US 6,982,264 B2 | ||
Substituted alcohols useful in treatment of Alzheimer's disease | ||
Varghese John, San Francisco, Calif. (US); Roy Hom, San Francisco, Calif. (US); and John Tucker, San Mateo, Calif. (US) | ||
Assigned to Elan Pharmaceuticals, Inc., South San Francisco, Calif. (US) | ||
Filed on Jun. 27, 2002, as Appl. No. 10/183,126. | ||
Claims priority of provisional application 60/301210, filed on Jun. 27, 2001. | ||
Claims priority of provisional application 60/323396, filed on Sep. 18, 2001. | ||
Claims priority of provisional application 60/332736, filed on Nov. 19, 2001. | ||
Prior Publication US 2003/0083518 A1, May 01, 2003 | ||
Int. Cl. C07D 401/12 (2006.01); C07D 401/14 (2006.01); C07D 403/12 (2006.01); A61K 31/4178 (2006.01); A61P 25/28 (2006.01) |
U.S. Cl. 514—241 | 10 Claims |
1. A compound of the formula I: ![]() wherein X is CR2R3, C1-6 alkylene or alkenyl, O, S, SO, or SO2;
wherein R1 is
(I) C1-C6 alkyl, optionally substituted with one, two or three substituents selected from the group consisting of C1-C3 alkyl, C1-C7 alkyl (optionally substituted with C1-C3 alkyl and C1-C3 alkoxy), —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF3, C1-C3 alkoxy, —NR1-aR1-b where R1-a and R1-b are independently —H or C1-C6 alkyl, and —OC═O NR1-aR1-b,
(II) —CH2—S(O)0-2—(C1-C6 alkyl),
(III) —CH2—CH2—S(O)0-2—(C1-C6 alkyl),
(IV) C2-C6 alkenyl with one or two double bonds, optionally substituted with one, two or three substituents selected from the group consisting
of —F, —Cl, —OH, —SH, —C≡N, —CF3, C1-C3 alkoxy, and —NR1-aR1-b,
(V) C2-C6 alkynyl with one or two triple bonds, optionally substituted with one, two or three substituents selected from the group consisting
of —F, —Cl, —OH, —SH, —C≡N, —CF3, C1-C3 alkoxy, and —NR1-aR1-b,
(VI) —(CH2)n1—(R1-aryl) where n1 is zero or one and where R1-aryl is phenyl, 1-naphthyl, 2-naphthyl and indanyl, indenyl, dihydronaphthalyl, or tetralinyl optionally substituted with one,
two, three or four of the following substituents on the aryl ring:
(A) C1-C6 alkyl optionally substituted with one, two or three substituents selected from the group consisting of C1-C3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF3, C1-C3 alkoxy, and —NR1-aR1-b,
(B) C2-C6 alkenyl with one or two double bonds, optionally substituted with one, two or three substituents selected from the group consisting
of —F, —Cl, —OH, —SH, —C≡N, —CF3, C1-C3 alkoxy, and —NR1-aR1-b,
(C) C2-C6 alkynyl with one or two triple bonds, optionally substituted with one, two or three substituents selected from the group consisting
of —F, —Cl, —OH, —SH, —C≡N, —CF3, C1-C3 alkoxy, and —NR1-aR1-b,
(D) —F, Cl, —Br or —I,
(F) —C1-C6 alkoxy optionally substituted with one, two or three of —F,
(G) —NRN-2RN-3 where RN-2 and RN-3 are as defined below,
(H) —OH,
(I) —C≡N,
(J) C3-C7 cycloalkyl, optionally substituted with one, two or three substituents selected from the group consisting of —F, —Cl, —OH,
—SH, —C≡N, —CF3, C1-C3 alkoxy, and —NR1-aR1-b,
(K) —CO—(C1-C4 alkyl),
(L) —SO2—NR1-aR1-b,
(M) —CO—NR1-aR1-b,
(N) —SO2—(C1-C4 alkyl),
(VII) —(CH2)n1—(R1-heteroaryl) where n1 is as defined above and where R1-heteroaryl is selected from the group consisting of:
