HIV reverse transcriptase inhibitors
View Patent ↗Compounds having the structure: are HIV reverse transcriptase inhibitors, wherein A, X, Y, Z, R 1 and R 2 are defined herein. The compounds and their pharmaceutically acceptable salts are useful in the inhibition of HIV reverse transcriptase, the prophylaxis and treatment of infection by HIV and in the prophylaxis, delay in the onset, and treatment of AIDS. The compounds and their salts can be employed as ingredients in pharmaceutical compositions, optionally in combination with other antivirals, immunomodulators, antibiotics or vaccines.
1. A compound of Formula I, or a pharmaceutically acceptable salt thereof:
wherein:
R 1 and R 2 are independently selected from the group consisting of
a) H,
b) C 1-6 alkyl,
c) C 3-6 cycloalkyl,
d) C 1-3 fluoroalkyl,
e) NO 2 ,
f) halogen,
g) OR 3 ,
h) O(CH 2 ) S OR 3 ,
i) CO 2 R 3 ,
j) (CO)NR 3 R 4 ,
k) O(CO)NR 3 R 4 ,
l) N(R 3 )(CO)NR 3 R 4 ,
m) N(R 3 )(CO)R 4 ,
n) N(R 3 )(CO)OR 3 ,
o) SO 2 NR 3 R 4 ,
p) N(R 3 )SO 2 R 4 ,
q) S(O) m R 3 ,
r) CN,
s) NR 3 R 4 ,
t) N(R 3 )(CO)NR 3 R 4 , and
u) O(CO)R 3 ;
A is phenyl;
V is —C(R 5 R 6 )—;
X is —O—;
Y is —O—;
R 5 and R 6 are independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-3 fluoroalkyl, and OR 3 ;
R 10 is a heterocyclyl selected from the group consisting of:
R 3 and R 4 are independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-3 fluoroalkyl, and C 3-6 cycloalkyl;
or, alternatively and optionally, when R 3 and R 4 are in an NR 3 R 4 group, then:
(A) one of R 3 and R 4 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-3 fluoroalkyl, and C 3-6 cycloalkyl, and the other of R 3 and R 4 is C 1-6 alkyl substituted with O—C 1-6 alkyl, C(O)R A , CO 2 R A , C(O)N(R A )R B , SR A , S(O)R A , SO 2 R A , or SO 2 N(R A )R B ; or
(B) R 3 and R 4 together with the nitrogen atom to which they are both attached form
(i) a 4- to 7-membered, saturated or unsaturated monocyclic ring optionally containing 1 or 2 heteroatoms in addition to the nitrogen attached to R 3 and R 4 selected from N, O, and S, where the S is optionally oxidized to S(O) or S(O) 2 , or
(ii) a 7- to 12-membered bicyclic ring system wherein each ring in (ii) is independent of, fused to, or bridged with the other ring and each ring is saturated or unsaturated, and wherein the bicyclic ring system optionally contains from 1 to 3 heteroatoms in addition to the nitrogen attached to R 3 and R 4 selected from N, O, and S, where the S is optionally oxidized to S(O) or S(O) 2 , and
wherein the monocyclic ring or the bicyclic ring system is optionally substituted with from 1 to 3 substituents each of which is independently: (1) C 1-6 alkyl, (2) C 1-6 haloalkyl, (3) C 1-6 alkyl substituted with OH, O—C 1-6 alkyl, O—C 1-6 haloalkyl, CN, NO 2 , N(R A )R B , C(O)N(R A )R B , C(O)R A , CO 2 R A , SR A , S(O)R A , SO 2 R A , or SO 2 N(R A )R B , (4) O—C 1-6 alkyl, (5) O—C 1-6 haloalkyl, (6) OH, (7) oxo, (8) halogen, (9) CN, (10) NO 2 , (11) N(R A )R B , (12) C(O)N(R A )R B , (13) C(O)R A , (14) C(O)—C 1-6 haloalkyl, (15) C(O)OR A , (16) OC(O)N(R A )R B , (17) SR A , (18) S(O)R A , (19) S(O) 2 R A , (20) S(O) 2 N(R A )R B , (21) N(R A )COR B , or (22) N(R A )SO 2 R B and
wherein each R A is independently H or C 1-6 alkyl, and each R B is independently H or C 1-6 alkyl;
R 12 and R 13 are independently selected from the group consisting of hydrogen, halogen, oxo, NO 2 , CN, OR 3 , O(CH 2 ) t CF 3 , CO 2 R 3 , CONR 3 R 4 , O(CH 2 ) t NR 3 R 4 , O(CH 2 ) v COR 3 , S(O) m R 3 , SO 2 NR 3 R 4 , C 1-6 alkyl, C 1-3 fluoroalkyl, C 3-6 cycloalkyl, and NR 3 R 4 ;
HetA is heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, and pyrazinyl;
s is 1-5;
t is 2-3;
v is 1-2; and
m, in each instance in which it appears, is independently selected from 0-2.
2. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, which is a compound of Formula Ic-1:
3. A compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 and R 2 are independently selected from the group consisting of hydrogen, halogen, and C 1-6 alkyl;
R 5 and R 6 are independently selected from the group consisting of hydrogen and C 1-6 alkyl;
R 10 is selected from the group consisting of:
R 12 and R 13 are independently selected from the group consisting of hydrogen, halogen, oxo, NO 2 , CN, OR 3 , O(CH 2 ) t CF 3 , CO 2 R 3 , CONR 3 R 4 , O(CH 2 ) t NR 3 R 4 , O(CH 2 ) v COR 3 , S(O) m R 3 , SO 2 NR 3 R 4 , C 1-6 alkyl and C 1-3 fluoroalkyl.
4. A compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein:
V is —CH 2 —; and
R 10 is selected from the group consisting of
5. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, which is a compound of Formula Ic-2;
6. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
3-[3-(1,3-benzothiazol-2-ylmethoxy)-5-chlorophenoxy]-5-chlorobenzonitrile,
3-[3-(1,3-benzothiazol-2-ylmethoxy)-5-methylphenoxy]-5-chlorobenzonitrile,
3-[5-(1,3-benzothiazol-2-ylmethoxy)-2-chlorophenoxy]-5-chlorobenzonitrile,
3-chloro-5-{3-chloro-5-[(7-chloro-1,3-benzothiazol-2-yl)methoxy]phenoxy}benzonitrile,
3-chloro-5-{2-chloro-5-[(7-chloro-1,3-benzothiazol-2-yl)methoxy]phenoxy}benzonitrile,
3-chloro-5-{2-chloro-5-[(7-chloro-1,3-benzoxazol-2-yl)methoxy]phenoxy}benzonitrile,
3-chloro-5-[3-chloro-5-(1H-indazol-3-ylmethoxy)phenoxy]benzonitrile,
3-chloro-5-{2-chloro-5-[(1-methyl-1H-benzimidazol-2-yl)methoxy]phenoxy}benzonitrile,
3-chloro-5-{2-chloro-5-[(1-phenyl-1H-1,2,3-triazol-4-yl)methoxy]phenoxy}benzonitrile,
3-chloro-5-[2-chloro-5-(1H-indazol-3-ylmethoxy)phenoxy]benzonitrile,
3-chloro-5-{2-chloro-5-[(3-phenyl-1,2,4-oxadiazol-5-yl)methoxy]phenoxy}benzonitrile,
3-chloro-5-(3-chloro-5-{([3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methoxy}phenoxy)-benzonitrile,
3-chloro-5-(2-chloro-5-{[5-(4-methylphenyl)-1,3,4-oxadiazol-2-yl]methoxy}phenoxy)-benzonitrile, and
3-chloro-5-[2-chloro-5-(1H-pyrazolo[3,4-b]pyridin-3-ylmethoxy)phenoxy]benzonitrile,
3-{5-[(1H-pyrazolo[3,4-b]pyridin-3-yl)methoxy]-3-fluorophenoxy}-5-chlorobenzonitrile,
3-{5-[(1H-pyrazolo[3,4-b]pyridin-3-yl)methoxy]-2-chloro-3-fluorophenoxy}-5-chlorobenzonitrile,
3-{5-[(1H-pyrazolo[3,4-b]pyridin-3-yl)methoxy]-4-chloro-3-fluorophenoxy}-5-chlorobenzonitrile, and
3-{5-[(7-oxo-1H-pyrazolo[3,4-b]pyridin-3-yl)methoxy]-4-chloro-3-fluorophenoxy}-5-chlorobenzonitrile.
7. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, and C 1-4 alkyl;
A is phenyl optionally substituted with from 1 to 3 substituents each of which is independently halogen, C 1-4 alkyl, or CN;
V is —CH 2 —;
one of R 3 and R 4 is H, C 1-4 alkyl, or C 3-6 cycloalkyl, and the other of R 3 and R 4 is H, C 1-4 alkyl, or C 1-4 alkyl substituted with O—C 1-4 alkyl, C(O)R A , CO 2 R A , C(O)N(R A )R B , or SO 2 R A ;
or alternatively R 3 and R 4 together with the nitrogen atom to which they are both attached form a 4- to 7-membered, saturated monocyclic ring optionally containing 1 heteroatom in addition to the nitrogen attached to R 3 and R 4 selected from N, O, and S, where the S is optionally oxidized to S(O) or S(O) 2 , wherein the monocyclic ring is optionally substituted with 1 or 2 substituents each of which is independently: (1) C 1-4 alkyl, (2) CF 3 , (3) (CH 2 ) 1-2 T wherein T is OH, O—C 1-4 alkyl, OCF 3 , N(R A )R B , C(O)N(R A )R B , C(O)R A , CO 2 R A , or SO 2 R A , (4) O—C 1-4 alkyl, (5) OCF 3 , (6) OH, (7) oxo, (8) halogen, (9) C(O)N(R A )R B , (10) C(O)R A , (11) C(O)—CF 3 , (12) C(O)OR A , or (13) S(O) 2 R A ;
each R A is independently H or C 1-4 alkyl, and
each R B is independently H or C 1-4 alkyl.
8. A compound of claim 7 , or a pharmaceutically acceptable salt thereof, which is a compound of Formula Ic-1.
9. A compound of claim 7 , or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
3-{5-[(6-amino-1H-pyrazolo[3,4-b]pyridin-3-yl)methoxy]-2-chlorophenoxy}-5-chlorobenzonitrile,
3-chloro-5-(2-chloro-5-{[6-methylamino)-1H-pyrazolo[3,4-b]-pyridin-3-yl]methoxy}phenoxy)-benzonitrile,
3-chloro-5-(2-chloro-5-{[6-dimethylamino)-1H-pyrazolo[3,4-b]-pyridin-3-yl]methoxy}phenoxy)-benzonitrile,
3-chloro-5-[2-chloro-5-({6-[(2-methoxyethyl)(methyl)amino]-1H-pyrazolo[3,4-b]-pyridin-3-yl}methoxy)phenoxy)benzonitrile,
3-chloro-5-(2-chloro-5-[(6-morpholin-4-yl-1H-pyrazolo[3,4-b]-pyridin-3-yl)methoxy]phenoxy)-benzonitrile,
N2-(3-{[4-chloro-3-(3-chloro-5-cyanophenoxy)phenoxy]methyl}-1H-pyrazolo[3,4-b]pyridin-6-yl)-N2-methylglycinamide,
3-chloro-5-(2-chloro-5-{[6-(3-methoxyazetidin-1-yl)-1H-pyrazolo[3,4-b]-pyridin-3-yl]methoxy}phenoxy)-benzonitrile,
3-chloro-5-(2-chloro-5-{[6-(azetidin-1-yl)-1H-pyrazolo[3,4-b]-pyridin-3-yl]methoxy}phenoxy)-benzonitrile,
3-chloro-5-{2-chloro-5-[(6-piperazin-1-yl-1H-pyrazolo[3,4-b]-pyridin-3-yl)methoxy]phenoxy}-benzonitrile,
3-(5-{[6-(3-aminopyrrolidin-1-yl)-1H-pyrazolo[3,4-b]-pyridin-3-yl]methoxy}-2-chlorophenoxy)-5-chlorobenzonitrile,
3-[5-({6-[3-(aminomethyl)azetidin-1-yl]-1H-pyrazolo[3,4-b]-pyridin-3-yl}methoxy)-2-chlorophenoxy]-5-chlorobenzonitrile, and
3-(5-{[6-(3-aminoazetidin-1-yl)-1H-pyrazolo[3,4-b]-pyridin-3-yl]methoxy}-2-chlorophenoxy)-5-chlorobenzonitrile,
3-{5-[(6-amino-1H-pyrazolo[3,4-b]pyridin-3-yl)methoxy]-2-chloro-3-fluorophenoxy}-5-chlorobenzonitrile,
3-{5-[(6-amino-1H-pyrazolo[3,4-b]pyridin-3-yl)methoxy]-3-fluorophenoxy}-5-chlorobenzonitrile, and
3-{5-[(6-amino-1H-pyrazolo[3,4-b]pyridin-3-yl)methoxy]-4-chloro-3-fluorophenoxy}-5-chlorobenzonitrile.
10. A compound of Formula I-P:
wherein:
R 1 and R 2 are independently selected from the group consisting of
a) H,
b) C 1-6 alkyl,
c) C 3-6 cycloalkyl,
d) C 1-3 fluoroalkyl,
e) NO 2 ,
f) halogen,
g) OR 3 ,
h) O(CH 2 ) S OR 3 ,
i) CO 2 R 3 ,
j) (CO)NR 3 R 4 ,
k) O(CO)NR 3 R 4 ,
l) N(R 3 )(CO)NR 3 R 4 ,
m) N(R 3 )(CO)R 4 ,
n) N(R 3 )(CO)OR 3 ,
o) SO 2 NR 3 R 4 ,
p) N(R 3 ) SO 2 R 4 ,
q) S(O) m R 3 ,
r) CN,
s) NR 3 R 4 ,
t) N(R 3 )(CO)NR 3 R 4 , and
u) O(CO)R 3 ;
A is phenyl;
V is —C(R 5 R 6 )—;
X is —O—;
Y is —O—;
Z P is R 10 *;
R 5 and R 6 are independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-3 fluoroalkyl, and OR 3 ;
R 10 * is a heterocycle selected from the group consisting of:
R 12 and R 13 are independently selected from the group consisting of hydrogen, halogen, oxo, NO 2 , CN, OR 3 , O(CH 2 ) t CF 3 , CO 2 R 3 , CONR 3 R 4 , O(CH 2 ) t NR 3 R 4 , O(CH 2 ) v COR 3 , S(O) m R 3 , SO 2 NR 3 R 4 , C 1-6 alkyl, C 1-3 fluoroalkyl, C 3-6 cycloalkyl, and NR 3 R 4 ;
R 3 and R 4 are independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-3 fluoroalkyl, and C 3-6 cycloalkyl;
or, alternatively and optionally, when R 3 and R 4 are in an NR 3 R 4 group, then:
(A) one of R 3 and R 4 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-3 fluoroalkyl, and C 3-6 cycloalkyl, and the other of R 3 and R 4 is C 1-6 alkyl substituted with O—C 1-6 alkyl, C(O)R A , CO 2 R A , C(O)N(R A )R B , SR A , S(O)R A , SO 2 R A , or SO 2 N(R A )R B ; or
(B) R 3 and R 4 together with the nitrogen atom to which they are both attached form
(i) a 4- to 7-membered, saturated or unsaturated monocyclic ring optionally containing 1 or 2 heteroatoms in addition to the nitrogen attached to R 3 and R 4 selected from N, O, and S, where the S is optionally oxidized to S(O) or S(O) 2 , or
(ii) a 7- to 12-membered bicyclic ring system wherein each ring in (ii) is independent of, fused to, or bridged with the other ring and each ring is saturated or unsaturated, and wherein the bicyclic ring system optionally contains from 1 to 3 heteroatoms in addition to the nitrogen attached to R 3 and R 4 selected from N, O, and S, where the S is optionally oxidized to S(O) or S(O) 2 , and
wherein the monocyclic ring or the bicyclic ring system is optionally substituted with from 1 to 3 substituents each of which is independently: (1) C 1-6 alkyl, (2) C 1-6 haloalkyl, (3) C 1-6 alkyl substituted with OH, O—C 1-6 alkyl, O—C 1-6 haloalkyl, CN, NO 2 , N(R A )R B , C(O)N(R A )R B , C(O)R A , CO 2 R A , SR A , S(O)R A , SO 2 R A , or SO 2 N(R A )R B , (4) O—C 1-6 alkyl, (5) O—C 1-6 haloalkyl, (6) OH, (7) oxo, (8) halogen, (9) CN, (10) NO 2 , (11) N(R A )R B , (12) C(O)N(R A )R B , (13) C(O)R A , (14) C(O)—C 1-6 haloalkyl, (15) C(O)OR A , (16) OC(O)N(R A )R B , (17) SR A , (18) S(O)R A , (19) S(O) 2 R A , (20) S(O) 2 N(R A )R B , (21) N(R A )COR B , or (22) N(R A )SO 2 R B and
wherein each R A is independently H or C 1-6 alkyl, and each R B is independently H or C 1-6 alkyl;
HetA is heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, and pyrazinyl;
R 14 is PO(OH)O − .M + ; PO(O − ) 2 .2M + ; PO(O − ) 2 .M +2 ; or an acid salt of:
M + is a pharmaceutically acceptable monovalent counterion;
M +2 is a pharmaceutically acceptable divalent counterion;
R 15 is H, C 1-6 alkyl, (CH 2 ) 2-3 CF 3 , AryA, or HetB;
R 16a and R 16b are each independently H, C 1-6 alkyl, (CH 2 ) 2-3 CF 3 , AryA, or HetB;
each R 17 is independently H or C 1-6 alkyl;
each R 18 is independently H or C 1-6 alkyl;
alternatively, R 15 together with an R 17 or R 18 and the atoms to which each is attached and any carbons in a chain therebetween form a 5- to 7-membered, saturated or unsaturated monocyclic ring optionally containing a heteroatom in addition to the N atom to which R 15 is attached, wherein the optional heteroatom is selected from N, O and S, where the S is optionally oxidized to S(O) or S(O) 2 ;
alternatively, R 16a together with an R 17 or R 18 and the atoms to which each is attached and any carbons in a chain therebetween form a 5- to 7-membered, saturated or unsaturated monocyclic ring optionally containing a heteroatom in addition to the N atom to which R 16a is attached, wherein the optional heteroatom is selected from N, O and S, where the S is optionally oxidized to S(O) or S(O) 2 ;
alternatively, an R 17 together with the R 18 attached to the same carbon atom form a 5- or 6-membered, saturated monocyclic ring optionally containing a heteroatom, wherein the optional heteroatom is selected from N, O and S, where the S is optionally oxidized to S(O) or S(O) 2 ;
R 19 is H or C 1-6 alkyl;
R 20 is H or C 1-6 alkyl;
R 21 is H or C 1-6 alkyl;
R 22a and R 22b are each independently H, C 1-6 alkyl, (CH 2 ) 2-3 CF 3 , AryA, or HetB;
R 23 is H or C 1-6 alkyl;
R 24 is H or C 1-6 alkyl;
alternatively, R 19 together with R 23 or R 24 and the atoms to which each is attached form a 5- to 7-membered, saturated or unsaturated monocyclic ring optionally containing a heteroatom in addition to the N atom to which R 19 is attached, wherein the optional heteroatom is selected from N, O and S, where the S is optionally oxidized to S(O) or S(O)2;
alternatively, R 20 and R 21 together with the carbon atom to which both are attached form a 5- or 6-membered, saturated monocyclic ring optionally containing a heteroatom, wherein the optional heteroatom is selected from N, O and S, where the S is optionally oxidized to S(O) or S(O) 2 ;
alternatively, R 22a together with an R 20 or R 21 and the atoms to which each is attached form a 5- to 7-membered, saturated or unsaturated monocyclic ring optionally containing a heteroatom in addition to the N atom to which R 22a is attached, wherein the optional heteroatom is selected from N, O and 5, where the S is optionally oxidized to S(O) or S(O)2;
alternatively, R 23 and R 24 together with the carbon atom to which both are attached form a 5- or 6-membered, saturated monocyclic ring optionally containing a heteroatom, wherein the optional heteroatom is selected from N, O and S, where the S is optionally oxidized to S(O) or S(O) 2 ;
wherein the monocyclic ring formed by combining R 15 together with an R 17 or R 18 , the monocyclic ring formed by combining R 16a together with an R 17 or R 18 , the monocyclic ring formed by combining R 17 together with an R 18 , the monocyclic ring formed by combining R 19 together with an R 23 or R 24 , the monocyclic ring formed by combining R 20 together with an R 21 , the monocyclic ring formed by combining R 22a together with an R 20 or R 21 , and the monocyclic ring formed by combining R 23 together with an R 24 , are each independently and optionally substituted with from 1 to 3 substituents each of which is independently: (1) C 1-6 alkyl, (2) C 1-6 haloalkyl, (3) C 1-6 alkyl substituted with OH, O—C 1-6 alkyl, O—C 1-6 haloalkyl, CN, NO 2 , N(R A )R B , C(O)N(R A )R B , C(O)R A , CO 2 R A , SR A , S(O)R A , SO 2 R A , or SO 2 N(R A )R B , (4) O—C 1-6 alkyl, (5) O—C 1-6 haloalkyl, (6) OH, (7) oxo, (8) halogen, (9) CN, (10) NO 2 , (11) N(R A )R B , (12) C(O)N(R A )R B , (13) C(O)R A , (14) C(O)—C 1-6 haloalkyl, (15) C(O)OR A , (16) OC(O)N(R A )R B , (17) SR A , (18) S(O)R A , (19) S(O) 2 R A , (20) S(O) 2 N(R A )R B , (21) N(R A )COR B , or (22) N(R A )SO 2 R B ;
AryA is aryl;
HetB is heteroaryl;
d is 2-4;
s is 1-5;
t is 2-3;
v is 1-2; and
m, in each instance in which it appears, is independently selected from 0-2.
11. A compound according to claim 9 , or a pharmaceutically acceptable salt thereof, which is 3-{5-[(6-amino-1H-pyrazolo[3,4-b]pyridin-3-yl)methoxy]-2-chlorophenoxy}-5-chlorobenzonitrile and which has the following structure:
12. A pharmaceutical composition comprising an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
13. A pharmaceutical composition comprising an effective amount of a compound according claim 11 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
14. A method of inhibiting HIV reverse transcriptase, for treating HIV infection, or for treating or delaying the onset of AIDS, which comprises administering to a subject in need thereof an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.
15. A method of inhibiting HIV reverse transcriptase, for treating HIV infection, or for treating or delaying the onset of AIDS, which comprises administering to a subject in need thereof an effective amount of a compound according to claim 11 , or a pharmaceutically acceptable salt thereof.