Tetrahydropyridopyrimidines and tetrahydropyridopyridines for the treatment and prophylaxis of hepatitis B virus infection
AssigneeHoffmann-La Roche Inc.
InventorsZhanling Cheng, Xingchun Han, Min Jiang, Jianhua Wang, Min Wang, Yongguang Wang, Song Yang
Life of this patent
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Abstract
The present invention provides novel compounds having the general formula: wherein R1, R2, U, W, X, Y and Z are as described herein, compositions including the compounds and methods of using the compounds.
Claims46
A compound of formula I,
- wherein
- R1 is C1-6alkyl, C3-7cycloalkyl, haloC1-6alkyl, hydroxyC1-6alkyl, nitroC1-6alkyl, C1-6alkoxycarbonylC1-6alkyl, carboxyC1-6alkyl, di(C1-6alkoxycarbonyl)methylenyl, cyanoC1-6alkyl, C3-7cycloalkylC1-6alkyl, phenylC1-6alkyl, C1-6alkylsulfanylC1-6alkyl, C1-6alkylsufonylC1-6alkyl, aminoC1-6alkyl, C1-6alkylcarbonylaminoC1-6alkyl, C1-6alkylsufonylaminoC1-6alkyl, C1-6alkoxycarbonyl aminoC1-6alkyl, aminocarbonylC1-6alkyl, diC1-6alkylaminocarbonylC1-6alkyl, monocyclic heterocycloalkylC1-6alkyl or imidazolylC1-6alkyl;
- R2 is aryl or heteroaryl, said aryl or heteroaryl being unsubstituted, or substituted by one, two, three or four substituents independently selected from C1-6alkyl, C3-7cycloalkyl, halogen, haloC1-6alkyl, cyano, nitro, hydroxy, haloC1-6alkoxy, —O—CxH2x—R3, —O—Cy—H2y—NHR6, —NR9R10, —SO2—R11, —SO2—NR12R13, carboxy, C1-6alkoxycarbonyl, —C(═O)—NR12R13, aryl, heteroaryl, monocyclic heterocycloalkyl and —O-monocyclic heterocycloalkyl;
- wherein monocyclic heterocycloalkyl is unsubstituted or substituted by C1-6alkyl, C3-7cycloalkyl, C1-6alkylcarbonyl, C1-6alkylsufonyl or C1-6alkoxycarbonyl;
- R3 is hydrogen;
- C3-7cycloalkyl;
- haloC3-7cycloalkyl;
- hydroxy;
- hydroxyC1-6alkylC3-7cycloalkyl;
- C1-6alkoxy;
- monocyclic heterocycloalkyl;
- monocyclic heterocycloalkyl substituted by C1-6alkyl, C1-6alkylcarbonyl, C1-6alkylsufonyl, C3-7cycloalkyl or C1-6alkoxycarbonyl;
- —C(═O)—R4;
- C1-6alkylsulfinyl;
- —SO2—R5;
- —C(NHR7)—C(═O)—R8;
- carboxyC1-6alkoxy or aminocarbonylC1-6alkoxy;
- wherein
- R4 is hydroxy, C1-6alkoxy, amino, C1-6alkylamino, diC1-6alkylamino, tetrahydrofuranylamino, pyrrolidinyl or morpholinyl;
- R5 is C1-6alkyl, C3-7cycloalkyl, hydroxy, amino, C1-6alkylamino or diC1-6alkylamino;
- R7 is hydrogen or C1-6alkoxycarbonyl;
- R8 is hydroxy or C1-6alkoxy;
- R6 is hydrogen, C1-6alkylcarbonyl, haloC1-6alkylcarbonyl, C1-6alkoxycarbonyl, C1-6alkylsulfonyl, C3-7cycloalkylsulfonyl or C1-6alkoxyC1-6alkylsulfonyl;
- R9 and R10 are independently selected from hydrogen, C1-6alkyl, C3-7cycloalkyl, C1-6alkylcarbonyl, C1-6alkylsulfonyl, C3-7cycloalkylcarbonyl and C3-7cycloalkylsulfonyl;
- or
- R9 and R10 together with the nitrogen to which they are attached form monocyclic heterocycloalkyl;
- R11 is C1-6alkyl, haloC1-6alkyl, C3-7cycloalkyl, haloC3-7cycloalkyl, hydroxyC1-6alkyl, C1-6alkoxyC1-6alkyl, haloC1-6alkoxyC1-6alkyl, C3-7cycloalkylC1-6alkyl, aminoC1-6alkyl, C1-6alkylaminoC1-6alkyl, diC1-6alkylaminoC1-6alkyl, C1-6alkylcarbonylaminoC1-6alkyl, C1-6alkylsulfonylaminoC1-6alkyl, C1-6alkoxycarbonylaminoC1-6alkyl, C1-6alkylsulfenylC1-6alkyl, C1-6alkylsulfanylC1-6alkyl or C1-6alkylsulfonylC1-6alkyl;
- R12 and R13 are independently selected from hydrogen, C1-6alkyl, C1-6alkoxyC1-6alkyl, haloC1-6alkyl, C3-7cycloalkyl and haloC3-7cycloalkyl;
