TLR7 agonists
阅读说明：本技术 Tlr7激动剂 (TLR7 agonists ) 是由 S·E·韦伯 J·R·爱普曼 于 2019-05-24 设计创作，主要内容包括：本发明涉及式I的TLR7激动剂及其在疾病如癌症和感染性疾病的治疗中的用途。(The present invention relates to TLR7 agonists of formula I and their use in the treatment of diseases such as cancer and infectious diseases.)
1. A compound having the structure of formula I:
wherein
R1is-H, -OH, -O-C (O) -R6Or a group of the formula-F,
R2is a group of the formula-H or-F,
R3independently is-OH or-O-C (O) -R7，
R4Is- (C)1-C8) Alkyl, - (C)1-C8) Alkenyl, - (C)1-C8) Alkynyl, - (C)1-C8) Haloalkyl, - (CH)2)n(cycloalkyl), - (CH)2)n(heterocyclic group), - (CH)2)n(aryl), - (CH)2)n(heteroaryl) or- (CH)2)nC(O)OR6，
R5is-H, -OH, -OCH3-SH or-Cl,
R6and R7Independently is- (C)1-C8) An alkyl group or an aryl group, or a salt thereof,
n is an integer of 1, 2, 3, 4 or 5,
wherein each alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, heteroaryl and heterocyclyl is independently substituted with CN, NO 2Halogen, (C)1-C3) Alkyl, (C)1-C3) Haloalkyl, aryl, heteroaryl, OH, alkenyl, alkynyl, O- (C)1-C3) Alkyl, O- (hydrocarbylene) aryl, O- (hydrocarbylene) heteroaryl, C (O) R8、S(C1-C8) Alkyl, S (O) alkyl, SO2Alkyl, C (O) OR8、C(O)NR8R8、C(O)NR8SO2Alkyl, NR8R8、NR8(CO)OR8、NH(CO)R8、NH(SO2) Alkyl or NH (SO)2)NR8R8Optionally substituted, and (c) optionally substituted,
and R is8Independently is-H, -OH, - (C)1-C8) Alkyl, cycloalkyl, heterocyclyl, or C (O) NR8R8Or NR8R8Two of R8Taken together with the nitrogen atom to form a heterocyclic ring;
or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, or a pharmaceutically acceptable hydrate thereof.
2. The compound of claim 1, wherein R1And R2is-H, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable hydrate thereof.
3. The compound of claim 1, wherein R1is-H and R2is-F, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable hydrate thereof.
4. The compound of claim 2, wherein R3is-OH and R5is-OH or-H, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable hydrate thereof.
5. The compound of claim 2, wherein R 3is-OC (O) CH3And R is5is-H, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable hydrate thereof.
6. The compound of claim 3, wherein R3is-OH and R5is-OH or-H, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable hydrate thereof.
7. The compound of claim 3, wherein R3is-OC (O) CH3And R is5is-H, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable hydrate thereof.
8. The compound of claim 1, wherein R4Is- (CH)2) (cyclopropyl), -CH2C≡CH、-(CH2)3CH3or-CH2CF3Or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, or a pharmaceutically acceptable hydrate thereof.
9. The compound of claim 1, wherein R8is-H, -OH, -CH3or-CH2CH3Or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, or a pharmaceutically acceptable hydrate thereof.
10. The compound of claim 1, wherein the compound is selected from the group consisting of:
2-amino-7- (cyclopropylmethyl) -9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione;
7-allyl-2-amino-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione;
(2R,3S,4R,5R) -2- (acetoxymethyl) -5- (2-amino-7- (cyclopropylmethyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-3, 4-diyl diacetate;
2-amino-7- (cyclopropylmethyl) -9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-one;
2-amino-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-7- (but-2-yn-1-yl) -9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-7- ((E) -but-2-en-1-yl) -9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- ((E) -4-hydroxybut-2-en-1-yl) -7, 9-dihydro-1H-purine-6, 8-dione;
(E) -4- (2-amino-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) but-2-enoic acid;
(E) -methyl 4- (2-amino-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) but-2-enoate;
2-amino-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (4-hydroxybut-2-yn-1-yl) -7, 9-dihydro-1H-purine-6, 8-dione;
methyl 2- (2-amino-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) acetate;
2-amino-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (2,2, 2-trifluoroethyl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-7- (2, 2-difluoroethyl) -9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7-methyl-7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7-ethyl-7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7-propyl-7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-7-butyl-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (4-hydroxybutyl) -7, 9-dihydro-1H-purine-6, 8-dione;
4- (2-amino-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) butanoic acid;
4- (2-amino-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) butanoic acid methyl ester;
2-amino-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (2-methoxyethyl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-7- (2-aminoethyl) -9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione hydrochloride;
(2R,3S,4R,5R) -2- (acetoxymethyl) -5- (2-amino-8-oxo-7- (prop-2-yn-yl) -7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-3, 4-diyl diacetate;
2-amino-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-8H-purin-8-one;
2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-9- ((2R,3S,4R,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-1H-purine-6, 8-dione;
((2S,4R,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (prop-2-yn-1-yl) -7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate;
2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-8H-purin-8-one;
((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (prop-2-yn-1-yl) -7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) methyl acetate;
2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-8H-purin-8-one;
2-amino-7-benzyl-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-7- (3-fluorobenzyl) -9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (4- (trifluoromethyl) benzyl) -7, 9-dihydro-1H-purine-6, 8-dione;
7-allyl-2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-7-butyl-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-7- (4-fluorobenzyl) -9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-7- (3, 4-difluorobenzyl) -9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-7- (4-chlorobenzyl) -9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-7- (3-chlorobenzyl) -9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-7-benzyl-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-7- (4-fluorobenzyl) -9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-7- (3-fluorobenzyl) -9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-7- (3, 4-difluorobenzyl) -9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-7- (4-chlorobenzyl) -9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-7- (3-chlorobenzyl) -9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-7- (3, 4-dichlorobenzyl) -9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione;
4- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) benzonitrile;
3- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) benzonitrile;
4- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) benzoic acid;
methyl 4- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) benzoate;
3- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) benzoic acid;
methyl 3- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) benzoate;
2- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) benzoic acid;
methyl 2- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) benzoate;
2-amino-7- (E) -cinnamyl-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione;
7- ((1H-pyrazol-5-yl) methyl) -2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- ((1-methyl-1H-pyrazol-3-yl) methyl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (thiophen-2-ylmethyl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (thiophen-3-ylmethyl) -7, 9-dihydro-1H-purine-6, 8-dione;
2- (2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) acetic acid;
2- (2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) acetonitrile;
2- (2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) acetaldehyde;
7- ((1H-tetrazol-5-yl) methyl) -2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione;
2- (2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) -N- (methylsulfonyl) acetamide;
2- (2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) -N-hydroxyacetamide;
2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- ((3-hydroxyisoxazol-5-yl) methyl) -7, 9-dihydro-1H-purine-6, 8-dione;
5- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) thiophene-2-carboxylic acid;
methyl 5- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) thiophene-2-carboxylate;
5- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) thiophene-3-carboxylic acid;
ethyl 5- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) thiophene-3-carboxylate;
4- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) thiophene-2-carboxylic acid;
4- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) thiophene-2-carboxylic acid methyl ester;
(1R,2R) -2- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) cyclopropane-1-carboxylic acid;
7- ((E) -3- (1H-tetrazol-5-yl) allyl) -2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione;
4- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) benzaldehyde;
2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (4-methoxybenzyl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (3-methoxybenzyl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (3-hydroxybenzyl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (4- (trifluoromethyl) benzyl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (pyridin-3-ylmethyl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (2-oxo-2- (pyrrolidin-1-yl) ethyl) -7, 9-dihydro-1H-purine-6, 8-dione;
7-allyl-2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-7- (cyclopropylmethyl) -9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-7-butyl-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (methoxymethyl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- ((methylthio) methyl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (2,2, 2-trifluoroethyl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-7- (2, 2-difluoroethyl) -9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (3,3, 3-trifluoropropyl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (2,2,3,3, 3-pentafluoropropyl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (4,4, 4-trifluorobutyl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (3,3,4,4, 4-pentafluorobutyl) -7, 9-dihydro-1H-purine-6, 8-dione;
3- (2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) propionitrile;
4- (2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) butyronitrile;
2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7-isobutyl-7, 9-dihydro-1H-purine-6, 8-dione;
1- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) cyclopropane-1-carbonitrile;
1- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) cyclopropane-1-carboxylic acid;
2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- ((1- (trifluoromethyl) cyclopropyl) methyl) -7, 9-dihydro-1H-purine-6, 8-dione;
((2S,4R,5R) -4-acetoxy-5- (2-amino-7-benzyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate;
2-amino-7-benzyl-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-one;
((2S,4R,5R) -4-acetoxy-5- (2-amino-7- (4-fluorobenzyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate;
2-amino-7- (4-fluorobenzyl) -9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-one;
((2S,4R,5R) -4-acetoxy-5- (2-amino-7- (3-fluorobenzyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate;
2-amino-7- (3-fluorobenzyl) -9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-one;
((2S,4R,5R) -4-acetoxy-5- (2-amino-7- (3, 4-difluorobenzyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate;
2-amino-7- (3, 4-difluorobenzyl) -9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-one;
((2S,4R,5R) -4-acetoxy-5- (2-amino-7- (4-chlorobenzyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate;
2-amino-7- (4-chlorobenzyl) -9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-one;
((2S,4R,5R) -4-acetoxy-5- (2-amino-7- (3-chlorobenzyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate;
2-amino-7- (3-chlorobenzyl) -9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-one;
((2S,4R,5R) -4-acetoxy-5- (2-amino-7- (3, 4-dichlorobenzyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate;
2-amino-7- (3, 4-dichlorobenzyl) -9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-one;
((2S,4R,5R) -4-acetoxy-5- (2-amino-7- (4-cyanobenzyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate;
4- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) benzonitrile;
((2S,4R,5R) -4-acetoxy-5- (2-amino-7- (3-cyanobenzyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate;
3- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) benzonitrile;
4- ((9- ((2R,3R,5S) -3-acetoxy-5- (acetoxymethyl) tetrahydrofuran-2-yl) -2-amino-8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) benzoic acid;
4- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) benzoic acid;
methyl 4- ((9- ((2R,3R,5S) -3-acetoxy-5- (acetoxymethyl) tetrahydrofuran-2-yl) -2-amino-8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) benzoate;
Methyl 4- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) benzoate;
3- ((9- ((2R,3R,5S) -3-acetoxy-5- (acetoxymethyl) tetrahydrofuran-2-yl) -2-amino-8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) benzoic acid;
3- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) benzoic acid;
methyl 3- ((9- ((2R,3R,5S) -3-acetoxy-5- (acetoxymethyl) tetrahydrofuran-2-yl) -2-amino-8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) benzoate;
methyl 3- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) benzoate;
2- ((9- ((2R,3R,5S) -3-acetoxy-5- (acetoxymethyl) tetrahydrofuran-2-yl) -2-amino-8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) benzoic acid;
2- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) benzoic acid;
methyl 2- ((9- ((2R,3R,5S) -3-acetoxy-5- (acetoxymethyl) tetrahydrofuran-2-yl) -2-amino-8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) benzoate;
Methyl 2- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) benzoate;
((2S,4R,5R) -4-acetoxy-5- (2-amino-7- (E) -cinnamyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate;
2-amino-7- (E) -cinnamyl-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-one;
((2S,4R,5R) -5- (7- ((1H-pyrazol-5-yl) methyl) -2-amino-8-oxo-7, 8-dihydro-9H-purin-9-yl) -4-acetoxytetrahydrofuran-2-yl) methyl acetate;
7- ((1H-pyrazol-5-yl) methyl) -2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-one;
((2S,4R,5R) -4-acetoxy-5- (2-amino-7- ((1-methyl-1H-pyrazol-3-yl) methyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate;
2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- ((1-methyl-1H-pyrazol-3-yl) methyl) -7, 9-dihydro-8H-purin-8-one;
((2S,4R,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (thiophen-2-ylmethyl) -7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate;
2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (thiophen-2-ylmethyl) -7, 9-dihydro-8H-purin-8-one;
((2S,4R,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (thiophen-3-ylmethyl) -7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate;
2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (thiophen-3-ylmethyl) -7, 9-dihydro-8H-purin-8-one;
methyl 2- (9- ((2R,3R,5S) -3-acetoxy-5- (acetoxymethyl) tetrahydrofuran-2-yl) -2-amino-8-oxo-8, 9-dihydro-7H-purin-7-yl) acetate;
2- (2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) acetic acid methyl ester;
2- (2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) acetic acid;
((2S,4R,5R) -4-acetoxy-5- (2-amino-7- (cyanomethyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate;
2- (2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) acetonitrile;
((2S,4R,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (2-oxoethyl) -7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate;
2- (2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) acetaldehyde;
((2S,4R,5R) -5- (7- ((1H-tetrazol-5-yl) methyl) -2-amino-8-oxo-7, 8-dihydro-9H-purin-9-yl) -4-acetoxytetrahydrofuran-2-yl) methyl acetate;
7- ((1H-tetrazol-5-yl) methyl) -2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-one;
((2S,4R,5R) -4-acetoxy-5- (2-amino-7- (2- (methylsulfonamido) -2-oxoethyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate;
2- (2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) -N- (methylsulfonyl) acetamide;
((2S,4R,5R) -4-acetoxy-5- (2-amino-7- (2-hydroxyamino-2-oxoethyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate;
2- (2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) -N-hydroxyacetamide;
((2S,4R,5R) -4-acetoxy-5- (2-amino-7- ((3-hydroxyisoxazol-5-yl) methyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate;
2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- ((3-hydroxyisoxazol-5-yl) methyl) -7, 9-dihydro-8H-purin-8-one;
5- ((9- ((2R,3R,5S) -3-acetoxy-5- (acetoxymethyl) tetrahydrofuran-2-yl) -2-amino-8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) thiophene-2-carboxylic acid;
5- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) thiophene-2-carboxylic acid;
methyl 5- ((9- ((2R,3R,5S) -3-acetoxy-5- (acetoxymethyl) tetrahydrofuran-2-yl) -2-amino-8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) thiophene-2-carboxylate;
methyl 5- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) thiophene-2-carboxylate;
5- ((9- ((2R,3R,5S) -3-acetoxy-5- (acetoxymethyl) tetrahydrofuran-2-yl) -2-amino-8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) thiophene-3-carboxylic acid;
5- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) thiophene-3-carboxylic acid;
ethyl 5- ((9- ((2R,3R,5S) -3-acetoxy-5- (acetoxymethyl) tetrahydrofuran-2-yl) -2-amino-8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) thiophene-3-carboxylate;
Ethyl 5- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) thiophene-3-carboxylate;
4- ((9- ((2R,3R,5S) -3-acetoxy-5- (acetoxymethyl) tetrahydrofuran-2-yl) -2-amino-8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) thiophene-2-carboxylic acid;
4- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) thiophene-2-carboxylic acid;
4- ((9- ((2R,3R,5S) -3-acetoxy-5- (acetoxymethyl) tetrahydrofuran-2-yl) -2-amino-8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) thiophene-2-carboxylic acid methyl ester;
4- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) thiophene-2-carboxylic acid methyl ester;
(1R,2R) -2- ((9- ((2R,3R,5S) -3-acetoxy-5- (acetoxymethyl) tetrahydrofuran-2-yl) -2-amino-8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) cyclopropane-1-carboxylic acid;
(1R,2R) -ethyl 2- ((9- ((2R,3R,5S) -3-acetoxy-5- (acetoxymethyl) tetrahydrofuran-2-yl) -2-amino-8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) cyclopropane-1-carboxylate;
(1R,2R) -ethyl 2- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) cyclopropane-1-carboxylate;
(1R,2R) -2- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) cyclopropane-1-carboxylic acid;
((2S,4R,5R) -5- (7- ((E) -3- (1H-tetrazol-5-yl) allyl) -2-amino-8-oxo-7, 8-dihydro-9H-purin-9-yl) -4-acetoxytetrahydrofuran-2-yl) methyl acetate;
7- ((E) -3- (1H-tetrazol-5-yl) allyl) -2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-one;
((2S,4R,5R) -4-acetoxy-5- (2-amino-7- (4-formylbenzyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate;
4- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) benzaldehyde;
((2S,4R,5R) -4-acetoxy-5- (2-amino-7- (4-methoxybenzyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate;
2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (4-methoxybenzyl) -7, 9-dihydro-8H-purin-8-one;
((2S,4R,5R) -4-acetoxy-5- (2-amino-7- (3-methoxybenzyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate;
2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (3-methoxybenzyl) -7, 9-dihydro-8H-purin-8-one;
((2S,4R,5R) -4-acetoxy-5- (2-amino-7- (3-hydroxybenzyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate;
2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (3-hydroxybenzyl) -7, 9-dihydro-8H-purin-8-one;
((2S,4R,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (4- (trifluoromethyl) benzyl) -7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate;
2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (4- (trifluoromethyl) benzyl) -7, 9-dihydro-8H-purin-8-one;
((2S,4R,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (pyridin-3-ylmethyl) -7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate;
2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (pyridin-3-ylmethyl) -7, 9-dihydro-8H-purin-8-one;
((2S,4R,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (2-oxo-2- (pyrrolidin-1-yl) ethyl) -7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate;
2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (2-oxo-2- (pyrrolidin-1-yl) ethyl) -7, 9-dihydro-8H-purin-8-one;
((2S,4R,5R) -4-acetoxy-5- (7-allyl-2-amino-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate;
7-allyl-2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-one;
((2S,4R,5R) -4-acetoxy-5- (2-amino-7- (cyclopropylmethyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate;
2-amino-7- (cyclopropylmethyl) -9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-one;
((2S,4R,5R) -4-acetoxy-5- (2-amino-7-butyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate;
2-amino-7-butyl-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-one;
((2S,4R,5R) -4-acetoxy-5- (2-amino-7- (methoxymethyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate;
2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (methoxymethyl) -7, 9-dihydro-8H-purin-8-one;
((2S,4R,5R) -4-acetoxy-5- (2-amino-7- ((methylthio) methyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate;
2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- ((methylthio) methyl) -7, 9-dihydro-8H-purin-8-one;
((2S,4R,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (2,2, 2-trifluoroethyl) -7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate;
2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (2,2, 2-trifluoroethyl) -7, 9-dihydro-8H-purin-8-one;
((2S,4R,5R) -4-acetoxy-5- (2-amino-7- (2, 2-difluoroethyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate;
2-amino-7- (2, 2-difluoroethyl) -9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-one;
((2S,4R,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (3,3, 3-trifluoropropyl) -7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate;
2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (3,3, 3-trifluoropropyl) -7, 9-dihydro-8H-purin-8-one;
((2S,4R,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (2,2,3,3, 3-pentafluoropropyl) -7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate;
2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (2,2,3,3, 3-pentafluoropropyl) -7, 9-dihydro-8H-purin-8-one;
((2S,4R,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (4,4, 4-trifluorobutyl) -7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate;
2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (4,4, 4-trifluorobutyl) -7, 9-dihydro-8H-purin-8-one;
((2S,4R,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (3,3,4,4, 4-pentafluorobutyl) -7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate;
2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (3,3,4,4, 4-pentafluorobutyl) -7, 9-dihydro-8H-purin-8-one;
((2S,4R,5R) -4-acetoxy-5- (2-amino-7- (2-cyanoethyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate;
3- (2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) propionitrile;
((2S,4R,5R) -4-acetoxy-5- (2-amino-7- (3-cyanopropyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate;
4- (2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) butanenitrile;
((2S,4R,5R) -4-acetoxy-5- (2-amino-7-isobutyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate;
2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7-isobutyl-7, 9-dihydro-8H-purin-8-one;
((2S,4R,5R) -4-acetoxy-5- (2-amino-7- ((1-cyanocyclopropyl) methyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate;
1- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) cyclopropane-1-carbonitrile;
ethyl 1- ((9- ((2R,3R,5S) -3-acetoxy-5- (acetoxymethyl) tetrahydrofuran-2-yl) -2-amino-8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) cyclopropane-1-carboxylate;
ethyl 1- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) cyclopropane-1-carboxylate;
1- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) cyclopropane-1-carboxylic acid;
((2S,4R,5R) -4-acetoxy-5- (2-amino-8-oxo-7- ((1- (trifluoromethyl) cyclopropyl) methyl) -7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate;
2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- ((1- (trifluoromethyl) cyclopropyl) methyl) -7, 9-dihydro-8H-purin-8-one;
2-amino-7-benzyl-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (4-fluorobenzyl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (3-fluorobenzyl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-7- (3, 4-difluorobenzyl) -9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-7- (4-chlorobenzyl) -9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-7- (3-chlorobenzyl) -9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-7- (3, 4-dichlorobenzyl) -9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione;
4- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) benzonitrile;
3- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) benzonitrile;
4- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) benzoic acid;
methyl 4- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) benzoate;
3- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) benzoic acid;
3- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) methylbenzoate;
2- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) benzoic acid;
methyl 2- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) benzoate;
2-amino-7- (E) -cinnamyl-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione;
7- ((1H-pyrazol-5-yl) methyl) -2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- ((1-methyl-1H-pyrazol-3-yl) methyl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (thiophen-2-ylmethyl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (thiophen-3-ylmethyl) -7, 9-dihydro-1H-purine-6, 8-dione;
2- (2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) acetic acid;
2- (2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) acetonitrile;
2- (2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) acetaldehyde;
7- ((1H-tetrazol-5-yl) methyl) -2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione;
2- (2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) -N- (methylsulfonyl) acetamide;
2- (2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) -N-hydroxyacetamide;
2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- ((3-hydroxyisoxazol-5-yl) methyl) -7, 9-dihydro-1H-purine-6, 8-dione;
5- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) thiophene-2-carboxylic acid;
methyl 5- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) thiophene-2-carboxylate;
5- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) thiophene-3-carboxylic acid;
ethyl 5- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) thiophene-3-carboxylate;
4- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) thiophene-2-carboxylic acid;
4- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) thiophene-2-carboxylic acid methyl ester;
(1R,2R) -2- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) cyclopropane-1-carboxylic acid;
7- ((E) -3- (1H-tetrazol-5-yl) allyl) -2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione;
4- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) benzaldehyde;
2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (4-methoxybenzyl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (3-methoxybenzyl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (3-hydroxybenzyl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (4- (trifluoromethyl) benzyl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (pyridin-3-ylmethyl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (2-oxo-2- (pyrrolidin-1-yl) ethyl) -7, 9-dihydro-1H-purine-6, 8-dione;
7-allyl-2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-7- (cyclopropylmethyl) -9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-7-butyl-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (methoxymethyl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- ((methylthio) methyl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (2,2, 2-trifluoroethyl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-7- (2, 2-difluoroethyl) -9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (3,3, 3-trifluoropropyl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (2,2,3,3, 3-pentafluoropropyl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (4,4, 4-trifluorobutyl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (3,3,4,4, 4-pentafluorobutyl) -7, 9-dihydro-1H-purine-6, 8-dione;
3- (2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) propionitrile;
4- (2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) butyronitrile;
2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7-isobutyl-7, 9-dihydro-1H-purine-6, 8-dione;
1- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) cyclopropane-1-carbonitrile;
1- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) cyclopropane-1-carboxylic acid;
2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- ((1- (trifluoromethyl) cyclopropyl) methyl) -7, 9-dihydro-1H-purine-6, 8-dione;
((2R,3S,4S,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (prop-2-yn-1-yl) -7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) methyl acetate;
2-amino-9- ((2R,3S,4R,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-8H-purin-8-one;
((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-7-benzyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydro-furan-2-yl) methyl acetate;
2-amino-7-benzyl-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-one;
((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-7- (4-fluorobenzyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydro-furan-2-yl) methyl acetate;
2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (4-fluorobenzyl) -7, 9-dihydro-8H-purin-8-one;
((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-7- (3-fluorobenzyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydro-furan-2-yl) methyl acetate;
2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (3-fluorobenzyl) -7, 9-dihydro-8H-purin-8-one;
((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-7- (3, 4-difluorobenzyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) methyl acetate;
2-amino-7- (3, 4-difluorobenzyl) -9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-one;
((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-7- (4-chlorobenzyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydro-furan-2-yl) methyl acetate;
2-amino-7- (4-chlorobenzyl) -9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-one;
((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-7- (3-chlorobenzyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydro-furan-2-yl) methyl acetate;
2-amino-7- (3-chlorobenzyl) -9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-one;
((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-7- (3, 4-dichlorobenzyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) methyl acetate;
2-amino-7- (3, 4-dichlorobenzyl) -9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-one;
((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-7- (4-cyanobenzyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydro-furan-2-yl) methyl acetate;
4- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) benzonitrile;
((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-7- (3-cyanobenzyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydro-furan-2-yl) methyl acetate;
3- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) benzonitrile;
4- ((9- ((2R,3S,4R,5R) -3-acetoxy-5- (acetoxymethyl) -4-fluorotetrahydrofuran-2-yl) -2-amino-8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) benzoic acid;
4- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) benzoic acid;
methyl 4- ((9- ((2R,3S,4R,5R) -3-acetoxy-5- (acetoxymethyl) -4-fluorotetrahydrofuran-2-yl) -2-amino-8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) benzoate;
methyl 4- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) benzoate;
3- ((9- ((2R,3S,4R,5R) -3-acetoxy-5- (acetoxymethyl) -4-fluorotetrahydrofuran-2-yl) -2-amino-8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) benzoic acid;
3- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) benzoic acid;
methyl 3- ((9- ((2R,3S,4R,5R) -3-acetoxy-5- (acetoxymethyl) -4-fluorotetrahydrofuran-2-yl) -2-amino-8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) benzoate;
methyl 3- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) benzoate;
2- ((9- ((2R,3S,4R,5R) -3-acetoxy-5- (acetoxymethyl) -4-fluorotetrahydrofuran-2-yl) -2-amino-8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) benzoic acid;
2- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) benzoic acid;
methyl 2- ((9- ((2R,3S,4R,5R) -3-acetoxy-5- (acetoxymethyl) -4-fluorotetrahydrofuran-2-yl) -2-amino-8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) benzoate;
methyl 2- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) benzoate;
((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-7- (E) -cinnamyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) methyl acetate;
2-amino-7- (E) -cinnamyl-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-one;
((2R,3R,4S,5R) -5- (7- ((1H-pyrazol-5-yl) methyl) -2-amino-8-oxo-7, 8-dihydro-9H-purin-9-yl) -4-acetoxy-3-fluorotetrahydrofuran-2-yl) methyl acetate;
7- ((1H-pyrazol-5-yl) methyl) -2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-one;
((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-7- ((1-methyl-1H-pyrazol-3-yl) methyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) methyl acetate;
2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- ((1-methyl-1H-pyrazol-3-yl) methyl) -7, 9-dihydro-8H-purin-8-one;
((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (thiophen-2-ylmethyl) -7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) methyl acetate;
2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (thiophen-2-ylmethyl) -7, 9-dihydro-8H-purin-8-one;
((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (thiophen-3-ylmethyl) -7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) methyl acetate;
2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (thiophen-3-ylmethyl) -7, 9-dihydro-8H-purin-8-one;
methyl 2- (9- ((2R,3S,4R,5R) -3-acetoxy-5- (acetoxymethyl) -4-fluorotetrahydrofuran-2-yl) -2-amino-8-oxo-8, 9-dihydro-7H-purin-7-yl) acetate;
methyl 2- (2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) acetate;
2- (2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) acetic acid;
((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-7- (cyanomethyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydro-furan-2-yl) methyl acetate;
2- (2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) acetonitrile;
((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (2-oxoethyl) -7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydro-furan-2-yl) methyl acetate;
2- (2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) acetaldehyde;
((2R,3R,4S,5R) -5- (7- ((1H-tetrazol-5-yl) methyl) -2-amino-8-oxo-7, 8-dihydro-9H-purin-9-yl) -4-acetoxy-3-fluorotetrahydrofuran-2-yl) methyl acetate;
7- ((1H-tetrazol-5-yl) methyl) -2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-one;
((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-7- (2- (methylsulfonylamino) -2-oxoethyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) methyl acetate;
2- (2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) -N- (methylsulfonyl) acetamide;
((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-7- (2-hydroxyamino-2-oxoethyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) methyl acetate;
2- (2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) -N-hydroxyacetamide;
((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-7- ((3-hydroxyisoxazol-5-yl) methyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) methyl acetate;
2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- ((3-hydroxyisoxazol-5-yl) methyl) -7, 9-dihydro-8H-purin-8-one;
5- ((9- ((2R,3S,4R,5R) -3-acetoxy-5- (acetoxymethyl) -4-fluorotetrahydrofuran-2-yl) -2-amino-8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) thiophene-2-carboxylic acid;
5- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) thiophene-2-carboxylic acid;
methyl 5- ((9- ((2R,3S,4R,5R) -3-acetoxy-5- (acetoxymethyl) -4-fluorotetrahydrofuran-2-yl) -2-amino-8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) thiophene-2-carboxylate;
Methyl 5- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) thiophene-2-carboxylate;
5- ((9- ((2R,3S,4R,5R) -3-acetoxy-5- (acetoxymethyl) -4-fluorotetrahydrofuran-2-yl) -2-amino-8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) thiophene-3-carboxylic acid;
5- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) thiophene-3-carboxylic acid;
ethyl 5- ((9- ((2R,3S,4R,5R) -3-acetoxy-5- (acetoxymethyl) -4-fluorotetrahydrofuran-2-yl) -2-amino-8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) thiophene-3-carboxylate;
ethyl 5- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) thiophene-3-carboxylate;
4- ((9- ((2R,3S,4R,5R) -3-acetoxy-5- (acetoxymethyl) -4-fluorotetrahydrofuran-2-yl) -2-amino-8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) thiophene-2-carboxylic acid;
4- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) thiophene-2-carboxylic acid;
4- ((9- ((2R,3S,4R,5R) -3-acetoxy-5- (acetoxymethyl) -4-fluorotetrahydrofuran-2-yl) -2-amino-8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) thiophene-2-carboxylic acid methyl ester;
4- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) thiophene-2-carboxylic acid methyl ester;
(1R,2R) -ethyl 2- ((9- ((2R,3S,4R,5R) -3-acetoxy-5- (acetoxymethyl) -4-fluorotetrahydrofuran-2-yl) -2-amino-8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) cyclopropane-1-carboxylate;
(1R,2R) -ethyl 2- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) cyclopropane-1-carboxylate;
(1R,2R) -2- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) cyclopropane-1-carboxylic acid;
((2R,3R,4S,5R) -5- (7- ((E) -3- (1H-tetrazol-5-yl) allyl) -2-amino-8-oxo-7, 8-dihydro-9H-purin-9-yl) -4-acetoxy-3-fluorotetrahydrofuran-2-yl) methyl acetate;
7- ((E) -3- (1H-tetrazol-5-yl) allyl) -2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-one;
((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-7- (4-formylbenzyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydro-furan-2-yl) methyl acetate;
4- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) benzaldehyde;
((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-7- (4-methoxybenzyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydro-furan-2-yl) methyl acetate;
2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (4-methoxybenzyl) -7, 9-dihydro-8H-purin-8-one;
((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-7- (3-methoxybenzyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydro-furan-2-yl) methyl acetate;
2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (3-methoxybenzyl) -7, 9-dihydro-8H-purin-8-one;
((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-7- (3-hydroxybenzyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydro-furan-2-yl) methyl acetate;
2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (3-hydroxybenzyl) -7, 9-dihydro-8H-purin-8-one;
((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (4- (trifluoromethyl) benzyl) -7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) methyl acetate;
2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (4- (trifluoromethyl) benzyl) -7, 9-dihydro-8H-purin-8-one;
((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (pyridin-3-ylmethyl) -7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) methyl acetate;
2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (pyridin-3-ylmethyl) -7, 9-dihydro-8H-purin-8-one;
((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (2-oxo-2- (pyrrolidin-1-yl) ethyl) -7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) methyl acetate;
2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (2-oxo-2- (pyrrolidin-1-yl) ethyl) -7, 9-dihydro-8H-purin-8-one;
((2R,3R,4S,5R) -4-acetoxy-5- (7-allyl-2-amino-8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) methyl acetate;
7-allyl-2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-one;
((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-7- (cyclopropylmethyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydro-furan-2-yl) methyl acetate;
2-amino-7- (cyclopropylmethyl) -9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-one;
((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-7-butyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) methyl acetate;
2-amino-7-butyl-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-one;
((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-7- (methoxymethyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) methyl acetate;
2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (methoxymethyl) -7, 9-dihydro-8H-purin-8-one;
((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-7- ((methylthio) methyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydro-furan-2-yl) methyl acetate;
2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- ((methylthio) methyl) -7, 9-dihydro-8H-purin-8-one;
((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (2,2, 2-trifluoroethyl) -7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) methyl acetate;
2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (2,2, 2-trifluoroethyl) -7, 9-dihydro-8H-purin-8-one;
((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-7- (2, 2-difluoroethyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) methyl acetate;
2-amino-7- (2, 2-difluoroethyl) -9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-one;
((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (3,3, 3-trifluoropropyl) -7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) methyl acetate;
2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (3,3, 3-trifluoropropyl) -7, 9-dihydro-8H-purin-8-one;
((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (2,2,3,3, 3-pentafluoropropyl) -7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) methyl acetate;
2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (2,2,3,3, 3-pentafluoropropyl) -7, 9-dihydro-8H-purin-8-one;
((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (4,4, 4-trifluorobutyl) -7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) methyl acetate;
2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (4,4, 4-trifluorobutyl) -7, 9-dihydro-8H-purin-8-one;
((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (3,3,4,4, 4-pentafluorobutyl) -7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) methyl acetate;
2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (3,3,4,4, 4-pentafluorobutyl) -7, 9-dihydro-8H-purin-8-one;
((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-7- (2-cyanoethyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydro-furan-2-yl) methyl acetate;
3- (2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) propionitrile;
((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-7- (3-cyanopropyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydro-furan-2-yl) methyl acetate;
4- (2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) butanenitrile;
((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-7-isobutyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) methyl acetate;
2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7-isobutyl-7, 9-dihydro-8H-purin-8-one;
((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-7- ((1-cyanocyclopropyl) methyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) methyl acetate;
1- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) cyclopropane-1-carbonitrile;
ethyl 1- ((9- ((2R,3S,4R,5R) -3-acetoxy-5- (acetoxymethyl) -4-fluorotetrahydrofuran-2-yl) -2-amino-8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) cyclopropane-1-carboxylate;
ethyl 1- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) cyclopropane-1-carboxylate;
1- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) cyclopropane-1-carboxylic acid;
((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-8-oxo-7- ((1- (trifluoromethyl) cyclopropyl) methyl) -7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) methyl acetate;
And 2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- ((1- (trifluoromethyl) cyclopropyl) methyl) -7, 9-dihydro-8H-purin-8-one, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable hydrate thereof.
11. The compound of claim 10, wherein the compound is selected from the group consisting of: 2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-8H-purin-8-one;
((2S,4R,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (prop-2-yn-1-yl) -7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate;
2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-8H-purin-8-one;
((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (prop-2-yn-1-yl) -7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) methyl acetate;
2-amino-9- ((2R,3S,4R,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-9- ((2R,3S,4R,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-8H-purin-8-one;
((2R,3S,4S,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (prop-2-yn-1-yl) -7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) methyl acetate;
2-amino-7-butyl-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-7-butyl-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-one;
((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-7-butyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) methyl acetate;
2-amino-7-butyl-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-7-butyl-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-one;
((2S,4R,5R) -4-acetoxy-5- (2-amino-7-butyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate;
2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (2,2, 2-trifluoroethyl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (2,2, 2-trifluoroethyl) -7, 9-dihydro-8H-purin-8-one;
((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (2,2, 2-trifluoroethyl) -7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) methyl acetate;
2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (2,2, 2-trifluoroethyl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (2,2, 2-trifluoroethyl) -7, 9-dihydro-8H-purin-8-one;
((2S,4R,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (2,2, 2-trifluoroethyl) -7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate;
2-amino-7- (cyclopropylmethyl) -9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-7- (cyclopropylmethyl) -9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-one;
((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-7- (cyclopropylmethyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydro-furan-2-yl) methyl acetate;
2-amino-7- (cyclopropylmethyl) -9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione;
2-amino-7- (cyclopropylmethyl) -9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-one;
and ((2S,4R,5R) -4-acetoxy-5- (2-amino-7- (cyclopropylmethyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable hydrate thereof.
12. A pharmaceutical composition comprising one or more compounds of claim 1, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable hydrate thereof, and a pharmaceutically acceptable excipient.
13. The pharmaceutical composition of claim 12, further comprising one or more agents, wherein each of the one or more agents is independently an immune checkpoint inhibitor, an OX40 agonist, a 4-1BB agonist, an ICOS agonist, a GITR agonist, or an IL 2-receptor agonist.
14. The pharmaceutical composition of claim 13, wherein each of the one or more agents is independently an inhibitor of PD-1, PD-L1, CTLA4, TIM3, LAG3, sirpa, or CD 47.
15. The pharmaceutical composition of claim 12, further comprising one or more agents, wherein each of the one or more agents is independently an antibody mediated by ADCC.
16. The pharmaceutical composition of claim 15, wherein the antibody is independently rituximab, trastuzumab, or alemtuzumab.
17. A method of treating a subject having an infectious disease, a precancerous condition, or a cancer, the method comprising administering to the subject an effective amount of one or more compounds of claim 1, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable hydrate thereof.
18. The method of claim 17, further comprising administering one or more agents, wherein each of the one or more agents is independently an immune checkpoint inhibitor, an OX40 agonist, a 4-1BB agonist, an ICOS agonist, a GITR agonist, or an IL 2-receptor agonist.
19. The method of claim 18, wherein each of the one or more agents is independently an inhibitor of PD-1, PD-L1, CTLA4, TIM3, LAG3, sirpa, or CD 47.
20. The method of claim 17, further comprising administering one or more agents, wherein each of the one or more agents is independently an antibody mediated by ADCC.
Technical Field
The present invention provides TLR7 agonists and their use in therapeutic applications. The present invention provides methods of treating infections, immune disorders and cancer using TLR7 agonists.
Background
The ultimate goal of cancer immunotherapy is to eradicate tumor cells through the immune system. Both the innate and adaptive arms of the immune system can help to destroy tumor cells, of which Natural Killer (NK) cells and T cells, respectively, are key roles. The key to the adaptive immune response to tumor cells is the activation of CD8+ Cytotoxic T Lymphocytes (CTLs) that are able to exploit their cytotoxic potential against tumor cells upon recognition of Tumor Associated Antigens (TAAs). Activation of naive CD8+ cells is performed by Antigen Presenting Cells (APCs), while Dendritic Cells (DCs) are considered to be the most specialized APCs. These cells capture and process TAAs, presenting epitopes and histocompatibility complex (MHC) molecules on their membranes. Maturation of APCs based on danger signals is crucial for presentation to T cells in a stimulatory manner.
Despite the potential of TAA-specific T cells to destroy tumor cells, tolerance of peripheral T cells to TAAs prevents an effective immune response to tumors. Methods for breaking the tolerance of T cells to TAAs can be divided into two categories: (a) active specific immunotherapy (also known as cancer vaccine) and (b) passive specific immunotherapy (by adoptive transfer of anti-tumor T cells or by monoclonal antibodies). The low immunogenicity of tumor cells is also a potential problem for cancer immunotherapy. The reason for this low immunogenicity is that TAAs are mainly self-antigens and also due to down-regulation of co-stimulatory molecules on human leukocyte antigens and tumor cell membranes. Furthermore, tumor cells actively suppress the immune system by secreting immunosuppressive molecules that interfere with DC and T cell function.
Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. A TLR is a Pattern Recognition Receptor (PRR) that recognizes molecules that are widely shared by pathogens but are distinct from host molecules, collectively referred to as pathogen-associated molecular patterns (PAMPs). They are single, transmembrane non-catalytic receptors, usually expressed on sentinel cells such as macrophages and dendritic cells, that recognize structurally conserved molecules derived from microorganisms.
TLRs 3, 7, 8, and 9 form a group of intracellular TLRs and recognize bacterial or viral nucleic acids. Natural ligands for TLR7 and TLR8 are single stranded RNAs rich in guanosine and/or uridine. TLR7 and TLR8 are also activated by certain small synthetic compounds. The imidazoquinoline derivatives imiquimod (R837) and resiquimod (R848) are described as TLR7 ligands in mice (Hemmi et al, 2002, nat. Immunol.3: 196-200). In addition, the guanosine analog Loxoribine (Loxoribine) was identified as a TLR7 ligand (Heil et al, 2003, Eur. J. Immunol.33: 2987-. Other TLR7 and/or TLR8 ligands include CL097(3M-001), 852A, and CL 075.
Although TLR7 and TLR8 are structurally similar, their activation has a clear effect on innate immune cells and subsequent cytokine production. TLR8 agonists have been reported to be more effective than TLR7 agonists in inducing pro-inflammatory cytokines and chemokines, such as Tumor Necrosis Factor (TNF) - α, Interleukin (IL) -12, and Macrophage Inflammatory Protein (MIP) -1 α in Peripheral Blood Mononuclear Cells (PBMCs). Conversely, TLR7 agonists have been reported to activate plasmacytoid dendritic cells and induce the production of Interferon (IFN) - α.
After finding the efficacy of the TLR7/8 agonist imiquimod in protecting guinea pigs from herpes virus infection, imiquimod has also been shown to be effective against several transplantable murine tumors. It is reported that for imiquimod: (Cream) the clinical responsiveness of topical treatment is effective for both primary skin tumors and skin metastases. In these reports, the immunopotentiation effect of imiquimod was sufficient to elicit an anti-tumor response without the addition of TAA. Imiquimod treatment has also been reported to be associated, in part or in whole, with the abnormal expression of certain genes in reversing premalignant actinic keratosis, thus demonstrating the ability of imiquimod to prevent cancer development.
Although treatment with TLR7 agonists has shown good anti-cancer effects in local cancers, administration of these agonists by oral or systemic routes remains challenging. In a phase II clinical study of patients infected with hepatitis c virus, R848, administered by the oral route, showed therapeutic efficacy against plasma hepatitis virus titers but had dose-limiting toxicity. In another study, the TLR7 agonist 852A was tested for intravenous dose in a phase II study for three weeks in patients with metastatic melanoma. This study showed that some patients had prolonged disease stability and elevated serum IFN α and IP-10, but two patients had dose-limiting toxicity. These studies indicate that systemic use of TLR7 agonists in patients can be a challenge due to the narrow therapeutic window.
Disclosure of Invention
The present invention relates generally to compounds useful as agonists of TLR7, compositions thereof, methods of making the same, and methods of using the same.
In one embodiment, the invention relates to TLR7 agonist compounds according to formula I:
wherein
R1is-H, -OH, -O-C (O) -R6Or a group of the formula-F,
R2is a group of the formula-H or-F,
R3independently is-OH or-O-C (O) -R7，
R4Is- (C)1-C8) Alkyl, - (C)1-C8) Alkenyl, - (C)1-C8) Alkynyl, - (C)1-C8) Haloalkyl, - (CH)2)n(cycloalkyl), - (CH)2)n(heterocyclic group), - (CH)2)n(aryl), - (CH)2)n(heteroaryl) or- (CH)2)nC(O)OR6，
R5is-H, -OH, -OCH3-SH or-Cl,
R6and R7Independently is- (C)1-C8) An alkyl group or an aryl group, or a salt thereof,
n is an integer of 1, 2, 3, 4 or 5,
wherein each alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, heteroaryl and heterocyclyl is independently substituted with CN, NO2Halogen, (C)1-C3) Alkyl, (C)1-C3) Halogenated alkyl, aryl, heteroaromaticRadical, OH, alkenyl, alkynyl, O- (C)1-C3) Alkyl, O- (hydrocarbylene) aryl, O- (hydrocarbylene) heteroaryl, C (O) R8、S(C1-C8) Alkyl, S (O) alkyl, SO2Alkyl, C (O) OR8、C(O)NR8R8、C(O)NR8SO2Alkyl, NR8R8、NR8(CO)OR8、NH(CO)R8、NH(SO2) Alkyl or NH (SO)2)NR8R8Is optionally substituted, and R8Independently is-H, -OH, - (C)1-C8) Alkyl, cycloalkyl, heterocyclyl, or C (O) NR8R8Or NR8R8Two of R 8Taken together with the nitrogen atom to form a heterocyclic ring;
or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, or a pharmaceutically acceptable hydrate thereof.
