Substituted alcohols useful in treatment of Alzheimer's disease

Abstract

The invention relates to substituted alcohol compounds of the formula (I): wherein X, R 1 , R 2 , R 3 , R N , R 20 and R C 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.

1 . A compound of the formula I:  
       
         
           
           
               
               
           
         
       
       wherein X is CR 2 R 3 , C 1-6  alkyl or alkenyl, O, S, SO, or SO 2 ;  
       wherein R 1  is 
 (I) C 1 -C 6  alkyl, optionally substituted with one, two or three substituents selected from the group consisting of C 1 -C 3  alkyl, C 1 -C 7  alkyl (optionally substituted with C 1 -C 3  alkyl and C 1 -C 3  alkoxy), —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3  alkoxy, —NR 1-a R 1-b  where R 1-a  and R 1-b  are independently —H or C 1 -C 6  alkyl, and —OC═O NR 1-a R 1-b ,  
 (II) —CH 2 —S(O) 0-2 -(C 1 -C 6  alkyl),  
 (III) —CH 2 —CH 2 -S(O) 0-2 -(C 1 -C 6  alkyl),  
 (IV) C 2 -C 6  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, —CF 3 , C 1 -C 3  alkoxy, and —NR 1-a R 1-b ,  
 (V) C 2 -C 6  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, —CF 3 , C 1 -C 3  alkoxy, and —NR 1-a R 1-b ,  
 (VI) —(CH 2 ) n1 —(R 1-aryl ) where n, is zero or one and where R 1-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) C 1 -C 6  alkyl optionally substituted with one, two or three substituents selected from the group consisting of C 1 -C 3  alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3  alkoxy, and —NR 1-a R 1-b ,  
 (B) C 2 -C 6  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, —CF 3 , C 1 -C 3  alkoxy, and —NR 1-a R 1-b ,  
 (C) C 2 -C 6  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, —CF 3 , C 1 -C 3  alkoxy, and —NR 1-a R 1-b ,  
 (D) —F, Cl, —Br or —I,  
 (F) —C 1 -C 6  alkoxy optionally substituted with one, two or three of —F,  
 (G) —NR N-2 R N-3  where R N-2  and R N-3  are as defined below,  
 (H) —OH,  
 (I) —C≡N,  
 (J) C 3 -C 7  cycloalkyl, optionally substituted with one, two or three substituents selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3  alkoxy, and —NR 1-a R 1-b ,  
 (K) —CO—(C 1 -C 4  alkyl),  
 (L) —SO 2 —NR 1-a R 1-b ,  
 (M) —CO—NR 1-a R 1-b ,  
 (N) —SO 2 —(C 1 -C 4  alkyl),  
 
 (VII) —(CH 2 ) n1 -(R 1-heteroaryl ) where n, is as defined above and where R 1-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, naphthidinyl, 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 R 1-heteroaryl  group is bonded to —CH 2 ) n1 — 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 optionally substituted with one, two, three or four of: 
 (1) C 1 -C 6  alkyl optionally substituted with one, two or three substituents selected from the group consisting of C 1 -C 3  alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3  alkoxy, and —NR 1-a R 1-b ,  
 (2) C 2 -C 6  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, —CF 3 , C 1 -C 3  alkoxy, and —NR 1-a R 1-b ,  
 (3) C 2 -C 6  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, —CF 3 , C 1 -C 3  alkoxy, and —NR 1-a R 1-b ,  
 (4) —F, Cl, —Br or —I,  
 (6) —C 1 -C 6  alkoxy optionally substituted with one, two, or three of —F,  
 (7) —NR N-2 R N-3  where R N-2  and R N-3  are as defined below,  
 (8) —OH,  
 (9) —C≡N,  
 (10) C 3 -C 7  cycloalkyl, optionally substituted with one, two or three substituents selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3  alkoxy, and —NR 1-a R 1-b ,  
 (11) —CO—(C 1 -C 4  alkyl),  
 (12) —SO 2 —NR 1-a R 1-b ,  
 (13) —CO—NR 1-a R 1-b , or  
 (14) —SO 2 —(C 1 -C 4  alkyl), with the proviso that when n 1  is zero R 1-heteroaryl  is not bonded to the carbon chain by nitrogen, or  
 
