Aminediols for the treatment of Alzheimer's disease

A compound of the formula I:

• 165
• or a pharmaceutically acceptable salt thereof, wherein
• R1 and R1′ are the same or different and are
• C1-C10 alkyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, —OH, ═O, —SH, —C≡N, —CF3, —C1—C3 alkoxy, amino, mono- or dialkylamino, —N(R)C(O)R′—, —OC(═O)-amino and —OC(═O)-mono- or dialkylamino, or
• C2-C6 alkenyl or C2-C6 alkynyl, each of which is optionally substituted with 1, 2, or 3 groups independently selected from halogen, —OH, —SH, —C≡N, —CF3, C1-C3 alkoxy, amino, and mono- or dialkylamino, or
• aryl, heteroaryl, heterocyclyl, aryl (C1—C6) alkyl-, heteroaryl (C1-C6)alkyl-, or heterocyclyl(C1-C6)alkyl-, where the ring portions of each are optionally substituted with 1, 2, 3, or 4 groups independently selected from halogen, —OH, —SH, —C≡N, —NO2, —NR105R′105, —CO2R, —N(R)COR′, —N(R)SO2R′, —C(═O)—(C1-C4) alkyl, —SO2-amino, —SO2-monoalkylamino, —SO2-dialkylamino, —C(═O)-amino, —C(═O)-monoalkylamino, —C(═O)-dialkylamino, —SO2—(C1-C4) alkyl,
• C1-C6 alkoxy optionally substituted with 1, 2, or 3 groups which are independently selected from halogen,
• C3-C7 cycloalkyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, —OH, —SH, —C≡N, —CF3, C1-C3 alkoxy, amino, —C1-C6 alkyl and mono- or dialkylamino,
• C1-C10 alkyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, —OH, —SH, —C≡N, —CF3, —C1-C3 alkoxy, amino, mono- or dialkylamino and —C1-C3 alkyl, and
• C2-C10 alkenyl or C2-C10 alkynyl each of which is optionally substituted with 1, 2, or 3 groups independently selected from halogen, —OH, —SH, —C≡N, —CF3, C1-C3 alkoxy, amino, C1-C6 alkyl and mono- or dialkylamino;
• and the heterocyclyl group is optionally further substituted with oxo;
• or
• R1 is as defined above and R1′ is hydrogen;
• R and R′ independently are hydrogen, C1-C10 alkyl, C1-C10 alkylaryl or C1-C10 alkylheteroaryl;
• R2 are the same or different and are H or C1-C6 alkyl;
• Rc is hydrogen, —(CR245R250)0-4-aryl, —(CR245R250)0-4-heteroaryl, —(CR245R250)0-4-heterocyclyl, —(CR245R250)0-4-aryl-heteroaryl, —(CR245R250)0-4-aryl-heterocyclyl, —(CR245R250)0-4-aryl-aryl, —(CR245R250)0-4-heteroaryl-aryl, —(CR245R250)0-4-heteroaryl-heterocyclyl, —(CR245R250)0-4-heteroaryl-heteroaryl, —(CR245R250)0-4-heterocyclyl-heteroaryl, —(CR245R250)0-4-heterocyclyl-heterocyclyl, —(CR245R250)0-4-heterocyclyl-aryl, —CH(aryl)2, —CH (heteroaryl)2, —CH (heterocyclyl)2, —CH(aryl) (heteroaryl), —(CH2)0-1—CH((CH2)0-6-—OH)—(CH2)0-1-aryl, —(CH2)0-1—CH((CH2)0-6—OH) —(CH2)0-1-heteroaryl, —CH(-aryl or -heteroaryl)—CO—O(C1-C4 alkyl), —(C1-C6 alkyl)—O—(C1-C6 alkyl)-OH;
• —CH2—NH—CH2—CH (—O—CH2—CH3)2, —(CH2)0-6—C(═NR235)(NR235R240), C1—C10 alkyl optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of R110, R120 and R130,