In other embodiments, the TLR7 agonist compounds of the invention can be used alone, or in combination with other additional therapeutic agents and therapeutic procedures, to treat or prevent cancer or infection or infectious disease in a subject in need of such treatment or prevention.
In other embodiments, the present invention provides pharmaceutical compositions comprising: (i) a therapeutically effective amount of at least one compound of formula I or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof; (ii) in combination with a pharmaceutically acceptable carrier, diluent or excipient. Pharmaceutical compositions comprising a pharmaceutically acceptable carrier, diluent, or excipient, as well as other therapeutic agents, are also part of the invention.
The above-described embodiments and other aspects of the present invention are apparent from the following detailed description of the invention. To this end, various references are set forth herein which describe in more detail certain background information, procedures, compounds and/or compositions, and are each incorporated by reference in its entirety.
Detailed Description
The present invention provides compounds that are agonists of TLR 7. The invention includes TLR7 agonists that activate TLR7 without substantially activating TLR 8.
Definition of
In order that the invention may be more readily understood, certain technical terms are specifically defined below. Unless specifically defined otherwise herein, all other technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
In the following description, numerous specific details are set forth in order to provide a thorough understanding of various embodiments of the invention. However, it will be understood by those skilled in the art that the present invention may be practiced without these details. Unless the context requires otherwise, throughout the description and the claims, the word "comprise" and variations such as "comprises" and "comprising" are to be interpreted in an open, inclusive sense (i.e., "including but not limited to").
Reference in the specification to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the invention. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
As used herein, including the appended claims, the singular forms of words such as "a," "an," and "the" include their corresponding plural references unless the context clearly dictates otherwise.
"administration" and "treatment" as applied to an animal, human, subject, cell, tissue, organ, or biological fluid means contact of an exogenous drug, therapeutic agent, diagnostic agent, or composition with the animal, human, subject, cell, tissue, organ, or biological fluid. Cellular therapy includes contact of an agent with a cell and contact of an agent with a liquid, where the liquid is in contact with the cell. "administration" and "treatment" also refer to in vitro and ex vivo treatment of a cell, for example, by an agent, diagnosis, binding compound, or by another cell.
"treatment" or "treating" refers to the internal or external administration of a therapeutically active therapeutic agent, such as a composition comprising any of the antibodies or antigen-binding fragments of the invention, to a subject or patient having one or more symptoms of a disease or suspected of having a disease. Typically, the therapeutic agent is administered in an amount effective to reduce one or more symptoms of the disease in the subject or population being treated, whether by inducing regression of such symptoms or inhibiting them to any clinically measurable degree. The amount of therapeutic agent effective to alleviate any particular disease symptom may vary depending on factors such as the disease state, age and weight of the patient, and the ability of the drug to elicit a desired response in the subject. Whether a symptom of the disease is reduced can be assessed by any clinical measurement commonly used by physicians or other skilled healthcare providers to assess the severity or progression of the symptom.
"amino" means-NH2And (4) a substituent.
"aminocarbonyl" refers to-C (O) NH2And (4) a substituent.
"carboxy" means-CO2And (4) an H substituent.
"carbonyl" refers to a-C (O) -or-C (═ O) -group. Both symbols may be used interchangeably in the specification.
"cyano" means a-C.ident.N substituent.
"acetyl" means-C (O) CH3And (4) a substituent.
"hydroxy" means an-OH substituent.
"oxo" refers to an ═ O substituent.
"thiol" or "mercapto" refers to the-SH substituent.
"alkyl" refers to a saturated, straight or branched hydrocarbon chain radical consisting only of carbon and hydrogen atoms, having from one to twelve carbon atoms (C)1-C12Alkyl), one to eight carbon atoms (C)1-C8Alkyl) or one to six carbon atoms (C)1-C6Alkyl) which is connected to the rest of the molecule by a single bond. Exemplary alkyl packetsIncluding methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1-dimethylethyl (tert-butyl), 3-methylhexyl, 2-methylhexyl, and the like. Moieties that may be substituted with alkyl are selected from, but not limited to: hydroxy, amino, alkylamino, arylamino, alkoxy, thioalkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate or phosphonate, as known to those skilled in the art, may be unprotected or protected as desired, for example, as described by Greene et al Protective Groups in Organic Synthesis (John Wiley and Sons, second edition, 1991).
"lower alkyl" has the same meaning as alkyl defined above, but has one to three carbon atoms (C)1-C3Alkyl groups).
"alkenyl" means having at least one double bond, and two to twelve carbon atoms (C)2-C12Alkenyl), two to eight carbon atoms (C)2-C8Alkenyl), or two to six carbon atoms (C)2-C6Alkenyl) and which is attached to the remainder of the molecule by a single bond, such as ethenyl, propenyl, butenyl, pentenyl, hexenyl, and the like.
"alkynyl" means having at least one triple bond, and from two to twelve carbon atoms (C)2-C12Alkynyl), two to ten carbon atoms (C)2-C10Alkynyl), two to eight carbon atoms (C)2-C8Alkynyl), or two to six carbon atoms (C)2-C6Alkynyl) and which is linked to the remainder of the molecule by a single bond, e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
"hydrocarbylene" or "hydrocarbylene chain" refers to a straight or branched divalent hydrocarbon (alkyl) chain, consisting only of carbon and hydrogen, that connects the remainder of the molecule to a group. The alkylene group may have one to twelve carbon atoms, such as methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain is connected to the rest of the molecule by a single or double bond. The point of attachment of the alkylene chain to the rest of the molecule may be through one or any two carbons in the chain. "optionally substituted hydrocarbylene" refers to hydrocarbylene or substituted hydrocarbylene.
"alkoxy" means a group of the formula-ORaWherein R isaIs an alkyl group as defined above having the indicated number of carbon atoms. Examples of alkoxy include, but are not limited to, -O-methyl (methoxy), -O-ethyl (ethoxy), -O-propyl (propoxy), -O-isopropyl (isopropoxy), and the like.
"aryl" refers to a hydrocarbon ring system radical comprising hydrogen, 6 to 18 carbon atoms, and at least one aromatic ring. Exemplary aryl groups are hydrocarbon ring system groups containing hydrogen and 6 to 9 carbon atoms and at least one aromatic ring; a hydrocarbon ring system group containing hydrogen and 9 to 12 carbon atoms and at least one aromatic ring; a hydrocarbon ring system group containing hydrogen and 12 to 15 carbon atoms and at least one aromatic ring; or a hydrocarbon ring system group containing hydrogen and 15 to 18 carbon atoms and at least one aromatic ring. For the purposes of the present invention, aryl may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems. Aryl groups include, but are not limited to, those derived from aceanthrylene (aceanthrylene), acenaphthylene (acephathylene), acephenanthrylene (aceanthrylene), anthracene, citrus rings (azulene), benzene, and mixtures thereof,(chrysene), fluoranthene (fluoranthene), fluorene, asymmetric benzdiene (as-indacene), symmetric benzdiene (s-indacene), indane (indane), indene, naphthalene, phenalene (phenalene), phenanthrene, pleiadene, pyrene, and triphenylene (triphenylene). "optionally substituted aryl" refers to an aryl group or a substituted aryl group. The aryl group may be substituted with one or more substituents selected from, but not limited to, hydroxy, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, as known to those skilled in the art, either unprotected, or protected as desired, for example, Protective Groups in Organic Synthesis (John Wiley Synthesis) by Greene et al and Sons, second edition, 1991).
"cycloalkyl" refers to a stable, non-aromatic, monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which may include fused or bridged ring systems having three to fifteen carbon atoms, preferably three to ten carbon atoms, three to nine carbon atoms, three to eight carbon atoms, three to seven carbon atoms, three to six carbon atoms, three to five carbon atoms, rings having four carbon atoms, or rings having three carbon atoms. The cycloalkyl ring may be saturated or unsaturated and is attached to the rest of the molecule by a single bond. Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, and cyclooctyl. Polycyclic groups include, for example, adamantyl, norbornyl, decahydronaphthyl, 7-dimethyl-bicyclo [2.2.1] heptyl, and the like.
By "fused" is meant that any of the ring structures described herein are fused to an existing ring structure of a compound of the invention. When the fused ring is a heterocyclyl or heteroaryl ring, any carbon atom on the existing ring structure that is part of the fused heterocyclyl or heteroaryl ring may be substituted with a nitrogen atom.
"halogen" or "halo" refers to bromine, chlorine, fluorine or iodine.
As defined herein, "haloalkyl" refers to an alkyl group having the indicated number of carbon atoms, wherein one or more hydrogen atoms of the alkyl group are substituted with a halogen (halo) group as defined above. The halogen atoms may be the same or different. Exemplary haloalkyl groups are trifluoromethyl, difluoromethyl, trichloromethyl, 2,2, 2-trifluoroethyl, 1, 2-difluoroethyl, 3-bromo-2-fluoropropyl, 1, 2-dibromoethyl, and the like.
"heterocyclyl" or "heterocycle" refers to a stable 3 to 18-membered saturated or unsaturated group consisting of two to twelve carbon atoms and one to six heteroatoms selected from nitrogen, oxygen, and sulfur, e.g., one to five heteroatoms, one to four heteroatoms, one to three heteroatoms, or one to two heteroatoms. Exemplary heterocycles include, but are not limited to: a stable 3-15 membered saturated or unsaturated group, a stable 3-12 membered saturated or unsaturated group, a stable 3-9 membered saturated or unsaturated group, a stable 8 membered saturated or unsaturated group, a stable 7 membered saturated or unsaturated group, a stable 6 membered saturated or unsaturated group, or a stable 5 membered saturated or unsaturated group.
Unless otherwise specifically stated in the specification, a heterocyclyl group may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; the nitrogen, carbon or sulfur atom in the heterocyclic group may be optionally oxidized; the nitrogen atoms may optionally be quaternized; the heterocyclic group may be partially or fully saturated. Examples of non-aromatic heterocyclyl groups include, but are not limited to: azetidinyl, dioxolanyl, thienyl [1,3] dithienyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-piperazinyl, 2-piperidinyl, 2-pyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidinonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, thietanyl, trithioenyl, tetrahydropyranyl, thiomorpholinyl (thiomorpholinyl), 1-oxo-thiomorpholinyl, and 1, 1-dioxo-thiomorpholinyl. Heterocyclyl includes heteroaryl as defined herein, and examples of aromatic alkyl groups are set forth in the definition of heteroaryl below.
"heteroaryl" refers to a 5 to 14 membered ring system group containing hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from nitrogen, oxygen and sulfur, and at least one aromatic ring. For the purposes of the present invention, a heteroaryl group can be a stable 5-12 membered ring, a stable 5-10 membered ring, a stable 5-9 membered ring, a stable 5-8 membered ring, a stable 5-7 membered ring, or a stable 6 membered ring comprising at least 1 heteroatom, at least 2 heteroatoms, at least 3 heteroatoms, at least 4 heteroatoms, at least 5 heteroatoms, or at least 6 heteroatoms. Heteroaryl groups may be monocyclic, bicyclic, tricyclic or tetracyclic ring systems, which may include fused or bridged ring systems; the nitrogen, carbon or sulfur atoms in the heteroaryl group may be optionally oxidized; the nitrogen atoms may optionally be quaternized. The hetero atoms may be members of aromatic or non-aromatic rings, but hetero aromatic At least one ring in the radical is aromatic. Examples include, but are not limited to, azaA radical, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolonyl, benzothiazolyl, benzothiadiazolyl, benzo [ b ]][1,4]Dioxepin trienyl (benzol [ b ]][1,4]dioxinyl), 1, 4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo [4,6 ] carbonyl]Imidazo [1,2-a ]]Pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolyl, isoquinolinyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxopyridyl, 1-oxopyrimidinyl, 1-oxopyridyl, 1-oxopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazine, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalyl, quinolyl, quinuclidinyl, isoquinolyl, tetrahydroquinolyl, thiazolyl, thiadiazolyl, Triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl).
The compounds of the present invention may exhibit tautomerism. Although formula I does not explicitly indicate all possible tautomeric forms, it is to be understood that formula I is intended to represent any tautomeric form of the depicted compound and is not to be limited solely to the specific compound form depicted by the formula diagram. For example, when R is5In the case of OH, it is understood for formula I that the substituents represent the same compounds regardless of whether they are shown in their enol or keto form as shown below. As will be apparent to those skilled in the art, compounds such as compound 1:
can exist in tautomeric forms as compounds 1A and 1B:
an "isolated nucleic acid molecule" or "isolated polynucleotide" refers to genomic DNA or RNA, mRNA, cDNA, or synthetic sources or some combination thereof, that is unrelated to all or part of the polynucleotides found in nature in an isolated polynucleotide, or to polynucleotides unrelated in nature. For the purposes of this disclosure, it is understood that a nucleic acid molecule "comprising" a particular nucleotide sequence does not comprise a complete chromosome. In addition to a particular sequence, an isolated nucleic acid molecule "comprising" a particular nucleic acid sequence may include a coding sequence for up to ten or up to twenty or more other proteins, or portions or fragments thereof, or may include operably linked regulatory sequences that control the expression of the coding region of the nucleic acid sequence, and/or may include vector sequences.
The phrase "control sequences" refers to DNA sequences necessary for the expression of an operably linked coding sequence in a particular host organism. Suitable control sequences for prokaryotes include, for example, promoters, optional operator sequences, and ribosome binding sites. Eukaryotic cells are known to use promoters, polyadenylation signals, and enhancers.
A nucleic acid is "operably linked" when it is placed into a functional relationship with another nucleic acid sequence. For example, DNA of a precursor sequence or secretion leader is operably linked to DNA of a polypeptide if it is expressed as a precursor protein involved in the secretion of the polypeptide; a promoter or enhancer is operably linked to a coding sequence if it affects the transcription of the coding sequence; or a ribosome binding site is operably linked to a coding sequence if it is positioned so as to facilitate translation. Typically, but not always, "operably linked" means that the DNA sequences being linked are contiguous and, in the case of a secretory leader, contiguous and in reading frame. However, enhancers need not be contiguous. Ligation is accomplished by ligation at convenient restriction sites. If such sites are not present, synthetic oligonucleotide adaptors or linkers are used according to conventional practice.
As used herein, the terms "cell," "cell line," and "cell culture" are used interchangeably, and all such designations include progeny. Thus, the words "transformant" and "transformed cell" include the primary subject cell and cultures derived therefrom, regardless of the number of passages. It is also understood that not all progeny may have exactly the same DNA content due to deliberate or accidental mutation. Mutant progeny that have the same function or biological activity as the function or biological activity screened for in the originally transformed cell are included. If different names are intended, it is clear from the context.
As used herein, "germline sequence" refers to the sequence of an unrearranged immunoglobulin DNA sequence. Any suitable source of non-recombinant immunoglobulin sequences may be used. Human germline sequences can be obtained, for example, from the JOINSOLVER germline database on the website of the National Institute of Arthritis, Musculoskeletal and dermatological Diseases, National Institute of Arthritis and musculoskeleals and Skin Diseases, National Institutes of Health, of the United States National Institutes of Health. Mouse germline sequences can be determined, for example, according to Giudicelli et al (2005) Nucleic Acids Res.33: obtained as described in D256-D261.
The term "in combination with … …" means that the components administered in the methods of the invention can be formulated as a single composition for simultaneous delivery, or separately as two or more compositions (e.g., kits). Each component may be administered to the subject at a different time than the other components; for example, each administration may be provided non-simultaneously (e.g., separately or sequentially) at several intervals over a given period of time. Furthermore, the separate components may be administered to the subject by the same or different routes.
As used herein, the term "effective amount" refers to an amount of a TLR7 agonist compound of the invention that is effective to cause a measurable improvement in one or more disease symptoms, e.g., cancer or cancer progression, when administered to a cell, tissue, or subject, alone or in combination with an additional therapeutic agent. An effective dose also refers to an amount of a compound or pharmaceutical composition thereof sufficient to at least partially ameliorate symptoms (e.g., tumor shrinkage or elimination, tumor growth insufficiency, survival time prolongation). Where individual active ingredients are referred to, an effective dose is simply that ingredient. When applied to a combination, an effective dose refers to the combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, sequentially or simultaneously. An effective amount of treatment will result in at least a 10% improvement in the diagnostic measure or parameter; usually at least 20%; preferably at least about 30%; more preferably at least 40%, most preferably at least 50%. In the case of using subjective indicators to assess the severity of the disease, the effective amount may also improve the subjective indicators.
The "subject" may be a mammal, such as a human, dog, cat, horse, cow, mouse, rat, monkey (e.g. cynomolgus monkey, e.g. Macaca fascicularis) or rabbit. In a preferred embodiment of the invention, the subject is a human subject.
TLR7 agonists
One aspect of the invention includes TLR7 agonist compounds of formula I:
wherein
R1is-H, -OH, -O-C (O) -R6Or a group of the formula-F,
R2is a group of the formula-H or-F,
R3independently is-OH or-O-C (O) -R7，
R4Is- (C)1-C8) Alkyl, - (C)1-C8) Alkenyl, - (C)1-C8) Alkynyl, - (C)1-C8) Haloalkyl group、–(CH2)n(cycloalkyl), - (CH)2)n(heterocyclic group), - (CH)2)n(aryl), - (CH)2)n(heteroaryl) or- (CH)2)nC(O)OR6，
R5is-H, -OH, -OCH3-SH or-Cl,
R6and R7Independently is- (C)1-C8) An alkyl group or an aryl group, or a salt thereof,
n is an integer of 1, 2, 3, 4 or 5,
wherein each alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, heteroaryl and heterocyclyl is independently substituted with CN, NO2Halogen, (C)1-C3) Alkyl, (C)1-C3) Haloalkyl, aryl, heteroaryl, OH, alkenyl, alkynyl, O- (C)1-C3) Alkyl, O- (hydrocarbylene) aryl, O- (hydrocarbylene) heteroaryl, C (O) R8、S(C1-C8) Alkyl, S (O) alkyl, SO2Alkyl, C (O) OR8、C(O)NR8R8、C(O)NR8SO2Alkyl, NR8R8、NR8(CO)OR8、NH(CO)R8、NH(SO2) Alkyl or NH (SO)2)NR8R8Is optionally substituted, and R 8Independently is-H, -OH, - (C)1-C8) Alkyl, cycloalkyl, heterocyclyl, or C (O) NR8R8Or NR8R8Two of R8Taken together with the nitrogen atom to form a heterocyclic ring;
or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, or a pharmaceutically acceptable hydrate thereof.
In one embodiment R1is-H, -OH, or-F.
In one embodiment R1is-OH.
In one embodiment R1is-H.
In one embodiment R1is-F.
In one embodimentIn the formula R2is-H or-F.
In one embodiment R2is-H.
In one embodiment R2is-F.
In one embodiment R3is-OH or-O-C (O) -CH3。
In one embodiment R3is-OH.
In one embodiment R3is-O-C (O) -CH3。
In one embodiment R1And R3Independently is-OH.
In one embodiment R1And R3Independently is-O-C (O) -CH3。
In one embodiment R4Is- (CH)2) (cyclopropyl), -CH2CCH、-(CH2)3CH3or-CH2CF3。
In one embodiment R4Is- (CH)2) (cyclopropyl).
In one embodiment R4is-CH2CCH。
In one embodiment R4Is- (CH)2)3CH3。
In one embodiment R4is-CH2CF3。
In one embodiment R5is-H or-OH.
In one embodiment R5is-H.
In one embodiment R 5is-OH.
In one embodiment R7Is- (C)1-C8) An alkyl group.
In one embodiment R7is-CH3。
In one embodiment R8is-H, -OH, -CH3or-CH2CH3。
In one embodiment R8is-H.
In one embodiment R8is-OH.
In one embodiment R8is-CH3。
In one embodiment R8is-CH2CH3。
In one embodiment the compound of formula I is compound 1, which may be referred to as 2-amino-7- (cyclopropylmethyl) -9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) -tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable hydrate thereof.
In another embodiment the compound of formula I is compound 2, which may be referred to as 7-allyl-2-amino-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) -tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione; or 7-allyl-2-amino-9- (beta-D-xylofuranosyl) -7, 9-dihydro-1H-purine-6, 8-dione, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable hydrate thereof.
In one embodiment the compound of formula I is compound 3, which may be referred to as 2-amino-7- (cyclopropylmethyl) -9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) -tetrahydrofuran-2-yl) -7, 9-dihydro-purin-8-one, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable hydrate thereof.
In one embodiment the compound of formula I is compound 4, which may be referred to as (2R,3R,4R,5R) -2- (acetoxymethyl) -5- (2-amino-7- (cyclopropylmethyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-3, 4-diacetic acid diester, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable hydrate thereof.
In one embodiment the compound of formula I is compound 27, which may be referred to as 2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-1H-purine-6, 8-dione, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable hydrate thereof.
In one embodiment the compound of formula I is compound 30, which may be referred to as 2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-8H-purin-8-one, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable hydrate thereof.
In one embodiment the compound of formula I is compound 29, which may be referred to as methyl ((2S,4R,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (prop-2-yn-1-yl) -7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) acetate, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable hydrate thereof.
In one embodiment the compound of formula I is compound 26, which may be referred to as 2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-1H-purine-6, 8-dione, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable hydrate thereof.
In one embodiment the compound of formula I is compound 32, which may be referred to as 2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-8H-purin-8-one, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable hydrate thereof.
In one embodiment the compound of formula I is compound 31, which may be referred to as methyl ((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (prop-2-yn-1-yl) -7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) acetate, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable hydrate thereof.
In one embodiment the compound of formula I is compound 28, which may be referred to as 2-amino-9- ((2R,3S,4R,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-1H-purine-6, 8-dione, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable hydrate thereof.
In one embodiment the compound of formula I is compound 32S, which may be referred to as 2-amino-9- ((2R,3S,4R,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-8H-purin-8-one, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable hydrate thereof.
In one embodiment the compound of formula I is compound 31S, which may be referred to as methyl ((2R,3S,4S,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (prop-2-yn-1-yl) -7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) acetate, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable hydrate thereof.
In one embodiment the compound of formula I is compound 135, which may be referred to as 2-amino-7-butyl-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable hydrate thereof.
In one embodiment the compound of formula I is compound 337, which may be referred to as 2-amino-7-butyl-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-one, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable hydrate thereof.
In one embodiment the compound of formula I is compound 336, which may be referred to as methyl ((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-7-butyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) acetate, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable hydrate thereof.
In one embodiment the compound of formula I is compound 37, which may be referred to as 2-amino-7-butyl-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable hydrate thereof.
In one embodiment the compound of formula I is compound 225, which may be referred to as 2-amino-7-butyl-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-one, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable hydrate thereof.
In one embodiment the compound of formula I is compound 224, which may be referred to as methyl ((2S,4R,5R) -4-acetoxy-5- (2-amino-7-butyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) acetate, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable hydrate thereof.
In one embodiment the compound of formula I is compound 138, which may be referred to as 2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (2,2, 2-trifluoroethyl) -7, 9-dihydro-1H-purine-6, 8-dione, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable hydrate thereof.
In one embodiment the compound of formula I is compound 343, which may be referred to as 2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (2,2, 2-trifluoroethyl) -7, 9-dihydro-8H-purin-8-one, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable hydrate thereof.
In one embodiment the compound of formula I is compound 342, which may be referred to as methyl ((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (2,2, 2-trifluoroethyl) -7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) acetate, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable hydrate thereof.
In one embodiment the compound of formula I is compound 80, which may be referred to as 2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (2,2, 2-trifluoroethyl) -7, 9-dihydro-1H-purine-6, 8-dione, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable hydrate thereof.
In one embodiment the compound of formula I is compound 231, which may be referred to as 2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (2,2, 2-trifluoroethyl) -7, 9-dihydro-8H-purin-8-one, or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, or a pharmaceutically acceptable hydrate thereof.
In one embodiment the compound of formula I is compound 230, which may be referred to as methyl ((2S,4R,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (2,2, 2-trifluoroethyl) -7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) acetate, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable hydrate thereof.
In one embodiment the compound of formula I is compound 134, which may be referred to as 2-amino-7- (cyclopropylmethyl) -9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable hydrate thereof.
In one embodiment the compound of formula I is compound 335, which may be referred to as 2-amino-7- (cyclopropylmethyl) -9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-one, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable hydrate thereof.
In one embodiment the compound of formula I is compound 334, which may be referred to as methyl ((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-7- (cyclopropylmethyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) acetate, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable hydrate thereof.
In one embodiment the compound of formula I is compound 77, which may be referred to as 2-amino-7- (cyclopropylmethyl) -9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable hydrate thereof.
In one embodiment the compound of formula I is compound 223, which may be referred to as 2-amino-7- (cyclopropylmethyl) -9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-one, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable hydrate thereof.
In one embodiment the compound of formula I is compound 222, which may be referred to as methyl ((2S,4R,5R) -4-acetoxy-5- (2-amino-7- (cyclopropylmethyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) acetate, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable hydrate thereof.
In another embodiment the compound of formula I is selected from table 1, in comparison to Loxoribine (Loxoribine).
TABLE 1 Compounds of formula I
General experiments
The compounds of formula I can be prepared by the following general methods.
In one approach (scheme 1), the synthetic preparation may be derived from guanosine nucleoside analog II, where R is1Can be H, OH, F, and R2Is H or F and R3Is OH. C-8 of the guanine base can be brominated under the conditions described by Holmes et al, JACS, 1964, page 1242 and Sheu et al, JACS, 1995, page 6439 to give 8-bromo-guanosine derivative III. Oxygen can be used to S-react III bromine by means of benzyl alcohol alkoxides as described by Holmes et al, JACS, 1964, 1242 and Sheu et al, JACS, 1995, 6439NAr is introduced at C-8 by displacement to give 8-benzyloxy-guanosine derivative IV. Protection of the nitrogen at N-1 prior to oxygen debenzylation at C-8 is required to achieve N-7 selectivityAnd (4) selective alkylation. Broom et al, JOC, 1969, page 1025 describe the amination of guanosine N-1, which essentially acts as a protecting group. Thus, intermediate IV can be exposed to hydroxylamine-O-sulfonic acid under basic conditions to give N-1 aminoguanosine derivative V. The benzyl group can then be removed from the C-8 oxygen under a number of de-etherization reaction conditions, preferably by catalytic hydrogenation with palladium metal, to give the cyclic urea intermediate VI. N-7 alkylation of intermediate VI with R under basic conditions 4Completion of-Lv gives the N-7 alkyl intermediate VII. R4Is C1-C8Alkyl group and Lv is defined as a leaving group such as halogen atom, OSO2CH3(methanesulfonate), OSO2CF3(triflate), or OSO2Ar wherein Ar is 4-methylphenyl (tosylate). The final step of the synthesis is as described in us patent 5,093,318, and the N-1 deamination of VII is achieved by forming a diazonium salt with sodium nitrite under aqueous acidic conditions to give the desired compound of formula I, wherein R is5Is OH.
Scheme 1
Another method (scheme 2) begins with intermediate IV (described above) in which the amide oxygen can be converted to 6-chloropurine intermediate VIII, typically using phosphorus oxychloride. It may then be hydrogenated catalytically or with boron trihalides such as BCl3The benzyl ether at C-8 is selectively removed to give intermediate IX. N-7 alkylation of intermediate IX with R under basic conditions4-Lv to give the N-7 alkyl compound of formula I. R4And Lv is defined in method a.
R5Compounds of formula I which are chloro may be further converted to R5Is H, OH or OCH3Other compounds of formula I. To obtain wherein R5The compound of formula I, which is H, may be hydrodehalogenated. The conversion can generally be carried out under hydrogenation conditions of Pt on Pd or activated zinc in acetic acid. The substitution of C-6 chloro to hydroxy may be carried out in aqueous alkaline or acidic conditions. The chlorine may also be Replacement with a methanolate anion to produce R wherein5Is OCH3A compound of formula I.
Scheme 2
Yet another method (scheme 3) begins with intermediate IV (described above) in which the amide oxygen can be converted to 6-thiopurine intermediate X, typically using phosphorus pentasulfide, Lawesson's reagent, or similar products. The sulfur group can be reduced with Raney nickel (Raney nickel) to give intermediate XI. It may then be hydrogenated catalytically or with boron trihalides such as BCl3The benzyl ether at C-8 is selectively removed to give intermediate XII. N-7 alkylation of intermediate XII may be carried out with R under basic conditions4-Lv to give the N-7 alkyl compound of formula I. R4And Lv is as defined above.
Scheme 3
In another approach (scheme 4), 6-chloro-2, 4-diaminopyrimidine [156-83-2 ]]Halogenation with bromine, N-bromosuccinimide or N-iodosuccinimide can be carried out to obtain 5-halo-6-chloro-2, 4-diaminopyrimidine XIII. The exposure of the intermediate xiii to an alkyl isocyanate can form the corresponding urea xiv. Intramolecular cyclization of intermediate XIV can be accomplished under reaction conditions using an appropriate Pd catalyst and phosphine ligand, or by heating with copper (I) iodide in a polar aprotic solvent with an amine base to provide 2-amino-6-chloro-7-alkyl-7, 9-dihydro-8H-purin-8-one of formula XV. The 6-chloro group can then be hydrodehalogenated with hydrogen and a Pd or Pt metal to form XVI, where R 5Is H. To form R therein56, 8-Dioxopurine XVII, which is OH, XV can be exposed to aqueous HCl or aqueous NaOH. The 6-chloro group of XV may also be replaced with a methanolate anion to give XVIII, where R5Is OCH3Or by replacement with sodium hydrosulfide to give XIX, wherein R5Is SH. Typically, the purine intermediate XV-XIX may then be exposed to the sugar derivative XX under various nucleoside forming reaction conditions, followed by hydroxy deprotection to give a 9- β -furan-purine nucleoside analogue of formula I. For a comprehensive review of the conditions of nucleoside formation synthesis, see Romeo et al, chem.Rev.2010,110, pages 3337-3370.
Scheme 4
Another method for preparing 2-amino-6-chloro-7-alkyl-7, 9-dihydro-8H-purin-8-one of formula XV is outlined below (scheme 5).
Scheme 5
Starting from the common intermediate XIII, XXI can be formed from tert-butyl carbamates under the reaction conditions of a palladium catalyst and a phosphine ligand. The carbamate intermediate may then undergo intramolecular cyclization under thermal conditions to form the purine of formula XV.
Alternatively, intermediate XXI can be prepared by a similar two-step process by forming XXII from XIII and tert-butyl carbamate under the reaction conditions of the appropriate Pd catalyst and phosphine ligand (scheme 6). R may then be used under alkaline conditions 4-Lv alkylates the carbamate nitrogen to yield XXI.
Scheme 6
2-amino-6-chloro-7-alkyl-7, 9-dihydro-8H-purin-8-ones of formula XV can also be synthesized in two steps by XXI, as shown below (scheme 7).
Scheme 7
Exposure of XXI to trifluoroacetic acid can yield pyrimidine XXIII, which can be further converted to XV with carbonyldiimidazole or bis (trichloromethyl) carbonate or bis (4-nitrophenyl) carbonate or other suitable urea forming reagent.
An alternative method for preparing intermediate XVII is schematically described below (scheme 8). The chlorine of pyrimidine XIII can be directly replaced with the sodium salt of benzyl alcohol to form XXIV. Under appropriate reaction conditions with a Pd catalyst, a phosphine ligand and an alkylamine, 6- (benzyloxy) -N can be formed5-alkyl substituted 2,4, 5-pyrimidine XXV. XXVI can be generated from carbonyldiimidazole or bis (trichloromethyl) carbonate or bis (4-nitrophenyl) carbonate or other suitable urea forming reagent. Purine intermediate XXVI can be reacted under catalytic hydrogenation or other ether cleavage conditions to form XVII.
Scheme 8
The second method for the preparation of 2-amino-6-benzyloxy-7-alkyl-7, 9-dihydro-8H-purin-8-one of formula XXVI (scheme 9) is outlined below.
Scheme 9
Intermediate XXVII can be formed using appropriate reaction conditions with Pd catalyst, phosphine ligand and tert-butyl carbamate alkyl ester. The carbamate intermediate may then undergo intramolecular cyclization under thermal conditions to form a purine of formula XXVI.
Alternatively, exposure of XXVII to trifluoroacetic acid can yield pyrimidine XXV, which can be subsequently converted to XXVI with carbonyldiimidazole or bis (trichloromethyl) carbonate or bis (4-nitrophenyl) carbonate or other suitable urea forming reagent.
The N-9 of the purine base was glycosylated using the above conditions (scheme 4),XXVI and XX can be used to generate XXVII (scheme 10). The benzyl ether can be removed by catalytic hydrogenation or sequentially with a boron trihalide reagent to give a compound of formula I wherein R is5Is OH.
Scheme 10
Another route that may be used to synthesize the purine intermediate XXVI involves exposing intermediate XXIV to an alkyl isocyanate that can form the corresponding urea XXVIII (scheme 11). Intramolecular cyclization of intermediate XXVIII can be accomplished under reaction conditions using an appropriate Pd catalyst and phosphine ligand, or by heating with copper (I) iodide in a polar aprotic solvent with an amine base to provide 2-amino-6-benzyloxy-7-alkyl-7, 9-dihydro-8H-purin-8-one of formula XXVI.
Scheme 11
In another approach (scheme 12), symmetrical 4, 6-dichloropyrimidine-2, 5-diamine [55583-59-0 ]]The chlorine atom of (A) may be replaced with XXIX by benzylamine such as 4-methoxybenzylamine. Exposure of intermediate XXIX to phosgene or a phosgene-like product (e.g., carbonyldiimidazole) can form the corresponding cyclic urea XXX. The primary amino group can then be protected to form XXXI, where P is a protecting group such as acyl or carbamoyl. The intermediate XXXI can be hydrodehalogenated under acidic conditions with hydrogen and Pd or Pt metal or activated Zn to form XXXII. Alternatively, the chlorine atom of XXXI may be substituted with an appropriate alcohol, preferably benzyl alcohol, to form XXXIII. N-protected-N-9-benzyl-7, 9-dihydro-8H-purin-8-ones XXXI, XXXII and XXXIII can be further substituted with R at N-7 under basic conditions 4-Lv alkylation to give the N-7 alkyl compounds XXXIV, XXXV and XXXVI, respectively. R4And Lv is defined hereinabove. After N-7 alkylation, the N-9 of XXXIV and XXXV may be deprotected under appropriate conditions. Depending on the protecting group used on the primary amine, this group can also be removed simultaneously. Example (b)For example, intermediates XV and XVI may be formed from XXXIV and XXXV, respectively, under acidic conditions, such as trifluoroacetic acid in combination with trifluoromethanesulfonic acid. Under similar acid conditions, XVII may be formed from XXXVI. In a similar manner, intermediates XVIII and XIX can be synthesized using the general procedure described in scheme 12. The purine intermediate XV-XIX may then be exposed to the sugar derivative XX under various nucleoside forming reaction conditions and the hydroxy group deprotected if desired to give a 9- β -furanpurine nucleoside analogue of formula I. Likewise, the primary amino group of intermediate XV-XVII may be protected to form XXXVII-XLI, wherein P is a protecting group, such as an acyl or carbamoyl group. The purine intermediate XXXVII-XLI may then be exposed to the sugar derivative XX under various nucleoside forming reaction conditions and then deprotected to give the 9- β -furan-purine nucleoside analogue of formula I.
Scheme 12
Therapeutic uses of TLR7 agonists
Activation of TLR7 by innate immunity is mediated primarily by plasmacytoid dendritic cells (pdcs). These cells are the major physiological producers of type I interferons, up to 1000-fold higher than any other cell type. Thus, activation of TLR7 is an important "gatekeeper" in overall induction of innate immune responses. TLR7 has significant advantages as a therapeutic target compared to other TLRs. For example, it may be activated by small molecules capable of oral administration. Unlike several other TLRs, systemic activation of TLR7 may avoid stimulation of TNF overproduction.
Direct or indirect administration of TLR7 agonists involves a variety of anti-tumor mechanisms, including: production of cytokines and chemokines with direct antitumor activity; control the activation of Natural Killer (NK) cells, the main effector cells of the innate immune system of cancer, which are then able to lyse tumor cells by antibody-dependent (antibody-dependent cellular cytotoxicity or ADCC) and independent mechanisms; activation of T cells and reversal of T cell exhaustion by antigen presentation through direct cellular interaction with pDC and production of cytokines and chemokines by pDC, all of which result in increased T cell-mediated attack on tumor cells; increased proliferation and maturation of normal B cells and their precursors can enhance endogenous production of antibodies with anti-tumor activity; direct activity of abnormal B cells can be induced by activation of TLR7 on these cells, thereby inducing apoptosis and hypersensitivity to chemotherapy.
In one embodiment, the TLR7 agonist compounds of the invention can be used alone or in combination with other additional therapeutic agents and therapeutic procedures to treat or prevent cancer or an infection or infectious disease in a subject in need of such treatment or prevention.
In one embodiment, the TLR7 agonist compounds of the invention can be used alone or in combination with a tumor vaccine.
In one embodiment, the TLR7 agonist compounds of the invention can be used alone or in combination with a chemotherapeutic agent.
In one embodiment, the TLR7 agonist compounds of the invention can be used alone or in combination with radiation therapy.
In one embodiment, the TLR7 agonist compounds of the invention can be used alone or in combination with targeted therapies. Examples of targeted therapies include: hormone therapy, signal transduction inhibitors (e.g., EGFR inhibitors such as cetuximab (cetuximab) (Erbitux) and erlotinib (Tarceva)); HER2 inhibitors (e.g., trastuzumab (trastuzumab) (Herceptin) and pertuzumab (pertuzumab) (Perjeta)); BCR-ABL inhibitors (such as imatinib (imatinib) (Gleevec) and dasatinib (Sprycel)); ALK inhibitors (such as crizotinib (crizotinib) (xalkorri) and ceritinib (ceritinib) (Zykadia)); BRAF inhibitors (such as vemurafenib (Zelboraf) and dabrafenib (dabrafenib) (tafinar)), gene expression modulators, apoptosis inducers (e.g., bortezomib (bortezomib) (Velcade) and carfilzomib (kyrolis)), angiogenesis inhibitors (e.g., bevacizumab (bevacizumab) (Avastin) and ramucizumab (ramucirumab) (Cyramza), toxin-attached monoclonal antibodies (e.g., brentuximab vedox (adotricins) and adotuzumab emtansine (ado-trastuzumab emtansine) (Kadcyla)).
In one embodiment, the TLR7 agonist compounds of the invention can be used in combination with an anti-cancer therapeutic, or an immunomodulatory drug such as an immunomodulatory receptor inhibitor, or an antibody or antigen-binding fragment thereof that specifically binds to a receptor.
In one embodiment, the TLR7 agonist compounds of the invention can be used in combination with an immune checkpoint inhibitor, an OX40 agonist, a 4-1BB agonist, an ICOS agonist, a GITR agonist, or an IL 2-receptor agonist.
In one embodiment, the TLR7 agonist compounds of the invention can be used in combination with an inhibitor or antagonist of PD-1, PD-L1, CTLA4, TIM3, LAG3, sirpa, CD47, VISTA, BTLA, or TIGIT.
In one embodiment, the TLR7 agonist compounds of the invention can be used in combination with a therapeutic antibody having anti-tumor activity that is mediated, at least in part, by ADCC.
In one embodiment, the TLR7 agonist compounds of the invention can be used in combination with a therapeutic antibody having anti-tumor activity that is mediated at least in part by ADCC, including rituximab (rituximab), trastuzumab (trastuzumab), and alemtuzumab (alemtuzumab).
In one embodiment of the invention, the TLR7 agonist compounds of the invention bind to anti-OX 40 antibodies (including MOXR0916 and GSK3174998) or other pathway agonists.
In one embodiment of the invention, the TLR7 agonist compounds of the invention bind to anti-4-1 BB antibodies, including uulizumab (ureluumab), utolizumab (utolizumab), or other pathway agonists.
In one embodiment of the invention, the TLR7 agonist compounds of the invention bind to an anti-ICOS antibody or other pathway agonist.
In one embodiment of the invention, the TLR7 agonist compounds of the invention bind to an anti-GITR antibody or other pathway agonist.
In one embodiment of the invention, the TLR7 agonist compounds of the invention bind to IL-2-receptor or other pathway agonists.
In one embodiment of the invention, the TLR7 agonist compounds of the invention bind to anti-PD 1 or anti-PDL 1 antibodies, including nivolumab (nivlumab) (opsivo), pembrolizumab (keytrudab) (keytruruda), attuzumab (atezoluzimab) (Tecentriq), dewaluumab (durvalumab) (infinzi), or avizumab (avelumab) (Bavencio).
In one embodiment of the invention, the TLR7 agonist compounds of the invention bind to CTLA-4/CD80-CD86 antagonists, including ipilimumab (Yervoy).
In one embodiment of the invention, the TLR7 agonist compounds of the invention bind to Tim-3 pathway antagonists, including MBG453 and TSR-022.
In one embodiment of the invention, the TLR7 agonist compounds of the invention bind to LAG-3 pathway antagonists, including BMS-986016, GSK2831781, and IMP 321.
In one embodiment of the invention, the TLR7 agonist compounds of the invention bind to an anti-sirpa antibody.
In one embodiment of the invention, the TLR7 agonist compounds of the invention bind to an anti-CD 47 antibody.
In one embodiment of the invention, the TLR7 agonist compounds of the invention bind to a Vista pathway antagonist.
In one embodiment of the invention, the TLR7 agonist compounds of the invention bind to a BTLA pathway antagonist.
In one embodiment of the invention, the TLR7 agonist compounds of the invention bind to a TIGIT pathway antagonist.
In another embodiment, the TLR7 agonist compounds of the invention increase the activity of an immune cell. The increase in activity of the immune cells can be detected using any method known in the art. In one embodiment, the increase in activity of the immune cells can be detected by measuring proliferation of the immune cells. For example, an increase in T cell activity can be detected by measuring proliferation of T cells or signal transduction events, such as tyrosine phosphorylation of immune receptors or downstream kinases, which transmit signals to transcriptional regulators. In other embodiments, the increase in activity of the immune cell can be detected by measuring the cytotoxicity or IFN γ cytokine response of CTL or NK cells on specific target cells, which is associated with stimulation of anti-tumor immunity. In other embodiments, the increase in activity of the immune cell can be detected by measuring T cell activation ex vivo in a subject-derived sample.
Other agents useful for increasing cytolytic T cell responses may be used in combination with the TLR7 agonist compounds of the invention. These include, but are not limited to: b7 co-stimulatory molecules, interleukin-2 (e.g., NKTR-214), interferon- γ, GM-CSF, CTLA-4 antagonists, OX-40/OX-40 ligands, CD40/CD40 ligands, sargramostim (sargramostim), levamisole, vaccinia virus, BCG, liposomes, alum, Freund's complete or incomplete adjuvant, detoxified endotoxin, mineral oil, surface active substances (e.g., lecithin), polyols, polyanions, peptides, and oil or hydrocarbon emulsions.
In one embodiment of the invention, the TLR7 agonist compounds of the invention are conjugated to one or more anti-emetics, including but not limited to: casopritant (GlaxoSmithKline), Netupitant (MGI-hercin (hellinn)) and other NK-1 receptor antagonists, palonosetron (palonosetron) (sold by MGI pharmacy (MGI Pharma) as Aloxi), aprepitant (sold by Merck and Co.) as enden, lakawei, nj, diphenhydramine (diphenhydramine) (sold by Pfizer) as pyroxen (Pfizer) Selling; new york, new york), hydroxyzine (from fevery)Selling; new york, new york), metoclopramide (AH robins, incSelling; riston, Virginia), lorazepam (Lorazepam) (by Huishi asSelling; madison, new jersey), alprazolam (alprazolam) (from feverfewSelling; new york, new york), haloperidol (by Ortho-McNeil asSelling; leen, new jersey), droperidolDronabinol (available from Solvay Pharmaceuticals, Inc.) asSelling; marieuta, Georgia), dexamethasone (available from Merck, Inc.)Selling; navelb, new jersey), methylprednisolone (by fevery asSelling; new york, new york), chlorpromazine (from Kurarin Schk asSelling; northern carolina triangle research park), granisetron (by Hoffmann-La Roche Inc.)Selling; natriel, N.J.), ondansetron (Kurarin Schk asSelling; northern carolina delta research park), dolasetron (produced by Sanofi-Aventis)Selling; new york, new york), toposetron (Novartis) as Selling; eastern hannover, new jersey).
