2′-spiro-nucleosides and derivatives thereof useful for treating hepatitis C virus and dengue virus infections
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Abstract
Disclosed herein are 2′-spiro-nucleosides and derivatives thereof useful for treating a subject infected by hepatitis C virus or dengue virus.
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Citations
57 Claims
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1. A compound represented by formula I:
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39)
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2. The compound according to claim 1, wherein B is B2 having the structure represented by formula I-2
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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(C1-6alkyl))2,d) —
P(O)(O(CH2)1-3OC(O)(C1-6alkyl))2,e) —
P(O)(O(CH2)1-3SC(O)(C1-6alkyl))2,f) —
P(O)(O(CH2)1-3OCH2(aryl))2,g) —
P(O)(O(CH2)1-3SCH2(aryl))2,h) —
P*(O)(OR1a)(NHCHR1bC(O)OR1c),wherein R1a is i) hydrogen, ii) C1-6alkyl, iii) C3-6cycloalkyl, or iv) aryl, R1b is i) hydrogen, ii) C1-6alkyl, iii) C3-6cycloalkyl, iv) C1-3alkaryl, or v) alk(heteroaryl), and R1c is i) hydrogen ii) C1-6alkyl, iii) C3-6cycloalkyl, or iv) C1-3 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)(OR1c)˜
, 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 C2-7acyl, p) an aminoacyl, q) a C1-6-alkylene-oxy-C2-7acyl, and r) a —
C(O)—
O—
C1-6alkyl;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)(OR1c)˜
,e) —
O(C2-7acyl),f) —
O(aminoacyl),g) —
O(C1-6-alkylene-oxy-acyl),h) —
O—
C(O)—
O—
C1-6alkyl,i) —
NH2,j) —
NH(C2-7acyl),k) —
NH(aminoacyl),l) —
NH—
C(O)—
O—
C1-6alkyl, andm) azido; 5) X is selected from the group consisting of a) —
O— andb) —
S—
;6)
- P(O)(OH)2,
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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)(C1-6alkyl))2,e) —
P(O)(O(CH2)1-3SC(O)(C1-6alkyl))2,f) —
P(O)(O(CH2)1-3OCH2(aryl))2,g) —
P(O)(O(CH2)1-3SCH2(aryl))2,h) —
P*(O)(OR1a)(NHCHR1bC(O)OR1c),wherein R1a is i) hydrogen, ii) C1-6alkyl, iii) C3-6cycloalkyl, or iv) aryl, R1b is i) hydrogen, ii) C1-6alkyl, iii) C3-6cycloalkyl, iv) C1-3alkaryl, or v) alk(heteroaryl), and R1c is i) hydrogen ii) C1-6alkyl, iii) C3-6cycloalkyl, or iv) C1-3alkaryl, 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)(OR1c)˜
, 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 C2-7acyl, p) an aminoacyl, q) a C1-6-alkylene-oxy-C2-7acyl, and r) a —
C(O)—
O—
C1-6alkyl;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)(OR1c)˜
,c) —
O(C2-7acyl),d) —
O(aminoacyl),e) —
O(C1-6-alkylene-oxy-acyl), andf) —
O—
C(O)—
O—
C1-6alkyl;5) X is —
O—
;6)
- P(O)(OH)2,
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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(C1-6alkyl))2,d) —
P(O)(O(CH2)1-3OC(O)(C1-6alkyl))2,e) —
