Purine nucleosides, their intermediates, and methods of preparation thereof

A method of preparing a compound of Formula C:

• wherein:
• R1 is C1-8 alkyl, —(C1-4 alkylene)-Ar, —(C1-4 alkylene)-Cy, C2-8 alkenyl, —(C2-4 alkenylene)-Ar, —(C2-4 alkenylene)-Cy, C2-8 alkynyl, —(C2-4 alkynylene)-Ar, —(C2-4 alkynylene)-Cy, phenyl, Cy, or a 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• each of which is substituted with n instances of R3;
• Ar is phenyl or a 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• Cy is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, or a 3-6-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• R2A is a suitable amino protecting group or R2;
• or R2A and PG1 are taken together to form a suitable bivalent nitrogen protecting group;
• R2 is hydrogen, C1-4 alkyl, or C3-5 cycloalkyl;
• wherein said C1-4 alkyl and C3-5 cycloalkyl are optionally substituted with 1, 2, or 3 deuterium or halogen atoms;
• each R3 is independently deuterium, halogen, —CN, —O—(C1-4 alkyl), —OH, —S—(C1-4 alkyl-, or —SH;
• X is S or O;
• n is 0, 1, 2, or 3;
• and
• PG1 is a suitable amino protecting group or is taken together with R2A to form a suitable bivalent nitrogen protecting group,
• comprising the steps of:
• (a) providing a compound of Formula E:
• wherein:
• R2 is hydrogen, C1-4 alkyl, or C3-5 cycloalkyl;
• wherein said C1-4 alkyl and C3-5 cycloalkyl are optionally substituted with 1, 2, or 3 deuterium or halogen atoms;
• and
• LG1 is a suitable leaving group;
• (b) coupling said compound of Formula E to form a compound of Formula D:
• wherein:
• R1 is C1-8 alkyl, —(C1-4 alkylene)-Ar, —(C1-4 alkylene)-Cy, C2-8 alkenyl, —(C2-4 alkenylene)-Ar, —(C2-4 alkenylene)-Cy, C2-8 alkynyl, —(C2-4 alkynylene)-Ar, —(C2-4 alkynylene)-Cy, phenyl, Cy, or a 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• each of which is substituted with n instances of R3;
• Ar is phenyl or a 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• Cy is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, or a 3-6-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• R2 is hydrogen, C1-4 alkyl, or C3-5 cycloalkyl;
• wherein said C1-4 alkyl and C3-5 cycloalkyl are optionally substituted with 1, 2, or 3 deuterium or halogen atoms;
• each R3 is independently deuterium, halogen, —CN, —O—(C1-4 alkyl), —OH, —S—(C1-4 alkyl), or —SH;
• X is S or O;
• and
• n is 0, 1, 2, or 3;
• and
• (c) protecting said compound of Formula D to form said compound of Formula C.

A compound of Formula I-A:

• or a pharmaceutically acceptable salt thereof, wherein:
• R1 is (i) C1-2 alkyl substituted with 1, 2, or 3 instances of R3, or (ii) C3-8 alkyl, —(C1-4 alkylene)-phenyl, —(C1-4 alkylene)-(C3-8 cycloalkyl), C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, phenyl, or a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• each of which is substituted with n instances of R3;
• R2 is hydrogen, C1-4 alkyl, or C3-5 cycloalkyl;
• each R3 is independently halogen, —O—(C1-4 alkyl), —OH, —S—(C1-4 alkyl), or —SH;
• X is S or O;
• and
• n is 0, 1, 2, or 3.

A compound of Formula A:

• wherein:
• R1 is C1-8 alkyl, —(C1-4 alkylene)-Ar, —(C1-4 alkylene)-Cy, C2-8 alkenyl, —(C2-4 alkenylene)-Ar, —(C2-4 alkenylene)-Cy, C2-8 alkynyl, —(C2-4 alkynylene)-Ar, —(C2-4 alkynylene)-Cy, phenyl, Cy, or a 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• each of which is substituted with n instances of R3;
• or
• R1 is a halogen when X is a covalent bond;
• Ar is phenyl or a 5-6 membered monocyclic heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• Cy is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, or a 3-6-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• R2A is a suitable amino protecting group or R2;
• or R2A and PG1 are taken together to form a suitable bivalent nitrogen protecting group;
• R2 is hydrogen, C1-4 alkyl, or C3-5 cycloalkyl;
• wherein said C1-4 alkyl and C3-5 cycloalkyl are optionally substituted with 1, 2, or 3 deuterium or halogen atoms;
• each R3 is independently deuterium, halogen, —CN, —O—(C1-4 alkyl), —OH, —S—(C1-4 alkyl), or —SH;
• X is S or O;
• or X is a covalent bond when R1 is a halogen;
• n is 0, 1, 2, or 3;
• PG1 is a suitable amino protecting group or is taken together with R2A to form a suitable bivalent nitrogen protecting group;
• and
• each of PG2, PG3, and PG4 is independently a suitable hydroxyl protecting group.

A compound of Formula I-B:

• or a pharmaceutically acceptable salt thereof, wherein:
• R1 is a halogen;
• R2 is hydrogen, C1-4 alkyl, or C3-5 cycloalkyl;
• and
• X is a covalent bond.