Other side effects of cancer treatment include red blood cell and white blood cell deficiency. Thus, in one embodiment of the invention, a TLR7 agonist compound is conjugated to an agent that treats or prevents such deficiencies, including filgrastim, PEG-filgrastim, erythropoietin, epoetin (epoetin) α, and darbepoetin (darbepoetin) α.
In another embodiment, the invention relates to a composition comprising one or more TLR7 agonist compounds of the invention and a pharmaceutically acceptable carrier or diluent. Such compositions may further comprise one or more other therapeutically active ingredients such as agonist antibodies or antigen binding fragments thereof, or soluble fusions of TNF receptor proteins, immunoglobulin-like proteins, cytokine receptors, integrins, signaling lymphocyte activating molecules (SLAM proteins), OX40, 4-1BB (CD137), ICOS (CD278), GITR, IL2R beta (CD122), and/or IL2R γ.
The invention encompasses compositions comprising a TLR7 agonist compound of the invention and one or more antibodies that target the PD-1/PD-L1 interaction or the CTLA-4/CD80-CD86 interaction. Non-limiting examples of such antibodies include: pembrolizumab, nivolumab, avilumab, REGN2810, MEDI-0680, PDR-001, SHR-1210, BGB-A317, PF-06801591, TSR-042, attuzumab, Derwaluzumab, BMS-936559, ipilimumab, and tremelimumab.
Although those that stimulate both types of responses may also be used, compositions for inducing a T cell immune response that preferentially stimulates a cytolytic T cell response over an antibody response are preferred.
In another embodiment, a composition comprising one or more TLR7 agonist compounds may further comprise one or more other therapeutically active ingredients that are immune checkpoint inhibitors, OX40 agonists, 4-1BB agonists, ICOS agonists, GITR agonists, or IL 2-receptor agonists.
In another embodiment, a composition comprising one or more TLR7 agonist compounds may further comprise one or more additional therapeutically active ingredients that are inhibitors or antagonists of PD-1, PD-L1, CTLA4, TIM3, LAG3, sirpa, CD47, VISTA, BTLA, or TIGIT.
In another embodiment, a composition comprising one or more TLR7 agonist compounds may further comprise one or more other therapeutically active ingredients that are therapeutic antibodies having anti-tumor activity mediated at least in part by ADCC.
In another embodiment, a composition comprising one or more TLR7 agonist compounds may further comprise one or more additional therapeutically active ingredients that are therapeutic antibodies having anti-tumor activity mediated at least in part by ADCC, including rituximab (rituximab), trastuzumab (trastuzumab), and alemtuzumab (alemtuzumab).
The invention also provides methods of treating or preventing cancer or an infection or an infectious disease in a subject in need of such treatment or prevention with the TLR7 agonist compounds disclosed herein in subjects, including human subjects. In one embodiment of the invention, such a subject suffers from cancer or a precancerous condition. In another embodiment of the invention, such a subject suffers from an infection or infectious disease.
In another embodiment the invention also relates to a method of treating or preventing cancer in a human subject comprising administering to the subject an effective amount of one or more TLR7 agonist compounds of the invention, optionally further in combination with a therapeutic agent or therapeutic procedure; and to methods of treating infections or infectious diseases in a human subject comprising administering to the subject an effective amount of one or more TLR7 agonist compounds of the invention, optionally in further combination with a therapeutic agent or therapeutic procedure.
In yet another embodiment, the invention also relates to a method of increasing the activity of an immune cell comprising administering to a subject in need thereof an effective amount of one or more TLR7 agonist compounds of the invention to treat or prevent cancer; treating infections or infectious diseases; as a vaccine adjuvant; or enhance immune cell activation.
In one embodiment, the invention provides methods of using the TLR7 agonist compounds of the invention to treat a subject, wherein the subject has cancer or a precancerous condition. In one embodiment the cancer is, for example, osteosarcoma, rhabdomyosarcoma, neuroblastoma, renal cancer, leukemia, renal metastatic cell cancer, bladder cancer, Wilm's cancer, ovarian cancer, pancreatic cancer, breast cancer, prostate cancer, bone cancer, lung cancer (e.g., non-small cell lung cancer), gastric cancer, colorectal cancer, cervical cancer, synovial sarcoma, head and neck cancer, squamous cell carcinoma, multiple myeloma, renal cell carcinoma, retinoblastoma, hepatoblastoma, hepatocellular carcinoma, melanoma, rhabdomyoma of the kidney, Ewing's sarcoma, chondrosarcoma, brain cancer, glioblastoma, meningioma, pituitary adenoma, vestibular schwannoma, primitive neuroectodermal tumor, medulloblastoma, astrocytoma, anaplastic astrocytoma, oligodendroglioma, ependymoma, choroideremia, polycythemia vera, Thrombocythemia, idiopathic myelofibrosis, soft tissue sarcoma, thyroid cancer, endometrial cancer, carcinoid or liver cancer, breast cancer or gastric cancer. In one embodiment of the invention, the cancer is a metastatic cancer, such as a variant described above.
In one embodiment, the invention provides methods of using the TLR7 agonist compounds of the invention to treat a subject, wherein the subject has a viral infection. In one embodiment, the viral infection is selected from the group consisting of: human Immunodeficiency Virus (HIV), hepatitis virus (A, B or C), herpes virus (e.g. VZV, HSV-1, HAV-6, HSV-II and CMV, Epstein-Barr virus), adenovirus, influenza virus, flavivirus, echovirus, rhinovirus, coxsackievirus, coronavirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papilloma virus, mollusca virus, poliovirus, rabies virus, JC virus or arbovirus encephalitis virus.
In one embodiment, the invention provides methods of using the TLR7 agonist compounds of the invention to treat a subject, wherein the subject has a bacterial infection. In one embodiment, the bacterial infection is selected from the group consisting of: chlamydia (Chlamydia), rickettsia (rickettsia), Mycobacterium (mycobacteriia), staphylococcus (staphylococci), streptococcus (streptococci), pneumococcus (pneumonococci), meningococcus and gonococcus (meningococci and gonococcus), klebsiella (klebsiella), proteus (proteus), serratia (serratia), pseudomonas (pseudomonas), Legionella (Legionella), Corynebacterium diphtheriae (Corynebacterium diphteriae), Salmonella (Salmonella), Bacillus (Bacillus), Vibrio cholerae (Vibrio cholerae), Clostridium (Clostridium tetani), Clostridium botulinum (Clostridium tetanium), Bacillus anthracis (Bacillus anthracis), Yersinia (Yersinia), Yersinia pestis (Yersinia), Clostridium perfoliatus (Mycobacterium), Mycobacterium (Mycobacterium tuberculosis), Mycobacterium tuberculosis (Mycobacterium tuberculosis), and Mycobacterium (Mycobacterium tuberculosis).
In one embodiment, the invention provides methods of using the TLR7 agonist compounds of the invention to treat a subject, wherein the subject has a fungal infection. In one embodiment, the fungal infection is infected with a fungus selected from the group consisting of: candida (Candida) (Candida albicans), Candida krusei (Krusei), Candida glabrata (glabrata), Candida tropicalis (tropicalis), etc.), Cryptococcus neoformans (Cryptococcus neoformans), Aspergillus (Aspergillus fumigatus), Aspergillus niger (niger, etc.), Mucor (Genus Mucorales) (Mucor), Absidia (ABSIDIA), Rhizobium (rhizobium)), Sporothrix schenckii (Sporothrix schenkii), Blastomyces dermatitidis (Blastomyces dermatitidis), Paracoccus braziliensis (Paracoccus braziliensis), Coccidioides immitis (Coccidioides immitis), and Histoplasma capsulatum (Histoplasma capsulatum).
In one embodiment, the invention provides methods of using the TLR7 agonist compounds of the invention to treat a subject, wherein the subject has a parasitic infection. In one embodiment, the parasitic infection is selected from the group consisting of parasitic infections of: entamoeba histolytica (Entamoeba histolytica), Zona coli (Ballantidiam coli), Naegleria gordonii (Naegleria foeteri), Acanthamoeba (Acanthamoeba), Giardia lamblia (Giardia lamblia), Cryptosporidium japonicum (Cryptosporidium), Pneumocystis carinii (Pneumocystis carinii), Plasmodium vivax (Plasmodium vivax), Babesia micrti (Babesia micoti), Trypanosoma brucei (Trypanosoma brucei), Trypanosoma cruzi (Trypanosoma cruzi), Leishmania donovani (Toxoma gondii), Toxoplasma gondii (Toxoa ndii) and Nippostrongoni brasiliensis (Nippostrongonii).
The invention encompasses methods of treating or preventing cancer in a subject comprising administering an effective amount of a TLR7 agonist compound of the invention and one or more antibodies that target the PD-1/PD-L1 or CTLA-4/CD80-CD86 interaction in the subject. In one embodiment of the invention, the TLR7 agonist compounds of the invention bind to an anti-PD 1 or anti-PDL 1 antibody.
The invention encompasses methods of treating or preventing cancer in a subject comprising administering an effective amount of a TLR7 agonist compound of the invention in combination with an immune checkpoint inhibitor, an OX40 agonist, a 4-1BB agonist, an ICOS agonist, a GITR agonist, or an IL 2-receptor agonist.
The invention encompasses methods of treating or preventing cancer in a subject comprising administering an effective amount of a TLR7 agonist compound of the invention in combination with an inhibitor or antagonist of PD-1, PD-L1, CTLA4, TIM3, LAG3, sirpa, CD47, VISTA, BTLA, or TIGIT.
The invention encompasses methods of treating or preventing cancer in a subject comprising administering an effective amount of a TLR7 agonist compound of the invention in combination with a therapeutic antibody having anti-tumor activity mediated at least in part by ADCC.
The invention encompasses methods of treating or preventing cancer in a subject comprising administering an effective amount of a TLR7 agonist compound of the invention in combination with a therapeutic antibody having anti-tumor activity mediated at least in part by ADCC, the therapeutic antibody comprising rituximab (rituximab), trastuzumab (trastuzumab), and alemtuzumab (alemtuzumab).
The invention encompasses methods of treating or preventing cancer in a subject comprising administering an effective amount of a TLR7 agonist compound of the invention in combination with an anti-OX 40 antibody, including MOXR0916 and GSK3174998, or other pathway agonist.
The invention encompasses methods of treating or preventing cancer in a subject comprising administering an effective amount of a TLR7 agonist compound of the invention in combination with an anti-4-1 BB antibody, including lumumab (urelumab), utomiumamab (utomicumab), or other pathway agonist.
The invention encompasses methods of treating or preventing cancer in a subject comprising administering an effective amount of a TLR7 agonist compound of the invention in combination with an anti-ICOS antibody or other pathway agonist.
The invention encompasses methods of treating or preventing cancer in a subject comprising administering an effective amount of a TLR7 agonist compound of the invention in combination with an anti-GITR antibody or other pathway agonist.
The invention encompasses methods of treating or preventing cancer in a subject comprising administering an effective amount of a TLR7 agonist compound of the invention in combination with an IL-2-receptor or other pathway agonist.
The invention encompasses methods of treating or preventing cancer in a subject comprising administering an effective amount of a TLR7 agonist compound of the invention in combination with an anti-PD 1 or anti-PDL 1 antibody, including nivolumab (nivlumab) (opsivo), pembrolizumab (keytrudab), attuzumab (ateuzumab) (Tecentriq), devaluzumab (bervalumab) (infizi), or avizumab (avelumab) (Bavencio).
The invention encompasses methods of treating or preventing cancer in a subject comprising administering an effective amount of a TLR7 agonist compound of the invention in combination with a CTLA-4/CD80-CD86 antagonist, including ipilimumab (Yervoy).
The invention encompasses methods of treating or preventing cancer in a subject comprising administering an effective amount of a TLR7 agonist compound of the invention in combination with a Tim-3 pathway antagonist (including MBG453 and TSR-022).
The invention encompasses methods of treating or preventing cancer in a subject comprising administering an effective amount of a TLR7 agonist compound of the invention in combination with a LAG-3 pathway antagonist (including BMS-986016, GSK2831781, and IMP 321).
The invention encompasses methods of treating or preventing cancer in a subject comprising administering an effective amount of a TLR7 agonist compound of the invention in combination with an anti-sirpa antibody.
The invention encompasses methods of treating or preventing cancer in a subject comprising administering an effective amount of a TLR7 agonist compound of the invention in combination with an anti-CD 47 antibody.
The invention encompasses methods of treating or preventing cancer in a subject comprising administering an effective amount of a TLR7 agonist compound of the invention in combination with a Vista pathway antagonist.
The invention encompasses methods of treating or preventing cancer in a subject comprising administering an effective amount of a TLR7 agonist compound of the invention in combination with a BTLA pathway antagonist.
The invention encompasses methods of treating or preventing cancer in a subject comprising administering an effective amount of a TLR7 agonist compound of the invention in combination with a TIGIT pathway antagonist.
Pharmaceutical compositions and administration
The present invention also provides a pharmaceutical composition comprising: (i) a therapeutically effective amount of at least one compound of formula I, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof; (ii) in combination with a pharmaceutically acceptable carrier, diluent or excipient. Pharmaceutical compositions comprising a pharmaceutically acceptable carrier, diluent, or excipient, as well as other therapeutic agents, are also part of the invention.
As used herein, the term "drug" refers to a chemical substance intended for the alleviation, treatment, or prevention of a disease that is approved by the U.S. food and drug administration (or other similar agency not in the united states) as a prescribed drug or over-the-counter product. Details of the formulation and administration techniques for such compositions may be found in remington: pharmaceutical sciences and practices (Remington: The Science and Practice of Pharmacy) 21 st edition (Mack Publishing Co., Isston, Pa.) and Nielloud and Marti-Mestres "pharmaceutical emulsions and suspensions" (Marcel Dekker, Inc., N.Y.) 2 nd edition. To prepare a pharmaceutical or sterile composition of the TLR7 agonist compounds of the invention, the compounds are mixed with a pharmaceutically acceptable carrier or excipient. See, e.g., remington: pharmaceutical sciences and practices mike publishing company, easton, pa (1984).
Formulations of therapeutic and diagnostic agents may be prepared by mixing with acceptable carriers, excipients or stabilizers, for example, in The form of lyophilized powders, slurries, aqueous solutions or suspensions (see, e.g., Hardman et al (2001) Pharmacological Basis for The treatment of Goldmann and Kelman's The Pharmacological Basis of Therapeutics, McGraw-Hill, New York, Gennaro (2000), Remington, science and practice, Lippincott, Williams and Williams, New York, Avis et al (1993) Pharmaceutical Dosage Forms Parenteral (Pharmaceutical Dosage Forms: Parenteral pharmaceuticals), Decker, New York, Lieberman et al (1990) Pharmaceutical Dosage Forms: Tablets (Pharmaceutical Dosage Forms: Parenteral pharmaceuticals: Markeral pharmaceuticals, Decker, New York, Lipbeman et al (1990) Dosage Forms, tablet (Pharmaceutical Dosage Forms: tablet), Mark tablet dispersion Systems (1990) and Lipman et al (Pharmaceutical Dosage Systems: Western research Systems, Inc.; Pharmaceutical Dosage Systems: Decker, Inc.; tablet Systems, Inc.; Pharmaceutical Dosage Systems, Inc. and drug dispersion Systems, toxicity and Safety of excipients (Excipient Toxicity and Safety), Marcel Dekker, N.Y.).
Toxicity and therapeutic efficacy of a compound or composition of the invention administered alone or in combination with another therapeutic agent Standard pharmaceutical procedures are determined in cell cultures or experimental animals, e.g. determining LD50(lethal dose for 50% of the population) and ED50(therapeutic dose effective for 50% of the population). The dose ratio between toxic and therapeutic efficacy is the therapeutic index (LD)50/ED50). The data obtained from these cell culture experiments and animal studies can be used to formulate a range of dosage for humans. The dose of such a compound is preferably in a circulating concentration range including ED with little or no toxicity50. The dosage may vary within this range depending upon the dosage form and route of administration.
In yet another embodiment, a further therapeutic agent for administration to a subject in combination with a TLR7 agonist compound of the invention is according to "Physician's Desk Reference" 2003 (Thomson Healthcare); 57 th edition (11/1/2002)).
The mode of administration may vary. For the purposes of this disclosure, the pharmaceutical compositions may be administered by a variety of means, including parenteral, by inhalation spray, topical, or rectal administration in a formulation containing pharmaceutically acceptable carriers, adjuvants, and excipients. "parenteral administration" includes oral, buccal, sublingual, topical, transdermal, ocular, otic, nasal, rectal, cervical, pulmonary, mucosal and vaginal routes. As used herein, the term parenteral includes, but is not limited to, subcutaneous, intravenous, intramuscular, intraarterial, intradermal, intrathecal and epidural injections by various infusion techniques. As used herein, intra-arterial and intravenous injections include administration via a catheter. It is also contemplated that the compounds of the invention are administered intratumorally (directly into the tumor mass) or peritumorally (around the tumor mass). The term oral as used herein includes, but is not limited to, oral ingestion or delivery by the sublingual or buccal route. Oral administration includes liquid beverages, energy bars, and pill formulations.
The pharmaceutical composition may be in any form suitable for the intended method of administration. When used orally, for example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared. Compositions for oral use may be prepared according to any method known to the manufacturer of pharmaceutical compositions and may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide palatable preparations. Tablets containing the pharmaceutical compound in admixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets are acceptable. These excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as corn starch or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or they may be coated by known techniques including enteric coating, colon coating or microencapsulation to delay disintegration and absorption in the gastrointestinal tract and/or to provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
The invention provides a container (e.g., a plastic or glass vial, e.g., with a cap or chromatographic column, hollow needle, or syringe barrel) containing one or more compounds of the invention or pharmaceutical compositions thereof. The invention also provides an injection device comprising one or more compounds of the invention or pharmaceutical compositions thereof. Injection devices are devices that introduce a substance into a patient's body by a parenteral route, such as intramuscularly, subcutaneously or intravenously. For example, the injection device may be a syringe (e.g., a pre-filled pharmaceutical composition, such as an auto-injector), e.g., comprising a barrel or syringe for containing a fluid to be injected, a needle for puncturing the skin and/or blood vessels to inject the fluid (e.g., one or more compounds of the present invention or pharmaceutical compositions thereof); and a plunger for pushing fluid out of the cylinder and through the needle hole. In one embodiment of the invention, the injection device comprising one or more compounds of the invention or pharmaceutical compositions thereof is an Intravenous (IV) injection device. Such devices include one or more compounds in a cannula or cannula/needle that can be attached to a catheter that can be attached to a containment flow Body (e.g. brine; or comprising NaCl, sodium lactate, KCl, CaCl)2And optionally lactated ringers containing glucose) into which the fluid is introduced through the cannula or cannula/needle. In one embodiment of the invention, one or more compounds of the invention or pharmaceutical compositions thereof may be introduced into the device once the trocar and cannula are inserted into the vein of the subject and the trocar removed from the inserted cannula. The IV device may, for example, be inserted into a peripheral vein (e.g., in a hand or arm); the superior or inferior vena cava, or within the right atrium of the heart (e.g., central vein); or into the subclavian, internal jugular or femoral vein, e.g., to the heart until reaching the superior vena cava or right atrium (e.g., central venous line). In one embodiment of the invention, the injection device is an auto-injector; jet injector or external infusion pump. Jet injectors use a high pressure narrow liquid jet to penetrate the epidermis to introduce one or more compounds of the present invention or pharmaceutical compositions thereof into the body of a patient. An external infusion pump is a medical device that delivers a pharmaceutical composition in controlled amounts to a patient. The external infusion pump may be electrically or mechanically powered. Different pumps operate in different ways, for example, a syringe pump holds fluid in the reservoir of a syringe, a movable piston controls the delivery of the liquid, an elastomeric pump holds fluid in an expandable balloon reservoir, and the pressure of the elastomeric wall of the balloon drives the delivery of the fluid. In a peristaltic pump, a set of rollers presses down on a length of flexible tubing, pushing the fluid forward. In a multi-channel pump, fluid may be delivered from multiple reservoirs at multiple rates.
The compounds and pharmaceutical compositions disclosed herein may also be administered with a needleless hypodermic injection device; for example, U.S. patent nos. 6,620,135; 6,096,002; 5,399,163; 5,383,851, respectively; 5,312,335, respectively; 5,064,413, respectively; 4,941,880, respectively; 4,790,824 or 4,596,556. Such needleless devices comprising a pharmaceutical composition are also part of the present invention. The pharmaceutical compositions disclosed herein may also be administered by infusion. Examples of well-known implants and modules for administering pharmaceutical compositions include those disclosed in: U.S. patent No. 4,487,603 discloses an implantable micro-infusion pump for dispensing a drug at a controlled rate; U.S. patent No. 4,447,233 discloses a medication infusion pump for delivering medication at a precise infusion rate; U.S. patent No. 4,447,224 discloses a variable flow implantable infusion device for continuous drug delivery; U.S. patent No. 4,439,196 discloses an osmotic drug delivery system having multiple chambers. Many other such implants, delivery systems and modules are well known to those skilled in the art, and those comprising the pharmaceutical compositions of the present invention are also within the scope of the present invention.
Alternatively, the TLR7 agonist compounds of the invention can be administered locally, rather than systemically, e.g., by injecting the compounds into a tumor. Furthermore, the TLR7 agonist compounds of the invention can be administered in a targeted drug delivery system, e.g., in liposomes coated with tissue-specific antibodies, which target tumors characterized by, e.g., immunopathology. The liposomes will be targeted and selectively absorbed by the corresponding tissue. Such methods and liposomes are part of the present invention.
When a disclosed compound or salt thereof is named or depicted by structure, it is understood that the compound or salt thereof, including solvates (particularly hydrates) thereof, may exist in crystalline form, amorphous form, or mixtures thereof. The compound or salt thereof or solvate (particularly hydrate) thereof may also exhibit polymorphism (i.e., ability to occur in different crystalline forms). These different crystalline forms are commonly referred to as "polymorphs". It is to be understood that when named or depicted by structure, the disclosed compounds or solvates (particularly hydrates) thereof also include all polymorphs thereof. Polymorphs have the same chemical composition, but differ in stacking, geometric arrangement, and other descriptive aspects of the crystalline solid state. Polymorphs can have different physical properties such as density, shape, hardness, stability and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra and X-ray powder diffraction patterns, which can be used for identification. One of ordinary skill in the art will appreciate that different polymorphs can be produced, for example, by varying or adjusting the conditions used during crystallization or recrystallization of a compound.
For solvates of the crystalline forms of the compounds of the invention or salts thereof, those skilled in the art will appreciate that pharmaceutically acceptable solvates may be formed wherein solvent molecules are incorporated into the crystal lattice during the crystallization process. Solvates may involve non-aqueous solvents such as ethanol, isopropanol, dimethyl sulfoxide, acetic acid, ethanolamine and ethyl acetate, or they may involve water as the solvent incorporated into the crystal lattice. Solvates in which water is the solvent incorporated into the crystal lattice are commonly referred to as "hydrates". Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water. The present invention includes all such solvates.
Because of their potential use in medicine, salts of the compounds of the present invention are preferably pharmaceutically acceptable. Suitable pharmaceutically acceptable salts include those described in p.heinrich Stahl and camile g.wermuth in the handbook of pharmaceutical salts: properties, Selection and Use (Handbook of Pharmaceutical Salts, Selection, and Use) second edition (Wiley-VCH: 2011) and Remington Pharmaceutical sciences, 18 th edition (Mac Press, 1990, Iston, Pa.) and Remington: science and practice of pharmacy, 19 th edition (Mic Press, Iston, Pa.: 1995).
Typical pharmaceutically acceptable salts include, for example, alkali metal salts, alkaline earth metal salts, ammonium salts, water-soluble salts and water-insoluble salts, such as acetate, astraganesulfonate (4, 4-diaminostilbene-2, 2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium edetate, camphorsulfonate, carbonate, chloride, citrate, clavulanate (clavulanate), dihydrochloride, edetate, edisylate, propionate laureate (estolate), ethanesulfonate, fumarate, glucoheptonate, gluconate, glutamate, glycollylalkanoate (glycopyrrolylate), hexafluorophosphate, hexylisophthalate (hexylresorcinate), hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodate, isothionate, isothiosulphate, isothionate, iso, Lactate, lactobionate, laurate, malate, maleate, mandelate, methanesulfonate, methylbromide, methylnitrate, methanesulfonate, mucate, naphthalenesulfonate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (1, 1-methylene-bis-2, 2-hydroxy-3-naphthoate, pamoate (einbonate)), pantothenate, phosphate/diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, suramate (suramate), tannate, tartrate, 8-chlorothalolate (teoclate), Tosylate, triethyliodide, trifluoroacetate and valerate. Pharmaceutically acceptable salts may have more than one charged atom in the structure. In this case, the pharmaceutically acceptable salt may have a plurality of counterions. Thus, a pharmaceutically acceptable salt may have one or more charged atoms and/or one or more counterions.
Salts of the compounds of the invention may be prepared by any suitable method known in the art, including treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, formic acid, alginic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosyl acids, such as glucuronic acid or galacturonic acid, amino acids, such as alpha hydroxy acids, such as citric acid or tartaric acid, amino acids, such as aspartic acid or glutamic acid, aromatic acids, such as benzoic acid or cinnamic acid, sulfonic acids, such as p-toluenesulphonic acid or ethanesulphonic acid.
Pharmaceutically acceptable salts can be prepared with bases which provide pharmaceutically acceptable cations, including alkali metal salts (especially sodium and potassium), alkaline earth metal salts (especially calcium and magnesium), aluminum salts and ammonium salts, zinc, and from physiologically acceptable organic bases such as diethylamine, isopropylamine, hydroxylamine, benzathine, phenethylamine, tromethamine (2-amino-2- (hydroxymethyl) propane-1, 3-diol), morpholine, pyrrolyl ethanol, piperidine, piperazine, picoline, dicyclohexylamine, N' -dibenzylethylenediamine, 2-hydroxyethylamine, tris (2-hydroxyethyl) amine, chloroprocaine, choline, danol (deanol), imidazole, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), procaine, dibenzylpiperidine, dehydroabietylamine, glucosamine, Collidine, quinine, quinolone, tert-butylamine, and basic amino acids such as lysine and arginine.
If the compound containing the basic amine or other basic functional group is isolated as a salt, the corresponding free base form of the compound may be prepared by any suitable method known in the art, including treating the salt with an inorganic or organic base, suitably an inorganic or organic base having a higher pKa than the free base form of the compound. Similarly, if a compound containing a phosphodiester, phosphorothioate diester or other acidic functional group is isolated as a salt, the corresponding free acid form of the compound may be prepared by any suitable method known in the art, including treatment of the salt with an inorganic or organic acid, suitably an inorganic or organic acid having a lower pKa than the free acid form of the compound.
As described herein, the dosage of an effective amount of a compound, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable hydrate thereof, for a particular patient may vary depending on a variety of factors, such as the disease being treated, the overall health of the patient, the route and dosage of administration, and the severity of side effects.
A "pharmaceutically acceptable prodrug" is a compound that can be converted under physiological conditions or by solvolysis to a specified compound or a pharmaceutically acceptable salt of such a compound before exhibiting its pharmacological effect. In general, prodrugs are formulated with the aim of improving chemical stability, improving patient acceptance and compliance, improving bioavailability, prolonging duration of action, improving organ selectivity, improving formulation (e.g., increasing water solubility) and/or reducing side effects (e.g., toxicity). Prodrugs can be readily prepared from compounds of formula I using methods known in the art, for example, the methods described in Burger's Medicinal Chemistry and Drug Chemistry, 1, 172-178, 949-982 (1995). See also Bertolini et al, j.med.chem.1997,40, 2011-2016; shan et al, J.pharm.Sci.1997,86(7), 765-; bagshawe, Drug Dev. Res.1995,34, 220-; bodor, adv. drug Res.1984,13, 224-331; bundgaard, Design of produgs (prodrug Design) (Elsevier Press, 1985); and Larsen, Design and Application of Prodrugs (prodrug Design and Application), Drug Design and Development (Drug Design and Development) (Krogsgaard-Larsen et al, Harwood Academic Publishers, 1991); dear et al j.chromatogr.b (journal of chromatography B), 748,281-293 (2000); spraul et al, J.pharmaceutical & Biomedical Analysis (J.J.Pharma & Biomedical Analyzer), 10,601-605 (1992); and Prox et al, Xenobiol. ("heterologous biology"), 3,103-112 (1992).
Methods of co-administration with additional therapeutic agents are well known in The art (Hardman et al, eds. (2001) Pharmacological Basis for Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10 th edition, McGraw-Hill, New York, Poole and Peterson, eds. (2001) pharmaceutical Practice Advanced: Practical methods (Pharmacetherapeutics for Advanced Practice: A Practical application), Lippincott, Williams and Wilkins Press, Philadelphia, Chabner and Longo, 2001 Chemotherapy and biological therapy for Cancer (Cancer Chemotherapy and biological therapy), Lippincott, Williams and Wilkins Press, Philadelphia, Williams and Wilkins, Pa., Rabbit and Pa., U.S.). Generally, co-administration or co-administration means treating a subject with two or more agents, wherein the agents may be administered simultaneously or at different times. For example, these agents may be delivered to a single subject as separate administrations, which may be performed at substantially the same time or different times, and which may be performed by the same route or different routes of administration. Such agents may be delivered to a single subject in the same manner of administration (e.g., the same formulation) such that they may be administered at the same time by the same route of administration.
Typically, each administration of a compound of the invention comprises from about 10mg to about 2000mg, for example, from about 10mg to about 50mg, from about 50mg to about 100mg, from about 100mg to about 250mg, from about 250mg to about 500mg, from about 500mg to about 1000mg, from about 1000mg to about 2000mg, in a subject.
General procedure
Unless otherwise stated in the examples, all synthetic chemistry was performed in standard laboratory glassware. Commercial reagents were used as received. The microwave reaction was performed in the Initiator of the Bytaizil company (Biotage) using instrument software to control the heating time and pressure. The LC/MS analysis was performed in Agilent 1290 limits, Mass: 6150SQD (ESI/APCI) or Agilent 1200 series, quality: 6130SQD (ESI/APCI); a variable wavelength detector and agilent 6130 single quadrupole mass spectrometer, alternately scanned for positive and negative ions using Chemistation software. Retention time was determined from the extracted 220nm UV chromatogram. HPLC was performed on a Waters 2695 system with variable wavelength detector using Empower software. Retention times were determined from extracted 210nm and 300nm UV chromatograms. The procedure was performed on either Bruker Avance 400 at 400MHz or Bruker Avance DRX-500 at 500MHz using Topspin software 1H NMR. For complex splitting patterns, the apparent splits are listed. Analytical thin layer chromatography (Macherey-Nagel ALUMRA Xtra SIL G, 0.2mm, UV254 indicator) was performed on silica gel and visualized under UV light. Silica gel chromatography was performed manually or gradient elution was performed using Grace automated chromatography. Melting points were collected using a B ü chi B-540 melting point apparatus.
Standard methods of molecular biology are described in Sambrook, Fritsch and Maniatis (1982&1989 second edition, 2001 third edition) molecular cloning: a Laboratory Manual (Molecular Cloning: A Laboratory Manual) Cold Spring Harbor Press (Cold Spring Harbor Laboratory Press), Cold Spring Harbor, N.Y.; sambrook and Russell (2001) Molecular Cloning, third edition, Cold spring harbor Press, Cold spring harbor, N.Y.; wu (1993) Recombinant DNA 217, Academic Press, san Diego, Calif. Standard methods are also presented in Ausbel et al (2001) New compiled Molecular Biology Protocols (Current Protocols in Molecular Biology), John Wiley father publishing Co., John Wiley & Sons, Inc., N.Y., which describes cloning and DNA mutagenesis of bacterial cells (Vol.1), cloning of mammalian cells and yeast (Vol.2), glycoconjugates and protein expression (Vol.3), and bioinformatics (Vol.4).
Standard methods of Histology of the immune system are also described (see, e.g., Muller-Harmelink eds (1986) Histopathology and Pathology of the Human Thymus, Springer Frigger, New York, N.Y. (Human Thymus, Histopathology and Pathology), Lippincott, Williams and Wilkins publishers, Philadelphia, Pa., Louis et al (2002) Basic Histology: Text and Atlas (Basic Histology: Text and Atlas) McGraw-Hill, N.Y.).
Software packages and databases are available for determining, for example, antigen fragments, leader sequences, protein folds, functional domains, glycosylation sites and sequence alignments (see, e.g., GenBank(Informatx, Inc, Besserda, Maryland); the GCG wisconsin state software package (Accelrys Inc., san diego, california);(TimeLogic Corp., Crystal gulf, Nevada); menne et al (2000) Bioinformatics 16: 741-742; menne et al (2000) Bioinformatics Applications Note 16: 741-742; wren et al (2002) Compout. methods Programs biomed.68: 177-181; von Heijne (1983) Eur.J.biochem.133: 17-21; von Heijne (1986) Nucleic Acids Res.14: 4683-4690).
Examples
Example 1:2-amino-7- (cyclopropylmethyl) -9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 1
Compound 1 was prepared according to the following multi-step procedure.
Step 1:2-amino-8-bromo-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -1, 9-dihydro-6H-purin-6-one (2)
To a stirred solution of 2-amino-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -1, 9-dihydro-6H-purin-6-one (1) [27462-39-1] (15.0g, 53mmol) in 250mL of water prepared according to the procedure of zuo et al can.j.chem., 1987, page 1436 and Robins et al JOC, 1996, page 9207, aqueous bromine solution (4.5mL, 1.5 equiv) was slowly added at room temperature. In a closed round bottom flask, the reaction mixture was stirred at room temperature overnight. An aqueous solution of sodium thiosulfate was added to destroy excess bromine. The reaction mixture was filtered, and the filtrate was washed with water and acetone. The solid was dried under vacuum to afford 15.4g of the desired product 2-amino-8-bromo-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -1, 9-dihydro-6H-purin-6-one (2) as an off-white solid in 80% yield.
Step 2:2-amino-8- (benzyloxy) -9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -1, 9-dihydro-6H-purin-6-one (3)
In a round bottom flask, sodium chips (6.0gm, 260.9mmol) were added to 60mL of benzyl alcohol. The mixture was stirred at room temperature for 0.5h, then heated until a solution was obtained. A solution of 2-amino-8-bromo-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -1, 9-dihydro-6H-purin-6-one (2) (15.4g, 42mmol) in 60mL DMSO was added to the stirred solution obtained above. It was stirred for 10 h. Glacial acetic acid was added to the stirred reaction mixture to adjust to neutrality. The mixture was treated with diethyl ether. The ether layer was decanted and the remaining material was treated with acetone. The solid was filtered and washed with water. The crude product was recrystallized from ethanol-water (1: 1) to give 11.0g of 2-amino-8- (benzyloxy) -9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -1, 9-dihydro-6H-purin-6-one (3) as an off-white solid in 67% yield.
And step 3:1, 2-diamino-8- (benzyloxy) -9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -1, 9-dihydro-6H-purin-6-one (4)
2-amino-8- (benzyloxy) -9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -1, 9-dihydro-6H-purin-6-one (3) (11.0g, 28mmol) was dissolved in 150mL of 2N aqueous sodium hydroxide solution. hydroxylamine-O-sulfonic acid (9.35g, 82mmol, 3 equivalents) was added. The reaction mixture was stirred at room temperature overnight and filtered. The solid was washed with acetone to give 5.8g of the product 1, 2-diamino-8- (benzyloxy) -9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -1, 9-dihydro-6H-purin-6-one (4) as a white solid in 51% yield.
And 4, step 4:1, 2-diamino-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione (5)
1, 2-diamino-8- (benzyloxy) -9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -1, 9-dihydro-6H-purin-6-one (4) (5.8g, 14mmol) was dissolved by heating to 90 ℃ in 200mL of ethanol and 200mL of water in a hydrogenation flask. 1g of 5% Pd/C was added. In a parr reactor, the reaction mixture was kept overnight under a hydrogen atmosphere at 40-50 psi. Hydrogen was withdrawn from the reactor and the catalyst was filtered off and washed with hot water. The filtrate was concentrated under reduced pressure to give the crude product, which was recrystallized from water to give 3.6g of 1, 2-diamino-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione (5) as a white solid in 81% yield.
And 5:1, 2-diamino-7- (cyclopropylmethyl) -9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione (6)
1, 2-diamino-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione (5) (3.6g, 11.4mmol, 1.0 equiv.) was dissolved in 50mL anhydrous DMF. NaH (0.5g, 12.6mmol, 1.1 equiv.) was added to the stirred solution and stirred for a further 1 hour. Cyclopropylmethyl bromide (1.70g, 12.6mmol, 1.1 equiv.) was added to the reaction mixture and stirring was continued at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using dichloromethane-methanol (15: 1) as eluent. 1, 2-diamino-7- (cyclopropylmethyl) -9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione (6) (2.5g) was obtained as a white solid in 65% yield.
Step 6:2-amino-7- (cyclopropylmethyl) -9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 1
1, 2-diamino-7- (cyclopropylmethyl) -9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione (6) (0.50g, 1.4mmol) was charged to a flask containing 10mL of DMF. Concentrated hydrochloric acid (1.0mL) was added at 0 ℃. An aqueous solution of sodium nitrite (113mg, 1.7mmol) in 5mL of water was added with stirring. After stirring for 30 min, sodium acetate (0.50g, 6.3mmol) was added. The reaction mixture was stirred for 25 minutes and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using dichloromethane-methanol (10: 1) as eluent to give 0.30g of the product 2-amino-7- (cyclopropylmethyl) -9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione, compound 1, as a white solid in 63% yield. HPLC purity 99.5%.1H NMR(DMSO-d6,400MHz)δ11.03(s,1H),6.64(s,2H),5.69-5.77(m,2H),5.51(d,1H,J＝4Hz),4.63(t,1H,J＝8Hz),4.46-4.54(m,1H),3.83-3.94(m,2H),3.61-3.73(m,3H),3.51-3.60(m,1H),1.12-1.25(m,1H),0.31-0.46(m,4H).MS(ESI),m/z 354.3[M+H]+.
Example 2:7-allyl-2-amino-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7,9-dihydro-1H-purine-6, 8-dione, Compound 2
Compound 2 was prepared according to the following multi-step procedure.
Step 1:8- (allyloxy) -2-amino-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -1, 9-dihydro-6H-purin-6-one (7)
The small pieces of sodium metal (0.4g, 17.4mmol) were added portionwise to stirred allyl alcohol (10mL, 8.5g, 146mmol) with stirring, and continued until all the sodium was completely dissolved and no more hydrogen evolved. Anhydrous DMSO (10mL) was added followed by 2-amino-8-bromo-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -1, 9-dihydro-6H-purin-6-one (2) (example 1) (1.0g, 2.8 mmol). The reaction mixture was heated to 65 ℃ with stirring and continued until TLC indicated that the dichloromethane was depleted of the 8-bromopurine starting material (dichloromethane-methanol: 2: 1; R)f0.6). The solvent was concentrated under reduced pressure and the residue was treated with diethyl ether. The ether layer was decanted and the residue was purified by flash chromatography on a silica gel column with dichloromethane-methanol: 8: 1 as eluent gave 190mg of 8- (allyloxy) -2-amino-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -1, 9-dihydro-6H-purin-6-one (7) as an off-white solid in 21% yield.
Step 2:7-allyl-2-amino-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 2
8- (allyloxy) -2-amino-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -1, 9-dihydro-6H-purin-6-one (7) (190mg, 0.6mmol) was dissolved in 15mL of methanol and 150mL of water. The reaction mixture was heated to reflux for 5 h. The solvent was concentrated under reduced pressure and the residue was purified by flash chromatography on a silica gel column with dichloromethane-methanol: 10: 1 as eluent, to give 134mg of 7-allyl-2-amino-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 2 as an off-white foam in 70.5% yield;
1H NMR(DMSO-d6,400MHz)δ5.86-5.95(m,1H),5.67-5.74(m,2H),5.50(d,1H,J＝3.2Hz),5.02-5.12(m,2H),4.60-4.63(m,1H),4.41-4.50(m,3H),3.85-3.92(m,2H),3.64-3.69(m,1H),3.53-3.58(m,1H),MS(ESI),m/z 340.2
[M+H]+.
example 3:(2R,3S,4R,5R) -2- (acetoxymethyl) -5- (2-amino-7- (cyclopropylmethyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-3, 4-diacetic acid diester, Compound 3
Compound 3 was prepared according to the following multi-step procedure.
Step 1:(2R,3S,4R,5R) -2- (acetoxymethyl) -5- (2-amino-8- (benzyloxy) -6-oxo-1, 6-dihydro-9H-purin-9-yl) tetrahydrofuran-3, 4-diacetic acid diester (8)
A solution of 2-amino-8- (benzyloxy) -9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -1, 9-dihydro-6H-purin-6-one (3) (16.0g, 41.1mmol) in anhydrous pyridine (250mL) was treated with acetic anhydride (15.5mL, 164.4mmol, 4.0 equiv.) and a catalytic amount of DMAP (50mg, 0.41mmol, 0.01 equiv.). The reaction mixture was stirred at room temperature overnight. After monitoring the completion of the reaction by TLC, the reaction mixture was diluted with ethyl acetate (300mL) and poured into 500mL water. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with a saturated aqueous salt solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure And (4) shrinking. The resulting residue was purified by silica gel column chromatography using dichloromethane-methanol (20: 1) as eluent to give 10g of (2R,3S,4R,5R) -2- (acetoxymethyl) -5- (2-amino-8- (benzyloxy) -6-oxo-1, 6-dihydro-9H-purin-9-yl) tetrahydrofuran-3, 4-diacetic acid diester (8) as a white foam in 47.2% yield; rf0.30 (dichloromethane-methanol 18: 1).