pyridinyl, pyrimidinyl, quinolinyl, benzothienyl, indolyl, indolinyl, pryidazinyl, pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl,
quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl,
benzimidazolyl, benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, oxazolopyridinyl,
imidazopyridinyl, isothiazolyl, naphthyridinyl, cinnolinyl, carbazolyl, beta-carbolinyl, isochromanyl, chromanyl, tetrahydroisoquinolinyl,
isoindolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl, benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl,
benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, phenoxazinyl, phenothiazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl,
imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl, dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl,
coumarinyl, isocoumarinyl, chromonyl, chromanonyl, pyridinyl-N-oxide, tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl,
dihydroisoquinolinonyl, dihydrocoumarinyl, dihydroisocoumarinyl,isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyrrolyl
N-oxide, pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, quinolinyl N-oxide, indolyl N-oxide, indolinyl N-oxide,
isoquinolyl N-oxide, quinazolinyl N-oxide, quinoxalinyl N-oxide, phthalazinyl N-oxide, imidazolyl N-oxide, isoxazolyl N-oxide,
oxazolyl N-oxide, thiazolyl N-oxide, indolizinyl N-oxide, indazolyl N-oxide, benzothiazolyl N-oxide, benzimidazolyl N-oxide,
pyrrolyl N-oxide, oxadiazolyl N-oxide, thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolyl N-oxide, benzothiopyranyl S-oxide,
benzothiopyranyl S,S-dioxide,
where the R1-heteroaryl group is bonded to —(CH2)n1— by any ring atom of the parent RN-heteroaryl group substituted by hydrogen such that the new bond to the R1-heteroaryl group replaces the hydrogen atom and its bond, where heteroaryl is optionally substituted with one, two, three or four of:
(1) C1-C6 alkyl optionally substituted with one, two or three substituents selected from the group consisting of C1-C3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF3, C1-C3 alkoxy, and —NR1-aR1-b,
(2) C2-C6 alkenyl with one or two double bonds, optionally substituted with one, two or three substituents selected from the group consisting
of —F, —Cl, —OH, —SH, —C≡N, —CF3, C1-C3 alkoxy, and —NR1-aR1-b,
(3) C2-C6 alkynyl with one or two triple bonds, optionally substituted with one, two or three substituents selected from the group consisting
of —F, —Cl, —OH, —SH, —C≡N, —CF3, C1-C3 alkoxy, and —NR1-aR1-b,
(4) —F, Cl, —Br or —I,
(6) —C1-C6 alkoxy optionally substituted with one, two, or three of —F,
(7) —NRN-2RN-3 where RN-2 and RN-3 are as defined below,
(8) —OH,
(9) —C≡N,
(10) C3-C7 cycloalkyl, optionally substituted with one, two or three substituents selected from the group consisting of —F, —Cl, —OH,
—SH, —C≡N, —CF3, C1-C3 alkoxy, and —NR1-aR1-b,
(11) —CO—(C1-C4 alkyl),
(12) —SO2—NR1-aR1-b,
(13) —CO—NR1-aR1-b, or
(14) —SO2—(C1-C4 alkyl), with the proviso that when n1 is zero R1-heteroaryl is not bonded to the carbon chain by nitrogen, or
(VIII) —(CH2)n1—(R1-heterocycle) where n1 is as defined above and R1-heterocycle is selected from the group consisting of:
morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S,S-dioxide, piperazinyl, homopiperazinyl, pyrrolidinyl,
