Histamine-3 receptor modulators

A compound of formula I

• or a pharmaceutically acceptable salt thereof, wherein:
• R1 is selected from the group consisting of N3, OR4, and NR2R3;
• R2 and R3 are each independently selected from the group consisting of hydrogen;
• C1–C8 alkyl optionally substituted with 1 to 4 halogens;
• C1–C4 alkyl group optionally substituted with a substituent selected from the group consisting of OH, one to four C1–C4 alkyl, C3–C7 cycloalkyl, C1–C4 dialkylamino, C6–C14 aryl optionally substituted with a halogen and optionally substituted with C6–C10 aryloxy optionally substituted with one to two halogens, and 5–10-membered heteroaryl optionally substituted with a C6–C10 aryl group and optionally substituted with one to three C1–C4 alkyl groups;
• C3–C7 cycloalkyl;
• C6–C14 aryl;
• 3–8-membered heterocycloalkyl optionally substituted with one or more C1–C4 alkyl-carbonyl group;
• C6–C10 arylsulfonyl optionally substituted with one or more C1–C2 alkyl;
• 5–10-membered heteroaryl;
• and
• C6–C14 aryl-C0–C4 alkylene-O—C0–C4 alkyl, wherein each C0–C4 alkyl and each C0–C4 alkylene is optionally substituted with one to four C1–C4 alkyl;
• wherein R3 can be further selected from the group consisting of
• C6–C14 arylcarbonyl-C6–C14 aryl;
• C6–C14 arylcarbonyl-3–8-membered heterocycloalkyl;
• C3–C8 cycloalkylcarbonyl-C6–C14 aryl;
• C3–C8 cycloalkylcarbonyl-3–8-membered heterocycloalkyl;
• 3–8-membered heterocycloalkylcarbonyl-C6–C14 aryl;
• and 3–8-membered heterocycloalkylcarbonyl-3–8-membered heterocycloalkyl;
• or R3 and R2 together with the nitrogen of the NR2R3 group form a first 5-, 6-, or 7-membered aliphatic ring, wherein one of the carbons in the first 5-, 6-, or 7-membered aliphatic ring is optionally replaced by O, S, NR2′, or CO, and the first 5-, 6-, or 7-membered aliphatic ring is optionally fused to a C6–C10 arylene and is optionally substituted at a ring carbon with a substituent selected from the group consisting of
• 5–10-membered heteroaryl optionally substituted with one or more halogens and optionally substituted with one or more C1–C2 alkyl,
• C1–C4 alkoxy optionally substituted with one or more C1–C2 alkoxy and optionally substituted with one or more C1–C4 dialkylaminocarbonyl, and
• one or two C1–C4 alkyl optionally and independently substituted with one or more C1–C2 alkoxy;
• wherein R2′ is
• hydrogen;
• C1–C8 alkyl optionally substituted with 1 to 4 halogens;
• 5–10-membered heteroaryl optionally substituted with a substituent selected from the group consisting of halogen, C1–C4 alkyl, C1–C2 alkoxy, C6–C10 aryl, C1–C4 alkylaminocarbonyl, and cyano;
• C1–C4 alkyl group optionally substituted with a substituent selected from the group consisting of C1–C2 alkoxycarbonyl, 5–10-membered heteroaryl optionally substituted with one or more C1–C2 alkyl, one to four C1–C4 alkyl, C3–C7 cycloalkyl, and C6–C14 aryl;
• C6–C10 aryl optionally substituted with one or two C1–C2 alkyl;
• C1–C4 alkylcarbonyl;
• or C6–C14 aryl-C0–C4 alkylene-O—C0–C4 alkyl, wherein each C0–C4 alkyl and each C0–C4 alkylene is optionally substituted with one to four C1–C4 alkyl;
• R4 is
• hydrogen;
• C1–C8 alkyl optionally substituted with 1 to 4 halogens;
• C1–C4 alkyl optionally substituted with a substituent selected from the group consisting of C3–C7 cycloalkyl,
• 5–10-membered heteroaryl, and
• C6–C14 aryl optionally substituted with a substituent selected from the group consisting of one, two or three halogens, cyano, one or two C1–C2 alkoxy, C1–C2 di- or tri-fluoroalkyl, C1–C4 alkyl optionally substituted with C6–C10 arylsulfonyl, nitro, and 5–10-membered heteroaryl;
• 5–10-membered heteroaryl optionally fused to a C6–C10 arylene group that is optionally substituted with one or more halogens or one or more C1–C2 alkoxy, wherein the 5–10-membered heteroaryl is optionally substituted with a substituent selected from the group consisting of:
• C6–C10 aryl optionally substituted with one or more halogens, one or more C1–C2 alkoxy, or one or more C1–C2 alkyl;
• C6–C10 arylcarbonyl optionally substituted with one or more halogens;
• one or more halogens;
• one to three C1–C4 alkyl groups optionally substituted with one or more C6–C10 aryl optionally and independently substituted with one or more halogens or one or more C1–C2 alkoxy;
• C1–C2 di- or tri-fluoroalkyl;
• 1 to 2 C1–C2 alkoxy groups;
• 3–8-membered heterocycloalkyl;
• 5–10-membered heteroarylamino;
• C1–C2 alkylaminocarbonyl-C1–C2-alkylamino;
• C6–C10 arylaminocarbonyl;
• C6–C10 arylaminocarbonyl-C1–C2-alkylamino optionally substituted with one or more halogens at the C6–C10 aryl moiety of C6–C10 arylaminocarbonyl;
• 5–10-membered heteroaryl optionally substituted with one or more C6–C10 aryl or one or more C1–C2 alkyl;
• C6–C10 aryloxy optionally substituted with one or more C1–C2 alkoxy or one or more halogens;
• and
• C1–C4 dialkylamino;
• C6–C14 aryl optionally substituted with one or more halogens and optionally substituted with one or more C6–C10 aryloxy optionally and independently substituted with one to two halogens;
• C6–C14 aryl-C0–C4 alkylene-O—C0–C4 alkyl, wherein each C0–C4 alkyl and each C0–C4 alkylene is optionally substituted with one to four C1–C4 alkyl;
• or
• C6–C10 arylsulfonyl optionally substituted with C1–C2 alkyl;
• R6 is hydrogen, C1–C4 alkyl or halogen;
• R7 is hydrogen, SO2C1–C10 alkyl, C1–C8 alkyl optionally substituted with 1 to 4 halogens, C3–C7 cycloalkyl-C0–C4 alkyl, C6–C14 aryl-C0–C4 alkyl, 5–10-membered heteroaryl-C0–C4 alkyl, or C6–C14 aryl-C0–C4 alkylene-O—C0–C4 alkyl, wherein each C0–C4 alkyl and each C0–C4 alkylene is optionally substituted with one to four C1–C4 alkyl;
• R10 is OH, halogen or hydrogen;
• R8 is CN, —CHR7′NR2″, R3″ or C(═NR12)—NR13R13′, wherein R13 and R13′ are each independently hydrogen or C1–C6 alkyl and R12 is hydrogen, C1–C6 alkyl OH, O—C1–C6 alkyl, NH2, NHC1–C6alkyl, or N(C1–C6alkyl)2,
• or wherein C(═NR12)—NR13R13′ represents a five-membered heteroaryl group, wherein R12 is O, NH, or NC1–C6 alkyl, R13 and R13′ taken together represent N or CR13″ double bonded to the nitrogen of the NR13R13′ group, and R13″ is hydrogen or C1–C6 alkyl;
• or when R8 is ortho to R6, R6 and R8 together with the carbons of the aromatic ring to which R6 and R8 are attached may form a 5-membered carbocyclic ring;
• R2″ is hydrogen, C1–C8 alkyl optionally substituted with 1 to 4 halogens, C3–C7 cycloalkyl-C0–C4 alkyl, C6–C14 aryl-C0–C4 alkyl, 5–10-membered heteroaryl-C0–C4 alkyl, or C6–C14 aryl-C0–C4 alkylene-O—C0–C4 alkyl, wherein each C0–C4 alkyl and each C0–C4 alkylene is optionally substituted with one to four C1–C4 alkyl;
• R3″ is hydrogen, C1–C8 alkyl optionally substituted with 1 to 4 halogens, C6–C14 aryl, C6–C14 arylcarbonyl-C6–C14 aryl, C6–C14 arylcarbonyl-3–8-membered heterocycloalkyl, C3–C8 cycloalkylcarbonyl-C6–C14 aryl, C3–C8 cycloalkylcarbonyl-3–8-membered heterocycloalkyl, 3–8-membered heterocycloalkyl, 3–8-membered heterocycloalkylcarbonyl-C6–C14 aryl, or 3–8-membered heterocycloalkylcarbonyl-3–8-membered heterocycloalkyl;
• or R3″ and R2″ together with the nitrogen of the CHR7′NR2″R3″ group form a second 5-, 6- or 7-membered aliphatic ring, wherein one of the carbons in the second 5-, 6-, or 7-membered aliphatic ring is optionally replaced by O, S, NR11, or C═O and the second 5-, 6-, or 7-membered aliphatic ring is optionally substituted with one or two C1–C4 alkyl or optionally substituted with OH, wherein R11 is hydrogen, C1–C8 alkyl optionally substituted with 1 to 4 halogens, C3–C7 cycloalkyl-C0–C4 alkyl, C6–C14 aryl-C0–C4 alkyl, 5–10-membered heteroaryl-C0–C4 alkyl, or C6–C14 aryl-C0–C4 alkylene-O—C0–C4 alkyl, wherein each C0–C4 alkyl and each C0–C4 alkylene is optionally substituted with one to four C1–C4 alkyl;
• and
• R7′ is hydrogen, C1–C8 alkyl optionally substituted with 1 to 4 halogens, C3–C7 cycloalkyl-C0–C4 alkyl, C6–C14 aryl-C0–C4 alkyl, 5–10-membered heteroaryl-C0–C4 alkyl, C6–C14 aryl-C0–C4 alkylene-O—C0–C4 alkyl, wherein each C0–C4 alkyl and each C0–C4 alkylene is optionally substituted with one to four C1–C4 alkyl, or SO2C1–C10 alkyl.