alkyl);
(XIV) —CH(—CH 2 —OH)—CH(—OH)-φ-NO 2 ;
(XV) —(CH 2 ) 2 —O—(CH 2 ) 2 —OH;
(XVI) —CH 2 —NH—CH 2 —CH(—O—CH 2 —CH 3 ) 2;
(XVII) —(C 2 -C 8 )alkynyl; or
(XVIII) —H; or a pharmaceutically acceptable salt thereof.
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