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Tetrahydro-pyrimidoazepines as modulators of TRPV1

  • US 9,738,649 B2
  • Filed: 07/12/2016
  • Issued: 08/22/2017
  • Est. Priority Date: 03/21/2006
  • Status: Active Grant
First Claim
Patent Images

1. A compound selected from the group consisting of:

  • (4-tert-Butyl-phenyl)-[7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;

    (4-Trifluoromethyl-phenyl)-[7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetra-hydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;

    (4-tert-Butyl-phenyl)-[2-cyclopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;

    (4-Chloro-phenyl)-[2-cyclopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;

    [2-Cyclopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;

    (4-tert-Butyl-phenyl)-[2-phenyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;

    [2-Phenyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;

    (4-tert-Butyl-phenyl)-[2-isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;

    [2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;

    [2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(3-trifluoromethyl-phenyl)-amine;

    [2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethoxy-phenyl)-amine;

    [2-(4-Fluoro-phenyl)-ethyl]-[2-isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;

    [2-(2-Chloro-phenyl)-ethyl]-[2-isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;

    (3,4-Dichloro-benzyl)-[2-isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;

    (4-tert-Butyl-phenyl)-[2-methyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;

    [2-Methyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido-[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;

    (5-Trifluoromethyl-pyridin-2-yl)-[7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;

    Isoquinolin-1-yl-[7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;

    [2-Cyclopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine;

    [2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine;

    [2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-quinolin-3-yl-amine;

    [2-Phenyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine;

    [2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine;

    [2-Methyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine;

    [2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-phenoxy-phenyl)-amine;

    (4-Trifluoromethyl-phenyl)-[7-(4-trifluoromethyl-pyrimidin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;

    (7-Pyrimidin-2-yl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl)-(4-trifluoromethyl-phenyl)-amine;

    (7-Pyrazin-2-yl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl)-(4-trifluoromethyl-phenyl)-amine;

    (7-Quinoxalin-2-yl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl)-(4-trifluoromethyl-phenyl)-amine;

    [7-(3-Chloro-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;

    (4-tert-Butyl-phenyl)-[7-(6-chloro-5-methyl-pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;

    (4-tert-Butyl-phenyl)-[7-(3-methyl-quinoxalin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;

    (4-tert-Butyl-phenyl)-[2-isopropyl-7-(3-methyl-quinoxalin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;

    [2-Isopropyl-7-(3-trifluoromethyl-quinoxalin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;

    [2-Isopropyl-7-(3-methanesulfonyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;

    (4-tert-Butyl-phenyl)-(7-phthalazin-1-yl-6,7,8,9-tetrahydro-5H-pyrimido-[4,5-d]azepin-4-yl)-amine;

    (4-tert-Butyl-phenyl)-[7-(5-methyl-pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;

    [2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine;

    N2,N2-Dimethyl-N4-(6-trifluoromethyl-pyridin-3-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;

    N2,N2-Dimethyl-N4-(5-trifluoromethyl-pyridin-2-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;

    [2-Methyl sulfanyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;

    [2-Methanesulfonyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;

    N2-Phenyl-N4-(4-trifluoromethyl-phenyl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;

    N2-Cyclopropyl-N4-(4-trifluoromethyl-phenyl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;

    N2-(2-Piperidin-1-yl-ethyl)-N4-(4-trifluoromethyl-phenyl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;

    N2-(Tetrahydro-pyran-4-yl)-N4-(4-trifluoromethyl-phenyl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;

    [2-Methoxy-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;

    N4-(3,4-Dichloro-phenyl)-N2,N2-dimethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;

    N4-(4-Methoxy-3-trifluoromethyl-phenyl)-N2,N2-dimethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;

    2-{4-[2-Dimethylamino-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-2-methyl-propionitrile;

    (4-tert-Butyl-phenyl)[2-piperidin-1-ylmethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;

    (4-tert-Butyl-phenyl)-[2-methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;

    N4-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-N2,N2-dimethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;

    N4-Benzyl-N2,N2-dimethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;

    4-[2-Dimethylamino-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-benzenesulfonamide;

    N2,N2-Dimethyl-N4-(4-nitro-phenyl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;

    N4-(3,4-Dichloro-benzyl)-N2,N2-dimethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;

    [2-Methylsulfanyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine;

    [2-Methylsulfanyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine;

    [2-Methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;

    4-[2-Dimethylamino-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-benzoic acid methyl ester;

    4-[2-Dimethylamino-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-benzonitrile;

    N4-(4-Dimethylamino-phenyl)-N2,N2-dimethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;

    (3-Chloro-4-trifluoromethyl-phenyl)-[2-methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;

    N4-(4-Methoxy-phenyl)-N2,N2-dimethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;

    N4-Indan-2-yl-N2,N2-dimethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;

    [7-(5-Amino-3-methyl-pyridin-2-yl)-2-isopropyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;

    [7-(2-Amino-phenyl)-2-isopropyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;

    [2-Isopropyl-7-(2-nitro-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;

    [7-(3-Amino-pyridin-2-yl)-2-isopropyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;

    [2-Isopropyl-7-(3-methyl-5-nitro-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;

    [2-Isopropyl-7-(3-nitro-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;

    N-{2-[2-Isopropyl-4-(4-trifluoromethyl-phenylamino)-5,6,8,9-tetrahydro-pyrimido[4,5-d]azepin-7-yl]-phenyl}-methanesulfonamide;

    N2-(2-Methoxy-ethyl)-N2-methyl-N4-(4-trifluoromethyl-phenyl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;

    N2-Cyclopropylmethyl-N4-(4-trifluoromethyl-phenyl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;

    1-{4-[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-ethanone;

    4-[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-benzonitrile;

    (3,4-Dichloro-benzyl)-[2-methylsulfanyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;

    [2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethanesulfonyl-phenyl)-amine;

    4-[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-benzoic acid methyl ester;

    [2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethylsulfanyl-phenyl)-amine;

    [2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-pyrimidin-4-yl-amine;

    [2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-pyrimidin-2-yl-amine;

    [2-(3,4-Dichloro-phenyl)-ethyl]-[2-isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine; and

    (3,4-Dichloro-phenyl)-[2-isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine; and

    pharmaceutically acceptable salts thereof.

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