Macrocycles useful in the treatment of alzheimer's disease

A method of treating a patient who has Alzheimer's disease, which comprises administration of a therapeutically effective amount of a compound of the formula:

• or a pharmaceutically acceptable salt thereof, wherein
• U is
• - - - is an optional bond;
• J is —CH2OH or —NH—Rc when - - - is not a bond, or absent when - - - is a bond;
• G is OH when - - - is not a bond or —O— when - - - is a bond;
• R is hydrogen or C1-C6 alkyl;
• m is 1-6;
• R4 and R5 are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C7 cycloalkyl, C4-C12 cycloalkylalkyl, C1-C6 alkoxyalkyl, or C3-C6 cycloalkyl;
• X represents —(CR4R5)m—;
• Y is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C7 cycloalkyl, C4-C12 cycloalkylalkyl, C1-C6 alkoxyalkyl, C3-C6 cycloalkyl, or
• Y together with the carbon to which it is attached is a D or L amino acid side chain;
• R6, R6′ and R6″ independently are
• C1-C6 alkyl optionally substituted with one, two or three groups independently selected from C1-C3 alkyl, halogen, —OH, —SH, —C≡N, —CF3, C1-C3 alkoxy, amino, and mono- or dialkylamino;
• or
• C2-C6 alkenyl or C2-C6 alkynyl, each of which is optionally substituted with one, two or three groups independently selected from C1-C3 alkyl, halogen, —OH, —SH, —C≡N, —CF3, C1-C3 alkoxy, amino, and mono- or dialkylamino;
• or
• —(CH2)0-4—O—(C1-C6 alkyl), where the alkyl portion is optionally substituted with one, two, three, four, or five groups independently selected from halogen;
• or
• —OH, —NO2, halogen, —CO2H, —C≡N, —(CH2)0-4—CO—NR8R9, —(CH2)0-4—CO—(C1C12 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—Raryl, —(CH2)0-4—Rheteroaryl, —(CH2)0-4—CO—Raryl, —(CH2)0-4—CO—Rheteroaryl, —(CH2)0-4—CO—Rheterocyclyl, —(CH2)0-4—CO—R10, —(CH2)0-4—CO—O—R11, —(CH2)0-4—SO2—NR8R9, —(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 R11)—CO—O—R11, —(CH2)0-4—N(H or R11)—CO—N(R11)2, —(CH2)0-4—N—CS—N(R11)2, —(CH2)0-4—N(—H or R11)—CO—R8, —(CH2)0-4—NR8R9, —(CH2)0-4—R10, —(CH2)0-4—O—CO—(C1-C6 alkyl), —(CH2)0-4—O-P(O)—(O—Raryl)2, —(CH2)0-4—O—CO—N(R11)2, —(CH2)0-4—O—CS—N(R11)2, —(CH2)0-4—O—(R11), —(CH2)0-4—O—(R11)—COOH, —(CH2)0-4—S—(R11), C3-C7 cycloalkyl, —(CH2)0-4—N(—H or R11)—SO2—R7, or —(CH2)0-4—C3-C7 cycloalkyl;
• R8 and R9 are the same or different and represent —H, —C3-C7 cycloalkyl, —(C1-C2 alkyl)-(C3-C7 cycloalkyl), —(C1-C6 alkyl)-O—(C1-C3 alkyl), —C1-C6 alkenyl, —C1C6 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 one, two or three groups independently selected from halogen;
• or
• heterocyclyl optionally substituted with one, two or three groups selected from 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—NH—C1-C6 alkyl, oxo, —CO—N(C1-C6 alkyl)2,
• C1-C6 alkyl optionally substituted with one, two or three groups independently selected from C1-C3 alkyl, halogen, —OH, —SH, —C≡N, —CF3, C1-C3 alkoxy, amino, and mono- or dialkylamino,
• C2-C6 alkenyl or C2-C6 alkynyl, each of which is optionally substituted with one, two or three groups independently selected from C1-C3 alkyl, halogen, —OH, —SH, —C≡N, —CF3, C1-C3 alkoxy, amino, and mono- or dialkylamino, and
• C1-C6 alkoxy optionally substituted with one, two or three groups independently selected from halogen;
• or
• aryl or heteroaryl, each of which is optionally substituted with one, two or three groups independently selected from 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, and —CO—N(C1-C6 alkyl)2,
• C1-C6 alkyl optionally substituted with one, two or three groups independently selected from C1-C3 alkyl, halogen, —OH, —SH, —C≡N, —CF3, C1-C3 alkoxy, amino, and mono- or dialkylamino,
• C2-C6 alkenyl or C2-C6 alkynyl, each of which is optionally substituted with one, two or three groups independently selected from C1-C3 alkyl, halogen, —OH, —SH, —C≡N, —CF3, C1-C3 alkoxy, amino, and mono- or dialkylamino, and
• C1-C6 alkoxy optionally substituted with one, two or three of halogen;
• R10 is heterocyclyl optionally substituted with one, two, three or four groups independently selected from C1-C6 alkyl;
• R11 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, —(CH2)0-2—Raryl, or —(CH2)0-2—Rheteroaryl;
• Raryl is aryl optionally substituted with one, two or three groups independently selected from 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, —CO—N(C1-C6 alkyl)2,
• C1-C6 alkyl optionally substituted with one, two or three groups independently selected from C1-C3 alkyl, halogen, —OH, —SH, —C≡N, —CF3, C1-C3 alkoxy, amino, and mono- or dialkylamino,