pyrrolinyl, tetrahydropyranyl, piperidinyl, tetrahydrofuranyl, tetrahydrothienyl, homopiperidinyl, homomorpholinyl, homomorpholinyl
S-oxide, homothiomorpholinyl S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl dihydropyrazinyl dihydropyridinyl
dihydropyrimidinyl, dihydrofuryl, dihydropyranyl, tetrahydrothienyl S-oxide, tetrahydrothienyl S,S-dioxide, homothiomorpholinyl
S-oxide,
where the R1-heterocycle group is bonded by any atom of the parent R1-heterocycle group substituted by hydrogen such that the new bond to the R1-heterocycle group replaces the hydrogen atom and its bond, where heterocycle is optionally substituted with one, two, three or four:
(1) C1-C6 alkyl optionally substituted with one, two or three substituents selected from the group consisting of C1-C3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF3, C1-C3 alkoxy, and —NR1-aR1-b,
(2) C2-C6 alkenyl with one or two double bonds, optionally substituted with one, two or three substituents selected from the group consisting
of —F, —Cl, —OH, —SH, —C≡N, —CF3, C1-C3 alkoxy, and —N1-aR1-b,
(3) C2-C6 alkynyl with one or two triple bonds, optionally substituted with one, two or three substituents selected from the group consisting
of —F, —Cl, —OH, —SH, —C≡N, —CF3, C1-C3 alkoxy, and —NR1-aR1-b,
(4) —F, Cl, —Br, or —I,
(5) C1-C6 alkoxy,
(6) —C1-C6 alkoxy optionally substituted with one, two, or three —F,
(7) —NRN-2RN-3 where RN-2 and RN-3 are as defined below,
(8) —OH,
(9) —C≡N,
(10) C3-C7 cycloalkyl, optionally substituted with one, two or three substituents selected from the group consisting of —F, —Cl, —OH,
—SH, —C≡N, —CF3, C1-C3 alkoxy, and —NR1-aR1-b,
(11) —CO—(C1-C4 alkyl),
(12) —SO2—NR1-aR1-b,
(13) —CO—NR1-aR1-b,
(14) —SO2—(C1-C4 alkyl),
(15) ═O, with the proviso that when n1 is zero R1-heterocycle is not bonded to the carbon chain by nitrogen;
wherein R2 is
(I) —H,
(II) C1-C6 alkyl, optionally substituted with one, two or three substituents selected from the group consisting of C1-C3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF3, C1-C3 alkoxy, and —NR1-aR1-b,
(III) —(CH2)0-4—R2-1 where R2-1 is R1-aryl or R1-heteroaryl;
(IV) C2-C6 alkenyl with one or two double bonds, optionally substituted with one, two or three substituents selected from the group consisting
of —F, —Cl, —OH, —SH, —C≡N, —CF3, C1-C3 alkoxy, and —NR1-aR1-b,
(V) C2-C6 alkynyl with one or two triple bonds, optionally substituted with one, two or three substituents selected from the group consisting
of —F, —Cl, —OH, —SH, —C≡N, —CF3, C1-C3 alkoxy, and —NR1-aR1-b,
(VI) —(CH2)0-4—C3-C7 cycloalkyl, optionally substituted with one, two or three substituents selected from the group consisting of —F, —Cl, —OH,
—SH, —C≡N, —CF3, C1-C3 alkoxy, and —NR1-aR1-b;
wherein R3 is
(I) —H,
(II) C1-C6 alkyl, optionally substituted with one, two or three substituents selected from the group consisting of C1-C3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF3, C1-C3 alkoxy, and —NR1-aR1-b,
(III) —(CH2)0-4—R2-1 where R2-1 is R1--aryl or R1-heteroaryl;
(IV) C2-C6 alkenyl with one or two double bonds,
(V) C2-C6 alkynyl with one or two triple bonds, or
(VI) —(CH2)0-4—C3-C7 cycloalkyl, optionally substituted with one, two or three substituents selected from the group consisting of —F, —Cl, —OH,
