2′-spiro-nucleosides and derivatives thereof useful for treating hepatitis C virus and dengue virus infections

• US 8,841,275 B2
• Filed: 11/30/2011
• Issued: 09/23/2014
• Est. Priority Date: 11/30/2010
• Status: Active Grant

• Current Assignee: Gilead Sciences Inc.
• Original Assignee: Gilead Pharmasset LLC (Gilead Sciences Inc.)
• Inventors: Du, Jinfa, Sofia, Michael Joseph
• Primary Examiner(s): LEWIS, PATRICK T
• Application Number:
  US13/307,256
• Publication Number:
  US 20120142626A1
• Time in Patent Office: 1,028 Days
• Field of Search: None
• US Class Current: 514/45
• CPC Class Codes: A61K 31/7052 having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
• CPC Class Codes: A61K 31/706 containing six-membered rings with nitrogen as a ring hetero atom
• CPC Class Codes: A61K 31/7064 containing condensed or non-condensed pyrimidines
• CPC Class Codes: A61K 31/7076 containing purines, e.g. adenosine, adenylic acid
• CPC Class Codes: A61K 31/708 having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 31/22 for herpes viruses
• CPC Class Codes: C07H 19/06 Pyrimidine radicals
• CPC Class Codes: C07H 19/10 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 19/16 Purine radicals
• CPC Class Codes: C07H 19/20 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 19/207 the phosphoric or polyphosphoric acids being esterified by a further hydroxylic compound, e.g. flavine adenine dinucleotide or nicotinamide-adenine dinucleotide
• CPC Class Codes: C07H 23/00 Compounds containing boron, silicon, or a metal, e.g. chelates, vitamin B12 esters with inorganic acids C07H11/00; metal salts, see parent compounds
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Disclosed herein are 2′-spiro-nucleosides and derivatives thereof useful for treating a subject infected by hepatitis C virus or dengue virus.

Claims

1. A compound represented by formula I:

2. The compound according to claim 1, wherein B is B2 having the structure represented by formula I-2

3. The compound or its stereoisomer or its salt or its metabolite or its deuteride thereof according to claim 2, whereinR¹ is selected from the group consisting of

a) hydrogen,

b) —

P(O)(OH)₂,

c) —

P(O)(O(CH₂)_1-3OC(O)O(C_1-6alkyl))₂,

d) —

P(O)(O(CH₂)_1-3OC(O)(C_1-6alkyl))₂,

e) —

P(O)(O(CH₂)_1-3SC(O)(C_1-6alkyl))₂,

f) —

P(O)(O(CH₂)_1-3OCH₂(aryl))₂,

g) —

P(O)(O(CH₂)_1-3SCH₂(aryl))₂,

h) —

P*(O)(OR^1a)(NHCHR^1bC(O)OR^1c),

wherein

R^1a is

i) hydrogen,

ii) C_1-6alkyl,

iii) C_3-6cycloalkyl, or

iv) aryl,

R^1b is

i) hydrogen,

ii) C_1-6alkyl,

iii) C_3-6cycloalkyl,

iv) C_1-3alkaryl, or

v) alk(heteroaryl), and

R^1c is

i) hydrogen

ii) C_1-6alkyl,

iii) C_3-6cycloalkyl, or

iv) C_1-3 alkaryl.

i) —

P*(O)(NH(alkaryl)(O(CH₂)_1-3SC(O)(alkyl)),

j) a 1,3,2-dioxaphosphinane-2-oxide,

k) a 4H-benzo[d][1,3,2]dioxaphosphinine-2-oxide,

l) —

P*(O)(OR^1c)˜

, when Y is —

O˜

,

m) —

P(O)(OH)—

O—

P(O)(OH)₂,

n) —

P(O)(OH)—

O—

P(O)(OH)—

O—

P(O)(OH)₂,

o) a C_2-7acyl,

p) an aminoacyl,

q) a C_1-6-alkylene-oxy-C_2-7acyl, and

r) a —

C(O)—

O—

C_1-6alkyl;

2) R² is selected from the group consisting of

a) hydrogen,

b) fluoro,

c) azido, and

d) cyano;

3) R³ is selected from the group consisting of

a) hydrogen,

b) methyl, and

c) cyano,

4) Y is selected from the group consisting of

a) hydrogen,

b) fluoro,

c) —

OH,

d) —

O˜

, when R¹ is —

P(O)(OR^1c)˜

,

e) —

O(C_2-7acyl),

f) —

O(aminoacyl),

g) —

O(C_1-6-alkylene-oxy-acyl),

h) —

O—

C(O)—

O—

C_1-6alkyl,

i) —

NH₂,

j) —

NH(C_2-7acyl),

k) —

NH(aminoacyl),

l) —

NH—

C(O)—

O—

C_1-6alkyl, and

m) azido;

5) X is selected from the group consisting of

a) —

O— and

b) —

S—

;

6)