P(O)(O(CH2)1-3SC(O)(C1-6alkyl))2,f) —
P(O)(O(CH2)1-3OCH2(aryl))2,g) —
P(O)(O(CH2)1-3SCH2(aryl))2,h) —
P* (O)(OR1a)(NHCHR1bC(O)OR1c),wherein R1a is i) hydrogen, ii) C1-6alkyl, iii) C3-6cycloalkyl, or iv) aryl, R1b is i) hydrogen, ii) C1-6alkyl, iii) C3-6cycloalkyl, iv) C1-3alkaryl, or v) alk(heteroaryl), and R1c is i) hydrogen ii) C1-6alkyl, iii) C3-6cycloalkyl, or iv) C1-3 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)(OR1c)˜
, 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 C2-7acyl, p) an aminoacyl, q) a C1-6-alkylene-oxy-C2-7acyl, and r) a —
C(O)—
O—
C1-6alkyl;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)(OR1c)˜
,c) —
O(C2-7acyl),d) —
O(aminoacyl),e) —
O(C1-6-alkylene-oxy-acyl), andf) —
O—
C(O)—
O—
C1-6alkyl;5) X is —
O—
;6)
- P(O)(OH)2,
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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(C1-6alkyl))2,d) —
P(O)(O(CH2)1-3OC(O)(C1-6alkyl))2,e) —
P(O)(O(CH2)1-3SC(O)(C1-6alkyl))2,f) —
P(O)(O(CH2)1-3OCH2(aryl))2,g) —
P(O)(O(CH2)1-3SCH2(aryl))2,h) —
P*(O)(OR1a)(NHCHR1bC(O)OR1c),wherein R1a is i) hydrogen or iv) aryl, R1b is i) hydrogen or ii) C1-6alkyl, and R1c is i) hydrogen ii) C1-6alkyl, iii) C3-6cycloalkyl, or iv) C1-3alkaryl, 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)(OR1c)˜
, 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 C2-7acyl, p) an aminoacyl, q) a C1-6-alkylene-oxy-C2-7acyl, and r) a —
C(O)—
O—
C1-6alkyl;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)(OR1c)˜
,c) —
O(C2-7acyl), andd) —
O(aminoacyl);5) X is —
O—
;6)
- P(O)(OH)2,
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7. The compound according to claim 1, wherein B is B3 having the structure represented by formula I-3
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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(C1-6alkyl))2,d) —
P(O)(O(CH2)1-3OC(O)(C1-6alkyl))2,e) —
P(O)(O(CH2)1-3SC(O)(C1-6alkyl))2,f) —
P(O)(O(CH2)1-3OCH2(aryl))2,g) —
P(O)(O(CH2)1-3SCH2(aryl))2,h) —
P*(O)(OR1a)(NHCHR1bC(O)OR1c),wherein R1a is i) hydrogen, ii) C1-6alkyl, iii) C3-6cycloalkyl, or iv) aryl, R1b is i) hydrogen, ii) C1-6alkyl, iii) C3-6cycloalkyl, iv) C1-3alkaryl, or v) alk(heteroaryl), and R1c is i) hydrogen ii) C1-6alkyl, iii) C3-6cycloalkyl, or iv) C1-3alkaryl, 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)(OR1c)˜
, 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 C2-7acyl, p) an aminoacyl, q) a C1-6-alkylene-oxy-C2-7acyl, and r) a —
C(O)—
O—
C1-6alkyl;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)(OR1c)˜
,e) —
O(C2-7acyl),f) —
O(aminoacyl),g) —
O(C1-6-alkylene-oxy-acyl),h) —
O—
C(O)—
O—
C1-6alkyl,i) —
NH2,j) —
NH(C2-7acyl),k) —
NH(aminoacyl),l) —
NH—
C(O)—
O—
C1-6alkyl, andm) azido; 5) X is selected from the group consisting of a) —
O— andb) —
S—
;6)
- P(O)(OH)2,
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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(C1-6alkyl))2,d) —
P(O)(O(CH2)1-3OC(O)(C1-6alkyl))2,e) —
P(O)(O(CH2)1-3SC(O)(C1-6alkyl))2,f) —
P(O)(O(CH2)1-3OCH2(aryl))2,g) —
P(O)(O(CH2)1-3SCH2(aryl))2,h) —
P*(O)(OR1a)(NHCHR1bC(O)OR1c),wherein R1a is i) hydrogen, ii) C1-6alkyl, iii) C3-6cycloalkyl, or iv) aryl, R1b is i) hydrogen, ii) C1-6alkyl, iii) C3-6cycloalkyl, iv) C1-3alkaryl, or v) alk(heteroaryl), and R1c is i) hydrogen ii) C1-6alkyl, iii) C3-6cycloalkyl, or iv) C1-3alkaryl, 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)(OR1c)˜
, 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 C2-7acyl, p) an aminoacyl, q) a C1-6-alkylene-oxy-C2-7acyl, and r) a —
C(O)—
O—
C1-6alkyl;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)(OR1c)˜
,c) —
O(C2-7acyl),d) —
O(aminoacyl),e) —
O(C1-6-alkylene-oxy-acyl), andf) —
O—
C(O)—
O—
C1-6alkyl;5) X is —
O—
;6)
- P(O)(OH)2,
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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(C1-6alkyl))2,d) —
P(O)(O(CH2)1-3OC(O)(C1-6alkyl))2,e) —
P(O)(O(CH2)1-3SC(O)(C1-6alkyl))2,f) —
P(O)(O(CH2)1-3OCH2(aryl))2,g) —
P(O)(O(CH2)1-3SCH2(aryl))2,h) —
P*(O)(OR1a)(NHCHR1bC(O)OR1c),wherein R1a is i) hydrogen, ii) C1-6alkyl, iii) C3-6cycloalkyl, or iv) aryl, R1b is i) hydrogen, ii) C1-6alkyl, iii) C3-6cycloalkyl, iv) C1-3alkaryl, or v) alk(heteroaryl), and R1c is i) hydrogen ii) C1-6alkyl, iii) C3-6cycloalkyl, or iv) C1-3alkaryl, 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)(OR1c)˜
, 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 C2-7acyl, p) an aminoacyl, p) a C1-6-alkylene-oxy-C2-7acyl, and q) a —
C(O)—
O—
C1-6alkyl;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)(OR1c)˜
,c) —
O(C2-7acyl),d) —
O(aminoacyl),e) —
O(C1-6-alkylene-oxy-acyl), andf) —
O—
C(O)—
O—
C1-6alkyl;5) X is —
O˜
;6)
- P(O)(OH)2,
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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(C1-6alkyl))2,d) —
P(O)(O(CH2)1-3OC(O)(C1-6alkyl))2,e) —
P(O)(O(CH2)1-3SC(O)(C1-6alkyl))2,f) —
P(O)(O(CH2)1-3OCH2(aryl))2,g) —
P(O)(O(CH2)1-3SCH2(aryl))2,h) —
P*(O)(OR1a)(NHCHR1bC(O)OR1c),wherein R1a is i) hydrogen or iv) aryl, R1b is i) hydrogen or ii) C1-6alkyl, and R1c is i) hydrogen ii) C1-6alkyl, iii) C3-6cycloalkyl, or iv) C1-3alkaryl, 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)(OR1c)˜
, 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 C2-7acyl, p) an aminoacyl, q) a C1-6-alkylene-oxy-C2-7acyl, and r) a —
C(O)—
O—
C1-6alkyl;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)(OR1c)˜
,c) —
O(C2-7acyl), andd) —
O(aminoacyl);5) X is —
O—
;6)
- P(O)(OH)2,
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12. The compound according to claim 7, wherein W1, W2, W3, and W4 are as represented by formula I-3-1
