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US 2016/0257706 A1Published application
Beta-D-2'-DEOXY-2'-alpha-FLUORO-2'-beta-C-SUBSTITUTED-2-MODIFIED-N6-SUBSTITUTED PURINE NUCLEOTIDES FOR HCV TREATMENT
AssigneeAtea Pharmaceuticals, Inc.
InventorsJean-Pierre Sommadossi, Adel Moussa
Life of this patent
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Abstract
A compound of the structure: or a pharmaceutically acceptable salt or composition thereof for the treatment of a host infected with or exposed to an HCV virus or other disorders more fully described herein.
Claims14
A compound of Formula I:
- wherein:
- Y is NR1R2;
- R1 is C1-C5alkyl (including methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl and pentyl), C1-C5haloalkyl (including CH2F, CHF2, CF3, CH2CF3, CF2CH3 and CF2CF3), C2-C6 alkenyl, C2-C6 alkynyl, —(C0-C2alkyl)(C3-C6cycloalkyl), —(C0-C2alkyl)(heterocycle), —(C0-C2alkyl)(aryl), —(C0-C2alkyl)(heteroaryl), —OR25, —C(O)R3C (including —C(O)CH3, —C(O)CH2CH3, —C(O)CH(CH3)2, —C(O)OCH3, —C(O)OC2H5, —C(O)OC3H7, —C(O)OC4H9, and —C(O)OC5H11), —C(S)R3D, or —SO2R28 each of which can be optionally substituted;
- R2 is hydrogen, optionally substituted C1-C5alkyl (including methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl and pentyl), C1-C5haloalkyl (including CHF2, CHF2, CF3, CH2CF3 and CF2CF3), optionally substituted —(C0-C2alkyl)(C3-C6cycloalkyl), optionally substituted —(C0-C2alkyl)(heterocycle), optionally substituted —(C0-C2alkyl)(aryl), optionally substituted —(C0-C2alkyl)(heteroaryl), —C(O)R3C (including —C(O)CH3, —C(O)CH2CH3—C(O)CH(CH3)2, —C(O)OCH3, —C(O)OC2H5, —C(O)OC3H7, —C(O)OC4H9, and
- —C(O)OC5H11), —C(S)R3D, or —SO2R28;
- and
- wherein at least one of R1 and R2 is methyl, CH2F, CHF2 or CF3;
- R3 is hydrogen,
- diphosphate, triphosphate, an optionally substituted carbonyl linked amino acid, or —C(O)R3C;
- R3A can be selected from O−, OH, an —O-optionally substituted aryl, an —O-optionally substituted heteroaryl, or an optionally substituted heterocyclyl;
- R3B can be selected from O−, OH, an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester;
- R3C is alkyl, alkenyl, alkynyl, —(C0-C2)(cycloalkyl), —(C0-C2)(heterocyclo), —(C0-C2)(aryl), —(C0-C2)(heteroaryl), —O-alkyl, —O-alkenyl, —O-alkynyl, —O—(C0-C2)(cycloalkyl), —O—(C0-C2)(heterocyclo), —O—(C0-C2)(aryl), or —O—(C0-C2)(heteroaryl), each of which can be optionally substituted;
- R4 is a monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug, including but not limited to a phosphoramidate, a thiophosphoramidate, or any other moiety that is metabolized to a monophosphate, diphosphate or triphosphate in vivo in the host human or animal;
- or
- R3 and R4 together with the oxygens that they are bonded to can form a 3′,5′-cyclic prodrug;
- R12 is CH3, CH2F, CHF2, CF3, or ethynyl;
- R25 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, —(C0-C2alkyl)(C3-C6cycloalkyl), —(C0-C2alkyl)(C3-C6heterocycle), —(C0-C2alkyl)(aryl) or —(C0-C2alkyl)(heteroaryl) wherein except for the hydrogen each of which can be optionally substituted;
- R28 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, —(C0-C2alkyl)(C3-C6cycloalkyl), —(C0-C2alkyl)(C3-C6heterocycle), —(C0-C2alkyl)(aryl) or —(C0-C2alkyl)(heteroaryl) each of which can be optionally substituted;
- or a pharmaceutically acceptable salt thereof.