Step 2:(2R,3S,4R,5R) -2- (acetoxymethyl) -5- (2-amino-6-chloro-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-3, 4-diacetic acid diester (9)
In an oven dried flask, (2R,3S,4R,5R) -2- (acetoxymethyl) -5- (2-amino-8- (benzyloxy) -6-oxo-1, 6-dihydro-9H-purin-9-yl) tetrahydrofuran-3, 4-diacetic acid diester (8) (10g, 19.4mmol), benzyltriethylammonium chloride (8.8g, 38.8mmol, 2.0 equivalents) and N, N-dimethylaniline (2.7mL, 21.3mmol, 1.1 equivalents) were dissolved in 300mL of anhydrous MeCN. Then phosphorus oxychloride (9.0mL, 97mmol, 5.0 equiv.) was added with stirring at room temperature. The reaction mixture was stirred at room temperature for 1h or TLC showed disappearance of the starting material (8). At this point, the reaction mixture was transferred to a pre-heated oil bath at 90 ℃ and heated for 3 h. After completion of the reaction was monitored by TLC, the reaction mixture was concentrated in vacuo. The resulting residue was dissolved in ethyl acetate (200mL) and poured into 200mL of saturated sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with a saturated brine solution, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography using dichloromethane-methanol (30: 1) as eluent to give 1.8g of the product (2R,3S,4R,5R) -2- (acetoxymethyl) -5- (2-amino-6-chloro-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-3, 4-diacetic acid diester (9) as a white foam in 22% yield. R f0.60 (dichloromethane-methanol 18: 1)
And step 3:(2R,3S,4R,5R) -2- (acetoxymethyl) -5- (2-amino-6-chloro-7- (cyclopropylmethyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-3, 4-diacetic acid diester (10)
Mixing (2R,3S,4R,5R) -2- (acetoxymethyl) -5- (2-amino-6-chloro-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetraTetrahydrofuran-3, 4-diacetic acid diester (9) (1.4g, 3.2mmol, 1.0 equiv.) was dissolved in 50mL of anhydrous DMF. Will K2CO3(655mg, 4.7mmol, 1.5 equiv.) was added to the stirred solution and it was further stirred for 10 minutes. Cyclopropylmethyl bromide (0.37mL, 3.84mmol, 1.2 equiv.) was then added to the reaction mixture and stirring was continued at room temperature overnight. After monitoring the completion of the reaction by TLC, the reaction mixture was diluted with ethyl acetate (100mL) and treated with 100mL water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with a saturated brine solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography using dichloromethane-methanol (50: 1) as eluent to give 1.18g of the product (2R,3S,4R,5R) -2- (acetoxymethyl) -5- (2-amino-6-chloro-7- (cyclopropylmethyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-3, 4-diacetic acid diester (10) as a white foam in 75% yield. R f0.70 (dichloromethane-methanol 30: 1)
And 4, step 4:(2R,3S,4R,5R) -2- (acetoxymethyl) -5- (2-amino-7- (cyclopropylmethyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-3, 4-diacetic acid diester, Compound 3
(2R,3S,4R,5R) -2- (acetoxymethyl) -5- (2-amino-6-chloro-7- (cyclopropylmethyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-3, 4-diacetic acid diester (10) (1.0g, 2.0mmol) was dissolved in a mixture of anhydrous methanol (50mL) and tetrahydrofuran (10 mL). 10% Pd/C (120mg) was added and the mixture was washed with H2Stirring was carried out at room temperature for 5 hours and 2 days under an atmosphere of (50 Psi). After completion of the reaction was monitored by TLC, the catalyst was removed by filtration through a celite pad. The solvent was evaporated and the crude product was purified by flash chromatography on silica gel column using dichloromethane-methanol (50: 1) as eluent to afford 650mg of (2R,3S,4R,5R) -2- (acetoxymethyl) -5- (2-amino-7- (cyclopropylmethyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-3, 4-diacetic acid diester, compound 3, 70% yield, 98.2% HPLC purity as a white solid. Rf0.20 (dichloromethane-methanol 30: 1).1H NMR(CDCl3,400MHz)δ7.87(s,1H),6.41–6.46(m,1H),5.85(d,1H,J＝6.0Hz),5.48(t,1H,J＝4.8Hz),4.83(s,2H),4.50–4.56(m,2H),4.36–4.44(m,1H),3.64–3.69(m,1H),2.17(s,3H),2.03(s,3H),2.06(s,3H),1.08–1.19(m,1H),0.55–0.65(m,2H),0.35–0.41(m,2H)；MS(ESI),m/z 464.2[M+H]+.
Example 4:2-amino-7- (cyclopropylmethyl) -9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-one, Compound 4
Compound 4 was prepared from compound 3 according to the following procedure.
(2R,3S,4R,5R) -2- (acetoxymethyl) -5- (2-amino-7- (cyclopropylmethyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-3, 4-diacetic acid diester, Compound 3(400mg, 0.86mmol) was dissolved in NH3-MeOH (20 mL). The mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was purified on silica gel column to give 240mg of 2-amino-7- (cyclopropylmethyl) -9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-one, compound 4, as a white solid in 82% yield, 97.9% purity by HPLC; rf0.30 (dichloromethane-methanol 10: 1).1H NMR(DMSO-d6,400MHz)δ8.14(s,1H),6.34(s,2H),5.72(d,1H,J＝4.8Hz),5.61–5.67(m,1H),5.57(d,1H,J＝4.0Hz),4.61–4.66(m,1H),4.57(t,1H,J＝5.6Hz),3.91–3.99(m,2H),3.55–3.75(m,4H),1.10–1.20(m,1H),0.45–0.53(m,2H),0.32–0.40(m,2H)；MS(ESI),m/z 338.4[M+H]+,360.4[M+Na]+.
Example 5:2-amino-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-1H-purine-6, 8-dione, compound 5
Compound 5 was prepared according to the following procedure using an improved method for the synthesis of compound 1.
Step 1:1, 2-diamino-8- (benzyloxy) -9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -1, 9-dihydro-6H-purin-6-one (4)
To a stirred solution of 2-amino-8- (benzyloxy) -9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -1, 9-dihydro-6H-purin-6-one (3) (5.1g, 13mmol) in 100mL anhydrous DMF at 0 deg.C was added NaH (0.7g, 16.9mmol, 1.3 equiv.). The reaction mixture was stirred for 30 min and O- (diphenylphosphinyl) hydroxylamine (4.5g, 19.5mmol, 1.5 eq) was added. The reaction mixture was stirred at room temperature until completion by TLC (dichloromethane-methanol: 3: 1). The precipitate was filtered and dried under vacuum to give 3.7g of 1, 2-diamino-8- (benzyloxy) -9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -1, 9-dihydro-6H-purin-6-one (4) as a white solid in 70% yield.
Step 2:1, 2-diamino-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione (5)
1, 2-diamino-8- (benzyloxy) -9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -1, 9-dihydro-6H-purin-6-one (4) (3.7g, 9.1mmol) was dissolved by heating to 90 ℃ in 500mL ethanol and 500mL water in a hydrogenation flask. 0.8g of 5% Pd/C was added. In a parr reactor, the reaction mixture was kept overnight under a hydrogen atmosphere at 40-50 psi. Hydrogen was withdrawn from the reactor and the catalyst was filtered off and washed with hot water. The filtrate was concentrated under reduced pressure to give the crude product, which was recrystallized from water to give 2.1g of 1, 2-diamino-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione (5) as a white solid in 72% yield.
And step 3:1, 2-diamino-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-1H-purine-6, 8-dione (11)
1, 2-diamino-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione (5) (850mg, 2.7mmol, 1.0 equiv.) was dissolved in 30mL anhydrous DMF. Will K 2CO3(410mg, 3.8mmol, 1.4 equiv.) was added to the stirred solution and it was further stirred for 30 minutes. 3-bromo-1-propyne (453mg, 4.8mmol, 1.8 equivalents) was added to the reaction mixture and it was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was taken up in methanol and purified by flash chromatography on a silica gel column using dichloromethane-methanol (20: 1) as eluent to give 610mg of 1, 2-diamino-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-1H-purine-6, 8-dione (11) as a white solid in 74% yield.
And 4, step 4:2-amino-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-1H-purine-6, 8-dione, compound 5
1, 2-diamino-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-1H-purine-6, 8-dione (11) (610mg, 1.7mmol) was added to a flask containing 10mL of DMF. Concentrated hydrochloric acid (0.65mL) was added at 0 ℃. An aqueous solution of sodium nitrite (132mg, 2.04mmol, 1.2 equiv.) in 3mL of water was added with stirring. After stirring at 0 ℃ for 30 minutes, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using dichloromethane-methanol (10: 1) as eluent to give 408mg of 2-amino-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-1H-purine-6, 8-dione, compound 5, as a white solid in 71% yield;
1H NMR(DMSO-d6,400MHz)δ11.33(s,1H),6.78(br,2H),5.73–5.76(m,2H),5.48–5.47(d,1H,J＝3.2Hz),4.62–4.63(m,2H),4.50(s,1H),3.9(s,2H),3.30–3.65(m,2H),3.25(s,1H).MS(ESI)m/z 338.1(M+H)+,360.1[M+Na]+.
The synthesis of compounds 6-8, 10-19 and 21-23 was accomplished using the same methods as described for compounds 1 or 5. Compounds 9 and 20 were initially prepared by simultaneous hydrolysis of nitrile groups in the final N-1-deammoniation step under acidic conditions. Compounds 10 and 21 can also be prepared from compounds 9 and 20, respectively, by esterification.
Example 6:2-amino-7- (but-2-yn-1-yl) -9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 6
Off-white solid:1H NMR(DMSO-d6,400MHz)δ:7.02(s,2H),5.82-5.83(d,1H,J＝4.0Hz),5.66–5.68(d,1H,J＝8.0Hz),5.46-5.47(d,1H,J＝4.0Hz),4.66(t,1H),4.57(t,1H,J＝5.6Hz),4.56(m,1H),3.9(m,2H),3.11–3.37(m,2H),1.75(s,3H).MS(ESI)m/z 352.2(M+H)+,374.1[M+Na]+.
example 7:2-amino-7- ((E) -but-2-en-1-yl) -9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 7
Off-white solid: MS (ESI) M/z 354.2(M + H)+,376.1[M+Na]+.
Example 8:2-amino-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- ((E) -4-hydroxybut-2-en-1-yl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 8
Off-white solid:1H NMR(DMSO-d6,400MHz)δ6.71(s,2H),5.75(d,1H,J＝4.8Hz),5.66–5.73(m,2H),5.46(m,1H),4.74(t,1H,J＝5.6Hz),4.62(t,1H,J＝5.6Hz),4.41–4.48(m,1H),4.40–4.41(m,2H),3.80–3.98(m,4H),3.51–3.70(m,2H),3.17(d,1H,J＝5.2Hz).MS(ESI)m/z 370.1(M+H)+,392.1[M+Na]+.
example 9:(E) -4- (2-amino-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) but-2-enoic acid, compound 9
Off-white solid:1H NMR(DMSO-d6,400MHz)δ11.15(s,1H),6.64–7.08(m,3H),5.59–5.69(m,1H),5.49(d,1H,J＝3.2Hz),4.48–4.68(m,3H),3.82–4.01(m,2H),3.49–3.74(m,2H).MS(ESI)m/z 384.1(M+H)+,422.0[M+K]+.
example 10:(E) -methyl 4- (2-amino-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) but-2-enoate, Compound 10
Off-white solid: MS (ESI) M/z 398.1(M + H)+,420.1[M+Na]+.
Example 11:2-amino-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (4-hydroxybut-2-yn-1-yl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 11
Off-white solid: MS (ESI) M/z 368.1(M + H)+,390.1[M+Na]+.
Example 12:methyl 2- (2-amino-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) acetate, Compound 12
Off-white solid: MS (ESI) M/z 372.1(M + H)+.
Example 13:2-amino-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (2,2, 2-trifluoroethyl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 13
Off-white solid:1H NMR(DMSO-d6,400MHz)δ11.09(s,1H),6.86(s,2H),5.78(d,1H,J＝4Hz),5.54(d,1H,J＝4Hz),5.48(d,1H,J＝4Hz),4.55-4.67(m,4H),3.90-3.92(m,2H),3.64-3.69(m,1H),3.54-3.60(m,1H).MS(ESI)m/z 382.1(M+H)+,404.2[M+Na]+.
example 14:2-amino-7- (2, 2-difluoroethyl) -9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 14
Off-white solid:1H NMR(DMSO-d6,400MHz)δ11.09(s,1H),6.67(s,2H),6.14-6.44(m,1H),5.74(d,1H,J＝4Hz),5.57(d,1H,J＝8Hz),5.48(d,1H,J＝4Hz),4.61(d,1H,J＝4Hz),4.53(s,1H),4.18-4.26(m,2H),3.88-3.93(m,2H),3.64-3.69(m,1H),3.53-3.59(m,1H).MS(ESI)m/z 386.0[M+Na]+.
example 15:2-amino-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7-methyl-7, 9-dihydro-1H-purine-6, 8-dione, Compound 15
Off-white solid:1H NMR(DMSO-d6,400MHz)δ11.14(s,1H),6.79(s,2H),5.74-5.78(m,2H),5.51(d,1H,J＝4Hz),4.63(t,1H,J＝8Hz),4.48-4.52(m,1H),3.85-3.92(m,2H),3.63-3.69(m,1H),3.51-3.57(m,1H),3.36(s,3H).MS(ESI)m/z 314.1(M+H)+,336.0[M+Na]+.
example 16:2-amino-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7-ethyl-7, 9-dihydro-1H-purine-6, 8-dione, Compound 16
Off-white solid:1H NMR(DMSO-d6,400MHz)δ11.01(s,1H),6.61(s,2H),5.72-5.76(m,2H),5.51(d,1H,J＝4Hz),4.63(t,1H,J＝8Hz),4.47-4.49(m,1H),3.81-3.91(m,4H),3.64-3.69(m,1H),3.52-3.58(m,1H),1.20(t,3H,J＝8Hz).MS(ESI)m/z 328.1(M+H)+.
example 17:2-amino-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7-propyl-7, 9-dihydro-1H-purine-6, 8-dione, Compound 17
Off-white solid:1H NMR(DMSO-d6,400MHz)δ10.95(s,1H),6.58(s,2H),5.71-5.74(m,2H),5.51(d,1H,J＝4Hz),4.63(t,1H,J＝8Hz),4.47-4.49(m,1H),3.84-3.92(m,2H),3.76(t,2H,J＝8Hz),3.64-3.69(m,1H),3.52-3.58(m,1H),1.60-1.69(m,2H),0.83(t,3H,J＝8Hz).MS(ESI)m/z 342.2(M+H)+,364.1[M+Na]+.
example 18:2-amino-7-butyl-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 18
Tan solid:1H NMR(DMSO-d6,400MHz)δ11.02(s,1H),6.58(s,2H),5.71-5.74(m,2H),5.51(d,1H,J＝4Hz),4.63(t,1H,J＝8Hz),4.47-4.49(m,1H),3.84-3.92(m,2H),3.76(t,2H,J＝8Hz),3.64-3.69(m,1H),3.52-3.58(m,1H),1.58-1.65(m,2H),1.21-1.30(m,2H),0.88(t,3H,J＝8Hz).MS(ESI)m/z 356.1(M+H)+,378.1[M+Na]+.
example 19:2-amino-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (4-hydroxybutyl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 19
Off-white solid: MS (ESI) M/z 372.4(M + H)+,394.4[M+Na]+.
Example 20:4- (2-amino-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) butyric acid, Compound 20
Off-white solid:1H NMR(DMSO-d6,400MHz)δ11.06(s,1H),6.69(bs,2H),5.50(d,1H J＝3.2Hz),5.48–4.65(b,3H),4.49(dd,1H,J＝3.0,1.8Hz),4.89(m,4H),3.85(ddd,1H,J＝10.4,6.4,4.8,1.6Hz),3.61(dd,1H,J＝6.4,4.8Hz),2.21(t,2H,J＝7.2Hz),1.88(m,2H).MS(ESI)m/z 386.1(M+H)+,324.1[M+K]+.
example 21:methyl 4- (2-amino-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) butanoate, Compound 21
Off-white solid: MS (ESI) M/z 400.2(M + H)+,422.1[M+Na]+.
Example 22:2-amino-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (2-methoxyethyl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 22
Off-white solid: MS (ESI) M/z 358.2(M + H)+.
Example 23:2-amino-7- (2-difluoroethyl) -9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione hydrochloride, Compound 23
Off-white solid:1H NMR(DMSO-d6,400MHz)δ5.63(s,1H,J＝4.0Hz),4.71(m,1H),4.13–4.21(m,4H),3.72–3.85(m,2H),3.25–3.33(m,2H).MS(ESI)m/z343.1(M+H)+.
example 24:(2R,3S,4R,5R) -2- (acetoxymethyl) -5- (2-amino-8-oxo-7- (prop-2-yn-yl) -7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-3, 4-diacetic acid diester, Compound 24
Compound 24 was prepared from (2R,3S,4R,5R) -2- (acetoxymethyl) -5- (2-amino-6-chloro-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-3, 4-diacetic acid diester (9) according to the following synthetic method.
Step 1:(2R,3S,4R,5R) -2- (acetoxymethyl) -5- (2-amino-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-3, 4-diacetic acid diester (12)
(2R,3S,4R,5R) -2- (acetoxymethyl) -5- (2-amino-6-chloro-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-3, 4-diacetic acid diester (9) (6.0g, 13.6mmol) was dissolved in a mixture of anhydrous methanol (100mL) and tetrahydrofuran (10 mL). Catalyst Pd/C (150mg, 10%) was added and the mixture was cooled to room temperature under H2Stirring for 5h under an atmosphere of (50 Psi). The catalyst was filtered off through celite. The solvent was evaporated and the crude product was used in the next step without further purification.
Step 2:(2R,3S,4R,5R) -2- (acetoxymethyl) -5- (2-amino-8-oxo-7- (prop-2-yn-1-yl) -7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-3, 4-diacetic acid diester, Compound 24
(2R,3S,4R,5R) -2- (acetoxymethyl) -5- (2-amino-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-3, 4-diacetic acid diester (12) (13.6mmol) was dissolved in 150mL anhydrous DMF. Potassium carbonate (2.8g, 20.4mmol, 1.5 equivalents) was added to the stirred solution and stirred for a further 5 minutes. At this time, 3-bromopropyne (1.9mg, 16.32mmol, 1.2 equivalents) was added to the reaction mixture and stirred at 45 ℃ for 5 h. The mixture was concentrated under reduced pressure and the resulting residue was purified by column chromatography using dichloromethane-methanol (70: 1) as eluent to give 3.5g of (2R,3S,4R,5R) -2- (acetoxymethyl) -5- (2-amino-8-oxo-7- (prop-2-yn-yl) -7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-3, 4-diacetic acid diester, compound 24, as a white foam in 60% yield in two steps with HPLC purity of 98%. Rf0.50 (dichloromethane-methanol)＝30：1)。1H NMR(CDCl3,400MHz)δ8.01(s,1H),6.35–6.43(m,1H),5.83(d,1H,J＝5.6Hz),6.43–6.51(m,1H),4.91(s,2H),4.59(t,1H,J＝1.6Hz),4.46–4.56(m,2H),4.36–4.45(m,1H),2.37(t,1H,J＝2.4Hz),2.17(s,3H),2.07(s,3H),2.06(s,3H).MS(ESI)m/z 448.2[M+H]+,470.2[M+Na]+.
Example 25:2-amino-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-8H-purin-8-one, compound 25
Compound 25 was prepared from compound 24 using the outlined method for preparing compound 4 from compound 3.
(2R,3S,4R,5R) -2- (Acetoxymethyl) -5- (2-amino-8-oxo-7- (prop-2-yn-yl) -7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-3, 4-diacetic acid diester, Compound 24(600mg, 1.3mmol) was dissolved in saturated NH in MeOH (50mL)3. The mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was purified on a silica gel column to give 300mg of 2-amino-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-8H-purin-8-one, compound 25 as a white solid in 72% yield with HPLC purity 98.8%; rf0.50 (dichloromethane-methanol 6: 1).1H NMR(CDCl3,400MHz)δ8.08(s,1H),6.44(s,2H),5.72(d,1H,J＝4.8Hz),5.49–5.60(m,2H),4.46–4.76(m,4H),3.92–4.03(m,2H),3.55–3.71(m,2H),3.41(t,1H,J＝2.4Hz).MS(ESI)m/z 322.1(M+H)+,344.1[M+Na]+.
Example 26:2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 26
Synthesis of 2-amino-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 5 Using general procedure 2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-1H-purine-6, 8-dione, starting from 3 '-deoxy-guanosine [3608-58-0] and its corresponding 3' -deoxy-8-bromoguanosine [847649-68-7], Compound 5, as shown in the following synthetic scheme Yl) -7, 9-dihydro-1H-purine-6, 8-dione, compound 26.
Step 1:2-amino-8-bromo-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -1, 9-dihydro-6H-purin-6-one (12)
To 3' -deoxyguanosine (2g, 7.49mmol, 1 eq.) in H at 0 deg.C2NBS (2.6g, 14.98mmol, 2 equiv.) was added to a solution of O (20mL) and the reaction mixture was stirred at 0 ℃ for 1 h. The reaction was monitored by TLC. The reaction mixture was diluted with water (50mL) and extracted with n-butanol (3X 100 mL); extracting with ethyl acetate; the organic layer was washed with water (100mL), brine (100mL) and concentrated. The residue was triturated with ether, filtered and dried under reduced pressure to give 1.7g (65%) of 2-amino-8-bromo-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -1, 9-dihydro-6H-purin-6-one (12) as an off-white solid.1H NMR(400MHz,DMSO-d6):δ10.81(brs,1H),6.53(s,2H),5.62(d,J＝3.2Hz,1H),5.54(s,1H),4.94(s,1H),4.80(s,1H),4.24–4.18(m,1H),3.50(d,J＝3.6Hz,2H),2.47–2.43(m,1H),1.91–1.86(m,1H).(ESI)m/z344.0,346.0(M-H)-.
Step 2:2-amino-8- (benzyloxy) -9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -1, 9-dihydro-6H-purin-6-one (13)
Sodium metal (339mg, 14.78mmol, 3 equiv.) was dissolved in benzyl alcohol (7.9g, 73.91mmol, 15 equiv.) and heated to 65 ℃ until a clear solution was observed. The reaction mixture was then warmed to room temperature, and 2-amino group was added dropwise thereto at room temperature-a solution of 8-bromo-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -1, 9-dihydro-6H-purin-6-one (1.7g, 4.92mmol, 1 eq) in DMSO (8 mL). The reaction mixture was then stirred at 80 ℃ for 5 h. The reaction was monitored by TLC. The reaction mixture was diluted with water (50mL) and washed with diethyl ether (2X 100mL), and the aqueous layer was extracted with n-butanol (3X 100 mL). The organic layer was washed with water (100mL), brine (100mL) and concentrated to give the crude product, which was triturated with ether to give 1.6g (87%) of 2-amino-8- (benzyloxy) -9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -1, 9-dihydro-6H-purin-6-one (13) as an off-white solid. 1H NMR(500MHz,DMSO-d6):δ11.65(brs,1H),7.48(d,J＝7Hz,2H),7.42–7.30(m,3H),6.31(brs,2H),5.54(d,J＝3.5Hz,1H),5.48(s,1H),5.39(d,,J＝4Hz,2H),5.31(brs,1H),4.75(s,1H),4.16–4.11(m,1H),3.45–3.43(m,2H),2.21–2.15(m,1H),1.85–1.80(m,1H).(ESI)m/z 374.1(M+H)+.
And step 3:1, 2-diamino-8- (benzyloxy) -9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -1, 9-dihydro-6H-purin-6-one (14)
To a solution of 2-amino-8- (benzyloxy) -9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -1, 9-dihydro-6H-purin-6-one (1.6g, 4.28mmol, 1 eq) in DMF (20mL) at 0 deg.C was added 60% NaH (2.5mg, 5.14mmol, 1.2 eq). After stirring for 30 minutes, O- (diphenylphosphoryl) hydroxylamine (1.59g, 6.86mmol, 1.6 equivalents) was added portionwise at the same temperature. The reaction mixture was stirred at room temperature for 2h and the precipitate formed was removed by filtration. The filtrate was diluted with water (50mL) and extracted with n-butanol (3X 100 mL). The organic layer was washed with water (100mL), brine solution (100mL) and concentrated to give a crude solid which was triturated with ether to give 1.3g (78%) of 1, 2-diamino-8- (benzyloxy) -9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -1, 9-dihydro-6H-purin-6-one (14) as an off-white solid.1H NMR(400MHz,DMSO-d6):δ7.49(d,J＝8Hz,2H),7.43–7.35(m,3H),6.97(s,2H),5.58–5.56(m,2H),5.40(s,2H),5.38(s,2H),4.79–4.77(m,1H),4.72–4.71(m,1H),4.14–4.09(m,1H),3.39–3.35(m,2H),2.20–2.13(m,1H),1.80–1.75(m,1H).(ESI)m/z 389.1(M+H)+.
And 4, step 4:1, 2-diamino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione (15)
To 1, 2-diamino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione (1.3g, 3.35mmol, 1 equiv.) in a Parr shaker vessel was added 2To a solution of O (1: 1; 60mL) was added 10% Pd/C (400 mg). The reaction mixture was shaken with hydrogen (70psi) at room temperature for 2 hours. The progress of the reaction was monitored by TLC. After the starting material was consumed, the reaction mixture was filtered through a celite bed and washed with ethanol. The combined filtrates were concentrated and the residue triturated with ether to give 1.2g (crude) of 1, 2-diamino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione (15) as an off-white solid. The product can be used as such or can be recrystallized from water.1H NMR(400MHz,DMSO-d6):δ10.64(s,1H),7.04(s,2H),5.50(d,J＝4.4Hz,1H),5.41–5.36(m,1H),5.37(s,2H),4.82–4.80(m,1H),4.73(t,J＝5.6Hz,1H),4.13–4.12(m,1H),3.50–3.38(m,2H),2.40–2.32(m,1H),1.85–1.79(m,1H).(ESI)m/z 299.1(M+H)+.
And 5:1, 2-diamino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-1H-purine-6, 8-dione (16)
1, 2-diamino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione (15) (650mg, 2.18mmol, 1.0 equiv.) was dissolved in 50mL anhydrous DMF. Will K2CO3(402mg, 3.05mmol, 1.4 equiv.) was added to the stirred solution and it was further stirred for 30 minutes. 3-bromo-1-propyne (458mg, 3.92mmol, 1.8 equiv.) was added to the reaction mixture and it was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the remaining residue was taken up in methanol and purified by flash chromatography on a silica gel column using dichloromethane-methanol (20: 1) as eluent to give 505mg of 1, 2-diamino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (propane) -2-yn-1-yl) -7, 9-dihydro-1H-purine-6, 8-dione (16) as a white solid in 69% yield. MS (ESI) M/z 337.1(M + H)+.
Step 6:2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 26
1, 2-diamino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-1H-purine-6, 8-dione (16) (400mg, 1.19mmol) was added to a flask containing 10mL of DMF. Concentrated hydrochloric acid (0.44mL) was added at 0 ℃. An aqueous solution of sodium nitrite (98mg, 0.98mmol, 1.2 equiv.) in 2mL of water was added with stirring. Stirring was carried out at 0 ℃ for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using dichloromethane-methanol (10: 1) as eluent to give 240mg of 2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-1H-purine-6, 8-dione, compound 26, as a white solid in 67% yield;1H NMR(400MHz,DMSO-d6):δ10.98(s,1H),6.55(s,2H),5.51(d,J＝3.6Hz,1H),5.39(d,J＝4.4Hz,1H),4.81–4.77(m,1H),4.68(t,J＝5.6Hz,1H),4.56(d,J＝2Hz,2H),4.16–4.12(m,1H),3.48–3.41(m,2H),3.22(s,1H),2.38–2.31(m,1H),1.85–1.79(m,1H).MS(ESI)m/z 322.1(M+H)+,344.1[M+Na]+.
example 27:2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-1H-purine-6, 8-dione, compound 27
Synthesis of 2-amino-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 5 Using general procedure 2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydro-guanosine [847649-50-7] was prepared starting from 3 '-deoxy- (3' S) -fluoro-guanosine [123402-21-1] and its corresponding 3 '-deoxy- (3' S) -fluoro-8-bromoguanosine [847649-50-7], as shown in the following synthetic scheme Furan-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-1H-purine-6, 8-dione, compound 27.
Step 1:2-amino-8-bromo-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -1, 9-dihydro-6H-purin-6-one (17)
In a fume hood, aqueous bromine (5.4mL, 2 equiv.) was slowly added to a stirred solution of 3 '-deoxy- (3' S) -fluoro-guanosine [123402-21-1] (15g, 52.6mmol) in 300mL at room temperature. The reaction mixture was stirred in a closed round bottom flask at room temperature overnight or until monitoring by TLC was complete. An aqueous solution of sodium thiosulfate was added to destroy excess bromine. The reaction mixture was filtered, and the filtrate was washed with water and acetone. The solid was dried under vacuum to give 13g of 2-amino-8-bromo-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -1, 9-dihydro-6H-purin-6-one (17) as an off-white solid in 68% yield.
Step 2:2-amino-8- (benzyloxy) -9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -1, 9-dihydro-6H-purin-6-one (18)
In a round bottom flask, a small piece of sodium (1.2g) was added to 28mL of benzyl alcohol. The mixture was stirred at room temperature for 0.5h, then heated to 65 ℃ as a solution. A solution of 2-amino-8-bromo-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -1, 9-dihydro-6H-purin-6-one (17) (7g, 19.2mmol) in 28mL DMSO was added to the stirred solution obtained above. The reaction mixture was stirred for 5h until completion by TLC monitoring. Glacial acetic acid was added to the stirred reaction mixture to adjust the pH to 7. The mixture was poured into 1L of diethyl ether with vigorous stirring. The upper ether layer was decanted and the remaining material was added to a large amount of acetone (800mL) with stirring. The solid was filtered and the crude product was washed with water. The crude product was heated in a mixture of ethanol-water (1: 1). The mixture was cooled to room temperature. The precipitate was filtered and dried under vacuum to give 4g of 2-amino-8- (benzyloxy) -9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -1, 9-dihydro-6H-purin-6-one (18) as an off-white solid in 53% yield.
And step 3:1, 2-diamino-8- (benzyloxy) -9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -1, 9-dihydro-6H-purin-6-one (19)
To a stirred solution of 2-amino-8- (benzyloxy) -9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -1, 9-dihydro-6H-purin-6-one (18) (2g, 5.1mmol) in 40mL anhydrous DMF at 0 deg.C was slowly added NaH (0.24g, 6.1 mmol). The mixture was stirred for 30 min and O- (diphenylphosphinyl) hydroxylamine (1.9g, 8.2mmol) was added. The reaction mixture was stirred at room temperature until consumption of starting material as indicated by TLC monitoring. The precipitate was filtered and dried under reduced pressure. The residue was purified by flash chromatography on silica gel column using dichloromethane-methanol (10: 1) as eluent to give 1g of 1, 2-diamino-8- (benzyloxy) -9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -1, 9-dihydro-6H-purin-6-one (19) as a white solid in 50% yield.
And 4, step 4:1, 2-diamino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione (20)
1, 2-diamino-8- (benzyloxy) -9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -1, 9-dihydro-6H-purin-6-one (19) (1g, 2.5mmol) was dissolved in 1000mL of ethanol and 1000mL of water by heating to 90 ℃ and 10% Pd/C (0.2g) was added. The reaction mixture was hydrogenated under 1atm hydrogen atmosphere overnight. The catalyst was filtered off and washed with hot water. The filtrate was concentrated under reduced pressure and the remaining crude solid was recrystallized from water to give 0.65g of 1, 2-diamino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione (20) as a white solid in 84% yield.
And 5:1, 2-diamino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-1H-purine-6, 8-dione (21)
1, 2-diamino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione (20) (650mg, 2mmol, 1.0 equiv.) was dissolved in 20mL anhydrous DMF. Adding K2CO3(414mg, 3mmol, 1.5 equiv.) and stirred for a further 30 minutes. 3-bromopropyne (476mg, 4mmol, 2 equiv.) was added to the reaction mixture and it was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was taken up in methanol and purified by flash chromatography on a silica gel column using dichloromethane-methanol (15: 1) as eluent to give 580mg of 1, 2-diamino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-1H-purine-6, 8-dione (21) as a white solid in 79% yield.
Step 6:2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-1H-purine-6, 8-dione, compound 27
1, 2-diamino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-1H-purine-6, 8-dione (21) (580mg, 1.63mmol) was added to a flask containing 10mL of DMF. Concentrated hydrochloric acid (0.6mL) was added at 0 ℃. An aqueous solution of sodium nitrite (135mg, 1.96mmol, 1.2 equiv.) in 5mL of water was added with stirring. Stirring was continued at 0 ℃ for 30 minutes and then the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using dichloromethane-methanol (10: 1) as eluent to give 465mg of 2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-1H-purine-6, 8-dione, compound 27 as a white solid in 83% yield; HPLC purity 96.5%; 1H NMR(DMSO-d6,400MHz)δ11.07(s,1H),6.81(s,2H),5.81(d,1H,J＝4Hz),5.63(d,1H,J＝8Hz),5.19–5.11(m,1H),5.10-4.97(m,2H),4.60(s,2H),4.14–4.08(m,1H),3.59–3.52(m,2H),3.25(s,1H).ESI-MS m/z 340.1[M+H]+,362.1[M+Na]+.
Example 28:2-amino-9- ((2R,3S,4R,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-1H-purine-6, 8-dione, compound 28
Synthesis of 2-amino-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 5 Using general procedure 2-amino-9- ((2R,3S,4R,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7-amino-9- ((2R,3S,4R,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7-is prepared starting from 3 '-deoxy- (3' R) -fluoro-guanosine [125291-15-8], as shown in the following synthetic scheme, 9-dihydro-1H-purine-6, 8-dione, Compound 28.
Step 1:2-amino-8-bromo-9- ((2R,3S,4R,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -1, 9-dihydro-6H-purin-6-one (22)
In a fume hood, aqueous bromine (2.4mL, 2 equiv.) was slowly added to a stirred solution of 3 '-deoxy- (3' R) -fluoro-guanosine [125291-15-8] (6.7g, 23mmol) in 100mL of water at room temperature. The reaction mixture was sealed in a round bottom flask and stirred at room temperature overnight or until completion as indicated by TLC. Aqueous sodium thiosulfate solution was added to destroy excess bromine, the reaction mixture was filtered and the filtrate was washed with water and acetone. The solid was dried under vacuum to give 6.5g of 2-amino-8-bromo-9- ((2R,3S,4R,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -1, 9-dihydro-6H-purin-6-one (22) as an off-white solid in 76% yield.
Step 2:2-amino-8- (benzyloxy) -9- ((2R,3S,4R,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -1, 9-dihydro-6H-purin-6-one (23)
In a round bottom flask, a small piece of sodium (1.2g, 3 equivalents) was added to 25mL of benzyl alcohol. The mixture was stirred at room temperature for 0.5h, then heated to 65 ℃ until the sodium disappeared. A solution of 2-amino-8-bromo-9- ((2R,3S,4R,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -1, 9-dihydro-6H-purin-6-one (22) (6.5g, 17.8mmol) in 30mL DMSO was added to the stirred sodium alkoxide solution obtained above. It was stirred at 65 ℃ for 10h and determined by TLC until (22) was consumed. Glacial acetic acid was added to the stirred reaction mixture to adjust the pH to 7. The mixture was poured into 1.5L of diethyl ether with vigorous stirring. The solid was filtered and the crude product was washed with water. The crude product was heated in a mixture of ethanol-water (1: 1) and then cooled to room temperature. The precipitate was filtered and dried under vacuum to give 3.8g of 2-amino-8- (benzyloxy) -9- ((2R,3S,4R,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -1, 9-dihydro-6H-purin-6-one (23) as an off-white solid in 54% yield.
And step 3:1, 2-diamino-8- (benzyloxy) -9- ((2R,3S,4R,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -1, 9-dihydro-6H-purin-6-one (24)
To a stirred solution of 2-amino-8- (benzyloxy) -9- ((2R,3S,4R,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -1, 9-dihydro-6H-purin-6-one (23) (3.8g, 9.7mmol) in 80mL anhydrous DMF at 0 deg.C was slowly added NaH (0.46g, 11.6 mmol). The reaction mixture was stirred for 30 min and O- (diphenylphosphinyl) hydroxylamine (3.3g, 14.5mmol) was added and stirring was continued at room temperature until completion by TLC. The precipitate was filtered and dried under reduced pressure. The residue was purified by flash chromatography on silica gel column using dichloromethane-methanol (10: 1) as eluent to give 2g of 1, 2-diamino-8- (benzyloxy) -9- ((2R,3S,4R,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -1, 9-dihydro-6H-purin-6-one (24) as a white solid in 51% yield.
And 4, step 4:1, 2-diamino-9- ((2R,3S,4R,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione (25)
1, 2-diamino-8- (benzyloxy) -9- ((2R,3S,4R,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -1, 9-dihydro-6H-purin-6-one (24) (2g, 5mmol) was dissolved in 1200mL of ethanol and 1200mL of water by heating to 90 ℃. 0.4g of Pd/C catalyst (10%) was added. The reaction mixture was kept under 1 atmosphere of hydrogen overnight. The catalyst was filtered through celite and washed with hot water. The filtrate was concentrated under reduced pressure to give a solid which was recrystallized from water to give 1.3g of 1, 2-diamino-9- ((2R,3S,4R,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione (25) as a white solid at 84%.
And 5:1, 2-diamino-9- ((2R,3S,4R,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-1H-purine-6, 8-dione (26)
1, 2-diamino-9- ((2R,3S,4R,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione (25) (1.3g, 4.1mmol, 1.0 equiv.) was dissolved in 40mL anhydrous DMF. Will K2CO3(854mg, 6.1mmol, 1.5 equiv.) was added to the stirred solution and it was stirred for a further 30 minutes. 3-Bromopropyne (976mg, 8.2mmol, 2 equiv.) was added to the reaction mixture and it was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the remaining residue was taken up in methanol and purified by flash chromatography on a silica gel column using dichloromethane-methanol (15: 1) as eluent to give 1.2g of 1, 2-diamino-9- ((2R,3S,4R,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-1H-purine-6, 8-dione (26) as a white solid in 82% yield.
Step 6:2-amino-9- ((2R,3S,4R,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-1H-purine-6, 8-dione, compound 28
1, 2-diamino-9- ((2R,3S,4R,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-1H-purine-6, 8-dione (26) (1.2g, 3.39mmol) was added to a flask containing 20mL of DMF. Concentrated hydrochloric acid (1.2mL) was added at 0 ℃. An aqueous solution of sodium nitrite (280mg, 4.07mmol, 1.2 equiv.) in 10mL of water was added with stirring. After stirring at 0 ℃ for 30 minutes, the reaction mixture was concentrated under reduced pressure. Will be provided with The residue was purified by flash chromatography on silica gel column using dichloromethane-methanol (10: 1) as eluent to give 960mg of 2-amino-9- ((2R,3S,4R,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-1H-purine-6, 8-dione, compound 28, as a white solid in 83% yield; HPLC purity 96.3%;1H NMR(DMSO-d6,400MHz)δ10.98(s,1H),6.60(s,2H),5.95(s,1H),5.35–5.37(m,2H),4.74–5.08(m,2H),4.60(s,2H),4.00–4.08(m,1H),3.56–3.63(m,2H),3.24(t,1H,J＝4Hz).ESI-MS m/z 340.1[M+H]+,362.1[M+Na]+.
example 29:((2S,4R,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (prop-2-yn-1-yl) -7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate, Compound 29
Compound 29 was prepared according to the following multi-step procedure.
Step 1:((2S,4R,5R) -4-acetoxy-5- (2-amino-8- (benzyloxy) -6-oxo-1, 6-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate (27)
A solution of 2-amino-8- (benzyloxy) -9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -1, 9-dihydro-6H-purin-6-one (13) (22g, 58.9mmol) in anhydrous MeCN (300mL) containing triethylamine (40.8mL) was treated with acetic anhydride (12.3mL, 129.7mmol, 2.2 equivalents). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane (800mL) and poured into 800mL water. The layers were separated and the aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous Na 2SO4Dried and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using methylene chloride-methanol (50: 1) as eluent,18.1g of ((2S,4R,5R) -4-acetoxy-5- (2-amino-8- (benzyloxy) -6-oxo-1, 6-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate (28) was obtained as a yellow solid in 67% yield; rf0.5 (dichloromethane-methanol 10: 1).
Step 2:((2S,4R,5R) -4-acetoxy-5- (2-amino-6, 8-dioxo-1, 6,7, 8-tetrahydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate (28)
In an oven dried flask ((2S,4R,5R) -4-acetoxy-5- (2-amino-8- (benzyloxy) -6-oxo-1, 6-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate (27) (18.1g, 39.6mmol) was dissolved in 200mL of dry MeCN. Phosphorus oxychloride (3.6mL, 39.6mmol, 1.0 equiv) was added and stirred at room temperature for 1 h. The reaction mixture was diluted with dichloromethane (800mL) and poured into saturated aqueous sodium bicarbonate. The aqueous layer was extracted with dichloromethane. The combined organic layers were passed over anhydrous Na2SO4The residue obtained is purified by column chromatography using dichloromethane-methanol (30: 1) as eluent to yield 13g of ((2S,4R,5R) -4-acetoxy-5- (2-amino-6, 8-dioxo-1, 6,7, 8-tetrahydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate (28) as a white solid in 89% yield, R f0.40 (dichloromethane-methanol 10: 1).
And step 3:((2S,4R,5R) -4-acetoxy-5- (2-amino-6-chloro-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate (29)
In an oven-dried flask ((2S,4R,5R) -4-acetoxy-5- (2-amino-6, 8-dioxo-1, 6,7, 8-tetrahydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate (28) (13g, 35.4mmol), benzyltriethylammonium chloride (16.1g, 70.8mmol) and N, N-dimethylaniline (4.9mL, 38.9mmol) were dissolved in 400mL of dried MeCN. Adding POCl3(16.2mL, 177.0 mmol). The reaction mixture was stirred at 105 ℃ for 8 h. The reaction mixture was concentrated in vacuo. The resulting residue was dissolved in dichloromethane, then water and 5% NaHCO were used3And (4) washing with an aqueous solution. The organic phase is passed through anhydrous Na2SO4Dried and concentrated under reduced pressure. By column chromatographyThe crude product was purified using dichloromethane-methanol (120: 1) as eluent to give 6.1g of ((2S,4R,5R) -4-acetoxy-5- (2-amino-6-chloro-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate (29) as a white solid in 45% yield. Rf0.60 (dichloromethane-methanol 40: 1)
And 4, step 4:((2S,4R,5R) -4-acetoxy-5- (2-amino-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate (30)
To ((2S,4R,5R) -4-acetoxy-5- (2-amino-6-chloro-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate (29) (6.1g, 15.8mmol), dissolved in a mixture of THF (150mL) and triethylamine (2.2mL, 15.8mmol), was added 10% Pd/C (610 mg). The mixture was stirred at room temperature under an atmosphere of hydrogen (50psi) for 5 h. The catalyst was then filtered through a pad of celite and the solvent was evaporated to give the crude product, which was purified by column chromatography using dichloromethane-methanol (60: 1) as eluent. ((2S,4R,5R) -4-acetoxy-5- (2-amino-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate (30) (3.2g) was isolated as a white foam in 57% yield. Rf0.4 (dichloromethane-methanol 20: 1).
And 5:((2S,4R,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (prop-2-yn-1-yl) -7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate, Compound 29
To ((2S,4R,5R) -4-acetoxy-5- (2-amino-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate (30) (2.2g, 6.3mmol) dissolved in 50mL of anhydrous DMF was added K2CO3(1.3g, 9.4mmol, 1.5 equiv.). The reaction mixture was stirred for 30 min and 3-bromopropyne (0.98mL, 12.6mmol, 2 equiv.) was added. The stirred reaction mixture was kept at 45 ℃ for 3 h. The mixture was then concentrated under reduced pressure, and the resulting residue was purified by column chromatography using dichloromethane-methanol (160: 1) as eluent to give 1.8g of ((2S,4R,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (prop-2-yn-1-yl) -7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methylethyl ether The acid ester, compound 29, was a white foam in 75% yield. HPLC purity (98.2%). Rf0.50 (dichloromethane-methanol 40: 1).1H NMR(CDCl3,400MHz)δ8.00(s,1H),5.98-5.99(d,1H,J＝1.6Hz),5.80-5.82(d,1H,J＝6.4Hz),4.91(s,2H),4.59(d,2H,J＝2.4Hz),4.44-4.51(m,2H),4.16-4.21(m,1H),2.39(t,1H,J＝2.4Hz),2.12(s,3H),2.07(s,3H).ESI-MS m/z 390.1[M+H]+,412.1[M+Na]+.
Example 30:2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-
Yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-8H-purin-8-one, Compound 30
Compound 30 was prepared from compound 29 using the outlined method for preparing compound 4 from compound 3.
((2S,4R,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (prop-2-yn-1-yl) -7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate, compound 29(1.37g, 3.52mmol) was treated with saturated ammonia in methanol. The flask was sealed and the reaction mixture was heated at 40 ℃ and stirred overnight. The volatiles were evaporated under reduced pressure and the residue was purified by column chromatography using dichloromethane-methanol (30: 1) as eluent to give 800mg of 2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-8H-purin-8-one as a white solid, compound 30, 75% yield, HPLC purity 98.9%. Rf0.30 (dichloromethane-methanol 10: 1).1H NMR(DMSO,400MHz)δ8.01(s,1H),6.37(s,1H),5.61(d,1H,J＝2.8Hz),5.43-5.44(d,1H,J＝4.4Hz),4.84-4.88(m,1H),4.68-4.71(t,1H,J＝2Hz),4.62-4.63(d,2H,J＝2.4Hz),4.17-4.20(m,1H,),3.42-3.49(m,2H,),3.39-3.40(t,1H,J＝2Hz),2.37-2.44(m,1H),1.83-1.88(m,1H).ESI-MS m/z 306.1[M+H]+,328.1[M+Na]+.
