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US 8,946,230 B2Granted
Aryl- and heteroaryl- nitrogen-heterocyclic compounds as PDE10 inhibitors
AssigneeAmgen Inc.
InventorsJennifer R. Allen, Kristin L. Andrews, Michael J. Frohn, Paul E. Harrington, Alexander J. Pickrell, Robert M. Rzasa
Life of this patent
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Abstract
Aryl- and heteroaryl-nitrogen heterocyclic compounds of formula (I): or a pharmaceutically acceptable salt thereof, wherein m, p, q, R1, R2, R3, X1, X2, X3, Y1 and Y2 are defined herein; and compositions containing them, and processes for preparing such compounds. Provided herein also are methods of treating disorders or diseases treatable by inhibition of PDE10, such as obesity, non-insulin dependent diabetes, schizophrenia, Huntington's Disease, bipolar disorder, obsessive-compulsive disorder, and the like.
Claims24
A compound of formula I:
- or a pharmaceutically acceptable salt thereof, wherein:
- the group
- wherein the group
- is azetidinyl;
- R1 is halo, ORa, —ORc, —C(═O)Rc, —NRaRc, —C(═O)NRaRb, —C(═O)NRa(C0-4alk)Rc, or C0-4alk-L1;
- R2 is unsaturated 9- or 10-membered bicyclo-heterocyclic ring;
- wherein each R2 is substituted by 0, 1, 2 or 3 R5 groups;
- R3 is halo, OH, OC1-4alk, C1-4alk, C1-4haloalk, or oxo;
- R4 is independently H, halo, OH, OC1-4alk, C1-4alk or C1-4haloalk;
- R5 is independently halo, CN, or C1-4alk;
- m is 0;
- each of p and q is independently 1;
- the ring containing p and q contains 0 double bonds;
- Ra is independently H or Rb;
- Rb is independently phenyl, benzyl, or C1-6alk, wherein said phenyl, benzyl, and C1-6alk are being substituted by 0, 1, 2 or 3 substituents which are independently halo, C1-4alk, C1-3haloalk, —OH, —OC1-4alk, —NH2, —NHC1-4alk, —OC(═O)C1-4alk, or —N(C1-4alk)C1-4alk;
- Rc is C0-4alk-L2;
- and
- each of L1 and L2 is independently a carbon-linked or nitrogen-linked saturated, partially-saturated or unsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic ring or a saturated, partially-saturated or unsaturated 8-, 9-, 10-, 11-, or 12-membered bicyclic ring, wherein each said ring contains 0, 1, 2, 3, or 4 N atoms and 0, 1, or 2 atoms which are independently O or S;
- wherein each L1 and L2 is independently substituted by 0, 1, 2 or 3 R6 groups which are independently F, Cl, Br, C1-6alk, C1-4haloalk, —ORa, —OC1-4haloalk, CN, —C(═O)Rb, —C(═O)ORa, or —C(═O)NRaRa.
16 more elements
A compound of formula II:
- or a pharmaceutically acceptable salt thereof, having the formula:
- ring D is -L1;
- each of X1, X2, Y1 and Y2 is independently N or CR4;
- wherein no more than two of X1, X2, Y1 and Y2 are N;
- R2 is of formula:
- wherein each of R5a, R5b, R5c, and R5d is R5;
- Z is S, O, or NR7;
- and R7 is H or C1-6alk;
- R3 is halo, OH, OC1-4alk, C1-4alk, C1-4haloalk, or oxo;
- R4 is independently H, halo, OH, OC1-4alk, C1-4alk, or C1-4haloalk;
- R5 is independently halo, CN, or C1-4alk;
- m is 0;
- each of p and q is independently 1;
- Ra is independently H or Rb;
- Rb is independently phenyl, benzyl, or C1-6alk, wherein said phenyl, benzyl, and C1-6alk are being substituted by 0, 1, 2 or 3 substituents which are independently halo, C1-4alk, C1-3haloalk, —OH, —OC1-4alk, —NH2, —NHC1-4alk, —OC(═O)C1-4alk, or —N(C1-4alk)C1-4alk;
- and
- each of L1 is independently a carbon-linked or nitrogen-linked saturated, partially-saturated or unsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic ring or a saturated, partially-saturated or unsaturated 8-, 9-, 10-, 11-, or 12-membered bicyclic ring, wherein each said ring contains 0, 1, 2, 3, or 4 N atoms and 0, 1, or 2 atoms which are independently O or S;
- wherein each L1 is independently substituted by 0, 1, 2 or 3 R6 groups which are independently F, Cl, Br, C1-6alk, C1-4haloalk, —ORa, —OC1-4haloalk, CN, —C(═O)Rb, —C(═O)ORa, or —C(═O)NRaRa;
- with the proviso that when R2 is
- then at least one of X1, X2, Y1 and Y2 must be N.