16 more elements
A compound of Formula II:
- wherein:
- Y is NR1R2;
- R1 is C1-C5alkyl (including methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl and pentyl), C1-C5haloalkyl (including CH2F, CHF2, CF3, CH2CF3, CF2CH3 and CF2CF3), C2-C6 alkenyl, C2-C6 alkynyl, —(C0-C2alkyl)(C3-C6cycloalkyl), —(C0-C2alkyl)(heterocycle), —(C0-C2alkyl)(aryl), —(C0-C2alkyl)(heteroaryl), —OR25, —C(O)R3C (including —C(O)CH3, —C(O)CH2CH3—C(O)CH(CH3)2, —C(O)OCH3, —C(O)OC2H5, —C(O)OC3H7, —C(O)OC4H9, and —C(O)OC5H11), —C(S)R3D, or —SO2R28 each of which can be optionally substituted;
- R2 is hydrogen, optionally substituted C1-C5alkyl (including methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl and pentyl), C1-C5haloalkyl (including CHF2, CHF2, CF3, CH2CF3 and CF2CF3), optionally substituted —(C0-C2alkyl)(C3-C6cycloalkyl), optionally substituted —(C0-C2alkyl)(heterocycle), optionally substituted —(C0-C2alkyl)(aryl),
- optionally substituted —(C0-C2alkyl)(heteroaryl), —C(O)R3C (including —C(O)CH3, —C(O)CH2CH3—C(O)CH(CH3)2, —C(O)OCH3, —C(O)OC2H5, —C(O)OC3H7, —C(O)OC4H9, and —C(O)OC5H11), —C(S)R3D, or —SO2R28;
- and
- wherein at least one of R1 and R2 is methyl, CH2F, CHF2 or CF3;
- R3 is hydrogen,
- diphosphate, triphosphate, an optionally substituted carbonyl linked amino acid, or —C(O)R3C;
- R3A can be selected from O−, OH, an —O-optionally substituted aryl, an —O-optionally substituted heteroaryl, or an optionally substituted heterocyclyl;
- R3B can be selected from O−, OH, an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester;
- R3C is alkyl, alkenyl, alkynyl, —(C0-C2)(cycloalkyl), —(C0-C2)(heterocyclo), —(C0-C2)(aryl), —(C0-C2)(heteroaryl), —O-alkyl, —O-alkenyl, —O-alkynyl, —O—(C0-C2)(cycloalkyl), —O—(C0-C2)(heterocyclo), —O—(C0-C2)(aryl), —O—(C0-C2)(heteroaryl), —S-alkyl, —S-alkenyl, —S-alkynyl, —S—(C0-C2)(cycloalkyl), —S—(C0-C2)(heterocyclo), —S—(C0-C2)(aryl), or —S—(C0-C2)(heteroaryl) each of which can be optionally substituted;
- R3D is alkyl, alkenyl, alkynyl, —(C0-C2)(cycloalkyl), —(C0-C2)(heterocyclo), —(C0-C2)(aryl), —(C0-C2)(heteroaryl), —O-alkyl, —O-alkenyl, —O-alkynyl, —O—(C0-C2)(cycloalkyl), —O—(C0-C2)(heterocyclo), —O—(C0-C2)(aryl), or —O—(C0-C2)(heteroaryl), each of which can be optionally substituted;
- R4 is a monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug, including but not limited to a phosphoramidate, a thiophosphoramidate, or any other moiety that is metabolized to a monophosphate, diphosphate or triphosphate in vivo in the host human or animal;
- or
- R3 and R4 together with the oxygens that they are bonded to can form a 3′,5′-cyclic prodrug, including but not limited to, a 3′,5′-cyclic phosphate prodrug;
- R5 is C1-C5alkyl (including methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl and pentyl), C1-C5haloalkyl (including CHF2, CHF2, CF3, CH2CF3 and CF2CF3), C2-C6 alkenyl, C2-C6 alkynyl, —(C0-C2alkyl)(C3-C6cycloalkyl), —(C0-C2alkyl)(heterocycle), —(C0-C2alkyl)(aryl), —(C0-C2alkyl)(heteroaryl), —OR25, —C(O)R3C (including —C(O)CH3, —C(O)CH2CH3—C(O)CH(CH3)2, —C(O)OCH3, —C(O)OC2H5, —C(O)OC3H7, —C(O)OC4H9, and
- —C(O)OC5H11), —C(S)R3D, or —SO2R28 each of which can be optionally substituted;