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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)(OR1a)(NHCHR1bC(O)OR1c),wherein R1a is i) hydrogen, ii) phenyl, iii) p-fluorophenyl, iv) p-chlorophenyl, v) p-bromophenyl, or vi) naphthyl, R1b is i) hydrogen or ii) C1-6alkyl, and R1c is i) hydrogen ii) C1-6alkyl, iii) C3-6cycloalkyl, or iv) C1-3 alkaryl, d) —
P*(O)(OR1c)˜
, 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 C2-7acyl, and h) an aminoacyl; 2) Y is selected from the group consisting of a) —
OH,b) —
O˜
, when R1 is —
P(O)(OR1c)˜
,c) —
O(C2-7acyl), andd) —
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)(OR1a)(NHCHR1bC(O)OR1c),wherein R1a is i) hydrogen, ii) phenyl, iii) p-fluorophenyl, iv) p-chlorophenyl, v) p-bromophenyl, or vi) naphthyl, R1b is i) hydrogen or ii) C1-6alkyl, and R1c is i) hydrogen ii) C1-6alkyl, iii) C3-6cycloalkyl, or iv) C1-3 alkaryl, d) —
P*(O)(OR1c)˜
, 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 C2-7acyl, and h) an aminoacyl; 2) Y is selected from the group consisting of a) —
OH,b) —
O˜
, when R1 is —
P(O)(OR1c)˜
,c) —
O(C2-7acyl), andd) —
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)(OR1a)(NHCHR1bC(O)OR1c),wherein R1a is i) hydrogen, ii) phenyl, iii) p-fluorophenyl, iv) p-chlorophenyl, v) p-bromophenyl, or vi) naphtyl, R1b is i) hydrogen or ii) C1-6alkyl, and R1c is i) hydrogen ii) iii) C3-6cycloalkyl, or vi) C1-3alkaryl, d) —
P*(O)(OR1c)˜
, 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 C2-7acyl, and h) an aminoacyl; 2) Y is selected from the group consisting of a) —
OH,b) —
O˜
, when R1 is —
P(O)(OR1c)˜
,c) —
O(C2-7acyl), andd) —
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, whereinR1a is
a) hydrogen, b) phenyl, or c) naphthyl; -
2) R1c is a) hydrogen b) C1-6alkyl, c) C3-6cycloalkyl, or d) C1-3alkaryl; and 3a) m is 0, is a double-bond 3a1) R16 is —
O(C1-6alkyl), —
OC1-3alkaryl, —
S(C1-6alkyl), —
NH(C1-6alkyl), or -cycloalkylamino, and3a2) R17 is —
NH2, or3a3) R16 is —
NH2, —
O(C1-6alkyl), —
OC1-3alkaryl, —
NH(C1-6alkyl), —
S(C1-6alkyl), or -cycloalkylamino, and3a4) R17 is hydrogen, or 3b) m is 1, is a single-bond 3b1) R16 is ═
O and3b2) R17 is —
NH2.
-
-
21. The compound or its stereoisomer or its salt or its metabolite or its deuteride thereof according to claim 19, whereinR1a is
a) hydrogen, b) phenyl, or c) naphthyl; -
2) R1c is a) hydrogen b) C1-6alkyl, c) C3-6cycloalkyl, or d) C1-3alkaryl; and 3a) m is 0, is a double-bond 3a1) R16 is —
O(C1-6alkyl) —
OC1-3alkaryl, and3a2) R17 is —
NH2, or3a3) R16 is —
NH2, and3a4) R17 is hydrogen, or 3b) m is 1, is a single-bond 3b1) R16 is ═
O and3b2) 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(C1-6alkyl))2,d) —
P(O)(O(CH2)1-3OC(O)(C1-6alkyl))2,e) —
P(O)(O(CH2)1-3SC(O)(C1-6alkyl))2,f) —
P(O)(O(CH2)1-3OCH2(aryl))2,g) —
P(O)(O(CH2)1-3SCH2(aryl))2,h) —