17 more elements
A compound, or a pharmaceutically acceptable salt thereof, which is:
- 5-methyl-2-(1-(3-(tetrahydro-2H-pyran-4-yloxy)pyrazin-2-yl)azetidin-3-yl)-1H-benzo[d]imidazole;
- 2-[1-(3,5-dichloro-pyridin-4-yl)-azetidin-3-yl]-5-methyl-1H-benzoimidazole;
- 2-[1-(3-chloro-5-phenyl-pyridin-4-yl)-azetidin-3-yl]-5-methyl-1H-benzoimidazole;
- {2-[3-(5-chloro-1H-benzoimidazol-2-yl)-azetidin-1-yl]-pyridin-3-yl}-(3-hydroxy-azetidin-1-yl)-methanone;
- 3-[3-(5-chloro-1H-benzoimidazol-2-yl)-azetidin-1-yl]-pyrazine-2-carboxylic acid methylamide;
- 5-chloro-2-(1-(4-(tetrahydro-2H-pyran-4-yloxy)pyridin-2-yl)azetidin-3-yl)-1H-benzo[d]imidazole;
- 5-chloro-2-(1-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)azetidin-3-yl)-1H-benzo[d]imidazole;
- 5-chloro-2-(1-(3-(tetrahydro-2H-pyran-4-yloxy)pyrazin-2-yl)azetidin-3-yl)-1H-benzo[d]imidazole;
- 2-[1-(3-phenyl-pyrazin-2-yl)-azetidin-3-yl]-1H-benzoimidazole-5-carbonitrile;
- azetidin-1-yl-{2-[3-(5-chloro-1H-benzoimidazol-2-yl)-azetidin-1-yl]-pyridin-3-yl}-methanone;
- {2-[3-(5-chloro-1H-benzoimidazol-2-yl)-azetidin-1-yl]-pyridin-3-yl}-morpholin-4-yl-methanone;
- 2-[3-(5-chloro-1H-benzoimidazol-2-yl)-azetidin-1-yl]-N-phenyl-nicotinamide;
- N-benzyl-2-[3-(5-chloro-1H-benzoimidazol-2-yl)-azetidin-1-yl]-nicotinamide;
- 2-[3-(5-chloro-1H-benzoimidazol-2-yl)-azetidin-1-yl]-N-phenethyl-nicotinamide;
- 2-[3-(5-chloro-1H-benzoimidazol-2-yl)-azetidin-1-yl]-N-isopropyl-nicotinamide;
- 2-[3-(5-chloro-1H-benzoimidazol-2-yl)-azetidin-1-yl]-N-isobutyl-nicotinamide;
- 2-[3-(5-chloro-1H-benzoimidazol-2-yl)-azetidin-1-yl]-N-(tetrahydro-pyran-4-ylmethyl)-nicotinamide;
- 5-chloro-2-[1-(3-o-tolyl-pyrazin-2-yl)-azetidin-3-yl]-1H-benzoimidazole;
- 5-chloro-2-[1-(3-m-tolyl-pyrazin-2-yl)-azetidin-3-yl]-1H-benzoimidazole;
- 5-chloro-2-[1-(3-p-tolyl-pyrazin-2-yl)-azetidin-3-yl]-1H-benzoimidazole;
- 5-chloro-2-{1-[3-(2-methoxy-phenyl)-pyrazin-2-yl]-azetidin-3-yl}-1H-benzoimidazole;
- 5-chloro-2-{1-[3-(3-methoxy-phenyl)-pyrazin-2-yl]-azetidin-3-yl}-1H-benzoimidazole;
- 5-chloro-2-{1-[3-(4-methoxy-phenyl)-pyrazin-2-yl]-azetidin-3-yl}-1H-benzoimidazole;
- 5-chloro-2-{1-[3-(2-chloro-phenyl)-pyrazin-2-yl]-azetidin-3-yl}-1H-benzoimidazole;
- 5-chloro-2-{1-[3-(3-chloro-phenyl)-pyrazin-2-yl]-azetidin-3-yl}-1H-benzoimidazole;
- 5-chloro-2-{1-[3-(4-chloro-phenyl)-pyrazin-2-yl]-azetidin-3-yl}-1H-benzoimidazole;
- 5-chloro-2-[1-(3-pyridin-3-yl-pyrazin-2-yl)-azetidin-3-yl]-1H-benzoimidazole;
- 5-chloro-2-[1-(3-pyridin-4-yl-pyrazin-2-yl)-azetidin-3-yl]-1H-benzoimidazole;
- 3-[3-(5-chloro-1H-benzoimidazol-2-yl)-azetidin-1-yl]-pyrazine-2-carboxylic acid dimethylamide;
