US 9,809,571 B2
Deoxyuridine triphosphatase inhibitors
Robert D. Ladner, Santa Monica, CA (US); and Bruno Giethlen, Altorf (FR)
Assigned to University of Southern California, Los Angeles, CA (US)
Appl. No. 14/759,386
Filed by University of Southern California, Los Angeles, CA (US)
PCT Filed Jan. 3, 2014, PCT No. PCT/US2014/010247
§ 371(c)(1), (2) Date Jul. 6, 2015,
PCT Pub. No. WO2014/107622, PCT Pub. Date Jul. 10, 2014.
Claims priority of provisional application 61/874,643, filed on Sep. 6, 2013.
Claims priority of provisional application 61/749,791, filed on Jan. 7, 2013.
Prior Publication US 2016/0039788 A1, Feb. 11, 2016
Int. Cl. C07D 401/06 (2006.01); C07D 277/34 (2006.01); C07D 471/04 (2006.01); C07D 401/12 (2006.01); C07D 403/06 (2006.01); C07D 215/16 (2006.01); C07D 231/56 (2006.01); C07D 265/18 (2006.01); C07D 498/04 (2006.01); C07D 277/36 (2006.01); C07D 211/88 (2006.01); C07D 239/54 (2006.01); C07D 215/26 (2006.01)
CPC C07D 401/06 (2013.01) [C07D 211/88 (2013.01); C07D 215/26 (2013.01); C07D 231/56 (2013.01); C07D 239/54 (2013.01); C07D 265/18 (2013.01); C07D 277/34 (2013.01); C07D 277/36 (2013.01); C07D 401/12 (2013.01); C07D 403/06 (2013.01); C07D 471/04 (2013.01); C07D 498/04 (2013.01)] 49 Claims
 
1. A compound of formula (I) or (II):

OG Complex Work Unit Drawing
or a tautomer thereof, including any stereoisomer, enantiomer or diastereoisomer,
or a pharmaceutically acceptable salt of each thereof, wherein

OG Complex Work Unit Drawing
is a uracil isostere;
W is a bond or optionally substituted —CH2—;
W1 is a bond, N, or an optionally substituted CH group;
X is a bond, O, S, NR19, optionally substituted C1-C6 alkylene, optionally substituted C2-C6 alkenylene, or optionally substituted C2-C6 alkynylene group, a divalent optionally substituted C6-C10 aromatic hydrocarbon group, or a divalent optionally substituted saturated or unsaturated C2-C10 heterocyclic or optionally substituted C1-C10 heteroaryl group;
R19 is hydrogen, optionally substituted C1-C6 alkyl or optionally substituted C3-C8 cycloalkyl;
Y is a bond or a linear or branched optionally substituted C1-C10 alkylene which further optionally has a cycloalkylidene structure on one carbon atom, or is optionally substituted C2-C6 alkenylene, or optionally substituted C2-C6 alkynylene group;
Z is —PO2—NR31R32, —SO2NR31R32, —NR3PO2—R4, or —NR3SO2—R4, wherein R31 and R32 are the same or different and each represents a hydrogen atom, optionally substituted C1-C6 alkyl group optionally substituted with an optionally substituted aryl group, wherein the aryl group, together with the R31 or R32, may form a condensed bicyclic hydrocarbon, or R31 and R32 taken together with the adjacent nitrogen atom form an optionally substituted C2-C10 heterocyclic group;
R3 is hydrogen or optionally substituted C1-C6 alkyl; and
R4 is optionally substituted C6-C10 aryl or an optionally substituted C2-C10 heterocyclic group; or
—W—X—Y—Z is —W—X—Y—Z′, wherein
—W—X—Y— is
—CH2—X—SO2—NH—CH(RY)—, —CH2—X—SO2—NH—C(RY)2—, or —CH2—X—B—CH2CRZRW—,
X is optionally substituted C1-C6 alkylene wherein one of the methylene groups within the alkylene chain is optionally replaced with an O or S atom, such that X is optionally substituted alkylene or a heteroalkylene,
B is an optionally substituted C3-C10 heteroaryl,
RY and RW are independently hydrogen or optionally substituted C1-C6 alkyl; and
RZ is hydrogen or hydroxy; or
—W—X—Y— is

OG Complex Work Unit Drawing
wherein
X10 is NH, NCO2R20, O, or CH2,
R20 is C1-C6 alkyl optionally substituted with 1-3 C6-C10 aryl groups,
u is 0, 1, 2, 3, or 4,
Y1 is CH2, O or S,
RZ is hydroxy or hydrogen,
RW is C1-C6 alkyl or hydrogen, and
the phenylene and the heteroarylene rings are optionally substituted; and
Z′ is

OG Complex Work Unit Drawing
wherein
R6 is hydrogen, optionally substituted C1-C6 alkoxy, or halo, and
R7 is optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C10 heteroaryl, optionally substituted C3-C10 heterocyclyl, or optionally substituted phenyl; or
Z′ is a phenyl substituted with an R6 and an R60 groups, wherein
the R6 and the R60 groups are positioned 1, 2 with respect to each other,
R60 is —OR7 or —NHR7R70 ,
R7 is optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C10 heteroaryl, optionally substituted C3-C10 heterocyclyl, or optionally substituted phenyl, and
R70 is hydrogen or R7;
provided that when
W is a bond,
Y is a bond,
Z is —SO2NR31R32, and
one of R31 or R32 is H and the other is a C1-C2 alkyl substituted with a phenyl,
then X is not C2 alkylene;
provided that when
W is CH2,
Y is a bond,
Z is —SO2NR31R32, and
one of R31 or R32 is H and the other is a C1 alkyl substituted with a single phenyl that is substituted with a single halo substituted phenoxy,
then X is not a divalent aromatic hydrocarbon group mono-substituted with a methoxy group.