- R6 is hydrogen, optionally substituted C1-C5alkyl (including methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl and pentyl), C1-C5haloalkyl (including CHF2, CHF2, CF3, CH2CF3 and CF2CF3), optionally substituted —(C0-C2alkyl)(C3-C6cycloalkyl), optionally substituted —(C0-C2alkyl)(heterocycle), optionally substituted —(C0-C2alkyl)(aryl), optionally substituted —(C0-C2alkyl)(heteroaryl), —C(O)R3C (including —C(O)CH3, —C(O)CH2CH3—C(O)CH(CH3)2, —C(O)OCH3, —C(O)OC2H5, —C(O)OC3H7, —C(O)OC4H9, and —C(O)OC5H11), —C(S)R3D, or —SO2R28;
- or
- R5 and R6 together with the nitrogen that they are bonded to can form a heterocyclic ring;
- R12 is CH3, CH2F, CHF2, CF3, or ethynyl;
- R22 is F, Cl, Br, CN, N3, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, —(C1-C2alkyl)(C3-C6cycloalkyl), —(C0-C2alkyl)(C3-C6heterocycle), —(C0-C2alkyl)(aryl), —(C0-C2alkyl)(heteroaryl);
- —ONHC(═O)OR23, —NHOR24, —OR25, —SR25, —NH(CH2)1-4N(R26)2, —NHNHR26, —N═NR27, —NHC(O)NHNHR27, —NHC(S)NHNHR27, —C(O)NHNHR27, —NR27SO2R28, —SO2NR27R29, —C(O)NR27R29, —CO2R29, —SO2R29,
- —P(O)H(OR29), —P(O)(OR29)(OR30), —P(O)(OR29)(NR29R30) or —NR5R6;
- R23 is C1-C5alkyl, —(C0-C2alkyl)(C3-C6cycloalkyl), —(C0-C2alkyl)(heterocycle)-(C0-2alkyl)(aryl) or —(C0-C2alkyl)(heteroaryl) each of which can be optionally substituted;
- R24 is hydrogen, C1-C6 alkyl, —(C1-C2alkyl)(C3-C6cycloalkyl), —(C1-C2alkyl)(C3-C6heterocycle) —(C0-C2alkyl)(aryl) or —(C0-C2alkyl)(heteroaryl) wherein except for the hydrogen each of which can be optionally substituted;
- R25 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, —(C0-C2alkyl)(C3-C6cycloalkyl), —(C0-C2alkyl)(C3-C6heterocycle), —(C0-C2alkyl)(aryl) or —(C0-C2alkyl)(heteroaryl) wherein except for the hydrogen each of which can be optionally substituted;
- R26 is independently selected from hydrogen, C1-C6alkyl, —(C0-C2alkyl)(C3-C6cycloalkyl), —(C0-C2alkyl)(heterocycle), —(C0-C2alkyl)(aryl), or —(C0-C2alkyl)(heteroaryl) wherein except for the hydrogen each of which can be optionally substituted;
- R27 hydrogen or optionally substituted C1-C6 alkyl;
- R28 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, —(C0-C2alkyl)(C3-C6cycloalkyl), —(C0-C2alkyl)(C3-C6heterocycle), —(C0-C2alkyl)(aryl) or —(C0-C2alkyl)(heteroaryl) each of which can be optionally substituted;
- R29 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, —(C0-C2alkyl)(C3-C6cycloalkyl), —(C0-C2alkyl)(C3-C6heterocycle), —(C0-C2alkyl)(aryl) or —(C0-C2alkyl)(heteroaryl) wherein except for the hydrogen each of which can be optionally substituted;
- or
- R27 and R29 together with the nitrogen that they are bonded to can form a heterocyclic ring;
- R30 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, —(C0-C2alkyl)(C3C6cycloalkyl), —(C0-C2alkyl)(C3-C6heterocycle), —(C0-C2alkyl)(aryl) or —(C0-C2alkyl)(heteroaryl) wherein except for the hydrogen each of which can be optionally substituted;
- or
- R29 and R30 can be bonded together to form a heterocyclic ring;
- x is 1, 2 or 3;
- or a pharmaceutically acceptable salt thereof.
36 more elements
A compound of the formula:
- wherein R4 is a stabilized phosphate prodrug or a pharmaceutically acceptable salt thereof.
A compound of the formula:
- wherein R4 is a stabilized phosphate prodrug or a pharmaceutically acceptable salt thereof.
A compound of the structure:
- wherein R4 is a stabilized phosphate prodrug or a pharmaceutically acceptable salt thereof.
Dependencies are inferred from the claim text.