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US 2006/0154931 A1Published application
Heteroaromatic quinoline compounds
AssigneePfizer Inc.
InventorsPatrick Verhoest, Christopher Helal, Dennis Hoover, John Humphrey
Life of this patent
Estimating the term…
Abstract
The invention pertains to heteroaromatic compounds that serve as effective phosphodiesterase (PDE) inhibitors. In particular, the invention relates to said compounds which are selective inhibitors of PDE10. The invention also relates to intermediates for preparation of said compounds; pharmaceutical compositions comprising said compounds; and the use of said compounds in a method for treating certain central nervous system (CNS) or other disorders.
Claims20
A compound of formula I or a pharmaceutical acceptable salt thereof,
- wherein Z is
- R1 is each independently selected from a group consisting of hydrogen, halogen, hydroxyl, cyano, C1 to C8 alkyl, C2 to C8 alkenyl, C2 to C8 alkynyl, C1 to C8 alkoxy, C1 to C8 haloalkyl, C3 to C8 cycloalkyl, C3 to C8 cycloalkyl-C1 to C8 alkyl, 4 to 7 membered heterocycloalkyl, C1 to C8 alkylthio, —NR3R3—O—CF3, —S(O)n—R3, C(O)—NR3R3, and C1 to C8 alkyl substituted with a heteroatom wherein the heteroatom is selected from a group consisting of nitrogen, oxygen and sulfur and wherein the heteroatom may be further substituted with a substituent selected from a group consisting of hydrogen, C1 to C8 alkyl, C3 to C8 cycloalkyl, C2 to C8 alkenyl, C2 to C8 alkynyl, and C1 to C8 haloalkyl;
- each R3 is independently selected from a group consisting of hydrogen, C1 to C8 alkyl, C2 to C8 alkenyl, C2 to C8 alkynyl, C1 to C8 haloalkyl, C3 to C8 cycloalkyl;
- R2 is selected from a group consisting of hydrogen, C1 to C8 alkyl, C3 to C8 cycloalkyl-C1 to C8 alkyl, C2 to C8 alkenyl, C2 to C8 alkynyl, C1 to C8 haloalkyl and C3 to C8 cycloalkyl;
- HET1 is selected from a group consisting of a monocyclic heteroaryl and a bicyclic heteroaryl, wherein the monocyclic and bicyclic heteroaryl may be optionally substituted with at least one R4;
- R4 is selected from a group consisting of halogen, hydroxyl, cyano, C1 to C8 alkyl, C2 to C8 alkenyl, C2 to C8 alkynyl, C1 to C8 alkoxy, C3 to C8 cycloalkyl, C3 to C8 cycloalkyl-C1 to C8 alkyl, C1 to C8 alkylthiol and C1 to C8 alkyl substituted with a substituent selected from a group consisting of —OR8, —NR8R8, and —SR8, wherein R8 is independently selected from a group consisting of hydrogen and C1 to C8 alkyl;
- HET2 is a monocyclic or bicyclic heteroaryl, wherein the monocyclic and bicyclic heteroaryl may be substituted with at least one R5, with the proviso that HET2 is not tetrazole;
- R5 is independently selected from a group consisting of halogen, hydroxyl, cyano, C1 to C8 alkyl, C2 to C8 alkenyl, C2 to C8 alkynyl, C1 to C8 alkoxy, C3 to C8 cycloalkyl, C3 to C8 cycloalkyl-C1 to C8 alkyl, C1 to C8 alkylthio, —NR7R7, and C1 to C8 haloalkyl;
- B1 and B2 are adjacent atoms in Het1 which are independently selected from a group consisting of carbon and nitrogen;
- bond j is a covalent bond between Z and B2;
- bond k is a bond in Het1 between B1 and B2;
- X and X1 are each independently selected from a group consisting of oxygen, sulfur, C(R2)2 and NR2;
- provided that at least one of X and X1 is carbon;
- Y is selected from a group consisting of carbon and nitrogen, provided that when Y is carbon it is substituted with R6;
- wherein each R6 is independently selected from a group consisting of hydrogen, halogen, hydroxyl, cyano, C1 to C8 alkyl, C2 to C8 alkenyl, C2 to C8 alkynyl, C1 to C8 alkoxy, C1 to C8 cycloalkyl, C1 to C8 alkylthio, C1 to C8 haloalkyl, NR7R7—O—CF3, —S(O)m-R7, and C(O)—NR7R7, C1 to C8 alkyl substituted with a heteroatom wherein the heteroatom is selected from a group consisting of nitrogen, oxygen and sulfur and wherein the heteroatom may be further substituted with a substituent selected from a group consisting of hydrogen, C1 to C8 alkyl, C3 to C8 cycloalkyl, C3 to C8 cycloalkyl-C1 to C8 alkyl, C2 to C8 alkenyl, C2 to C8 alkynyl, and C1 to C8 haloalkyl;
- wherein each R7 is independently selected from a group consisting of hydrogen and C1-C8alkyl;
- p is 1,2 or 3;
- n is 0, 1 or 2;
- and m is 0, 1 or 2.
16 more elements
A compound of formula I or a pharmaceutical salt thereof,
- wherein Z is
- R1 is each independently selected from a group consisting of hydrogen, halogen, hydroxyl, cyano, C1 to C8 alkyl, C2 to C8 alkenyl, C2 to C8 alkynyl, C1 to C8 alkoxy, C1 to C8 haloalkyl, C3 to C8 cycloalkyl, C3 to C8 cycloalkyl-C1 to C8 alkyl, 4 to 7 membered heterocycloalkyl, C1 to C8 alkylthio, —NR3R3—O—CF3, —S(O)n—R3, C(O)—NR3R3, and C1 to C8 alkyl substituted with a heteroatom wherein the heteroatom is selected from a group consisting of nitrogen, oxygen and sulfur and wherein the heteroatom may be further substituted with a substituent selected from a group consisting of hydrogen, C1 to C8 alkyl, C3 to C8 cycloalkyl, C2 to C8 alkenyl, C2 to C8 alkynyl, and C1 to C8 haloalkyl;
- each R3 is independently selected from a group consisting of hydrogen, C1 to C8 alkyl, C2 to C8 alkenyl, C2 to C8 alkynyl, C1 to C8 haloalkyl, C3 to C8 cycloalkyl;
- R2 is selected from the group consisting of hydrogen and C1 to C8 alkyl, C3 to C8 cycloalkyl-C1 to C8 alkyl, C2 to C8 alkenyl, C2 to C8 alkynyl, C1 to C8 haloalkyl and C3 to C8 cycloalkyl;
- HET1 is selected from a group consisting of a monocyclic heteroaryl and a bicyclic heteroaryl, wherein the monocyclic and bicyclic heteroaryl is substituted with at least one R4;
- R4 is a C1 to C8 haloalkyl;
- HET2 is a monocyclic or bicyclic heteroaryl, wherein the monocyclic and bicyclic heteroaryl and may be substituted with at least one R5;
- R5 is independently selected from a group consisting of halogen, hydroxyl, cyano, C1 to Ca alkyl, C2 to C8 alkenyl, C2 to C8 alkynyl, C1 to C8 alkoxy, C3 to C8 cycloalkyl, C3 to C8 cycloalkyl-C1 to C8 alkyl , C1 to C8 alkylthio, —NR7R7and C1 to C8 haloalkyl;
- B1 and B2 are adjacent atoms in Het1 which are independently selected from a group consisting of carbon and nitrogen;
- bond j is a covalent bond between Z and B2;
- bond k is a bond in Het1 between B1 and B2;
- X and X1 are each independently selected from the group consisting of oxygen, sulfur, C(R2)2 and NR2;
- provided that at least one of X or X1 is carbon;
- Y is selected from a group consisting of carbon and nitrogen, provided that when Y is carbon it is substituted with R6;
- wherein each R6 is independently selected from a group consisting of hydrogen, halogen, hydroxyl, cyano, C1 to C8 alkyl, C2 to C8 alkenyl, C2 to C8 alkynyl, C1 to C8 alkoxy, C1 to C8 cycloalkyl, C3to C8 cycloalkyl-C1 to C8 alkyl, C1 to C8 alkylthio, C1 to C8 haloalkyl, —NR7R7, —O—CF3, —S(O)m-R7, and C(O)—NR7R7C1 to C8 alkyl substituted with a heteroatom wherein the heteroatom is selected from a group consisting of nitrogen, oxygen and sulfur and wherein the heteroatom may be further substituted with a substituent selected from the group consisting of hydrogen, C1 to C8 alkyl, C3 to C8 cycloalkyl, C2 to C8 alkenyl, C2 to C8 alkynyl, and C1 to C8 haloalkyl;
- wherein each R7 is independently selected from the group consisting of hydrogen and C1-C8alkyl;
- p is 1, 2 or 3;
- n is 0, 1 or 2;
- and m is 0, 1 or 2.
16 more elements
Dependencies are inferred from the claim text.