• C2-C6 alkenyl or C2-C6 alkynyl, each of which is optionally substituted with one, two or three groups independently selected from C1-C3 alkyl, halogen, —OH, —SH, —C≡N, —CF3, C1-C3 alkoxy, amino, and mono- or dialkylamino, and
• C1-C6 alkoxy optionally substituted with one, two or three groups independently selected from halogen;
• Rheteroaryl is heteroaryl optionally substituted with one, two or three groups independently selected from 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, —CO—N(C1-C6 alkyl)2,
• C1-C6 alkyl optionally substituted with one, two or three groups independently selected from C1-C3 alkyl, halogen, —OH, —SH, —C≡N, —CF3, C1-C3 alkoxy, amino, and mono- or dialkylamino,
• C2-C6 alkenyl or C2-C6 alkynyl, each of which is optionally substituted with one, two or three groups independently selected from C1-C3 alkyl, halogen, —OH, —SH, —C≡N, —CF3, C1-C3 alkoxy, amino, and mono- or dialkylamino, and
• C1-C6 alkoxy optionally substituted with one, two or three groups independently selected from halogen;
• Rheterocyclyl is heterocyclyl optionally substituted with one, two or three groups independently selected from 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, ═O, —CO—N(C1-C6 alkyl)2,
• C1-C6 alkyl optionally substituted with one, two or three groups independently selected from C1-C3 alkyl, halogen, —OH, —SH, —C≡N, —CF3, C1-C3 alkoxy, amino, and mono- or dialkylamino,
• C2-C6 alkenyl or C2-C6 alkynyl, each of which is optionally substituted with one, two or three groups independently selected from C1-C3 alkyl, halogen, —OH, —SH, —C≡N, —CF3, C1-C3 alkoxy, amino, and mono- or dialkylamino, and
• C1-C6 alkoxy optionally substituted with one, two or three groups independently selected from halogen;
• R2 is —H;
• or —(CH2)0-4—Raryl and —(CH2)0-4—Rheteroaryl;
• or
• C1-C6 alkyl optionally substituted with one, two or three groups independently selected from C1-C3 alkyl, halogen, —OH, —SH, —C≡N, —CF3, C1-C3 alkoxy, amino, and mono- or dialkylamino;
• or
• C2-C6 alkenyl, C2-C6 alkynyl or —(CH2)0-4—C3-C7 cycloalkyl, each of which is optionally substituted with one, two or three groups independently selected from C1-C3 alkyl, halogen, —OH, —SH, —C≡N, —CF3, C1-C3 alkoxy, amino, and mono- or dialkylamino;
• R3 is —H, C2-C6 alkenyl, C2-C6 alkynyl, —(CH2)0-4—Raryl, or —(CH2)0-4—Rheteroaryl;
• or
• C1-C6 alkyl optionally substituted with one, two or three groups independently selected from C1-C3 alkyl, halogen, —OH, —SH, —C≡N, —CF3, C1-C3 alkoxy, amino, and mono- or dialkylamino;
• or
• —(CH2)0-4—C3-C7 cycloalkyl optionally substituted with one, two or three groups independently selected from C1-C3 alkyl, halogen, —OH, —SH, —C≡N, —CF3, C1-C3 alkoxy, amino, and mono- or dialkylamino;
• or
• R2 and R3 taken together with the carbon atom to which they are attached form a carbocycle of three, four, five, six, or seven carbon atoms, where one atom is optionally a heteroatom selected from the group consisting of —O—, —S—, —SO2—, and —NR8—;
• 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, —[C(R255)(R260)]1-3—CO—N—(R255)2, —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)0-4—CH((CH2)0-6—OH—(CH2)0-1-heteroaryl, —CH(-aryl or -heteroaryl)-CO—O(C1-C4 alkyl), —CH(—CH2—OH)—CH(OH)-phenyl-NO2, (C1-C6 alkyl)-O—(C1-C6 alkyl)-OH;
• —CH2—NH—CH2—CH(—O—CH2—CH3)2, —(CH2)0-6—C(═NR235)(NR235R240), or
• —(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, or S(═O)0-2, and wherein the cyclopentyl, cyclohexyl, or cycloheptyl group can be 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 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 R210;
• R200 at each occurrence is independently selected from —OH, —NO2, halogen, —CO2H, C≡N, —(CH2)0-4—CO—NR220R225, —(CH2)0-4—CO—(C1-C12 alkyl), —(CH2)0-4—CO—(C2-C12alkenyl), —(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)0-4N(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, 3, or 5-F), C3-C7 cycloalkyl, —(CH2)0-4—N(H or R215)—SO2—R220, —(CH2)0-4—C3-C7 cycloalkyl, or
• C1-C10 alkyl optionally substituted with 1, 2, or 3 R205 groups, or
• C2-C10 alkenyl or C2-C10 alkynyl, each of which is optionally substituted with 1 or 2 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, —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 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, or
• —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 R270 groups
• 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, 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, 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.