Diaminediols for the treatment of Alzheimer's disease

A compound of the formula I:

• or a pharmaceutically acceptable salt thereof, wherein
• R1 is
• C1–C10 alkyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, —OH, ═O, —SH, —C≡N, —CF3, —C1–C3 alkoxy, —S—(C1–C3)alkyl, 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 or aryl(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;
• R and R′ independently are hydrogen, C1–C10 alkyl, C1–C10 alkylaryl or C1–C10 alkylheteroaryl;
• R1′ is phenyl-(C1–C6)alkyl- where the phenyl ring is 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;
• with the proviso that R1 and R1′ are not simultaneously unsubstituted phenyl-(CH2)—,
• RN is —C(═O)—(CRR′)0-6R100;
• RN′ is —C(═O)—(CRR′)0-6R′100, —C(═O)—(CRR′)1-6—S—R′100, —C(═O)—(CRR′)1-6—S—R′100, or —C(═O)—(CRR′)1-6—NR100—R′100;
• R100 is heteroaryl 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;
• R′100 is 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, 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), —(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;
• 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 carbocyclic ring, where one member is optionally a heteroatom 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′105, —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;
• 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;
• 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.