• C2-C10 alkyl optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of R205, R110, R120, R130, —OC═ONR235R240, —S(═O)0-2 (C1-C6 alkyl), —SH, and —S(═O)2NR235R240, —(CH2)0-3—(C3-C8) cycloalkyl wherein the cycloalkyl is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of R205, —CO2H, and —CO2—(C1-C4 alkyl), or
• cyclopentyl, cyclohexyl, or cycloheptyl ring fused to aryl, heteroaryl, or heterocyclyl wherein one, two or three carbons of the cyclopentyl, cyclohexyl, or cycloheptyl is optionally replaced with a heteroatom independently selected from NH, NR215, O, and S(═O)0-2, and wherein the cyclopentyl, cyclohexyl, or cycloheptyl group is optionally substituted with one or two groups that are independently R205, ═O, —CO—NR235R240, or —SO2—(C1-C4 alkyl), or
• C2-C10 alkenyl or C2-C10 alkynyl, each of which is optionally substituted with 1, 2, or 3 independently selected R205 groups, wherein
• each aryl and heteroaryl is optionally substituted with 1, 2, or 3 R200, and wherein each heterocyclyl is optionally substituted with 1, 2, 3, or 4 independently selected R210;
• R200 at each occurrence is independently selected from —OH, —NO2, halogen, —CO2H, C≡N, —(CH2)0-4—CO—NR220OR225, —(CH2)0-4—CO—(C1-C12 alkyl), —(CH2)0-4—CO—(C2-C12 alkenyl), —(CH2)0-4—CO—(C2-C12 alkynyl), —(CH2)0-4—CO—(C3-C7 cycloalkyl), —(CH2)0-4—CO-aryl, —(CH2)0-4—CO-heteroaryl, —(CH2)0-4—CO-heterocyclyl, —(CH2)0-4—CO—O—R215, —(CH2)0-4—SO2—NR220R225, —(CH2)0-4—SO—(C1-C8 alkyl), —(CH2)0-4—SO2—(C1-C12 alkyl), —(CH2)0-4—SO2—(C3-C7 cycloalkyl), —(CH2)0-4—N(H or R215)—CO—O—R215, —(CH2)0-4—N(H or R215)—CO—N(R215)2, —(CH2)0-4—N—CS—N(R215)2, —(CH2)0-4—N(—H or R215)—CO—R220, —(CH2)0-4—NR220R225, —(CH2)0-4—O—CO—(C1-C6 alkyl), —(CH2) 0-4—O—P(O)—(OR240)2, —(CH2)0-4—O—CO—N(R215)2, —(CH2)0-4—O—CS—N(R215)2, —(CH2)0-4—O—(R215), —(CH2)0-4—O—(R215)—COOH, —(CH2)0-4—S—(R215), —(CH2)0-4—O—(C1-C6) alkyl optionally substituted with 1, 2, or 3-F, C3-C7 cycloalkyl, —(CH2)0-4—N(H or R215)—SO2—R220, —(CH2)0-4—C3-C7 cycloalkyl,
• C1-C10 alkyl optionally substituted with 1, 2, or 3 independently selected R205 groups,
• C2-C10 alkenyl and C2-C10 alkynyl, each of which is optionally substituted with 1 or 2 independently selected R205 groups, wherein
• the aryl and heteroaryl groups at each occurrence are optionally substituted with 1, 2, or 3 groups that are independently R205, R210, or
• C1-C6 alkyl substituted with 1, 2, or 3 groups that are independently R205 or R210, and wherein
• the heterocyclyl group at each occurrence is optionally substituted with 1, 2, or 3 groups that are independently R210;
• R205 at each occurrence is independently selected from C1-C6 alkyl, halogen, —OH, —O-phenyl, —SH, —S—C1-C6 alkyl, —C≡N, —CF3, C1-C6 alkoxy, NH2, NH(C1-C6 alkyl) or N—(C1-C6 alkyl) (C1-C6 alkyl);
• R210 at each occurrence is independently selected from halogen, C1-C6 alkoxy, C1-C6 haloalkoxy, —NR220R225, OH, C≡N, —CO—(C1-C4 alkyl), —SO2—NR235R240, —CO—NR235R240, —SO2—(C1-C4 alkyl), ═O, or
• C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C7 cycloalkyl, each of which is optionally substituted with 1, 2, or 3 R205 groups;