—SH, —C≡N, —CF3, C1-C3 alkoxy, and —NR1-aR1-b,
and where R2 and R3 are taken together with the carbon to which they are attached to form a carbocycle of three, four, five, six, or seven carbon
atoms, optionally where one carbon atom is replaced by a heteroatom selected from the group consisting of —O—, —S—, —SO2—, and —NRN-2—, where RN-2 is as defined below;
wherein RN is
(I) RN-1—XN— where XN is selected from the group consisting of:
(A) —CO—,
(B) —SO2—,
(C) —(CR′R″)1-6 where R′ and R″ are the same or different and are —H and C1-C4 alkyl,
(D) —CO—(CR′R″)1-6—XN-1 where XN-1 is selected from the group consisting of —O—, —S— and —NR′— and where R′ and R″ are as defined above, or
(E) a single bond;
where RN-1 is selected from the group consisting of:
(A) RN-aryl where RN-aryl is phenyl, 1-naphthyl, 2-naphthyl, tetralinyl, indanyl, or 6,7,8,9-tetrahydro-5H-benzo[a]cycloheptenyl, optionally substituted
with one, two or three of the following substituents which can be the same or different and are:
(1) C1-C6 alkyl, optionally substituted with one, two or three substituents selected from the group consisting of C1-C3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF3, C1-C3 alkoxy, and —NR1-aR1-b,
(2) —OH,
(3) —NO2,
(4) —F, —Cl, —Br, or —I,
(5) —CO—OH,
(6) —C≡N,
(7) (CH2)0-4—CO—NRN-2RN-3 where RN-2 and RN-3 are the same or different and are selected from the group consisting of:
(a) —H,
(b) —C1-C6 alkyl optionally substituted with one substitutent selected from the group consisting of:
(i) —OH, and
(ii) —NH2,
(c) —C1-C6 alkyl optionally substituted with one, two, or three —F, —Cl, —Br, or —I,
(d) —C3-C7 cycloalkyl,
(e) —(C1-C2 alkyl)-(C3-C7 cycloalkyl),
(f) —(C1-C6 alkyl)-O—(C1-C3 alkyl),
(g) —C2-C6 alkenyl with one or two double bonds,
(h) —C2-C6 alkynyl with one or two triple bonds,
(i) —C1-C6 alkyl chain with one double bond and one triple bond,
(j) —R1-aryl, and
(k) —R1-heteroaryl,
(8) —(CH2)0-4—CO—(C1-C12 alkyl),
(9) —(CH2)0-4—CO—(C2-C12 alkenyl with one, two or three double bonds),
(10) —(CH2)0-4—CO—(C2-C12 alkynyl with one, two or three triple bonds),
(11) —(CH2)0-4—CO—(C3-C7 cycloalkyl),
(12) —(CH2)0-4—CO—R1-aryl,
(13) —(CH2)0-4—CO—R1-heteroaryl,
(14) —(CH2)0-4—CO—R1-heterocycle,
(15) (CH2)0-4—CO—RN-4 where RN-4 is selected from the group consisting of morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl, homomorpholinyl, homothiomorpholinyl,
homomorpholinyl S-oxide, homothiomorpholinyl S,S-dioxide, pyrrolinyl and pyrrolidinyl where each group is optionally substituted
with one, two, three, or four of C1-C6 alkyl,
(16) —(CH2)0-4—CO—O—RN-5 where RN-5 is selected from the group consisting of:
(a) C1-C6 alkyl,
(b) —(CH2)0-2—(R1-aryl),
(c) C2-C6 alkenyl containing one or two double bonds,
(d) C2-C6 alkynyl containing one or two triple bonds,
(e) C3-C7 cycloalkyl, and
(f) —(CH2)0-2—(R1-heteroaryl),
(17) —(CH2)0-4—SO2—NRN-2RN-3,
(18) —(CH2)0-4—SO—(C1-C8 alkyl),
(19) —(CH2)0-4—SO2—(C1-C12 alkyl),
(20) —(CH2)0-4—SO2—(C3-C7 cycloalkyl),
(21) —(CH2)0-4—N(H or RN-5)—CO—O—RN-5 where RN-5 can be the same or different,
(22) —(CH2)0-4—N(H or RN-5)—CO—N(RN-5)2, where RN-5 can be the same or different,
(23) —(CH2)0-4—N—CS—N(RN-5)2, where RN-5 can be the same or different,
(24) —(CH2)0-4—N(—H or RN-5)—CO—RN-2 where RN-5 and RN-2 can be the same or different,