 (VIII) —(CH 2 ) n1 —(R 1-heterocycle ) where n 1  is as defined above and R 1-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 R 1-heterocycle  group is bonded by any atom of the parent R 1-heterocycle  group substituted by hydrogen such that the new bond to the R 1-heterocycle  group replaces the hydrogen atom and its bond, where heterocycle is optionally substituted with one, two, three or four: 
 (1) C 1 -C 6  alkyl optionally substituted with one, two or three substituents selected from the group consisting of C 1 -C 3  alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3  alkoxy, and —NR 1-a R 1-b ,  
 (2) C 2 -C 6  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, —CF 3 , C 1 -C 3  alkoxy, and —NR 1-a R 1-b ,  
 (3) C 2 -C 6  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, —CF 3 , C 1 -C 3  alkoxy, and —NR 1-a R 1-b ,  
 (4) —F, Cl, —Br, or —I,  
 (5) C 1 -C 6  alkoxy,  
 (6) —C 1 -C 6  alkoxy optionally substituted with one, two, or three —F,  
 (7) —NR N-2 R N-3  where R N-2  and R N-3  are as defined below,  
 (8) —H,  
 (9) —C≡N,  
 (10) C 3 -C 7  cycloalkyl, optionally substituted with one, two or three substituents selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3  alkoxy, and —NR 1-a R 1-b ,  
 (11) —CO—(C 1 -C 4  alkyl),  
 (12) —SO 2 —NR 1-a R 1-b ,  
 (13) —CO—NR 1-a R 1-b ,  
 (14) —SO 2 —(C 1 -C 4  alkyl),  
 (15) ═O, with the proviso that when n, is zero R 1-heterocycle  is not bonded to the carbon chain by nitrogen;  
 wherein R 2  is  
 
 (I) —H,  
 (II) C 1 -C 6  alkyl, optionally substituted with one, two or three substituents selected from the group consisting of C 1 -C 3  alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3  alkoxy, and —NR 1-a R 1-b ,  
 (III) —(CH 2 ) 0-4 —R 2-1  where R 2-1  is R 1-aryl  or R 1-heteroaryl ;  
 (IV) C 2 -C 6  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, —CF 3 , C 1 -C 3  alkoxy, and —NR 1-a R 1-b ,  
 (V) C 2 -C 6  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, —CF 3 , C 1 -C 3  alkoxy, and —NR 1-a R 1-b ,  
 (VI) —(CH 2 ) 0-4 —C 3 -C 7  cycloalkyl, optionally substituted with one, two or three substituents selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3  alkoxy, and —NR 1-a R 1-b ;  
 wherein R 3  is  
 (I) —H,  
 (II) C 1 -C 6  alkyl, optionally substituted with one, two or three substituents selected from the group consisting of C 1 -C 3  alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3  alkoxy, and —NR 1-a R 1-b ,  
 (III) —(CH 2 ) 0-4 —R 2-1  where R 2-1  is R 1-aryl  or R 1-heteroaryl ;  
 (IV) C 2 -C 6  alkenyl with one or two double bonds,  
 (V) C 2 -C 6  alkynyl with one or two triple bonds, or  
 (VI) —(CH 2 ) 0-4 —C 3 -C 7  cycloalkyl, optionally substituted with one, two or three substituents selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3  alkoxy, and —NR 1-a R 1-b ,  
 and where R 2  and R 3  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—, —SO 2 —, and —NR N-2 —, where R N-2  is as defined below;  
 wherein R N  is  
 (I) R N-1 —X N — where X N  is selected from the group consisting of: 
 (A) —CO—,  
 (B) —SO 2 —,  
 (C) —(CR′R″) 1-6  where R′ and R″ are the same or different and are —H and C 1 -C 4  alkyl,  
 (D) —CO—(CR′R″) 1-6 —X N-1  where X N-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 R N-1  is selected from the group consisting of: 
 (A) R N-aryl  where R N-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) C 1 -C 6  alkyl, optionally substituted with one, two or three substituents selected from the group consisting of C 1 -C 3  alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3  alkoxy, and —NR 1-a R 1-b ,  
 (2) —OH,  
 (3) —NO 2 ,  
 (4) —F, —Cl, —Br, or —I,  
 (5) —CO—OH,  
 (6) —C≡N,  
 (7) —(CH 2 ) 0-4 —CO—NR N-2 R N-3  where R N-2  and R N-3  are the same or different and are selected from the group consisting of: 
 (a) —H,  
 (b) —C 1 -C 6  alkyl optionally substituted with one substitutent selected from the group consisting of:  
  (i) —OH, and  
  (ii) —NH 2 ,  
 (c) —C 1 -C 6  alkyl optionally substituted with one, two, or three —F, —Cl, —Br, or —I,  
 (d) —C 3 -C 7  cycloalkyl,  
 (e) —(C 1 -C 2  alkyl)-(C 3 -C 7  cycloalkyl),  
 (f) —(C 1 -C 6  alkyl)-O—(C 1 -C 3  alkyl),  
 (g) —C 2 -C 6  alkenyl with one or two double bonds,  
 (h) —C 2 -C 6  alkynyl with one or two triple bonds,  
 (i) —C 1 -C 6  alkyl chain with one double bond and one triple bond,  
 (j) —R 1-aryl , and  
 (k) —R 1-heteroaryl ,  
 