• R215 at each occurrence is independently selected from C1-C6 alkyl, —(CH2)0-2-(aryl), C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, and —(CH2)0-2—(heteroaryl), —(CH2)0-2-(heterocyclyl), wherein
• the aryl group at each occurrence is optionally substituted with 1, 2, or 3 groups that are independently R205 or R210, and wherein
• the heterocyclyl and heteroaryl groups at each occurrence are optionally substituted with 1, 2, or 3 independently selected R210;
• R220 and R225 at each occurrence are independently selected from —H, —C3-C7 cycloalkyl, —(C1-C2 alkyl)—(C3-C7 cycloalkyl), —(C1-C6 alkyl)—O—(C1-C3 alkyl), —C2-C6 alkenyl, —C2-C6 alkynyl, —C1-C6 alkyl chain with one double bond and one triple bond, -aryl, -heteroaryl, and -heterocyclyl, and
• —C1-C10 alkyl optionally substituted with —OH, —NH2 or halogen, wherein
• the aryl, heterocyclyl and heteroaryl groups at each occurrence are optionally substituted with 1, 2, or 3 independently selected R270groups
• R235 and R240 at each occurrence are independently H, or C1-C6 alkyl;
• R245 and R250 at each occurrence are independently selected from —H, C1-C4 alkyl, C1-C4 alkylaryl, C1-C4 alkylheteroaryl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, —(CH2)0-4—C3-C7 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, and phenyl;
• or
• R245 and R250 are taken together with the carbon to which they are attached to form a carbocycle of 3, 4, 5, 6, or 7 carbon atoms, where one carbon atom is optionally replaced by a heteroatom selected from —O—, —S—, —SO2—, and —NR220—;
• R255 and R260 at each occurrence are independently selected from —H, —(CH2)1-2—S(O)0-2—(C1-C6 alkyl), —(C1-C4 alkyl)-aryl, —(C1-C4 alkyl)-heteroaryl, —(C1-C4 alkyl)-heterocyclyl, -aryl, -heteroaryl, -heterocyclyl, —(CH2)1-4—R265—(CH2)0-4-aryl, —(CH2)1-4—R265—(CH2)0-4-heteroaryl, —(CH2)1-4—R265—(CH2)0-4-heterocyclyl, and C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl and —(CH2)0-4—C3-C7 cycloalkyl, each of which is optionally substituted with 1, 2, or 3 independently selected R205 groups, wherein
• each aryl or phenyl is optionally substituted with 1, 2, or 3 groups that are independently R205, R210, or C1-C6 alkyl substituted with 1, 2, or 3 groups that are independently R205 or R210, and wherein
• each heterocyclyl is optionally substituted with 1, 2, 3, or 4 R210;
• R265 at each occurrence is independently —O—, —S—or —N(C1-C6 alkyl)-;
• R270 at each occurrence is independently R205, halogen C1-C6 alkoxy, C1-C6 haloalkoxy, NR235R240, —OH, —C≡N, —CO—(C1-C4 alkyl), —SO2—NR235R240, —CO—NR235R240 —SO2—(C1-C4 alkyl) —O, or
• C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or —(CH2)0-4—C3-C7 cycloalkyl, each of which is optionally substituted with 1, 2, or 3 R205 groups;
• RN is R′100, —SO2R′100, —(CRR′)1-6R′100, —C(═O)—(CRR′)0-6R100, —C(═O)—(CRR′)1-6—O—R′100, —C(═O)—(CRR′)1-6—S—R′100, —C(═O)—(CRR′)1-6—C(═O)—R100, —C(═O)—(CRR′)1-6—SO2—R100 or —C(═O)—(CRR′)1-6—NR100—R′100;
