21875YS
WHAT IS CLAIMED IS:
1.A compound of Formula Ic, or a pharmaceutically acceptable salt thereof:
(Ic)
wherein:
R1 and R2 are independently selected from the group consisting of:
a)H,
b)C1-6 alkyl,
c)C3-6 cycloalkyl,
d)C1-3 fluoroalkyl,
e)NO2,
f)halogen,
g)OR3,
h)O(CH2)sOR3,
i)CO2R3,
j)(CO)NR3R4,
k)O(CO)NR3R4,
l)N(R3)(CO)NR3R4,
m)N(R3)(CO)R4,
n)N(R3)(CO)OR3,
o)SO2NR3R4,
p)N(R3) SO2R4,
q)S(O)mR3,
r)CN,
s)NR3R4,
t)N(R3)(CO)NR3R4, and
u)O(CO)R3;
A is aryl or C3-7 cycloalkyl; wherein the cycloalkyl or aryl in the definition of A are each independently unsubstituted or substituted with from 1 to 3 substituents each of which is independently halo, C1-C6 alkyl, CF3, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, NO2, oxo, CN, OH, O(C1-C6 alkyl), C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, S(O)0-2(C1-C6 alkyl), (C1-C6 alkylene)S(O)0-2(C1-C6 alkyl), NHC(O)(C1-C6 alkyl), C(=NH)NH2, O(C1-C6 alkylene)CF3, C(O)(C1-C6 alkyl), C(O)H, OC(O)(C1-C6 alkyl), (C1-C6 alkylene)O(C1-C6 alkyl), C(O)NH2, C(O)NH(C1-C6 alkyl), C(O)N(C1-C6 alkyl)2, C(O)2H, C(O)2(C1-C6 alkyl), (C1-C6 alkylene)C(O)1-2(C1-C6 alkyl), NHC(O)O(C1-C6 alkyl), NH(C1-C6 alkyl)NHC(O)NH(C1-C6 alkyl), NHSO2NH2, NH(C1-C6 alkyl)NHSO2(C1-C6 alkyl), NHSO2(C1-C6 alkyl), (C1-C6 alkyl)NHSO2(C1-C6 alkyl), phenyl, or benzyl;
V is C(R5R6);
X is selected from the group consisting of -O-, -NH-, and C(R5R6);
Y is selected from the group consisting of -O-, C(R5R6), and –S(O)m-;
R5 and R6 are independently selected from the group consisting of hydrogen, C1-6 alkyl, C1-3 fluoroalkyl, and OR3;
R10 is a heterocyclyl selected from the group consisting of:
, , , ,
, , , , ,
, , ,
, , , ,
, , , , ,
, , , , and ;
R12 and R13 are independently selected from the group consisting of hydrogen, halogen, oxo, NO2, CN, OR3, O(CH2)tCF3, CO2R3, CONR3R4, O(CH2)tNR3R4, O(CH2)vCOR3, S(O)mR3, SO2NR3R4, C1-6 alkyl, C1-3 fluoroalkyl, C3-6 cycloalkyl, and NR3R4;
R3 and R4 are independently selected from the group consisting of hydrogen, C1-6 alkyl, C1-3 fluoroalkyl, and C3-6 cycloalkyl;
or, alternatively and optionally, when R3 and R4 are in an NR3R4 group, then:
(A)one of R3 and R4 is selected from the group consisting of hydrogen, C1-6 alkyl, C1-3 fluoroalkyl, and C3-6 cycloalkyl, and the other of R3 and R4 is C1-6 alkyl substituted with OC16 alkyl,C(O)RA, CO2RA, C(O)N(RA)RB, SRA, S(O)RA, SO2RA, or SO2N(RA)RB; or
(B)R3 and R4 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 R3 and R4 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 R3 and R4 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) C16 alkyl, (2) C1-6 haloalkyl, (3) C1-6 alkyl substituted with OH, OC1-6 alkyl, OC1-6 haloalkyl, CN, NO2, N(RA)RB, C(O)N(RA)RB, C(O)RA, CO2RA, SRA, S(O)RA, SO2RA, or SO2N(RA)RB, (4) OC16 alkyl, (5) OC16 haloalkyl, (6) OH, (7) oxo, (8) halogen, (9) CN, (10) NO2, (11) N(RA)RB, (12) C(O)N(RA)RB, (13) C(O)RA, (14) C(O)C1-6 haloalkyl, (15) C(O)ORA, (16) OC(O)N(RA)RB, (17) SRA, (18)S(O)RA, (19) S(O)2RA, (20) S(O)2N(RA)RB, (21) N(RA)CORB, or (22) N(RA)SO2RB and
wherein each RA is independently H or C1-6 alkyl, and each RB is independently H or C1-6 alkyl;
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;
and provided that when X is C(R5R6), then neither R1 nor R2 is OR3.
2.A compound of Claim 1, or a pharmaceutically acceptable salt thereof, which is a compound of Formula Ic-1:
(Ic1) ;
and provided that when X is C(R5R6), then neither R1 nor R2 is OR3.
3.A compound of Claim 2, or a pharmaceutically acceptable salt thereof, wherein
R1 and R2 are independently selected from the group consisting of hydrogen, halogen, and C1-6 alkyl;
A is unsubstituted or substituted aryl;
V is C(R5R6);
X is selected from the group consisting of -O- and -NH-;
Y is selected from the group consisting of -O-, CH2, and –S(O)m-;
R5 and R6 are independently selected from the group consisting of hydrogen and C1-6 alkyl;
R10 is selected from the group consisting of:
, , , ,
, , , , ,
, , and ; and
R12 and R13 are independently selected from the group consisting of hydrogen, halogen, oxo, NO2, CN, OR3, O(CH2)tCF3, CO2R3, CONR3R4, O(CH2)tNR3R4, O(CH2)vCOR3, S(O)mR3, SO2NR3R4, C1-6 alkyl and C1-3 fluoroalkyl.
4.A compound of Claim 1, or a pharmaceutically acceptable salt thereof, which is a compound of Formula Ic-2;
(Ic-2) ;
and provided that (i) when X is C(R5R6), then neither R1 nor R2 is OR3, and (ii) R1 is other than H.
5.A compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein
R1 and R2 are independently selected from the group consisting of hydrogen, halogen, and C1-6 alkyl;
A is unsubstituted or substituted aryl;
R10 is selected from the group consisting of:
, , , ,
, , , , ,
, , and ; and
R12 and R13 are independently selected from the group consisting of hydrogen, halogen, oxo, NO2, CN, OR3, O(CH2)tCF3, CO2R3, CONR3R4, O(CH2)tNR3R4, O(CH2)vCOR3, S(O)mR3, SO2NR3R4, C1-6 alkyl, C1-3 fluoroalkyl, and NR3R4.
6.A compound of Claim 5, or a pharmaceutically acceptable salt thereof, wherein:
V is -CH2-;
X is -O-; and
Y is -O-.
7.A compound of Claim 6, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
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.
8.A compound of Claim 5, or a pharmaceutically acceptable salt thereof, wherein:
R1 and R2 are each independently selected from the group consisting of hydrogen, halogen, and C1-4 alkyl;
A is phenyl optionally substituted with from 1 to 3 substituents each of which is independently halogen, C1-4 alkyl, or CN;
V is -CH2-;
X is -O-;
Y is -O-;
R10 is ;
one of R3 and R4 is H, C1-4 alkyl, or C3-6 cycloalkyl, and the other of R3 and R4 is H, C1-4 alkyl, or C14 alkyl substituted with OC14 alkyl,C(O)RA, CO2RA, C(O)N(RA)RB, or SO2RA;
or alternatively R3 and R4 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 R3 and R4 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) C14 alkyl, (2) CF3, (3) (CH2)12T wherein T is OH, OC1-4 alkyl, OCF3, N(RA)RB, C(O)N(RA)RB, C(O)RA, CO2RA, or SO2RA, (4) OC14 alkyl, (5) OCF3, (6) OH, (7) oxo, (8) halogen, (9) C(O)N(RA)RB, (10) C(O)RA, (11) C(O)CF3, (12) C(O)ORA, or (13)S(O)2RA;
each RA is independently H or C1-4 alkyl, and
each RB is independently H or C1-4 alkyl.
9.A compound of Claim 8, 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 Claim 8, or a pharmaceutically acceptable salt thereof, which is a compound of Formula Ic1a:
(Ic1a).
11.A pharmaceutical composition comprising an effective amount of a compound according to any one of Claims 1 to 10, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
12.A method for inhibiting HIV reverse transcriptase, for treating or prophylaxis of HIV infection, or for treating, prophylaxis of, or delaying the onset of AIDS, which comprises administering to a subject in need thereof an effective amount of a compound according to any one of Claims 1 to 10, or a pharmaceutically acceptable salt thereof.
13.Use of a compound according to any one of Claims 1 to 10, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting HIV reverse transcriptase, for treating or prophylaxis of HIV infection, or for treating, prophylaxis of, or delaying the onset of AIDS.
14.A compound of Formula IP:
(I-P)
wherein:
R1, R2, A, V, X and Y have the same definition as set forth for a compound of Formula Ic of Claim 1;
ZP is R10*;
R10* is a heterocycle selected from the group consisting of:
, , , , , , , and ,
R12, R13, and HetA are as defined in Claim 1;
R14 is PO(OH)O- M+; PO(O-)2 .2M+; PO(O-)2 .M+2; or an acid salt of:
or ;
M+ is a pharmaceutically acceptable monovalent counterion;
M+2 is a pharmaceutically acceptable divalent counterion;
R15 is H, C1-6 alkyl, (CH2)2-3CF3, AryA, or HetB;
R16a and R16b are each independently H, C1-6 alkyl, (CH2)2-3CF3, AryA, or HetB;
each R17 is independently H or C1-6 alkyl;
each R18 is independently H or C1-6 alkyl;
alternatively, an R17 together with the R18 attached to the same carbon atom form a 5- or 6membered, 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;
R19 is H or C1-6 alkyl;
R20 is H or C1-6 alkyl;
R21 is H or C1-6 alkyl;
R22a and R22b are each independently H, C1-6 alkyl, (CH2)2-3CF3, AryA, or HetB;
R23 is H or C1-6 alkyl;
R24 is H or C1-6 alkyl;
AryA is phenyl, wherein the phenyl is optionally substituted with from 1 to 3 substituents each of which is independently Cl, Br, F, CH3, CF3, NH2, NH(CH3), N(CH3)2, CN, OH, OCH3, cyclohexyl, ethenyl, ethynyl, SCH3, S(O)2CH3, (CH2)1-2SCH3, (CH2)12S(O)2CH3, NHC(O)CH3, O(CH2)1-2CF3, C(O)CH3, OC(O)CH3, (CH2)1-2OCH3, C(O)NH2, C(O)NHCH3, C(O)N(CH32, C(O)2H, C(O)2CH3, (CH2)1-2C(O)2CH3, NHC(O)OCH3, NH(CH3)NHC(O)NH(CH3), phenyl, or benzyl; and
HetB is a 5- or 6-membered heteroaromatic ring containing from 1 to 3 heteroatoms selected from N, O and S, wherein the heteroaromatic ring is optionally substituted with from 1 to 3 substituents each of which is independently Cl, Br, F, CH3, CF3, NH2, NH(CH3), N(CH3)2, CN, OH, OCH3, cyclohexyl, ethenyl, ethynyl, SCH3, S(O)2CH3, (CH2)1-2SCH3, (CH2)12S(O)2CH3, NHC(O)CH3, O(CH2)1-2CF3, C(O)CH3, OC(O)CH3, (CH2)1-2OCH3, C(O)NH2, C(O)NHCH3, C(O)N(CH32, C(O)2H, C(O)2CH3, (CH2)1-2C(O)2CH3, NHC(O)OCH3, NH(CH3)NHC(O)NH(CH3), phenyl, or benzyl.
- A compound according to claim 7, or a pharmaceutically acceptable salt thereof, which is 3-chloro-5-[2-chloro-5-(1H-pyrazolo[3,4-b]pyridine-3-ylmethoxy)phenoxy]benzonitrile
- A pharmaceutical composition comprising an effective amount of a compound according to claim 15, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
- A compound according to claim 15 for use in the manufacture of a medicament for inhibiting HIV reverse transcriptase, for treating or prophylaxis of HIV infection, or for treating, prophylaxis of, or delaying the onset of AIDS.
- 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.
- A Pharmaceutical composition comprising an effective amount of a compound according to claim 18, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
- A compound according to claim 18 for use in the manufacture of a medicament for inhibiting HIV reverse transcriptase, for treating or prophylaxis of HIV infection, or for treating, prophylaxis of, or delaying the onset of AIDS.
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