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US 2024/0366649 A1Published application
4-ethynyl-3-hydroxy-tetrahydrofuranyl-adenine phosphoramidates and related compounds and their use in treating medical conditions
AssigneeROME Therapeutics, Inc.
InventorsDonna L. ROMERO, Oliver SAUNDERS, Gregory BISACCHI, Dennis ZALLER
Life of this patent
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Abstract
The invention provides substituted 4-ethynyl-3-hydroxy-tetrahydrofuranyl-adenine phosphoramidates and related compounds, pharmaceutical compositions, their use for inhibiting LINE1 reverse transcriptase and/or HERV-K reverse transcriptase activity, and their use in the treatment of medical disorders, such as cancer.
Claims78
A compound represented by Formula I:
- or a pharmaceutically acceptable salt thereof, wherein:
- R1 is —P(O)(OR3)(N(R4)(R5)) or —P(O)(N(R4)(R5))2;
- R2 is chloro, fluoro, or hydrogen;
- R3 is:
- a. phenyl, naphthyl, a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
- wherein said phenyl, naphthyl, 5-6 membered monocyclic heteroaryl, and 8-10 membered bicyclic heteroaryl are substituted with m instances of R8;
- or
- b. C1-20 alkyl, C1-20 haloalkyl, hydrogen, —(C1-10 alkylene)-OC(O)O—(C1-20 alkyl), or —(C1-10 alkylene)-OC(O)—(C1-20 alkyl);
- R4 represents independently for each occurrence hydrogen or C1-4 alkyl;
- R5 represents independently for each occurrence —C(R6)2—CO2R7;
- R6 represents independently for each occurrence C1-6 alkyl, C1-6 haloalkyl, C3-5 cycloalkyl, or hydrogen, wherein said C1-6 alkyl is optionally substituted with phenyl;
- or two instances of R6 are taken together with the carbon atom to which they are attached to form a 3-5 membered saturated carbocyclic ring;
- R7 represents independently for each occurrence C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, or C3-7 cycloalkyl;
- wherein said C1-6 alkyl is optionally substituted with C1-4 alkoxyl, phenyl, or C3-7 cycloalkyl;
- R8 represents independently for each occurrence halo, C1-4 alkyl, C1-4 haloalkyl, or C1-4 alkoxyl;
- and
- m is 0, 1, 2, or 3.
14 more elements
A compound represented by Formula II:
- or a pharmaceutically acceptable salt thereof, wherein:
- R1 is —OR3 or —N(R4)(R5);
- R2 is chloro, fluoro, or hydrogen;
- R3 is:
- a. phenyl, naphthyl, a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
- wherein said phenyl, naphthyl, 5-6 membered monocyclic heteroaryl, and 8-10 membered bicyclic heteroaryl are substituted with m instances of R8;
- or
- b. C1-20 alkyl, C1-20 haloalkyl, hydrogen, —(C1-10 alkylene)-OC(O)O—(C1-20 alkyl), or —(C1-10 alkylene)-OC(O)—(C1-20 alkyl);
- R4 is hydrogen or C1-4 alkyl;
- R5 is —C(R6)2—CO2R7;
- R6 represents independently for each occurrence C1-6 alkyl, C1-6 haloalkyl, C3-5 cycloalkyl, or hydrogen, wherein said C1-6 alkyl is optionally substituted with phenyl;
- or two instances of R6 are taken together with the carbon atom to which they are attached to form a 3-5 membered saturated carbocyclic ring;
- R7 is C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, or C3-7 cycloalkyl;
- wherein said C1-6 alkyl is optionally substituted with C1-4 alkoxyl, phenyl, or C3-7 cycloalkyl;
- R8 represents independently for each occurrence halo, C1-4 alkyl, C1-4 haloalkyl, or C1-4 alkoxyl;
- and
- m is 0, 1, 2, or 3.
14 more elements
A compound represented by Formula III:
- or a pharmaceutically acceptable salt thereof, wherein:
- R1 is —OR3 or —N(R4)(R5);
- R2 is chloro, fluoro, or hydrogen;
- R3 is:
- a. phenyl, naphthyl, a 5-6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
- wherein said phenyl, naphthyl, 5-6 membered monocyclic heteroaryl, and 8-10 membered bicyclic heteroaryl are substituted with m instances of R8;
- or
- b. C1-20 alkyl, C1-20 haloalkyl, hydrogen, —(C1-10 alkylene)-OC(O)O—(C1-20 alkyl) or —(C1-10 alkylene)-OC(O)—(C1-20 alkyl);
- R4 is hydrogen or C1-4 alkyl;
- R5 is —C(R6)2—CO2R7;
- R6 represents independently for each occurrence C1-6 alkyl, C1-6 haloalkyl, C3-5 cycloalkyl, or hydrogen, wherein said C1-6 alkyl is optionally substituted with phenyl;
- or two instances of R6 are taken together with the carbon atom to which they are attached to form a 3-5 membered saturated carbocyclic ring;
- R7 is C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, or C3-7 cycloalkyl;
- wherein said C1-6 alkyl is optionally substituted with C1-4 alkoxyl, phenyl, or C3-7 cycloalkyl;
- R8 represents independently for each occurrence halo, C1-4 alkyl, C1-4 haloalkyl, or C1-4 alkoxyl;
- and
- m is 0, 1, 2, or 3.
14 more elements
A compound in Table 1-A, 2, 3, or 4 herein, or a pharmaceutically acceptable salt thereof.
A compound in Table 1, selected from compound I-1 through I-17, I-19 through I-26, and I-28 through I-50, or a pharmaceutically acceptable salt thereof.
Dependencies are inferred from the claim text.