• R100 and R′100 independently represent aryl, heteroaryl, heterocyclyl, -aryl-W-aryl, -aryl-W-heteroaryl, -aryl-W-heterocyclyl, -heteroaryl-W-aryl, -heteroaryl-W-heteroaryl, -heteroaryl-W-heterocyclyl, -heterocyclyl-W-aryl, -heterocyclyl-W-heteroaryl, -heterocyclyl-W-heterocyclyl, —CH[(CH2)0-2—O—R150]—(CH2)0-2-aryl, —CH[(CH2)0-2—O—R150]—(CH2)0-2-heterocyclyl or —CH[(CH2)0-2—O—R150]—(CH2)0-2-heteroaryl, where the ring portions of each are optionally substituted with 1, 2, or 3 groups independently selected from
• —OR, —NO2, C1-C6 alkyl, halogen, —C≡N, —OCF3, —CF3, —(CH2)0-4—O—P(═O) (OR) (OR′), —(CH2)0-4—CO—NR105R′105, —(CH2)0-4—O—(CH2)0-4—CONR102R102′, —(CH2)0-4—CO—(C1-C12 alkyl), —(CH2)0-4—CO—(C2-C12 alkenyl), —(CH2)0-4—CO—(C2-C12 alkynyl), —(CH2)0-4—CO—(CH2)0-4 (C3-C7 cycloalkyl), —(CH2)0-4—R110, —(CH2)0-4—R120, —(CH2)0-4—R130, —(CH2)0-4—CO—R110, —(CH2)0-4—CO—R120, —(CH2)0-4—CO—R130, —(CH2)0-4—CO-R140, —(CH2)0-4—CO—O—R150, —(CH2)0-4—SO2—NR105R′105, —(CH2)0-4—SO—(C1-C8 alkyl), —(CH2)0-4—SO2—(C1-C12 alkyl), —(CH2)0-4—SO2—(CH2)0-4—(C3-C7 cycloalkyl), —(CH2)0-4—N(R150)—CO—O—R150, —(CH2)0-4—N(R150)—CO—N(R150)2, —(CH2)0-4—N(R150)—CS—N(R150)2, —(CH2)0-4—N(R150) —CO—R105, —(CH2)0-4—NR105R′105, —(CH2)0-4—R140, —(CH2)0-4—O—CO—(C1-C6 alkyl), —(CH2)0-4—O—P(O)—(O—R110)2, —(CH2)0-4—O—CO—N(R150)2, —(CH2)0-4—O—CS—N(R150)2, —(CH2)0-4—O—(R150), —(CH2)0-4—O—R150′—COOH, —(CH2)0-4—S—(R150), —(CH2)0-4—N(R150)—SO2—R105, —(CH2)0-4—C3-C7 cycloalkyl, (C2-C10)alkenyl, and (C2-C10)alkynyl, or
• R100 is C1-C10 alkyl optionally substituted with 1, 2, or 3 R115 groups, or
• R100 is —(C1-C6 alkyl)—O—C1-C6 alkyl) or —(C1-C6 alkyl)-S—(C1-C6 alkyl), each of which is optionally substituted with 1, 2, or 3 R115 groups, or
• R100 is C3-C8 cycloalkyl optionally substituted with 1, 2, or 3 R115 groups;
• W is —(CH2)0-4—, —O—, —S(O)0-2—, —N(R135) —, —CR(OH)— or —C(O)—;
• R102 and R102′ independently are hydrogen, or
• C1-C10 alkyl optionally substituted with 1, 2, or 3 groups that are independently halogen, aryl or —R110;
• R105 and R′105 independently represent —H, —R110, —R120, C3-C7 cycloalkyl, —(C1-C2 alkyl)-(C3-C7 cycloalkyl), (C1-C6 alkyl)-O—(C1-C3 alkyl), C2-C6 alkenyl, C2-C6 alkynyl, or
• C1-C6 alkyl chain with one double bond and one triple bond, or
• C1-C6 alkyl optionally substituted with —OH or —NH2;
• or,
• C1-C6 alkyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, or
• R105 and R′105 together with the atom to which they are attached form a 3 to 7 membered carbocylic ring, where one member is optionally a heteratom selected from —O—, —S(O)0-2—, —N(R135)—, the ring being optionally substituted with 1, 2 or 3 independently selected R140 groups;
• R115 at each occurrence is independently halogen, —OH, —CO2R102, —C1-C6 thioalkoxy, —CO2-phenyl, —NR105R′135, —SO2—(C1-C8 alkyl), —C(═O)R180, R180, —CONR105R′105, —SO2NR105R′105, —NH—CO—(C1-C6 alkyl), —NH—CO—R110, —NH—CO—R120, —NH—C(═O)—OH, —NH—C(═O)—OR, —NH—C(═O)—O-phenyl, —O—C(═O)—(C1-C6 alkyl), —O—C(═O)-amino, —O—C(═O)-mono- or dialkylamino, —O—C(═O) -phenyl, —O—(C1-C6 alkyl)-CO2H, —NH—SO2—(C1-C6 alkyl), C1-C6 alkoxy or C1-C6 haloalkoxy;
