Substituted alcohols useful in treatment of Alzheimer's disease
First Claim
Patent Images
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.
1 Assignment
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Accused Products
Abstract
The invention relates to substituted alcohol compounds of the formula (I):
wherein X, R1, R2, R3, RN, R20 and RC are defined herein. The compounds are useful in the treatment or prevention of Alzheimer'"'"'s disease and more specifically to compounds that are capable of inhibiting beta-secretase, an enzyme that cleaves amyloid precursor protein to produce amyloid beta peptide (A-beta), a major component of the amyloid plaques found in the brains of Alzheimer'"'"'s sufferers.
165 Citations
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.- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9)
or a pharmaceutically acceptable salt or ester thereof, wherein R1, R2, R3, X, RN, R20 and RC are as defined in claim 1. -
9. A method of treating a patient who has Alzheimer'"'"'s disease, and who is in need of such treatment which comprises administration of a therapeutically effective amount of a compound selected from the group consisting of a substituted alcohol of formula (I)
where R1, R2, R3, X, RN, R20 and RC are as defined in claim 1, or pharmaceutically acceptable salt or ester thereof.
-
-
10. A compound selected from the group consisting of:
Specification