(25) —(CH2)0-4—NRN-2RN-3 where RN-2 and RN-3 can be the same or different,
(26) (CH2)0-4—RN-4,
(27) —(CH2)0-4—O—CO—(C1-C6 alkyl),
(28) —(CH2)0-4—P(O)—(ORN-aryl-1)2 where RN-aryl-1 is —H or C1-C4 alkyl,
(29) —(CH2)0-4—O—CO—N(RN-5)2,
(30) —(CH2)0-4—O—CS—N(RN-5)2,
(31) —(CH2)0-4—O—(RN-5)2,
(32) —(CH2)0-4—O—(RN-5)2—COOH,
(33) —(CH2)0-4—S—(RN-5)2,
(34) —(CH2)0-4—O—(C1-C6 alkyl optionally substituted with one, two, three, four, or five of —F),
(35) C3-C7 cycloalkyl,
(36) C2-C6 alkenyl with one or two double bonds optionally substituted with C1-C3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF3, C1-C3 alkoxy, or —NR1-aR1-b,
(37) C2-C6 alkynyl with one or two triple bonds optionally substituted with C1-C3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF3, C1-C3 alkoxy, or —NR1-aR1-b,
(38) —(CH2)0-4—N(—H or RN-5)—SO2—RN-2 where RN-5 and RN-2 can be the same of different, or
(39) —(CH2)0-4—C3-C7 cycloalkyl,
(B) —RN-heteroaryl where RN-heteroaryl is selected from the group consisting of:
pyridinyl, pyrimidinyl, quinolinyl, benzothienyl, indolyl, indolinyl, pryidazinyl, pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl,
quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl,
benzimidazolyl, benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, oxazolopyridinyl,
imidazopyridinyl, isothiazolyl, naphthyridinyl, cinnolinyl, carbazolyl, beta-carbolinyl, isochromanyl, chromanyl, tetrahydroisoquinolinyl,
isoindolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl, benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl,
benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, phenoxazinyl, phenothiazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl,
imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl, dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl,
coumarinyl, isocoumarinyl, chromonyl, chromanonyl, pyridinyl-N-oxide,
where the RN-heteroaryl group is bonded by any atom of the parent RN-heteroaryl group substituted by hydrogen such that the new bond to the RN-heteroaryl group replaces the hydrogen atom and its bond, where heteroaryl is optionally substituted with one, two, three, or four of:
(1) C1-C6 alkyl, optionally substituted with one, two or three substituents selected from the group consisting of C1-C3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF3, C1-C3 alkoxy, and —NR1-aR1-b,
(2) —OH,
(3) —NO2,
(4) —F, —Cl, —Br, or —I,
(5) —CO—OH,
(6) —C≡N,
(7) —(CH2)0-4—CO—NRN-2RN-3 where RN-2 and RN-3 are the same or different and are selected from the group consisting of:
(a) —H,
(b) —C1-C6 alkyl optionally substituted with one substitutent selected from the group consisting of:
(i) —OH, and
(ii) —NH2,
(c) —C1-C6 alkyl optionally substituted with one, two, or three —F, —Cl, —Br, or —I,
(d) —C3-C7 cycloalkyl,
(e) —(C1-C2 alkyl)-(C3-C7 cycloalkyl),
(f) —(C1-C6 alkyl)-O—(C1-C3 alkyl),
(g) —C2-C6 alkenyl with one or two double bonds,
(h) —C2-C6 alkynyl with one or two triple bonds,
(i) —C1-C6 alkyl chain with one double bond and one triple bond,
(j) —R1-aryl, and
(k) —R1-heteroaryl,
(8) —(CH2)0-4—CO—(C1-C12 alkyl),
(9) —(CH2)0-4—CO—(C2-C12 alkenyl with one, two or three double bonds),
(10) —(CH2)0-4—CO—(C2-C12 alkynyl with one, two or three triple bonds),
(11) —(CH2)0-4—CO—(C3-C7 cycloalkyl),
(12) —(CH2)0-4—CO—R1-aryl,
(13) —(CH2)0-4—CO—R1-heteroaryl,
(14) —(CH2)0-4—CO—R1-heterocycle,
(15) —(CH2)0-4—CO—RN-4 where RN-4 is selected from the group consisting of morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl, homomorpholinyl, homothiomorpholinyl,
homomorpholinyl S-oxide, homothiomorpholinyl S,S-dioxide, pyrrolinyl and pyrrolidinyl where each group is optionally substituted
with one, two, three, or four of C1-C6 alkyl,
(16) —(CH2)0-4—CO—O—RN-5 where RN-5 is selected from the group consisting of:
(a) C1-C6 alkyl,
(b) —(CH2)0-2—(R1-aryl),
(c) C2-C6 alkenyl containing one or two double bonds,
(d) C2-C6 alkynyl containing one or two triple bonds,
(e) C3-C7 cycloalkyl, and
(f) —(CH2)0-2—(R1-heteroaryl),
(17) —(CH2)0-4—SO2—NRN-2RN-3,
(18) —(CH2)0-4—SO—(C1-C8 alkyl),
(19) —(CH2)0-4—SO2—(C1-C12 alkyl),
(20) —(CH2)0-4—SO2—(C3-C7 cycloalkyl),
(21) —(CH2)0-4—N(H or RN-5)—CO—O—RN-5 where RN-5 can be the same or different,
(22) —(CH2)0-4—N(H or RN-5)—CO—N(RN-5)2, where RN-5 can be the same or different,
(23) —(CH2)0-4—N—CS—N(RN-5)2, where RN-5 can be the same or different,
(24) —(CH2)0-4—N(—H or RN-5)—CO—RN-2 where RN-5 and RN-2 can be the same or different,
(25) —(CH2)0-4—NRN-2RN-3 where RN-2 and RN-3 can be the same or different,
(26) —(CH2)0-4—RN-4,
(27) —(CH2)0-4—O—CO—(C1-C6 alkyl),
(28) —(CH2)0-4—O—P(O)—(ORN-aryl-1)2 where RN-aryl-1 is —H or C1-C4 alkyl,
(29) —(CH2)0-4—O—CO—N(RN-5)2,
(30) —(CH2)0-4—O—CS—N(RN-5)2,
(31) —(CH2)0-4—O—(RN-5)2,
(32) —(CH2)0-4—O—(RN-5)2—COOH,
(33) —(CH2)0-4—S—(RN-5)2,
(34) —(CH2)0-4—O—(C1-C6 alkyl optionally substituted with one, two, three, four, or five of —F),
(35) C3-C7 cycloalkyl,
(36) C2-C6 alkenyl with one or two double bonds optionally substituted with C1-C3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF3, C1-C3 alkoxy, or —NR1-aR1-b,
(37) C2-C6 alkynyl with one or two triple bonds optionally substituted with C1-C3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF3, C1-C3 alkoxy, or —NR1-aR1-b,
(38) —(CH2)0-4—N(—H or RN-5)—SO2—RN-2 where RN-5 and RN-2 can be the same of different,
(39) —(CH2)0-4—C3-C7 cycloalkyl,
(C) RN-aryl—W—RN-aryl,
(D) RN-aryl—W—RN-heteroaryl,
(E) RN-aryl—W—RN-1-heterocycle, where RN-1-heterocycle is the same as R1-heterocycle,
(F) RN-heteroaryl—W—RN-aryl,
(G) RN-heteroaryl—W—RN-heteroaryl,
(H) RN-heteroaryl—W—RN-heterocycle,
(I) RN-heterocycle—W—RN-aryl, where RN-heterocycle is the same as R1-heterocycle,
(J) RN-heterocycle—W—RN-heteroaryl,
(K) RN-heterocycle—W—RN-1-heterocycle,
where W is
(1) —(CH2)0-4—,
(2) —O—,
(3) —S(O)0-2—,
(4) —N(RN-5)— where RN-5 is as defined above, or
(5) —CO—;
(II) —CO—(C1-C10 alkyl) where alkyl is optionally substituted with one three substitutents selected from the group consisting of:
(A) —OH,
(B) —C1-C6 alkoxy,
(C) —C1-C6 thioalkoxy,
(D) —CO—O—RN-8 where RN-8 is —H, C1-C6 alkyl or -phenyl,
(E) —CO—NRN-2RN-3 where RN-2 and RN-3 are the same or different,
(F) —CO—RN-4 where RN-4,
(G) —SO2—(C1-C8 alkyl),
(H) —SO2—NRN-2RN-3 where RN-2 and RN-3 are the same or different,
(I) —NH—CO—(C1-C6 alkyl),
(J) —NH—CO—O—RN-8 where RN-8,
(K) —NRN-2RN-3 where RN-2 and RN-3 are the same or different,
(L) —RN-4,
(M) —O—CO—(C1-C6 alkyl),
(N) —O—CO—NRN-8RN-8 where the RN-8s are the same or different,
(O) —O—(C1-C5 alkyl)-COOH,
(P) —O—(C1-C6 alkyl optionally substitued with one, two, or three of —F, —CI, —Br, or —I),
(Q) —NH—SO2—(C1-C6 alkyl), and
(R) —F, —Cl,
(III) —CO—(C1-C6 alkyl)-O—(C1-C6 alkyl) where alkyl is optionally substituted with one, two, or three substitutents selected from the group consisting of
(A) —OH,
(B) —C1-C6 alkoxy,
(C) —C1-C6 thioalkoxy,
(D) —CO—O—RN-8 where RN-8 is —H, C1-C6 alkyl or -φ,
(E) —CO—NRN-2RN-3 where RN-2 and RN-3 are the same or different,
(F) —CO—RN-4 where RN-4 is as defined above,
(G) —SO2—(C1-C8 alkyl),
(H) —SO2—NRN-2RN-3 where RN-2 and RN-3 are the same or different,
(I) —NH—CO—(C1-C6 alkyl),
(J) —NH—CO—O—RN-8 where RN-8,
(K) —NRN-2RN-3 where RN-2 and RN-3 are the same or different,
(L) —RN-4,
(M) —O—CO—(C1-C6 alkyl),
(N) —O—CO—NRN-8RN-8 where RN-8 are the same or different,
(O) —O—(C1-C5 alkyl)-COOH,
(P) —O—(C1-C6 alkyl optionally substitued with one, two, or three of —F, —CI, —Br, or —I),
(Q) —NH—SO2—(C1-C6 alkyl), and
(R) —F, or —Cl,
(IV) —CO—(C1-C6 alkyl)-S—(C1-C6 alkyl) where alkyl is optionally substituted with one, two, or three of substitutents selected from the group consisting of
(A) —OH,
(B) —C1-C6 alkoxy,
(C) —C1-C6 thioalkoxy,
(D) —CO—O—RN-8,
(E) —CO—NRN-2RN-3 where RN-2 and RN-3 are the same or different,
(F) —CO—RN-4 where RN-4 is as defined above,
(G) —SO2—(C1-C8 alkyl),
(H) —SO2—NRN-2RN-3 where RN-2 and RN-3 are the same or different,
(I) —NH—CO—(C1-C6 alkyl),
(J) —NH—CO—O—RN-8 where RN-8 is as defined above,
(K) —NRN-2RN-3 where RN-2 and RN-3 are the same or different,
(L) —RN-4 where RN-4 is as defined above,
(M) —O—CO—(C1-C6 alkyl),
(N) —O—CO—NRN-8RN-8 where the RN-8s are the same or different,
(O) —O—(C1-C5 alkyl)-COOH,
(P) —O—(C1-C6 alkyl optionally substitued with one, two, or three of —F, —Cl, —Br, or —I),
(Q) —NH—SO2—(C1-C6 alkyl), and
(R) —F, or —Cl,
(V) —CO—CH(—(CH2)0-2—O—RN-10)—(CH2)0-2—RN-aryl/RN-heteroaryl), where RN-10 is selected from the group consisting of:
(A) —H,
(B) C1-C6 alkyl,
(C) C3-C7 cycloalkyl,
(D) C2-C6 alkenyl with one double bond,
(E) C2-C6 alkynyl with one triple bond,
(F) R1-aryl, and
(G) RN-heteroaryl, or
(VI) —CO—(C3-C8 cycloalkyl) where alkyl is optionally substituted with one or two substitutents selected from the group consisting of:
(A) —(CH2)0-4—OH,
(B) —(CH2)0-4—C1-C6 alkoxy,
(C) —(CH2)0-4—C1-C6 thioalkoxy,
(D) —(CH2)0-4—CO—O—RN-8 where RN-8 is —H, C1-C6 alkyl or -phenyl,
(E) —(CH2)0-4—CO—NRN-2RN-3 where RN-2 and RN-3 are the same or different,
(F) —(CH2)0-4—CO—RN-4,
(G) —(CH2)0-4—SO2—(C1-C8 alkyl),
(H) —(CH2)0-4—SO2—NRN-2RN-3 where RN-2 and RN-3 are the same or different,
(I) —(CH2)0-4—NH—CO—(C1-C6 alkyl),
(J) —NH—CO—O—RN-8,
(K) —(CH2)0-4-NRN-2RN-3 where RN-2 and RN-3 are the same or different,
(L) —(CH2)0-4—RN-4,
(M) —O—CO—(C1-C6 alkyl),
(N) —O—CO—NRN-8RN-8 where RN-8 are the same or different,
(O) —O—(C1-C5 alkyl)-COOH,
(P) —O—(C1-C6 alkyl optionally substitued with one, two, or three of —F, —Cl, —Br, or —I),
(Q) —NH—SO2—(C1-C6 alkyl), and
(R) —F, or —Cl,
wherein RC is:
(IV) RC-heteroaryl where RC-heteroaryl is imidazolyl optionally substituted as defined above for RN-heteroaryl; and wherein R20 is H or C1-6 alkyl or alkenyl.
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