 (8) —(CH 2 ) 0-4 —CO—(C 1 -C 12  alkyl),  
 (9) —(CH 2 ) 0-4 —CO—(C 2 -C 12  alkenyl with one, two or three double bonds),  
 (10) —(CH 2 ) 0-4 —CO—(C 2 -C 12  alkynyl with one, two or three triple bonds),  
 (11) —(CH 2 ) 0-4 —CO—(C 3 -C 7  cycloalkyl),  
 (12) —(CH 2 ) 0-4 —CO-R 1-aryl ,  
 (13) —(CH 2 ) 0-4 —CO—R 1-heteroaryl ,  
 (14) —(CH 2 ) 0-4 —CO—R 1-heterocycle ,  
 (15) —(CH 2 ) 0-4 —CO—R N-4  where R N-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 C 1 -C 6  alkyl,  
 (16) —(CH 2 ) 0-4 —CO—O—R N-5  where R N-5  is selected from the group consisting of: 
 (a) C 1 -C 6  alkyl,  
 (b) —(CH 2 ) 0-2 -(R 1-aryl ),  
 (c) C 2 -C 6  alkenyl containing one or two double bonds,  
 (d) C 2 -C 6  alkynyl containing one or two triple bonds,  
 (e) C 3 -C 7  cycloalkyl, and  
 (f) —(CH 2 ) 0-2 —(R 1-heteroaryl ),  
 
 (17) —(CH 2 ) 0-4 —SO 2 —NR N-2 R N-3 ,  
 (18) —(CH 2 ) 0-4 —SO—(C 1 -C 8  alkyl),  
 (19) —(CH 2 ) 0-4 —SO 2 —(C 1 -C 12  alkyl),  
 (20) —(CH 2 ) 0-4 —SO 2 —(C 3 -C 7  cycloalkyl),  
 (21) —(CH 2 ) 0-4 —N(H or R N-5 )—CO—O—R N-5  where R N-5  can be the same or different,  
 (22) —(CH 2 ) 0-4 —N(H or R N-5 )—CO—N(R N-5 ) 2 , where R N-5  can be the same or different,  
 (23) —(CH 2 ) 0-4 —N—CS—N(R N-5 ) 2 , where R N-5  can be the same or different,  
 (24) —(CH 2 ) 0-4 —N(—H or R N-5 )—CO—R N-2  where R N-5  and R N-2  can be the same or different,  
 (25) —(CH 2 ) 0-4 —NR N-2 R N-3  where R N-2  and R N-3  can be the same or different,  
 (26) —(CH 2 ) 0-4 —R N-4 ,  
 (27) —(CH 2 ) 0-4 —O—CO—(C 1 -C 6  alkyl),  
 (28) —(CH 2 ) 0-4 —O—P(O)—(OR N-aryl-1 ) 2  where R N-aryl-1  is —H or C 1 -C 4  alkyl,  
 (29) —(CH 2 ) 0-4 —O—CO—N(R N-5 ) 2 ,  
 (30) —(CH 2 ) 0-4 —O—CS—N(R N-5 ) 2 ,  
 (31) —(CH 2 ) 4 —O—(R N-5 ) 2 ,  
 (32) —(CH 2 ) 0-4 —O—(R N-5 ) 2 —COOH,  
 (33) —(CH 2 ) 0-4 —S—(R N-5 ) 2 ,  
 (34) —(CH 2 ) 0 -4-O—(C 1 -C 6  alkyl optionally substituted with one, two, three, four, or five of —F),  
 (35) C 3 -C 7  cycloalkyl,  
 (36) C 2 -C 6  alkenyl with one or two double bonds optionally substituted with C 1 -C 3  alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3  alkoxy, or —NR 1-a R 1-b ,  
 (37) C 2 -C 6  alkynyl with one or two triple bonds optionally substituted with C 1 -C 3  alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3  alkoxy, or —NR 1-a R 1-b ,  
 (38) —(CH 2 ) 0-4 —N(—H or R N-5 )—SO 2 —R N-2  where R N-5  and R N-2  can be the same of different, or  
 (39) —(CH 2 ) 0-4 —C 3 -C 7  cycloalkyl,  
 