- 3-[3-(5-chloro-1H-benzoimidazol-2-yl)-azetidin-1-yl]-pyrazine-2-carboxylic acid (tetrahydro-pyran-4-yl)-amide;
- 3-[3-(5-chloro-1H-benzoimidazol-2-yl)-azetidin-1-yl]-pyrazine-2-carboxylic acid (tetrahydro-furan-2-ylmethyl)-amide;
- 5-methyl-2-(1-(3-phenylpyrazin-2-yl)azetidin-3-yl)-1H-benzo[d]imidazole;
- 3-(3-(5-chloro-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)-N-phenylpyrazin-2-amine;
- 3-(3-(5-chloro-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)-N-methyl-N-phenylpyrazin-2-amine;
- 5-chloro-2-(1-(3-phenoxypyrazin-2-yl)azetidin-3-yl)-1H-benzo[d]imidazole;
- 5-chloro-2-(1-(3-(4-methylpiperazin-1-yl)pyrazin-2-yl)azetidin-3-yl)-1H-benzo[d]imidazole;
- 5-chloro-2-(1-(3-(piperidin-1-yl)pyrazin-2-yl)azetidin-3-yl)-1H-benzo[d]imidazole;
- 5-chloro-2-(1-(3-methoxypyrazin-2-yl)azetidin-3-yl)-1H-benzo[d]imidazole;
- 4-(3-(3-(5-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrazin-2-yl)morpholine;
- 2-(1-(3-chloropyridin-2-yl)azetidin-3-yl)-5-methyl-1H-benzo[d]imidazole;
- 2-(1-(3-chloropyrazin-2-yl)azetidin-3-yl)-5-methyl-1H-benzo[d]imidazole;
- 5-chloro-2-(1-(3-(tetrahydro-2H-pyran-4-yloxy)pyridin-2-yl)azetidin-3-yl)-1H-benzo[d]imidazole;
- 4-(3-(3-(5-chloro-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrazin-2-yl)morpholine;
- 5-chloro-2-(1-(3-(3,6-dihydro-2H-pyran-4-yl)pyrazin-2-yl)azetidin-3-yl)-1H-benzo[d]imidazole;
- 2-(1-(3-bromopyridin-2-yl)azetidin-3-yl)-5-chloro-1H-benzo[d]imidazole;
- 5-chloro-2-(1-(3-chloropyrazin-2-yl)azetidin-3-yl)-1H-benzo[d]imidazole;
- 5-chloro-2-(1-(3-chloropyridin-2-yl)azetidin-3-yl)-1H-benzo[d]imidazole;
- 5-chloro-2-(1-(2,5-dichloropyrimidin-4-yl)azetidin-3-yl)-1H-benzo[d]imidazole;
- or
- 5-chloro-2-(1-(3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)azetidin-3-yl)-1H-benzo[d]imidazole.
47 more elements
A compound, or a pharmaceutically acceptable salt thereof, which is:
- 2-[1-(3-Piperidin-1-yl-pyrazin-2-yl)-azetidin-3-yl]-quinoline;
- 2-[1-(3-m-Tolyl-pyrazin-2-yl)-azetidin-3-yl]-quinoline;
- 2-{1-[3-(3-Methoxy-phenyl)-pyridin-2-yl]-azetidin-3-yl}-quinoline;
- 2′-(3-Quinolin-2-yl-azetidin-1-yl)-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl;
- 2-{1-[3-(4-Methyl-piperidin-1-yl)-pyrazin-2-yl]-azetidin-3-yl}-quinoline;
- {1-[3-(3-Quinolin-2-yl-azetidin-1-yl)-pyrazin-2-yl]-piperidin-4-yl}-methanol;
- 2-{1-[3-(3-Methyl-pyrrolidin-1-yl)-pyrazin-2-yl]-azetidin-3-yl}-quinoline;
- or
- 2-{1-[3-(3-Methoxy-phenyl)-pyrazin-2-yl]-azetidin-3-yl}-quinoline.
6 more elements
Dependencies are inferred from the claim text.