P*(O)(OR1a)(NHCHR1bC(O)OR1c),wherein R1a is i) hydrogen or ii) aryl, R1b is i) hydrogen or ii) C1-6alkyl, and R1c is i) hydrogen ii) alkyl, iii) cycloalkyl, or iv) —
C1-3alkaryl,i) —
P*(O)(NH(alkaryl)(O(CH2)1-3SC(O)(C1-6alkyl)),j) a 1,3,2-dioxaphosphinane-2-oxide, k) a 4H-benzo[d][1,3,2]dioxaphosphinine-2-oxide, l) —
P*(O)(OR1c)˜
, 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 C2-7acyl, p) an aminoacyl, q) a C1-6-alkylene-oxy-acyl, and r) a —
C(O)—
O—
C1-6alkyl;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)(OR1c)˜
,c) —
O(acyl), andd) —
O(C1-6-alkylene-oxyC2-7acyl);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(C1-6alkyl))2,d) —
P(O)(O(CH2)1-3OC(O)(C1-6alkyl))2,e) —
P(O)(O(CH2)1-3SC(O)(C1-6alkyl))2,f) —
P(O)(O(CH2)1-3OCH2(aryl))2,g) —
P(O)(O(CH2)1-3SCH2(aryl))2,h) —
Pt (O)(OR1a)(NHCHR1bC(O)OR1c),wherein R1a is i) hydrogen or ii) aryl, R1b is i) hydrogen or ii) C1-6alkyl, and R1c is i) hydrogen, ii) alkyl, iii) cycloalkyl, or vi) —
C1-3alkaryl,i) —
P*(O)(NH(alkaryl)(O(CH2)1-3SC(O)(C1-6alkyl)),j) a 1,3,2-dioxaphosphinane-2-oxide, k) a 4H-benzo[d][1,3,2]dioxaphosphinine-2-oxide, l) —
P*(O)(OR1c)˜
, 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 C2-7acyl, p) an aminoacyl, q) a C1-6-alkylene-oxy-acyl, and r) a —
C(O)—
O—
C1-6alkyl;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)(OR1c)˜
,c) —
O(acyl), andd) —
O(C1-6-alkylene-oxyC2-7acyl);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(C1-6alkyl))2,d) —
P(O)(O(CH2)1-3OC(O)(C1-6alkyl))2,e) —
P(O)(O(CH2)1-3SC(O)(C1-6alkyl))2,f) —
P(O)(O(CH2)1-3OCH2(aryl))2,g) —
P(O)(O(CH2)1-3SCH2(aryl))2,h) —
P*(O)(OR1a)(NHCHR1bC(O)OR1c),wherein R1a is i) hydrogen or ii) aryl, R1b is i) hydrogen or ii) C1-6alkyl, and R1c is i) hydrogen ii) alkyl, iii) cycloalkyl, or vi) —
C1-3alkaryl,i) —
P*(O)(NH(alkaryl)(O(CH2)1-3 SC(O)(C1-6alkyl)),j) a 1,3,2-dioxaphosphinane-2-oxide, k) a 4H-benzo[d][1,3,2]dioxaphosphinine-2-oxide, l) —
P*(O)(OR1c)˜
, 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 C2-7acyl, p) an aminoacyl, q) a C1-6-alkylene-oxy-acyl, and r) a —
C(O)—
O—
C1-6alkyl;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)(OR1c)˜
,c) —
O(C2-7acyl),d) —
O(aminoacyl), andd) —
O(C1-6-alkylene-oxyC2-7acyl);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)(OR1a)(NHCHR1bC(O)OR1c),wherein R1a is i) hydrogen or ii) aryl, R1b is i) hydrogen or ii) C1-6alkyl, and R1c is i) hydrogen ii) alkyl, iii) cycloalkyl, or iv) —
C1-3alkaryl,d) a 1,3,2-dioxaphosphinane-2-oxide, e) a 4H-benzo[d][1,3,2]dioxaphosphinine-2-oxide, f) —
P*(O)(OR1c)˜
, 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 C2-7acyl, j) an aminoacyl, k) a C1-6-alkylene-oxy-acyl, and l) a —
C(O)—
O—
C1-6alkyl;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)(OR1c)˜
,c) —
O(C2-7acyl),d) —
O(aminoacyl), ande) —
O(C1-6-alkylene-oxyC2-7acyl);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.
-
2. The compound according to claim 1, wherein B is B2 having the structure represented by formula I-2
-
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
- View Dependent Claims (41, 42)
-
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.
-
41. The method of claim 40, which comprises adding the radical or its salt thereof to the 3′
-
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
- View Dependent Claims (44, 45)
-
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.
-
44. The method of claim 43, which comprises increasing the intracellular concentration of the triphosphate (P3) compound in an HCV 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′
- View Dependent Claims (48, 49, 50, 51)
-
48. The process according to claim 47 for preparing the compound represented by formula I-3-5′
- , wherein R16 is a —
O(C1-6alkyl) a —
OC1-3alkaryl, a —
NH(C1-6alkyl), and a C3-6cycloalkylamino and wherein the nucleophile is comprised of a radical selected from the group consisting of a —
O(C1-6alkyl), a —
OC1-3alkaryl, a —
NH(C1-6alkyl), and a C3-6cycloalkylamino.
- , wherein R16 is a —
-
49. The process according to claim 47 for preparing the compound represented by formula I-3-5′
- , wherein R16 is a —
O(C1-6alkyl) or a —
OC1-3alkaryl, and wherein the nucleophile is comprised of a radical selected from the group consisting of a —
O(C1-6alkyl) and a —
OC1-3alkaryl.
- , wherein R16 is a —
-
50. The process according to claim 47 for preparing the compound represented by formula I-3-5′
- , wherein R16 is a —
O(C1-6alkyl), and wherein the nucleophile is comprised of a —
O(C1-6alkyl).
- , wherein R16 is a —
-
51. The process according to claim 48 for preparing the compound represented by formula I-3-5′
- , wherein R16 is a —
OC1-3alkaryl, and wherein the nucleophile is comprised of a —
OC1-3alkaryl.
- , wherein R16 is a —
-
48. The process according to claim 47 for preparing the compound represented by formula I-3-5′
-
52. A process for preparing a compound represented by formula I-3-5″
- ,
- View Dependent Claims (53, 54, 55)
-
53. The process according to claim 52, wherein R16 is —
- O(C1-6alkyl), —
S(C1-6alkyl), —
NH(C1-6alkyl), or —
NHC3-6cycloalkyl.
- O(C1-6alkyl), —
-
54. The process according to claim 52, wherein the mole ratio of the SP-diastereomer to the RP-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 RP-diastereomer to the SP-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.
-
53. The process according to claim 52, wherein R16 is —
-
56. A process for preparing a compound represented by formula I-3-5′
- ″
- ″
-
57. A compound that is selected from the group consisting of:
Specification
- Resources
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-
Current AssigneeGilead Sciences Inc.
-
Original AssigneeGilead Pharmasset LLC (Gilead Sciences Inc.)
-
InventorsDu, Jinfa, Sofia, Michael Joseph
-
Primary Examiner(s)LEWIS, PATRICK T
-
Application NumberUS13/307,256Publication NumberTime in Patent Office1,028 DaysField of SearchNoneUS Class Current514/45CPC Class CodesA61K 31/7052 having nitrogen as a ring h...A61K 31/706 containing six-membered rin...A61K 31/7064 containing condensed or non...A61K 31/7076 containing purines, e.g. ad...A61K 31/708 having oxo groups directly ...A61K 45/06 Mixtures of active ingredie...A61P 31/00 Antiinfectives, i.e. antibi...A61P 31/12 AntiviralsA61P 31/14 for RNA virusesA61P 31/22 for herpes virusesC07H 19/06 Pyrimidine radicalsC07H 19/10 with the saccharide radical...C07H 19/16 Purine radicalsC07H 19/20 with the saccharide radical...C07H 19/207 the phosphoric or polyphosp...C07H 23/00 Compounds containing boron,...Y02A 50/30 Against vector-borne diseas...