- or
- R12 and R13 together with the nitrogen to which they are attached form monocyclic heterocycloalkyl;
- x is 1, 2, 3, 4, 5, 6, 7 or 8;
- y is 1, 2, 3, 4, 5, 6, 7 or 8;
- U, W and Z are independently selected from CH and N;
- one of X and Y is N, and the other one is N;
- or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof.
A compound which is 6-(3,4-difluoro-5-methoxy-phenyl)-5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine, or a pharmaceutically acceptable salt thereof.
A compound which is (−)-6-(3,4-difluoro-5-methoxy-phenyl)-5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine, or a pharmaceutically acceptable salt thereof.
A compound which is (+)-6-(3,4-difluoro-5-methoxy-phenyl)-5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine, or a pharmaceutically acceptable salt thereof.
A compound which is 6-(3-chloro-4-fluoro-5-methoxy-phenyl)-5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine, or a pharmaceutically acceptable salt thereof.
A compound which is (+)-6-(3-chloro-4-fluoro-5-methoxy-phenyl)-5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine, or a pharmaceutically acceptable salt thereof.
A compound which is (−)-6-(3-chloro-4-fluoro-5-methoxy-phenyl)-5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine, or a pharmaceutically acceptable salt thereof.
A compound which is (−)-6-[2,3-difluoro-5-[5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]phenoxy]hexan-1-amine, or a pharmaceutically acceptable salt thereof.
A compound which is (+)-6-[2,3-difluoro-5-[5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]phenoxy]hexan-1-amine, or a pharmaceutically acceptable salt thereof.
A compound which is 6-(3-fluoro-5-methoxy-phenyl)-5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine, or a pharmaceutically acceptable salt thereof.
A compound which is (−)-6-(3-fluoro-5-methoxy-phenyl)-5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine, or a pharmaceutically acceptable salt thereof.
A compound which is (+)-6-(3-fluoro-5-methoxy-phenyl)-5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine, or a pharmaceutically acceptable salt thereof.
A compound which is 6-(6-fluoro-4-methoxy-2-pyridyl)-5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine, or a pharmaceutically acceptable salt thereof.
A compound which is (−)-6-(6-fluoro-4-methoxy-2-pyridyl)-5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine, or a pharmaceutically acceptable salt thereof.
A compound which is (+)-6-(6-fluoro-4-methoxy-2-pyridyl)-5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine, or a pharmaceutically acceptable salt thereof.
A compound which is 6-[3-(2,2-difluoroethoxy)-5-fluoro-phenyl]-5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine, or a pharmaceutically acceptable salt thereof.
A compound which is 6-[4-(cyclopropylmethoxy)-6-fluoro-2-pyridyl]-5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine, or a pharmaceutically acceptable salt thereof.
A compound which is (−)-6-(6-fluoro-4-pyrrolidin-1-yl-2-pyridyl)-5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine, or a pharmaceutically acceptable salt thereof.
A compound which is (+)-6-(6-fluoro-4-pyrrolidin-1-yl-2-pyridyl)-5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine, or a pharmaceutically acceptable salt thereof.
Dependencies are inferred from the claim text.