Example 31:((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (propane) -2-yn-1-yl) -7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) methyl acetate, Compound 31
Compound 31 was prepared according to the following multi-step procedure.
Step 1:((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-8- (benzyloxy) -6-oxo-1, 6-dihydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) methyl acetate (31)
A solution of 2-amino-8- (benzyloxy) -9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -1, 9-dihydro-6H-purin-6-one (18) (11.2g, 28.6mmol) in anhydrous MeCN (150mL) containing triethylamine (15.9mL, 4.0 equiv.) was treated with acetic anhydride (6.8mL, 71.6mmol, 2.5 equiv.). The reaction mixture was stirred at room temperature overnight, diluted with ethyl acetate (500mL) and poured into water. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4Dried and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using dichloromethane-methanol (40: 1) as eluent to give 9.2g of ((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-8- (benzyloxy) -6-oxo-1, 6-dihydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) methyl acetate (31) as a white foam, 67.6% yield; r f0.2 (dichloromethane-methanol 20: 1).
Step 2:((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-6, 8-dioxo-1, 6,7, 8-tetrahydro-9H-purin-9-yl) -3-fluorotetrahydro-furan-2-yl) methyl acetate (32)
To ((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-8- (benzyloxy) -6-oxo-1, 6-dihydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) methyl acetate (31) (8.5g, 17.9 mmo) dissolved in 100mL of anhydrous MeCN was added under stirringl) phosphorus oxychloride (1.7mL, 17.9mmol, 1.0 equiv) was added and continued at room temperature for 1 h. MeOH (10mL) and excess solid NaHCO3Added to the reaction mixture. The mixture was stirred for 20 minutes and then concentrated in vacuo. The resulting residue was purified by column chromatography using dichloromethane-methanol (30: 1) as eluent to give 5.7g of ((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-6, 8-dioxo-1, 6,7, 8-tetrahydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) methyl acetate (32) as a white foam in 82% yield; rf0.30 (dichloromethane-methanol 10: 1).
And step 3:((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-6-chloro-8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) methyl acetate (33)
In an oven dried flask ((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-6, 8-dioxo-1, 6,7, 8-tetrahydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) methyl acetate (32) (5.7g, 14.8mmol) was dissolved in 60mL of phosphorus oxychloride. The reaction mixture was stirred at 75 ℃ overnight and concentrated in vacuo. The resulting residue was purified by column chromatography using dichloromethane-methanol (100: 1) as eluent to give 2.7g of ((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-6-chloro-8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) methyl acetate (33) as a white solid in 45% yield. Rf0.60 (dichloromethane-methanol 30: 1).
And 4, step 4:((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydro-furan-2-yl) methyl acetate (34)
To ((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-6-chloro-8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) methyl acetate (33) (2.7g, 6.7mmol), dissolved in a mixture of anhydrous methanol (30mL) and tetrahydrofuran (10mL), was added 10% Pd/C (270 mg). The mixture was stirred at room temperature under an atmosphere of hydrogen (50psi) for 5 h. The catalyst was filtered off through celite, the solvent was evaporated, and the crude product was purified by column chromatography using dichloromethane-methanol (40: 1) as eluent to give 1g of ((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-8) -oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) methyl acetate (34) as a white foam in 42% yield. Rf0.2 (dichloromethane-methanol 20: 1).
And 5:((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (prop-2-yn-1-yl) -7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) methyl acetate, Compound 31
To ((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) methyl acetate (34) (1g, 2.7mmol), dissolved in 20mL of anhydrous DMF was added K with stirring2CO3(0.56g, 4mmol, 1.5 equiv.). 3-Bromopropyne (0.43mL, 5.4mmol, 2 equiv.) was added to the reaction mixture and stirring was continued at 45 ℃ for 5 h. The mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography using dichloromethane-methanol (100: 1) as eluent to give 750mg of ((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (prop-2-yn-1-yl) -7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) methyl acetate, compound 31, as a white foam, 70% yield, HPLC purity 98.4%. Rf0.60 (dichloromethane-methanol 30: 1). 1H NMR(CDCl3,400MHz)δ8.03(s,1H),6.10-6.15(m,2H),5.53-5.55(m,0.5H),5.40-5.42(m,0.5H),4.96(s,2H),4.60(d,2H,J＝4Hz),4.44-4.57(m,2H),4.29-4.33(m,1H),2.39(t,1H,J＝4Hz),2.15(s,3H),2.10(s,3H).ESI-MS m/z408.1[M+H]+,430.1[M+Na]+.
Example 32:2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-8H-purin-8-one, compound 32
Compound 32 was prepared from compound 31 using the outlined method for preparing compound 4 from compound 3.
To ((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (prop-2-yn-1-yl)) -7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) methyl acetate, compound 31(500mg, 1.23mmol) was added to a saturated methanolic ammonia solution. The reaction mixture was heated to 40 ℃ and stirred overnight. The volatiles were evaporated under reduced pressure and the solid residue was purified by column chromatography using dichloromethane-methanol (40: 1) as eluent to give 300mg of 2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-8H-purin-8-one, compound 32 as a white solid in 76% yield with HPLC purity 98.6%. Rf0.30 (dichloromethane-methanol 10: 1).1H NMR(DMSO,400MHz)δ8.06(s,1H),6.44(s,2H,NH2),5.85(d,1H,J＝4Hz,1’-H),5.71(d,1H,J＝4Hz,2’-OH),5.25-5.35(m,1H,2’-H),5.14-5.15(m,0.5H,4’-H),5.00-5.10(m,0.5H,half 4’-H),4.96(t,1H,J＝4Hz,5’-OH),4.65(d,2H,J＝4Hz,CH2),4.09-4.19(m,1H,3’-H),3.51-3.62(m,2H,5’-H),3.41(t,1H,J＝4Hz).ESI-MS m/z 324.1[M+H]+,346.1[M+Na]+.
Alternative synthesis methods for compounds 5, 26 and 27.
Example 5A:2-amino-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-1H-purine-6, 8-dione, compound 5
Compound 5 was also prepared according to the following alternative multistep method.
Step-1:6-chloro-N4- (4-methoxybenzyl) pyrimidine-2, 4, 5-triamine (35)
4-Methoxybenzylamine (114.8g, 83.728mol) was added to 4, 6-dichloropyrimidine-2, 5-diamine [55583-59-0 ] at 0 deg.C](100g, 55.81mol) and TEA (169mL, 167.45mol) in ethanol (1.0L) in a stirred solution mixtureThe resulting reaction mixture was stirred at reflux temperature for 18 h. The solvent was evaporated under reduced pressure, the thick material was poured into ice-cold water and stirred for 30 minutes. The precipitated solid was collected by filtration, washed with water and dried under vacuum to give 6-chloro-N as a brown solid4- (4-methoxybenzyl) pyrimidine-2, 4, 5-triamine (35) (100g, 64%). ES +, M/z 280.1[ M + H ]]+；C12H14ClN5O；1H NMR(500MHz,DMSO-d6):δ8.25(d,J＝8.5Hz,2H),6.92(t,J＝6.0Hz,1H),7.87(d,J＝8.5Hz,2H),5.63(s,2H),4.47(d,J＝5.5Hz,2H),3.91(s,2H),3.72(s,3H).
Step-2:2-amino-6-chloro-9- (4-methoxybenzyl) -7, 9-dihydro-8H-purin-8-one (36)
Reacting 6-chloro-N4A mixture of (4-methoxybenzyl) pyrimidine-2, 4, 5-triamine (35) (50g, 17.92mol) and 1,1' -carbonyldiimidazole (100g, 61.64mol) in acetonitrile (500mL) was stirred at reflux temperature for 18 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. To the resulting residue was added ice-cold water, and stirred at room temperature for 30 minutes. The precipitated solid was filtered, washed with water and dried to give 2-amino-6-chloro-9- (4-methoxybenzyl) -7, 9-dihydro-8H-purin-8-one (36) (50g, 91%) as a brown solid; c 13H12ClN5O2；1H NMR(500MHz,DMSO-d6):δ11.31(s,1H),7.23(d,J＝9.0Hz,2H),6.88(d,J＝5.0Hz,2H),6.62(s,2H),4.80(s,2H),3.71(s,3H).
Step-3:2-amino-6- (benzyloxy) -9- (4-methoxybenzyl) -7, 9-dihydro-8H-purin-8-one (37)
Sodium hydroxide (9.967g, 262.29mmol) was added to a suspension of 2-amino-6-chloro-9- (4-methoxybenzyl) -7, 9-dihydro-8H-purin-8-one (36) (40g, 131.14mmol) in benzyl alcohol (45.0 mL). The resulting reaction mixture was stirred at 120 ℃ for 18 h. The reaction mixture was quenched with ice water (200mL), diethyl ether (150mL) was added, and stirred for 15 min. The resulting precipitated solid was filtered, washed with water and dried to give 2-amino-6- (benzyloxy) -9- (4-methoxybenzyl) -7, 9-dihydro-8H-purin-8-one as a brown solid (30g, 60%). ES +, M/z 378.1[ M + H ]]+；C20H19N5O3；1H NMR(400MHz,DMSO-d6):δ10.81(s,1H),7.48(d,J＝7.2Hz,2H),7.40–7.36(t,J＝7.6Hz,2H),7.34–7.31(t,J＝5.2Hz,1H),7.21(d,J＝8.4Hz,2H),6.87(d,J＝8.4Hz,2H),6.27(s,2H),5.41(s,2H),4.78(s,2H),3.71(s,3H).
Step-4:2-amino-6- (benzyloxy) -9- (4-methoxybenzyl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-8H-purin-8-one (38)
Bromopropyne (7.1ml, 63.66mmol) was added to 2-amino-6- (benzyloxy) -9- (4-methoxybenzyl) -7, 9-dihydro-8H-purin-8-one (37) (20g, 53.05mmol), K at 0 deg.C2CO3(10.98g, 79.57mmol) in DMF (100mL) and stirred at room temperature for 18 h. The reaction mixture was quenched with ice water (200mL), diethyl ether (150mL) was added, and stirred for 15 min. The resulting precipitated solid was filtered, washed with water and dried to give 2-amino-6- (benzyloxy) -9- (4-methoxybenzyl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-8H-purin-8-one (20g, 91%) as a brown solid. ES +, M/z 416.1[ M + H ] ]+；C23H21N5O3；1H NMR(400MHz,DMSO-d6):δ7.52(d,J＝7.2Hz,2H),7.38(t,J＝7.6Hz,2H),7.32(t,J＝5.2Hz,1H),7.22(d,J＝8.4Hz,2H),6.81(d,J＝8.4Hz,2H),6.27(s,2H),5.44(s,2H),4.82(s,2H),4.56(s,2H),3.71(s,3H),3.32-3.26(m,1H).
Step-5:2-amino-7- (prop-2-yn-1-yl) -7, 9-dihydro-1H-purine-6, 8-dione (39)
Trifluoromethanesulfonic acid (27g, 180.72mmol) was added to a suspension of 2-amino-6- (benzyloxy) -9- (4-methoxybenzyl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-8H-purin-8-one (25g, 60.24mmol) in trifluoroacetic acid (21mL, 180.72mmol) at 0 ℃ under an argon atmosphere and the resulting reaction mixture was stirred at room temperature for 18H under an argon atmosphere. The reaction mixture was quenched with ice-cold water and with saturated NaHCO under vigorous stirring3The solution was basified and filtered. The residual solid was dissolved in ethyl acetate, stirred for 30 min, filtered and dried to give 2-amino-7- (prop-2-yn-1-yl) -7, 9-dihydro-1H-purine-6, 8-dione (12g, 36%) as brownA colored solid. ES +, M/z 206.1[ M + H ]]+；C8H7N5O2；1H NMR(400MHz,DMSO-d6):δ11.32(s,1H),6.74(s,2H),4.53(s,2H),3.14(s,1H).
Step-6:n- (6, 8-dioxo-7- (prop-2-yn-1-yl) -6,7,8, 9-tetrahydro-1H-purin-2-yl) acetamide (40)
Acetic anhydride (4.85mL, 47.56mmol) was added to a solution of 2-amino-7- (prop-2-yn-1-yl) -7, 9-dihydro-1H-purine-6, 8-dione (6.5g, 31.70mmol) in DMF (65mL) at room temperature under an argon atmosphere and the resulting reaction mixture was stirred at room temperature for 18H under an argon atmosphere. The reaction mixture was cooled to 0 ℃ (solid formed under stirring) and stirred for 30 minutes. The product was filtered, washed with ethanol and dried in vacuo to give N- (6, 8-dioxo-7- (prop-2-yn-1-yl) -6,7,8, 9-tetrahydro-1H-purin-2-yl) acetamide (4g, 51.2%) as a brown solid. ES +, M/z 248.1[ M + H ] ]+；C10H9N5O3；1H NMR(400MHz,DMSO-d6):δ11.83(s,2H),4.61(s,2H),3.23(s,1H),2.16(s,3H).
Step-6:(2R,3S,4R,5R) -5- (2-acetamido-6, 8-dioxo-7- (prop-2-yn-1-yl) -1,6,7, 8-tetrahydro-9H-purin-9-yl) -4-acetoxy-2- ((benzoyloxy) methyl) tetrahydrofuran-3-benzoic acid ester (41)
N- (6, 8-dioxo-7- (prop-2-yn-1-yl) -6,7,8, 9-tetrahydro-1H-purin-2-yl) acetamide (400mg, 1.61mmol), (3R,4S,5R) -4- (benzoyloxy) -5- ((benzoyloxy) methyl) tetrahydrofuran-2, 3-diacetic acid diester (716mg, 1.61mmol) [85026-60-4](see m.popswavin et al, bioorg.med.chem.lett., 2012, 22, 6700 and g.gosselin et al, j.het.chem., 1982, 19, 597), BSA (983mg, 4.85mmol) and MeCN (40mL) were mixed vigorously for 45 minutes until a homogeneous solution was obtained. TMSOTf (540mg, 2.42mmol) was then added to the reaction and placed in a preheated oil bath at 75 ℃. After 4 hours, the reaction was cooled to room temperature and the solvent was removed by rotary evaporation. The resulting solid was dissolved in ethyl acetate (100mL) and saturated NaHCO was used3Aqueous solution (2X 30 mL). With Na2SO4The organic phase was dried and concentrated. By column chromatography (SiO)2Ethyl acetate-petroleum ether 0-40%) to yield 190mg (18.64%) of (2R,3S,4R,5R) -5- (2-acetamido-6, 8-dioxo-7- (prop-2-yn-1-yl) -1,6,7, 8-tetrahydro-9H-purin-9-yl) -4-acetoxy-2- ((benzoyloxy) methyl) tetrahydrofuran-3-benzoic acid ester as a pale yellow solid. ES +, M/z 630.1[ M + H ] ]+；C31H27N5O10；1H NMR(400MHz,DMSO-d6):δ11.89(s,1H),8.02(d,J＝6.8Hz,2H),7.86(d,J＝7.2Hz,2H),7.68–7.61(m,2H),7.54–7.45(m,5H),6.48–6.46(m,1H),5.83–5.79(m,2H),4.76(d,J＝6.0Hz,1H),4.68(s,2H),4.64(d,J＝4.8Hz,1H),4.57–4.53(m,1H),3.29(s,1H),2.15(s,3H),2.07(s,3H).
And 7:2-amino-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-1H-purine-6, 8-dione, compound 5
(2R,3S,4R,5R) -5- (2-acetamido-6, 8-dioxo-7- (prop-2-yn-1-yl) -1,6,7, 8-tetrahydro-9H-purin-9-yl) -4-acetoxy-2- ((benzoyloxy) methyl) tetrahydrofuran-3-benzoate (500mg, 0.79mmol) was dissolved in methanol (10 mL). Adding K2CO3(164mg, 1.19mmol) and the reaction stirred at room temperature for 16 h. Acetic acid (96mg, 1.58mmol) was added and the reaction was concentrated by rotary evaporation. The crude product was purified by GRACE reverse phase (MeCN-0.01% HCO)2H of H2O solution) to yield 120mg (45%) of 2-amino-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-1H-purine-6, 8-dione, compound 5 as an off-white solid. ES +, M/z 338.0[ M + H ]]+；C13H15N5O6；1H NMR(500MHz,DMSO-d6):δ11.56(s,1H),6.94(s,2H),5.73(s,2H),5.47(d,J＝2.8Hz,1H),4.62(d,J＝2Hz,2H),4.50(s,2H),3.91–3.88(m,2H),3.68–3.65(m,1H),3.59–3.54(m,1H),3.25–3.24(m,1H).
Example 26A:2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-1H-purine-6, 8-bisKetones, Compound 26
Compound 26 was also synthesized according to the following alternative multistep procedure using the same general procedure as described in example 5A.
Step-1:((2S,4R,5R) -5- (2-acetamido-6, 8-dioxo-7- (prop-2-yn-1-yl) -1,6,7, 8-tetrahydro-9H-purin-9-yl) -4-acetoxytetrahydrofuran-2-yl) methylbenzoate (42)
N- (6, 8-dioxo-7- (prop-2-yn-1-yl) -6,7,8, 9-tetrahydro-1H-purin-2-yl) acetamide (1g, 4.04mmol), (2S,3R,5S) -5- ((benzoyloxy) methyl) tetrahydrofuran-2, 3-diacetic acid diester [ 4613-71-2-yl ] acetate](see P.J. Bolon et al Tetrahedron, 1994, 50, 7747 p.) (1.30g, 4.04mmol) and BSA (2.45g, 12.14mmol) in dichloromethane (100mL) were stirred vigorously at 70 ℃ for 45 minutes until a homogeneous solution formed. The reaction mixture was cooled to room temperature and concentrated under vacuum. The crude concentrate was dissolved in MeCN (50mL), followed by the addition of TMSOTf (1.35mL, 6.07mmol) and placed in a pre-heated oil bath at 90 ℃. After 16 h, the reaction was cooled to room temperature and the solvent was removed by rotary evaporation. The resulting solid was dissolved in EtOAc (200mL) and washed with saturated NaHCO3Aqueous solution (2X 50 mL). With Na2SO4The organic phase was dried and concentrated. By column chromatography (SiO)2Ethyl acetate-petroleum ether 0-40%) to yield 700mg (33.98%) of methyl benzoate as a pale yellow solid ((2S,4R,5R) -5- (2-acetamido-6, 8-dioxo-7- (prop-2-yn-1-yl) -1,6,7, 8-tetrahydro-9H-purin-9-yl) -4-acetoxytetrahydrofuran-2-yl). ES +, M/z 510.1[ M + H ] ]+；C24H23N5O8.
Step 2:2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7-, (Prop-2-yn-1-yl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 26
To ((2S,4R,5R) -5- (2-acetamido-6, 8-dioxo-7- (prop-2-yn-1-yl) -1,6,7, 8-tetrahydro-9H-purin-9-yl) -4-acetoxytetrahydrofuran-2-yl) methylbenzoate (1g, 1.96mmol) dissolved in methanol (20mL) was added K2CO3(407mg, 2.9 mmol). The reaction mixture was stirred at room temperature for 16 hours. Acetic acid (236mg, 3.9mmol) was added and the mixture was concentrated by rotary evaporation. The crude product was purified by GRACE reverse phase (MeCN-0.01% HCO)2H of H2O solution) to yield 200mg (32%) of 2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-1H-purine-6, 8-dione as an off-white solid. ES +, M/z322.0[ M + H ]]+；C13H15N5O5.1H NMR(400MHz,DMSO-d6):δ11.03(s,1H),6.59(s,2H),5.51(d,J＝2.8Hz,1H),5.40(d,J＝4.0Hz,1H),4.80(d,J＝2.8Hz,1H)4.70(s,1H),4.58(d,J＝1.6Hz,2H),4.14(m,1H),3.45(m,2H),3.22(s,1H),2.34(m,1H),1.82(m,1H).
Example 27A:2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-1H-purine-6, 8-dione, compound 27
Compound 27 was also synthesized according to the following alternative multistep procedure using the same general procedure as described in example 5A.
Step-1:((2R,3R,4S,5R) -5- (2-acetamido-6, 8-dioxo-7- (prop-2-yn-1-yl) -1,6,7, 8-tetrahydro-9H-purin-9-yl) -4-acetoxy-3-fluorotetrahydrofuran-2-yl) methylbenzoate (43)
Reacting N- (6, 8-dioxo-7- (prop-2-yne-1-)1, 2-dichloroethane (50mL) solution of Yl) -6,7,8, 9-tetrahydro-1H-purin-2-yl) acetamide (500mg, 2.042mmol), (2S,3S,4R,5R) -5- ((benzoyloxy) methyl) -4-fluorotetrahydrofuran-2, 3-diacetic acid diester (see R.F. Schinazi et al, het. Comm, 2015, page 21, 315) (1.376g, 4.04mmol) and BSA (331mg, 2.2mmol) was stirred vigorously at 70 ℃ for 45 minutes until a homogeneous solution was formed. The reaction mixture was cooled to room temperature and concentrated under vacuum. The crude concentrate was dissolved in MeCN (50mL), followed by the addition of TMSOTf (0.186mL, 0.81mmol) and placed in a pre-heated oil bath at 90 ℃. After 16 h, the reaction was cooled to room temperature and the solvent was removed by rotary evaporation. The resulting solid was dissolved in ethyl acetate (200mL) and saturated NaHCO was used3Aqueous solution (2X 50 mL). With Na2SO4The organic layer was dried and concentrated. By column chromatography (SiO)2Ethyl acetate-petroleum ether 0-40%) to yield 200mg (18.25%) of a light yellow solid ((2R,3R,4S,5R) -5- (2-acetamido-6, 8-dioxo-7- (prop-2-yn-1-yl) -1,6,7, 8-tetrahydro-9H-purin-9-yl) -4-acetoxy-3-fluorotetrahydrofuran-2-yl) methylbenzoate. ES +, M/z 528.1[ M + H ] ]+；C24H22FN5O8.1H NMR(400MHz,DMSO-d6):δ11.80(s,1H),9.32(s,1H),8.03(d,J＝7.2Hz,2H),7.64–7.60(t,J＝7.2Hz,1H),7.49–7.45(t,J＝8.0Hz,2H),6.22(d,J＝5.6Hz,1H),5.93–5.87(m,1H),5.53–5.48(m,1H),5.14–5.09(m,1H),4.82(s,2H),4.75–4.69(m,1H),4.68–4.54(m,1H),2.33(s,3H),2.29(m,1H),2.14(s,3H).
Step-2:2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-1H-purine-6, 8-dione, compound 27
To ((2R,3R,4S,5R) -5- (2-acetamido-6, 8-dioxo-7- (prop-2-yn-1-yl) -1,6,7, 8-tetrahydro-9H-purin-9-yl) -4-acetoxy-3-fluorotetrahydrofuran-2-yl) methylbenzoate (500mg, 0.948mmol) in MeOH (10mL) was added K2CO3(131mg, 0.948 mmol). The reaction mixture was stirred at room temperature for 16 hours. Acetic acid (114mg, 1.896mmol) was added and the reaction mixture was concentrated by rotary evaporation. The crude product is passed throughGRACE reverse phase purification (MeCN-0.01% HCO)2H of H2O solution) to yield 120mg (37.38%) of 2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-1H-purine-6, 8-dione, compound 27 as a pale brown solid. ES +, M/z 340.1[ M + H ]]+；C13H14FN5O5.1H NMR(400MHz,DMSO-d6):δ11.00(s,1H),6.59(s,2H),5.79(d,J＝6.4Hz,1H),5.62(d,J＝7.6Hz,1H),5.24–5.17(m,1H),5.09(d,J＝3.6Hz,1H),4.96–4.93(t,J＝6.8Hz,1H),4.60(s,2H),4.15–4.16(m,1H),3.59–3.50(m,2H),3.24(s,1H).
Alternative synthesis of compound 32.
Example 32A:2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-8H-purin-8-one, compound 32
Compound 32 was also prepared according to the following alternative multistep method.
Step-1:n- (6-chloro-9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide (44)
Acetic anhydride (13.04mL, 85.224mmol) was added to a solution of 2-amino-6-chloro-9- (4-methoxybenzyl) -7, 9-dihydro-8H-purin-8-one (36) (13.0g, 42.622mmol) in DMF (100mL) at room temperature under an argon atmosphere and the resulting reaction mixture was stirred at 140 ℃ for 18H. The reaction mixture was cooled to 0 ℃ (solid formed under stirring) and stirred for 30 minutes. The product was filtered, washed with water and dried in vacuo to give N- (6-chloro-9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide (9.0g, 51.2%) as a brown solid; ES +, M/z 348.1[ M + H ]]+,C15H14ClN5O3；1H NMR(400MHz,DMSO-d6):δ11.90(s,1H),10.55(s,1H),7.33(d,J＝8.8Hz,2H),6.87(d,J＝8.4Hz,2H),4.87(s,2H),3.71(s,3H),2.13(s,3H).
Step-2:n- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide (45)
10% Pd/C (3.5g) was added to a solution of N- (6-chloro-9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide (15.0g, 28.81mmol) in methanol (200mL) and THF (400 mL). The reaction mixture was hydrogenated with hydrogen at room temperature for 24 hours in a Parr shaker under a pressure of 80 psi. The reaction mixture was filtered through a pad of celite and the filtrate was evaporated to give a crude solid. The solid was dissolved in ether, stirred for 15 minutes, filtered and repeated. The solid was dried under vacuum to a light brown solid to give N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide (10.5g, 77.6%). 1H NMR and LC-MS showed acetylation (37%) of ES +, M/z 314.2[ M + H ]]+；C15H15N5O3(ii) a And deacetylation (43%) of ES +, M/z 272.2[ M + H ]]+；C13H13N5O2(ii) a A compound is provided. The crude mixture was used in the next step.1H NMR(400MHz,DMSO-d6):δ10.55(s,1H),8.09(s,1H),7.33(d,J＝8.8Hz,2H),6.87(d,J＝8.8Hz,2H),4.93(s,2H),3.72(s,3H),2.24(s,3H).
Step-3:n- (9- (4-methoxybenzyl) -8-oxo-7- (prop-2-yn-1-yl) -8, 9-dihydro-7H-purin-2-yl) acetamide (46)
Bromopropyne (6.0mL, 40.255mmol) was added to N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide (45) (10.5g, 33.546mmol), K at 0 deg.C2CO3(6.95g, 50.319mmol) in DMF (50mL) and stirred at room temperature for 18 h. The reaction mixture was quenched with ice water (200mL), diethyl ether (150mL) was added, and stirred for 15 min. The resulting precipitated solid was filtered, washed with water and dried to give N- (9- (4-methoxybenzyl) -8-oxo-7- (prop-2-yn-1-yl) -8, 9-dihydro-7H-purin-2-yl) acetamide as a brown solid (8.5g, 72.21%). ES +, m/z352.2[M+H]+；C18H17N5O3；1H NMR(400MHz,DMSO-d6):δ10.41(s,1H),8.32(s,1H),7.35(d,J＝8.4Hz,2H),6.88(d,J＝8.4Hz,2H),4.92(s,2H),4.73(s,2H),3.71(s,3H),3.42(s,1H),2.15(s,3H).
Step-4:2-amino-7- (prop-2-yn-1-yl) -7, 9-dihydro-8H-purin-8-one (47)
Trifluoromethanesulfonic acid (4.5mL) was added to a suspension of N- (9- (4-methoxybenzyl) -8-oxo-7- (prop-2-yn-1-yl) -8, 9-dihydro-7H-purin-2-yl) acetamide (4.5g, 12.82mmol) in trifluoroacetic acid (4.5mL) at 0 ℃ under an argon atmosphere and the resulting reaction mixture was stirred at room temperature for 18H. The reaction mixture was quenched with ice-cold water and with saturated NaHCO under vigorous stirring 3The solution was basified and filtered. The residual solid was dissolved in ethyl acetate, stirred for 30 min, filtered and dried to give 2-amino-7- (prop-2-yn-1-yl) -7, 9-dihydro-8H-purin-8-one (2.0g, 82.64%) as a brown solid. ES +, M/z 190.1[ M + H ]]+；C8H7N5O2；1H NMR(400MHz,DMSO-d6):δ11.32(s,1H),7.57(s,1H),5.60(s,2H),4.46(s,2H),3.22(s,1H).
Step-5:n- (8-oxo-7- (prop-2-yn-1-yl) -8, 9-dihydro-7H-purin-2-yl) acetamide (48)
Acetic anhydride (7mL, 68.78mmol) was added to a solution of 2-amino-7- (prop-2-yn-1-yl) -7, 9-dihydro-8H-purin-8-one (6.5g, 34.39mmol) in DMF (65mL) at room temperature under an argon atmosphere and the resulting reaction mixture was stirred at 140 ℃ for 18H. The reaction mixture was cooled to 0 ℃ and stirred for 30 minutes, whereby a solid was formed. The product was filtered, washed with water and dried in vacuo to give N- (8-oxo-7- (prop-2-yn-1-yl) -8, 9-dihydro-7H-purin-2-yl) acetamide (4g, 50.34%) as a brown solid; c10H9N5O3；1H NMR(500MHz,DMSO-d6):δ9.80(s,1H),7.76(s,1H),6.17(s,1H),4.53(s,2H),3.24(s,1H),2.11(s,3H).
Step-6:((2R,3R,4S,5R) -5- (2-acetamido-8-oxo-7- (prop-2-yn-1-yl)) -7, 8-dihydro-9H-purin-9-yl) -4-acetoxy-3-fluorotetrahydrofuran-2-yl) methylbenzoate (49)
N- (8-oxo-7- (prop-2-yn-1-yl) -8, 9-dihydro-7H-purin-2-yl) acetamide (2.0g, 8.65mmol), (2S,3S,4R,5R) -5- ((benzoyloxy) methyl) -4-fluorotetrahydrofuran-2, 3-diacetic acid diester (5.887g, 17.316mmol), BSA (5.283g, 25.974mmol), and dichloroethane (50 mL). The resulting reaction mixture was stirred under argon at 80 ℃ for 30 minutes. The reaction mixture was concentrated under reduced pressure and the residue was diluted with ACN (100mL) and TMSOTf (2.886g, 12.987mmol) was added and placed in a pre-heated oil bath at 80 ℃. After 18 hours, the reaction was cooled to room temperature and the solvent was removed by rotary evaporation. The resulting solid was dissolved in ethyl acetate (100mL) and saturated NaHCO was used 3Aqueous (2X 30mL) wash. With Na2SO4The organic phase was dried and concentrated. By column chromatography (SiO)20-40% ethyl acetate-petroleum ether) to give ((2 g, 47.16%) as a pale yellow solid ((2R,3R,4S,5R) -5- (2-acetamido-8-oxo-7- (prop-2-yn-1-yl) -7, 8-dihydro-9H-purin-9-yl) -4-acetoxy-3-fluorotetrahydrofuran-2-yl) methylbenzoate. ES +, M/z 512.2[ M + H ]]+；C24H22FN5O7(ii) a LC-MS showed 83.5% of the desired m/z,1H-NMR showed the desired signal as well as some solvent residues. The crude compound was used next without isolation.
And 7:2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-8H-purin-8-one, compound 32
((2R,3R,4S,5R) -5- (2-acetamido-8-oxo-7- (prop-2-yn-1-yl) -7, 8-dihydro-9H-purin-9-yl) -4-acetoxy-3-fluorotetrahydrofuran-2-yl) methylbenzoate (5.0g, 11.13mmol) was dissolved in methanolic ammonia (7M) (500mL) in a closed vessel. The reaction was stirred at room temperature for 5 days. The reaction mixture was concentrated by rotary evaporation to give a thick solid. The solid was dissolved in a minimum amount of methanol and acetonitrile (50mL), added and stirred for 2 hours. The solid was filtered to give (1.4g, 38.93%) 2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2 -yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-8H-purin-8-one, compound 32, as a light brown solid. ES +, M/z 324.1[ M + H ]]+；C13H14N5O4；1H NMR(500MHz,DMSO-d6):δ8.05(s,1H),6.42(s,2H),5.84(d,J＝6Hz,1H),5.71(d,J＝7.5Hz,1H),5.32–5.27(m,1H),),5.12–5.01(m,1H),4.96–4.93(t,J＝6Hz,1H),4.65(s,2H),4.17–4.10(m,1H),3.63–3.51(m,2H),3.40(s,1H).
Example 33:2-amino-7-benzyl-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 33
Compound 33 was also synthesized according to the following multistep procedure using the same general procedure as described in example 5A.
Step-1:2-amino-7-benzyl-6- (benzyloxy) -9- (4-methoxybenzyl) -7, 9-dihydro-8H-purin-8-one (50)
Benzyl bromide (1.36g, 7.95mmol) was added to 2-amino-6- (benzyloxy) -9- (4-methoxybenzyl) -7, 9-dihydro-8H-purin-8-one (2g, 5.305mmol) and K at 0 deg.C2CO3(2.1g, 15.91mmol) in DMF (20mL) and stirred at room temperature for 18 h. The reaction mixture was quenched with ice water (120mL), diluted with ether (80mL) and stirred for 15 min. The resulting precipitated solid was filtered, washed with water and dried to give 2-amino-7-benzyl-6- (benzyloxy) -9- (4-methoxybenzyl) -7, 9-dihydro-8H-purin-8-one as an off-white solid (2.0g, 83%); ES +, M/z 468.2[ M + H ]]+；C27H25N5O3:1H NMR(400MHz,DMSO-d6):δ7.32–7.20(m,10H),7.12–7.09(m,2H),6.87(d,J＝12Hz,2H),6.41(s,2H),5.34(s,2H),4.95(s,2H),4.85(s,2H),3.71(s,3H).
Step-2:2-amino-7-benzyl-7, 9-dihydro-1H-purine-6, 8-dione (51)
Trifluoromethanesulfonic acid (2.2mL, 25.64mmol) was added to a suspension of 2-amino-7-benzyl-6- (benzyloxy) -9- (4-methoxybenzyl) -7, 9-dihydro-8H-purin-8-one (2g, 4.28mmol) in trifluoroacetic acid (2.09mL, 25.64mmol) at 0 ℃ under an argon atmosphere, and the resulting reaction mixture was slowly warmed to room temperature and stirred for 3 hours. The reaction mixture was quenched with ice-cold water and with saturated NaHCO under vigorous stirring 3The solution was basified and filtered. The residual solid was dissolved in ethyl acetate, stirred for 30 min, filtered and dried to give 2-amino-7-benzyl-7, 9-dihydro-1H-purine-6, 8-dione (0.5g, 45%) as a brown solid. ES +, M/z 258.1[ M + H ]]+；C12H11N5O2；1H NMR(400MHz,DMSO-d6):1H NMR:δ11.16(s,1H),10.64(s,1H),7.30–7.22(s,5H),6.37(s,2H),4.93(s,2H).
Step-3:n- (7-benzyl-6, 8-dioxo-6, 7,8, 9-tetrahydro-1H-purin-2-yl) acetamide (52)
Acetic anhydride (0.28mL, 5.36mmol) was added to a solution of 2-amino-7-benzyl-7, 9-dihydro-1H-purine-6, 8-dione (0.500g, 1.945mmol) in DMF (5mL) at ambient temperature under an argon atmosphere and the resulting reaction mixture was heated at 130 ℃ for 3 hours under an argon atmosphere. The reaction mixture was cooled to 0 ℃ (solid formed under stirring) and stirred for 30 minutes. The product was filtered, washed with ethanol and dried in vacuo to give N- (7-benzyl-6, 8-dioxo-6, 7,8,9 tetrahydro-1H-purin-2-yl) acetamide (0.3g, 51%) as a brown solid. This crude compound was used directly in the next step. C14H13N5O3:1H NMR(400MHz,DMSO-d6):δ12.01(s,1H),11.76(s,1H),11.65(s,1H),7.32–7.31(m,5H),5.01(s,2H),2.14(s,3H).
Step-4:((2S,4R,5R) -5- (2-acetamido-7-benzyl-6, 8-dioxo-1, 6,7, 8-tetrahydro-9H-purin-9-yl) -4-acetoxytetrahydrofuran-2-yl) methylbenzoate (53)
Dissolving in 1, 2-diN- (7-benzyl-6, 8-dioxo-6, 7,8, 9-tetrahydro-1H-purin-2-yl) acetamide (300mg, 1.0mmol), (3R,5S) -5- ((benzoyloxy) methyl) tetrahydrofuran-2, 3-diacetic acid diester (387.6mg, 1.204mmol), BSA (0.76mL, 3.010mmol) in ethyl chloride (10mL) was stirred under argon at 80 ℃ for 30 min. The reaction mixture was concentrated under reduced pressure, the residue was diluted with anhydrous acetonitrile (10mL), and TMSOTf (0.12mL, 0.707mmol) was added to the solution. The reaction mixture was placed in a pre-heated oil bath at 80 ℃ and stirred. After 3 hours, the reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The resulting solid was dissolved in ethyl acetate (80mL) and the solution was taken up with saturated NaHCO 3The aqueous solution (2X 30mL) was stirred together. Separating the organic phase with Na2SO4Dried and concentrated. By column chromatography (SiO)20-60% ethyl acetate-petroleum-ether) to give ((2S,4R,5R) -5- (2-acetamido-7-benzyl-6, 8-dioxo-1, 6,7, 8-tetrahydro-9H-purin-9-yl) -4-acetoxytetrahydrofuran-2-yl) methylbenzoate (100mg, 17%) as an off-white solid;
ES+,m/z 262.2[M+H]+；C28H27N5O8.
step-5:2-amino-7-benzyl-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 33
To a solution of ((2S,4R,5R) -5- (2-acetamido-7-benzyl-6, 8-dioxo-1, 6,7, 8-tetrahydro-9H-purin-9-yl) -4-acetoxytetrahydrofuran-2-yl) methylbenzoate (0.1g, 0.178mmol) in methanol (5mL) at room temperature was added K2CO3(122.9mg, 0.891mmol) and the reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by LC-MS. After complete consumption of the starting material, the reaction mixture was concentrated under reduced pressure. The crude product was purified by Grace flash chromatography using methanol and dichloromethane to give 92% of 40mg product by LC-MS. The compound was further dissolved in 1mL of methanol and stirred for 20 minutes. The precipitated compound was collected by filtration and dried to give 2-amino-7-benzyl-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione Compound 33(15mg, 22%) as an off-white solid. ES +, M/z 374.2[ M + H ]]+；C17H19N5O5；1H NMR(500MHz,DMSO-d6):δ10.97(s,1H),7.32–7.31(s,5H),6.52(s,2H),5.52(d,J＝5Hz,1H),5.35(d,J＝5Hz,1H),4.98(s,2H),4.82–4.78(m 1H),4.69(t,J＝10Hz,1H),4.14–412(m,1H),3.48–3.41(m,2H),2.37–2.32(m,1H),1.84–1.79(m,1H).
Example 34:2-amino-7- (3-fluorobenzyl) -9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 34
Compound 34 was also synthesized according to the following multistep procedure using the same general procedure as described in example 5A.
Step-1:2-amino-6- (benzyloxy) -7- (3-fluorobenzyl) -9- (4-methoxybenzyl) -7, 9-dihydro-8H-purin-8-one (54)
3-Fluorobenzyl bromide (0.75ml, 5.96mmol) was added to 2-amino-6- (benzyloxy) -9- (4-methoxybenzyl) -7, 9-dihydro-8H-purin-8-one (2g, 5.305mmol) and K at 0 deg.C2CO3(1.64g, 11.93mmol) in DMF (20mL) and stirred at room temperature for 18 h. The reaction mixture was quenched with ice water (120mL), diluted with ether (80mL) and stirred for 15 min. The resulting precipitated solid was filtered, washed with water and dried to give 2-amino-6- (benzyloxy) -7- (3-fluorobenzyl) -9- (4-methoxybenzyl) -7, 9-dihydro-8H-purin-8-one as an off-white solid (1.7g, 89%); ES +, M/z 486.1[ M + H ]]+；C27H24FN5O3；1H NMR(400MHz,DMSO-d6):δ7.31–7.29(m 4H),7.26–7.21(m,4H),7.09–7.04(m 1H),6.93–6.87(m,4H),6.44(s,1H),5.33(s,2H),4.96(s,2H),4.86(s,2H),3.71(s,3H).
Step-2:2-amino-7- (3-fluorobenzyl) -7, 9-dihydro-1H-purine-6, 8-dione (55)
Trifluoromethanesulfonic acid (1.85mL, 21.03mmol) was added to a suspension of 2-amino-6- (benzyloxy) -7- (3-fluorobenzyl) -9- (4-methoxybenzyl) -7, 9-dihydro-8H-purin-8-one (1.7g, 3.50mmol) in trifluoroacetic acid (2.09mL, 21.03mmol) at 0 deg.C under an argon atmosphere, and the resulting reaction mixture was slowly warmed to room temperature and stirred for 3 hours. The reaction mixture was quenched with ice-cold water and with saturated NaHCO under vigorous stirring 3The solution was basified and filtered. The residual solid was dissolved in ethyl acetate, stirred for 30 minutes, filtered and dried to give 2-amino-7- (3-fluorobenzyl) -7, 9-dihydro-1H-purine-6, 8-dione (0.7g, 72%) as a brown solid; ES +, M/z 276.1[ M + H ]]+；C12H10FN5O2；1H NMR(400MHz,DMSO-d6):δ11.2(s,1H),10.67(s,1H),7.36–7.33(m,1H),7.13–7.05(m,4H),6.39(s,2H),4.94(s,2H).
Step-3:n- (7- (3-Fluorobenzyl) -6, 8-dioxo-6, 7,8, 9-tetrahydro-1H-purin-2-yl) acetamide (56)
Acetic anhydride (0.76mL, 7.63mmol) was added to a solution of 2-amino-7- (3-fluorobenzyl) -7, 9-dihydro-1H-purine-6, 8-dione (0.7g, 2.545mmol) in DMF (10mL) at ambient temperature under an argon atmosphere and the resulting reaction mixture was stirred at 130 ℃ for 3H under an argon atmosphere. The reaction mixture was cooled to 0 ℃ (solid formed under stirring) and stirred for 30 minutes. The product was filtered, washed with ethanol and dried in vacuo to give N- (7- (3-fluorobenzyl) -6, 8-dioxo-6, 7,8, 9-tetrahydro-1H-purin-2-yl) acetamide (600mg, 75%) as a brown solid. This crude compound was used directly in the next step. ES-, M/z316.1[ M-H ]]-；C14H12FN5O3；1H NMR(400MHz,DMSO-d6):δ12.02(s,1H),11.80(s,1H),11.66(s,1H),7.38–7.34(m,1H),7.16–7.07(m,4H),5.02(s,2H),2.14(s,3H).
Step-4:((2S,4R,5R) -5- (2-acetamido-7- (3-fluorobenzyl) -6, 8-dioxo-1, 6,7, 8-tetrahydro-9H-purine-9-Yl) -4-acetoxytetrahydrofuran-2-Yl) methylbenzoate (57)
N- (7-3-Fluorobenzyl) -6, 8-dioxo-6, 7,8, 9-tetrahydro-1H-purin-2-yl) acetamide (440mg, 1.338mmol), (3R,5S) -5- ((benzoyloxy) methyl) tetrahydrofuran-2, 3-diacetic acid diester (536mg, 1.66mmol), BSA (1.0mL, 4.16mmol) were dissolved in 1, 2-dichloromethane (10mL), and the resulting reaction mixture was stirred under argon at 80 ℃ for 30 minutes. The reaction mixture was concentrated under reduced pressure, the residue diluted with anhydrous acetonitrile (10mL), and TMSOTf (0.17mL, 0.97mmol) was added. The reaction mixture was placed in a pre-heated oil bath at 80 ℃ and stirred. After 3 hours, the reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The resulting solid was dissolved in ethyl acetate (80mL) and the solution was taken up with saturated NaHCO 3The aqueous solution (2X 30mL) was stirred together. Separating the organic phase with Na2SO4Dried and concentrated. The crude compound was purified by column chromatography (SiO2, 0-60% ethyl acetate-petroleum-ether) to give ((2S,4R,5R) -5- (2-acetamido-7- (3-fluorobenzyl) -6, 8-dioxo-1, 6,7, 8-tetrahydro-9H-purin-9-yl) -4-acetoxytetrahydrofuran-2-yl) methylbenzoate (150mg, 18%) as an off-white solid; ES +, M/z 580.1[ M + H ]]+；C28H26FN5O8；1H NMR(400MHz,DMSO-d6):δ12.1(s,1H),11.55(s,1H),7.88(d,J＝8Hz,2H),7.64–7.60(m,2H),7.44(t,J＝8Hz,3H),7.16–7.07(m,3H),5.76–5.72(m,2H),5.05(S,2H),4.51(d,J＝8Hz,2H),4.40–4.36(m,1H),3.16(d,J＝4,1H),2.17(s,3H),2.15(s,3H).
Step-5:2-amino-7- (3-fluorobenzyl) -9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 34
To a solution of ((2S,4R,5R) -5- (2-acetamido-7- (3-fluorobenzyl) -6, 8-dioxo-1, 6,7, 8-tetrahydro-9H-purin-9-yl) -4-acetoxytetrahydrofuran-2-yl) methylbenzoate (150mg, 0.259mmol) in methanol (5mL) at room temperature was added K2CO3(177.4mg, 1.295mmol) and the reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by LC-MS. After completion of the reaction, the solvent was removed under reduced pressure. What is needed isThe crude compound was purified by GRACE flash chromatography using methanol and dichloromethane to yield 50mg of the product. LC-MS showed 75% product. The impure product was dissolved in 1mL of methanol, stirred for 20 minutes, then filtered and dried to give 2-amino-7- (3-fluorobenzyl) -9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione (compound 34) (16mg, 22%) as an off-white solid; ES +, M/z 392.1[ M + H ] ]+；C17H18FN5O5；1H NMR(500MHz,DMSO-d6):δ10.87(s,1H),7.39–7.35(m,1H),7.15–7.08(m,3H),6.52(s,2H),5.52(d,J＝5Hz,1H),5.36(d,J＝5Hz,1H),4.99(s,2H),4.82–4.79(s,1H),4.67(t,J＝10Hz,1H),4.15–4.11(m,1H),3.48–3.39(m,2H),2.36–2.32(m,1H),1.84–1.80(m,1H).
Example 35:2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (4- (trifluoromethyl) benzyl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 35
Compound 35 was also synthesized according to the following multistep procedure using the same general procedure as described in example 5A.
Step-1:2-amino-6- (benzyloxy) -9- (4-methoxybenzyl) -7- (4- (trifluoromethyl) benzyl) -7, 9-dihydro-8H-purin-8-one (58)
1- (bromomethyl) -4- (trifluoromethyl) benzene (2.28g, 9.54mmol) was added to 2-amino-6- (benzyloxy) -9- (4-methoxybenzyl) -7, 9-dihydro-8H-purin-8-one (3g, 7.95mmol) and K at 0 deg.C2CO3(1.64g, 11.93mmol) in DMF (30mL) and stirred at room temperature for 16 h. The reaction mixture was quenched with ice water (120mL), diluted with ether (80mL) and stirred for 15 min. The resulting precipitate was collected by filtration and washed with waterAnd dried to give 2-amino-6- (benzyloxy) -9- (4-methoxybenzyl) -7- (4- (trifluoromethyl) benzyl) -7, 9-dihydro-8H-purin-8-one (3.8g, 90%) as an off-white solid; ES +, M/z 536.2[ M + H ]]+；C28H24F3N5O3；1HNMR(400MHz,DMSO-d6):δ7.60(d,J＝8.4Hz,2H),7.31–7.21(m,7H),7.16(d,J＝6.4Hz,2H),6.89(d,J＝8.8Hz,2H),6.45(s,2H),5.31(s,2H),5.04(s,2H),4.87(s,2H),3.71(s,3H).
Step-2:2-amino-7- (4- (trifluoromethyl) benzyl) -7, 9-dihydro-1H-purine-6, 8-dione (59)
Trifluoromethanesulfonic acid (1.97mL, 22.42mmol) was added to a suspension of 2-amino-6- (benzyloxy) -9- (4-methoxybenzyl) -7- (4- (trifluoromethyl) benzyl) -7, 9-dihydro-8H-purin-8-one (2g, 3.73mmol) in trifluoroacetic acid (1.7mL, 3.73mmol) at 0 deg.C under an argon atmosphere, and the resulting reaction mixture was slowly warmed to room temperature and stirred for 3 hours. The reaction mixture was quenched with ice-cold water and with saturated NaHCO under vigorous stirring 3The solution was basified and filtered. The residual solid was taken up in ether (100mL), stirred for 30 min, filtered and dried to give 2-amino-7- (4- (trifluoromethyl) benzyl) -7, 9-dihydro-1H-purine-6, 8-dione (1 g; 83%) as an off-white solid: ES +, M/z 326.1[ M + H ]]+；C13H10F3N5O2:1H NMR(400MHz,DMSO-d6):δ11.24(s,1H),10.67(s,1H),7.69(d,J＝8.4Hz,2H),7.48(d,J＝8Hz,2H),6.40(s,2H),5.02(s,2H).
Step-3:n- (6, 8-dioxo-7- (4- (trifluoromethyl) benzyl) -6,7,8, 9-tetrahydro-1H-purin-2-yl) acetamide (60)
Acetic anhydride (2mL) was added to a solution of 2-amino-7- (4- (trifluoromethyl) benzyl) -7, 9-dihydro-1H-purine-6, 8-dione (1.4g, 4.30mmol) in DMF (20mL) at ambient temperature under an argon atmosphere and the resulting reaction mixture was heated at 140 ℃ for 3H. The reaction mixture was cooled to 0 ℃ with stirring, whereby a solid was formed. Stirring was continued for 30 min, the product was filtered and dried in vacuo to give N- (6, 8-dioxo-7- (4- (trifluoromethyl) benzyl) -6,7,8, 9-tetrahydro-l-ethyl-1H-purin-2-yl) acetamide (1g, 63%) as an off-white solid: ES +, M/z 368.1[ M + H ]]+；C15H12F3N5O3:1H NMR(400MHz,DMSO-d6):δ12.36(s,1H),11.44(s,1H),7.70(d,J＝8Hz,2H),7.57(d,J＝8.4Hz,2H),6.98(br s,1H),5.19(s,2H),2.17(s,3H).
Step-4:((2S,4R,5R) -5- (2-acetamido-6, 8-dioxo-7- (4- (trifluoromethyl) benzyl) -1,6,7, 8-tetrahydro-9H-purin-9-yl) -4-acetoxytetrahydrofuran-2-yl) methylbenzoate (61)
N- (6, 8-dioxo-7- (4- (trifluoromethyl) benzyl) -6,7,8, 9-tetrahydro-1H-purin-2-yl) acetamide (350mg, 0.953mmol), (3R,5S) -5- ((benzoyloxy) methyl) tetrahydrofuran-2, 3-diacetic acid diester (368mg, 1.143mmol), and BSA (0.72mL, 2.859mmol) were dissolved in 1, 2-dichloroethane (10mL), and the resulting reaction mixture was stirred under argon at 80 ℃ for 30 minutes. The reaction mixture was cooled to room temperature and TMSOTf (0.12mL, 0.667mmol) was added. The reaction mixture was kept at 80 ℃ for 3 hours, then cooled to room temperature, diluted with water and CH 2Cl2(3X 100 mL). The combined organic layers were washed with water (100mL), brine (100mL) and Na2SO4Dried and concentrated under reduced pressure. By flash chromatography (SiO)20-60% EtOAc-petroleum-ether) to give ((2S,4R,5R) -5- (2-acetamido-6, 8-dioxo-7- (4- (trifluoromethyl) benzyl) -1,6,7, 8-tetrahydro-9H-purin-9-yl) -4-acetoxytetrahydrofuran-2-yl) methylbenzoate (70mg, 11%) as an off-white solid: c29H26F3N5O8LC-MS indicates 84% of the desired mass; ES +, M/z 368.1[ M + H ]]+.
Step-5:2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (4- (trifluoromethyl) benzyl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 35
To ((2S,4R,5R) -5- (2-acetamido-6, 8-dioxo-7- (4- (trifluoromethyl) benzyl) -1,6,7, 8-tetrahydro-9H-purin-9-yl) -4-acetoxytetrahydrofuran-2-yl) methylbenzoate (70mg, 0.111 m) at 0 deg.Cmol) of methanol (5mL) was added K2CO3(61mg, 0.445mmol) and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was directly purified by RP flash chromatography and the fractions prepared were lyophilized to give compound 2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (4- (trifluoromethyl) benzyl) -7, 9-dihydro-1H-purine-6, 8-dione (compound 35) as a white solid (25mg, 51%); ES +, M/z 442.1[ M + H ] ]+；C18H18F3N5O5:1H NMR(500MHz,DMSO-d6):δ10.95(s,1H),7.70(d,J＝8.5Hz,2H),7.51(d,J＝8Hz,2H),6.58(s,2H),5.54(d,J＝3Hz,1H),5.37(d,J＝4.5Hz,1H),5.07(s,2H),4.82–4.80(m,1H),4.69–4.67(m,1H),4.15–4.13(m,1H),3.47–3.40(s,2H),2.38–2.32(m,1H),1.84–1.80(m,1H).
Example 36:7-allyl-2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 36
Compound 36 was also synthesized according to the following multistep procedure using the same general procedure as described in example 5A.
Step-1: 7-allyl-2-amino-6- (benzyloxy) -9- (4-methoxybenzyl) -7, 9-dihydro-8H-purin-8-one (62)
Allyl bromide (0.767g, 5.30mmol) was added to 2-amino-6- (benzyloxy) -9- (4-methoxybenzyl) -7, 9-dihydro-8H-purin-8-one (2g, 5.298mmol) and K at 0 deg.C2CO3(1.09g, 7.95mmol) in DMF (20mL) and stirred at room temperature for 18 h. The reaction mixture was quenched with ice water (120mL), diluted with ether (80mL) and stirred for 15 min. The resulting precipitated solid was collected by filtration, washed with water and dried to give 7-allyl alcoholYl-2-amino-6- (benzyloxy) -9- (4-methoxybenzyl) -7, 9-dihydro-8H-purin-8-one (2.0g, 76%) as an off-white solid; ES +, M/z418.1[ M + H ]]+；C23H23N5O3；1H NMR(400MHz,DMSO-d6):δ7.44(d,J＝7.5Hz,2H),7.40–7.36(m,2H),7.30(d,J＝4.5Hz,1H),7.21(d,J＝8.5Hz,2H),6.8(d,J＝8.5Hz,2H),6.40(s,2H),5.89–5.82(m,1H),5.37(s,2H),5.05(d,J＝10Hz,1H),5.04(d,J＝15Hz,1H),4.83(s,2H),4.37(d,J＝5Hz,2H),3.71(s,3H).
Step-2:7-allyl-2-amino-7, 9-dihydro-1H-purine-6, 8-dione (63)
Trifluoromethanesulfonic acid (1.268mL, 14.37mmol) was added to a suspension of 7-allyl-2-amino-6- (benzyloxy) -9- (4-methoxybenzyl) -7, 9-dihydro-8H-purin-8-one (2g, 4.79mmol) in trifluoroacetic acid (1.09mL, 14.37mmol) at 0 ℃ under an argon atmosphere, and the resulting reaction mixture was slowly warmed to room temperature and stirred for 3 hours. The reaction mixture was quenched with ice-cold water and with saturated NaHCO under vigorous stirring 3The solution was basified and filtered. The residual solid was dissolved in ethyl acetate, stirred for 30 minutes and filtered; the residue was dried to give 7-allyl-2-amino-7, 9-dihydro-1H-purine-6, 8-dione (0.54g, 56%) as a brown solid. ES +, M/z 208.1[ M + H ]]+；C8H9N5O2；1H NMR(400MHz,DMSO-d6):1H NMR(500MHz,DMSO-d6):δ11.15(s,1H),10.81(s,1H),6.36(s,2H),5.92–5.85(m,1H),5.07(d,J＝12.5Hz,1H),5.04(d,J＝478Hz,1H),4.33(d,J＝5.5Hz,2H).
Step-3:n- (7-allyl-6, 8-dioxo-6, 7,8, 9-tetrahydro-1H-purin-2-yl) acetamide (64)
Acetic anhydride (0.74mL) was added to a solution of 7-allyl-2-amino-7, 9-dihydro-1H-purine-6, 8-dione (0.54g, 7.82mmol) in DMF (5mL) at ambient temperature under an argon atmosphere and the resulting reaction mixture was heated at 130 ℃ for 3H under an argon atmosphere. The reaction mixture was cooled to 0 ℃ and a solid formed after 30 minutes with stirring. Collecting the product by filtration, washing with ethanol, and vacuum drying to obtainN- (7-allyl-6, 8-dioxo-6, 7,8, 9-tetrahydro-1H-purin-2-yl) acetamide (0.50g, 61%) as a brown solid. This crude compound was used directly in the next step. ES +, M/z 250.1[ M + H ]]+；C10H11N5O3；1H NMR(400MHz,DMSO-d6):δ11.99(s,1H),11.74(s,1H),11.67(s,1H),5.96–5.87(m,1H),5.10(d,J＝1.6Hz,1H),5.04(d,J＝1.6Hz,1H),4.4(d,J＝5.6Hz,2H),2.19(s,3H).
Step-4:((2S,4R,5R) -5- (2-acetamido-7-allyl-6, 8-dioxo-1, 6,7, 8-tetrahydro-9H-purin-9-yl) -4-acetoxytetrahydrofuran-2-yl) methylbenzoate (65)
N- (7-allyl-6, 8-dioxo-6, 7,8, 9-tetrahydro-1H-purin-2-yl) acetamide (500mg, 2.01mmol), (3R,5S) -5- ((benzoyloxy) methyl) tetrahydrofuran-2, 3-diacetic acid diester (969mg, 3.01mmol), BSA (1.47mL, 6.08mmol) were dissolved in ACN (10 mL). The resulting reaction mixture was stirred under argon at 80 ℃ for 30 minutes. The reaction mixture was concentrated under reduced pressure, the residue was diluted with anhydrous acetonitrile (9.5mL, 1.40mmol), and TMSOTf (0.254mL, 1.40mmol) was added. The reaction mixture was placed in a pre-heated oil bath at 80 ℃ and stirred. After 3 hours, the reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The resulting solid was dissolved in ethyl acetate (80mL) and the solution was taken up with saturated NaHCO 3The aqueous solution (2X 30mL) was shaken together. Separating the organic phase with Na2SO4Dried and concentrated. By column chromatography (SiO)20-60% EtOAc-Petroleum-ether) to afford ((2S,4R,5R) -5- (2-acetamido-7-allyl-6, 8-dioxo-1, 6,7, 8-tetrahydro-9H-purin-9-yl) -4-acetoxytetrahydrofuran-2-yl) methylbenzoate (180mg, 24%) as an off-white solid.1H NMR(500MHz,DMSO-d6):δ12.1(s,1H),11.51(s,1H),7.90(d,J＝10Hz,2H),7.65–7.61(m,1H),7.46(t,J＝8.5Hz,2H),5.87–5.75(m,1H),5.75–5.72(m,2H),5.11–5.01(m,2H),4.53(d,J＝5Hz,2H),4.46(d,J＝2.5Hz,2H),4.40–4.36(m,1H),2.92(m,1H),2.14(s,3H),2.10(m,1H),2.08(s,3H).
Step-5:7-allyl-2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxy)Methyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 36
The resulting solution of ((2S,4R,5R) -5- (2-acetamido-7-allyl-6, 8-dioxo-1, 6,7, 8-tetrahydro-9H-purin-9-yl) -4-acetoxytetrahydrofuran-2-yl) methylbenzoate (180mg, 0.352mmol) in 7M ammonia in methanol (5mL) was stirred at room temperature in a sealed vessel. The progress of the reaction was monitored by LC-MS. After complete consumption of the starting material, the reaction mixture was concentrated under reduced pressure. The resulting thick solid was dissolved in a minimum amount of methanol and diethyl ether (10mL) was added, stirred for 30 minutes and filtered. After drying, 7-allyl-2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione (compound 36) (60mg, 51%) was isolated as an off-white solid. ES +, M/z 324.1[ M + H ] ]+；C13H17N5O5；1H NMR(500MHz,DMSO-d6):δ10.91(s,1H),6.51(s,2H),5.90(m,1H),5.53(d,J＝2.5Hz,1H),5.37(d,J＝4Hz,1H),5.06(dd,J＝10Hz,2H),4.72(bs,2H),4.39(d,J＝4Hz,2H),4.14(s,1H),3.44(m,2H),2.35(m,1H),1.82(m,1H).m.p.＝199-203℃.
Example 37:2-amino-7-butyl-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 37
Compound 37 was also synthesized according to the following multistep procedure using the same general procedure as described in example 5A.
Step-1:2-amino-6- (benzyloxy) -7-butyl-9- (4-methoxybenzyl) -7, 9-dihydro-8H-purin-8-one (66)
Butyl bromide (0.43ml, 3.183mmol) was added to 2-amino-6- (benzyloxy) -9- (4-methoxybenzyl) -7, 9-dihydro-8H-purine at 0 deg.C-8-one (1g, 2.65mmol) and K2CO3(0.548g, 3.97mmol) in DMF (10mL) and stirred at room temperature for 18 h. The reaction mixture was quenched with ice water (120mL), diluted with ether (80mL) and stirred for 15 min. The resulting precipitated solid was collected by filtration, washed with water and dried to give 2-amino-6- (benzyloxy) -7-butyl-9- (4-methoxybenzyl) -7, 9-dihydro-8H-purin-8-one as a brown solid (0.80g, 69%); ES +, M/z433.1[ M + H ]]+；C24H27N5O3；1H NMR(400MHz,DMSO-d6):δ7.4(d,J＝6.8Hz,2H),7.34–7.41(m,3H),7.20(d,J＝8Hz,2H),6.8(d,J＝8.8Hz,2H),6.4(s,2H),5.4(s,2H),4.8(s,2H),3.7(t,J＝15.6Hz,5H),1.5(t,J＝14.4Hz,2H),1.11–1.17(m,2H),0.76(t,J＝14.8Hz,3H).
Step-2:2-amino-7-butyl-7, 9-dihydro-1H-purine-6, 8-dione (67)
Trifluoromethanesulfonic acid (1.03g, 6.89mmol) was added to a suspension of 2-amino-6- (benzyloxy) -7-butyl-9- (4-methoxybenzyl) -7, 9-dihydro-8H-purin-8-one (1.0g, 2.30mmol) in trifluoroacetic acid (0.786mL, 6.89mmol) at 0 ℃ under an argon atmosphere. The reaction mixture was slowly warmed to room temperature and stirred for 3 hours. The reaction mixture was quenched with ice cold water and saturated NaHCO was added under vigorous stirring 3And (3) solution. The solid was filtered, dissolved in ethyl acetate, stirred for 30 minutes, filtered and dried to give 2-amino-7-butyl-7, 9-dihydro-1H-purine-6, 8-dione (0.30g, 58%) as a brown solid. ES +, M/z 224.1[ M + H ]]+；C9H13N5O2；1H NMR(400MHz,DMSO-d6):δ11.0(s,1H),10.6(s,1H),6.3(s,2H),3.7(t,J＝16Hz,2H),1.5–1.6(m,2H),1.25–1.20(m,2H),0.8(t,J＝12Hz,3H).
Step-3:n- (7-butyl-6, 8-dioxo-6, 7,8, 9-tetrahydro-1H-purin-2-yl) acetamide (68) and N-acetyl-N- (7-butyl-6, 8-dioxo-6, 7,8, 9-tetrahydro-1H-purin-2-yl) acetamide (68a)
Acetic anhydride (0.20ml, 2.01mmol) was added to 2-amino-7-butyl-7, 9-dihydro-1H-purine-6, 8-dione (R) at ambient temperature under an argon atmosphere0.300g, 1.345mmol) in DMF (5 mL). The resulting reaction mixture was stirred at 130 ℃ for 3h under an argon atmosphere. The reaction mixture was cooled to 0 ℃ (solid formed under stirring) and stirred for 30 minutes. The product was filtered, washed with ethanol and dried in vacuo to give a mixture of N- (7-butyl-6, 8-dioxo-6, 7,8, 9-tetrahydro-1H-purin-2-yl) acetamide (68) and N-acetyl-N- (7-butyl-6, 8-dioxo-6, 7,8, 9-tetrahydro-1H-purin-2-yl) acetamide (68a) (0.150g, 42%) as a brown solid. LC-MS indicated 20% (68); ES +, M/z 266.1[ M + H ]]+；C11H15N5O3(ii) a And 49% (68 a); ES +, M/z 308.1[ M + H ]]+；C13H17N5O4(ii) a The mixture was used directly in the next step.
Step-4:((2S,4R,5R) -5- (2-acetamido-7-butyl-6, 8-dioxo-1, 6,7, 8-tetrahydro-9H-purin-9-yl) -4-acetoxytetrahydrofuran-2-yl) methylbenzoate (69)
A mixture of N- (7-butyl-6, 8-dioxo-6, 7,8, 9-tetrahydro-1H-purin-2-yl) acetamide (68) and N-acetyl-N- (7-butyl-6, 8-dioxo-6, 7,8, 9-tetrahydro-1H-purin-2-yl) acetamide (68a) (1.433mmol), (2S,3R,5S) -5- ((benzoyloxy) methyl) tetrahydrofuran-2, 3-diacetic acid diester (0.692g, 2.150mmol) and BSA (0.58g, 2.86mmol) was dissolved in dichloroethane (9.5mL) and stirred under argon at 80 ℃ for 30 minutes. The reaction mixture was concentrated under reduced pressure, the residue was diluted with anhydrous acetonitrile (9.5mL), and TMSOTf (0.2g, 0.931mmol) was added. The reaction mixture was placed in a pre-heated oil bath at 80 ℃ and stirred. After 3 hours, the reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The resulting solid was dissolved in ethyl acetate (80mL) and the solution was taken up with saturated NaHCO3The aqueous solution (2X 30mL) was shaken together. With Na2SO4The organic phase was dried and concentrated. Purification of crude compound (SiO) by column chromatography20-60% EtOAc-petroleum ether as eluent) to give 200mg (26%) of ((2S,4R,5R) -5- (2-acetamido-7-butyl-6, 8-dioxo-1, 6,7, 8-tetrahydro-9H-purin-9-yl) -4-acetoxytetrahydrofuran-2-yl) methylbenzoate as a light yellow solid (78% purity by LC/MS); ES +, m /z 528.2[M+H]+；C25H29N5O8.
Step-5:2-amino-7-butyl-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 37
((2S,4R,5R) -5- (2-acetamido-7-butyl-6, 8-dioxo-1, 6,7, 8-tetrahydro-9H-purin-9-yl) -4-acetoxytetrahydrofuran-2-yl) methylbenzoate (0.150g, 0.285mmol) was dissolved in methanolic ammonia (10mL) and the reaction mixture was stirred at room temperature for 18H. The reaction mixture was concentrated under reduced pressure. The crude product was purified by GRACE reverse phase purification system (MeCN-0.01% HCO)2H of H2O solution as eluent) to yield 0.060g (62%) of 2-amino-7-butyl-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione (compound 37) as a white solid. ES +, M/z 340.2[ M + H ]]+,C14H21N5O5；1H NMR(400MHz,DMSO-d6):δ10.87(s,1H),6.4(s,2H),5.5(d,J＝4Hz,1H),5.3(d,J＝4Hz,1H),4.70–4.8(m,1H),4.7(t,J＝12Hz,1H),4.1(t,J＝12Hz,1H),3.7(t,J＝16Hz,2H),3.3–3.4(m,2H),2.3–2.5(m,1H),1.7–1.8(m,1H),1.5–1.6(m,2H),1.21–1.27(m,2H),0.8(t,J＝16Hz 3H).
Preparation of intermediates (70), (71), (72), (73) and (74)
The intermediate compounds (70-74) were synthesized according to the following multi-step procedure.
Step-1:2-amino-6-chloro-7- (cyclopropylmethyl) -9- (4-methoxybenzyl) -7, 9-dihydro-8H-purin-8-one (70)
Cyclopropylmethyl bromide (32.9g, 24.39mol) was added to 2-amino-6-chloro-9- (4-methoxybenzyl) -7, 9-dihydro-8H-purin-8-one (36) (62g, 20.32mol), K at 0 deg.C 2CO3(42g, 30.49mol) in DMF (500mL) and then stirred at room temperature 18And (4) hours. The reaction mixture was poured into ice-cold water and stirred at room temperature for 30 minutes. The precipitated solid product was collected by filtration and dried under vacuum to give 2-amino-6-chloro-7- (cyclopropylmethyl) -9- (4-methoxybenzyl) -7, 9-dihydro-8H-purin-8-one (70) (60g, 82%) as a brown solid. TLC: 30% ethyl acetate in hexane; rf:0.4；ES+,m/z 360.1[M+H]+；C17H18ClN5O2；1H NMR(400MHz,DMSO-d6):δ7.23(d,J＝8.4Hz,2H),6.89(d,J＝8.8Hz,2H),6.75(s,2H),4.86(s,2H),3.80(d,J＝6.8Hz,2H),3.71(s,3H),1.21-1.17(m,1H),0.50-0.46(m,2H),0.37-0.34(m,2H).
Step-2:2-amino-7- (cyclopropylmethyl) -7, 9-dihydro-8H-purin-8-one (71)
10% Pd-C (5.0g) was added to a suspension of 2-amino-6-chloro-7- (cyclopropylmethyl) -9- (4-methoxybenzyl) -7, 9-dihydro-8H-purin-8-one (70) (20g, mmol) in methanol (500 mL). The reaction mixture was hydrogenated with hydrogen at room temperature for 24 hours in a Parr shaker under a pressure of 80 psi. The reaction mixture was filtered through a pad of celite and the filtrate was evaporated to give the crude product. Acetonitrile was added to the crude compound, stirred for 15 minutes, and filtered. This procedure was repeated and the solid was dried in vacuo to give 2-amino-7- (cyclopropylmethyl) -7, 9-dihydro-8H-purin-8-one (71) (11g, 64%) as an off white solid. TLC: 70% ethyl acetate in hexane; r f:0.2；ES+,m/z 206.2[M+H]+；C9H11N5O.1H NMR(500MHz,DMSO-d6):δ12.68(s,1H),8.11(s,1H),7.87(s,2H),3.60–3.59(d,J＝7.5Hz,2H),1.18–1.12(m,1H),0.50-0.46(m,2H),0.37-0.34(m,2H).m.p.245-249℃.
Step-3:2-amino-6-chloro-7- (cyclopropylmethyl) -7, 9-dihydro-8H-purin-8-one (72)
Anhydrous AlCl is added at room temperature under argon atmosphere3The resulting reaction mixture was mixed by adding powder (25g, 187mmol) to a stirred solution of 2-amino-6-chloro-7- (cyclopropylmethyl) -9- (4-methoxybenzyl) -7, 9-dihydro-8H-purin-8-one (70) (50g, 139.2mmol) in 1, 2-dichlorobenzene (250mL)The mixture was stirred at 100 ℃ for 18 hours under an argon atmosphere. The reaction mixture was cooled to room temperature and quenched with ice-cold water and with saturated NaHCO while stirring vigorously3The solution was basified and filtered. The filtered solid was dissolved in 10% MeOH in dichloromethane, stirred for 30 min and filtered (repeated three times, volume 1.0L solvent). The filtrate was passed through a celite plate and concentrated under reduced pressure. The solid thus obtained was washed twice with 10% methanol in dichloromethane and filtered. The filtered solid was washed twice again with acetonitrile, filtered and dried to give 2-amino-6-chloro-7- (cyclopropylmethyl) -7, 9-dihydro-8H-purin-8-one (72) (12g, 36%) as a brown solid. TLC: 50% ethyl acetate in hexane; rf:0.3；ES+,m/z 240.1[M+H]+；C9H10ClN5O.1H NMR(500MHz,DMSO-d6):δ11.81(s,1H),6.58(s,2H),3.73-3.72(d,J＝7.0Hz,2H),1.21-1.17(m,1H),0.50-0.46(m,2H),0.37-0.34(m,2H).m.p.286-290℃.
Step-4:2-amino-6- (benzyloxy) -7- (cyclopropylmethyl) -7, 9-dihydro-8H-purin-8-one (73)
Metallic sodium (1.43g, 62.6mmol) was added to benzyl alcohol (25.0mL) for 1 hour (until all sodium was dissolved). The resulting viscous liquid was cooled to room temperature and 2-amino-6-chloro-7- (cyclopropylmethyl) -7, 9-dihydro-8H-purin-8-one (72) (5.0g, 20.86mmol) was added. The resulting reaction mixture was stirred at 100 ℃ for 1h and quenched with ice water (200 mL). Ether (150mL) was added and stirred for 15 min. The resulting precipitated solid was filtered, washed with water and dried. The solid was dissolved in 15% methanol-dichloromethane (500mL), filtered through a pad of celite, washed with brine and concentrated. The resulting solid was washed with ether and filtered to give 2-amino-6- (benzyloxy) -7- (cyclopropylmethyl) -7, 9-dihydro-8H-purin-8-one (73) (3.5g, 54%) as an off-white solid. TLC: 70% ethyl acetate in petroleum ether; rf:0.6；ES+,m/z 312.2[M+H]+；C16H17N5O2.1H NMR(500MHz,DMSO-d6):δ11.30(brs,1H),7.48-7.46(m,2H),7.41-7.38(m,2H),7.35–7.30(m,1H),6.15(s,2H),5.41(s,2H),3.56(d,J＝7.0Hz,2H),1.14-1.10(m,1H),0.36-0.32(m,2H),0.23-0.21(m,2H).m.p.238-242℃.
Step-5:2-amino-7- (cyclopropylmethyl) -7, 9-dihydro-1H-purine-6, 8-dione (74)
A suspension of 2-amino-6- (benzyloxy) -7- (cyclopropylmethyl) -7, 9-dihydro-8H-purin-8-one (73) (10.0g, 32.15mmol), anhydrous LiBr (3.34g, 38.58mmol), chlorotrimethylsilane (4.53g, 108.6mmol) in acetonitrile (700mL) was stirred at room temperature for 16H. Methanol (60mL) was added to the reaction mixture and stirred for 30 minutes. The solvent was distilled off to reduce the volume by about 100mL and filtered. The filter cake was washed with acetonitrile and dried. The solid was dissolved in saturated NaHCO 3To the solution (200mL), stir 1h, filter, wash with water and dry. The solid was stirred in 10% methanol/dichloromethane (50mL), filtered and dried to give 2-amino-7- (cyclopropylmethyl) -7, 9-dihydro-1H-purine-6, 8-dione (74) (8.5g, 80%) as a light brown solid. TLC: 10% methanol in dichloromethane; rf:0.4；ES+,m/z222.1[M+H]+；C9H11N5O2.1H NMR(500MHz,DMSO-d6):δ11.06(s,1H),10.68(s,1H),6.36(s,2H),3.58(d,J＝7.0Hz,2H),1.19-1.14(m,1H),0.40-0.36(m,2H),0.33-0.30(m,2H).m.p.364-368℃.
Example 31S: ((2R,3S,4S,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (prop-2-yn-1-yl) -7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydro-furan-2-yl) methyl acetate (Compound 31S)
Compound 31S can be prepared using the procedure described in example 31, substituting (23) for (18).
Example 32S: 2-amino-9- ((2R,3S,4R,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (prop-2-yn-1-yl) -7, 9-dihydro-8H-purin-8-one (Compound 32S)
Compound 32S can be prepared from compound 31S using the methods described in example 32.
Example 38:2-amino-7- (4-fluorobenzyl) -9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 38
Compound 38 can be prepared according to the procedure in example 26 or examples 5A and 26A, together with 4-fluorobenzyl bromide.
Example 39:2-amino-7- (3, 4-difluorobenzyl) -9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 39
Compound 39 can be prepared according to the procedure in example 26 or examples 5A and 26A, together with 3, 4-difluorobenzyl bromide.
Example 40:2-amino-7- (4-chlorobenzyl) -9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 40
Compound 40 can be prepared according to the method in example 26 or examples 5A and 26A, together with 4-chlorobenzyl bromide.
Example 41:2-amino-7- (3-chlorobenzyl) -9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 41
Compound 41 can be prepared according to the method in example 26 or examples 5A and 26A, together with 3-chlorobenzyl bromide.
Example 42:2-amino-7- (3, 4-dichlorobenzyl) -9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 42
Compound 42 can be prepared according to the method in example 26 or examples 5A and 26A, together with 3, 4-dichlorobenzyl bromide.
Example 43:4- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) benzonitrile, compound 43
Compound 43 can be prepared according to the method in example 26 or examples 5A and 26A, together with 4-cyanobenzyl bromide.
Example 44:3- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) benzonitrile, compound 44
Compound 44 can be prepared according to the method in example 26 or examples 5A and 26A, together with 3-cyanobenzyl bromide.
Example 45:methyl 4- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) benzoate, Compound 45
Compound 45 can be prepared according to the method in example 26 or examples 5A and 26A together with methyl 4- (bromomethyl) benzoate.
Example 46:4- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) benzoic acid, compound 46
Compound 46 can be prepared by ester hydrolysis of compound 45.
Example 47:methyl 3- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) benzoate, compound 47
Compound 47 can be prepared according to the method in example 26 or examples 5A and 26A, together with methyl 3- (bromomethyl) benzoate.
Example 48:3- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) benzoic acid, compound 48
Compound 48 can be prepared by ester hydrolysis of compound 47.
Example 49:methyl 2- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) benzoate, Compound 49
Compound 49 can be prepared according to the method in example 26 or examples 5A and 26A, together with methyl 2- (bromomethyl) benzoate.
Example 50:2- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) benzoic acid, compound 50
Compound 50 can be prepared by ester hydrolysis of compound 49.
Example 51:2-amino-7- (E) -cinnamyl-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione, compound 51
Compound 51 can be prepared according to the method in example 26 or examples 5A and 26A together with (E) -cinnamyl bromide.
Example 52:7- ((1H-pyrazol-5-yl) methyl) -2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 52
Compound 52 can be prepared according to the procedure in example 26 or examples 5A and 26A together with a mesylate of tert-butyl 5- (bromomethyl) -1H-pyrazole-1-carboxylate [1001096-27-0] or 5- (bromomethyl) -1- (4-methoxybenzyl) -1H-pyrazole [1313409-97-0] or (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) methanol [1823866-20-1 ].
Example 53:2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- ((1-methyl-1H-pyrazol-3-yl) methyl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 53 can be reacted with 3- (bromomethyl) -1-methyl-1H-pyrazole [102846-13-9 ] according to the method in example 26 or examples 5A and 26A]Are prepared together.
Example 54:2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (thien-2-ylmethyl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 54
Compound 54 can be prepared according to the method in example 26 or examples 5A and 26A together with 2- (bromomethyl) -thiophene.
Example 55:2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (thien-3-ylmethyl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 55
Compound 55 can be prepared according to the method in example 26 or examples 5A and 26A together with 3- (bromomethyl) -thiophene.
Example 56:2- (2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) ethaneAcid, Compound 56
Compound 56 can be prepared according to the method in example 26 or examples 5A and 26A using methyl 2-bromoacetate and subsequent ester hydrolysis.
Example 57:2- (2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) acetaldehyde, Compound 57
Compound 57 can be prepared according to the procedure for example 26 from 2-bromo-1, 1-dimethoxyethane.
Example 58:2- (2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) acetonitrile, Compound 58
Compound 58 can be prepared from compound 57 by converting the aldehyde to the corresponding oxime and then dehydrating it.
Example 59:7- ((1H-tetrazol-5-yl) methyl) -2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 59
Compound 59 can be prepared according to the methods in example 26 or examples 5A and 26A, together with 5- (chloromethyl) -1H-tetrazole [55408-11-2 ].
Example 60:2- (2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) -N- (methylsulfonyl) acetamide, compound 60 can be prepared from compound 56 and methanesulfonamide.
Example 61:2- (2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) -N-hydroxyacetamide, Compound 61
Compound 61 can be prepared from compound 56 and hydroxylamine.
Example 62:2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- ((3-hydroxyisoxazol-5-yl) methyl) -7, 9-dihydro-1H-purine-6, 8-dione, compound 62
Compound 62 can be prepared according to the method in example 26 or examples 5A and 26A, together with the mesylate of (3- ((4-methoxybenzyl) oxy) isoxazol-5-yl) methanol.
Example 63:methyl 5- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) thiophene-2-carboxylate, Compound 63
Compound 63 can be prepared according to the method in example 26 or examples 5A and 26A, together with methyl 5- (bromomethyl) thiophene-2-carboxylate [108499-32-7 ].
Example 64:5- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) thiophene-2-carboxylic acid, Compound 64
Compound 64 can be prepared from compound 63 by ester hydrolysis.
Example 65:ethyl 5- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) thiophene-3-carboxylate, Compound 65
Compound 65 can be prepared according to the method in example 26 or examples 5A and 26A, together with ethyl 5- (bromomethyl) thiophene-3-carboxylate [206860-16-4 ].
Example 66:5- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) thiophene-3-carboxylic acid, Compound 66
Compound 66 can be prepared from compound 65 by ester hydrolysis.
Example 67: 4- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) thiophene-2-carboxylic acid methyl ester, Compound 67
Compound 67 can be prepared according to the method in example 26 or examples 5A and 26A, together with methyl 4- (bromomethyl) thiophene-2-carboxylate [54796-51-9 ].
Example 68:4- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) thi-nePhen-2-carboxylic acid, Compound 68
Compound 68 can be prepared from compound 67 by ester hydrolysis.
Example 69:(1R,2R) -2- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) cyclopropane-1-carboxylic acid, Compound 69
Compound 69 can be prepared according to the method in example 26 or examples 5A and 26A from the mesylate of ethyl (1R,2R) -2- (hydroxymethyl) cyclopropane-1-carboxylate followed by ester hydrolysis.
Example 70:7- ((E) -3- (1H-tetrazol-5-yl) allyl) -2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 70
Compound 70 can be prepared from compound 36 and 5-vinyl-1H-tetrazole [18755-47-0 ].
Example 71:4- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) benzaldehyde, compound 71
Compound 71 can be prepared according to the method in example 26 or examples 5A and 26A, together with methyl 4- (bromomethyl) benzaldehyde.
Example 72:2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (4-methoxybenzyl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 72
Compound 72 can be prepared according to the method in example 26 or examples 5A and 26A, together with 4-methoxy-benzyl bromide.
Example 73:2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (3-methoxybenzyl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 73
Compound 73 can be prepared according to the method in example 26 or examples 5A and 26A together with 3-methoxy-benzyl bromide.
Example 74:2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (3-hydroxybenzyl)-7, 9-dihydro-1H-purine-6, 8-dione, Compound 74
Compound 74 can be prepared by using BBr3Compound 73 is demethylated.
Example 75:2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (pyridin-3-ylmethyl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 75
Compound 75 can be prepared according to the method in example 26 or examples 5A and 26A, together with 3-bromomethylpyridine.
Example 76:2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (2-oxo-2- (pyrrolidin-1-yl) ethyl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 76 can be reacted with bromoacetylpyrrolidine [90892-09-4 ] according to the procedure in example 26 or examples 5A and 26A ]Are prepared together.
Example 77:2-amino-7- (cyclopropylmethyl) -9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 77
Compound 77 can be prepared by the method of example 1 substituting 3' -deoxy-guanosine [3608-58-0] for 2-amino-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -1, 9-dihydro-6H-purin-6-one (1) [27462-39-1] or by the method of example 26A substituting (74) for (40).
Example 78:2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (methoxymethyl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 78
Compound 78 can be prepared according to the procedure in example 26 using chloromethyl methyl ether.
Example 79:2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- ((methylthio) methyl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 79
Compound 79 can be prepared according to the procedure in example 26 using chloromethyl methyl sulfide.
Example 80:2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydro-lFuran-2-yl) -7- (2,2, 2-trifluoroethyl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 80
Compound 80 can be prepared according to the method in example 26 or examples 5A and 26A, together with 2-bromo-1, 1, 1-trifluoroethane [421-06-7 ].
Example 81:2-amino-7- (2, 2-difluoroethyl) -9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 81
Compound 81 may be prepared according to the method in example 26 or examples 5A and 26A together with 2-bromo-1, 1-difluoroethane [359-07-9 ].
Example 82:2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (3,3, 3-trifluoropropyl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 82
Compound 82 can be prepared according to the method in example 26 or examples 5A and 26A, together with 3-bromo-1, 1, 1-trifluoropropane [460-32-2 ].
Example 83:2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (2,2,3,3, 3-pentafluoropropyl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 83
Compound 83 can be prepared according to the method in example 26 or examples 5A and 26A, together with 3-bromo-1, 1,1,2, 2-pentafluoropropane [422-01-5] or 2,2,3,3, 3-pentafluoropropyl methanesulfonate [813-31-0 ].
Example 84:2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (4,4, 4-trifluorobutyl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 84
Compound 84 can be prepared according to the methods in example 26 or examples 5A and 26A, together with 4-bromo-1, 1, 1-trifluorobutane [406-81-5 ].
Example 85:2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (3,3,4,4, 4-pentafluorobutyl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 85
Compound 85 can be prepared according to the methods in example 26 or examples 5A and 26A, together with 1,1,1,2, 2-pentafluoro-4-bromobutane [52671-70-2 ].
Example 86:3- (2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) propionitrile, Compound 86
Compound 86 can be prepared according to the method in example 26 or examples 5A and 26A, together with 3-bromopropionitrile [2417-90-5 ].
Example 87:4- (2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) butyronitrile, Compound 87
Compound 87 can be prepared according to the method in example 26 or examples 5A and 26A, together with 4-bromobutyronitrile [5332-06-9 ].
Example 88:2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7-isobutyl-7, 9-dihydro-1H-purine-6, 8-dione, Compound 88
Compound 88 can be prepared according to the methods in example 26 or examples 5A and 26A, along with 1-bromo-2-methylpropane.
Example 89:1- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) cyclopropane-1-carbonitrile, Compound 89
Compound 89 can be prepared according to the procedure in example 26 or examples 5A and 26A, together with the mesylate of 1- (hydroxymethyl) cyclopropane-1-carbonitrile [98730-77-9 ].
Example 90:1- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) cyclopropane-1-carboxylic acid, Compound 90 can be reacted with ethyl 1- (hydroxymethyl) cyclopropane-1-carboxylate [3697-68-5 ] according to the method in example 26 or examples 5A and 26A]Together with the mesylate of (a).
Example 91:2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- ((1- (trifluoromethyl) cyclopropyl) methyl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 91
Compound 91 can be prepared according to the procedure in example 26 or examples 5A and 26A, together with the mesylate of (1- (trifluoromethyl) cyclopropyl) methanol [371917-17-8 ].
Example 92:2-amino-7-benzyl-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 92
Compound 92 can be prepared according to the methods in example 27 or examples 5A and 27A, together with benzyl bromide.
Example 93:2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (4-fluorobenzyl) -7, 9-dihydro-1H-purine-6, 8-dione, compound 93
Compound 93 may be prepared according to the procedures in example 27 or examples 5A and 27A together with 4-fluorobenzyl bromide.
Example 94:2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (3-fluorobenzyl) -7, 9-dihydro-1H-purine-6, 8-dione, compound 94
Compound 94 can be prepared according to the procedure in example 27 or examples 5A and 27A, together with 3-fluorobenzyl bromide.
Example 95:2-amino-7- (3, 4-difluorobenzyl) -9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 95
Compound 95 can be prepared according to the procedure in example 27 or examples 5A and 27A, together with 3, 4-difluorobenzyl bromide.
Example 96:2-amino-7- (4-chlorobenzyl) -9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 96
Compound 96 can be prepared according to the method in example 27 or examples 5A and 27A, together with 4-chlorobenzyl bromide.
Example 97:2-amino-7- (3-chlorobenzyl) -9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 97
Compound 97 can be prepared according to the method in example 27 or examples 5A and 27A, together with 3-chlorobenzyl bromide.
Example 98:2-amino-7- (3, 4-dichlorobenzyl) -9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 98
Compound 98 can be prepared according to the method in example 27 or examples 5A and 27A, together with 3, 4-dichlorobenzyl bromide.
Example 99:4- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) benzonitrile, compound 99
Compound 99 can be prepared according to the method in example 27 or examples 5A and 27A, together with 4-cyanobenzyl bromide.
Example 100:3- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) benzonitrile Compound 100 can be prepared according to the method in example 27 or examples 5A and 27A together with 3-cyanobenzylbromide.
Example 101:methyl 4- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) benzoate, compound 101
Compound 101 can be prepared according to the methods in example 27 or examples 5A and 27A, together with methyl 4- (bromomethyl) benzoate.
Example 102:4- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) benzoic acid, compound 102 can be prepared by ester hydrolysis of compound 101.
Example 103:methyl 3- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) benzoate, compound 103
Compound 103 can be prepared according to the methods in example 27 or examples 5A and 27A, together with methyl 3- (bromomethyl) benzoate.
Example 104:3- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) benzoic acid, compound 104 can be prepared by ester hydrolysis of compound 103.
Example 105:methyl 2- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) benzoate, Compound 104
Compound 104 can be prepared according to the methods in example 27 or examples 5A and 27A, together with methyl 2- (bromomethyl) benzoate.
Example 105:2- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) benzoic acid, compound 105 can be prepared by ester hydrolysis of compound 104.
Example 106:2-amino-7- (E) -cinnamyl-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione, compound 106
Compound 106 can be prepared according to the method in example 27 or examples 5A and 27A, together with (E) -cinnamyl bromide.
Example 107:7- ((1H-pyrazol-5-yl) methyl) -2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 107
Compound 107 can be prepared according to the procedure in example 27 or examples 5A and 27A together with a mesylate of tert-butyl 5- (bromomethyl) -1H-pyrazole-1-carboxylate [1001096-27-0] or 5- (bromomethyl) -1- (4-methoxybenzyl) -1H-pyrazole [1313409-97-0] or (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) methanol [1823866-20-1 ].
Example 108:2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- ((1-methyl-1H-pyrazol-3-yl)) Methyl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 108
Compound 108 can be prepared according to the method in example 27 or examples 5A and 27A and 26A, together with 3- (bromomethyl) -1-methyl-1H-pyrazolo [102846-13-9 ].
Example 109:2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (thiophen-2-ylmethyl) -7, 9-dihydro-1H-purine-6, 8-dione, compound 109
Compound 109 can be prepared according to the method in example 27 or examples 5A and 27A and 26A, together with 2- (bromomethyl) -thiophene.
Example 110:2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (thiophen-3-ylmethyl) -7, 9-dihydro-1H-purine-6, 8-dione, compound 110
Compound 110 can be prepared according to the method in example 27 or examples 5A and 27A and 26A, together with 3- (bromomethyl) -thiophene.
Example 111:2- (2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) acetic acid, Compound 111
Compound 111 can be prepared according to the method in example 27 or examples 5A and 27A and 26A using methyl 2-bromoacetate and subsequent ester hydrolysis.
Example 112:2- (2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) acetaldehyde, Compound 112
Compound 112 can be prepared according to the procedure for example 27 from 2-bromo-1, 1-dimethoxyethane.
Example 113:2- (2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) acetonitrile), Compound 113
Compound 113 can be prepared from compound 112 by converting the aldehyde to the corresponding oxime and then dehydrating it.
Example 114：7- ((1H-tetrazol-5-yl) methyl) -2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 114
Compound 114 can be prepared according to the method in example 27 or examples 5A and 27A and 26A, together with 5- (chloromethyl) -1H-tetrazole [55408-11-2 ].
Example 115:2- (2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) -N- (methylsulfonyl) acetamide, compound 115
Compound 115 can be prepared from compound 111 and methanesulfonamide.
Example 116:2- (2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) -N-hydroxyacetamide, Compound 116
Compound 116 can be prepared from compound 111 and hydroxylamine.
Example 117:2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- ((3-hydroxyisoxazol-5-yl) methyl) -7, 9-dihydro-1H-purine-6, 8-dione, compound 117
Compound 117 can be prepared according to the procedure in example 27 or examples 5A and 27A and 26A, together with the mesylate of (3- ((4-methoxybenzyl) oxy) isoxazol-5-yl) methanol.
Example 118:methyl 5- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) thiophene-2-carboxylate, Compound 118
Compound 118 can be prepared according to the method in example 27 or examples 5A and 27A and 26A, together with methyl 5- (bromomethyl) thiophene-2-carboxylate [108499-32-7 ].
Example 119:5- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) thiophene-2-carboxylic acid, Compound 119
Compound 119 can be prepared by ester hydrolysis of compound 118.
Example 120:ethyl 5- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) thiophene-3-carboxylate, compound 120
Compound 120 can be prepared according to the method in example 27 or examples 5A and 27A and 26A, together with ethyl 5- (bromomethyl) thiophene-3-carboxylate [206860-16-4 ].
Example 121:5- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) thiophene-3-carboxylic acid, Compound 121
Compound 121 can be prepared by ester hydrolysis of compound 120.
Example 122:4- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) thiophene-2-carboxylic acid methyl ester, Compound 122
Compound 122 can be prepared according to the method in example 27 or examples 5A and 27A and 26A, together with methyl 4- (bromomethyl) thiophene-2-carboxylate [54796-51-9 ].
Example 123:4- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) thiophene-2-carboxylic acid, compound 123
Compound 123 can be prepared by ester hydrolysis of compound 122.
Example 124:(1R,2R) -2- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) cyclopropane-1-carboxylic acid, Compound 124
Compound 124 can be prepared according to the procedure in example 27 or examples 5A and 27A and 26A using a mesylate ester of ethyl (1R,2R) -2- (hydroxymethyl) cyclopropane-1-carboxylate followed by ester hydrolysis.
Example 125:7- ((E) -3- (1H-tetrazol-5-yl) allyl) -2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione, compound 125
Compound 125 can be prepared from 7-allyl-2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione and 5-vinyl-1H-tetrazole [18755-47-0 ].
Example 126:4- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) benzaldehyde compound 126 can be prepared according to the method in example 27 or examples 5A and 27A and 26A together with methyl 4- (bromomethyl) benzaldehyde.
Example 127:2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (4-methoxybenzyl) -7, 9-dihydro-1H-purine-6, 8-dione, compound 127
Compound 127 can be prepared according to the method in example 26 or examples 5A and 27A and 26A, together with 4-methoxy-benzyl bromide.
Example 128:2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (3-methoxybenzyl) -7, 9-dihydro-1H-purine-6, 8-dione, compound 128
Compound 128 can be prepared according to the method in example 26 or examples 5A and 27A and 26A, together with 3-methoxy-benzyl bromide.
Example 129:2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (3-hydroxybenzyl) -7, 9-dihydro-1H-purine-6, 8-dione, compound 129
Compound 129 can be prepared by using BBr3Compound 128 is demethylated.
Example 130:2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (4- (trifluoromethyl) benzyl) -7, 9-dihydro-1H-purine-6, 8-dione, compound 130
Compound 130 can be prepared from 2-amino-7- (4- (trifluoromethyl) benzyl) -7, 9-dihydro-1H-purine-6, 8-dione and (2S,3S,4R,5R) -5- ((benzoyloxy) methyl) -4-fluorotetrahydrofuran-2, 3-diacetic acid diester using the same general procedure described for example 35 (compound 35).
Example 131:2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (pyridin-3-ylmethyl) -7, 9-dihydro-1H-purine-6, 8-dione, compound 131
Compound 131 can be prepared according to the method in example 27 or examples 5A and 27A and 26A, together with 3-bromomethylpyridine.
Example 132:2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (2-oxo-2- (pyrrolidin-1-yl) ethyl) -7, 9-dihydro-1H-purine-6, 8-dione, compound 132
Compound 132 can be prepared according to the procedure in example 27 or examples 5A and 27A and 26A, together with bromoacetylpyrrolidine [90892-09-4 ].
Example 133:7-allyl-2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 133
Compound 133 can be prepared from N- (7-allyl-6, 8-dioxo-6, 7,8, 9-tetrahydro-1H-purin-2-yl) acetamide and (2S,3S,4R,5R) -5- ((benzoyloxy) methyl) -4-fluorotetrahydrofuran-2, 3-diacetic acid diester using the same general procedure described for example 36 (compound 36).
Example 134:2-amino-7- (cyclopropylmethyl) -9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 134
Compound 134 can be prepared according to the method in example 1 substituting 3 '-deoxy- (3' S) -fluoro-guanosine [123402-21-1] for 2-amino-9- ((2R,3R,4R,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -1, 9-dihydro-6H-purin-6-one (1) [27462-39-1] or substituting (74) for (40) according to the method in example 27A.
Example 135:2-amino-7-butyl-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione,compound 135
Compound 135 can be prepared from N- (7-butyl-6, 8-dioxo-6, 7,8, 9-tetrahydro-1H-purin-2-yl) acetamide (68) and/or N-acetyl-N- (7-butyl-6, 8-dioxo-6, 7,8, 9-tetrahydro-1H-purin-2-yl) acetamide (68a) and (2S,3S,4R,5R) -5- ((benzoyloxy) methyl) -4-fluorotetrahydrofuran-2, 3-diacetic acid diester using the same general procedure described for example 37 (compound 37).
Example 136:2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (methoxymethyl) -7, 9-dihydro-1H-purine-6, 8-dione, compound 136
Compound 136 can be prepared according to the procedure in example 27 using chloromethyl methyl ether.
Example 137:2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- ((methylthio) methyl) -7, 9-dihydro-1H-purine-6, 8-dione, compound 137
Compound 137 can be prepared according to the procedure in example 27 using chloromethyl methyl sulfide.
Example 138:2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (2,2, 2-trifluoroethyl) -7, 9-dihydro-1H-purine-6, 8-dione, compound 138
Compound 138 can be prepared according to the procedure in example 27 or examples 5A and 27A and 26A, together with 2-bromo-1, 1, 1-trifluoroethane [421-06-7 ].
Example 139:2-amino-7- (2, 2-difluoroethyl) -9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 139
Compound 139 can be prepared according to the procedure in example 27 or examples 5A and 27A and 26A, together with 2-bromo-1, 1-difluoroethane [359-07-9 ].
Example 140:2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (3,3, 3-trifluoropropyl) -7, 9-dihydro-1H-purine-6, 8-dione, compound 140
Compound 140 can be prepared according to the method in example 26 or examples 5A and 27A and 26A, together with 3-bromo-1, 1, 1-trifluoropropane [460-32-2 ].
Example 141:2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (2,2,3,3, 3-pentafluoropropyl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 141
Compound 141 can be prepared according to the method in example 27 or examples 5A and 27A and 26A, together with 3-bromo-1, 1,1,2, 2-pentafluoropropane [422-01-5] or 2,2,3,3, 3-pentafluoropropyl methanesulfonate [813-31-0 ].
Example 142:2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (4,4, 4-trifluorobutyl) -7, 9-dihydro-1H-purine-6, 8-dione, compound 142
Compound 142 can be prepared according to the method in example 27 or examples 5A and 27A and 26A, together with 4-bromo-1, 1, 1-trifluorobutane [406-81-5 ].
Example 143:2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (3,3,4,4, 4-pentafluorobutyl) -7, 9-dihydro-1H-purine-6, 8-dione, compound 143
Compound 143 can be prepared according to the method in example 27 or examples 5A and 27A and 26A, together with 1,1,1,2, 2-pentafluoro-4-bromobutane [52671-70-2 ].
Example 144:3- (2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) propionitrile, compound 144
Compound 144 can be prepared according to the procedure in example 27 or examples 5A and 27A and 26A, together with 3-bromopropionitrile [2417-90-5 ].
Example 145:4- (2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) butyronitrile, Compound 145
Compound 145 can be prepared according to the procedure in example 27 or examples 5A and 27A and 26A, together with 3-bromobutyronitrile [5332-06-9 ].
Example 146:2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7-isobutyl-7, 9-dihydro-1H-purine-6, 8-dione, Compound 146
Compound 146 can be prepared according to the method in example 27 or examples 5A and 27A and 26A, together with 1-bromo-2-methylpropane.
Example 147:1- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) cyclopropane-1-carbonitrile, Compound 147
Compound 147 can be prepared according to the procedure in example 27 or examples 5A and 27A and 26A, together with the mesylate of 1- (hydroxymethyl) cyclopropane-1-carbonitrile [98730-77-9 ].
Example 148:1- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -6, 8-dioxo-1, 6,8, 9-tetrahydro-7H-purin-7-yl) methyl) cyclopropane-1-carboxylic acid, compound 148
Compound 148 can be prepared according to the procedure in example 27 or examples 5A and 27A and 26A, together with the mesylate of ethyl 1- (hydroxymethyl) cyclopropane-1-carboxylate [3697-68-5 ].
Example 149:2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- ((1- (trifluoromethyl) cyclopropyl) methyl) -7, 9-dihydro-1H-purine-6, 8-dione, Compound 149
Compound 149 may be prepared according to the procedure in example 27 or examples 5A and 27A and 26A together with (1- (trifluoromethyl) cyclopropyl) methanol [371917-17-8 ].
Example 150:((2S,4R,5R) -4-acetoxy-5- (2-amino-7-benzyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate, Compound 150
Compound 150 can be prepared according to the procedure outlined in example 29, substituting benzyl bromide for propargyl bromide.
Example 151:2-amino-7-benzyl-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-one, Compound 151
Compound 151 can be prepared by ester hydrolysis of compound 150 according to the procedure outlined in example 30, or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide and (2S,3R,5S) -5- ((benzoyloxy) methyl) tetrahydrofuran-2, 3-diacetic acid diester with benzyl bromide instead of propargyl bromide.
Example 152:((2S,4R,5R) -4-acetoxy-5- (2-amino-7- (4-fluorobenzyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate, Compound 152
Compound 152 can be prepared according to the procedure outlined in example 29 substituting 4-fluorobenzyl bromide for propargyl bromide.
Example 153:2-amino-7- (4-fluorobenzyl) -9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-one, Compound 153
Compound 153 can be prepared by ester hydrolysis of compound 150 according to the procedure outlined in example 30, or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide and (2S,3R,5S) -5- ((benzoyloxy) methyl) tetrahydrofuran-2, 3-diacetic acid diester, substituting 4-fluorobenzyl bromide for propargyl bromide.
Example 154:((2S,4R,5R) -4-acetoxy-5- (2-amino-7- (3-fluorobenzyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate, Compound 154
Compound 154 can be prepared according to the procedure outlined in example 29 substituting 3-fluorobenzyl bromide for propargyl bromide.
Example 155:2-amino-7- (3-fluorobenzyl) -9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-one, Compound 155
Compound 155 can be prepared by ester hydrolysis of compound 154 according to the procedure outlined in example 30, or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide and (2S,3R,5S) -5- ((benzoyloxy) methyl) tetrahydrofuran-2, 3-diacetic acid diester, substituting 3-fluorobenzyl bromide for propargyl bromide.
Example 156:((2S,4R,5R) -4-acetoxy-5- (2-amino-7- (3, 4-difluorobenzyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate, Compound 156
Compound 156 can be prepared according to the procedure outlined in example 29 substituting 3, 4-difluorobenzyl bromide for propargyl bromide.
Example 157:2-amino-7- (3, 4-difluorobenzyl) -9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-one, compound 157
Compound 157 can be prepared according to the procedure outlined in example 30 by ester hydrolysis of compound 156 or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide and (2S,3R,5S) -5- ((benzoyloxy) methyl) tetrahydrofuran-2, 3-diacetic acid diester with 3, 4-difluorobenzyl bromide replacing propargyl bromide.
Example 158:((2S,4R,5R) -4-acetoxy-5- (2-amino-7- (4-chlorobenzyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate, Compound 158
Compound 158 can be prepared according to the procedure outlined in example 29 substituting 4-chlorobenzyl bromide for propargyl bromide.
Example 159:2-amino-7- (4-chlorobenzyl) -9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-one, Compound 159
Compound 159 can be prepared by ester hydrolysis of compound 158 according to the procedure outlined in example 30, or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide and (2S,3R,5S) -5- ((benzoyloxy) methyl) tetrahydrofuran-2, 3-diacetic acid diester, substituting 4-chlorobenzyl bromide for propargyl bromide.
Example 160:((2S,4R,5R) -4-acetoxy-5- (2-amino-7- (3-chlorobenzyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate, Compound 160
Compound 160 can be prepared according to the procedure outlined in example 29, substituting 3-chlorobenzyl bromide for propargyl bromide.
Example 161:2-amino-7- (3-chlorobenzyl) -9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-one, Compound 161
Compound 161 can be prepared by ester hydrolysis of compound 160 according to the procedure outlined in example 30, or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide and (2S,3R,5S) -5- ((benzoyloxy) methyl) tetrahydrofuran-2, 3-diacetic acid diester, substituting 3-chlorobenzyl bromide for propargyl bromide.
Example 162:((2S,4R,5R) -4-acetoxy-5- (2-amino-7- (3, 4-dichlorobenzyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate, Compound 162
Compound 162 can be prepared according to the procedure outlined in example 29 substituting 3, 4-dichlorobenzyl bromide for propargyl bromide.
Example 163:2-amino-7- (3, 4-dichlorobenzyl) -9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-one, compound 163
Compound 163 can be prepared by ester hydrolysis of compound 162 according to the procedure outlined in example 30, or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide and (2S,3R,5S) -5- ((benzoyloxy) methyl) tetrahydrofuran-2, 3-diacetic acid diester, substituting 3, 4-dichlorobenzyl bromide for propargyl bromide.
Example 164:((2S,4R,5R) -4-acetoxy-5- (2-amino-7- (4-cyanobenzyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate, Compound 164
Compound 164 can be prepared according to the procedure outlined in example 29, substituting 4-cyanobenzyl bromide for propargyl bromide.
Example 165:4- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5)- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) benzonitrile compound 165
Compound 165 can be prepared by ester hydrolysis of compound 164 according to the procedure outlined in example 30, or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide and the diester of (2S,3R,5S) -5- ((benzoyloxy) methyl) tetrahydrofuran-2, 3-diacetic acid using 4-cyanobenzylbromide instead of propargyl bromide.
Example 166:((2S,4R,5R) -4-acetoxy-5- (2-amino-7- (3-cyanobenzyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate, Compound 166
Compound 166 can be prepared according to the procedure outlined in example 29, substituting 3-cyanobenzyl bromide for propargyl bromide.
Example 167: 3- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) benzonitrile compound 167
Compound 167 can be prepared according to the procedure outlined in example 30 by ester hydrolysis of compound 166 or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide and (2S,3R,5S) -5- ((benzoyloxy) methyl) tetrahydrofuran-2, 3-diacetic acid diester using 3-cyanobenzylbromide instead of propargyl bromide.
Example 168:methyl 4- ((9- ((2R,3R,5S) -3-acetoxy-5- (acetoxymethyl) tetrahydrofuran-2-yl) -2-amino-8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) benzoate compound 168 can be prepared according to the procedure outlined in example 29, substituting methyl 4-bromomethylbenzoate for propargyl bromide.
Example 168 a:methyl 4- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) benzoate, Compound 168a
Compound 168a can be prepared by exposing compound 168 to potassium carbonate in anhydrous methanol.
Example 169:4- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) benzoic acid, compound 169
Compound 169 can be prepared by ester hydrolysis of compound 168 according to the procedure outlined in example 30, or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide and (2S,3R,5S) -5- ((benzoyloxy) methyl) tetrahydrofuran-2, 3-diacetic acid diester, substituting methyl 4-bromomethylbenzoate for propargyl bromide.
Example 170:methyl 3- ((9- ((2R,3R,5S) -3-acetoxy-5- (acetoxymethyl) tetrahydrofuran-2-yl) -2-amino-8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) benzoate, Compound 170
Compound 170 can be prepared according to the procedure outlined in example 29 substituting methyl 3-bromomethylbenzoate for propargyl bromide.
Example 170 a:methyl 3- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) benzoate, Compound 170a
Compound 170a can be prepared by exposing compound 170 to potassium carbonate in anhydrous methanol.
Example 171:3- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) benzoic acid, compound 171
Compound 171 can be prepared by ester hydrolysis of compound 170 according to the procedure outlined in example 30, or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide and (2S,3R,5S) -5- ((benzoyloxy) methyl) tetrahydrofuran-2, 3-diacetic acid diester, replacing propargyl bromide with methyl 3-bromomethylbenzoate.
Example 172:2- ((9- ((2R,3R,5S) -3-acetoxy-5- (acetoxymethyl) tetrahydrofuran-2-yl) -2-amino-8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) benzoic acidMethyl ester, Compound 172
Compound 172 can be prepared according to the procedure outlined in example 29 substituting methyl 2-bromomethylbenzoate for propargyl bromide.
Example 172 a:methyl 2- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) benzoate, Compound 172a
Compound 172a can be prepared by exposing compound 172 to potassium carbonate in anhydrous methanol.
Example 173:2- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) benzoic acid, compound 173
Compound 173 can be prepared according to the procedure outlined in example 30 by ester hydrolysis of compound 172 or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide and (2S,3R,5S) -5- ((benzoyloxy) methyl) tetrahydrofuran-2, 3-diacetic acid diester, substituting methyl 2-bromomethylbenzoate for propargyl bromide.
Example 174:((2S,4R,5R) -4-acetoxy-5- (2-amino-7- (E) -cinnamyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate, Compound 174
Compound 174 can be prepared according to the procedure outlined in example 29 substituting (E) -cinnamyl bromide for propargyl bromide.
Example 175:2-amino-7- (E) -cinnamyl-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-one, compound 175
Compound 175 can be prepared according to the procedure outlined in example 30 by ester hydrolysis of compound 174 or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide and (2S,3R,5S) -5- ((benzoyloxy) methyl) tetrahydrofuran-2, 3-diacetic acid diester with (E) -cinnamyl bromide instead of propargyl bromide.
Example 176:((2S,4R,5R) -5- (7- ((1H-pyrazol-5-yl) methyl) -2-amino-8-oxo-7, 8-dihydro-9H-purin-9-yl) -4-acetoxytetrahydrofuran-2-yl) methyl acetate, Compound 176
Compound 176 can be prepared according to the procedure for example 29, substituting propargyl bromide with the mesylate of tert-butyl 5- (bromomethyl) -1H-pyrazole-1-carboxylate [1001096-27-0] or 5- (bromomethyl) -1- (4-methoxybenzyl) -1H-pyrazole [1313409-97-0] or (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) methanol [1823866-20-1 ].
Example 177:7- ((1H-pyrazol-5-yl) methyl) -2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-one, Compound 177
Compound 177 can be hydrolyzed by the ester of compound 176 according to the procedure outlined in example 30, or prepared from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide and (2S,3R,5S) -5- ((benzoyloxy) methyl) tetrahydrofuran-2, 3-diacetic acid diester using the method described in example 32A, using a mesylate of 5- (bromomethyl) -1H-pyrazole-1-carboxylic acid tert-butyl ester or 5- (bromomethyl) -1- (4-methoxybenzyl) -1H-pyrazole or (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) methanol instead of propargyl bromide.
Example 178:((2S,4R,5R) -4-acetoxy-5- (2-amino-7- ((1-methyl-1H-pyrazol-3-yl) methyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate, Compound 178
Compound 178 can be prepared according to the procedure outlined in example 29, substituting 3- (bromomethyl) -1-methyl-1H-pyrazolo [102846-13-9] for propargyl bromide.
Example 179:2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- ((1-methyl-1H-pyrazol-3-yl) methyl) -7, 9-dihydro-8H-purin-8-one, compound 179
Compound 179 can be prepared according to the procedure outlined in example 30 by ester hydrolysis of compound 178, or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide and the diester of (2S,3R,5S) -5- ((benzoyloxy) methyl) tetrahydrofuran-2, 3-diacetic acid, replacing propargyl bromide with 3- (bromomethyl) -1-methyl-1H-pyrazole.
Example 180:((2S,4R,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (thiophen-2-ylmethyl) -7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate, Compound 180
Compound 180 can be prepared according to the procedure outlined in example 29, substituting 2- (bromomethyl) -thiophene for propargyl bromide.
Example 181:2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (thien-2-ylmethyl) -7, 9-dihydro-8H-purin-8-one, Compound 181
Compound 181 can be prepared by ester hydrolysis of compound 180 according to the procedure outlined in example 30, or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide and (2S,3R,5S) -5- ((benzoyloxy) methyl) tetrahydrofuran-2, 3-diacetic acid diester, substituting 2- (bromomethyl) -thiophene for propargyl bromide.
Example 182:((2S,4R,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (thiophen-2-ylmethyl) -7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-3-yl) methyl acetate, Compound 182
Compound 182 can be prepared according to the procedure outlined in example 29 substituting 3- (bromomethyl) -thiophene for propargyl bromide.
Example 183:2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (thien-3-ylmethyl) -7, 9-dihydro-8H-purin-8-one, compound 183
Compound 183 can be prepared according to the procedure outlined in example 30 by ester hydrolysis of compound 182, or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide and (3S,3R,5S) -5- ((benzoyloxy) methyl) tetrahydrofuran-2, 3-diacetic acid diester, substituting 2- (bromomethyl) -thiophene for propargyl bromide.
Example 184:2- (9- ((2R,3R,5S) -3-acetoxy-5- (acetoxy)Methyl) tetrahydrofuran-2-yl) -2-amino-8-oxo-8, 9-dihydro-7H-purin-7-yl) acetic acid methyl ester, Compound 184
Compound 184 can be prepared according to the procedure outlined in example 29 substituting propargyl bromide with methyl 2-bromoacetate.
Example 184 a:methyl 2- (2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) acetate Compound 184a
Compound 184a can be prepared by exposing compound 184 to potassium carbonate in anhydrous methanol.
Example 185:2- (2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) acetic acid, compound 185
Compound 185 can be prepared by ester hydrolysis of compound 184 under aqueous conditions using the modification procedure outlined in example 30, or from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide and (2S,3R,5S) -5- ((benzoyloxy) methyl) tetrahydrofuran-2, 3-diacetic acid diester using the procedure described in example 32A, replacing propargyl bromide with methyl 2-bromoacetate and subsequent ester hydrolysis.
Example 186: ((2S,4R,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (2-oxoethyl) -7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate, Compound 186
Compound 186 can be prepared according to the general method outlined in example 29, substituting 2-bromo-1, 1-dimethoxyethane for propargyl bromide, followed by aqueous acid treatment.
Example 187:2- (2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) acetaldehyde, compound 187
Compound 187 can be prepared by basic hydrolysis of compound 186, or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide and (2S,3R,5S) -5- ((benzoyloxy) methyl) tetrahydrofuran-2, 3-diacetic acid diester, substituting propargyl bromide with 2-bromo-1, 1-dimethoxyethane followed by acetal and ester hydrolysis.
Example 188:((2S,4R,5R) -4-acetoxy-5- (2-amino-7- (cyanomethyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate, Compound 188
Compound 188 can be prepared according to the general method outlined in example 29, substituting 2-bromoacetonitrile for propargyl bromide.
Example 189:2- (2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) acetonitrile, compound 189
Compound 189 can be prepared by hydrolyzing compound 188 or from compound 187 by converting the aldehyde to the corresponding oxime, which is then dehydrated.
Example 190:((2S,4R,5R) -5- (7- ((1H-tetrazol-5-yl) methyl) -2-amino-8-oxo-7, 8-dihydro-9H-purin-9-yl) -4-acetoxytetrahydrofuran-2-yl) methyl acetate Compound 190
Compound 190 can be prepared according to the procedure outlined in example 29 substituting 5- (chloromethyl) -1H-tetrazole [55408-11-2] for propargyl bromide.
Example 191:7- ((1H-tetrazol-5-yl) methyl) -2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-one, Compound 191
Compound 191 can be prepared by ester hydrolysis of compound 190 according to the procedure outlined in example 30, or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide and (2S,3R,5S) -5- ((benzoyloxy) methyl) tetrahydrofuran-2, 3-diacetic acid diester, using 5- (chloromethyl) -1H-tetrazole instead of propargyl bromide.
Example 192:2- (2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) -N- (methylsulfonyl) acetamide, compound 192
Compound 192 can be prepared from compound 185 and methanesulfonamide.
Example 193:2- (2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) -N-hydroxyacetamide, Compound 193
Compound 193 can be prepared from compound 185 and hydroxylamine.
Example 194:((2S,4R,5R) -4-acetoxy-5- (2-amino-7- ((3-hydroxyisoxazol-5-yl) methyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate, Compound 194
Compound 194 can be prepared according to the procedure outlined in example 29 together with the mesylate of (3- ((4-methoxybenzyl) oxy) isoxazol-5-yl) methanol.
Example 195:2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- ((3-hydroxyisoxazol-5-yl) methyl) -7, 9-dihydro-8H-purin-8-one, compound 195
Compound 195 can be prepared by ester hydrolysis of compound 194 according to the methods outlined in example 30.
Example 196:methyl 5- ((9- ((2R,3R,5S) -3-acetoxy-5- (acetoxymethyl) tetrahydrofuran-2-yl) -2-amino-8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) thiophene-2-carboxylate, Compound 196
Compound 196 can be prepared according to the procedure outlined in example 29, using methyl 5- (bromomethyl) thiophene-2-carboxylate [108499-32-7] together.
Example 196 a:methyl 5- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) thiophene-2-carboxylate, Compound 196a
Compound 196a can be prepared by exposing compound 196 to potassium carbonate in anhydrous methanol.
Example 197:5- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) thiophene-2-carboxylic acid, Compound 197
Compound 197 can be prepared by ester hydrolysis of compound 196 according to the procedure outlined in example 30.
Example 198:ethyl 5- ((9- ((2R,3R,5S) -3-acetoxy-5- (acetoxymethyl) tetrahydrofuran-2-yl) -2-amino-8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) thiophene-3-carboxylate, compound 198
Compound 198 can be prepared according to the procedure outlined in example 29, using ethyl 5- (bromomethyl) thiophene-3-carboxylate [206860-16-4] together.
Example 198 a:ethyl 5- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) thiophene-3-carboxylate, compound 198a
Compound 198a can be prepared by exposing compound 198 to potassium carbonate in dry ethanol.
Example 199:5- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) thiophene-3-carboxylic acid, Compound 199
Compound 199 can be prepared by ester hydrolysis of compound 198 according to the procedure outlined in example 30.
Example 200:4- ((9- ((2R,3R,5S) -3-acetoxy-5- (acetoxymethyl) tetrahydrofuran-2-yl) -2-amino-8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) thiophene-2-carboxylic acid methyl ester Compound 200 can be prepared according to the method outlined in example 29 using 4- (bromomethyl) thiophene-2-carboxylic acid methyl ester [54796-51-9]Are prepared together.
Example 200 a:4- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) thiophene-2-carboxylic acid methyl ester, Compound 200a
Compound 200a may be prepared by exposing compound 200 to potassium carbonate in anhydrous methanol.
Example 201:4- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) thiophene-2-carboxylic acid, compound 201
Compound 201 can be prepared by ester hydrolysis of compound 200 according to the procedure outlined in example 30.
Example 202:(1R,2R) -2- ((9- ((2R,3R,5S) -3-acetoxy-5- (acetoxymethyl) tetrahydrofuran-2-yl) -2-amino-8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) cyclopropane-1-carboxylic acid ethyl ester, Compound 202
Compound 202 can be prepared according to the procedure outlined in example 29, along with the mesylate of ethyl (1R,2R) -2- (hydroxymethyl) cyclopropane-1-carboxylate.
Example 202 a:(1R,2R) -2- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) cyclopropane-1-carboxylic acid ethyl ester, Compound 202a
Compound 202a can be prepared by exposing compound 202 to potassium carbonate in dry ethanol.
Example 203:(1R,2R) -2- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) cyclopropane-1-carboxylic acid, Compound 203
Compound 203 can be prepared by ester hydrolysis of compound 202 according to the methods outlined in example 30.
Example 204:((2S,4R,5R) -5- (7- ((E) -3- (1H-tetrazol-5-yl) allyl) -2-amino-8-oxo-7, 8-dihydro-9H-purin-9-yl) -4-acetoxytetrahydrofuran-2-yl) methyl acetate, Compound 204
Compound 204 can be prepared from ((2S,4R,5R) -4-acetoxy-5- (7-allyl-2-amino-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate and 5-vinyl-1H-tetrazole [18755-47-0] by an olefin metathesis-type reaction.
Example 205:7- ((E) -3- (1H-tetrazol-5-yl) allyl) -2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-one, Compound 205
Compound 205 can be prepared by ester hydrolysis of compound 204 according to the methods outlined in example 30.
Practice ofExample 206:((2S,4R,5R) -4-acetoxy-5- (2-amino-7- (4-formylbenzyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate, Compound 206
Compound 206 can be prepared according to the procedure outlined in example 29 substituting 4- (bromomethyl) benzaldehyde for propargyl bromide.
Example 207:4- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) benzaldehyde, compound 207
Compound 207 can be prepared by ester hydrolysis of compound 206 according to the procedure outlined in example 30, or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide and (4S,3R,5S) -5- ((benzoyloxy) methyl) tetrahydrofuran-2, 3-diacetic acid diester, replacing propargyl bromide with 4- (bromomethyl) benzaldehyde.
Example 208:((2S,4R,5R) -4-acetoxy-5- (2-amino-7- (4-methoxybenzyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate, Compound 208
Compound 208 can be prepared according to the procedure outlined in example 29, substituting 4-methoxy-benzyl bromide for propargyl bromide.
Example 209:2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (4-methoxybenzyl) -7, 9-dihydro-8H-purin-8-one, compound 209
Compound 209 can be prepared by ester hydrolysis of compound 208 according to the methods outlined in example 30.
Example 210:((2S,4R,5R) -4-acetoxy-5- (2-amino-7- (3-methoxybenzyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate, Compound 210
Compound 210 can be prepared according to the procedure outlined in example 29, substituting 3-methoxy-benzyl bromide for propargyl bromide.
Example 211:2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7-, (3-methoxybenzyl) -7, 9-dihydro-8H-purin-8-one, Compound 211
Compound 211 can be prepared by ester hydrolysis of compound 210 according to the procedure outlined in example 30, or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide and (2S,3R,5S) -5- ((benzoyloxy) methyl) tetrahydrofuran-2, 3-diacetic acid diester using 3-methoxy-benzyl bromide instead of propargyl bromide.
Example 212:((2S,4R,5R) -4-acetoxy-5- (2-amino-7- (3-hydroxybenzyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate, Compound 212
Compound 212 can be prepared by using BBr3Compound 211 is demethylated.
Example 213:2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (3-hydroxybenzyl) -7, 9-dihydro-8H-purin-8-one, Compound 213
Compound 213 can be prepared by ester hydrolysis of compound 212 according to the procedure outlined in example 30.
Example 214:((2S,4R,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (4- (trifluoromethyl) benzyl) -7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate, Compound 214
Compound 214 can be prepared according to the procedure outlined in example 29, substituting 4-trifluoromethyl-benzyl bromide for propargyl bromide.
Example 215:2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (4- (trifluoromethyl) benzyl) -7, 9-dihydro-8H-purin-8-one, compound 215
Compound 215 can be prepared according to the procedure outlined in example 30 by ester hydrolysis of compound 214, or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide and (2S,3R,5S) -5- ((benzoyloxy) methyl) tetrahydrofuran-2, 3-diacetic acid diester, using 4-trifluoromethyl-benzyl bromide instead of propargyl bromide.
Example 216:((2S,4R,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (pyridin-3-ylmethyl) -7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate, Compound 216
Compound 216 can be prepared according to the procedure outlined in example 29, substituting 3- (bromomethyl) pyridine for propargyl bromide.
Example 217:2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (pyridin-3-ylmethyl) -7, 9-dihydro-8H-purin-8-one, Compound 217
Compound 217 can be prepared by ester hydrolysis of compound 216 according to the procedure outlined in example 30, or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide and (3S,3R,5S) -5- ((benzoyloxy) methyl) tetrahydrofuran-2, 3-diacetic acid diester, replacing propargyl bromide with 3- (bromomethyl) pyridine.
Example 218:((2S,4R,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (2-oxo-2- (pyrrolidin-1-yl) ethyl) -7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate, Compound 218
Compound 218 can be prepared according to the procedure outlined in example 29 substituting bromoacetylpyrrolidine [90892-09-4] for propargyl bromide.
Example 219:2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (2-oxo-2- (pyrrolidin-1-yl) ethyl) -7, 9-dihydro-8H-purin-8-one, compound 219
Compound 219 can be prepared by ester hydrolysis of compound 218 according to the procedure outlined in example 30, or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide and (2S,3R,5S) -5- ((benzoyloxy) methyl) tetrahydrofuran-2, 3-diacetic acid diester, with pyrrolidine bromoacetate instead of propargyl bromide.
Example 220:((2S,4R,5R) -4-acetoxy-5- (7-allyl-2-amino-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate, Compound 220
Compound 220 can be prepared according to the procedure outlined in example 29, substituting allyl bromide for propargyl bromide.
Example 221:7-allyl-2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-one, Compound 221
Compound 221 can be prepared by ester hydrolysis of compound 220 according to the procedure outlined in example 30, or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide and (2S,3R,5S) -5- ((benzoyloxy) methyl) tetrahydrofuran-2, 3-diacetic acid diester with allyl bromide instead of propargyl bromide.
Example 222:((2S,4R,5R) -4-acetoxy-5- (2-amino-7- (cyclopropylmethyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate, Compound 222
Compound 222 can be prepared according to the procedure outlined in example 29 substituting (bromomethyl) cyclopropane for propargyl bromide.
Example 223:2-amino-7- (cyclopropylmethyl) -9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-one compound 223
Compound 223 can be prepared by ester hydrolysis of compound 222 according to the procedure outlined in example 30, or using the procedure described in example 32A from (2S,3R,5S) -5- ((benzoyloxy) methyl) tetrahydrofuran-2, 3-diacetic acid diester and replacing (45) with (71).
Example 224:((2S,4R,5R) -4-acetoxy-5- (2-amino-7-butyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate, Compound 224
Compound 224 can be prepared according to the procedure outlined in example 29, substituting propargyl bromide with n-butyl bromide.
Example 225:2-amino-7-butyl-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-one, Compound 225
Compound 225 can be prepared according to the procedure outlined in example 30 by ester hydrolysis of compound 224 or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide and (2S,3R,5S) -5- ((benzoyloxy) methyl) tetrahydrofuran-2, 3-diacetic acid diester with N-butyl bromide instead of propargyl bromide.
Example 226:((2S,4R,5R) -4-acetoxy-5- (2-amino-7- (methoxymethyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate, Compound 226
Compound 226 can be prepared according to the procedure outlined in example 29, substituting chloromethyl methyl ether for propargyl bromide.
Example 227:2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (methoxymethyl) -7, 9-dihydro-8H-purin-8-one, Compound 227
Compound 227 can be prepared according to the procedure outlined in example 30 by ester hydrolysis of compound 226, or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide and (2S,3R,5S) -5- ((benzoyloxy) methyl) tetrahydrofuran-2, 3-diacetic acid diester, using chloromethyl methyl ether instead of propargyl bromide.
Example 228:((2S,4R,5R) -4-acetoxy-5- (2-amino-7- ((methylthio) methyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate, Compound 228
Compound 228 can be prepared according to the procedure outlined in example 29 substituting chloromethyl methyl sulfide for propargyl bromide.
Example 229:2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- ((methylthio) methyl) -7, 9-dihydro-8H-purin-8-one, Compound 229
Compound 229 can be prepared by ester hydrolysis of compound 228 according to the procedure outlined in example 30, or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide and (2S,3R,5S) -5- ((benzoyloxy) methyl) tetrahydrofuran-2, 3-diacetic acid diester using chloromethyl methyl sulfide instead of propargyl bromide.
Example 230:((2S,4R,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (2,2, 2-trifluoroethyl) -7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate, Compound 230
Compound 230 can be prepared according to the general method outlined in example 29, substituting 2-bromo-1, 1, 1-trifluoroethane [421-06-7] for propargyl bromide.
Example 231:2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (2,2, 2-trifluoroethyl) -7, 9-dihydro-8H-purin-8-one, compound 231
Compound 231 can be prepared by ester hydrolysis of compound 230 according to the procedure outlined in example 30, or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide and the diester of (2S,3R,5S) -5- ((benzoyloxy) methyl) tetrahydrofuran-2, 3-diacetic acid, substituting 2-bromo-1, 1, 1-trifluoroethane for propargyl bromide.
Example 232:((2S,4R,5R) -4-acetoxy-5- (2-amino-7- (2, 2-difluoroethyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate, Compound 232
Compound 232 can be prepared according to the general method outlined in example 29, substituting 2-bromo-1, 1-difluoroethane [359-07-9] for propargyl bromide.
Example 233:2-amino-7- (2, 2-difluoroethyl) -9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-one, compound 233
Compound 233 can be prepared according to the procedure outlined in example 30 by ester hydrolysis of compound 232 or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide and (2S,3R,5S) -5- ((benzoyloxy) methyl) tetrahydrofuran-2, 3-diacetic acid diester, substituting 2-bromo-1, 1-difluoroethane for propargyl bromide.
Example 234:((2S,4R,5R) -4-acetoxy-5- (2-amino-8-oxo-7-)(3,3, 3-trifluoropropyl) -7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate, Compound 234
Compound 234 can be prepared according to the general method outlined in example 29, substituting 3-bromo-1, 1, 1-trifluoropropane [460-32-2] for propargyl bromide.
Example 235:2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (3,3, 3-trifluoropropyl) -7, 9-dihydro-8H-purin-8-one, compound 235
Compound 235 can be prepared according to the procedure outlined in example 30 by ester hydrolysis of compound 234, or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide and the diester of (3S,3R,5S) -5- ((benzoyloxy) methyl) tetrahydrofuran-2, 3-diacetic acid, substituting 3-bromo-1, 1, 1-trifluoropropane for propargyl bromide.
Example 236:((2S,4R,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (2,2,3,3, 3-pentafluoropropyl) -7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate, Compound 236
Compound 236 can be prepared according to the general method outlined in example 29, substituting 3-bromo-1, 1,1,2, 2-pentafluoropropane [422-01-5] or 2,2,3,3, 3-pentafluoropropyl methanesulfonate [813-31-0] for propargyl bromide.
Example 237:2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (2,2,3,3, 3-pentafluoropropyl) -7, 9-dihydro-8H-purin-8-one, Compound 237
Compound 237 can be prepared by ester hydrolysis of compound 236 according to the procedure outlined in example 30, or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide and (3S,3R,5S) -5- ((benzoyloxy) methyl) tetrahydrofuran-2, 3-diacetic acid diester using 3-bromo-1, 1,1,2, 2-pentafluoropropane or 2,2,3,3, 3-pentafluoropropylmethanesulfonate instead of propargyl bromide.
Example 238:((2S,4R,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (4,4, 4-trifluorobutyl) -7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methylAcetic acid ester, Compound 238
Compound 238 can be prepared according to the general method outlined in example 29, substituting 4-bromo-1, 1, 1-trifluorobutane [406-81-5] for propargyl bromide.
Example 239:2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (4,4, 4-trifluorobutyl) -7, 9-dihydro-8H-purin-8-one, compound 239
Compound 239 can be prepared according to the procedure outlined in example 30 by ester hydrolysis of compound 238, or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide and (4S,3R,5S) -5- ((benzoyloxy) methyl) tetrahydrofuran-2, 3-diacetic acid diester, using 4-bromo-1, 1, 1-trifluorobutane instead of propargyl bromide.
Example 240:((2S,4R,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (3,3,4,4, 4-pentafluorobutyl) -7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate compound 240
Compound 240 can be prepared according to the procedure outlined in example 29 substituting 1,1,1,2, 2-pentafluoro-4-bromobutane [52671-70-2] for propargyl bromide.
Example 241:2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (3,3,4,4, 4-pentafluorobutyl) -7, 9-dihydro-8H-purin-8-one, Compound 241
Compound 241 can be prepared by ester hydrolysis of compound 240 according to the procedure outlined in example 30, or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide and (2S,3R,5S) -5- ((benzoyloxy) methyl) tetrahydrofuran-2, 3-diacetic acid diester with 1,1,1,2, 2-pentafluoro-4-bromobutane instead of propargyl bromide.
Example 242:((2S,4R,5R) -4-acetoxy-5- (2-amino-7- (2-cyanoethyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate, Compound 242
Compound 242 can be prepared according to the procedure outlined in example 29, substituting 3-bromopropionitrile [2417-90-5] for propargyl bromide.
Example 243:3- (2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) propionitrile, Compound 243
Compound 243 can be prepared according to the procedure outlined in example 30 by ester hydrolysis of compound 242, or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide and the diester of (2S,3R,5S) -5- ((benzoyloxy) methyl) tetrahydrofuran-2, 3-diacetic acid, substituting 3-bromopropionitrile for propargyl bromide.
Example 244:((2S,4R,5R) -4-acetoxy-5- (2-amino-7- (3-cyanopropyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate, Compound 244
Compound 244 can be prepared according to the procedure outlined in example 29 substituting 4-bromobutyronitrile [5332-06-9] for propargyl bromide.
Example 245:4- (2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) butanenitrile, compound 245
Compound 245 can be prepared according to the procedure outlined in example 30 by ester hydrolysis of compound 244 or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide and the diester of (2S,3R,5S) -5- ((benzoyloxy) methyl) tetrahydrofuran-2, 3-diacetic acid, substituting 4-bromobutyronitrile for propargyl bromide.
Example 246:((2S,4R,5R) -4-acetoxy-5- (2-amino-7-isobutyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate, Compound 246
Compound 246 can be prepared according to the procedure outlined in example 29 substituting 1-bromo-2-methylpropane for propargyl bromide.
Example 247:2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7-isobutyl-7, 9-dihydro-8H-purin-8-one, Compound 247
Compound 247 can be prepared by ester hydrolysis of compound 246 according to the procedure outlined in example 30, or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide and (1S,3R,5S) -5- ((benzoyloxy) methyl) tetrahydrofuran-2, 3-diacetic acid diester, replacing propargyl bromide with 1-bromo-2-methylpropane.
Example 248:((2S,4R,5R) -4-acetoxy-5- (2-amino-7- ((1-cyanocyclopropyl) methyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate, Compound 248
Compound 248 can be prepared according to the procedure outlined in example 29, substituting 1- (hydroxymethyl) cyclopropane-1-carbonitrile [98730-77-9] with its mesylate instead of propargyl bromide.
Example 249:1- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) cyclopropane-1-carbonitrile, Compound 249
Compound 249 can be prepared by ester hydrolysis of compound 248 according to the procedure outlined in example 30, or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide and (2S,3R,5S) -5- ((benzoyloxy) methyl) tetrahydrofuran-2, 3-diacetic acid diester, using the mesylate of 1- (hydroxymethyl) cyclopropane-1-carbonitrile instead of propargyl bromide.
Example 250:ethyl 1- ((9- ((2R,3R,5S) -3-acetoxy-5- (acetoxymethyl) tetrahydrofuran-2-yl) -2-amino-8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) cyclopropane-1-carboxylate, compound 250
Compound 250 can be prepared according to the procedure outlined in example 29, together with the mesylate of ethyl 1- (hydroxymethyl) cyclopropane-1-carboxylate [3697-68-5 ].
Example 250 a:ethyl 1- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) cyclopropane-1-carboxylate, compound 250a
Compound 250a can be prepared by exposing compound 250 to potassium carbonate in dry ethanol.
Example 251:1- ((2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) cyclopropane-1-carboxylic acid, compound 251
Compound 251 can be prepared by ester hydrolysis of compound 250 according to the methods outlined in example 30.
Example 252:((2S,4R,5R) -4-acetoxy-5- (2-amino-8-oxo-7- ((1- (trifluoromethyl) cyclopropyl) methyl) -7, 8-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl acetate, Compound 252
Compound 252 can be prepared according to the procedure outlined in example 29 substituting propargyl bromide with the mesylate of (1- (trifluoromethyl) cyclopropyl) methanol [371917-17-8 ].
Example 253:2-amino-9- ((2R,3R,5S) -3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- ((1- (trifluoromethyl) cyclopropyl) methyl) -7, 9-dihydro-8H-purin-8-one, compound 253
Compound 253 can be prepared according to the procedure outlined in example 30 by ester hydrolysis of compound 252 or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide and the diester of (2S,3R,5S) -5- ((benzoyloxy) methyl) tetrahydrofuran-2, 3-diacetic acid using the mesylate of (1- (trifluoromethyl) cyclopropyl) methanol instead of propargyl bromide.
Example 254:((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-7-benzyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydro-furan-2-yl) methyl acetate, Compound 254
Compound 254 can be prepared according to the procedure outlined in example 31, substituting benzyl bromide for propargyl bromide.
Example 255:2-amino-7-benzyl-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-one, Compound 255
Compound 255 can be prepared by ester hydrolysis of compound 254 according to the procedure outlined in example 32, or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide, using benzyl bromide instead of propargyl bromide.
Example 256:((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-7- (4-fluorobenzyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydro-furan-2-yl) methyl acetate, Compound 256
Compound 256 can be prepared according to the procedure outlined in example 31 substituting 4-fluorobenzyl bromide for propargyl bromide.
Example 257:2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (4-fluorobenzyl) -7, 9-dihydro-8H-purin-8-one, Compound 257
Compound 257 can be prepared according to the procedure outlined in example 32 by ester hydrolysis of compound 256 or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide, replacing propargyl bromide with 4-fluorobenzyl bromide.
Example 258:((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-7- (3-fluorobenzyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydro-furan-2-yl) methyl acetate compound 258
Compound 258 can be prepared according to the procedure outlined in example 31 substituting 3-fluorobenzyl bromide for propargyl bromide.
Example 259:2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (3-fluorobenzyl) -7, 9-dihydro-8H-purin-8-one, compound 259
Compound 259 can be prepared according to the procedure outlined in example 32 by ester hydrolysis of compound 258 or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide, replacing propargyl bromide with 3-fluorobenzyl bromide.
Example 260:((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-7- (3, 4-difluorobenzyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydro-furan-2-yl) methyl acetate, Compound 260
Compound 260 can be prepared according to the procedure outlined in example 31 substituting 3, 4-difluorobenzyl bromide for propargyl bromide.
Example 261:2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (3, 4-difluorobenzyl) -7, 9-dihydro-8H-purin-8-one, compound 261
Compound 261 can be prepared according to the procedure outlined in example 32 by ester hydrolysis of compound 260 or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide, replacing propargyl bromide with 3, 4-difluorobenzyl bromide.
Example 262:((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-7- (4-chlorobenzyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydro-furan-2-yl) methyl acetate, Compound 262
Compound 262 can be prepared according to the procedure outlined in example 31 substituting 4-chlorobenzyl bromide for propargyl bromide.
Example 263:2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (4-chlorobenzyl) -7, 9-dihydro-8H-purin-8-one, Compound 263
Compound 263 can be prepared by ester hydrolysis of compound 262 according to the procedure outlined in example 32, or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide, replacing propargyl bromide with 4-chlorobenzyl bromide.
Example 264:((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-7- (3-chlorobenzyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydro-furan-2-yl) methyl acetate, Compound 264
Compound 264 can be prepared according to the procedure outlined in example 31 substituting 3-chlorobenzyl bromide for propargyl bromide.
Example 265:2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (3-chlorobenzyl) -7, 9-dihydro-8H-purin-8-one, Compound 265
Compound 265 can be prepared according to the procedure outlined in example 32 by ester hydrolysis of compound 264 or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide, replacing propargyl bromide with 3-chlorobenzyl bromide.
Example 266:((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-7- (3, 4-dichlorobenzyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) methyl acetate, compound 266 can be prepared according to the procedure outlined in example 31 substituting propargyl bromide with 3, 4-dichlorobenzyl bromide.
Example 267:2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (3, 4-dichlorobenzyl) -7, 9-dihydro-8H-purin-8-one, compound 267
Compound 267 can be prepared according to the procedure outlined in example 32 by ester hydrolysis of compound 266 or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide, substituting 3, 4-dichlorobenzyl bromide for propargyl bromide.
Example 268:((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-7- (4-cyanobenzyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydro-furan-2-yl) methyl acetate, Compound 268
Compound 268 can be prepared according to the procedure outlined in example 31, substituting 4-cyanobenzyl bromide for propargyl bromide.
Example 269:4- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) benzonitrile, compound 269
Compound 269 can be prepared according to the procedure outlined in example 32 by ester hydrolysis of compound 268, or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide, using 4-cyanobenzyl bromide instead of propargyl bromide.
Example 270:((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-7- (3-cyanobenzyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) - 3-Fluorotetrahydrofuran-2-yl) methyl acetate, Compound 270
Compound 270 can be prepared according to the procedure outlined in example 31, substituting 3-cyanobenzyl bromide for propargyl bromide.
Example 271:3- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) benzonitrile, compound 271
Compound 271 can be prepared by ester hydrolysis of compound 270 according to the procedure outlined in example 32, or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide, using 3-cyanobenzyl bromide instead of propargyl bromide.
Example 272:methyl 4- ((9- ((2R,3S,4R,5R) -3-acetoxy-5- (acetoxymethyl) -4-fluorotetrahydrofuran-2-yl) -2-amino-8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) benzoate, Compound 272
Compound 272 can be prepared according to the procedure outlined in example 31, substituting methyl 4-bromomethylbenzoate for propargyl bromide.
Example 273:methyl 4- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) benzoate, Compound 273
Compound 273 can be prepared by exposing compound 272 to potassium carbonate in anhydrous methanol.
Example 274:4- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) benzoic acid, compound 274
Compound 274 can be prepared by ester hydrolysis of compound 272 according to the procedure outlined in example 32, or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide, replacing propargyl bromide with methyl 4-bromomethylbenzoate.
Example 275:3- ((9- ((2R,3S,4R,5R) -3-acetoxy-5- (acetoxymethyl)-4-Fluorotetrahydrofuran-2-yl) -2-amino-8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) benzoic acid methyl ester, Compound 275
Compound 275 can be prepared according to the procedure outlined in example 31 substituting methyl 3-bromomethylbenzoate for propargyl bromide.
Example 276:methyl 3- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) benzoate, compound 276
Compound 276 can be prepared by exposing compound 275 to potassium carbonate in anhydrous methanol.
Example 277:3- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) benzoic acid, compound 277
Compound 277 can be prepared according to the procedure outlined in example 32 by ester hydrolysis of compound 275 or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide using methyl 3-bromomethylbenzoate instead of propargyl bromide.
Example 278:methyl 2- ((9- ((2R,3S,4R,5R) -3-acetoxy-5- (acetoxymethyl) -4-fluorotetrahydrofuran-2-yl) -2-amino-8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) benzoate, Compound 278
Compound 278 can be prepared according to the procedure outlined in example 31 substituting methyl 2-bromomethylbenzoate for propargyl bromide.
Example 279:methyl 2- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) benzoate, compound 279
Compound 279 may be prepared by exposing compound 278 to potassium carbonate in anhydrous methanol.
Example 280:2- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) benzoic acid, compound 280
Compound 280 can be prepared according to the procedure outlined in example 32 by ester hydrolysis of compound 278 or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide, replacing propargyl bromide with methyl 2-bromomethylbenzoate.
Example 281:((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-7- (E) -cinnamyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydro-furan-2-yl) methyl acetate, Compound 281
Compound 281 may be prepared according to the procedure outlined in example 31 substituting (E) -cinnamyl bromide for propargyl bromide.
Example 282:2-amino-7- (E) -cinnamyl-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-one, Compound 282
Compound 282 can be prepared according to the procedure outlined in example 32 by ester hydrolysis of compound 281 or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide with (E) -cinnamyl bromide instead of propargyl bromide.
Example 283:((2R,3R,4S,5R) -5- (7- ((1H-pyrazol-5-yl) methyl) -2-amino-8-oxo-7, 8-dihydro-9H-purin-9-yl) -4-acetoxy-3-fluorotetrahydrofuran-2-yl) methyl acetate, Compound 283
Compound 283 can be prepared according to the procedure for example 31 using tert-butyl 5- (bromomethyl) -1H-pyrazole-1-carboxylate [1001096-27-0] or the mesylate of 5- (bromomethyl) -1- (4-methoxybenzyl) -1H-pyrazole [1313409-97-0] or (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) methanol [1823866-20-1] in place of propargyl bromide.
Example 284:7- ((1H-pyrazol-5-yl) methyl) -2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-one, Compound 284
Compound 284 can be prepared according to the procedure outlined in example 32 by ester hydrolysis of compound 283 or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide, using the mesylate of 5- (bromomethyl) -1H-pyrazole-1-carboxylic acid tert-butyl ester or 5- (bromomethyl) -1- (4-methoxybenzyl) -1H-pyrazole or (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) methanol instead of propargyl bromide.
Example 285:((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-7- ((1-methyl-1H-pyrazol-3-yl) methyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) methyl acetate, Compound 285
Compound 285 can be prepared according to the procedure outlined in example 31 substituting 3- (bromomethyl) -1-methyl-1H-pyrazole [102846-13-9] for propargyl bromide.
Example 286:2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- ((1-methyl-1H-pyrazol-3-yl) methyl) -7, 9-dihydro-8H-purin-8-one, compound 286
Compound 286 can be prepared according to the procedure outlined in example 32 by ester hydrolysis of compound 285, or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide, replacing propargyl bromide with 3- (bromomethyl) -1-methyl-1H-pyrazole.
Example 287:((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (thien-2-ylmethyl) -7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydro-furan-2-yl) methyl acetate, Compound 287
Compound 287 can be prepared according to the method outlined in example 31, substituting 2- (bromomethyl) -thiophene for propargyl bromide.
Example 288:2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (thiophen-2-ylmethyl) -7, 9-dihydro-8H-purin-8-one, compound 288
Compound 288 can be prepared according to the procedure outlined in example 32 by ester hydrolysis of compound 287 or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide by substituting 2- (bromomethyl) -thiophene for propargyl bromide.
Example 289:((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (thiophen-3-ylmethyl) -7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) methyl acetate, Compound 289
Compound 289 can be prepared according to the procedure outlined in example 31 substituting 3- (bromomethyl) -thiophene for propargyl bromide.
Example 290:2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (thiophen-3-ylmethyl) -7, 9-dihydro-8H-purin-8-one, compound 290
Compound 290 can be prepared according to the procedure outlined in example 32 by ester hydrolysis of compound 289, or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide, replacing propargyl bromide with 3- (bromomethyl) -thiophene.
Example 291:methyl 2- (9- ((2R,3S,4R,5R) -3-acetoxy-5- (acetoxymethyl) -4-fluorotetrahydrofuran-2-yl) -2-amino-8-oxo-8, 9-dihydro-7H-purin-7-yl) acetate, Compound 291
Compound 291 may be prepared according to the procedure outlined in example 31, substituting methyl 2-bromoacetate for propargyl bromide.
Example 292:methyl 2- (2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) acetate, compound 292
Compound 292 can be prepared by exposing compound 291 to potassium carbonate in anhydrous methanol.
Example 293:2- (2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) acetic acid, compound 293
Compound 293 can be prepared by ester hydrolysis of compound 291 under aqueous conditions using the modification outlined in example 32 or from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide using the procedure described in example 32A, substituting 2-bromoacetic acid methyl ester for propargyl bromide and subsequent ester hydrolysis.
Example 294:((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (2-oxoethyl) -7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydro-furan-2-yl) methyl acetate, Compound 294
Compound 294 can be prepared according to the general procedure outlined in example 31, substituting 2-bromo-1, 1-dimethoxyethane for propargyl bromide, followed by aqueous acid treatment.
Example 295:2- (2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) acetaldehyde, compound 295
Compound 295 can be prepared by basic hydrolysis of compound 294 or by using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide, substituting 2-bromo-1, 1-dimethoxyethane for propargyl bromide followed by acetal and ester hydrolysis.
Example 296:((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-7- (cyanomethyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydro-furan-2-yl) methyl acetate, Compound 296
Compound 296 can be prepared according to the general procedure outlined in example 31, substituting 2-bromoacetonitrile for propargyl bromide.
Example 297:2- (2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) acetonitrile, compound 297
Compound 297 can be prepared from compound 295 by hydrolyzing compound 296 or by converting the aldehyde to the corresponding oxime, which is then dehydrated.
Example 298:((2R,3R,4S,5R) -5- (7- ((1H-tetrazol-5-yl) methyl) -2-amino-8-oxo-7, 8-dihydro-9H-purin-9-yl) -4-acetoxy-3-fluorotetrahydrofuran-2-yl) methyl acetate, Compound 298
Compound 298 can be prepared according to the procedure outlined in example 31, substituting 5- (chloromethyl) -1H-tetrazole [55408-11-2] for propargyl bromide.
Example 299:7- ((1H-tetrazol-5-yl) methyl) -2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-one, Compound 299
Compound 299 may be prepared according to the procedure outlined in example 32 by ester hydrolysis of compound 298, or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide, replacing propargyl bromide with 5- (chloromethyl) -1H-tetrazole.
Example 300:2- (2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) -N- (methylsulfonyl) acetamide, compound 300
Compound 300 can be prepared from compound 293 and methanesulfonamide.
Example 301:2- (2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) -N-hydroxyacetamide, compound 301
Compound 301 can be prepared from compound 293 and hydroxylamine.
Example 302:((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-7- ((3-hydroxyisoxazol-5-yl) methyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) methyl acetate, Compound 302
Compound 298 can be prepared according to the procedure outlined in example 31 substituting mesylate of (3- ((4-methoxybenzyl) oxy) isoxazol-5-yl) methanol for propargyl bromide.
Example 303:2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- ((3-hydroxyisoxazol-5-yl) methyl) -7, 9-dihydro-8H-purin-8-one, compound 303
Compound 303 can be prepared by ester hydrolysis of compound 302 according to the procedure outlined in example 32.
Example 304:2- ((9- ((2R,3S,4R,5R) -3-acetoxy-5- (acetoxymethyl) -4-fluorotetrahydrofuran-2-yl)) -2-amino-8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) benzoic acid methyl ester, compound 304
Compound 304 can be prepared according to the procedure outlined in example 31 substituting propargyl bromide with methyl 5- (bromomethyl) thiophene-2-carboxylate [108499-32-7 ].
Example 305:methyl 2- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) benzoate, compound 305
Compound 305 can be prepared by exposing compound 304 to potassium carbonate in anhydrous methanol.
Example 306:2- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) benzoic acid, compound 306
Compound 306 can be prepared by ester hydrolysis of compound 304 according to the procedure outlined in example 32.
Example 307:ethyl 5- ((9- ((2R,3S,4R,5R) -3-acetoxy-5- (acetoxymethyl) -4-fluorotetrahydrofuran-2-yl) -2-amino-8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) thiophene-3-carboxylate, compound 307
Compound 307 can be prepared according to the procedure outlined in example 31 substituting 5- (bromomethyl) thiophene-3-carboxylic acid ethyl ester [206860-16-4] for propargyl bromide.
Example 308:ethyl 5- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) thiophene-3-carboxylate, compound 308
Compound 308 can be prepared by exposing compound 307 to potassium carbonate in dry ethanol.
Example 309:5- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) thiophene-3-carboxylic acid, compound 309
Compound 309 can be prepared by ester hydrolysis of compound 307 according to the procedure outlined in example 32.
Example 310:4- ((9- ((2R,3S,4R,5R) -3-acetoxy-5- (acetoxymethyl) -4-fluorotetrahydrofuran-2-yl) -2-amino-8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) thiophene-2-carboxylic acid methyl ester, Compound 310
Compound 310 can be prepared according to the procedure outlined in example 31, substituting 4- (bromomethyl) thiophene-2-carboxylic acid methyl ester [54796-51-9] for propargyl bromide.
Example 311:4- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) thiophene-2-carboxylic acid methyl ester, Compound 311
Compound 311 can be prepared by exposing compound 310 to potassium carbonate in anhydrous methanol.
Example 312:4- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) thiophene-2-carboxylic acid, compound 312
Compound 312 can be prepared by ester hydrolysis of compound 310 according to the procedure outlined in example 32.
Example 313:(1R,2R) -2- ((9- ((2R,3S,4R,5R) -3-acetoxy-5- (acetoxymethyl) -4-fluorotetrahydrofuran-2-yl) -2-amino-8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) cyclopropane-1-carboxylic acid ethyl ester, Compound 313
Compound 313 can be prepared according to the procedure outlined in example 31 substituting propargyl bromide with the mesylate of ethyl (1R,2R) -2- (hydroxymethyl) cyclopropane-1-carboxylate.
Example 314:(1R,2R) -ethyl 2- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) cyclopropane-1-carboxylate, Compound 314
Compound 314 can be prepared by exposing compound 313 to potassium carbonate in dry ethanol.
Example 315:(1R,2R) -2- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo O-8, 9-dihydro-7H-purin-7-yl) methyl) cyclopropane-1-carboxylic acid, Compound 315
Compound 315 can be prepared by ester hydrolysis of compound 313 according to the procedure outlined in example 32.
Example 316:((2R,3R,4S,5R) -5- (7- ((E) -3- (1H-tetrazol-5-yl) allyl) -2-amino-8-oxo-7, 8-dihydro-9H-purin-9-yl) -4-acetoxy-3-fluorotetrahydrofuran-2-yl) methyl acetate, Compound 316
Compound 316 can be prepared from ((2R,3R,4S,5R) -4-acetoxy-5- (7-allyl-2-amino-8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) methyl acetate and 5-vinyl-1H-tetrazole [18755-47-0] by an olefin metathesis-type reaction.
Example 317:7- ((E) -3- (1H-tetrazol-5-yl) allyl) -2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-one, Compound 317
Compound 317 can be prepared by ester hydrolysis of compound 316 according to the procedure outlined in example 32.
Example 318:((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-7- (4-formylbenzyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydro-furan-2-yl) methyl acetate, Compound 318 can be prepared according to the procedure outlined in example 31, substituting 4- (bromomethyl) benzaldehyde for propargyl bromide.
Example 319:4- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) benzaldehyde, compound 319
Compound 319 can be prepared according to the procedure outlined in example 32 by ester hydrolysis of compound 318 or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide, replacing propargyl bromide with 4- (bromomethyl) benzaldehyde.
Example 320:((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-7- (4-methoxybenzyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-Fluorotetrahydrofuran-2-yl) methyl acetate, Compound 320
Compound 320 can be prepared according to the procedure outlined in example 31, substituting 4-methoxybenzyl bromide for propargyl bromide.
Example 321:2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (4-methoxybenzyl) -7, 9-dihydro-8H-purin-8-one, compound 321
Compound 321 can be prepared by ester hydrolysis of compound 320 according to the procedure outlined in example 32.
Example 322:((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-7- (3-methoxybenzyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydro-furan-2-yl) methyl acetate, Compound 322
Compound 322 can be prepared according to the procedure outlined in example 31, substituting 3-methoxybenzyl bromide for propargyl bromide.
Example 323:2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (3-methoxybenzyl) -7, 9-dihydro-8H-purin-8-one, compound 323
Compound 323 can be prepared by ester hydrolysis of compound 322 according to the procedure outlined in example 32, or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide, using 3-methoxybenzyl bromide instead of propargyl bromide.
Example 324:((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-7- (3-hydroxybenzyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydro-furan-2-yl) methyl acetate, Compound 324
Compound 324 can be prepared by using BBr3Compound 322 is demethylated.
Example 325:2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (3-hydroxybenzyl) -7, 9-dihydro-8H-purin-8-one, compound 325
Compound 325 can be prepared by ester hydrolysis of compound 324 according to the procedure outlined in example 32.
Example 326:((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-7- (4-trifluoromethylbenzyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) methyl acetate, Compound 326
Compound 326 can be prepared according to the procedure outlined in example 31, substituting 4-trifluoromethyl-benzyl bromide for propargyl bromide.
Example 327, the following:2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (4-trifluoromethylbenzyl) -7, 9-dihydro-8H-purin-8-one, compound 327
Compound 327 can be prepared according to the procedure outlined in example 32 by ester hydrolysis of compound 326 or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide using 4-trifluoromethyl-benzyl bromide instead of propargyl bromide.
Example 328:((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (pyridin-3-ylmethyl) -7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) methyl acetate, Compound 328
Compound 328 can be prepared according to the procedure outlined in example 31, substituting 3- (bromomethyl) pyridine for propargyl bromide.
Example 329:2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (pyridin-3-ylmethyl) -7, 9-dihydro-8H-purin-8-one, compound 329
Compound 329 can be prepared by ester hydrolysis of compound 328 according to the procedure outlined in example 32, or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide, replacing propargyl bromide with 3- (bromomethyl) pyridine.
Example 330:((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (2-oxo-2- (pyrrolidin-1-yl) ethyl) -7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) methyl acetate, Compound 330
Compound 330 can be prepared according to the procedure outlined in example 31 substituting bromoacetylpyrrolidine [90892-09-4] for propargyl bromide.
Example 331:2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (2-oxo-2- (pyrrolidin-1-yl) ethyl) -7, 9-dihydro-8H-purin-8-one, compound 331
Compound 331 can be prepared according to the procedure outlined in example 32 by ester hydrolysis of compound 330 or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide, replacing propargyl bromide with pyrrolidine bromoacetate.
Example 332:((2R,3R,4S,5R) -4-acetoxy-5- (7-allyl-2-amino-8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydro-furan-2-yl) methyl acetate, Compound 332
Compound 332 can be prepared according to the procedure outlined in example 31, substituting allyl bromide for propargyl bromide.
Example 333:7-allyl-2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-one, Compound 333
Compound 333 can be prepared according to the procedure outlined in example 32 by ester hydrolysis of compound 332 or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide using allyl bromide instead of propargyl bromide.
Example 334:((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-7- (cyclopropylmethyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydro-furan-2-yl) methyl acetate, Compound 334
Compound 334 can be prepared according to the procedure outlined in example 29 substituting (bromomethyl) cyclopropane for propargyl bromide.
Example 335:2-amino-7- (cyclopropylmethyl) -9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-one compound 335
Compound 334 can be prepared by ester hydrolysis of compound 334 according to the methods outlined in example 32, or using the methods described in example 32A, replacing (45) with (71).
Example 336:((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-7-butyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydro-furan-2-yl) methyl acetate, Compound 336
Compound 336 can be prepared according to the procedure outlined in example 31, substituting n-butyl bromide for propargyl bromide.
Example 337:2-amino-7-butyl-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-one, Compound 337
Compound 337 can be prepared by ester hydrolysis of compound 336 according to the procedure outlined in example 32, or from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide using the procedure described in example 32A, substituting N-butyl bromide for propargyl bromide.
Example 338:((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-7- (methoxymethyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydro-furan-2-yl) methyl acetate, Compound 338
Compound 338 can be prepared according to the procedure outlined in example 31, substituting chloromethyl methyl ether for propargyl bromide.
Example 339:2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (methoxymethyl) -7, 9-dihydro-8H-purin-8-one, compound 339
Compound 339 can be prepared by ester hydrolysis of compound 338 according to the procedure outlined in example 32, or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide, using chloromethyl methyl ether instead of propargyl bromide.
Example 340:((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-7- ((methylthio) methyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydro-furan-2-yl) methyl acetate, Compound 340
Compound 340 can be prepared according to the procedure outlined in example 31, substituting chloromethyl methyl sulfide for propargyl bromide.
Example 341:2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- ((methylthio) methyl) -7, 9-dihydro-8H-purin-8-one, compound 341
Compound 341 can be prepared according to the procedure outlined in example 32 by ester hydrolysis of compound 340 or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide using chloromethyl methyl sulfide instead of propargyl bromide.
Example 342:((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (2,2, 2-trifluoroethyl) -7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) methyl acetate, Compound 342
Compound 342 can be prepared according to the general method outlined in example 31, substituting 2-bromo-1, 1, 1-trifluoroethane [421-06-7] for propargyl bromide.
Example 343:2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (2,2, 2-trifluoroethyl) -7, 9-dihydro-8H-purin-8-one, compound 343
Compound 343 can be prepared according to the procedure outlined in example 32 by ester hydrolysis of compound 342, or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide, replacing propargyl bromide with 2-bromo-1, 1, 1-trifluoroethane.
Example 344:((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-7- (2, 2-difluoroethyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydro-furan-2-yl) methyl acetate, Compound 344
Compound 344 can be prepared according to the general procedure outlined in example 31, substituting 2-bromo-1, 1-difluoroethane [359-07-9] for propargyl bromide.
Example 345:2-amino-7- (2, 2-difluoroethyl) -9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7, 9-dihydro-8H-purin-8-oneCompound 345
Compound 345 may be prepared according to the procedure outlined in example 32 by ester hydrolysis of compound 344 or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide, replacing propargyl bromide with 2-bromo-1, 1-difluoroethane.
Example 346:((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (3,3, 3-trifluoropropyl) -7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydro-furan-2-yl) methyl acetate, Compound 346
Compound 346 can be prepared according to the general method outlined in example 31, substituting 3-bromo-1, 1, 1-trifluoropropane [460-32-2] for propargyl bromide.
Example 347:2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (3,3, 3-trifluoropropyl) -7, 9-dihydro-8H-purin-8-one, compound 347
Compound 347 can be prepared according to the procedure outlined in example 32 by ester hydrolysis of compound 346 or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide, replacing propargyl bromide with 3-bromo-1, 1, 1-trifluoropropane.
Example 348:((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (2,2,3,3, 3-pentafluoropropyl) -7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) methyl acetate, Compound 348
Compound 348 can be prepared according to the general method outlined in example 31, substituting 3-bromo-1, 1,1,2, 2-pentafluoropropane [422-01-5] or 2,2,3,3, 3-pentafluoropropyl methanesulfonate [813-31-0] for propargyl bromide.
Example 349:2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (2,2,3,3, 3-pentafluoropropyl) -7, 9-dihydro-8H-purin-8-one, compound 349
Compound 349 can be prepared according to the procedure outlined in example 32 by ester hydrolysis of compound 348 or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide using 3-bromo-1, 1,1,2, 2-pentafluoropropane or 2,2,3,3, 3-pentafluoropropylmethanesulfonate instead of propargyl bromide.
Example 350:((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (4,4, 4-trifluorobutyl) -7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) methyl acetate, Compound 350
Compound 350 can be prepared according to the general method outlined in example 31, substituting 4-bromo-1, 1, 1-trifluorobutane [406-81-5] for propargyl bromide.
Example 351:2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (4,4, 4-trifluorobutyl) -7, 9-dihydro-8H-purin-8-one, compound 351
Compound 351 can be prepared by ester hydrolysis of compound 350 according to the procedure outlined in example 32, or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide, replacing propargyl bromide with 4-bromo-1, 1, 1-trifluorobutane.
Example 352: ((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-8-oxo-7- (3,3,4,4, 4-pentafluorobutyl) -7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) methyl acetate, Compound 352
Compound 352 can be prepared according to the procedure outlined in example 31 substituting 1,1,1,2, 2-pentafluoro-4-bromobutane [52671-70-2] for propargyl bromide.
Example 353:2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- (3,3,4,4, 4-pentafluorobutyl) -7, 9-dihydro-8H-purin-8-one, compound 353
Compound 353 can be prepared according to the procedure outlined in example 32 by ester hydrolysis of compound 352 or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide using 1,1,1,2, 2-pentafluoro-4-bromobutane instead of propargyl bromide.
Example 354:((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-7- (2-cyanoethyl) -8-oxo-7, 8)-dihydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) methyl acetate, Compound 354
Compound 354 can be prepared according to the procedure outlined in example 31 substituting 3-bromopropionitrile [2417-90-5] for propargyl bromide.
Example 355:3- (2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) propionitrile, compound 355
Compound 355 can be prepared according to the procedure outlined in example 32 by ester hydrolysis of compound 354 or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide, substituting 3-bromopropionitrile for propargyl bromide.
Example 356:((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-7- (3-cyanopropyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydro-furan-2-yl) methyl acetate, Compound 356
Compound 356 can be prepared according to the procedure outlined in example 31 substituting 4-bromobutyronitrile [5332-06-9] for propargyl bromide.
Example 357:4- (2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) butanenitrile, compound 357
Compound 357 can be prepared according to the procedure outlined in example 32 by ester hydrolysis of compound 356 or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide, replacing propargyl bromide with 4-bromobutyronitrile.
Example 358:((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-7-isobutyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydro-furan-2-yl) methyl acetate, Compound 358
Compound 358 can be prepared according to the procedure outlined in example 31, substituting 1-bromo-2-methylpropane for propargyl bromide.
Example 359:2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl)-7-isobutyl-7, 9-dihydro-8H-purin-8-one, compound 359
Compound 359 can be prepared according to the procedure outlined in example 32 by ester hydrolysis of compound 358 or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide, replacing propargyl bromide with 1-bromo-2-methylpropane.
Example 360:((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-7- ((1-cyanocyclopropyl) methyl) -8-oxo-7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) methyl acetate, Compound 360
Compound 360 can be prepared according to the procedure outlined in example 31 substituting 1- (hydroxymethyl) cyclopropane-1-carbonitrile [98730-77-9] mesylate for propargyl bromide.
Example 361:1- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) cyclopropane-1-carbonitrile, compound 361
Compound 361 can be prepared by ester hydrolysis of compound 360 according to the procedure outlined in example 32, or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide, using the mesylate of 1- (hydroxymethyl) cyclopropane-1-carbonitrile instead of propargyl bromide.
Example 362:1- ((9- ((2R,3S,4R,5R) -3-acetoxy-5- (acetoxymethyl) -4-fluorotetrahydrofuran-2-yl) -2-amino-8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) cyclopropane-1-carboxylic acid ethyl ester, Compound 362
Compound 362 can be prepared according to the procedure outlined in example 31 substituting propargyl bromide with the mesylate of ethyl 1- (hydroxymethyl) cyclopropane-1-carboxylate [3697-68-5 ].
Example 363:1- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) cyclopropane-1-carboxylic acid ethyl ester, Compound 363
Compound 363 can be prepared by exposing compound 362 to potassium carbonate in dry ethanol.
Example 364:1- ((2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -8-oxo-8, 9-dihydro-7H-purin-7-yl) methyl) cyclopropane-1-carboxylic acid, compound 364
Compound 364 can be prepared by ester hydrolysis of compound 362 according to the procedure outlined in example 32.
Example 365:((2R,3R,4S,5R) -4-acetoxy-5- (2-amino-8-oxo-7- ((1- (trifluoromethyl) cyclopropyl) methyl) -7, 8-dihydro-9H-purin-9-yl) -3-fluorotetrahydrofuran-2-yl) methyl acetate, Compound 365
Compound 365 can be prepared according to the procedure outlined in example 31 substituting propargyl bromide with the mesylate of (1- (trifluoromethyl) cyclopropyl) methanol [371917-17-8 ].
Example 366:2-amino-9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -7- ((1- (trifluoromethyl) cyclopropyl) methyl) -7, 9-dihydro-8H-purin-8-one, compound 366
Compound 366 can be prepared by ester hydrolysis of compound 365 according to the procedure outlined in example 32, or using the procedure described in example 32A from N- (9- (4-methoxybenzyl) -8-oxo-8, 9-dihydro-7H-purin-2-yl) acetamide using the mesylate of (1- (trifluoromethyl) cyclopropyl) methanol instead of propargyl bromide.
Example 367. activity of compounds as TLR7 and TLR8 agonists as measured in reporter cell assays.
Binding of cognate ligands to TLRs triggers downstream signaling cascades leading to activation of NF- κ B and other transcription factors, thereby triggering a variety of immunomodulatory effects. The human embryonic kidney cell line HEK293 is essentially unresponsive to TLR agonists, but ectopic expression of TLRs in these cells allows for the activation of endogenous NF-. kappa.B by homologous agonists. Therefore, the HEK 293-TLR-NF-kappa B inducible reporter gene system was used to analyze TLR agonists. HEK293 cell line stably expressing human TLR7 or TLR8 and NF- κ B-driven secreted alkaline phosphatase (SEAP) reporter Gene, Invivogen (Calif., USA) San diego, rifam) and is used to evaluate compounds of the invention for TLR7 and TLR8 agonist activity. The cells are cultured at 2-5X 104The density of individual cells/well was seeded in 96-well plates (200. mu.l/well) and treated with various concentrations of compound (10. mu.l) for 15-24 hours. SEAP activity was determined by measuring the OD at 650 nm; the medium used to culture the cell lines contained the reagents required for SEAP detection. EC in Table 250Values were derived by fitting the dose response of each compound to the measured SEAP activity to the following equation: y ═ Ymax*cnh/(EC50 nh+cnh) + blank, where Y is the OD experimentally determined at the concentration c650Blank is the OD observed in the absence of TLR7 agonist650，ymaxIs OD measured in the presence of 28.5. mu.M resiquimod or 1.675. mu.M CL307650Difference between, and determination of blank sum EC by nonlinear least squares50And the value of nh.
Table 2 lists the results of testing selected compounds in TLR7 reporter cells.
TABLE 2 TLR7 reporter assay
Compound (I)
TLR7 reporter EC50(μM)
Loxoribin
322
1
188
2
298
5
292
6
835
7
535
8
413
9
15
10
248
11
249
12
407
13
151
14
180
15
>500*
16
534
17
337
18
330
19
491
20
79
21
520
22
567
23
>>500*
26
519
27
376
28
470
33
688
34
512
35
1155
36
1208
37
564
At 500 μ M, higher than baseline activity, but less than<10% of ymax. No activity was observed at the same concentration of compound 23. For all other compounds, the activity at 500. mu.M is at least y max15% of the total.
None of the compounds listed in table 2 showed significant activity in the TLR8 reporter cell assay at concentrations up to 500 μ M (2.5% y for TLR8 as measured by 28.5 μ M resiquimod)max). Substantial induction of SEAP production in the TLR8 reporter cell assay was observed upon incubation with resiquimod, a known agonist of TLR7 and TLR 8.
Example 368.Induces production of interferon alpha in hPBMC (human peripheral blood mononuclear cells).
Treatment of hPBMC with TLR7 agonists typically induces large amounts of interferon-alpha, as well as small amounts of various other cytokines and chemokines. One typical experiment used hPBMC isolated from healthy donors and placed in duplicate cell culture wells; typically 1.0-7.5X 10 is placed in each well6And (4) cells. Test compounds were added and after addition 5% CO was added2Culturing the cells at 37 ℃ for 24 hours in a humid atmosphere; untreated controls were included. Using luminex method, using a multi-subtype interferon-alpha ELISA kit (e.g., PBL Assay Sciences kit), or specifically binding IFNα2aAs part of a variety of cytokines and chemokines, to measure the production of secreted interferon- α. The Minimum Effective Concentration (MEC) is the minimum concentration in the dose response curve where a significant increase in interferon-gamma production (typically at least 20pg/ml) is observed above baseline. MEC values for each compound of at least three donors were determined. The weighted MEC for each compound is the geometric mean of all individual MECs in all donors. The concentration tested typically consisted of a two-fold dilution series starting at 100 μ M. In the calculation of the weighted MEC, any value > 100 μ M can be arbitrarily set to 200 μ M unless all MECs of the compound exceed 100 μ M.
When hPBMC was treated with the TLR7 agonist of the invention and Loxoribine (Loxoribine), several induced interferon-alpha production are shown in table 3. Of particular interest are compounds 5, 18, 26, 27, 28 and 34, which all have a weighted MEC value of less than or equal to 40 μ M and all individual MEC values are less than 100 μ M.
TABLE 3 weighted MEC values for interferon-alpha production from hPBMC after incubation with TLR7 agonist
For Loxoribine (Loxoribine), 5 of the 9 individual MEC values exceeded 100 μ M. For compound 1, 1 of the 15 individual MEC values exceeded 100 μ M. For compound 13, 1 of 5 individual MEC values exceeded 100 μ M. For compounds 14, 33 and 35, 1 of the 3 individual MEC values exceeded 100 μ M. For compound 17, 2 of the 6 individual MEC values exceeded 100 μ M. For compounds 8, 9, 10, 12, 16, 19, 20, 21 and 22, all the individual MEC values exceeded 100 μ M.
Example 369 oral bioavailability in cynomolgus monkeys.
Between 2 and 4 male or female cynomolgus monkeys were used for animal testing studies. The study compounds are formulated in a vehicle (e.g., 50mM phosphate buffered saline, pH 7.4) suitable for oral or intravenous administration to animals. Parent compounds 1, 5, 26 and 27 were administered by intravenous administration at 1mg/kg, while prodrugs of the corresponding compounds were administered at 2 mg/kg. Following administration, 0.5mL blood samples are typically taken at 0.083, 0.33, 1, 2, 4, 6, 8, 12 and 24 hours post-administration (intravenous administration), or at 0.25, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post-administration (oral administration). Plasma was isolated from blood and analyzed for active agonists by the well-known LC-MS technique. Area under the curve (AUC) values were calculated over a 0-24 hour period and normalized to the administered dose. The percent bioavailability (F%) of the compound when orally administered in prodrug form was calculated from the ratio of the normalized AUC for the parent dose given with the oral prodrug to the normalized parent AUC for the parent dose given intravenously and is reported in table 4.
The systemic delivery effect of the prodrug on compounds 1, 26 and 27 was significantly greater than that of loxoribine, whether administered orally as loxoribine itself or as a prodrug, as described in table 4. This is at least in part a function of the underlying agonist structure, as the prodrug methodology used with 7-allyl-2-amino-9- β -D-ribofuranosyl-7, 9-dihydropurin-8-one is the same as that described herein for prodrugs 4, 25, 30 and 32.
TABLE 4% bioavailability of TLR7 agonist administered as prodrug (weight/weight basis)
aValues from Table 23 of U.S. Pat. No. 7,575,068B2
bIntrinsic bioavailability of loxoribine in cynomolgus monkeys.
Example 370. antitumor activity in rodent models.
In the syngeneic model, B16-F10 rodent melanoma tumor cells were injected ventrally into 32 mice. Mice were divided into four treatment groups of eight animals each: (i) control group (untreated); (ii) compound 5(40mg/kg, by tail vein injection, BID for five consecutive days, daily, with dose intervals on each day of administration of about 8 hours; 10 total doses); (iii) compound 5(40mg/kg, via tail vein injection, BID, once every other day, at doses about 8 hours apart on each day of administration; 10 doses total); (iv) briprimine (bropirimine) (40mg/kg, oral gavage, BID for 5 consecutive days, daily dosing with approximately 8 hours interval per day of dosing, for a total of 10 doses). When the mean tumor volume is about 100mm3(actual average value is 99 mm)3(ii) a Minimum value of 60mm3(ii) a The maximum dimension is 150mm3) At time, animals were randomly grouped. The next day the drug administration was started. Tumor volume was monitored for two weeks. The mean tumor growth inhibition (% TGI) after two weeks of randomized assignment for groups (ii), (iii) and (iv) was 40%, 64% and 61%, respectively, compared to the control group. The average% TGI is calculated by the following formula: average% TGI ═ 1- (T-T0)/(C-C0)]100%, where T is the mean group tumor volume at D14, T0 is the mean group tumor volume at D0, C is the mean control group tumor volume at D14, and C0 is the mean control group tumor volume at D0. The animal weight gain was normal during the study and no adverse events were observed.
All references cited herein are incorporated by reference to the same extent as if each individual publication, database entry (e.g., Genbank sequence or GeneID entry), patent application, or patent was specifically and individually indicated. Applicants associate this incorporation by reference with each publication, database entry (e.g., Genbank sequence or GeneID entry), patent application, or patent, for the purpose of 37c.f.r. § 1.57(b) (1), each reference having been specifically identified by 37c.f.r. § 1.57(b) (2), even though such reference is not immediately adjacent to the specific statement incorporated by reference. The specification includes specific statements herein incorporated by reference, which do not preclude common statements herein incorporated by reference, if at all. Citation of a reference herein is not intended as an admission that the reference is pertinent prior art, nor does it constitute any admission as to the contents or date of these publications or documents.
The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description and accompanying drawings. Such modifications are intended to fall within the scope of the appended claims.
The foregoing written description is considered to be sufficient to enable those skilled in the art to practice the disclosure. Various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description and fall within the scope of the appended claims.