• R135 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, —(CH2)0-2-(aryl), —(CH2)0-2-(heteroaryl), or —(CH2)0-2-(heterocyclyl);
• R140 is heterocyclyl optionally substituted with 1, 2, 3, or 4 groups independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C1-C6)alkylamino, di(C1-C6)alkylamino, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, amino(C1-C6) alkyl, mono (C1-C6) alkylamino (C1-C6) alkyl, di (C1-C6)alkylamino(C1-C6)alkyl, and ═O;
• R145 is C1-C6 alkyl or CF3;
• R150 is hydrogen, C3-C7 cycloalkyl, —(C1-C2 alkyl)-(C3-C7 cycloalkyl), C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl with one double bond and one triple bond, —R110, —R120, or
• C1-C6 alkyl optionally substituted with 1, 2, 3, or 4 groups independently selected from —OH, —NH2, C1-C3 alkoxy, R110, and halogen;
• R150′ is C3-C7 cycloalkyl, —(C1-C3 alkyl)-(C3-C7 cycloalkyl), C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl with one double bond and one triple bond, —R110, —R120, or
• C1-C6 alkyl optionally substituted with 1, 2, 3, or 4 groups independently selected from —OH, —NH2, C1-C3 alkoxy, R110, and halogen;
• R155 is C3-C7 cycloalkyl, —(C1-C2 alkyl)-(C3-C7 cycloalkyl), C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl with one double bond and one triple bond, —R110, —R120, or
• C1-C6 alkyl optionally substituted with 1, 2, 3, or 4 groups independently selected from —OH, —NH2, C1-C3 alkoxy, and halogen;
• R180 is selected from morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl, homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S-oxide, homothiomorpholinyl S,S-dioxide, pyrrolinyl and pyrrolidinyl, each of which is optionally substituted with 1, 2, 3, or 4 groups independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, cyano, nitro, amino, mono (C1-C6)alkylamino, di(C1-C6)alkylamino, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, amino(C1-C6)alkyl, mono(C1-C6)alkylamino(C1-C6)alkyl, di(C1-C6)alkylamino(C1-C6)alkyl, and ═O;
• R110 is aryl optionally substituted with 1 or 2 R125 groups;
• R125 at each occurrence is independently halogen, amino, mono- or dialkylamino, —OH, —C≡N, —SO2—NH2, —SO2—NH—C1-C6 alkyl, —SO2—N(C1-C6 alkyl)2, —SO2—(C1-C4 alkyl), —CO—NH2, —CO—NH—C1-C6 alkyl, or —CO—N(C1-C6 alkyl)2, or
• C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, each of which is optionally substituted with 1, 2, or 3 groups that are independently selected from C1-C3 alkyl, halogen, —OH, —SH, —C≡N, —CF3, C1-C3 alkoxy, amino, and mono- and dialkylamino, or
• C1-C6 alkoxy optionally substituted with one, two or three of halogen;
• R120 is heteroaryl, which is optionally substituted with 1 or 2 R125 groups;
• and
• R130 is heterocyclyl optionally substituted with 1 or 2 R125 groups.