 (B) —R N-heteroaryl  where R N-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 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 optionally substituted with one, two, three, or four of: 
 (1) C 1 -C 6  alkyl, optionally substituted with one, two or three substituents selected from the group consisting of C 1 -C 3  alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3  alkoxy, and —NR 1-a R 1-b ,  
 (2) —OH,  
 (3) —NO 2 ,  
 (4) —F, —Cl, —Br, or —I,  
 (5) —CO—OH,  
 (6) —C≡N,  
 (7) —(CH 2 ) 0-4 -CO—NR N-2 R N-3  where R N-2  and R N-3  are the same or different and are selected from the group consisting of: 
 (a) —H,  
 (b) —C 1 -C 6  alkyl optionally substituted with one substitutent selected from the group consisting of: 
 (i) —OH, and  
 (ii) —NH 2 ,  
 
 (c) —C 1 -C 6  alkyl optionally substituted with one, two, or three —F, —Cl, —Br, or —I,  
 (d) —C 3 -C 7  cycloalkyl,  
 (e) —(C 1 -C 2  alkyl)-(C 3 -C 7  cycloalkyl),  
 (f) —(C 1 -C 6  alkyl)-O—(C 1 -C 3  alkyl),  
 (g) —C 2 -C 6  alkenyl with one or two double bonds, 
 (h) —C 2 -C 6  alkynyl with one or two triple bonds,  
 
 (i) —C 1 -C 6  alkyl chain with one double bond and one triple bond,  
 (j) —R 1-aryl , and  
 (k) —R 1-heteroaryl ,  
 
 (8) —(CH 2 ) 0-4 —CO—(C 1 -C 12  alkyl),  
 (9) —(CH 2 ) 0-4 —CO—(C 2 -C 12  alkenyl with one, two or three double bonds),  
 (10) —(CH 2 ) 0-4 —CO—(C 2 -C 12  alkynyl with one, two or three triple bonds),  
 (11) —(CH 2 ) 0-4 —CO—(C 3 -C 7  cycloalkyl),  
 (12) —(CH 2 ) 0-4 —CO—R 1-aryl ,  
 (13) —(CH 2 ) 0-4 —CO—R 1-heteroaryl ,  
 (14) —(CH 2 ) 0-4 —CO—R 1-heterocycle ,  
 (15) —(CH 2 ) 0-4 -CO—R N-4  where R N-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 C 1 -C 6  alkyl,  
 (16) —(CH 2 ) 0-4 —CO—O—R N-5  where R N-5  is selected from the group consisting of: 
 (a) C 1 -C 6  alkyl,  
 (b) —(CH 2 ) 0-2 —(R 1-aryl ),  
 (c) C 2 -C 6  alkenyl containing one or two double bonds, 
 (d) C 2 -C 6  alkynyl containing one or two triple bonds,  
 
 (e) C 3 -C 7  cycloalkyl, and  
 (f)-(CH 2 ) 0-2 -(R 1-heteroaryl ),  
 
 (17) —(CH 2 ) 0-4 —SO 2 —NR N-2 R N-3,    
 (18) —(CH 2 ) 0-4 —SO—(C 1 -C 8  alkyl),  
 (19) —(CH 2 ) 0-4 —SO 2 —(C 1 -C 12  alkyl),  
 (20) —(CH 2 ) 0-4 —SO 2 —(C 3 -C 7  cycloalkyl),  
 (21) —(CH 2 ) 0-4 —N(H or R N-5 )—CO—O—R N-5  where R N-5  can be the same or different,  
 (22) (CH 2 ) 0-4 —N(H or R N-5 )—CO—N(R N-5 ) 2 , where R N-5  can be the same or different,  
 (23) —(CH 2 ) 0-4 —N—CS—N(R N-5 ) 2 , where R N-5  can be the same or different,  
 (24) —(CH 2 ) 0-4 —N(—H or R N-5 )—CO—R N-2  where R N-5  and R N-2  can be the same or different,  
 (25) —(CH 2 ) 0-4 —NR N-2 R N-3  where R N-2  and R N-3  can be the same or different,  
 (26) —(CH 2 ) 0-4 —R N-4 ,  
 (27) —(CH 2 ) 0-4 —CO—(C 1 -C 6  alkyl),  
 (28) —(CH 2 ) 0-4 —O—P(O)—(OR N-aryl-1 ) 2  where R N-aryl-1  is —H or C 1 -C 4  alkyl,  
 (29) —(CH 2 ) 0-4 —O—CO—N(R N-5 ) 2 ,  
 (30) —(CH 2 ) 0-4 —O—CS—N(R N-5 ) 2 ,  
 (31) —(CH 2 ) 0-4 —O—(R N-5 ) 2 ,  
 (32) —(CH 2 ) 0-4 —O—(R N-5 ) 2 —COOH,  
 (33) —(CH 2 ) 0-4 —S—(R N-5 ) 2 ,  
 (34) —(CH 2 ) 0-4 —O—(C 1 -C 6  alkyl optionally substituted with one, two, three, four, or five of —F),  
 (35) C 3 -C 7  cycloalkyl,  
 (36) C 2 -C 6  alkenyl with one or two double bonds optionally substituted with C 1 -C 3  alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3  alkoxy, or —NR 1-a R 1-b ,  
 (37) C 2 -C 6  alkynyl with one or two triple bonds optionally substituted with C 1 -C 3  alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3  alkoxy, or —NR 1-a R 1-b ,  
 (38) —(CH 2 ) 0-4 —N(—H or R N-5 )—SO 2 —R N-2  where R N-5  and R N-2  can be the same of different,  
 (39) —(CH 2 ) 0-4 —C 3 -C 7  cycloalkyl,  
 
  (C)R N-aryl —W—R N-aryl ,  
  (D) R N-aryl —W—R N-heteroaryl ,  
  (E) R N-aryl —W—R N-1-heterocycle , where R N-1-heterocycle  is the same as R 1-heterocycle ,  
  (F) R N-heteroaryl —W—R N-aryl ,  
  (G) R N-heteroaryl —W—R N-heteroaryl ,  
  (H) R N-heteroaryl —W—R N-1-heterocycle ,  
  (I) R N-heterocycle —W—R N-aryl , where R N-heterocycle  is the same as R 1-heterocycle ,  
  (J) R N-heterocycle —W—R N-heteroaryl ,  
  (K) R N-heterocycle —W—R N-1-heterocycle , 
 where W is 
 (6) —(CH 2 ) 0-4 —,  
 (7) —O—,  
 (8) —S(O) 0-2 —,  
 (9) —N(R N-5 )— where R N-5  is as defined above, or  
 (10) —CO—;  
 
 
 (II) —CO—(C 1 -C 10  alkyl) where alkyl is optionally substituted with one three substitutents selected from the group consisting of: 
 (A) —OH,  
 (B) —C 1 -C 6  alkoxy,  
 (C) —C 1 -C 6  thioalkoxy,  
 (D) —CO—O—R N-8  where R N-8  is —H, C 1 -C 6  alkyl or -phenyl,  
 (E) —CO—NR N-2 R N-3  where R N-2  and R N-3  are the same or different,  
 (F) —CO—R N-4  where R N-4 ,  
 (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,  
 (I) —NH—CO—(C 1 -C 6  alkyl),  
 (J) —NH—CO—O—R N-8  where R N-8 ,  
 (K) —NR N-2 R N-3  where R N-2  and R N-3  are the same or different,  
 (L) —R N-4 ,  
 (M) —O—CO—(C 1 -C 6  alkyl),  
 (N) —O—CO—NR N-8 R N-8  where the R N-8 S are the same or different,  
 (O) —O—(C 1 -C 5  alkyl)-COOH,  
 (P) —O—(C 1 -C 6  alkyl optionally substitued with one, two, or three of —F, —CI, —Br, or —I),  
 (Q) —NH—SO 2 —(C 1 -C 6  alkyl), and  
 (R) —F, —Cl,  
 
 (III) —CO—(C 1 -C 6  alkyl)-O—(C 1 -C 6  alkyl) where alkyl is optionally substituted with one, two, or three substitutents selected from the group consisting of 
 (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,  
 (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,  
 (I) —NH—CO—(C 1 -C 6  alkyl),  
 (J) —NH—CO—O—R N-8  where R N-8 ,  
 (K) —NR N-2 R N-3  where R N-2  and R N-3  are the same or different,  
 (L) —R N-4 ,  
 (M) —O—CO—(C 1 -C 6  alkyl),  
 (N) —O—CO—NR N-8 R N-8  where R N-8  are the same or different,  
 (O) —O—(C 1 -C 5  alkyl)-COOH,  
 (P) —O—(C 1 -C 6  alkyl optionally substitued with one, two, or three of —F, —CI, —Br, or —I),  
 (Q) —NH—SO 2 —(C 1 -C 6  alkyl), and  
 (R) —F, or —Cl,  
 
 (IV) —CO—(C 1 -C 6  alkyl)-S—(C 1 -C 6  alkyl) where alkyl is optionally substituted with one, two, or three of substitutents selected from the group consisting of 
 (A) —OH,  
 (B) —C 1 -C 6  alkoxy,  
 (C) —C 1 -C 6  thioalkoxy,  
 (D) —CO—O—R N-8 ,  
 (E) —CO—NR N-2 R N-3  where R N-2  and R N-3  are the same or different,  
 (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,  
 (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,  
 (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 s are the same or different,  
 (O) —O—(C 1 -C 5  alkyl)-COOH,  
 (P) —O—(C 1 -C 6  alkyl optionally substitued with one, two, or three of —F, —Cl, —Br, or —I),  
 (Q) —NH—SO 2 —(C 1 -C 6  alkyl), and  
 (R) —F, or —Cl,  
 
 (V) —CO—CH(—(CH 2 ) 0-2 —O—R N-10 )—(CH 2 ) 0-2 —R N-aryl /R N-heteroaryl ), where R N-10  is selected from the group consisting of: 
 (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 , and  
 (G) R N-heteroaryl , or  
 
 (VI) —CO—(C 3 -C 8  cycloalkyl) where alkyl is optionally substituted with one or two substitutents selected from the group consisting of: 
 (A) —(CH 2 ) 0-4 —OH,  
 (B) —(CH 2 ) 0-4 —C 1 -C 6  alkoxy,  
 (C) —(CH 2 ) 0-4 —C 1 -C 6  thioalkoxy,  
 (D) —(CH 2 ) 0-4 —CO—O—R N-8  where R N-8  is —H, C 1 -C 6  alkyl or -phenyl,  
 (E) —(CH 2 ) 0-4 —CO—NR N-2 R N-3  where R N-2  and R N-3  are the same or different,  
 (F) —(CH 2 ) 0-4 -CO—R N-4 ,  
 (G) —(CH 2 ) 0-4 —SO 2 —(C 1 -C 8  alkyl),  
 (H) —(CH 2 ) 0-4 —SO 2 —NR N-2 R N-3  where R N-2  and R N-3  are the same or different,  
 (I) —(CH 2 ) 0-4 —NH—CO—(C 1 -C 6  alkyl),  
 (J) —NH—CO—O—R N-8 ,  
 (K) —(CH 2 ) 0-4 —NR N-2 R N-3  where R N-2  and R N-3  are the same or different,  
 (L) —(CH 2 ) 0 -4-R N-4 ,  
 (M) —O—CO—(C 1 -C 6  alkyl),  
 (N) —O—CO—NR N-8 R N-8  where R N-8  are the same or different,  
 (O) —O—(C 1 -C 5  alkyl)-COOH,  
 (P) —O—(C 1 -C 6  alkyl optionally substitued with one, two, or three of —F, —Cl, —Br, or —I),  
 (Q) —NH—SO 2 —(C 1 -C 6  alkyl), and  
 (R) —F, or —Cl,  
 wherein R C  is:  
 
 (I) —C 1 -C 10  alkyl optionally substituted with one, two or three substituents selected from the group consisting of C 1 -C 3  alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 6  alkoxy, —O-phenyl, —NR 1-a R 1-b , —OC═O NR 1-a R 1-b , —S(═O) 0-2 , —NR 1-a C═O NR 1-a R 1-b , —C═O NR 1-a R 1-b , and —S(═O) 2  NR 1-a R 1-b ,  
 (II) —(CH 2 ) 0-3 -(C 3 -C 8 ) cycloalkyl where cycloalkyl can be optionally substituted with one, two or three substituents selected from the group consisting of C 1 -C 3  alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 6  alkoxy, —O-phenyl, —CO—OH, —CO—O—(C 1 -C 4  alkyl), and —NR 1-a R 1-b ,  
 (III) —(CR C-x R C-y ) 0-4 —R C-1  where R C-x  and R C-y  are 
 (A) —H,  
 (B) C 1 -C 4  alkyl optionally substituted with one or two —OH,  
 (C) C 1 -C 4  alkoxy optionally substituted with one, two, or three —F,  
 (D) —(CH 2 ) 0-4 —C 3 -C 7  cycloalkyl,  
 (E) C 2 -C 6  alkenyl containing one or two double bonds,  
 (F) C 2 -C 6  alkynyl contianing one or two triple bonds,  
 (G) phenyl,  
 
 and where R C-x  and R C-y  are taken together with the carbon to which they are attached to form a carbocycle of three, four, five, six of seven carbon atoms, optionally where one carbon atom is replaced by a heteroatom selected from the group consisting of —O—, —S—, —SO 2 —, and —NR N-2 - and R C-aryl  is the same as R N-aryl ;  
 (IV) —(CR C-x R C-y ) 0-4 —R C-heteroaryl  where R C-heteroaryl  is the same as R N-heteroaryl ,  
 (V) —(CR C-x R C-y ) 0-4 -R C-aryl -R C-aryl ,  
 (VI) —(CR C-x R C-y ) 0-4 —R C-aryl -R C-heteroaryl ,  
 (VII) —(CR C-x R C-y ) 0-4 —R C-heteroaryl -R C-aryl )  
 (VIII) —(CR C-x R C-y ) 0-4 -R C-heteroaryl -R C-heteroaryl ,  
 (IX) —(CR C-x R C-y ) 0-4 —R C-aryl -R C-heterocycle  and where R C-heterocycle  is the same as R 1-heterocycle ,  
 (X) —(CR C-x R C-y ) 0-4 —R C-heteroaryl -R C-heterocycle )  
 (XI) —(CR C-x R C-y ) 0-4 -R C-heterocycle -R C-aryl ,  
 (XII) —(CR C-x R C-y ) 0-4 -R C-heterocycle -R C-heteroaryl ,  
 (XIII) —(CR C-x R C-y ) 0-4 —R C-heterocycle -R C-heterocycle ,  
 (XIV) —(CR C-x R C-y ) 0-4 —R C-heterocycle ,  
 (XV) —[C(R C-1 )(R C-2 )] 1-3 —CO—N—(R C-3 ) 2  where R C-1  and R C-2  are the same or different and are selected from the group consisting of: 
 (A) —H,  
 (B) —C 1 -C 6  alkyl, optionally substituted with one, two or three substituents selected from the group consisting of C 1 -C 3  alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 6  alkoxy, —O-phenyl, and —NR 1-a R 1-b ,  
 (C) C 2 -C 6  alkenyl with one or two double bonds, optionally substituted with one, two or three substituents selected from the group consisting of C 1 -C 3  alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 6  alkoxy, —O-phenyl, and —NR 1-a R 1-b ,  
 (D) C 2 -C 6  alkynyl with one or two triple bonds, optionally substituted with one, two or three substituents selected from the group consisting of C 1 -C 3  alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 6  alkoxy, —O-phenyl, and —NR 1-a R 1-b ,  
 (E) —(CH 2 ) 1-2 —S(O) 0-2 —(C 1 -C 6  alkyl),  
 (F) —(CH 2 ) 0-4 —C 3 -C 7  cycloalkyl, optionally substituted with one, two or three substituents selected from the group consisting of C 1 -C 3  alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 6  alkoxy, —O-phenyl, and —NR 1-a R 1-b ,  
 (G) —(C 1 -C 4  alkyl)-R C′-aryl  where R C′-aryl  is as defined for R 1-aryl ,  
 (H) —(C 1 -C 4  alkyl)-R C-heteroaryl ,  
 (I) —(C 1 -C 4  alkyl)-R C-heterocycle ,  
 (J) —R C-heteroaryl ,  
 (K) —R C-heterocycle ,  
 (M) —(CH 2 ) 1-4 -R C-4 —(CH 2 ) 0-4 -R C′-aryl  where R C-4  is —O—, —S— or —NR C-5 — where R C-5  is C 1 -C 6  alkyl,  
 (N) —(CH 2 ) 1-4 —R C-4 —(CH 2 ) 0-4 —R C-heteroaryl , and  
 (O) —R C′-aryl ,  
 
 and where R C-3  is the same or different and is: 
 (A) —H,  
 (B) —C 1 -C 6  alkyl optionally substituted with one, two or three substituents selected from the group consisting of C 1 -C 3  alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 6  alkoxy, —O-phenyl, and —NR 1-a R 1-b ,  
 (C) C 2 -C 6  alkenyl with one or two double bonds, optionally substituted with one, two or three substituents selected from the group consisting of C 1 -C 3  alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 6  alkoxy, —O-phenyl, and —NR 1-a R 1-b ,  
 (D) C 2 -C 6  alkynyl with one or two triple bonds, optionally substituted with one, two or three substituents selected from the group consisting of C 1 -C 3  alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 6  alkoxy, —O-phenyl, and —NR 1-a R 1-b ,  
 (E) —(CH 2 ) 0-4 —C 3 -C 7  cycloalkyl, optionally substituted with one, two or three substituents selected from the group consisting of C 1 -C 3  alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C—N, —CF 3 , C 1 -C 6  alkoxy, —O-phenyl, and —NR 1-a R 1-b ,  
 (F) —R C′-aryl ,  
 (G) —R C-heteroaryl ,  
 (H) —R C-heterocycle ,  
 (I) —(C 1 -C 4  alkyl)-R C′-aryl ,  
 (J) —(C 1 -C 4  alkyl)-R C-heteroaryl , or  
 (K) —(C 1 -C 4  alkyl)-R C-heterocycle ,  
 
 (XVI) —CH(R C-aryl ) 2  where R C-aryl  are the same or different and are as defined above,  
 (XVII) —CH(R C-heteroaryl ) 2  where R C-heteroaryl  are the same or different and are as defined above,  
 (XVIII) —CH(R C-aryl )(R C-heteroaryl ),  
 (XIX) -cyclopentyl, -cyclohexyl, or -cycloheptyl ring fused to R C-aryl  or R C-heteroaryl  or R C-heterocycle  where one carbon of cyclopentyl, cyclohexyl, or -cycloheptyl is optionally replaced with NH, NR N-5 , O, or S(═O) 0-2 , and where cyclopentyl, cyclohexyl, or -cycloheptyl can be optionally substituted with one or two —C 1 -C 3  alkyl, —F, —OH, —SH, —C≡N, —CF 3 , C 1 -C 6  alkoxy, ═O, or —NR 1-a R 1-b ,  
 (XX) C 2 -C 10  alkenyl containing one or two double bonds optionally substituted with one, two or three substituents selected from the group consisting of C 1 -C 3  alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 6  alkoxy, —O-phenyl, and —NR 1-a R 1-b ,  
 (XXI) C 2 -C 10  alkynyl containing one or two triple bonds optionally substituted with one, two or three substituents selected from the group consisting of C 1 -C 3  alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 6  alkoxy, —O-phenyl, and —NR 1-a R 1-b ,  
 (XXI) —(CH 2 ) 0-1 —CHR C-6 —(CH 2 ) 0-1 -R C-aryl  and R C-6  is —(CH 2 ) 0-6 —OH,  
 (XXII) —(CH 2 ) 0-1 —CHR C-6 (CH 2 ) 0-1 —R C-heteroaryl ,  
 (XXIII) —CH(—R C-aryl  or R C-heteroaryl )—CO—O(C 1 -C 4  alkyl),  
 (XXIV) —CH(—CH 2 —OH)—CH(—OH)—NO 2 ,  
 (XXV) (C 1 -C 6  alkyl)-O—(C 1 -C 6  alkyl)-OH,  
 (XXVII) —CH 2 —NH—CH 2 —CH(—O—CH 2 —CH 3 ) 2 ,  
 (XXVIII) —H,  
 (XXIX) —(CH 2 ) 0-6 —C(═NR 1-a )(NR 1-a R 1-b ); and  
 wherein R 20  is H or C 1-6  alkyl or alkenyl.  
 
     
     
         2 . A pharmaceutically acceptable salt or ester of a compound according to  claim 1 .  
     
     
         3 . A compound according to  claim 1 , wherein X is CR 2 R 3 .  
     
     
         4 . A compound according to  claim 1 , wherein X is O.  
     
     
         5 . A compound according to  claim 1 , wherein X is S.  
     
     
         6 . A compound according to  claim 1 , wherein X is SO.  
     
     
         7 . A compound according to  claim 1 , wherein X is SO 2 .  
     
     
         8 . A method for making a compound of formula (I)  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or ester thereof, wherein R 1 , R 2 , R 3 , X, R N , R 20  and R C  are as defined in  claim 1 .  
     
     
         9 . A method of treating a patient who has, or in preventing a patient from getting, a disease or condition selected from the group consisting of Alzheimer's disease, for helping prevent or delay the onset of Alzheimer's disease, for treating patients with mild cognitive impairment (MCI) and/or preventing or delaying the onset of Alzheimer's disease in those who would progress from MCI to AD, for treating Down's syndrome, for treating humans who have Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, for treating cerebral amyloid angiopathy and/or preventing its potential consequences, i.e. single and recurrent lobar hemorrhages, for treating other degenerative dementias, including dementias of mixed vascular and degenerative origin, dementia associated with Parkinson's disease, dementia associated with progressive supranuclear palsy, dementia associated with cortical basal degeneration, or diffuse Lewy body type of Alzheimer's disease and who is in need of such treatment which comprises administration of a therapeutically effective amount of a compound selected from the group consisting of a substituted alcohol of formula (I)  
       
         
           
           
               
               
           
         
       
       where R 1 , R 2 , R 3 , X, R N , R 20  and R C  are as defined in  claim 1 , or pharmaceutically acceptable salt or ester thereof.  
     
     
         10 . A compound selected from the group consisting of: