INHIBITORS OF INFLUENZA VIRUSES REPLICATION
First Claim
1. A method of inhibiting the replication of influenza viruses in a biological sample or patient, comprising the step of administering to said biological sample or patient an effective amount of a compound represented by the following structural formula (I):
2 Assignments
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Accused Products
Abstract
Methods of inhibiting the replication of influenza viruses in a biological sample or patient, of reducing the amount of influenza viruses in a biological sample or patient, and of treating influenza in a patient, comprises administering to said biological sample or patient an effective amount of a compound represented by Structural Formula (I):
or a pharmaceutically acceptable salt thereof, wherein the values of Structural Formula (IA) are as described herein. A compound is represented by Structural Formula (IA) or a pharmaceutically acceptable salt thereof, wherein the values of Structural Formula (IA) are as described herein. A pharmaceutical composition comprises an effective amount of such a compound or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle.
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Citations
156 Claims
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1. A method of inhibiting the replication of influenza viruses in a biological sample or patient, comprising the step of administering to said biological sample or patient an effective amount of a compound represented by the following structural formula (I):
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 29, 38, 39, 43, 46, 47, 48, 49, 51, 52, 53, 55, 56, 60, 62, 65, 66, 67, 69, 70, 145, 147, 151, 152, 153)
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2. The method of claim 1, represented by Structural Formula (I):
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3. The method of claim 2, wherein R1 is —
- H.
-
4. The method of claim 3, wherein R2 is —
- H, —
F, —
CH3, —
CH2OH, or —
NH2.
- H, —
-
5. The method of claim 4, wherein R2 is —
- H or —
CH3.
- H or —
-
6. The method of claim 5, wherein R3 is —
- H, —
Cl, —
F, —
Br, —
CN, —
CF3, —
O(C1-C4 alkyl), —
OH, —
NH2, —
NH(C1-C4 alkyl) or —
N(C1-C4 alkyl)2.
- H, —
-
7. The method of claim 6, wherein R4 is:
-
8. The method of claim 7, wherein:
-
n and m are each independently 0 or 1 when rings A and B are 3-6 membered;
or n and m are each independently 0, 1 or 2 when rings A and B are 7-10 membered;provided that if Y1 is a bond, then R5 is neither H nor a C1-6 aliphatic group; and provided that if each Q2 and Q3 independently is a bond, then R5 is neither —
H nor a C1-6 aliphatic group.
-
-
9. The method of claim 8, wherein:
-
ring A is a C3-C8 non-aromatic carbocycle or heterocycle, the carbocycle and heterocycle optionally further substituted with one or more instances of JA and JB, respectively; rings B and C are each independently a 4-8 membered non-aromatic heterocycle optionally and independently further substituted with one or more instances of JB; ring D is a 4-8 membered non-aromatic heterocycle optionally substituted with one or more instances of JD1; Q1 is independently a bond, —
O—
, —
S—
, —
NR′
—
, —
C(O)—
, —
C(═
NR)—
, —
CO2—
, —
OC(O)—
, —
C(O)NR′
—
, —
C(O)NRC(O)O—
, NRC(O)NRC(O)O—
, —
NRC(O)—
, —
NRC(O)NR′
—
, —
NRCO2—
, —
OC(O)NR′
—
, —
S(O)—
, —
SO2—
, —
SO2NR′
—
, —
NRSO2—
, or —
NRSO2NR′
—
, or —
(CR6R7)p—
Y1—
;Q2 is independently a bond, —
O—
, —
S—
, —
NR′
—
, —
C(O)—
, —
C(═
NR)—
, —
CO2—
, —
OC(O)—
, —
C(O)NR′
—
, —
C(O)NRC(O)O—
, NRC(O)NRC(O)O—
, —
NRC(O)—
, —
NRC(O)NR′
—
, —
NRCO2—
, —
OC(O)NR′
—
, —
S(O)—
, —
SO2—
, —
SO2NR′
—
, —
NRSO2—
, or —
NRSO2NR′
—
, or —
(CR6R7)p—
Y1—
;Q3 is independently a bond, —
C(O)—
, —
C(═
NR)—
, —
CO2—
, —
C(O)NR′
—
, —
SO2—
, —
SO2NR′
—
, —
C(O)NRC(O)O—
, or —
(CR6R7)p—
Y1—
;optionally, each of Q2 and Q3, together with R5, independently forms a 5-7 membered ring optionally substituted with one or more instances of JE1; Y1 is independently a bond, —
O—
, —
S—
, —
NR′
—
, —
C(O)—
, —
C(═
NR)—
, —
CO2—
, —
OC(O)—
, —
C(O)NR′
—
, —
C(O)NRC(O)O—
, —
NRC(O)NRC(O)O—
, —
NRC(O)—
, —
NRC(O)NR′
—
, —
NRCO2—
, —
OC(O)NR′
—
, —
S(O)—
, —
SO2—
, —
SO2NR′
—
, —
NRSO2—
, or —
NRSO2NR′
—
;R5 is;
i) —
H;
ii) a C1-C6 aliphatic group optionally substituted with one or more instances of JC1;
iii) a C3-C8 non-aromatic carbocycle, or a 6-10 membered carbocyclic aryl group, each optionally and independently substituted with one or more instances of JC1;
or iv) a 4-8 membered non-aromatic heterocycle, or a 5-10 membered heteroaryl group, each optionally and independently substituted with one or more instances of JD1;
orR5, together with Q1, optionally forms a 5-7 membered, non-aromatic ring optionally substituted with one or more instances of JE1; and R8 and R9 are each independently —
H, halogen, cyano, hydroxy, amino, carboxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 cyanoalkyl, C2-C6 alkoxyalkyl, C1-C6 aminoalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 aminoalkoxy, C1-C6 cyanoalkoxy, C1-C6 hydroxyalkoxy, or C2-C6 alkoxyalkoxy;R11, R12, R13 and R14 are each independently —
H, halogen, or C1-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, amino, carboxy, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 aminoalkoxy, C1-C6 cyanoalkoxy, C1-C6 hydroxyalkoxy, and C2-C6 alkoxyalkoxy;each of JA and JB is independently selected from the group consisting of halogen, cyano, oxo, —
NCO, and Q1-R5;
or optionally two JA and two JB, respectively, together with the atom(s) to which they are attached, independently form a 5-7 membered ring that is optionally substituted with one or more instances of JE1; andeach of JC1 and JD1 is independently selected from the group consisting of halogen, cyano, oxo, Ra, —
ORb, —
SRb, —
S(O)Ra, —
SO2Ra, —
NRbRc, —
C(O)Rb, —
C(O)ORb, —
OC(O)Rb, —
NRC(O)Rb, —
C(O)NRbRc, —
NRC(O)NRbRc, —
NRC(O)ORb, —
OCONRbRc, —
C(O)NRCO2Rb, —
NRC(O)NRC(O)ORb, —
C(O)NR(ORb), —
SO2NRcRb, —
NRSO2Rb, —
NRSO2NRcRb, and —
P(O)(ORa)2, or optionally, two JC1 and two JD1, respectively, together with the atoms to which they are attached, independently form a 5-7-membered ring that is optionally substituted with one or more instances of JE1, and fused to the respective ring to which they are attached.
-
-
10. The method of claim 9, wherein:
-
ring A is a C3-C8 non-aromatic carbocycle optionally and independently is further substituted with one or more instances of JA; rings B and C are each independently a 4-8 membered non-aromatic heterocycle optionally and independently further substituted with one or more instances of JB; ring D is a 4-8 membered non-aromatic heterocycle optionally substituted with one or more instances of Jp1; Q1 is independently a bond, —
O—
, —
S—
, —
NR′
—
, —
C(O)—
, —
CO2—
, —
OC(O)—
, —
C(O)NR′
—
, —
C(O)NRC(O)O—
, NRC(O)NRC(O)O—
, —
NRC(O)—
, —
NRC(O)NR′
—
, —
NRCO2—
, —
OC(O)NR′
—
, —
S(O)—
, —
SO2—
, —
SO2NR′
—
, —
NRSO2—
, or —
NRSO2NR′
—
, or —
(CR6R2)p—
Y1—
;Q2 is independently bond, —
O—
, —
S—
, —
NR—
, —
C(O)—
, —
CO2—
, —
OC(O)—
, —
C(O)NR—
, —
C(O)NRC(O)O—
, —
NRC(O)NRC(O)O—
, —
NRC(O)—
, —
NRC(O)NR—
, —
NRCO2—
, —
OC(O)NR—
, —
S(O)—
, —
SO2—
, —
N(R)SO2—
, —
SO2NR′
—
, —
NRSO2NR′
—
, or —
(CR6R2)p—
Y1—
;Q3 is independently a bond, —
C(O)—
, —
CO2—
, —
C(O)NR′
—
, —
SO2—
, —
SO2NR′
—
, —
C(O)NRC(O)O—
, or —
(CR6R2)p—
Y1—
;optionally, each of Q2 and Q3, together with R5, independently forms a 5-7 membered ring optionally substituted with one or more instances of JE1; Y1 is independently a bond, —
O—
, —
S—
, —
NR′
—
, —
C(O)—
, —
CO2—
, —
OC(O)—
, —
C(O)NR′
—
, —
C(O)NRC(O)O—
, —
NRC(O)NRC(O)O—
, —
NRC(O)—
, —
NRC(O)NR′
—
, —
NRCO2—
, —
OC(O)NR′
—
, —
S(O)—
, —
SO2—
, —
SO2NR′
—
, —
NRSO2—
, or —
NRSO2NR′
—
;each of JA and JB is independently selected from the group consisting of halogen, cyano, oxo, and Q1-R5;
or optionally two JA and two JB, respectively, together with the atom(s) to which they are attached, independently form a 5-7 membered ring that is optionally substituted with one or more instances of JE1 and fused to the ring to which they are attached; andeach of JC1 and JD1 is independently selected from the group consisting of halogen, cyano, oxo, Ra, —
ORb, —
SRb, —
S(O)Ra, —
SO2Ra, —
NRbRc, —
C(O)Rb, —
C(O)ORb, —
OC(O)Rb, —
NRC(O)Rb, —
C(O)NRbRc, —
NRC(O)NRbRc, —
NRC(O)ORb, —
OCONRbRc, —
C(O)NRCO2Rb, —
NRC(O)NRC(O)ORb, —
C(O)NR(ORb), —
SO2NRcRb, —
NRSO2Rb, and —
NRSO2NRcRb, or optionally, two JC1 and two JD1, respectively, together with the atoms to which they are attached, independently form a 5-7-membered ring that is optionally substituted with one or more instances of JE1, and fused to the respective ring to which they are attached.
-
-
11. The method of claim 10, wherein:
-
Z1 is —
H, C1-C6 alkyl, —
O(C1-C6 alkyl), —
F, —
Cl, —
CN, —
CO2H, —
CO2(C1-C6 alkyl), —
CONH2, —
CONH(C1-C6 alkyl), or —
CON(C1-C6 alkyl)2, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, —
NH2, —
NH(C1-C4 alkyl), —
N(C1-C4 alkyl)2, —
OCO(C1-C4 alkyl), —
CO(C1-C4 alkyl), —
CO2H, —
CO2(C1-C4 alkyl), and C1-C4 alkoxy; andZ2 is —
H, C1-C6 alkyl, —
O(C1-C6 alkyl), —
NH2, —
NH(C1-C6 alkyl), or —
N(C1-C6 alkyl)2, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, —
NH2, —
NH(C1-C4 alkyl), —
N(C1-C4 alkyl)2, —
OCO(C1-C4 alkyl), —
CO(C1-C4 alkyl), —
CO2H, —
CO2(C1-C4 alkyl), and C1-C4 alkoxy.
-
-
12. The method of claim 11, wherein:
-
Z1 is —
H, —
F, —
Cl, —
CF3, —
CH3, or —
CN; andZ2 is —
H or an optionally substituted C1-C6 alkyl.
-
-
13. The method of claim 12, wherein:
-
R2 is —
H; andR3 is —
H, —
F, —
Cl, —
CF3, —
CH3, —
C2H5, —
NH2, —
NH(CH3), or —
N(CH3)2.
-
-
14. The method of claim 13, wherein:
-
Z1 is —
H, —
F, —
Cl, —
CF3, —
CH3, or —
CN;Z2 is —
H or C1-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and —
O(C1-C4 alkyl);Z3 is —
H or C1-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and —
O(C1-C4 alkyl);R1 is —
H;R2 is —
H;R3 is independently —
H, —
Cl or —
F;R6 and R7 are each independently —
H or —
CH3, or together with the carbon atoms to which they are attached they form a cyclopropane ring;each R8 is independently —
H, halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, —
O(C1-C4 alkyl), —
NH2, —
NH(C1-C4 alkyl), or —
N(C1-C4 alkyl)2;each R9 is independently —
H or —
CH3;R11 and R12 are each independently —
H or —
CH3; andR13 and R14 are each independently —
H or —
CH3, or together with the carbon atoms to which they are attached they form a cyclopropane ring.
-
-
15. The method of claim 11, wherein the compound is represented by any one of the structural formulae below (II), (III), (IV) and (V):
-
16. The method of claim 15, wherein:
-
Z1 is —
H, —
F, —
Cl, —
CF3, —
CH3, or —
CN; andZ2 is —
H or an optionally substituted C1-C6 alkyl.
-
-
17. The method of claim 16, wherein R3 is independently —
- H, —
Cl or —
F.
- H, —
-
18. The method of claim 17, wherein:
-
R6 and R7 are each independently —
H or —
CH3, or together with the carbon atoms to which they are attached they form a cyclopropane ring;each R8 is independently —
H, halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, —
O(C1-C4 alkyl), —
NH2, —
NH(C1-C4 alkyl), or —
N(C1-C4 alkyl)2.each R9 is independently —
H or —
CH3;R11 and R12 are each independently —
H or —
CH3; andR13 and R14 are each independently —
H or —
CH3, or together with the carbon atoms to which they are attached they form a cyclopropane ring.
-
-
19. The method of claim 18, wherein the compound is represented by the following structural formula (XIA) or (XIB):
-
29. The method of claim 15, wherein the compound is represented by the following structural formula (XIIA) or (XIIB):
-
38. The method of claim 15, wherein the compound is represented by the following structural formula (XIII):
-
39. The method of claim 38, wherein R10 is —
- H or C1-C6-alkyl.
-
43. The method of claim 15, wherein the compound is represented by the following structural formula (XIV):
-
46. The method of claim 6, wherein R4 is:
-
47. The method of claim 46, wherein ring F is selected from any one of rings F1-F6:
-
48. The method of claim 47, wherein each rings F1-F6 are independently and optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, C1-C4 alkoxy, and C1-C4 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, and —
- O(C1-C4 alkyl).
-
49. The method of claim 48, wherein:
-
R9 is independently —
H, halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, —
O(C1-C4 alkyl), —
NH2, —
NH(C1-C4 alkyl), or —
N(C1-C4 alkyl)2; andring E is a C4-C8 non-aromatic carbocycle optionally further substituted with one or more instances of JA.
-
-
51. The method of claim 6, wherein R4 is:
-
52. The method of claim 51, wherein R4 is:
-
53. The method of claim 52, wherein
each of R8 and R9 is independently — - H, halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, Cz—
C4 alkoxyalkyl, —
O(C1-C4 alkyl), —
NH2, —
NH(C1-C4 alkyl), or —
N(C1-C4 alkyl)2; andR21, R22, R23, and R24 are each independently —
H, halogen, —
OH, or C1-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 aminoalkoxy, C1-C6 cyanoalkoxy, C1-C6 hydroxyalkoxy, and C2-C6 alkoxyalkoxy.
- H, halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, Cz—
-
55. The method of claim 53, wherein:
Q2 is independently —
O—
, —
CO2—
, —
OC(O)—
, —
C(O)NR—
, —
NRC(O)—
, —
NRC(O)NR—
, —
NRCO2—
, —
OC(O)NR—
, —
CO2SO2—
, —
P(O)2O—
, or —
(CR6R7)p—
Y1—
.
-
56. The method of claim 55, wherein Q2 is independently —
- O—
or —
CO2—
.
- O—
-
60. The method of claim 55, wherein:
-
R1 is —
H;R2 is —
H, —
CH3, —
CH2OH, or —
NH2;R3 is —
H, —
F, —
Cl, C1-4 alkyl, or C1-4 haloalkyl;Z1 is —
H, —
F, or —
Cl;Z2 is —
H or C1-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and —
O(C1-C4 alkyl);Z3 is —
H or C1-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and —
O(C1-C4 alkyl);R5 is;
i) —
H;
ii) an optionally substituted C1-C6 alkyl group;
iii) an optionally substituted, C3-C7 non-aromatic carbocycle;
iv) an optionally substituted, 4-7 membered non-aromatic heterocycle;
v))an optionally substituted phenyl group;
vi) an optionally substituted 5-6 membered heteroaryl ring;
or optionally, together with R and the nitrogen atom to which it is attached, form a 5-7 membered, optionally substituted non-aromatic heterocycle; andsaid alkyl group represented by R5 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, —
NH2, —
NH(C1-C4 alkyl), —
N(C1-C4 alkyl)2, —
OCO(O—
C4 alkyl), —
CO(C1-C4 alkyl), —
CO2H, —
CO2(O—
C4 alkyl), C1-C4 alkoxy, —
NRCO(C1-C4 alkyl), —
CONR(C1-C4 alkyl), —
NRCO2(C1-C4 alkyl), a C3-C7 non-aromatic carbocycle optionally substituted with one or more instances of JE1, a 4-7 membered non-aromatic heterocycle optionally substituted with one or more instances of JE1; and
a phenyl optionally substituted with one or more instances of JE1; andwherein each of said carbocycle, heterocycle, phenyl and heteroary represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, —
O(C1-C4 alkyl), —
NH2, —
NH(C1-C4 alkyl), —
N(C1-C4 alkyl)2, —
C(O)(C1-C4 alkyl), —
OC(O)(C1-C4 alkyl), —
C(O)O(C1-C4 alkyl) and —
CO2H, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, —
NH2, —
NH(C1-C4 alkyl), —
N(C1-C4 alkyl)2, —
OCO(C1-C4 alkyl), —
CO(C1-C4 alkyl), —
CO2H, —
CO2(C1-C4 alkyl), and C1-C4 alkoxy.
-
-
62. The method of claim 55, wherein:
-
R1 is —
H;R2 is —
H or —
CH2OH;R3 is —
H, —
F, or —
Cl;Z1 is —
H, —
F, or —
Cl;Z2 is —
H;Z3 is —
H;R5 is independently;
i) —
H or ii) a C1-C6-alkyl group optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, —
O(C1-C4 alkyl), —
NH2, —
NH(C1-C4 alkyl), —
N(C1-C4 alkyl)2, —
C(O)(C1-C4 alkyl), —
OC(O)(C1-C4 alkyl), —
C(O)O(C1-C4 alkyl), —
CO2H, C3-C8 non-aromatic carbocycle, 4-8 membered non-aromatic heterocycle, phenyl, and 5-6 membered heteroaryl;wherein each of said alkyl groups referred to in the substituents of the C1-C6-alkyl group represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, —
NH2, —
NH(C1-C4 alkyl), —
N(C1-C4 alkyl)2, —
OCO(C1-C4 alkyl), —
CO(C1-C4 alkyl), —
CO2H, —
CO2(C1-C4 alkyl), and C1-C4 alkoxy; andwherein each of said carbocycle, phenyl, heterocycle, and heteroaryl referred to in the substituents of the C1-C6-alkyl group represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, —
NH2, —
NH(C1-C4 alkyl), —
N(C1-C4 alkyl)2, —
OCO(C1-C4 alkyl), —
CO(C1-C4 alkyl), —
CO2H, —
CO2(C1-C4 alkyl), and C1-C4 alkoxy.
-
-
65. The method of claim 6, wherein:
R4 is;
-
66. The method of claim 65, wherein:
R4 is;
-
67. The method of claim 66, wherein:
-
R1 is —
H;R2 is —
H;R3 is —
H, —
F, or —
Cl;Z1 is —
H, —
F, or —
Cl;Z2 is —
H;Z3 is —
H;X is —
O—
;R5 is —
H, an optionally substituted C1-C6 alkyl, or optionally substituted phenyl;each R8 is independently —
H, halogen, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, or —
O(C1-C4 alkyl);each of R9, R13, and R14 is independently —
H or C1-C4 alkyl;R21, R22, R23, R24, and R25 are each independently —
H, halogen, —
OH, C1-C6 alkoxy, or C1-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C1-C6 alkyl, and —
O(C1-C6 alkyl); andeach rings G1-G5 are independently and optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, —
NH2, —
NH(C1-C6 alkyl), —
N(C1-C6 alkyl)2, —
O(C1-C6 alkyl), C1-C4 alkyl that is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, and C1-C4 alkoxy.
-
-
69. The method of claim 1, further comprising co-administering and additional therapeutic agent.
-
70. The method of claim 69, wherein the additional therapeutic agent is selected from an antiviral agent or an Influenza vaccine, or both.
-
145. A pharmaceutical composition, comprising an effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt of the same, and a pharmaceutically acceptable carrier, adjuvant or vehicle.
-
147. The method of claim 1, wherein t is 0 or 1;
- and j is 0 or 1.
-
151. The method of claim 1, wherein the compound is selected from the compounds depicted in
FIG. 3 ,FIG. 4 ,FIG. 5 ,FIG. 6 ,FIG. 7 , andFIG. 8 , or a pharmaceutically acceptable salt thereof. -
152. A method of reducing the amount of influenza viruses in a biological sample or in a patient, comprising administering to said biological sample or patient an effective amount of a compound as described in claim 1, or a combination of said compounds thereof.
-
153. A method of treating influenza in a patient, comprising administering to said patient an effective amount of a compound as described in claim 1, or a combination of said compounds thereof.
-
2. The method of claim 1, represented by Structural Formula (I):
-
20. (canceled)
-
21. (canceled)
-
22. (canceled)
-
23. (canceled)
-
24. (canceled)
-
25. (canceled)
-
26. (canceled)
-
27. (canceled)
-
28. (canceled)
-
30. (canceled)
-
31. (canceled)
-
32. (canceled)
-
33. (canceled)
-
34. (canceled)
-
35. (canceled)
-
36. (canceled)
-
37. (canceled)
-
40. (canceled)
-
41. (canceled)
-
42. (canceled)
-
44. (canceled)
-
45. (canceled)
-
50. (canceled)
-
54. (canceled)
-
57. (canceled)
-
58. (canceled)
-
59. (canceled)
-
61. (canceled)
-
63. (canceled)
-
64. (canceled)
-
68. (canceled)
-
71. A compound represented by structural formula (IA):
- View Dependent Claims (72, 73, 74, 75, 76, 78, 79, 80, 83, 84, 85, 86, 87, 88, 100, 109, 110, 114, 117, 118, 119, 120, 122, 123, 124, 126, 127, 131, 133, 136, 137, 138, 143, 154, 155)
-
72. The compound of claim 71, represented by structural formula (I):
-
73. The compound of claim 72, wherein:
-
ring A is a C3-C8 non-aromatic carbocycle optionally and independently further substituted with one or more instances of JA; rings B and C are each independently a 4-8 membered, non-aromatic heterocycle optionally and independently further substituted with one or more instances of JB; ring D is a 4-8 membered, non-aromatic heterocycle optionally substituted with one or more instances of JD1; each of JA and JB is independently selected from the group consisting of halogen, cyano, oxo, and Q1-R5;
or optionally two JA and two JB, respectively, together with the atom(s) to which they are attached, independently form a 5-7 membered ring that is optionally substituted with one or more instances of JE1 and fused to the ring to which they are attached; andeach of JC1 and JD1 is independently selected from the group consisting of halogen, cyano, oxo, Ra, —
ORb, —
SRb, —
S(O)Ra, —
SO2Ra, —
NRbRc, —
C(O)Rb, —
C(O)ORb, —
OC(O)Rb, —
NRC(O)Rb, —
C(O)NRbRc, —
NRC(O)NRbRc, —
NRC(O)ORb, —
OCONRbRc, —
C(O)NRCO2Rb, —
NRC(O)NRC(O)ORb, —
C(O)NR(ORb), —
SO2NRcRb, —
NRSO2Rb, and —
NRSO2NRcRb, or optionally, two JC1 and two JD1, respectively, together with the atoms to which they are attached, independently form a 5-7-membered ring that is optionally substituted with one or more instances of JE1, and fused to the respective ring to which they are attached;Q1 is independently a bond, —
O—
, —
S—
, —
NR—
, —
C(O)—
, —
CO2—
, —
OC(O)—
, —
C(O)NR—
, —
C(O)NRC(O)O—
, —
NRC(O)NRC(O)O—
, —
NRC(O)—
, —
NRC(O)NR—
, —
NRCO2—
, —
OC(O)NR—
, —
S(O)—
, —
SO2—
, —
N(R)SO2—
, —
SO2N(R)—
, —
NRSO2NR—
, or —
(CR6R7)p—
Y1—
;Q2 is independently a bond, —
O—
, —
S—
, —
NR—
, —
C(O)—
, —
CO2—
, —
OC(O)—
, —
C(O)NR—
, —
C(O)NRC(O)O—
, —
NRC(O)NRC(O)O—
, —
NRC(O)—
, —
NRC(O)NR—
, —
NRCO2—
, —
OC(O)NR—
, —
S(O)—
, —
SO2—
, —
N(R)SO2—
, —
SO2N(R)—
, —
NRSO2NR—
, or —
(CR6R7)p—
Y1—
; andQ3 is independently a bond, —
C(O)—
, —
CO2—
, —
C(O)NR—
, —
SO2—
, —
SO2N(R)—
, —
C(O)NRC(O)O—
or —
(CR6R7)p—
Y1—
;
oreach of Q2 and Q3, together with R5, optionally and independently forms a 5-7 membered, non-aromatic ring optionally substituted with one or more instances of JE1; each Y1 is independently a bond, —
O—
, —
S—
, —
NR—
, —
C(O)—
, —
CO2—
, —
OC(O)—
, —
C(O)NR—
, —
C(O)NRC(O)O—
, —
NRC(O)NRC(O)O—
, —
NRC(O)—
, —
NRC(O)NR—
, —
NRCO2—
, —
OC(O)NR—
, —
S(O)—
, —
SO2—
, —
N(R)SO2—
, —
SO2N(R)—
, or —
NRSO2NR—
;R5 is;
i) —
H;
ii) a C1-C6 aliphatic group optionally substituted with one or more instances of JC1;
iii) a C3-C8 non-aromatic carbocycle, or 6-10 membered carbocyclic aryl group, each optionally and independently substituted with one or more instances of JC1;
or iv) a 4-8 membered non-aromatic heterocycle, or a 5-10 membered heteroaryl group, each optionally and independently substituted with one or more instances of Jp1; andR8 and R9 are each independently —
H, halogen, cyano, hydroxy, amino, carboxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 cyanoalkyl, C2-C6 alkoxyalkyl, C1-C6 aminoalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 aminoalkoxy, C1-C6 cyanoalkoxy, C1-C6 hydroxyalkoxy, or C2-C6 alkoxyalkoxy.
-
-
74. The compound of any one of claims 71-73, wherein R1 is —
- H or C1-C6 alkyl.
-
75. The compound of claim 74, wherein R1 is —
- H.
-
76. The compound of claim 75, wherein R2 is —
- H, —
F, —
CH3, —
CH2OH, or —
NH2.
- H, —
-
78. The compound of claim 76, wherein R3 is —
- H, —
Cl, —
F, —
Br, —
CN, —
CF3, —
O(C1-C4 alkyl), —
OH, —
NH2, —
NH(C1-C4 alkyl), or —
N(C1-C4 alkyl)2.
- H, —
-
79. The compound of claim 73, wherein the compound is represented by the following structural formula (VI):
-
80. The compound of claim 79, wherein:
-
Z1 is —
H, C1-C6 alkyl, —
O(C1-C6 alkyl), —
F, —
Cl, —
CN, —
CO2H, —
CO2(O—
C6 alkyl), —
CONH2, —
CONH(C1-C6 alkyl), or —
CON(C1-C6 alkyl)2, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, —
NH2, —
NH(C1-C4 alkyl), —
N(C1-C4 alkyl)2, —
OCO(C1-C4 alkyl), —
OCO(C1-C4 alkyl), —
CO2H, —
CO2(C1-C4 alkyl), and C1-C4 alkoxy; andZ2 is —
H, C1-C6 alkyl, —
O(C1-C6 alkyl), —
NH2, —
NH(C1-C6 alkyl), or —
N(C1-C6 alkyl)2, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, —
NH2, —
NH(C1-C4 alkyl), —
N(C1-C4 alkyl)2, —
OCO(C1-C4 alkyl), —
CO(C1-C4 alkyl), —
CO2H, —
CO2(C1-C4 alkyl), and C1-C4 alkoxy.
-
-
83. The compound of claim 79, wherein:
-
Z1 is —
H, —
F, —
Cl, —
CF3, —
CH3, or —
CN;Z2 is —
H or C1-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and —
O(C1-C4 alkyl);Z3 is —
H or C1-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and —
O(C1-C4 alkyl);R1 is —
H;R2 is —
H;R3 is independently —
H, —
Cl or —
F;R6 and R2 are each independently —
H or —
CH3, or together with the carbon atoms to which they are attached they form a cyclopropane ring;each R8 is independently —
H, halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, —
O(C1-C4 alkyl), —
NH2, —
NH(C1-C4 alkyl), or —
N(C1-C4 alkyl)2.each R9 is independently —
H or —
CH3;R11 and R12 are each independently —
H or —
CH3; andR13 and R14 are each independently —
H or —
CH3, or together with the carbon atoms to which they are attached they form a cyclopropane ring.
-
-
84. The compound of claim 80, wherein the compound is represented by any one of structural formulae (II), (III), (IV) and (V):
-
85. The compound of claim 84, wherein:
-
Z1 is —
H, —
F, —
Cl, —
CF3, —
CH3, or —
CN; andZ2 is —
H or an optionally substituted C1-C6 alkyl.
-
-
86. The compound of claim 85, wherein R3 is —
- H, —
Cl or —
F.
- H, —
-
87. The compound of claim 86, wherein:
-
R6 and R7 are each independently —
H or —
CH3, or together with the carbon atoms to which they are attached they form a cyclopropane ring;each R8 is independently —
H, halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, —
O(C1-C4 alkyl), —
NH2, —
NH(C1-C4 alkyl), or —
N(C1-C4 alkyl)2.each R9 is independently —
H or —
CH3;R11 and R12 are each independently —
H or —
CH3; andR13 and R14 are each independently —
H or —
CH3, or optionally R13 and R14, together with the carbon atom to which they are attached, form a cyclopropane ring.
-
-
88. The compound of claim 87, wherein the compound is represented by structural formula (XIA) or (XIB):
-
100. The compound of claim 87, wherein the compound is represented by structural formula (XIIA) or (XIIB):
-
109. The compound of claim 87, wherein the compound is represented by structural formula (XIII):
-
110. The compound of claim 109, wherein R10 is —
- H or C1-C6-alkyl.
-
114. The compound of claim 87, wherein the compound is represented by the following structural formula (XIV):
-
117. The compound of claim 83, wherein R4 is:
-
118. The compound of claim 117, wherein ring F is selected from any one of rings F1-F6:
-
119. The compound of claim 118, wherein each rings F1-F6 are independently and optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, C1-C4 alkoxy, and C1-C4 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, and —
- O(C1-C4 alkyl).
-
120. The compound of claim 118, wherein:
-
R9 is independently —
H, halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, —
O(C1-C4 alkyl), —
NH2, —
NH(C1-C4 alkyl), or —
N(C1-C4 alkyl)2; andring E is a C4-C8 non-aromatic carbocycle optionally further substituted with one or more instances of JA.
-
-
122. The compound of claim 83, wherein R4 is:
-
123. The compound of claim 122, wherein R4 is:
-
124. The compound of claim 123, wherein:
-
each of R8 and R9 is independently —
H, halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, Cz—
C4 alkoxyalkyl, —
O(C1-C4 alkyl), —
NH2, —
NH(C1-C4 alkyl), or —
N(C1-C4 alkyl)2; andR21, R22, R23, and R24 are each independently —
H, halogen, —
OH, or C1-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 aminoalkoxy, C1-C6 cyanoalkoxy, C1-C6 hydroxyalkoxy, and C2-C6 alkoxyalkoxy.
-
-
126. The compound of claim 124, wherein:
Q2 is independently —
O—
, —
CO2—
, —
OC(O)—
, —
C(O)NR—
, —
NRC(O)—
, —
NRC(O)NR—
, —
NRCO2—
, —
OC(O)NR—
, —
CO2SO2—
, —
P(O)2O—
, or —
(CR6R2)p—
Y1—
.
-
127. The compound of claim 126, wherein Q2 is independently —
- O—
or —
CO2—
.
- O—
-
131. The compound of claim 126, wherein:
-
R1 is —
H;R2 is —
H, —
CH3, —
CH2OH, or —
NH2;R3 is —
H, —
F, —
Cl, C1-4 alkyl, or C1-4 haloalkyl;Z1 is —
H, —
F, or —
Cl;Z2 is —
H or C1-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and —
O(C1-C4 alkyl);Z3 is —
H or C1-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and —
O(C1-C4 alkyl);R5 is;
i) —
H;
ii) an optionally substituted C1-C6 alkyl group;
iii) an optionally substituted, C3-C2 non-aromatic carbocycle;
or iv) an optionally substituted, 4-7 membered non-aromatic heterocycle;
or optionally, together with R and the nitrogen atom to which it is attached, form a 5-7 membered, optionally substituted non-aromatic heterocycle; andsaid alkyl group represented by R5 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, —
NH2, —
NH(C1-C4 alkyl), —
N(C1-C4 alkyl)2, —
OCO(C1-C4 alkyl), —
CO(C1-C4 alkyl), —
CO2H, —
CO2(C1-C4 alkyl), C1-C4 alkoxy, a C3-C7 non-aromatic carbocycle optionally substituted with one or more instances of JE1, a 4-7 membered non-aromatic heterocycle optionally substituted with one or more instances of JE1; and
a phenyl optionally substituted with one or more instances of JE1; andwherein each of said carbocycles and heterocycles represented by R5, and referred to for the substituents of the C1-C6 alkyl group represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, —
O(C1-C4 alkyl), —
NH2, —
NH(C1-C4 alkyl), —
N(C1-C4 alkyl)2, —
C(O)(C1-C4 alkyl), —
OC(O)(C1-C4 alkyl), —
C(O)O(C1-C4 alkyl) and —
CO2H, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, —
NH2, —
NH(C1-C4 alkyl), —
N(C1-C4 alkyl)2, —
OCO(C1-C4 alkyl), —
CO(C1-C4 alkyl), —
CO2H, —
CO2(C1-C4 alkyl), and C1-C4 alkoxy.
-
-
133. The compound of claim 126, wherein:
-
R1 is —
H;R2 is —
H or —
CH2OH;R3 is —
H, —
F, or —
Cl;Z1 is —
H, —
F, or —
Cl;Z2 is —
H;Z3 is —
H;R5 is independently;
i) —
H or ii) a C1-C6-alkyl group optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, —
O(C1-C4 alkyl), —
NH2, —
NH(C1-C4 alkyl), —
N(C1-C4 alkyl)2, —
C(O)(C1-C4 alkyl), —
OC(O)(C1-C4 alkyl), —
C(O)O(C1-C4 alkyl), —
CO2H, C3-C8 non-aromatic carbocycle, 4-8 membered non-aromatic heterocycle, phenyl, and 5-6 membered heteroaryl;wherein each of said alkyl groups referred to in the substituents of the C1-C6-alkyl group represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, —
NH2, —
NH(C1-C4 alkyl), —
N(C1-C4 alkyl)2, —
OCO(C1-C4 alkyl), —
CO(C1-C4 alkyl), —
CO2H, —
CO2(C1-C4 alkyl), and C1-C4 alkoxy; andwherein each of said carbocycle, phenyl, heterocycle, and heteroaryl referred to in the substituents of the C1-C6-alkyl group represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, —
NH2, —
NH(C1-C4 alkyl), —
N(C1-C4 alkyl)2, —
OCO(C1-C4 alkyl), —
CO(C1-C4 alkyl), —
CO2H, —
CO2(C1-C4 alkyl), and C1-C4 alkoxy.
-
-
136. The compound of claim 71, wherein:
R4 is;
-
137. The compound of claim 136, wherein:
R4 is;
-
138. The compound of claim 137, wherein:
-
R1 is —
H;R2 is —
H;R3 is —
H, —
F, or —
Cl;Z1 is —
H, —
F, or —
Cl;Z2 is —
H;Z3 is —
H;X is —
O—
;R5 is —
H, an optionally substituted C1-C6 alkyl, or optionally substituted phenyl;each R8 is independently —
H, halogen, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, or —
O(C1-C4alkyl);each of R9, R13, and R14 is independently —
H or C1-C4 alkyl;R21, R22, R23, R24, and R25 are each independently —
H, halogen, —
OH, C1-C6 alkoxy, or C1-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C1-C6 alkyl, and —
O(C1-C6 alkyl); andeach rings G1-G5 are independently and optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, —
NH2, —
NH(C1-C6 alkyl), —
N(C1-C6 alkyl)2, —
O(C1-C6 alkyl), C1-C4 alkyl that is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, and C1-C4 alkoxy.
-
-
143. The compound of claim 71, wherein the compound is selected from any of the structures depicted in
FIG. 3 ,FIG. 4 ,FIG. 5 , andFIG. 6 , or a pharmaceutically acceptable salt thereof. -
154. A method preparing a compound represented by Structural Formula (IA):
-
155. A method preparing a compound represented by Structural Formula (IA):
-
72. The compound of claim 71, represented by structural formula (I):
-
77. (canceled)
-
81. (canceled)
-
82. (canceled)
-
89. (canceled)
-
90. (canceled)
-
91. (canceled)
-
92. (canceled)
-
93. (canceled)
-
94. (canceled)
-
95. (canceled)
-
96. (canceled)
-
97. (canceled)
-
98. (canceled)
-
99. (canceled)
-
101. (canceled)
-
102. (canceled)
-
103. (canceled)
-
104. (canceled)
-
105. (canceled)
-
106. (canceled)
-
107. (canceled)
-
108. (canceled)
-
111. (canceled)
-
112. (canceled)
-
113. (canceled)
-
115. (canceled)
-
116. (canceled)
-
121. (canceled)
-
125. (canceled)
-
128. (canceled)
-
129. (canceled)
-
130. (canceled)
-
132. (canceled)
-
134. (canceled)
-
135. (canceled)
-
139. (canceled)
-
140. (canceled)
-
141. (canceled)
-
142. (canceled)
-
144. A compound selected from any of the structures depicted in
FIG. 7 or a pharmaceutically acceptable salt thereof.
-
146. (canceled)
-
148. (canceled)
-
149. (canceled)
-
150. (canceled)
-
156. (canceled)
Specification
- Resources
-
Current AssigneeVertex Pharmaceuticals Incorporated
-
Original AssigneeVertex Pharmaceuticals Incorporated
-
InventorsCharifson, Paul S., Clark, Michael P., Bandarage, Upul K., Bethiel, Randy S., Court, John J., Deng, Hongbo, Duffy, John P., Gao, Huai, Ledeboer, Mark W., Ledford, Brian, Maltais, Francois, Perola, Emanuele, Wang, Tiansheng, Byrn, Randal, Zhou, Yi, Lin, Chao, Germann, Ursula A., Davies, Ioana, Farmer, Luc J., Gu, Wenxin, Jacobs, Dylan H., Kennedy, Joseph M., Wannamaker, M. Woods, Jiang, Min, Jones, Steven
-
Application NumberUS13/327,206Publication NumberTime in Patent OfficeDaysField of SearchUS Class Current424/209.1CPC Class CodesA61K 31/506 not condensed and containin...A61K 31/5377 not condensed and containin...A61K 31/55 having seven-membered rings...A61K 31/553 having at least one nitroge...A61P 31/00 Antiinfectives, i.e. antibi...A61P 31/16 for influenza or rhinovirusesA61P 37/04 ImmunostimulantsA61P 43/00 Drugs for specific purposes...C07D 239/30 Halogen atoms or nitro radi...C07D 401/04 directly linked by a ring-m...C07D 401/10 linked by a carbon chain co...C07D 471/04 Ortho-condensed systems