4. The compound or its stereoisomer or its salt or its metabolite or its deuteride thereof according to claim 2, whereinR¹ is selected from the group consisting of

a) hydrogen,

b) —

P(O)(OH)₂,

c) —

P(O)(O(CH₂)_1-3OC(O)O(C d) —

P(O)(O(CH₂)_1-3OC(O)(C_1-6alkyl))₂,

e) —

P(O)(O(CH₂)_1-3SC(O)(C_1-6alkyl))₂,

f) —

P(O)(O(CH₂)_1-3OCH₂(aryl))₂,

g) —

P(O)(O(CH₂)_1-3SCH₂(aryl))₂,

h) —

P*(O)(OR^1a)(NHCHR^1bC(O)OR^1c),

wherein

R^1a is

i) hydrogen,

ii) C_1-6alkyl,

iii) C_3-6cycloalkyl, or

iv) aryl,

R^1b is

i) hydrogen,

ii) C_1-6alkyl,

iii) C_3-6cycloalkyl,

iv) C_1-3alkaryl, or

v) alk(heteroaryl), and

R^1c is

i) hydrogen

ii) C_1-6alkyl,

iii) C_3-6cycloalkyl, or

iv) C_1-3alkaryl,

i) —

P*(O)(NH(alkaryl)(O(CH₂)_1-3SC(O)(alkyl)),

j) a 1,3,2-dioxaphosphinane-2-oxide,

k) a 4H-benzo[d][1,3,2]dioxaphosphinine-2-oxide,

l) —

P*(O)(OR^1c)˜

, when Y is —

O˜

,

m) —

P(O)(OH)—

O—

P(O)(OH)₂,

n) —

P(O)(OH)—

O—

P(O)(OH)—

O—

P(O)(OH)₂,

o) a C_2-7acyl,

p) an aminoacyl,

q) a C_1-6-alkylene-oxy-C_2-7acyl, and

r) a —

C(O)—

O—

C_1-6alkyl;

2) R² is hydrogen;

3) R³ is hydrogen;

4) Y is selected from the group consisting of

a) —

OH,

b) —

O˜

, when R¹ is —

P(O)(OR^1c)˜

,

c) —

O(C_2-7acyl),

d) —

O(aminoacyl),

e) —

O(C_1-6-alkylene-oxy-acyl), and

f) —

O—

C(O)—

O—

C_1-6alkyl;

5) X is —

O—

;

6)

5. The compound or its stereoisomer or its salt or its metabolite or its deuteride thereof according to claim 2, whereinR¹ is selected from the group consisting of

a) hydrogen,

b) —

P(O)(OH)₂,

c) —

P(O)(O(CH₂)_1-3OC(O)O(C_1-6alkyl))₂,

d) —

P(O)(O(CH₂)_1-3OC(O)(C_1-6alkyl))₂,

e) —

P(O)(O(CH₂)_1-3SC(O)(C_1-6alkyl))₂,

f) —

P(O)(O(CH₂)_1-3OCH₂(aryl))₂,

g) —

P(O)(O(CH₂)_1-3SCH₂(aryl))₂,

h) —

P* (O)(OR^1a)(NHCHR^1bC(O)OR^1c),

wherein

R^1a is

i) hydrogen,

ii) C_1-6alkyl,

iii) C_3-6cycloalkyl, or

iv) aryl,

R^1b is

i) hydrogen,

ii) C_1-6alkyl,

iii) C_3-6cycloalkyl,

iv) C_1-3alkaryl, or

v) alk(heteroaryl), and

R^1c is

i) hydrogen

ii) C_1-6alkyl,

iii) C_3-6cycloalkyl, or

iv) C_1-3 alkaryl,

i) —

P*(O)(NH(alkaryl)(O(CH₂)_1-3SC(O)(alkyl)),

j) a 1,3,2-dioxaphosphinane-2-oxide,

k) a 4H-benzo[d][1,3,2]dioxaphosphinine-2-oxide,

l) —

P*(O)(OR^1c)˜

, when Y is —

O˜

,

m) —

P(O)(OH)—

O—

P(O)(OH)₂,

n) —

P(O)(OH)—

O—

P(O)(OH)—

O—

P(O)(OH)₂,

o) a C_2-7acyl,

p) an aminoacyl,

q) a C_1-6-alkylene-oxy-C_2-7acyl, and

r) a —

C(O)—

O—

C_1-6alkyl;

2) R² is hydrogen;

3) R³ is hydrogen;

4) Y is selected from the group consisting of

a) —

OH,

b) —

O˜

, when R¹ is —

P(O)(OR^1c)˜

,

c) —

O(C_2-7acyl),

d) —

O(aminoacyl),

e) —

O(C_1-6-alkylene-oxy-acyl), and

f) —

O—

C(O)—

O—

C_1-6alkyl;

5) X is —

O—

;

6)

6. The compound or its stereoisomer or its salt or its metabolite or its deuteride thereof according to claim 2, whereinR¹ is selected from the group consisting of

a) hydrogen,

b) —

P(O)(OH)₂,

c) —

P(O)(O(CH₂)_1-3OC(O)O(C_1-6alkyl))₂,

d) —

P(O)(O(CH₂)_1-3OC(O)(C_1-6alkyl))₂,

e) —

P(O)(O(CH₂)_1-3SC(O)(C_1-6alkyl))₂,

f) —

P(O)(O(CH₂)_1-3OCH₂(aryl))₂,

g) —

P(O)(O(CH₂)_1-3SCH₂(aryl))₂,

h) —

P*(O)(OR^1a)(NHCHR^1bC(O)OR^1c),

wherein

R^1a is

i) hydrogen or

iv) aryl,

R^1b is

i) hydrogen or

ii) C_1-6alkyl, and

R^1c is

i) hydrogen

ii) C_1-6alkyl,

iii) C_3-6cycloalkyl, or

iv) C_1-3alkaryl,

i) —

P*(O)(NH(alkaryl)(O(CH₂)_1-3SC(O)(alkyl)),

j) a 1,3,2-dioxaphosphinane-2-oxide,

k) a 4H-benzo[d][1,3,2]dioxaphosphinine-2-oxide,

l) —

P*(O)(OR^1c)˜

, when Y is —

O˜

,

m) —

P(O)(OH)—

O—

P(O)(OH)₂,

n) —

P(O)(OH)—

O—

P(O)(OH)—

O—

P(O)(OH)₂,

o) an C_2-7acyl,

p) an aminoacyl,

q) a C_1-6-alkylene-oxy-C_2-7acyl, and

r) a —

C(O)—

O—

C_1-6alkyl;

2) R² is hydrogen;

3) R³ is hydrogen;

4) Y is selected from the group consisting of

a) —

OH,

b) —

O˜

, when R¹ is —

P(O)(OR^1c)˜

,

c) —

O(C_2-7acyl), and

d) —

O(aminoacyl);

5) X is —

O—

;

6)

7. The compound according to claim 1, wherein B is B3 having the structure represented by formula I-3

8. The compound or its stereoisomer or its salt or its metabolite or its deuteride thereof according to claim 7, whereinR¹ is selected from among the group consisting of

a) hydrogen,

b) —

P(O)(OH)₂,

c) —

P(O)(O(CH₂)_1-3OC(O)O(C_1-6alkyl))₂,

d) —

P(O)(O(CH₂)_1-3OC(O)(C_1-6alkyl))₂,

e) —

P(O)(O(CH₂)_1-3SC(O)(C_1-6alkyl))₂,

f) —

P(O)(O(CH₂)_1-3OCH₂(aryl))₂,

g) —

P(O)(O(CH₂)_1-3SCH₂(aryl))₂,

h) —

P*(O)(OR^1a)(NHCHR^1bC(O)OR^1c),

wherein

R^1a is

i) hydrogen,

ii) C_1-6alkyl,

iii) C_3-6cycloalkyl, or

iv) aryl,

R^1b is

i) hydrogen,

ii) C_1-6alkyl,

iii) C_3-6cycloalkyl,

iv) C_1-3alkaryl, or

v) alk(heteroaryl), and

R^1c is

i) hydrogen

ii) C_1-6alkyl,

iii) C_3-6cycloalkyl, or

iv) C_1-3alkaryl,

i) —

P*(O)(NH(alkaryl)(O(CH₂)_1-3SC(O)(alkyl)),

j) a 1,3,2-dioxaphosphinane-2-oxide,

k) a 4H-benzo[d][1,3,2]dioxaphosphinine-2-oxide,

l) —

P*(O)(OR^1c)˜

, when Y is —

O˜

,

m) —

P(O)(OH)—

O—

P(O)(OH)₂,

n) —

P(O)(OH)—

O—

P(O)(OH)—

O—

P(O)(OH)₂,

o) a C_2-7acyl,

p) an aminoacyl,

q) a C_1-6-alkylene-oxy-C_2-7acyl, and

r) a —

C(O)—

O—

C_1-6alkyl;

2) R² is selected from the group consisting of

a) hydrogen,

b) fluoro,

c) azido, and

d) cyano;

3) R³ is selected from the group consisting of

a) hydrogen,

b) methyl, and

c) cyano;

4) Y is selected from the group consisting of

a) hydrogen,

b) fluoro,

c) —

OH,

d) —

O˜

, when R¹ is —

P(O)(OR^1c)˜

,

e) —

O(C_2-7acyl),

f) —

O(aminoacyl),

g) —

O(C_1-6-alkylene-oxy-acyl),

h) —

O—

C(O)—

O—

C_1-6alkyl,

i) —

NH₂,

j) —

NH(C_2-7acyl),

k) —

NH(aminoacyl),

l) —

NH—

C(O)—

O—

C_1-6alkyl, and

m) azido;

5) X is selected from the group consisting of

a) —

O— and

b) —

S—

;

6)

9. The compound or its stereoisomer or its salt or its metabolite or its deuteride thereof according to claim 7, whereinR¹ is selected from the group consisting of

a) hydrogen,

b) —

P(O)(OH)₂,

c) —

P(O)(O(CH₂)_1-3OC(O)O(C_1-6alkyl))₂,

d) —

P(O)(O(CH₂)_1-3OC(O)(C_1-6alkyl))₂,

e) —

P(O)(O(CH₂)_1-3SC(O)(C_1-6alkyl))₂,

f) —

P(O)(O(CH₂)_1-3OCH₂(aryl))₂,

g) —

P(O)(O(CH₂)_1-3SCH₂(aryl))₂,

h) —

P*(O)(OR^1a)(NHCHR^1bC(O)OR^1c),

wherein

R^1a is

i) hydrogen,

ii) C_1-6alkyl,

iii) C_3-6cycloalkyl, or

iv) aryl,

R^1b is

i) hydrogen,

ii) C_1-6alkyl,

iii) C_3-6cycloalkyl,

iv) C_1-3alkaryl, or

v) alk(heteroaryl), and

R^1c is

i) hydrogen

ii) C_1-6alkyl,

iii) C_3-6cycloalkyl, or

iv) C_1-3alkaryl,

i) —

P*(O)(NH(alkaryl)(O(CH₂)_1-3SC(O)(alkyl)),

j) a 1,3,2-dioxaphosphinane-2-oxide,

k) a 4H-benzo[d][1,3,2]dioxaphosphinine-2-oxide,

l) —

P*(O)(OR^1c)˜

, when Y is —

O˜

,

m) —

P(O)(OH)—

O—

P(O)(OH)₂,

n) —

P(O)(OH)—

O—

P(O)(OH)—

O—

P(O)(OH)₂,

o) a C_2-7acyl,

p) an aminoacyl,

q) a C_1-6-alkylene-oxy-C_2-7acyl, and

r) a —

C(O)—

O—

C_1-6alkyl;

2) R² is hydrogen;

3) R³ is hydrogen;

4) Y is selected from the group consisting of

a) —

OH,

b) —

O˜

, when R¹ is —

P(O)(OR^1c)˜

,

c) —

O(C_2-7acyl),

d) —

O(aminoacyl),

e) —

O(C_1-6-alkylene-oxy-acyl), and

f) —

O—

C(O)—

O—

C_1-6alkyl;

5) X is —

O—

;

6)

10. The compound or its stereoisomer or its salt or its metabolite or its deuteride thereof according to claim 7, whereinR¹ is selected from the group consisting of

a) hydrogen,

b) —

P(O)(OH)₂,

c) —

P(O)(O(CH₂)_1-3OC(O)O(C_1-6alkyl))₂,

d) —

P(O)(O(CH₂)_1-3OC(O)(C_1-6alkyl))₂,

e) —

P(O)(O(CH₂)_1-3SC(O)(C_1-6alkyl))₂,

f) —

P(O)(O(CH₂)_1-3OCH₂(aryl))₂,

g) —

P(O)(O(CH₂)_1-3SCH₂(aryl))₂,

h) —

P*(O)(OR^1a)(NHCHR^1bC(O)OR^1c),

wherein

R^1a is

i) hydrogen,

ii) C_1-6alkyl,

iii) C_3-6cycloalkyl, or

iv) aryl,

R^1b is

i) hydrogen,

ii) C_1-6alkyl,

iii) C_3-6cycloalkyl,

iv) C_1-3alkaryl, or

v) alk(heteroaryl), and

R^1c is

i) hydrogen

ii) C_1-6alkyl,

iii) C_3-6cycloalkyl, or

iv) C_1-3alkaryl,

i) —

P*(O)(NH(alkaryl)(O(CH₂)_1-3 SC(O)(alkyl)),

j) a 1,3,2-dioxaphosphinane-2-oxide,

k) a 4H-benzo[d][1,3,2]dioxaphosphinine-2-oxide,

l) —

P*(O)(OR^1c)˜

, when Y is —

O˜

,

m) —

P(O)(OH)—

O—

P(O)(OH)₂,

n) —

P(O)(OH)—

O—

P(O)(OH)—

O—

P(O)(OH)₂,

o) a C_2-7acyl,

p) an aminoacyl,

p) a C_1-6-alkylene-oxy-C_2-7acyl, and

q) a —

C(O)—

O—

C_1-6alkyl;

2) R², is hydrogen;

3) R³ is hydrogen;

4) Y is selected from the group consisting of

a) —

OH,

b) —

O˜

, when R¹ is —

P(O)(OR^1c)˜

,

c) —

O(C_2-7acyl),

d) —

O(aminoacyl),

e) —

O(C_1-6-alkylene-oxy-acyl), and

f) —

O—

C(O)—

O—

C_1-6alkyl;

5) X is —

O˜

;

6)

11. The compound or its stereoisomer or its salt or its metabolite or its deuteride thereof according to claim 7, whereinR¹ is selected from the group consisting of

a) hydrogen,

b) —

P(O)(OH)₂,

c) —

P(O)(O(CH₂)_1-3OC(O)O(C_1-6alkyl))₂,

d) —

P(O)(O(CH₂)_1-3OC(O)(C_1-6alkyl))₂,

e) —

P(O)(O(CH₂)_1-3SC(O)(C_1-6alkyl))₂,

f) —

P(O)(O(CH₂)_1-3OCH₂(aryl))₂,

g) —

P(O)(O(CH₂)_1-3SCH₂(aryl))₂,

h) —

P*(O)(OR^1a)(NHCHR^1bC(O)OR^1c),

wherein

R^1a is

i) hydrogen or

iv) aryl,

R^1b is

i) hydrogen or

ii) C_1-6alkyl, and

R^1c is

i) hydrogen

ii) C_1-6alkyl,

iii) C_3-6cycloalkyl, or

iv) C_1-3alkaryl,

i) —

P*(O)(NH(alkaryl)(O(CH₂)_1-3SC(O)(alkyl)),

j) a 1,3,2-dioxaphosphinane-2-oxide,

k) a 4H-benzo[d][1,3,2]dioxaphosphinine-2-oxide,

l) —

P*(O)(OR^1c)˜

, when Y is —

O˜

,

m) —

P(O)(OH)—

O—

P(O)(OH)₂,

n) —

P(O)(OH)—

O—

P(O)(OH)—

O—

P(O)(OH)₂,

o) an C_2-7acyl,

p) an aminoacyl,

q) a C_1-6-alkylene-oxy-C_2-7acyl, and

r) a —

C(O)—

O—

C_1-6alkyl;

2) R² is hydrogen;

3) R³ is hydrogen;

4) Y is selected from the group consisting of

a) —

OH,

b) —

O˜

, when R¹ is —

P(O)(OR^1c)˜

,

c) —

O(C_2-7acyl), and

d) —

O(aminoacyl);

5) X is —

O—

;

6)

12. The compound according to claim 7, wherein W¹, W², W³, and W⁴ are as represented by formula I-3-1

13. The compound or its stereoisomer or its salt or its metabolite or its deuteride thereof according to claim 12, whereinR¹ is selected from the group consisting of:

a) hydrogen,

b) —

P(O)(OH)₂,

c) —

P*(O)(OR^1a)(NHCHR^1bC(O)OR^1c),

wherein

R^1a is

i) hydrogen,

ii) phenyl,

iii) p-fluorophenyl,

iv) p-chlorophenyl,

v) p-bromophenyl, or

vi) naphthyl,

R^1b is

i) hydrogen or

ii) C_1-6alkyl, and

R^1c is

i) hydrogen

ii) C_1-6alkyl,

iii) C_3-6cycloalkyl, or

iv) C_1-3 alkaryl,

d) —

P*(O)(OR^1c)˜

, when Y is —

O˜

,

e) —

P(O)(OH)—

O—

P(O)(OH)₂,

f) —

P(O)(OH)—

O—

P(O)(OH)—

O—

P(O)(OH)₂,

g) a C_2-7acyl, and

h) an aminoacyl;

2) Y is selected from the group consisting of

a) —

OH,

b) —

O˜

, when R¹ is —

P(O)(OR^1c)˜

,

c) —

O(C_2-7acyl), and

d) —

O(aminoacyl);

3)

14. The compound or its stereoisomer or its salt or its metabolite or its deuteride thereof according to claim 12, whereinR¹ is selected from the group consisting of:

a) hydrogen,

b) —

P(O)(OH)₂,

c) —

P*(O)(OR^1a)(NHCHR^1bC(O)OR^1c),

wherein

R^1a is

i) hydrogen,

ii) phenyl,

iii) p-fluorophenyl,

iv) p-chlorophenyl,

v) p-bromophenyl, or

vi) naphthyl,

R^1b is

i) hydrogen or

ii) C_1-6alkyl, and

R^1c is

i) hydrogen

ii) C_1-6alkyl,

iii) C_3-6cycloalkyl, or

iv) C_1-3 alkaryl,

d) —

P*(O)(OR^1c)˜

, when Y is —

O˜

,

e) —

P(O)(OH)—

O—

P(O)(OH)₂,

f) —

P(O)(OH)—

O—

P(O)(OH)—

O—

P(O)(OH)₂,

g) a C_2-7acyl, and

h) an aminoacyl;

2) Y is selected from the group consisting of

a) —

OH,

b) —

O˜

, when R¹ is —

P(O)(OR^1c)˜

,

c) —

O(C_2-7acyl), and

d) —

O(aminoacyl);

3)

15. The compound or its stereoisomer or its salt or its metabolite or its deuteride thereof according to claim 12, whereinR¹ is selected from the group consisting of:

a) hydrogen,

b) —

P(O)(OH)₂,

c) —

P*(O)(OR^1a)(NHCHR^1bC(O)OR^1c),

wherein

R^1a is

i) hydrogen,

ii) phenyl,

iii) p-fluorophenyl,

iv) p-chlorophenyl,

v) p-bromophenyl, or

vi) naphtyl,

R^1b is

i) hydrogen or

ii) C_1-6alkyl, and

R^1c is

i) hydrogen

ii)

iii) C_3-6cycloalkyl, or

vi) C_1-3alkaryl,

d) —

P*(O)(OR^1c)˜

, when Y is —

O˜

,

e) —

P(O)(OH)—

O—

P(O)(OH)₂,

f) —

P(O)(OH)—

O—

P(O)(OH)—

O—

P(O)(OH)₂,

g) a C_2-7acyl, and

h) an aminoacyl;

2) Y is selected from the group consisting of

a) —

OH,

b) —

O˜

, when R¹ is —

P(O)(OR^1c)˜

,

c) —

O(C_2-7acyl), and

d) —

O(aminoacyl);

3)

16. The compound according to claim 7, wherein Y, W¹, W², W³, and W⁴ are as represented by formula I-3-2

17. The compound according to claim 7, wherein R¹, Y, W¹, W², W³, and W⁴ are as represented by formula I-3-3

18. The compound according to claim 7, wherein Y, Z, W¹, W², W³, and W⁴ are as represented by formula I-3-4

19. The compound according to claim 7, wherein R¹, Y, Z, W¹, W², W³, and W⁴ are as represented by formula I-3-5

20. The compound or its stereoisomer or its salt or its metabolite or its deuteride thereof according to claim 19, whereinR^1a is

a) hydrogen,

b) phenyl, or

c) naphthyl;

2) R^1c is

a) hydrogen

b) C_1-6alkyl,

c) C_3-6cycloalkyl, or

d) C_1-3alkaryl; and

3a) m is 0, is a double-bond

3a1) R¹⁶ is —

O(C_1-6alkyl), —

OC_1-3alkaryl, —

S(C_1-6alkyl), —

NH(C_1-6alkyl), or -cycloalkylamino, and

3a2) R¹⁷ is —

NH₂, or

3a3) R¹⁶ is —

NH₂, —

O(C_1-6alkyl), —

OC_1-3alkaryl, —

NH(C_1-6alkyl), —

S(C_1-6alkyl), or -cycloalkylamino, and

3a4) R¹⁷ is hydrogen, or

3b) m is 1, is a single-bond

3b1) R¹⁶ is ═

O and

3b2) R¹⁷ is —

NH₂.

21. The compound or its stereoisomer or its salt or its metabolite or its deuteride thereof according to claim 19, whereinR^1a is

a) hydrogen,

b) phenyl, or

c) naphthyl;

2) R^1c is

a) hydrogen

b) C_1-6alkyl,

c) C_3-6cycloalkyl, or

d) C_1-3alkaryl; and

3a) m is 0, is a double-bond

3a1) R¹⁶ is —

O(C_1-6alkyl) —

OC_1-3alkaryl, and

3a2) R¹⁷ is —

NH₂, or

3a3) R¹⁶ is —

NH₂, and

3a4) R¹⁷ is hydrogen, or

3b) m is 1, is a single-bond

3b1) R¹⁶ is ═

O and

3b2) R¹⁷ is —

NH₂.

22. The compound according to claim 18, wherein m, R¹⁶, and R¹⁷ are as represented by formula I-3-6

23. The compound according to claim 7, wherein R¹, Y, W¹, W², W³, and W⁴ are as represented by formula I-3-7

24. The compound or its stereoisomer or its salt or its metabolite or its deuteride thereof according to claim 1, wherein B is selected from the group consisting of B5, B6, B7, B8, B9, and B10 represented by the following structures

25. The compound or its stereoisomer or its salt or its metabolite or its deuteride thereof according to claim 24, whereinR¹ is selected from the group consisting of:

a) hydrogen,

b) —

P(O)(OH)₂,

c) —

P(O)(O(CH₂)_1-3OC(O)O(C_1-6alkyl))₂,

d) —

P(O)(O(CH₂)_1-3OC(O)(C_1-6alkyl))₂,

e) —

P(O)(O(CH₂)_1-3SC(O)(C_1-6alkyl))₂,

f) —

P(O)(O(CH₂)_1-3OCH₂(aryl))₂,

g) —

P(O)(O(CH₂)_1-3SCH₂(aryl))₂,

h) —

P*(O)(OR^1a)(NHCHR^1bC(O)OR^1c),

wherein

R^1a is

i) hydrogen or

ii) aryl,

R^1b is

i) hydrogen or

ii) C_1-6alkyl, and

R^1c is

i) hydrogen

ii) alkyl,

iii) cycloalkyl, or

iv) —

C_1-3alkaryl,

i) —

P*(O)(NH(alkaryl)(O(CH₂)_1-3SC(O)(C_1-6alkyl)),

j) a 1,3,2-dioxaphosphinane-2-oxide,

k) a 4H-benzo[d][1,3,2]dioxaphosphinine-2-oxide,

l) —

P*(O)(OR^1c)˜

, when Y is —

O˜

,

m) —

P(O)(OH)—

O—

P(O)(OH)₂,

n) —

P(O)(OH)—

O—

P(O)(OH)—

O—

P(O)(OH)₂,

o) an C_2-7acyl,

p) an aminoacyl,

q) a C_1-6-alkylene-oxy-acyl, and

r) a —

C(O)—

O—

C_1-6alkyl;

2) R² is hydrogen;

3) R³ is hydrogen or cyano;

4) Y is selected from the group consisting of

a) —

OH,

b) —

O, when R¹ is —

P(O)(OR^1c)˜

,

c) —

O(acyl), and

d) —

O(C_1-6-alkylene-oxyC_2-7acyl);

5) X is —

O—

;

6)

26. The compound or its stereoisomer or its salt or its metabolite or its deuteride thereof according to claim 24, whereinR¹ is selected from the group consisting of:

a) hydrogen,

b) —

P(O)(OH)₂,

c) —

P(O)(O(CH₂)_1-3OC(O)O(C_1-6alkyl))₂,

d) —

P(O)(O(CH₂)_1-3OC(O)(C_1-6alkyl))₂,

e) —

P(O)(O(CH₂)_1-3SC(O)(C_1-6alkyl))₂,

f) —

P(O)(O(CH₂)_1-3OCH₂(aryl))₂,

g) —

P(O)(O(CH₂)_1-3SCH₂(aryl))₂,

h) —

Pt (O)(OR^1a)(NHCHR^1bC(O)OR^1c),

wherein

R^1a is

i) hydrogen or

ii) aryl,

R^1b is

i) hydrogen or

ii) C_1-6alkyl, and

R^1c is

i) hydrogen,

ii) alkyl,

iii) cycloalkyl, or

vi) —

C_1-3alkaryl,

i) —

P*(O)(NH(alkaryl)(O(CH₂)_1-3SC(O)(C_1-6alkyl)),

j) a 1,3,2-dioxaphosphinane-2-oxide,

k) a 4H-benzo[d][1,3,2]dioxaphosphinine-2-oxide,

l) —

P*(O)(OR^1c)˜

, when Y is —

O˜

,

m) —

P(O)(OH)—

O—

P(O)(OH)₂,

n) —

P(O)(OH)—

O—

P(O)(OH)—

O—

P(O)(OH)₂,

o) an C_2-7acyl,

p) an aminoacyl,

q) a C_1-6-alkylene-oxy-acyl, and

r) a —

C(O)—

O—

C_1-6alkyl;

2) R² is hydrogen;

3) R³ is hydrogen or cyano;

4) Y is selected from the group consisting of

a) —

OH,

b) —

O˜

, when R¹ is —

P(O)(OR^1c)˜

,

c) —

O(acyl), and

d) —

O(C_1-6-alkylene-oxyC_2-7acyl);

5) X is —

O—

;

6)

27. The compound or its stereoisomer or its salt or its metabolite or its deuteride thereof according to claim 24, whereinR¹ is selected from the group consisting of:

a) hydrogen,

b) —

P(O)(OH)₂,

c) —

P(O)(O(CH₂)_1-3OC(O)O(C_1-6alkyl))₂,

d) —

P(O)(O(CH₂)_1-3OC(O)(C_1-6alkyl))₂,

e) —

P(O)(O(CH₂)_1-3SC(O)(C_1-6alkyl))₂,

f) —

P(O)(O(CH₂)_1-3OCH₂(aryl))₂,

g) —

P(O)(O(CH₂)_1-3SCH₂(aryl))₂,

h) —

P*(O)(OR^1a)(NHCHR^1bC(O)OR^1c),

wherein

R^1a is

i) hydrogen or

ii) aryl,

R^1b is

i) hydrogen or

ii) C_1-6alkyl, and

R^1c is

i) hydrogen

ii) alkyl,

iii) cycloalkyl, or

vi) —

C_1-3alkaryl,

i) —

P*(O)(NH(alkaryl)(O(CH₂)_1-3 SC(O)(C_1-6alkyl)),

j) a 1,3,2-dioxaphosphinane-2-oxide,

k) a 4H-benzo[d][1,3,2]dioxaphosphinine-2-oxide,

l) —

P*(O)(OR^1c)˜

, when Y is —

O˜

,

m) —

P(O)(OH)—

O—

P(O)(OH)₂,

n) —

P(O)(OH)—

O—

P(O)(OH)—

O—

P(O)(OH)₂,

o) a C_2-7acyl,

p) an aminoacyl,

q) a C_1-6-alkylene-oxy-acyl, and

r) a —

C(O)—

O—

C_1-6alkyl;

2) R² is hydrogen;

3) R³ is hydrogen or cyano;

4) Y is selected from the group consisting of

a) —

OH,

b) —

O˜

, when R¹ is —

P(O)(OR^1c)˜

,

c) —

O(C_2-7acyl),

d) —

O(aminoacyl), and

d) —

O(C_1-6-alkylene-oxyC_2-7acyl);

5) X is —

O—

;

6)

28. The compound or its stereoisomer or its salt or its metabolite or its deuteride thereof according to claim 24, whereinR¹ is selected from the group consisting of:

a) hydrogen,

b) —

P(O)(OH)₂,

c) —

P*(O)(OR^1a)(NHCHR^1bC(O)OR^1c),

wherein

R^1a is

i) hydrogen or

ii) aryl,

R^1b is

i) hydrogen or

ii) C_1-6alkyl, and

R^1c is

i) hydrogen

ii) alkyl,

iii) cycloalkyl, or

iv) —

C_1-3alkaryl,

d) a 1,3,2-dioxaphosphinane-2-oxide,

e) a 4H-benzo[d][1,3,2]dioxaphosphinine-2-oxide,

f) —

P*(O)(OR^1c)˜

, when Y is —

O˜

,

g) —

P(O)(OH)—

O—

P(O)(OH)₂,

h) —

P(O)(OH)—

O—

P(O)(OH)—

O—

P(O)(OH)₂,

i) a C_2-7acyl,

j) an aminoacyl,

k) a C_1-6-alkylene-oxy-acyl, and

l) a —

C(O)—

O—

C_1-6alkyl;

2) R² is hydrogen;

3) R³ is hydrogen or cyano;

4) Y is selected from the group consisting of

a) —

OH,

b) —

O˜

, when R¹ is —

P(O)(OR^1c)˜

,

c) —

O(C_2-7acyl),

d) —

O(aminoacyl), and

e) —

O(C_1-6-alkylene-oxyC_2-7acyl);

5) X is —

O—

;

6)

29. The compound according to claim 24, wherein B′

is B5 as represented by formula I-3-9

30. The compound according to claim 24, wherein B′

is B7 as represented by formula I-3-10

31. The compound according to claim 24, wherein B′

is B8 as represented by formula I-3-11

32. The compound according to claim 24, wherein B′

is B9 as represented by formula I-3-12

33. The compound according to claim 24, wherein B′

is B10 as represented by formula I-3-13

34. A composition comprising the compound or its stereoisomer or its salt or its metabolite or its deuteride thereof as claimed in claim 1 and a pharmaceutically acceptable medium.

35. A composition for treating a hepatitis C virus, which comprises an effective amount of the compound as claimed in any claim 1 or a stereoisomer, a salt, a metabolite, or a deuteride thereof and a pharmaceutically acceptable medium.

36. A composition for treating a dengue virus, which comprises an effective amount of the compound or its stereoisomer or its salt or its metabolite or its deuteride thereof as claimed in claim 1 and a pharmaceutically acceptable medium.

37. A method of treating a subject infected by a virus, which comprises:

administering to the subject an effective amount of the compound or its stereoisomer or its salt or its metabolite or its deuteride thereof as claimed in claim 1;

wherein the virus is selected from the group consisting of hepatitis C virus, West Nile virus, a yellow fever virus, a dengue virus, a rhinovirus, a polio virus, a hepatitis A virus, a bovine viral diarrhea virus, and a Japanese encephalitis virus.

38. A method of treating a hepatitis C virus infection in a subject in need thereof, which comprises:

administering to the subject an effective amount of the compound or its stereoisomer or its salt or its metabolite or its deuteride thereof as claimed in claim 1.

39. A method of treating a dengue virus infection in a subject in need thereof, which comprises:

administering to the subject an effective amount of the compound or its stereoisomer or its salt or its metabolite or its deuteride thereof as claimed in claim 1.

40. A method of treating a hepatitis C virus (HCV) or dengue (DENV) infection, which comprises adding to the 3′

-terminus of an HCV or DENV RNA strand a radical or its salt thereof represented by

41. The method of claim 40, which comprises adding the radical or its salt thereof to the 3′

-terminus of an HCV RNA.

42. The method of claim 40, which comprises adding the radical or its salt thereof to the 3′

-terminus of a DENV RNA.

43. A method of treating a hepatitis C virus (HCV) or dengue (DENV) infection, which comprises increasing an intracellular concentration of a triphosphate (P₃) compound or its salt thereof or represented by

44. The method of claim 43, which comprises increasing the intracellular concentration of the triphosphate (P₃) compound in an HCV infected cell.

45. The method of claim 43, which comprises increasing the intracellular concentration of the triphosphate (P₃) compound in a DENV infected cell.

46. A compound or a salt thereof represented by formula A,

47. A process for preparing a compound represented by formula I-3-4′

48. The process according to claim 47 for preparing the compound represented by formula I-3-5′

, wherein R¹⁶ is a —

O(C_1-6alkyl) a —

OC_1-3alkaryl, a —

NH(C_1-6alkyl), and a C_3-6cycloalkylamino and wherein the nucleophile is comprised of a radical selected from the group consisting of a —

O(C_1-6alkyl), a —

OC_1-3alkaryl, a —

NH(C_1-6alkyl), and a C_3-6cycloalkylamino.

49. The process according to claim 47 for preparing the compound represented by formula I-3-5′

, wherein R¹⁶ is a —

O(C_1-6alkyl) or a —

OC_1-3alkaryl, and wherein the nucleophile is comprised of a radical selected from the group consisting of a —

O(C_1-6alkyl) and a —

OC_1-3alkaryl.

50. The process according to claim 47 for preparing the compound represented by formula I-3-5′

, wherein R¹⁶ is a —

O(C_1-6alkyl), and wherein the nucleophile is comprised of a —

O(C_1-6alkyl).

51. The process according to claim 48 for preparing the compound represented by formula I-3-5′

, wherein R¹⁶ is a —

OC_1-3alkaryl, and wherein the nucleophile is comprised of a —

OC_1-3alkaryl.

52. A process for preparing a compound represented by formula I-3-5″

,

53. The process according to claim 52, wherein R¹⁶ is —

O(C_1-6alkyl), —

S(C_1-6alkyl), —

NH(C_1-6alkyl), or —

NHC_3-6cycloalkyl.

54. The process according to claim 52, wherein the mole ratio of the S_P-diastereomer to the R_P-diastereomer is selected from the group consisting of 2, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 97, 98, 99, 99.9, and 99.99.

55. The process according to claim 52, wherein the mole ratio of the R_P-diastereomer to the S_P-diastereomer is selected from the group consisting of 2, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 97, 98, 99, 99.9, and 99.99.

56. A process for preparing a compound represented by formula I-3-5′

″

57. A compound that is selected from the group consisting of: