URACIL OR THYMINE DERIVATIVE FOR TREATING HEPATITIS C
CROSS-REFERENCE TO RELATED PATENT APPLICATIONS
IO00ll This patent application claims priority to U.S. Provisional Patent Application No. 60/972,877
(filed September 17,2007) and U.S. Provisional Patent Application No. 61 1096,791 (filed September 13,
2008). The entire text of those applications is incorporated by reference into this application.
FIELD OF THE INVENTION
(00021 This invention is directed to: (a) compounds and salts thereof that, infer alia, are useful as
hepatitis C virus (HCV) inhibitors; (b) intermediates useful for the preparation of such compounds and
salts; (c) compositions comprising such compounds and salts; (d) methods for preparing such
intermediates, compounds, salts, and compositions; (e) methods of usc of such compounds, salts, and
compositions; and (9 kits comprising such compounds, salts, and compositions.
BACKGROUND OF THE INVENTION
100031 Hepatitis C is a blood-borne, infectious, viral disease that is caused by a hepatotropic virus called
HCV. At least six different HCV genotypes (with several subtypes within each genotype) are known to
date. In North America, HCV genotype la predominates, followed by HCV genotypes 1 b, 2a, 2b, and 3a.
In the United States, HCV genotypes 1.2, and 3 are the most common, with about 80% of the hepatitis C
patients having HCV genotype 1. In Europe, HCV genotype 1 b is predominant, followed by HCV
genotypes 2a, 2b, 2c, and 3a. HCV genotypes 4 and 5 are found almost exclusively in Africa. As
discussed below, the patient's HCV genotype is clinically important in determining the patient's potential
response to therapy and the required duration of such therapy.
(00041 An HCV infection can cause liver inflammation (hepatitis) that is often asymptomatic, but
ensuing chronic hepatitis can result in cirrhosis of the liver (fibrotic scarring of the liver), liver cancer,
and/or liver failure. The World Health Organization estimates that about 170 million persons worldwide
are chronically infected with HCV, and fiom about three to about four million persons are newly infected
globally each year. According to the Centers for Disease Control and Prevention, about four million
people in the United States are infectcd with HCV. Co-infection with the human immunodeficiency virus
(HIV) is common, and rates of HCV infection among HIV positive populations are higher.
(0005j There is a small chance of clearing the virus spontaneously, but the majority of patients with
chronic hepatitis C will not clear it without treatment. Indications for treatment typically include proven
HCV infection and persistent abnormal liver function tests. There are two treatment regimens that are
primarily used to treat hepatitis C: monotherapy (using an interferon agent -either a "conventional" or
longer-acting pegylated interferon) and combination thcrapy (using an interferon agent and ribavirin).
Interferon, which is injected into the bloodstream, works by bolstering the immune response to HCV; and
ribavirin, which is taken orally, is believed to work by preventing HCV replication. Taken alone,
ribavirin does not effectively suppress HCV levels, but an interferonlribavirin combination is more
effective than interferon alone. Typically, hepatitis C is treated with a combination of pegylated
interferon alpha and ribavirin for a period of 24 or 48 weeks, depending on the HCV genotype.
[0006] The goal of treatment is sustained viral response -- meaning that HCV is not measurable in the
blood aRer therapy is completed. Following treatment with a combination of pegylated interferon alpha
and ribavirin, sustained cure rates (sustained viral response) of about 75% or better occur in people with
HCV genotypes 2 and 3 in 24 weeks of treatment, about 50% in those with HCV genotype 1 with 48
weeks of treatment, and about 65% in those with HCV genotype 4 in 48 weeks of treatment.
[0007] Treatment may be physically demanding, particularly for those with prior history of drug or
alcohol abuse, because both interferon and ribavirin have numerous side effects. Common interfemnassociated
side effects include flu-like symptoms, extreme fatigue, nausea, loss of appetite, thyroid
problems, high blood sugar, hair loss, and skin reactions at the injection site. Possible serious interferonassociated
side effects include psychoses (e.g., suicidal behavior), heart problems (e.g., heart attack, low
blood pressure), other internal organ damage, blood problems (e.g., blood counts falling dangerously
low), and new or worsening autoimmune disease (e.g., rheumatoid arthritis). Ribavirin-associated side
effects include anemia, fatigue, irritability, skin rash, nasal stuffiness, sinusitis, and cough. Ribavirin can
also cause birth defects, so pregnancy in female patients and female partners of male patients must be
avoided during treatment and for six months afterward.
[0008] Some patients do not complete treatment because of the serious side effects discussed above;
other patients (non-responders) continue to have measurable HCV levels despite treatment; and yet other
patients (relapsers) "clear" the virus during therapy, but the virus returns sometime after completion of the
treatment regimen. Thus, there continues to be a need for alternative compounds, compositions, and
methods of treatment (used either in combination with or in lieu of an interferon agent andlor ribavirin) to
alleviate the symptoms of hepatitis C, thereby providing partial or complete relief. This invention
provides compounds (including salts thereof), compositions, and methods of treatment that generally
address such a need.
SUMMARY OF THE INVENTION
[0009] This invention is directed to compounds that correspond in structure to formula I:
[0010] In formula I:
-- -*- - i s selected from the group consisting of single carbon-carbon bond and double carboncarbon
bond;
R' is selected from the group consisting of hydrogen, methyl, and nitrogen-protecting group;
R2 is selected Erom the group consisting of hydrogen, halo, hydroxy, methyl, cyclopropyl, and
cyclobutyl;
R3 is selected from the group consisting of hydrogen, halo, 0x0, and methyl;
R' is selected from the group consisting of halo, alkyl, alkenyl, alkynyl, nitro, cyano, azido,
alkyloxy, alkenyloxy, alkynyloxy, amino, aminocarbonyl, arninosulfonyl, alkylsulfonyl, carbocyclyl, and
heterocyclyl, wherein:
(a) the amino, aminocarbonyl, and aminosulfonyl optionally are substituted with:
(1) one or two substituents independently selected from the group
consisting of alkyl, alkenyl, alkynyl, and alkylsulfonyl, or
(2) two substituents that, together with the amino nitrogen, form a single
ring heterocyclyl, and
(b) the alkyl, alkenyl, alkynyl, alkyloxy, akenyloxy, alkynyloxy, and alkylsulfonyl,
optionally are substituted with one or more substituents independently selected from the group
consisting of halo, 0x0, nitro, cyano, azido, hydroxy, amino, alkyloxy, trimethylsilyl, carbocyclyl,
and heterocyclyl, wherein:
the amino optionally is substituted with:
(1) one or two substituents independently selected from the group
consisting of alkyl, alkenyl, alkynyl, alkylcarbonyl, alkylsulfonyl,
alkyloxycarbonyl, carbocyclyl, heterocyclyl, carbocyclylalkyl, and
heterocyclylalkyl, or
(2) two substituents that, together with the amino nitrogen, form a singlering
heterocyclyl, and
(c) the carbocyclyl and heterocyclyl optionally are substituted with up to three
substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo,
0x0, nitro, cyano, azido, hydroxy, amino, alkyloxy, trirnethylsilyl, carbocyclyl, and heterocyclyl,
wherein:
the amino optionally is substituted with:
(1) one or two substituents independently selected from the group
consisting of alkyl, alkenyl, alkynyl, alkylcarbonyl, alkylsulfonyl,
alkyloxycarbonyl, carbocyclyl, heterocyclyl, carbocyclylalkyl, and
heterocyclylalkyl, or
(2) two substituents that, together with the amino nitrogen, form a singlering
heterocyclyl;
R5 is selected from the group consisting of hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkyloxy,
alkenyloxy, allqnyloxy, alkylsulfonyloxy, carbocyclylsulfonyloxy, haloalkylsulfonyloxy, and halo;
L is selected from the group consisting of bond, c(RA)=c(RB), e C , c(o)N@), N(R~)c(o),
C1-C2-alkylene, C(H)20,OC(H)2, cyclopropyl-l,2-ene, c(H)~N(R~)N, (R~)C(H)C~(,0 )CH2, and
CHzC(0);
RA, RB, RL, and RM are independently selected fiom the group consisting of hydrogen, CI-C6-
alkyl, C1-C6-allcyloxy,C 3-CB-cycloalkyla, nd halo, wherein:
the C1-G-alkyl optionally is substituted with one or more substituents independently
selected from the group consisting of carboxy, halo, hydroxy, nitro, 0x0, amino, cyano,
~ alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl, and heterocyclyl;
RC is selected from the group consisting of hydrogen and alkyl;
RD is selected from the group consisting of hydrogen and alkyl;
R6 is selected fiom the group consisting of Cs-C6-~arb0~y~5ly-6l-,m embered heterocyclyl, fused
2-ring heterocyclyl, and fused 2-ring carbocyclyl, wherein each such substituent optionally is substituted
with one or more substituents independently selected from the group consisting of R ~R,F , R,'GR, R',
R~a,nd RK;
each R' is independently selected from the group consisting of halo, nitro, hydroxy, 0x0,
carboxy, cyano, amino, imino, azido, and aldehydo, wherein:
the amino optionally is substituted with one or two substituents independently selected
fiom the group consisting of alkyl, alkenyl, and alkynyl;
each R' is independently selected fiom the group consisting of alkyl, alkenyl, and alkynyl,
wherein:
each such substituent optionally is substituted with one or more substituents
independently selected from the group consisting of carboxy, hydroxy, halo, amino, imino, nitro,
azido, 0x0, aminosulfonyl, alkylsulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl,
alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy,
alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, wherein:
the amino, imino, aminosulfonyl, aminocarbonyl, carbocyclyl, and heterocyclyl
optionally are substituted with one or two substituents independently selected from the
group consisting of alkyl, alkenyl, alkynyl, alkylsulfonyl, alkenylsulfonyl,
alkynylsulfonyl, alkylsulfonylamino, hydroxy, and alkyloxy,
wherein:
amino portion of the alkylsulfonylamino optionally is substituted with a
substituent selected from the group consisting of alkyl, alkenyl, and alkynyl;
each R~ is independently selected from the group consisting of carbocyclyl and heterocyclyl,
wherein:
each such substituent optionally is substituted with one or more substituents
independently selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, hydroxy,
halo, amino, nitro, azido, 0x0, aminosulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl,
alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy,
alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, wherein:
the amino, aminosulfonyl, and aminocarbonyl optionally are substituted with one
or two substituents independently selected fiom the group consisting of alkyl, alkenyl,
alkynyl, alkylsulfonyl, alkenylsulfonyl, and alkynylsulfonyl;
each R~ is independently selected from the group consisting of alkyloxy, alkenyloxy, alkynyloxy,
alkylsulfonyloxy, alkenylsulfonyloxy, and alkynylsulfonyloxy, wherein:
each such substituent optionally is substituted with one or more substituents
independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, azido,
0x0, aminosulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl,
alblcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy, alkenyloxy, alkynyloxy,
carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, wherein:
the amino, aminosulfonyl, and aminocarbonyl optionally are substituted with one
or two substituents independently selected from the group consisting of alkyl, alkenyl,
alkynyl, alkylsulfonyl, alkenylsulfonyl, and alkynylsulfonyl;
each R' is independently selected from the group consisting of alkylcarbonyl, alkenylcarbonyl,
alkynyl~arbon~alm, inocarbonyl, alkyloxycarbonyl, carbocyclylcarbonyl, and heterocyclylcarbonyl,
6
wherein:
(a) the alkylcarbonyl, alkenylcarbonyl, and alkynylcarbonyl optionally are substituted
with one or more substituents independently selected from the group consisting of carboxy,
hydroxy, halo, amino, nitro, azido, 0x0, aminosulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl,
alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, a~ylcarbonyloxya,l kyloxy,
alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, and
(b) the aminocarbonyl optionally is substituted with one or two substituents
independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkyloxyalkyl,
carbocyclyl, heterocyclyl, alkylsulfonyl, and al~lsulfonylaminow, herein:
the carbocyclyl and heterocyclyl optionally are substituted with one or two
substituents independently selected from the group consisting of halo, alkyl, and 0x0;
each R~ is independently selected from the group consisting of carbocyclylsulfonylamino,
heterocyclylsulfonylamino, alkylcarbonylamino, alkenylcarbonylamino, alkynylcarbonylamino,
alkyloxycarbonylamino, alkenyloxycarbonylamino, alkynyloxycarbonylamino, alkylsulfonylamino,
alkenylsulfonylamino, alkynylsulfonylamino, aminocarbonylamino, alkyloxycarbonylaminoimino,
alkylsulfonylaminoimino, alkenylsulfonylaminoimino, and alkynylsulfonylaminoimino, wherein:
(a) the amino portion of such substituents optionally is substituted with a substituent
independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl,
alkylcarbonyloxy, aminocarbonylalkyl, a b l y alkenyl, akynyl, alkylcarbonyl, alkenylcarbonyl,
alkynylcarbonyl, alkyloxycarbonyl, alkyloxyalkyloxycarbonyl, alkylcarbonyloxyalkyl, and
alkylsulfonyl, wherein:
(1) the carbocyclyl portion of the carbocyclylalkyl and the heterocyclyl portion
of the heterocyclylalkyl optionally are substituted with one or more substituents
independently selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy,
hydroxy, alkyloxy, alkenyloxy, alkynyloxy, halo, nitro, cyano, azido, 0x0, and amino,
and
(2) the amino portion of the aminocarbonylalkyl optionally is substituted with
one or two substituents independently selected fiom the group consisting of alkyl,
alkenyl, and alkynyl,
(b) the alkyl, alkenyl, and alkynyl portion of such substituents optionally is substituted
with one or more substituents independently selected from the group consisting of carboxy, halo,
0x0, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl,
and cyano, wherein:
the amino optionally is substituted with one or two substituents independently
selected fiom the group consisting of alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, and
alkynyloxy, wherein:
the alkyl optionally is substituted with one or more hydroxy;
(c) the carbocyclyl and heterocyclyl portions of such substituents optionally are
substituted with one or more substituents independently selected fiom the group consisting of
alkyl, alkenyl, alkynyl, carboxy, hydroxy, alkyloxy, alkenyloxy, alkynyloxy, halo, nitro, cyano,
azido, and amino, wherein:
the amino optionally is substituted with one or two substituents independently
selected from the group consisting of alkyl, alkenyl, and alkynyl; and
each R~ is independently selected fiom the group consisting of aminosulfonyl, alkylsulfonyl,
alkenylsulfonyl, and alkynylsulfonyl, wherein:
(a) the alkylsulfonyl, alkenylsulfonyl, and alkynylsulfonyl optionally are substituted with
one or more substituents independently selected from the group consisting of carboxy, hydroxy,
halo, amino, nitro, azido, 0x0, aminosulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl,
alkynyloxy~81:bonyla,l kylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy,
alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, wherein:
the amino, arninosulfonyl, and aminocarbonyl optionally are substituted with one
or two substituents independently selected from the group consisting of alkyl, alkenyl,
and alkynyl; and
(b) the aminosulfonyl optionally is substituted with one or two substituents independently
selected from the group consisting of alkyl, alkenyl, and alkynyl.
[0011] This invention also is directed to the salts (including pharmaceutically acceptable salts) of the
compounds of the invention.
[0012] This invention also is directed to compositions (including pharmaceutical compositions) that
comprise one or more compounds and/or salts of the invention, and, optionally, one or more additional
therapeutic agents.
[0013] This invention also is directed to kits that comprise one or more compounds and/or salts of the
invention, and, optionally, one or more additional therapeutic agents.
[0014] This invention also is directed to methods of use of the compounds, salts, compositions, andor
kits of the invention to, for example, inhibit replication of an RNA virus (including HCV), treat a disease
treatable by inhibiting HCV ribonucleic acid (RNA) polymerase (including hepatitis C).
[0015] This invention also is directed to a use of one or more compounds and/or salts of the invention to
prepare a medicament. The medicament optionally can comprise one or more additional therapeutic
agents. In some embodiments, the medicament is usehl for treating hepatitis C.
(00161 Further benefits of Applicants' invention will be apparent to one skilled in the art from reading
this patent application.
BRIEF DESCRIPTION OF THE DRAWINGS
[0017] Figure 1 shows an illustrative PXRD pattern for the ethanol solvate of compound IB-LO-23.
[0018] Figure 2 shows an illustrative TGA profile of the ethanol solvate of compound IB-LO-2.3.
[0019] Figure 3 shows an illustrative PXRD pattern for the acetonitrile solvate of compound IB-LO-2.3.
[0020] Figure 4 shows an illustrative PXRD pattern for the ethyl acetate solvate of compound IB-M-2.3.
[0021] Figure 5 shows an illustrative PXRD pattern for the 2-propanol solvate of compound IB-LO-2.3.
[0022] Figure 6 shows an illustrative PXRD pattern for the methanol solvate of compound IB-LO-2.3.
(00231 Figure 7 shows an illustrative PXRD pattern for the I-propanol solvate of compound IB-LO-2.3.
I [0024] Figure 8 shows an illustrative PXRD pattern for the solvent free crystalline compound IB-LO-23.
[0025] Figure 9 shows an illustrative PXRD pattern for the hydrate of compound IB-LO-2.3.
[0026] Figure 10 shows an illustrative PXRD pattern for the pattern A monosodium salt of compound
IB-LO-23.
[0027l Figure 11 shows an illustrative TGA profile of the pattern A monosodium salt of compound IBLO-
23.
[0028] Figure 12 shows an illustrative PXRD pattern for the pattern B monosodium salt of compound
IB-LO-23.
[0029] Figure 13 shows an illustrative TGA profile of the pattern B monosodium salt of compound IBLO-
23.
[0030] Figure 14 shows an illustrative PXRD pattern for the pattern C monosodium salt of compound
IB-LO-23.
[0031] Figure 15 shows an illustrative PXRD pattern for the disodium salt of compound IB-LO-23.
(00321 Figure 16 shows an illustrative TGA profile of the disodium salt of compound IB-LO-2.3.
[0033] Figure 17 shows an illustrative PXRD pattern for the monopotassium salt of compound IB-LO-
23.
(00341 Figure 18 shows an illustrative TGA profile of the monopotassium salt of compound IB-LO-2.3.
100351 Figure 19 shows an illustrative PXRD pattern for the pattern A monocholine salt of compound
IB-LO-23.
[0036] Figure 20 shows an illustrative TGA profile of the pattern A monocholine salt of compound IBLO-
2.3.
(00371 Figure 21 shows an illustrative PXRD pattern for the pattern B monocholine salt of compound
IB-LO-23.
[0038] Figure 22 shows an illustrative TGA profile of the pattern B monocholine salt of compound IB-
9
[0039] Figure 23 shows an illustrative PXRD pattern for the dicholine salt of compound IB-LO-2.3.
I
[0040] Figure 24 shows an illustrative PXRD pattern for the disodium salt nonahydrate of compound IB-
[0041] Figure 25 shows an illustrative PXRD pattem for the disodium salt tetrahydrate of compound IBI
Ll-1.1.
[0042] Figure 26 shows an illustrative TGA profile of the disodium salt tetrahydrate of compound IB-
100431 Figure 27 shows an illustrative PXRD pattern for the dipotassium salt tetrahydrate of compound
I IB-L1-1.1.
[0044] Figure 28 shows an illustrative PXRD pattern for the monopotassium salt trihydrate of compound
IB-L1-1.1.
[0045] Figure 29 shows an illustrative PXRD pattern for the monopotassium salt dihydrate of compound
IB-L1-1.1.
[0046] Figure 30 shows an illustrative TGA profile of the monopotassium salt dihydrate of compound
IB-L1-1.1.
[0047] Figure 31 shows an illustrative PXRD pattern for the 117 potassium salt of compound IB-L1-1.1.
[0048] Figure 32 shows an illustrative PXRD pattern for the monodiethylamine salt tetrahydrate of
compound IB-L1-1.1.
[0049] Figure 33 shows an illustrative TGA profile of the monodiethylamine salt tetrahydrate of
compound IB-L1-1.1.
[0050] Figure 34 shows an illustrative PXRD pattern for the pattern A polymorph of compound IB-L1-
I 1.1.
[0051] Figure 35 shows an illustrative DSC profile of the pattern A polymorph of compound IB-L1-1.1.
[0052] Figure 36 shows an illustrative PXRD pattern for the pattem B polymorph of compound IB-L1-
1.1.
[0053] Figure 37 shows an illustrative PXRD pattern for the pattern C polymorph of compound IB-LI-
1.1.
[0054] Figure 38 shows an illustrative PXRD pattern for the pattern D polymorph of compound IB-L1-
1.1.
[0055] Figure 39 shows an illustrative PXRD pattern for the pattern A hydrate of compound IB-L1-1.1.
[0056] Figure 40 shows an illustrative TGA profile of the pattern A hydrate of compound IB-L1-1.1.
[0057] Figure 41 shows an illustrative PXRD pattern for the pattern B hydrate of compound IB-L1-1.1.
[0058] Figure 42 shows an illustrative TGA profile of the pattern B hydrate of compound IB-L1-1.1.
I00591 Figure 43 shows an illustrative PXRD pattern for the pattern C hydrate of compound IB-L1-1.1.
[0060] Figure 44 shows an illustrative TGA profile of the pattern C hydrate of compound IB-L1-1.1.
[0061] Figure 45 shows an illustrative PXRD pattern for the pattern D hydrate of compound IB-L1-1.1.
[0062] Figure 46 shows an illustrative PXRD pattern for the pattern E hydrate of compound IB-L1-1.1.
DETAILED DESCRIPTION OF THE INVENTION
[0063] This detailed description is intended only to acquaint others skilled in the art with Applicants'
invention, its principles, and its practical application so that others skilled in the art may adapt and apply
the invention in its numerous forms, as they may be best suited to the requirements of a particular use.
This description and its specific examples are intended for purposes of illustration only. This invention,
therefore, is not limited to the embodiments described in this patent application, and may be variously
modified.
A. Definitions.
[0064] The term walkylw(a lone or in combination with another term(s)) means a straight-or branchedchain
saturated hydrocarbyl substituent typically containing from 1 to about 20 carbon atoms, more
typically from 1 to about 8 carbon atoms, and even more typically fiom 1 to about 6 carbon atoms.
Examples of such substituents include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tertbutyl,
pentyl, iso-amyl, and hexyl. As in this definition, throughout this detailed description Applicants
have provided illustrative examples. The provision of such illustrative examples should not be interpreted
as if the provided illustrative examples are the only options available to one skilled in the art.
[0065] The term "alkenyl" (alone or in combination with another term(s)) means a straight- or branchedchain
hydrocarbyl substituent containing one or more double bonds and typically from 2 to about 20
carbon atoms, more typically from about 2 to about 8 carbon atoms, and even more typically from about 2
to about 6 carbon atoms. Examples of such substituents include ethenyl (vinyl), 2-propenyl, 3-propenyl,
1 ,Cpentadienyl, 1 ,Cbutadienyl, 1 -butenyl, 2-butenyl, and 3-butenyl.
[0066] The term "alkynyl" (alone or in combination with another term(s)) means a straight- or branchedchain
hydrocarbyl substituent containing one or more triple bonds and typically from 2 to about 20 carbon
atoms, more typically from about 2 to about 8 carbon atoms, and even more typically fiom about 2 to
about 6 carbon atoms. Examples of such substituents include ethynyl, 2-propynyl, 3-propynyl, 2-butynyl,
and 3-butynyl.
(0067) The term "carbocyclyl" (alone or in combination with another term@)) means a saturated cyclic
(i.e., "cycloalkyl"), partially saturated cyclic (i.e., "cycloalkenyl"), or completely unsaturated (i.e., "aryl")
hydrocarbyl substituent containing from 3 to 14 carbon ring atoms ("ring atomsw are the atoms bound
together to form the ring or rings of a cyclic substituent). A carbocyclyl may be a single ring, which
typically contains from 3 to 6 ring atoms. Examples of such single-ring carbocyclyls include cyclopropyl
(cyclopropanyl), cyclobutyl (cyclobutanyl), cyclopentyl (cyclopentanyl), cyclopentenyl,
cyclopentadienyl, cyclohexyl (cyclohexanyl), cyclohexenyl, cyclohexadienyl, and phenyl. A carbocyclyl
alternatively may be 2 or 3 rings fused together, such as naphthalenyl, tetrahydronaphthalenyl (tetralinyl),
indenyl, indanyl (dihydroindenyl), anthracenyl, phenanthrenyl, and decalinyl.
[0068] The term "cycloalkyl" (alone or in combination with another term@)) means a saturated cyclic
hydrocarbyl substituent containing from 3 to 14 carbon ring atoms. A cycloalkyl may be a single carbon
ring, which typically contains fiom 3 to 6 carbon ring atoms. Examples of single-ring cycloalkyls include
cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. A cycloalkyl alternatively may be 2 or 3 carbon
rings fused together, such as, decalinyl.
[0069] The term "aryl" (alone or in combination with another term(s)) means an aromatic carbocyclyl
containing from 6 to 14 carbon ring atoms. Examples of aryls include phenyl, naphthalenyl, and indenyl.
[0070] In some instances, the number of carbon atoms in a hydrocarbyl substituent (e.g., alkyl, alkenyl,
alkynyl, or cycloalkyl) is indicated by the prefix "G-C,-", wherein x is the minimum and y is the
maximum number of carbon atoms in the substituent. Thus, for example, "C1-Cs-alkyl" refers to an alkyl
substituent containing fiom 1 to 6 carbon atoms. Illustrating further, C3-Ca-cycloalkyl means a saturated
hydrocarbyl ring containing from 3 to 6 carbon ring atoms.
[0071] The term "hydrogen" (alone or in combination with another term(s)) means a hydrogen radical,
and may be depicted as -H.
[0072] The term "hydroxy" (alone or in combination with another term(s)) means -OH.
10073) The term "nitro" (alone or in combination with another term(s)) means -NO2.
[0074] The term "cyano" (alone or in combination with another tenn(s)) means -CN, which also may be
depicted as G N .
[0075] The term "keto" (alone or in combination with another term(s)) means an 0x0 radical, and may be
depicted as =O.
[0076] The term "carboxy" (alone or in combination with another term(s)) means -C(O)-OH.
[0077] The term "amino" (alone or in combination with another term(s)) means -NH2.
(00781 The term "imino" (alone or in combination with another term(s)) means =NH.
100791 The term "aminoimino" (alone or in combination with another term@)) means =m.
[0080] The term "halogen" or "halo" (alone or in combination with another term@)) means a fluorine
radical (which may be depicted as -F), chlorine radical (which may be depicted as -Cl), bromine radical
(which may be depicted as -Br), or iodine radical (which may be depicted as -I).
[0081] A substituent is "substitutable" if it comprises at least one carbon or nitrogen atom that is bonded
to one or more hydrogen atoms. Thus, for example, hydrogen, halogen, and cyano do not fall within this
definition. In addition, a sulfur atom in a heterocyclyl containing such atom is substitutable with one or
two 0x0 substituents.
[0082] If a substituent is described as being "substituted", a non-hydrogen radical is in the place of
hydrogen radical on a carbon or nitrogen of the substituent. Thus, for example, a substituted alkyl
substituent is an alkyl substituent in which at least one non-hydrogen radical is in the place of a hydrogen
radical on the alkyl substituent. To illustrate, monofluoroalkyl is alkyl substituted with a fluoro radical,
and difluomalkyl is alkyl substituted with two fluoro radicals. It should be recognized that if there are
more than one substitution on a substituent, each non-hydrogen radical may be identical or different
(unless otherwise stated).
[0083] If a substituent is described as being "optionally substituted", the substituent may be either (1) not
substituted or (2) substituted. If a substituent is described as being optionally substituted with up to a
particular number of non-hydrogen radicals, that substituent may be either (1) not substituted; or (2)
substituted by up to that particular number of non-hydrogen radicals or by up to the maximum number of
substitutable positions on the substituent, whichever is less. Thus, for example, if a substituent is
described as a heteroaryl optionally substituted with up to 3 non-hydrogen radicals, then any heteroaryl
with less than 3 substitutable positions would be optionally substituted by up to only as many nonhydrogen
radicals as the heteroaryl has substitutable positions. To illustrate, tetrazolyl (which has only
one substitutable position) would be optionally substituted with up to one non-hydrogen radical. To
illustrate further, if an amino nitrogen is described as being optionally substituted with up to 2 non-
I hydrogen radicals, then a primary amino nitrogen will be optionally substituted with up to 2 non-
I hydrogen radicals, whereas a secondary amino nitrogen will be optionally substituted with up to only 1
I
non-hydrogen radical.
I [0084] This patent application uses the terms "substituent" and "radical" interchangeably.
(00851 The prefix "halo" indicates that the substituent to which the prefix is attached is substituted with
l one or more independently selected halogen radicals. For example, haloalkyl means an alkyl substituent
in which at least one hydrogen radical is replaced with a halogen radical. Examples of haloalkyls include
chloromethyl, 1 -bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, and 1 , 1 $ 1-t rifluoroethyl. It
should be recognized that if a substituent is substituted by more than one halogen radical, those halogen
radicals may be identical or different (unless otherwise stated).
[0086] The prefix "perhalo" indicates that every hydrogen radical on the substituent to which the prefix
is attached is replaced with independently selected halogen radicals, ie., each hydrogen radical on the
~ substituent is replaced with a halogen radical. If all the halogen radicals are identical, the prefix typically will identify the halogen radical. Thus, for example, the tern "perfluoro" means that every hydrogen
radical on the substituent to which the prefix is attached is substituted with a fluorine radical. To ~ illustrate, the term "perfluoroalkyl" means an alkyl substituent wherein a fluorine radical is in the place of
each hydrogen radical.
[0087] The term "carbonyl" (alone or in combination with another term(s)) means -C(O)-.
[OOSS] The term "aminocarbonyl" (alone or in combination with another term(s)) means -C(O)-NH2.
[0089] The term "oxy" (alone or in combination with another term(s)) means an ether substituent, and
may be depicted as -0-.
100901 The term "alkoxy" (alone or in combination with another term(s)) means an alkylether
substituent, i.e., -0-alkyl. Examples of such a substituent include methoxy (-0-CH3), ethoxy, n-propoxy,
isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy.
[0091] The term "alkylcarbonyl" (alone or in combination with another term(s)) means -C(O)-alkyl.
100921 The term "aminoallqlcarbonyl" (alone or in combination with another term(s)) means -C(O)-
alkyl-N&.
[0093] The term "alkoxycarbonyl" (alone or in combination with another term(s)) means -C(O>O-alkyl.
10094) The term "carbocyclylcarbonyln (alone or in combination with another term(s)) means -C(O)- ~ carbocyclyl.
[0095] Similarly, the term "heterocyclylcarbonyl" (alone or in combination with another term(s)) means
-C(O)-heterocyclyl.
[0096] The term "carbocyclylallqlcarbonyl" (alone or in combination with another term(s)) means
-C(O)-alkyl-carbocyclyl .
[0097] Similarly, the term "heterocyclylalkylcarbonyl" (alone or in combination with another term(s))
means -C(O)-alkyl-heterocyclyl.
[0098] The term "carbocyclyloxycarbonyl" (alone or in combination with another term(s)) means -C(O)-
0-carbocyclyl.
(00991 The term "carbocyclylalkoxycarbonyl" (alone or in combination with another term(s)) means
-C(O>O-alkylcarbocyclyl.
[00100]The term "thio" or "thia" (alone or in combination with another term(s)) means a thiaether
substituent, Le., an ether substituent wherein a divalent sulfur atom is in the place of the ether oxygen
atom. Such a substituent may be depicted as -S-. This, for example, "alkyl-thio-alkyl" means alkyl-Salkyl
(alkyl-sulfanyl-alkyl).
[00101]The term "thiol" or "sulfhydryl" (alone or in combination with another term(s)) means a
sulfhydryl substituent, and may be depicted as -SH.
[00102] The term "(thiocarbonyl)" (alone or in combination with another term@)) means a carbonyl
wherein the oxygen atom has been replaced with a sulfur. Such a substituent may be depicted as -C(S)-.
[00103] The term "sulfonyl" (alone or in combination with another term(s)) means -S(0)2-.
1 [00104]The term "aminosulfonyl" (alone or in combination with another terrn(s)) means -S(0)2-NH2.
I [00105] The term "sulfinyl" or "sulfoxido" (alone or in combination with another term@)) means -S(O)-.
I
[00106] The term "heterocyclyl" (done or in combination with another term@)) means a saturated (i.e.,
"heterocycloalkyl"), partially saturated (i. e., "heterocycloalkenyl"), or completely unsaturated (i. e.,
"heteroaryl") ring structure containing a total of 3 to 14 ring atoms. At least one of the ring atoms is a
heteroatom (i.e., oxygen, nitrogen, or sulk), with the remaining ring atoms being independently selected
fiom the group consisting of carbon, oxygen, nitrogen, and sulfur.
[00107]A heterocyclyl may be a single ring, which typically contains from 3 to 7 ring atoms, more
typically fiom 3 to 6 ring atoms, and even more typically 5 to 6 ring atoms. Examples of single-ring
heterocyclyls include furanyl, dihydrofuranyl, tetrahydrofuranyl, thiophenyl (thiofuranyl),
dihydrothiophenyl, tetrahydrothiophenyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl,
imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, oxazolyl, oxazolidinyl,
isoxazolidinyl, isoxazolyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl,
isothiazolidinyl, thiodiazolyl, oxadiazolyl (including 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-
oxadiazolyl (hrazanyl), or 1,3,4-oxadiazolyl), oxatriazolyl (including 1,2,3,4-oxatriazolyl or 1,2,3,5-
I oxatriazolyl), dioxazolyl (including 1,2,3-dioxazolyl, 1,2,4-dioxazolyl, 1,3,2-dioxazolyl, or 1,3,4-
dioxazolyl), oxathiazolyl, oxathiolyl, oxathiolanyl, pyranyl, dihydropyranyl, thiopyranyl,
tetrahydrothiopyranyl, pyridinyl (azinyl), piperidinyl, diazinyl (including pyridazinyl(1,2diazinyl),
pyrimidinyl(1,3diazinyl), or pyrazinyl(1,4diazinyl)), piperazinyl, triazinyl (including 1,3,5-triazinyl,
1,2,4-triazinyl, and 1,2,3-triazinyl)), oxazinyl (including 1,2-oxazinyl, 1,3-oxazinyl, or 1 ,4-oxazinyl)),
oxathiazinyl (including 1,2,3-oxathiazinyl, 1,2,4-oxathiazinyl, 1,2,5-oxathiazinyl, or 1,2,6-oxathiazinyl)),
oxadiazinyl (including 1,2,3-oxadiazinyl, 1 ,2,4-oxadiazinylY 1,4,2-oxadiazinyl, or 1,3,5-oxadiazinyl)),
morpholinyl, azepinyl, oxepinyl, thiepinyl, and diazepinyl.
[00108] A heterocyclyl alternatively may be 2 or 3 rings fused together, such as, for example, indolizinyl,
pyranopyrrolyl, 4Hquinoluiy1, purinyl, naphthyridinyl, pyridopyridinyl (including pyrido[3,4-b]-
pyridinyl, pyrido[3,2-b]-pyridinyl, or pyrido[4,3-b]-pyridinyl), and pteridinyl. Other examples of fusedring
heterocyclyls include benzo-fused heterocyclyls, such as indolyl, isoindolyl (isobenzazolyl,
pseudoisoindolyl), indoleninyl (pseudoindolyl), isoindazolyl (benzpyrazolyl), benzazinyl (including
quinolinyl (I-benzazinyl) or isoquinolinyl(2-benzazinyl)), phthalazinyl, quinoxalinyl, quinazolinyl,
benzodiazinyl (including cinnolinyl(1,2-benzodiazinyl) or quinazolinyl (l,3-benzodiazinyl)),
benzopyranyl (including chromanyl or isochromanyl), benzoxazinyl (including l,3,2-benzoxazinyi, 1,4,2-
benzoxazinyl, 2,3,1-benzoxazinyl, or 3,1,4-benzoxazinyl), and benzisoxazinyl (including 1,2-
benzisoxazinyl or 1,4-benzisoxazinyl).
[00109] The term "2-hsed ring" heterocyclyl (alone or in combination with another term@)) means a ~ saturated, partially saturated, or aryl heterocyclyl containing 2 fused rings. Examples of 2-fused-ring I
heterocyclyls include indolizinyl, quinolizinyl, putinyl, naphthyridinyl, pteridinyl, indolyl, isoindolyl,
indoleninyl, isoindazolyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl, benzopyranyl,
benzothiopyranyl, benmxazolyl, antluanilyl, benzodioxolyl, benzodioxanyl, benzoxadiazolyl,
benzohanyl, isobenzofiuanyl, benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl,
benzoxazinyl, and tetrahydroisoquinolinyl.
[00110]The term "heteroaryl" (alone or in combination with another term@)) means an aromatic
heterocyclyl containing fiom 5 to 14 ring atoms. A heteroaryl may be a single ring or 2 or 3 fused rings.
Examples of heteroaryl substituents include 6-membered ring substituents such as pyridyl, pyrazyl,
pyrimidinyl, pyridazinyl, and 1,3,5-, 1,2,4- or 1,2,3-triazinyl; 5-membered ring substituents such as
imidazyl, furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-, 1,2,4-, 1,2,5-, or 1,3,4-
oxadiazolyl and isothiazolyl; 615-membered fused ring substituents such as benzothiofuranyl,
benzisoxazolyl, benzoxamlyl, purinyl, and anthranilyl; and 616-membered fused rings such as
benzopyranyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and bemxazinyl.
[00111]A prefix attached to a multi-component substituent only applies to the first component. To
illustrate, the term "alkylcycloalkyl" contains two components: aikyl and cycloalkyl. Thus, the CI-C6'
prefix on CI-C6-alkylcycloalkyl means that the alkyl component of the alkylcycloalkyl contains from 1 to
6 carbon atoms; the C1-C6-prefix does not describe the cycloalkyl component. To illustrate further, the
prefix "halo" on haloalkoxyalkyl indicates that only the alkoxy component of the alkoxyalkyl substituent
is substituted with one or more halogen radicals. If halogen substitution may alternatively or additionally
occur on the alkyl component, the substituent would instead be described as "halogen-substituted
alkoxyalkyl" rather than "haloalkoxyalkyl." And finally, if the halogen substitution may only occur on
the alkyl component, the substituent would instead be described as "alkoxyhaloalkyl."
[00112] If substituents are described as being "independently selected" fiom a group, each substituent is
selected independent of the other. Each substituent therefore may be identical to or different fiom the
other substituent(s).
[00113] When words are used to describe a substituent, the rightmostdescribed component of the
substituent is the component that has the free valence.
[00114] When a chemical formula is used to describe a substituent, the dash on the left side of the formula
indicates the portion of the substituent that has the free valence.
[00115] When a chemical formula is used to describe a linking element between two other elements of a
depicted chemical structure, the leftmost dash of the substituent indicates the portion of the substituent
that is bound to the left element in the depicted structure. The rightmost dash, on the other hand, indicates
the portion of the substituent that is bound to the right element in the depicted structure. To illustrate, if
the depicted chemical structure is X-L-Y and L is described as -C(O)-N(H)-, then the chemical would be
X-C(O)-N(H)-Y.
[00116] With reference to the use of the words "comprise" or "comprises" or "comprising" in this patent
application (including the claims), Applicants note that unless the context requires otherwise, those words
are used on the basis and clear understanding that they are to be interpreted inclusively, rather than
exclusively, and that Applicants intend each of those words to be so interpreted in construing this patent
application, including the claims below.
[00117] ChemDraw software has been used to generate the compound names in this patent application.
[00118] The term "amorphous" as applied to a compound refers to a solid-state in which the compound
molecules are present in a disordered arrangement and do not form a distinguishable crystal lattice or unit
cell. When subjected to X-ray powder diffraction, an amorphous compound does not produce any
characteristic crystalline peaks.
[00119]The term "crystalline form" as applied to a compound refers to a solid-state in which the
compound molecules are arranged to form a distinguishable crystal lattice (i) comprising distinguishable
unit cells, and (ii) yielding diffraction pattern peaks when subjected to X-ray radiation.
(001201 The term "purity", unless otherwise qualified, means the chemical purity of a compound
according to conventional HPLC assay.
[00121] The term "phase purity" means the solid-state purity of a compound with regard to a particular
crystalline or amorphous form of the compound as determined by X-ray powder diffraction analytical
methods.
[00122] The term "phase pure" refers to purity with respect to other solid-state forms of the compound,
and does not necessarily imply a high degree of chemical purity with respect to other compounds.
[00123] The term "PXRD" means X-ray powder dihction.
[00124] The term "TGA" means thermogravimetric analysis.
[0012q The term "DSC" means differential scanning calorimetry.
B. Compounh.
(001261 This invention is diiected, in part, to compounds that are phenyl-uracil derivatives that
correspond in structure to formula I:
R'
*
[00127] In these compounds, - is selected from the group consisting of single carbon-carbon bond and
double carbon-carbon bond.
[00128] In some embodiments, -A is a single carbon-carbon bond. In these embodiments, the
compounds of formula I correspond in structure to the following formula (i.e., formula IA):
*
[00129] In other embodiments, - is a double carbon-carbon bond. In these embodiments, the
compounds of formula I correspond in structure to the following formula (i. e., formula IB):
Bl. Substituent R'.
[00130]R ' is selected from the group consisting of hydrogen, methyl, and nitrogen-protecting group.
[00131] In some embodiments, R' is hydrogen.
[00132] In some embodiments, R' is methyl.
[00133]In some embodiments, R' is selected from the group consisting of hydrogen and methyl.
[00134] In some embodiments, R' is a nitrogen-protecting group. In these embodiments, the compounds
are usefit1 as intermediates for the preparation of compounds of formula I. Nitrogen-protecting groups
suitable for preparing compounds of formula I are known to those skilled in the art.
B2. Substituent R'.
[00135]R 2i s selected from the group consisting of hydrogen, halo, hydroxy, methyl, cyclopropyl, and
cyclobutyl.
[00136] In some embodiments, R' is hydrogen.
[00137]In some embodiments, R2 is halo. In some such embodiments, R' is selected from the group
consisting of fluoro and chloro. In other such embodiments, R' is fluoro. In yet other such embodiments,
R' is chloro. In yet other such embodiments, R' is bromo. In further such embodiments, RZ is iodo.
[00138]I n some embodiments, R' is hydroxy.
I00139)In some embodiments, R' is methyl.
[00140]In some embodiments, R' is cyclopropyl.
[00141]In some embodiments, R' is cyclobutyl.
[00142]In some embodiments, R' is selected from the group consisting of hydrogen, methyl, hydroxy,
and halo. In some such embodiments, R' is selected from the group consisting of hydrogen, methyl,
hydroxy, fluoro, and chloro. In other such embodiments, R' is selected from the group consisting of
hydrogen, methyl, hydroxy, and fluoro. In yet other such embodiments, RZ is selected from the group
consisting of hydrogen, methyl, hydroxy, and chloro. In yet other such embodiments, R' is selected from
the group consisting of hydrogen, methyl, hydroxy, and bromo. In further such embodiments, R' is
selected from the group consisting of hydrogen, methyl, hydroxy, and iodo.
[00143] In some embodiments, R' is selected from the group consisting of hydrogen, methyl, and halo. In
some such embodiments, R' is selected fiom the group consisting of hydrogen, methyl, fluoro, and
chloro. In other such embodiments, R2 is selected from the group consisting of hydrogen, methyl, and
fluoro. In yet other such embodiments, R' is selected from the group consisting of hydrogen, methyl, and
chloro. In yet other such embodiments, R' is selected from the group consisting of hydrogen, methyl, and
bromo. In further such embodiments, R' is selected fiom the group consisting of hydrogen, methyl, and
iodo.
[00144] In some embodiments, R' is selected fiom the group consisting of hydrogen and halo. In some
such embodiments, R~ is selected from the group consisting of hydrogen, fluoro, and chloro. In other
such embodiments, RZ is selected from the group consisting of hydrogen and fluoro. In yet other such
embodiments, RZ is selected fiom the group consisting of hydrogen and chloro. In yet other such
embodiments, R' is selected from the group consisting of hydrogen and bromo. In fiuther such
embodiments, R2 is selected fiom the group consisting of hydrogen and iodo.
B3. Substituent k.
[00145]R3is selected from the group consisting of hydrogen, halo, 0x0, and methyl. In some such
embodiments, R~ is selected fiom the group consisting of hydrogen, fluoro, 0x0, and methyl. In other
such embodiments, R3 is selected fiom the group consisting of hydrogen, chloro, 0x0, and methyl. In yet
other such embodiments, R3 is selected from the group consisting of hydrogen, bromo, 0x0, and methyl.
In yet other such embodiments, R3 is selected fiom the group consisting of hydrogen, iodo, 0x0, and
methyl.
I
I [00146] In some embodiments, R3 is selected from the group consisting of hydrogen, halo, and 0x0. In
some such embodiments, R3 is selected from the group consisting of hydrogen, fluoro, and 0x0. In other
such embodiments, R3 is selected from the group consisting of hydrogen, chloro, and 0x0. In yet other
such embodiments, R3 is selected from the group consisting of hydrogen, bromo, and 0x0. In yet other
such embodiments, R3 is selected from the group consisting of hydrogen, iodo, and 0x0.
[00147] In some embodiments, R3 is selected fiom the group consisting of hydrogen and methyl.
[00148]I n some embodiments, R~i s hydrogen.
[00149] In some embodiments, R3 is methyl.
[00150]I n some embodiments, R3i s 0x0.
[00151]In some embodiments, R3 is halo. In some such embodiments, R3 is fluoro. In other such
embodiments, R3 is chloro. In yet other such embodiments, R3 is bromo. In further such embodiments,
R3 is iodo.
B4. Substituent R'.
[00152]R4 is selected from the group consisting of halo, alkyl, alkenyl, alkynyl, nitro, cyano, azido,
alkyloxy, alkenyloxy, alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl, carbocyclyl, and
heterocyclyl, wherein:
(a) the amino, aminocarbonyl, and aminosulfonyl optionally are substituted with:
(1) one or two substituents independently selected from the group
consisting of alkyl, alkenyl, alkynyl, and alkylsulfonyl, or
(2) two substituents that, together with the amino nitrogen, form a singlering
heterocyclyl,
(b) the alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, and alkylsulfonyl,
optionally are substituted with one or more substituents independently selected from the group
consisting of halo, 0x0, nitro, cyano, azido, hydroxy, amino, alkyloxy, trimethylsilyl, carbocyclyl,
and heterocyclyl, wherein:
the amino optionally is substituted with:
(1) one or two substituents independently selected from the group
consisting of alkyl, alkenyl, alkynyl, alkylcarbonyl, alkylsulfonyl,
alkyloxycarbonyl, carbocyclyl, heterocyclyl, carbocyclylalkyl, and
heterocyclylalkyl, or
(2) two substituents that, together with the amino nitrogen, form a singlering
heterocyclyl, and
(c) the carbocyclyl and heterocyclyl optionally are substituted with up to three
substituents independently selected fiom the group consisting of alkyl, alkenyl, alkynyl, halo,
0x0, nitro, cyano, azid~h,y droxy, amino, alkyloxy, trimethylsilyl, carbocyclyl, and heterocyclyl,
20
wherein:
the amino optionally is substituted with:
(1) one or two substituents independently selected from the group
consisting of alkyl, alkenyl, alkynyl, alkylcarbonyl, alkylsulfonyl,
alkyloxycarbonyl, carbocyclyl, heterocyclyl, carbocyclylalkyl, and
heterocyclylalkyl, or
(2) two substituents that, together with the amino nitrogen, form a singlering
heterocyclyl.
(001531 In some embodiments, R" is selected from the group consisting of halo, alkyl, alkenyl, alkynyl,
nitro, cyano, azido, alkyloxy, alkenyloxy, alkynyloxy, amino, aminocarbonyl, aminosulfonyl,
alkylsulfonyl, carbocyclyl, and heterocyclyl, wherein:
the amino, aminocarbonyl, and aminosulfonyl optionally are substituted with:
(1) one or two substituents independently selected from the group
consisting of alkyl, alkenyl, alkynyl, and alkylsulfonyl, or
(2) two substituents that, together with the amino nitrogen, form a singlering
heterocyclyl.
[00154] In some embodiments, R' is selected from the group consisting of halo, alkyl, alkenyl, alkynyl,
nitro, cyano, azido, alkyloxy, alkenyloxy, alkynyloxy, amino, aminocarbonyl, aminosulfonyl,
alkylsulfonyl, carbocyclyl, and heterocyclyl, wherein:
the alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, and alkylsulfonyl,
optionally are substituted with one or more substituents independently selected from the group
consisting of halo, 0x0, nitro, cyano, azido, hydroxy, amino, alkyloxy, trimethylsilyl, carbocyclyl,
and heterocyclyl, wherein:
the amino optionally is substituted with:
(1) one or two substituents independently selected from the group
consisting of alkyl, alkenyl, akynyl, alkylcarbonyl, alkylsulfonyl,
alkyloxycarbonyl, carbocyclyl, heterocyclyl, carbocyclylalkyl, and
heterocyclylalkyl, or
(2) two substituents that, together with the amino nitrogen, form a single
ring heterocyclyl.
[00155] In some embodiments, R" is selected from the group consisting of halo, alkyl, alkenyl, alkynyl,
nitro, cyano, azido, alkyloxy, alkenyloxy, alkynyloxy, amino, aminocarbonyl, aminosulfonyl,
alkylsulfonyl, carbocyclyl, and heterocyclyl, wherein:
the carbocyclyl and heterocyclyl optionally are substituted with up to three substituents
independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, 0x0, nitro,
cyano, azido, hydroxy, amino, alkyloxy, trimethylsilyl, carbocyclyl, and heterocyclyl, wherein:
the amino optionally is substituted with:
(1) one or two substituents independently selected fiom the group
consisting of alkyl, alkenyl, alkynyl, alkylcarbonyl, alkylsulfonyl,
alkyloxycarbonyl, carbocyclyl, heterocyclyl, carbocyclylalkyl, and
heterocyclylalkyl, or
(2) two substituents that, together with the amino nitrogen, form a singlering
heterocyclyl.
[00156] In some embodiments, R~ is selected from the group consisting of halo, alkyl, alkenyl, alkynyl,
nitro, cyano, azido, alkyloxy, alkenyloxy, alkynyloxy, amino, aminocarbonyl, aminosulfonyl,
alkylsulfonyl, carbocyclyl, and heterocyclyl, wherein:
(a) the amino, aminocarbonyl, and aminosulfonyl optionally are substituted with:
(1) one or two substituents independently selected h m the group consisting of alkyl,
alkenyl, and alkynyl, or,
(2) two substituents that, together with the amino nitrogen, form a single-ring
heterocyclyl; and
(b) the alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, akylsulfonyl, carbocyclyl, and
heterocyclyl optionally are substituted with up to three substituents independently selected fiom the group
consisting of halo, 0x0, nitro, cyano, azido, hydroxy, amino, alkyloxy, carbocyclyl, and heterocyclyl,
wherein the amino optionally is substituted with:
(1) one or two substituents independently selected fiom the group consisting of alkyl,
alkenyl, alkynyl, alkylcarbonyl, alkylsulfonyl, alkyloxycarbonyl, carbocyclyl, heterocyclyl,
carbocyclylakyl, and heterocyclylalkyl, or,
(2) two substituents that, together with the amino nitrogen, form a singlering
heterocyclyl .
[00157] In some embodiments, R~ is selected from the group consisting of halo, alkyl, alkenyl, alkynyl,
nitro, cyano, azido, alkyloxy, alkenyloxy, alkynyloxy, amino, aminocarbonyl, arninosulfonyl,
alkylsulfonyl, carbocyclyl, and heterocyclyl, wherein:
the amino, aminocarbonyl, and aminosulfonyl optionally are substituted with:
(1) one or two substituents independently selected from the group consisting of alkyl,
alkenyl, and alkynyl, or,
(2) two substituents that, together with the amino nitrogen, form a single-ring
heterocyclyl.
~ [00158] In some embodiments, R4 is selected fiom the group consisting of halo, alkyl, alkenyl, alkynyl,
I nitro, cyano, azido, alkyloxy, alkenyloxy, alkynyloxy, amino, aminocarbonyl, aminosulfonyl,
alkylsulfonyl, carbocyclyl, and heterocyclyl, wherein:
the alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, alkylsulfonyl, carbocyclyl, and
heterocyclyl optionally are substituted with up to three substituents independently selected from the group
consisting of halo, 0x0, nitro, cyano, azido, hydroxy, amino, alkyloxy, carbocyclyl, and heterocyclyl,
wherein the amino optionally is substituted with:
(1) one or two substituents independently selected from the group consisting of alkyl,
alkenyl, alkynyl, alkylcarbonyl, alkylsulfonyl,. alkyloxycarbonyl, carbocyclyl, heterocyclyl,
carbocyclylalkyl, and heterocyclylalkyl, or,
(2) two substituents that, together with the amino nitrogen, form a single-ring
heterocyclyl.
I [00159] In some embodiments, R4 is selected from the group consisting of halo, C,-C4-alkyl, C2-C4-
alkenyl, C2-C4-alkynyl, amino, CI-C4-alkylsulfonyl, C~-~6-carbocyclyaln,d 5-6-membered heterocyclyl,
wherein:
(a) the amino optionally is substituted with one or two substituents independently
selected fiom the group consisting of alkyl, alkenyl, alkynyl, and alkylsulfonyl,
(b) the C,-C4-alkyl, C2-C4-alkenyl, and Cz-C4-alkynyl optionally are substituted with one
or more substituents independently selected fiom the group consisting of halo, 0x0, hydroxy,
alkyloxy, and trimethylsilyl, and
(c) the CYQ-carbocyclyl and 5-6-membered heterocyclyl optionally are substituted with
1 up to three substituents independently selected from the group consisting of alkyl, alkenyl,
alkynyl, halo, and amino, wherein:
the amino optionally is substituted with one or two substituents independently
selected from the group consisting of alkyl, alkenyl, alkynyl, and alkylsulfonyl.
[00160] In some embodiments, R4 is selected from the group consisting of C1-Cralkyl, C2-C4-akenyl, C2-
Cralkynyl, amino, CI-C4-alkylsulfonyl, C&-carbocyclyl, and 5-6-membered heterocyclyl, wherein:
(a) the amino optionally is substituted with one or two substituents independently
selected from the group consisting of alkyl, alkenyl, alkynyl, and alkylsulfonyl,
(b) the C1-C4-alkyl, C2-C4-alkenyl, and C2-C4-alkynyl optionally are substituted with one
or more substituents independently selected from the group consisting of halo, 0x0, hydroxy,
alkyloxy, and trimethylsilyl, and
(c) the C3-C6carbocyclyl and 5-6-membered heterocyclyl optionally are substituted with
up to three substituents independently selected from the group consisting of alkyl, akenyl,
1 alkynyl, halo, and amino, wherein:
the amino optionally is substituted with one or two substituents independently
selected from the group consisting of alkyl, alkenyl, alkynyl, and alkylsulfonyl.
[00161] In some embodiments, R' is selected from the group consisting of halo, Cl-(2.1-alkyl, C3-Cacarbocyclyl,
and 5-6-membered heterocyclyl, wherein:
(a) the CI-C4-alkyl optionally is substituted with up to three substituents independently
selected from the group consisting of halo, 0x0, hydroxy, allcyloxy, and trimethylsilyl, and
(b) the C3-C6-carbocyclyl and 5-6-membered heterocyclyl optionally are substituted with
one or two substituents independently selected from the group consisting of alkyl, halo, and
alkylsulfonylamino.
[00162] In some embodiments, R4 is selected from the group consisting of halo, C1-C4-alkyl, C3-C6-
carbocyclyl, and 5-6-membered heterocyclyl, wherein:
(a) the Cl-C4-alkyl optionally is substituted with one or two substituents independently
selected from the group consisting of halo, 0x0, hydroxy, alkyloxy, and trimethylsilyl, and
(b) the C3-Ca~bocyclyaln d 5-6-membered heterocyclyl optionally are substituted with
a substituent selected from the group consisting of alkyl, halo, and alkylsulfonylamino.
[00163] In some embodiments, R4 is selected from the group consisting of C1-C4-alkyl, C3-C6-
carbocyclyl, and 5-6-membered heterocyclyl, wherein:
(a) the C1-C4-alkyl optionally is substituted with up to three substituents independently
selected fiom the group consisting of halo, 0x0, hydroxy, alkyloxy, and trimethylsilyl, and
(b) the C3-C6~bocyclyal nd 5-6-membered heterocyclyl optionally are substituted with
one or two substituents independently selected fiom the group consisting of alkyl, halo, and
alkylsulfonylamino.
[00164] In some embodiments, R~ is selected from the group consisting of halo, tert-butyl, C3-C6-
carbocyclyl, and 5-6-membered heterocyclyl, wherein:
the C3-C6-carbocyclyl and 5-6-membered heterocyclyl optionally are substituted with a
substituent selected fiom the group consisting of alkyl, halo, and alkylsulfonylamino.
(001651 In some embodiments, R~ is selected from the group consisting of tert-butyl, C3-C6-carbocyclyl,
and 5-6-membered heterocyclyl, wherein:
the C3-C6-carbocyclyl and 5-6-membered heterocyclyl optionally are substituted with a
substituent selected from the group consisting of alkyl, halo, and alkylsulfonylamino.
[00166]In some embodiments, R4 is selected from the group consisting of halo, alkyl, haloalkyl,
carboxyalkyl, hydroxyalkyl, alkyloxyalkyl, trimethylsilylalkynyl, alkylcarbocyclyl, carbocyclyl,
alkylheterocyclyl, heterocyclyl, halocarbocyclyl, alkylsulfonylamino, and alkylsulfonyl.
I
[00167] In some embodiments, R' is selected from the group consisting of halo, alkyl; alkenyl, alkynyl,
nitro, cyano, azido, alkyloxy, alkenyloxy, alkynyloxy, amino, aminocarbonyl, aminosulfonyl,
alkylsulfonyl, carbocyclyl, and heterocyclyl.
[00168] In some embodiments, R4 is selected from the group consisting of halo, C1-C4-alkyl, C2-C4-
alkenyl, C2-C4-alkynyl, amino, C1-C4-alkylsulfonyl, C3-C6-carbocyclyl, and 5-6-membered heterocyclyl.
In some such embodiment, R4 is selected from the group consisting of halo, C1-C4-alkyl, C2-C4-alkenyl,
Cz-C4-alkynyl, amino, C1-Ctalkylsulfony1, c6-~arbocy~lyaln,d 5-6-membered heterocyclyl. In other
such embodiment, R4 is selected from the group consisting of halo, CI-C4-alkyl, C2-C4-alkenyl, C2-C4-
alkynyl, amino, C1-C4-alkylsulfonyl, phenyl, and 5-6-membered heteroaryl.
(001691 In some embodiments, R4 is selected from the group consisting of C1-C4-alkyl, C2-C4-alkenyl, Cz-
C4-alkynyl, amino, CI-C4-alkylsulfonyl, C3-Cs-carbocyclyl, and 5-6-membered heterocyclyl. In some
such embodiment, R4 is selected from the group consisting of C1-C4-alkyl,C 2-C4-alkenyl,C 2-C4-alkynyl,
amino, C1-C4-alkylsulfonyl, C6*art>ocyclyl, and 5-6-membered heterocyclyl. In other such embodiment,
R' is selected from the group consisting of C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, amino, C1-C4-
alkylsulfonyl, phenyl, and 5-6-membered heteroaryl.
[00170] In some embodiments, R4 is selected from the group consisting of halo, C1-C4-alkyl, C3-C6-
carbocyclyl, and 5-6-membered heterocyclyl. In some such embodiments, R' is selected from the group
consisting of halo, C1-C4-alkyl, C~-carbocyclyla, nd 5-6-membered heterocyclyl. In other such
embodiments, R' is selected from the group consisting of halo, C1-C4-alkyl, phenyl, and 5-6-membered
heteroaryl.
[00171] In some embodiments, R4 is selected from the group consisting of Cl-C4-alkyl, C3-C6-
carbocyclyl, and 5-6-membered heterocyclyl. In some such embodiments, R4 is selected from the group
consisting of C1-C4-alkyl, Cs-carbocyclyl, and 5-6-membered heterocyclyl. In other such embodiments,
R' is selected from the group consisting of C1-C4-alkyl, phenyl, and 5-6-membered heteroaryl.
[00172] In some embodiments, R' is selected from the group consisting of halo, tert-butyl, C3-C6-
carbocyclyl, and 5-6-membered heterocyclyl. In some such embodiments, R' is selected from the group
consisting of halo, tert-butyl, C6-carbocyclyl, and 5-6-membered heterocyclyl. In other such
embodiments, R4 is selected from the group consisting of halo, tert-butyl, phenyl, and 5-6-membered
heteroaryl.
[00173] In some embodiments, R4 is selected from the group consisting of tert-butyl, C3-C6-carbocyclyl,
and 5-6-membered heterocyclyl. In some such embodiments, R' is selected from the group consisting of
tert-butyl, Cscarbocyclyl, and 5-6-membered heterocyclyl. In other such embodiments, R' is selected
from the group consisting of tert-butyl, phenyl, and 5-6-membered heteroaryl.
I001741 In some embodiments, R4 is selected from the group consisting of C3-C6-carbocyclyl and 5-6-
membered heterocyclyl. In some such embodiments, R~ is selected from the group consisting of C6-
carbocyclyl, and 5-6-membered heterocyclyl. In other such embodiments, R4 is selected fiom the group
consisting of phenyl and 5-6-membered heteroaryl.
[00175j Suitable carbocyclyls for the above embodiments include, for example, cyclopropyl and phenyl.
[00176] Suitable heterocyclyls for the above embodiments include, for example, furanyl, thienyl, and
pyridinyl.
[00177] In some embodiments, R4 is selected from the group consisting of halo, alkyl, and alkyloxy.
[00178] In some embodiments, R4 is alkyl.
[00179]In some embodiments, R4 is tert-butyl.
B5. Substituent R'.
[00180] R= is selected fiom the group consisting of hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkyloxy,
alkenyloxy, alkynyloxy, alkylsulfonyloxy, carbocyclylsulfonyloxy, haloalkylsulfonyloxy, and halo.
[00181] In some embodiments, R' is selected from the group consisting of hydrogen, hydroxy, alkyloxy,
and halo. In some such embodiments, R' is selected fiom the group consisting of hydrogen, hydroxy,
alkyloxy, and fluoro. In other such embodiments, R' is selected from the group consisting of hydrogen,
hydroxy, alkyloxy, and fluoro. In yet other such embodiments, R' is selected from the group consisting
of hydrogen, hydroxy, alkyloxy, and chloro. In yet other such embodiments, R' is selected from the
group consisting of hydrogen, hydroxy, alkyloxy, and bromo. In further such embodiments, R' is
selected fiom the group consisting of hydrogen, hydroxy, alkyloxy, and iodo.
[00182] In some embodiments, R' is selected from the group consisting of hydrogen, hydroxy, methoxy,
and halo. In some such embodiments, R' is selected fiom the group consisting of hydrogen, hydroxy,
methoxy, and fluoro. In other such embodiments, RS is selected from the group consisting of hydrogen,
hydroxy, methoxy, and chloro. In yet other such embodiments, R' is selected from the group consisting
of hydrogen, hydroxy, methoxy, and bromo. In further such embodiments, RS is selected from the group
consisting of hydrogen, hydroxy, methoxy, and iodo.
[00183] In some embodiments, R' is selected fiom the group consisting of hydrogen, hydroxy, and
alkyloxy. In some such embodiments, R' is selected from the group consisting of hydrogen, hydroxy,
methoxy, and ethoxy.
[00184] In some embodiments, R' is s hydrogen.
[00185] In some embodiments, R' is hydroxy.
[00186] In some embodiments, R5 is alkyloxy.
[00187] In some embodiments, R' is rnethoxy.
[00188]I n some embodiments, R' is ethoxy.
B6. Substituent L.
[00189] L is selected h m the group consisting of bond, C(RA)=c(RB), =, c(0)N(RC), N(RD)C(0),
C1-Cz-alkylene, C(Hh0, OC(H)2, cyclopropyl-l,2-ene, c(H)~N(R~)N, (R~)c(H)~C, (0)CH2, and
i CH2C(0),w herein RAYR ~R,C ,R D,R ~an,d RMa re as discussed below.
[00190] In some embodiments, L is selected from the group consisting of bond, c(RA)=C(RB), =,
c(o)N(~), N(R~c(o), C1-C2-alkylene, C(H)20,OC(H)2, cyclopropyl- l,2ene, c(H)~N(R"), and
~ ( ~ ~ r n h .
[00191]I n some embodiments, L is selected from the group consisting of c(RA)=~(ItB)e,t hylene, and
cyclopropyl-l,2-ene.
[00192]In some embodiments, L is selected from the group consisting of c(R~)=C(R~), C=C,
c(o)N(R~), N(R%(o), C1-C2-alkylene, C(H)20, OC(H)2, cyclopropyl-1,2ene, c(H)~N(R~),
N(RM)~(W2C,( O)CH2, and CH2C(O).
[00193] In some embodiments, L is selected from the group consisting of =, c(o)N(RC), N(IR~)c(o),
~ ( H ) 2 0 , O o 2C, (H)ZN(R~)a,n d N(RM~(H)2.
[00194)In some embodiments, L is a bond. In these embodiments, the compounds of formula I
correspond in structure to formula I-LO:
[00195]In some such embodiments, the compounds correspond in structure to the following formula (i.e.,
formula IA-LO):
[00196]In other such embodiments, the compounds correspond in structure to the following formula (i.e.,
formula IB-LO):
[00197] In some embodiments, L is C(R*)=c(RB), wherein RA and R~ are as discussed below. In these
embodiments, the compounds of formula I correspond in structure to formula I-L1:
[00198] In some such embodiments, the compounds correspond in structure to formula IA-L1:
R'
(IA-Ll) R4
[00199] In other such embodiments, the compounds correspond in structure to formula IB-L1:
R 1
R4
[00200] Typically, the compounds of formula I-L1 are more potent if R~ and the phenyl-uracil are on
opposite sides of the double bond (i.e., in trans configuration in relation to the double bond).
[00201] In some embodiments, L is C g . In these embodiments, the compounds of formula I correspond
in structure to formula I-L2:
(1-u) R4
[00202] In some such embodiments, the compounds correspond in structure to IA-L2:
R '
[00203] In other such embodiments, the compounds correspond in structure to formula IB-L2:
[00204] In some embodiments, L is c(o)N(R'), wherein R' is as discussed below. In these
embodiments, the compounds of formula I correspond in structure to formula I-L3:
[00205] In some such embodiments, the compounds correspond in structure to formula IA-L3:
[00206] In other such embodiments, the compounds correspond in structure to formula IB-L3:
(002071 In some embodiments, L is N(R~)c(o), wherein R~ is as discussed below. In these
embodiments, the compounds of formula I correspond in structure to formula I-L4:
[00208] In some such embodiments, the compounds correspond in structure to formula IA-L4:
[00209] In other such embodiments, the compounds correspond in structure to formula IB-L4:
[00210]In some embodiments, L is C1-Cz-alkylene. In these embodiments, the compounds of formula I
correspond in structure to formula I-LS-1 (if L is methylene) or I-L5-2 (if L is ethylene):
R ' R'
I
0
I
O q Y 0
R2 R3 "TR6 R2 qy" R3
(I-M-I) R4 (I-LS-2)
TR6 R~
[00211] In some such embodiments, compounds correspond in structure to formula IA-W-1 (if L is
methylene) or IA-L5-2 (if L is ethylene):
[00212] In other such embodiments, the compounds correspond in structure to formula IB-U1 (if L is
methylene) or IB-L5-2 (if L is ethylene):
R 1 I R '
I
(IB-LS- 1) R4
[00213] In some embodiments, L is C(H)20. In these embodiments, the compounds of formula I
correspond in structure to formula I-M:
R '
[00214] In some such embodiments, the compounds correspond in structure to formula IA-L6:
R'
[00215] In other such embodiments, the compounds correspond in structure to formula 1,-L6:
R'
(IB-L6) I
R4
[00216] In some embodiments, L is OC(H)2. In these embodiments, the compounds of formula I
correspond in structure to formula I-L7:
R'
O-LV R4
[00217]In some such embodiments, the compounds correspond in structure to fomula IA-L7:
[00218] In other such embodiments, the compounds correspond in structure to formula IB-L7:
[00219]In some embodiments, L is cyclopropyl-l,2-ene. In these embodiments, the compounds of
formula I correspond in structure to formula I-LS:
[00220] In some such embodiments, the compounds correspond in structure to formula IA-LS:
[00221] In other such embodiments, the compounds correspond in structure to formula IB-L8:
[00222] In some embodiments, L is selected from the group consisting of C=C, ethylene, and
cyclopropyl-12-ene.
I002231 In some embodiments, L is c(H)~N(R~)I.n these embodiments, the compounds of formula I
correspond in structure to formula I-L9:
[00224] In some such embodiments, the compounds correspond in structure to formula IA-L9:
[00225] In other such embodiments, the compounds correspond in structure to formula IB-L9:
[00226] In some embodiments, L is N(R~)ccH)~In. these embodiments, the compounds of formula I
correspond in structure to formula I-L10:
[00227] In some such embodiments, the compounds correspond in structure to formula IA-L10:
[00228] In other such embodiments, the compounds correspond in structure to formula IB-L10:
[00229] In some embodiments, L is C(0)C(H)2. In these embodiments, the compounds of formula I
correspond in structure to formula I-L1 1 :
[00230] In some such embodiments, the compounds correspond in structure to formula IA-L11:
[00231]In other such embodiments, the compounds correspond in structure to formula IB-Lll:
R1
(002321 In some embodiments, L is C(QC(0). In these embodiments, the compounds of formula I
correspond in structure to formula I-L12:
[00233] In some such embodiments, the compounds correspond in structure to formula IA-L12:
Rl
I
"yNyO
[00234]In other such embodiments, the compounds correspond in structure to formula IB-LIZ:
B 7. Substituents and p.
[00235] RA and RB are independently selected fiom the group consisting of hydrogen, C1-C6-alkyl, C1-
Ca-alkyloxy, C3-C8-cycloalkyl, and halo, wherein:
the C1-Cs-alkyl optionally is substituted with one or more substituents independently
selected fiom the group consisting of carboxy, halo, hydroxy, nitro, 0x0, amino, cyano,
alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl, and heterocyclyl.
(002361111so me embodiments, one of RAa nd RBi s hydrogen, and the other is selected fiom the group
consisting of CI-C6-alkyl, C1 -C6-alkyloxy, C3-C8-cycloalkyl, and halo, wherein:
the CI-Cs-alkyl optionally is substituted with one or more substituents independently
selected from the group consisting of carboxy, halo, hydroxy, nitro, 0x0, amino, cyano,
alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl, and heterocyclyl.
1002371 In some embodiments, RA and RB are independently selected from the group consisting of
hydrogen, C1-G-alkyl, C1-C6-alkyloxy, C3-C8-cycloalkyl, and halo.
[00238] In some of the above embodiments, R~ is hydrogen. In other of the above embodiments, RB is
hydrogen.
[00239] In some embodiment, one of R~ and RB is hydrogen, and the other is selected fiom the group
consisting of hydrogen, methyl, methoxy, and halo.
[00240] In some embodiments, RA is hydrogen, and RB is selected from the group consisting of methyl,
methoxy, and halo. In some such embodiments, RB is selected fiom the group consisting of methyl,
methoxy, and fluoro. In other such embodiments, R~ is selected fiom the group consisting of methyl,
methoxy, and chloro. In yet other such embodiments, RB is selected fiom the group consisting of methyl,
methoxy, and bromo. In M e r such embodiments, RB is selected from the group consisting of methyl,
methoxy, and iodo. In yet hrther such embodiments, RB is selected fiom the group consisting of methyl,
methoxy, chloro, and fluoro.
[00241] In some embodiments, R~ is hydrogen, and R* is selected from the group consisting of methyl,
methoxy, and halo. In some such embodiments, RA is selected fiom the group consisting of methyl,
methoxy, and fluoro. In other such embodiments, RA is selected fiom the group consisting of methyl,
methoxy, and chloro. In yet other such embodiments, R* is selected fiom the group consisting of methyl,
methoxy, and bromo. In further such embodiments, R~ is selected from the group consisting of methyl,
methoxy, and iodo. In yet further such embodiments, RA is selected from the group consisting of methyl,
methoxy, chloro, and fluoro.
(002421 In some embodiments, RA is hydrogen, and RB is hydrogen.
B8. Substituen .'Rt
[00243]RC is selected from the group consisting of hydrogen and alkyl. In some such embodiments, RC
is selected fiom the group consisting of hydrogen and methyl.
(002441 In some embodiments, RC is hydrogen.
[00245] In some embodiments, RC is alkyl. In some such embodiments, RC is methyl.
B9. Substituent fl
[00246]is~ s~e lected from the group consisting of hydrogen and alkyl. In some such embodiments, RD
is selected fiom the group consisting of hydrogen and methyl.
[00247] In some embodiments, RD is hydrogen.
[00248] In some embodiments, RD is alkyl. In some such embodiments, RD is methyl.
BIO. Substituent p.
(002491 RL is selected from the group consisting of hydrogen, CI-C6-alkyl, C1-C6-alkyloxy, C3-C8-
cycloalkyl, and halo, wherein:
the C1-C6-alkyl optionally is substituted with one or more substituents independently
selected from the group consisting of carboxy, halo, hydroxy, nitro, 0x0, amino, cyano,
alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl, and heterocyclyl.
[00250] In some embodiments, RL is selected from the group consisting of hydrogen, C1-G-alkyl, C1-C6-
alkyloxy, C3-Cg-cycloalkyl, and halo.
[00251]In some embodiments, R~ is selected from the group consisting of hydrogen, C1-C6-alkyl, C1-C6'
alkyloxy, and halo, wherein:
the C1-C6-alkyl optionally is substituted with one or more substituents independently
selected from the group consisting of carboxy, halo, hydroxy, nitro, 0x0, amino, cyano,
alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl, and heterocyclyl.
[00252]I n some embodiments, RLi s selected from the group consisting of hydrogen, C1-C6-alkyl,C 1'C6'
alkyloxy, and halo.
(002531 In some of the above embodiments, RL is halo. In some such embodiments, the halo is fluoro. In
other such embodiments, the halo is chloro. In yet other such embodiments, the halo is bromo. In firther
such embodiments, the halo is iodo.
(002541 In some of the above embodiments, RL is hydrogen.
[00255]In some of the above embodiments, RL is C1-C6-alkyl.
[00256] In some of the above embodiments, RL is C1-G-alkyloxy.
Bll. Substituent p.
[00257] RM is selected from the group consisting of hydrogen, C1-C6-alkyl, C1-C6-alkyloxy, C3-Cscycloalkyl,
and halo, wherein:
the Cl-C6-alkyl optionally is substituted with one or more substituents independently
selected from the group consisting of carboxy, halo, hydroxy, nitro, 0x0, amino, cyano,
alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl, and heterocyclyl.
[00258] In some embodiments, RM is selected from the group consisting of hydrogen, C1-C6-alkyl,C l-C6-
alkyloxy, C3-C8-cycloalkyl, and halo.
[00259] In some embodiments, RM is selected from the group consisting of hydrogen, C1-G-alkyl, C1'C6'
alkyloxy, and halo, wherein:
the C1-C6-alkyl optionally is substituted with one or more substituents independently
selected from the group consisting of carboxy, halo, hydroxy, nitro, 0x0, amino, cyano,
alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl, and heterocyclyl.
(002601 In some embodiments, RM is selected from the group consisting of hydrogen, C1-G-alkyl, CI-C6-
alkyloxy, and halo.
[00261] In some of the above embodiments, RM is halo. In some such embodiments, the halo is fluoro.
In other such embodiments, the halo is chloro. In yet other such embodiments, the halo is bromo. In
further such embodiments, the halo is iodo.
[00262] In some of the above embodiments, RM is hydrogen.
[00263]In some of the above embodiments, RM is C1-C6-alkyl.
[00264] In some of the above embodiments, RM is CI-C6-alkyloxy.
B12. Substituent R'.
[00265] R6 is selected from the group consisting of C5-G-carbocyclyl, 5-6-membered heterocyclyl, fused
2-ring carbocyclyl, and fused 2-ring heterocyclyl, wherein each such substituent optionally is substituted
with one or more substituents independently selected from the group consisting of RE, RF, RG, RH, R',
R', and RK, wherein RE, R', RG, RH, R', RJ, and RK are as described below. In some such embodiments,
the Cs-C6-carbocyclyl,5-6-membered heterocyclyl, fused Zring carbocyclyl, and hsed 2-ring
heterocyclyl are not substituted. In other such embodiments, the Cs-C6-carbocyclyl, 5-6-membered
heterocyclyl, fused 2-ring carbocyclyl, and fused 2-ring heterocyclyl are substituted with a substituent
selected from the group consisting of RE,R ~R,G , RH,R ', RJ, and RK. In other such embodiments, the
I CS-c6~bo~y~5l-y6l-m, embered heterocyclyl, fused 2-ring carbocyclyl, and fused 2-ring heterocyclyl
are substituted with a substituent selected from the group consisting of RE, RF, R', RJ, and RK. In other
such embodiments, the CS-G-carbocyclyl, 5-6-membered heterocyclyl, fused 2-ring carbocyclyl, and
fused 2-ring heterocyclyl are substituted with a substituent selected fiom the group consisting of RE, RF,
and RJ. In other such embodiments, the Cs-C6-~arbocy~ly5l-, 6-membered heterocyclyl, fused 2-ring
carbocyclyl, and fused 2-ring heterocyclyl are substituted with a substituent selected from the group
consisting of RFa nd RJ. In other such embodiments, the Cs-c6-~itrbocyclyl5,- 6-membered heterocyclyl,
fused 2-ring carbocyclyl, and fused 2-ring heterocyclyl are substituted with RJ. In yet other such
embodiments, the Cs-C6-carbocyclyl, 5-6-membered heterocyclyl, fused 2-ring carbocyclyl, and fused 2-
ring heterocyclyl are substituted with two substituents independently selected fiom the group consisting
of RE,R F, RG, RH,R ', R ~a,n d RK. In yet other such embodiments, the C~-c6-carbocyclyl5, -6-membered
heterocyclyl, hsed 2-ring carbocyclyl, and fused 2-ring heterocyclyl are substituted with two substituents
independently selected from the group consisting of RE, RF, R', RJ, and RK. In yet other such ~ embodiments, the Cs-C6-carbocyclyl, 5-6-membered heterocyclyl, fused 2-ring carbocyclyl, and fused 2-
ring heterocyclyl are substituted with two substituents independently selected fiom the group consisting
of RE, R', and RJ. In yet other such embodiments, the Cs-C6.
813. Substituent R~.
I002971 Each RE is independently selected from the group consisting of halo, nitro, hydroxy, 0x0,
carboxy, cyano, amino, imino, azido, and aldehydo, wherein the amino optionally is substituted with one
or two substituents independently selected fiom the group consisting of alkyl, alkenyl, and alkynyl.
[00298) In some embodiment, each RE is independently selected from the group consisting of halo, nitro,
hydroxy, 0x0, carboxy, amino, imino, and aldehydo, wherein the amino optionally is substituted with one
or two independently selected alkyl.
[00299] In some embodiment, each RE is independently selected from the group consisting of halo, nitro,
hydroxy, 0x0, carboxy, amino, imino, aldehydo, and alkylamino.
I003001 In some embodiment, each RE is independently selected fiom the group consisting of chloro,
fluoro, nitro, hydroxy, 0x0, carboxy, amino, imino, aldehydo, and alkylamino.
[00301] In some embodiment, each RE is independently selected fiom the group consisting of halo, nitro,
hydroxy, 0x0, carboxy, cyano, amino, imino, and azido. In some such embodiments, each RE is halo. In
other such embodiments, each R~ is nitro. In yet other such embodiments, each is hydroxy. In yet
other such embodiments, each RE is 0x0. In yet other such embodiments, each RE is carboxy. In yet
other such embodiments, each RE is cyano. In yet other such embodiments, each RE is amino. In further
such embodiments, each RE is imino. In yet M e r such embodiments, each R~ is and azido.
[00302] In some embodiments, each RE is independently selected from the group consisting of halo, nitro,
hydroxy, 0x0, carboxy, cyano, amino, and imino.
Bl4. Substituent R*.
(003031 Each RF is independently selected from the group consisting of alkyl, alkenyl, and alkynyl,
wherein:
1 each such substituent optionally is substituted with one or more substituents
independently selected from the group consisting of carboxy, hydroxy, halo, amino, imino, nitro,
azido, 0x0, aminosulfonyl, alkylsulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl,
alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy,
alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, wherein:
the amino, imino, aminosulfonyl, aminocarbonyl, carbocyclyl, and heterocyclyl
optionally are substituted with one or two substituents independently selected from the
group consisting of alkyl, alkenyl, akynyl, alkylsulfonyl, alkenylsulfonyl,
alkynylsulfonyl, alkylsulfonylamino, hydroxy, and alkyloxy,
wherein:
amino portion of the alkylsulfonylamino optionally is substituted with a
substituent selected from the group consisting of alkyl, alkenyl, and alkynyl.
[00304] In some embodiment, each R' is independently selected from the group consisting of alkyl,
alkenyl, and alkynyl, wherein:
each such substituent optionally is substituted with one or more substituents
independently selected from the group consisting of carboxy, hydroxy, halo, amino, imino, nitro,
azido, 0x0, aminosulfonyl, alkylsulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl,
alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy,
alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, wherein:
the amino, imino, aminosulfonyl, and aminocarbonyl optionally are substituted
with one or two substituents independently selected from the group consisting of alkyl,
alkenyl, alkynyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, and alkylsulfonylamino,
wherein:
amino portion of the alkylsulfonylamino optionally is substituted with a
substituent selected from the group consisting of alkyl, alkenyl, and alkynyl.
(00305j In some of the above embodiments, each R' is independently selected from the group consisting
I
I
of the alkyl, alkynyl, and alkynyl, wherein such substituents are not substituted.
[00306] In some embodiments, each R' is independently selected from the group consisting of alkyl,
I
alkenyl, and alkynyl, wherein:
each such substituent optionally is substituted with one or two substituents independently
selected from the group consisting of carboxy, hydroxy, halo, amino, imino, nitro, 0x0,
aminosulfonyl, alkylsulfonyl, alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl,
heterocyclyl, cyano, and aminocarbonyl, wherein:
the amino, imino, aminosulfonyl, and aminocarbonyl optionally are substituted
with one or two substituents independently selected fiom the group consisting of alkyl,
akylsulfonyl, and alkylsulfonylamino,
wherein:
amino portion of the alkylsulfonylamino optionally is substituted with
akyl .
[00307] In some embodiments, each R' is an independently selected alkyl optionally substituted with a
substituent selected fiom the group consisting of carboxy, hydroxy, halo, amino, irnino, nitro, 0x0,
aminosulfonyl, alkylsulfonyl, alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl, heterocyclyl,
cyano, and aminocarbonyl, wherein:
the amino, imino, aminosulfonyl, and aminocarbonyl optionally are substituted with one
or two substituents independently selected from the group consisting of alkyl, alkylsulfonyl, and
alkylsulfonylamino, wherein:
amino portion of the alkylsulfonylamino optionally is substituted with alkyl.
[00308] In some embodiments, each R' is an independently selected alkyl optionally substituted with a
substituent selected fiom the group consisting of carboxy, halo, amino, imino, and aminosulfonyl,
wherein:
the amino, imino, and aminosulfonyl optionally are substituted with one or two
substituents independently selected from the group consisting of alkyl, alkylsulfonyl, and
alkylsulfonylamino.
[00309] In some embodiments, each R* is an independently selected alkyl optionally substituted with
amino, wherein the amino optionally is substituted with alkylsulfonyl.
[00310] In some embodiments, each R' is an independently selected alkyl substituted with amino,
wherein the amino is substituted with alkylsulfonyl. In some such embodiments, each R' is
methylsulfonylaminomethyl.
[00311] In some embodiments, each R' is independently selected from the group consisting of alkyl,
alkenyl, and alkynyl, wherein:
each such substituent optionally is substituted with one, two, or three substituents
independently selected from the group consisting of carboxy, hydroxy, halo, amino, imino, nitro,
azido, 0x0, aminosulfonyl, alkylsulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl,
alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy,
alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl.
(003121 In some embodiments, each R* is independently selected alkyl substituted with one or more
substituents independently selected fiom the group consisting of carboxy, hydroxy, halo, amino, imino,
nitro, azido, 0x0, aminosulfonyl, alkylsulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl,
alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy, alkenyloxy,
1 alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl.
BlS. Substituen .'tR
[00313] Each R' is independently selected fiom the group consisting of carbocyclyl and heterocyclyl,
wherein:
each such substituent optionally is substituted with one or more substituents
independently selected fiom the group consisting of alkyl, alkenyl, alkynyl, carboxy, hydroxy,
halo, amino, nitro, azido, 0x0, aminosulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl,
alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy,
alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, wherein:
the amino, aminosulfonyl, and aminocarbonyl optionally are substituted with one
or two substituents independently selected from the group consisting of alkyl, alkenyl,
alkynyl, alkylsulfonyl, alkenylsulfonyl, and alkynylsulfonyl.
[00314] In some of Qle above embodiments, each RG is independently selected fiom the group consisting
of carbocyclyl and heterocyclyl, wherein such substituents are not substituted.
[00315]In some embodiments, each RG is independently selected fiom the group consisting of
carbocyclyl and heterocyclyl, wherein:
each such substituent optionally is substituted with one or two substituents independently
selected from the group consisting of alkyl, carboxy, hydroxy, halo, amino, nitro, 0x0,
aminosulfonyl, alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl, heterocyclyl, cyano,
and aminocarbonyl, wherein:
the amino, aminosulfonyl, and aminocarbonyl optionally are substituted with one
or two substituents independently selected fiom the group consisting of alkyl and
alkylsulfonyl.
[00316] In some of the above embodiments, the carbocyclyl is C3-C6-carbocyclyl.
[00317]Jn some of the above embodiments, the heterocyclyl is 5-6-membered heterocyclyl.
B16. Substituent R ~ .
[00318] Each RH is independently selected from the group consisting of alkyloxy, alkenyloxy,
alkynyloxy, alkylsulfonyloxy, alkenylsulfonyloxy, and alkynylsulfonyloxy, wherein:
each such substituent optionally is substituted with one or more substituents
independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, azido,
0x0, aminosulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl,
alkylcarbonyloxy, alkenylcarbonyloxy, a~ylcarbonyloxy, alkyloxy, alkenyloxy, alkynyloxy,
carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, wherein:
the amino, aminosulfonyl, and aminocarbonyl optionally are substituted with one
or two substituents independently selected from the group consisting of alkyl, alkenyl,
alkynyl, alkylsulfonyl, alkenylsulfonyl, and alkynylsulfonyl.
(003191 In some of the above embodiments, each RH is independently selected fiom the group consisting
of awloxy, alkenyloxy, alkynyloxy, alkylsulfonyloxy, alkenylsulfonyloxy, and alkynylsulfonyloxy,
wherein such substituents are not substituted.
(003201 In some embodiments, each R' is independently selected from the group consisting of alkyloxy
and alkylsulfonyloxy, wherein:
each such substituent optionally is substituted with one or two substituents independently
selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, 0x0, aminosulfonyl,
alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl, heterocyclyl, cyano, and
aminocarbonyl, wherein:
the amino, aminosulfonyl, and aminocarbonyl optionally are substituted with one
or two substituents independently selected from the group consisting of alkyl and
alkylsulfonyl.
[00321] In some embodiments, each R~ is independently selected from the group consisting of alkyloxy
and alkylsulfonyloxy, wherein:
each such substituent optionally is substituted with one or two substituents independently
selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, 0x0, aminosulfonyl,
alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, cyano, and aminocarbonyl, wherein:
the amino, aminosulfonyl, and aminocarbonyl optionally are substituted with one
or two substituents independently selected from the group consisting of alkyl and
alkylsulfonyl.
[00322] In some embodiments, each R' is independently selected from the group consisting of alkyloxy
and alkylsulfonyloxy, wherein:
each such substituent optionally is substituted with one or two substituents
independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro,
0x0, aminosulfonyl, alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, cyano, and
aminocarbonyl.
[00323] In some embodiments, each RH is independently selected alkyloxy.
[00324]In some embodiments, each RH is independently selected alkylsulfonyloxy.
B17. Substituent 2.
[00325] Each R' is independently selected from the group consisting of alkylcarbonyl, alkenylcarbonyl,
alkynylcarbonyl, aminocarbonyl, alkyloxycarbonyl, carbocyclylcarbonyl, and heterocyclylcarbonyl,
wherein:
(a) the alkylcarbonyl, alkenylcarbonyl, and alkynylcarbonyl optionally are substituted
with one or more substituents independently selected from the group consisting of carboxy,
hydroxy, halo, amino, nitro, azido, 0x0, aminosulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl,
alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy,
alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, and
(b) the aminocarbonyl optionally is substituted with one or two substituents
independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkyloxyalkyl,
carbocyclyl, heterocyclyl, alkylsulfonyl, and alkylsulfonylamino, wherein:
the carbocyclyl and heterocyclyl optionally are substituted with one or two
substituents independently selected from the group consisting of halo, alkyl, and 0x0.
(0032611n some embodiments, each R' is independently selected from the group consisting of
alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, aminocarbonyl, alkyloxycarbonyl, carbocyclylcarbonyl,
and heterocyclylcarbonyl, wherein such substituents are not substituted.
[00327) In some embodiments, each R' is independently selected from the group consisting of
alkylcarbonyl, aminocarbonyl, alkyloxycarbonyl, carbocyclylcarbonyl, and heterocyclylcarbonyl,
wherein:
(a) the alkylcarbonyl optionally is substituted with a substituent selected from the group
consisting of carboxy, hydroxy, halo, amino, nitro, 0x0, aminosulfonyl, alkyloxycarbonyl,
alkylcarbonyloxy, alkyloxy, and aminocarbonyl, and
(b) the aminocarbonyl optionally is substituted with a substituent selected from the group
consisting of alkyl, alkyloxyalkyl, alkylsulfonyl, and alkylsulfonylamino.
[00328]In some embodiments, each R' is independently selected from the group consisting of
alkylcarbonyl and aminocarbonyl, wherein:
the aminocarbonyl optionally is substituted with a substituent selected from the group
consisting of alkyl, alkyloxyalkyl, alkylsulfonyl, and alkylsulfonylamino.
I003291 In some embodiment, each R' is independently selected from the group consisting of
alkylcarbonyl, alkenylcarbonyl, allpylcarbonyl, and aminocarbonyl, wherein:
(a) the alkylcarbonyl, alkenylcarbonyl, and alkynylcarbonyl optionally are substituted
with one or more substituents independently selected from the group consisting of carboxy,
hydroxy, halo, amino, nitro, azido, 0x0, aminosulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl,
alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy,
alkenyloxy, allqnyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, and
(b) the aminocarbonyl optionally is substituted with one or two substituents
independently selected from the group consisting of alkyl, alkenyl, alkynyl, and
alkylsulfonylamino.
[00330] In some of the above embodiments, each R' is independently selected from the group consisting
of alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, and aminocarbonyl, wherein such substituents are not
substituted.
[00331] In some embodiments, each R' is independently selected from the group consisting of
alkylcarbonyl and aminocarbonyl, wherein:
(a) the alkylcarbonyl optionally is substituted with one or two substituents independently
selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, azido, 0x0,
aminosulfonyl, alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl, heterocyclyl, cyano,
and aminocarbonyl, and
(b) the aminocarbonyl optionally is substituted with one or two substituents
independently selected from the group consisting of alkyl and alkylsulfonylamino.
I003321 In some embodiments, each R' is independently selected from the group consisting of
alkylcarbonyl and aminocarbonyl, wherein:
(a) the alkylcarbonyl optionally is substituted with one or two substituents independently
selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, 0x0, aminosulfonyl,
alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, cyano, and aminocarbonyl, and
(b) the aminocarbonyl optionally is substituted with one or two substituents
independently selected from the group consisting of alkyl and alkylsulforiylamino.
100333) In some embodiments, each R' is independently selected from the group consisting of
alkylcarbonyl and aminocarbonyl, wherein:
the alkylcarbonyl optionally is substituted with one or two substituents independently
selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, azido, 0x0,
aminosulfonyl, alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl, heterocyclyl, cyano,
and aminocarbonyl.
[00334] In some embodiments, each R' is independently selected alkylcarbonyl.
[00335] In some embodiments, each R' is independently selected aminocarbonyl.
B18. Substituent R'.
[00336] Each RJ is independently selected from the group consisting of carbocyclylsulfonylamino,
heterocyclylsulfonylamino, alkylcarbonylamino, alkenylcarbonylamino, alkynylcarbonylamino,
alkyloxycarbonylamino, alkenyloxycarbonylamino, akynyloxycarbonylamino, alkylsulfonylamino,
alkenylsulfonylamino, alkynylsulfonylamino, aminocarbonylamino, alkyloxycarbonylaminoimino,
alkylsulfonylaminoimino, alkenylsulfonylaminoimino, and alkynylsulfonylaminoimino, wherein:
(a) the amino portion of such substituents optionally is substituted with a substituent
independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl,
alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkenyl, alkynyl, akylcarbonyl, alkenylcarbonyl,
alkynylcarbonyl, alkyloxycarbonyl, akyloxyalkyloxycarbonyl, alkylcarbonyloxyalkyl, and
alkylsulfonyl, wherein:
(1) the carbocyclyl portion of the carbocyclylalkyl and the heterocyclyl portion
of the heterocyclylalkyl optionally are substituted with one or more substituents
independently selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy,
hydroxy, alkyloxy, alkenyloxy, alkynyloxy, halo, nitro, cyano, azido, 0x0, and amino,
and
(2) the amino portion of the aminocarbonylalkyl optionally is substituted with
one or two substituents independently selected fiom the group consisting of alkyl,
alkenyl, and alkynyl,
(b) the alkyl, alkenyl, and alkynyl portion of such substituents optionally is substituted
with one or more substituents independently selected from the group consisting of carboxy, halo,
0x0, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl,
and cyano, wherein:
the amino optionally is substituted with one or two substituents independently
selected from the group consisting of alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, and
alkynyloxy, wherein:
the alkyl optionally is substituted with one or more hydroxy;
(c) the carbocyclyl and heterocyclyl portions of such substituents optionally are
substituted with one or more substituents independently selected from the group consisting of
albl, alkenyl, alkynyl, carboxy, hydroxy, alkyloxy, alkenyloxy, alkynyloxy, halo, nitro, cyano,
azido, and amino, wherein:
the amino optionally is substituted with one or two substituents independently
55
selected from the group consisting of alkyl, alkenyl, and alkynyl.
[00337] In some embodiment, each R' is independently selected from the group consisting of
carbocyclylsulfonylamino, heterocyclylsulfonylamino, alkylcarbonylamino, alkenylcarbonylamino,
alkynylcarbonylamino, alkyloxycarbonylamino, alkenyloxycarbonylamino, alkynyloxycarbonylamino,
alkylsulfonylamino, alkenylsulfonylamino, alkynylsulfonylamino, aminocarbonylamino,
alkylsulfonylaminoimino, alkenylsulfonylaminoimino, and alkynylsulfonylaminoirnino, wherein:
(a) the amino portion of such substituents optionally is substituted with a substituent
independently selected fiom the group consisting of carbocyclylalkyl, heterocyclylalkyl,
alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkenyl, alkynyl, alkylcarbonyl, alkenylcarbonyl,
alkynylcarbonyl, alkyloxycarbonyl, alkyloxyalkyloxycarbonyl, alkylcarbonyloxyalkyI, and
alkylsulfonyl, wherein:
(1) the carbocyclyl portion of the carbocyclylalkyl and the heterocyclyl portion
of the heterocyclylalkyl optionally are substituted with one or more substituents
independently selected fiom the group consisting of alkyl, alkenyl, alkynyl, carboxy,
hydroxy, alkyloxy, alkenyloxy, alkynyloxy, halo, nitro, cyano, azido, 0x0, and amino,
and
(2) the amino portion of the aminocarbonylalkyl optionally is substituted with
one or two substituents independently selected fiom the group consisting of alkyl,
alkenyl, and alkynyl,
(b) the alkyl, alkenyl, and alkynyl portion of such substituents optionally is substituted
with one or more substituents independently selected fiom the group consisting of carboxy, halo,
0x0, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl,
and cyano, wherein:
the amino optionally is substituted with one or two substituents independently
selected fiom the group consisting of alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, and
alkynyloxy, wherein:
the alkyl optionally is substituted with one or more hydroxy;
(c) the carbocyclyl and heterocyclyl portions of such substituents optionally are
substituted with one or more substituents independently selected from the group consisting of
alkyl, alkenyl, alkynyl, carboxy, hydroxy, alkyloxy, alkenyloxy, alkynyloxy, halo, nitro, cyano,
azido, and amino, wherein:
the amino optionally is substituted with one or two substituents independently
selected fiom the group consisting of alkyl, alkenyl, and alkynyl; and
[00338] In some of the above embodiments, each R~ is independently selected fiom the group consisting
of carbocyclylsulfonylamino, heterocyclylsulfonylamino, alkylcarbonylamino, alkenylcarbonylamino,
alkynylcarbonylamino, alkyloxycarbonylamino, alkenyloxycarbonylamino, alkynyloxycarbonylamino,
alkylsulfonylamino, alkenylsulfonylamino, alkynylsulfonylamino, aminocarbonylamino,
alkylsulfonylaminoimino, alkenylsulfonylaminoimino, and alkynylsulfonylaminoimino, wherein such
substituents are not substituted.
[00339] In some embodiments, each R' is independently selected from the group consisting of
carbocyclylsulfonylamino, heterocyclylsulfonylamino, alkylcarbonylamino, alkyloxycarbonylamino,
alkylsulfonylamino, aminocarbonylamino, and alkylsulfonylaminoimino, wherein:
(a) the amino portion of such substituents optionally is substituted with a substituent
independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl,
alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl, alkyloxycarbonyl,
alkyloxyalkyloxycarbonyl, alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:
(1) the carbocyclyl portion of the carbocyclylalkyl and the heterocyclyl portion
of the heterocyclylalkyl optionally are substituted with one or two substituents
independently selected from the group consisting of alkyl, carboxy, hydroxy, alkyloxy,
halo, nitro, cyano, 0x0, and amino, and
(2) the amino portion of the aminocarbonylalkyl optionally is substituted with
one or two substituents independently selected from the group consisting of alkyl,
alkenyl, and alkynyl,
(b) the alkyl portion of such substituents optionally is substituted with one or two
substituents independently selected from the group consisting of carboxy, halo, 0x0, amino,
alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl, and cyano,
wherein:
the amino optionally is substituted with one or two substituents independently
selected h m the group consisting of alkyl and alkyloxy, wherein:
the alkyl optionally is substituted with one or more hydroxy;
(c) the carbocyclyl and heterocyclyl portions of such substituents optionally are
substituted with one or two substituents independently selected from the group consisting of
alkyl, carboxy, hydroxy, allcyloxy, halo, nitro, cyano, and amino, wherein:
the amino optionally is substituted with one or two substituents independently
selected alkyl.
(003401 In some embodiments, each R~ is independently selected from the group consisting of
carbocyclylsulfonylamino, heterocyclylsulfonylamino, alkylsulfonylamino, and alkylsulfonylaminoimino,
wherein:
(a) the amino portion of such substituents optionally is substituted with a substituent
independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl,
alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl, alkyloxycarbonyl,
alkyloxyalkyloxycarbonyl, alkylcarbonyloxyalkyl, and allcylsulfonyl, wherein:
(1) the carbocyclyl portion of the carbocyclylalkyl and the heterocyclyl portion
of the heterocyclylalkyl optionally are substituted with one or two substituents
independently selected from the group consisting of alkyl, carboxy, hydroxy, alkyloxy,
halo, nitro, cyano, 0x0, and amino, and
(2) the amino portion of the aminocarbonylalkyl optionally is substituted with
one or two substituents independently selected fiom the group consisting of alkyl,
alkenyl, and alkynyl,
(b) the alkyl portion of such substituents optionally is substituted with one or two
substituents independently selected from the group consisting of carboxy, halo, 0x0, amino,
alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, hetemyclyl, and cyano,
wherein:
the amino optionally is substituted with one or two substituents independently
selected fiom the group consisting of alkyl and alkyloxy, wherein:
the alkyl optionally is substituted with one or more hydroxy;
(c) the carbocyclyl and heterocyclyl portions of such substituents optionally are
substituted with one or two substituents independently selected h m the group consisting of
alkyl, carboxy, hydroxy, alkyloxy, halo, nitro, cyano, and amino, wherein:
the amino optionally is substituted with one or two substituents independently
selected alkyl.
[00341] In some embodiments, each R~ is independently selected from the group consisting of
carbocyclylsulfonylamino, heterocyciylsulfonylamino, alkylsulfonylamino, and alkylsulfony1aminoimino,
wherein:
the amino portion of such substituents optionally is substituted with a substituent
independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl,
alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl, alkyloxycarbonyl,
alkyloxyalkyloxycarbonyl, alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:
(1) the carbocyclyl portion of the carbocyclylalkyl and the heterocyclyl portion
of the heterocyclylalkyl optionally are substituted with one or two substituents
independently selected from the group consisting of alkyl, carboxy, hydroxy, alkyloxy,
halo, nitro, cyano, 0x0, and amino, and
(2) the amino portion of the aminocarbonylalkyl optionally is substituted with
one or two substituents independently selected from the group consisting of alkyl,
alkenyl, and alkynyl.
1003421 In some embodiments, each R' is independently selected fnnn the group consisting of
carbocyclylsulfonylamino, heterocyclylsulfonylamino, alkylsulfonylamino, and alkylsulfonylaminoimino,
wherein:
the alkyl portion of the alkylsulfonylamino and alkylsulfonylaminoimino optionally is
substituted with one or two substituents independently selected from the group consisting of
carboxy, halo, 0x0, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl,
heterocyclyl, and cyano, wherein:
the amino optionally is substituted with one or two substituents independently
selected from the group consisting of alkyl and allcyloxy, wherein: I
I the alkyl optionally is substituted with one or more hydroxy.
I
(003431 In some embodiments, each R~ is independently selected h m the group consisting of
carbocyclylsulfonylamino, heterocyclylsulfonylamino, alkylsulfonylamino, and alkylsulfonylaminoimino,
wherein:
the carbocyclyl and heterocyclyl portions of such substituents optionally are substituted
with one or two substituents independently selected fiom the group consisting of alkyl, carboxy,
hydroxy, alkyloxy, halo, nitro, cyano, and amino.
[00344] In some embodiments, each R~ is independently selected from the group consisting of
carbocyclylsulfonylarnino and heterocyclylsulfonylamino, wherein:
the carbocyclyl and heterocyclyl portions of such substituents optionally are substituted
with one or two substituents independently selected from the group consisting of alkyl, carboxy,
hydroxy, alkyloxy, halo, nitro, cyano, and amino.
[00345] In some embodiments, each R' is independently selected from the group consisting of
alkylsulfonylamino, alkenylsulfonylamino, alkynylsulfonylamino, and alkylsulfonylaminoimino,
wherein:
(a) the amino portion of such substituents optionally is substituted with a substituent
independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl,
akylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl, alkyloxycarbonyl,
alkyloxyalkyloxycarbonyl, alkylcarbonyloxyalkyl, and akylsulfonyl, wherein:
(1) the carbocyclyl portion of the carbocyclylalkyl and the heterocyclyl portion
of the heterocyclylalkyl optionally are substituted with one or two substituents
independently selected from the group consisting of alkyl, carboxy, hydroxy, alkyloxy,
halo, nitro, cyano, 0x0, and amino, and
(2) the amino portion of the aminocarbonylalkyl optionally is substituted with
one or two substituents independently selected fiom the group consisting of alkyl,
alkenyl, and alkynyl,
(b) the alkyl, alkenyl, and alkynyl portion of such substituents optionally is substituted
with one or two substituents independently selected from the group consisting of carboxy, halo,
0x0, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl,
and cyano, wherein:
the amino optionally is substituted with one or two substituents independently
selected from the group consisting of alkyl and alkyloxy, wherein:
the alkyl optionally is substituted with one or more hydroxy.
(00346]In some embodiments, each RJ is an independently selected alkylsulfonylamino, wherein:
(a) the amino portion of the alkylsulfonylamino optionally is substituted with a
substituent independently selected from the group consisting of carbocyclylalkyl,
heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl, alkyloxycarbonyl,
alkyloxyalkyloxycarbonyl, alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:
(1) the carbocyclyl portion of the carbocyclylalkyl and the heterocyclyl portion
of the heterocyclylalkyl optionally are substituted with one or two substituents
independently selected from the group consisting of alkyl, carboxy, hydroxy, alkyloxy,
halo, nitro, cyano, 0x0, and amino, and
(2) the amino portion of the aminocarbonylalkyl optionally is substituted with
one or two substituents independently selected from the group consisting of alkyl,
alkenyl, and alkynyl,
(b) the alkyl portion of the alkylsulfonylamino optionally is substituted with one or two
substituents independently selected from the group consisting of carboxy, halo, 0x0, amino,
alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl, and cyano,
wherein:
the amino optionally is substituted with one or two substituents independently
selected from the group consisting of alkyl and alkyloxy, wherein:
the alkyl optionally is substituted with one or more hydroxy.
I003471 In some embodiments, each RJ is an independently selected alkylsulfonylamino, wherein:
the amino portion of the alkylsulfonylamino optionally is substituted with a substituent
independently selected fiom the group consisting of carbocyclylalkyl, heterocyclylalkyl,
alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl, alkyloxycarbonyl,
alkyloxyalkyloxycarbonyl, alkylcarbonyloxyalkyI, and alkylsulfonyl, wherein:
(1) the carbocyclyl portion of the carbocyclylalkyl and the heterocyclyl portion
of the heterocyclylalkyl optionally are substituted with one or two substituents
independently selected fiom the group consisting of alkyl, carboxy, hydroxy, alkyloxy,
halo, nitro, cyano, 0x0, and amino, and
(2) the amino portion of the aminocarbonylalkyl optionally is substituted with
one or two substituents independently selected from the group consisting of alkyl,
alkenyl, and alkynyl.
[00348] In some embodiments, each RJ is an independently selected alkylsulfonylamino, wherein:
the amino portion of the alkylsulfonylamino optionally is substituted with a substituent
independently selected fiom the group consisting of carbocyclylalkyl, heterocyclylalkyl,
alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl, alkyloxycarbonyl,
alkyloxyalkyloxycarbonyl, alkylwbonyloxyakyl, and alkylsulfonyl.
[00349] In some embodiments, each RJ is an independently selected alkylsulfonylamino, wherein:
the alkyl portion of the alkylsulfonylamino optionally is substituted with one or two
substituents independently selected from the group consisting of carboxy, halo, 0x0, amino,
alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl, and cyano,
wherein:
the amino optionally is substituted with one or two substituents independently
selected from the group consisting of alkyl and alkyloxy, wherein:
the alkyl optionally is substituted with one or more hydroxy.
[00350] In some embodiments, each RJ is an independently selected alkylsulfonylamino, wherein:
the alkyl portion of the alkylsulfonylamino optionally is substituted with one or two
substituents independently selected fiom the group consisting of carboxy, halo, 0x0, amino,
alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl, and cyano.
[00351] In some embodiments, each RJ is an independently selected alkylsulfonylamino. In some such
embodiments, each R~ is methylsulfonylamino.
[00352] In some embodiments, each R~ is an independently selected alkylsulfonylaminoimino, wherein:
(a) the amino portion of the alkylsulfonylaminoimino optionally is substituted with a
substituent independently selected from the group consisting of carbocyclylalkyl,
heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl, alkyloxycarbonyl,
alkyloxyalkyloxycarbonyl, alkylcarbonyloxyaky1, and alkylsulfonyl, wherein:
(1) the carbocyclyl portion of the carbocyclylalkyl and the heterocyclyl portion
of the heterocyclylalkyl optionally are substituted with one or two substituents

Claims
1. A compound or salt thereof, wherein the compound corresponds in structure to
formula 11:
wherein is selected from the group consisting of single carbon-carbon bond and double carboncarbon
bond;
R' is selected from the group consisting of hydrogen, methyl, and nitrogen-protecting group;
R* is selected from the group consisting of hydrogen, halo, hydroxy, methyl, cyclopropyl, and
cyclobutyl;
R3 is selected from the group consisting of hydrogen, halo, 0x0, and methyl;
R4 is selected from the group consisting of halo, alkyl, alkenyl, alkynyl, nitro, cyano, azido,
alkyloxy, alkenyloxy, alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl, carbocyclyl,
and heterocyclyl, wherein:
(a) the amino, aminocarbonyl, and aminosulfonyl optionally are substituted with:
(1) one or two substituents independently selected from the
group consisting of alkyl, alkenyl, alkynyl, and alkylsulfonyl, or
(2) two substituents that, together with the amino nitrogen, form
a single-ring heterocyclyl, and
(b) the alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, and
alkylsulfonyl, optionally are substituted with one or more substituents independently selected
from the group consisting of halo, 0x0, nitro, cyano, azido, hydroxy, amino, alkyloxy,
trimethylsilyl, carbocyclyl, and heterocyclyl, wherein:
the amino optionally is substituted with:
(1) one or two substituents independently selected from the
group consisting of alkyl, alkenyl, alkynyl, alkylcarbonyl, alkylsulfonyl,
alkyloxycarbonyl, carbocyclyl, heterocyclyl, carbocyclylalkyl, and
heterocyclylalkyl, or
(2) two substituents that, together with the amino nitrogen, form
a single-ring heterocyclyl, and
(c) the carbocyclyl and heterocyclyl optionally are substituted with up to three
substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo,
0x0, nitro, cyano, azido, hydroxy, amino, alkyloxy, trimethylsilyl, carbocyclyl, and
heterocyclyl, wherein:
the amino optionally is substituted with:
(1) one or two substituents independently selected from the
group consisting of alkyl, alkenyl, alkynyl, alkylcarbonyl, alkylsulfonyl,
alkyloxycarbonyl, carbocyclyl, heterocyclyl, carbocyclylalkyl, and
heterocyclylalkyl, or
(2) two substituents that, together with the amino nitrogen, form
a single-ring heterocyclyl;
R5 is selected from the group consisting of hydrogen, hydroxy, alkyl, alkenyl, alkynyl,
alkyloxy, alkenyloxy, alkynyloxy, alkylsulfonyloxy, carbocyclylsulfonyloxy, haloalkylsulfonyloxy,
and halo; and
x2 is halo.
*
2, The compound or salt of claim 1, wherein -- is a single carbon-carbon bond.
3. The compound or salt of claim 1, wherein A is a double carbon-carbon bond.
4. The compound or salt of claim 1, wherein R' is selected from the group consisting of
hydrogen and methyl.
5. The compound or salt of claim 1, wherein R' is hydrogen.
6. The compound or salt of claim 1, wherein R2 is selected from the group consisting of
hydrogen, methyl, and halo.
7. The compound or salt of claim 1, wherein R2 is hydrogen.
8. The compound or salt of claim 1, wherein R3 is selected from the group consisting of
hydrogen and methyl.
9. The compound or salt of claim 1, wherein R3 is hydrogen.
10. The compound or salt of claim 1, wherein R4 is selected from the group consisting of
halo, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl,a mino, C1-C4-alkylsulfonylC, 3-C6-carbocyclyl,a nd
5-6-membered heterocyclyl, wherein:
the amino optionally is substituted with one or two substituents independently selected from
the group consisting of alkyl, alkenyl, alkynyl, and alkylsulfonyl,
0 the Cl-C4-alkyl, C2-C4-alkenyl, and C2-C4-alkynyl optionally are substituted with one or more
substituents independently selected from the group consisting of halo, 0x0, hydroxy, alkyloxy, and
trimethylsilyl, and
the C3-C6-carbocyclyl and 5-6-membered heterocyclyl optionally are substituted with up to
1 three substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo,
and amino, wherein:
the amino optionally is substituted with one or two substituents independently selected from
the group consisting of alkyl, alkenyl, alkynyl, and alkylsulfonyl.
11. The compound or salt of claim 1, wherein:
R~ is selected from the group consisting of halo, C1-C4-alkyl, C3-C6-carbocyclyl, and 5-6-
membered heterocyclyl, wherein:
(a) the C1-C4-alkyl optionally is substituted with up to three substituents
independently selected fiom the group consisting of halo, 0x0, hydroxy, alkyloxy, and
trimethylsilyl, and
(b) the C3-C6-carbocyclyl and 5-6-membered heterocyclyl optionally are
substituted with one or two substituents independently selected from the group consisting of
alkyl, halo, and alkylsulfonylamino.
12. The compound or salt of claim 1, wherein R~ is selected from the group consisting of
halo, alkyl, alkenyl, alkynyl, nitro, cyano, azido, alkyloxy, alkenyloxy, alkynyloxy, amino,
aminocarbonyl, aminosulfonyl, alkylsulfonyl, carbocyclyl, and heterocyclyl.
13. The compound or salt of claim 1, wherein R4 is selected from the group consisting of
C1-C4-alkyl, C3-C6-carbocyclyl, and 5-6-membered heterocyclyl.
14. The compound or salt of claim 1, wherein R4 is selected fiom the group consisting of
halo, tert-butyl, C3-C6-~arb0~y~alnydl ,5 -6-membered heterocyclyl.
15. The compound or salt of claim 1, wherein R4 is selected from the group consisting of
tert-butyl, C3-C6-~arb0~y~alynld, 5-6-membered heterocyclyl.
16. The compound or salt of claim 1, wherein R~ is alkyl.
17. The compound or salt of claim 1, wherein R4 is tert-butyl.
18. The compound or salt of claim 1, wherein R~ is selected from the group consisting of
hydrogen, hydroxy, alkyloxy, and halo.
38 1
19. The compound or salt of claim 1, wherein R' is selected from the group consisting of
hydrogen, methoxy, and halo.
20. The compound or salt of claim 1, wherein R' is methoxy.
21. The compound or salt of claim 1, wherein x2 is selected from the group consisting of
chloro, bromo, and iodo.
22. The compound or salt of claim 1, wherein x2 is iodo.
23. The compound or salt of claim 1, wherein
R' is selected from the group consisting of hydrogen, methyl, and nitrogen-protecting group;
R2 is selected from the group consisting of hydrogen and halo;
R3 is selected from the group consisting of hydrogen and halo;
R4 is selected from the group consisting of C1-C4-alkyl,C 3-C6-~arb0~y~a1nydl ,5 -6-
membered heterocyclyl, wherein:
(a) the C1-C4-alkyl optionally is substituted with up to three substituents
independently selected from the group consisting of halo, 0x0, hydroxy, alkyloxy, and
timethylsilyl, and
I
I (b) the C3-C6-~arb0cyclyaln d 5-6-membered heterocyclyl optionally are
substituted with one or two substituents independently selected from the group consisting of
alkyl, halo, and alkylsulfonylamino;
RS is selected from the group consisting of hydrogen, hydroxy, alkyloxy, and halo; and
x2 is selected from the group consisting of chloro, bromo, and iodo.
24. The compound or salt of claim 1, wherein
I -- -*- - i s a double carbon-carbon bond;
R' is hydrogen;
R2 is selected from the group consisting of hydrogen and halo;
R3 is hydrogen;
R4 is tert-butyl;
RS is selected from the group consisting of hydrogen, hydroxy, and methoxy; and
X* is selected from the group consisting of bromo and iodo.
25. The compound or salt of claim 1, wherein
R' is selected from the group consisting of hydrogen and methyl;
R2 is selected from the group consisting of hydrogen and methyl;
@ R3 is selected from the group consisting of hydrogen and methyl;
R4 is tert-butyl;
R5 is selected from the group consisting of hydroxy and methoxy; and
x2 is selected from the group consisting of chloro, bromo, and iodo.
26. The compound or salt of claim 1, wherein
-- * is a double carbon-carbon bond;
R' is hydrogen;
R2 is hydrogen;
R3 is hydrogen;
R4 is tert-butyl;
R5 is selected from the group consisting of hydroxy and methoxy; and
x2 is selected from the group consisting of chloro, bromo, and iodo.
27. The compound or salt of claim 1, wherein the compound is selected from the group
consisting of
28. A pharmaceutical composition comprising one or more of the compounds and/or salts
of claim 1 and one or more excipients.
29. The pharmaceutical composition of claim 28, wherein the pharmaceutical
composition further comprises one or more additional therapeutic agents.
30. The pharmaceutical composition of claim 29, wherein the one or more additional
therapeutic agents is selected from the group consisting of interferon agent, ribavirin, HCV inhibitor,
and HIV inhibitor.
31. The pharmaceutical composition of claim 30, wherein the one or more additional
therapeutic agents is an HCV inhibitor.
32. A pharmaceutical composition comprising one or more compounds or crystalline
383
forms or salts thereof prepared using the compound of claim 1 and a carrier.
33. The pharmaceutical composition of claim 32, wherein the compound corresponds in
structure to formula I-LO or a crystalline form or a salt thereof
(I-LO)
wherein
-* i s selected from the group consisting of single carbon-carbon bond and double carboncarbon
bond;
R' is selected from the group consisting of hydrogen, methyl, and nitrogen-protecting group;
R~ is selected from the group consisting of hydrogen, halo, hydroxy, methyl, cyclopropyl, and
cyclobutyl;
R3 is selected from the group consisting of hydrogen, halo, 0x0, and methyl;
R4 is selected from the group consisting of halo, alkyl, alkenyl, alkynyl, nitro, cyano, azido,
alkyloxy, alkenyloxy, alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl, carbocyclyl,
and heterocyclyl, wherein:
(a) the amino, aminocarbonyl, and aminosulfonyl optionally are substituted with:
(1) one or two substituents independently selected from the
group consisting of alkyl, alkenyl, alkynyl, and alkylsulfonyl, or
(2) two substituents that, together with the amino nitrogen, form
a single-ring heterocyclyl, and
(b) the alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, and
alkylsulfonyl, optionally are substituted with one or more substituents independently selected
from the group consisting of halo, 0x0, nitro, cyano, azido, hydroxy, amino, alkyloxy,
trimethylsilyl, carbocyclyl, and heterocyclyl, wherein:
the amino optionally is substituted with:
(1) one or two substituents independently selected from the
group consisting of alkyl, alkenyl, alkynyl, alkylcarbonyl, alkylsulfonyl,
I.
i alkyloxycarbonyl, carbocyclyl, heterocyclyl, carbocyclylalkyl, and
I I heterocyclylalkyl, or
I (2) two substituents that, together with the amino nitrogen, form
a single-ring heterocyclyl, and
(c) the carbocyclyl and heterocyclyl optionally are substituted with up to three
384
@ substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo,
0x0, nitro, cyano, azido, hydroxy, amino, alkyloxy, trimethylsilyl, carbocyclyl, and
heterocyclyl, wherein:
the amino optionally is substituted with:
(1) one or two substituents independently selected from the
group consisting of alkyl, alkenyl, alkynyl, alkylcarbonyl, alkylsulfonyl,
alkyloxycarbonyl, carbocyclyl, heterocyclyl, carbocyclylalkyl, and
heterocyclylalkyl, or
(2) two substituents that, together with the amino nitrogen, form
a single-ring heterocyclyl;
RS is selected from the group consisting of hydrogen, hydroxy, alkyl, alkenyl, alkynyl,
alkyloxy, alkenyloxy, alkynyloxy, alkylsulfonyloxy, carbocyclylsulfonyloxy, haloalkylsulfonyloxy,
and halo;
R6 is selected from the group consisting of fused 2-ring carbocyclyl and fused 2-ring
heterocyclyl, wherein each such substituent optionally is substituted with one or more substituents
independently selected from the group consisting of RE, R F, R G,'R, R', RJ, and RK;
each RE is independently selected from the group consisting of halo, nitro, hydroxy, 0x0,
carboxy, cyano, amino, imino, azido, and aldehydo, wherein:
the amino optionally is substituted with one or two substituents independently
selected from the group consisting of alkyl, alkenyl, and alkynyl;
each RF is independently selected from the group consisting of alkyl, alkenyl, and alkynyl,
wherein:
each such substituent optionally is substituted with one or more substituents
independently selected from the group consisting of carboxy, hydroxy, halo, amino, imino,
nitro, azido, 0x0, aminosulfonyl, alkylsulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl,
alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy,
alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, wherein:
the amino, imino, aminosulfonyl, aminocarbonyl, carbocyclyl, and
heterocyclyl optionally are substituted with one or two substituents independently
selected from the group consisting of alkyl, alkenyl, alkynyl, alkylsulfonyl,
alkenylsulfonyl, alkynylsulfonyl, alkylsulfonylamino, hydroxy, and alkyloxy,
wherein:
amino portion of the alkylsulfonylamino optionally is substituted
with a substituent selected from the group consisting of alkyl, alkenyl, and
alkynyl;
each R~ is independently selected from the group consisting of carbocyclyl and heterocyclyl,.
wherein:
each such substituent optionally is substituted with one or more substituents
independently selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy,
hydroxy, halo, amino, nitro, azido, 0x0, aminosulfonyl, alkyloxycarbonyl,
alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy,
alkynylcarbonyloxy, alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, and
aminocarbonyl, wherein:
the amino, aminosulfonyl, and aminocarbonyl optionally are substituted with
one or two substituents independently selected from the group consisting of alkyl,
alkenyl, alkynyl, alkylsulfonyl, alkenylsulfonyl, and alkynylsulfonyl;
each RH is independently selected from the group consisting of alkyloxy, alkenyloxy,
alkynyloxy, alkylsulfonyloxy, alkenylsulfonyloxy, and alkynylsulfonyloxy, wherein:
each such substituent optionally is substituted with one or more substituents
independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro,
azido, 0x0, aminosulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl,
alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy, alkenyloxy,
alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, wherein:
the amino, aminosulfonyl, and aminocarbonyl optionally are substituted with
one or two substituents independently selected from the group consisting of alkyl,
alkenyl, alkynyl, alkylsulfonyl, alkenylsulfonyl, and alkynylsulfonyl;
each R' is independently selected from the group consisting of alkylcarbonyl,
alkenylcarbonyl, alkynylcarbonyl, aminocarbonyl, alkyloxycarbonyl, carbocyclylcarbonyl, and
heterocyclylcarbonyl, wherein:
(a) the alkylcarbonyl, alkenylcarbonyl, and alkynylcarbonyl optionally are
substituted with one or more substituents independently selected from the group consisting of
carboxy, hydroxy, halo, amino, nitro, azido, 0x0, aminosulfonyl, alkyloxycarbonyl,
alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy,
alkynylcarbonyloxy, alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, and
aminocarbonyl, and
(b) the aminocarbonyl optionally is substituted with one or two substituents
independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkyloxyalkyl,
I carbocyclyl, heterocyclyl, alkylsulfonyl, and alkylsulfonylamino, wherein:
I
1 the carbocyclyl and heterocyclyl optionally are substituted with one or two
I I substituents independently selected from the group consisting of halo, alkyl, and 0x0;
each RJ is independently selected from the group consisting of carbocyclylsulfonylamino,
heterocyclylsulfonylamino, alkylcarbonylamino, alkenylcarbonylamino, alkynylcarbonylamino,
alkyloxycarbonylarnino, alke~yloxycarbonylaminoa,l kynyloxycarbonylamino, alkylsulfonylamino,
alkenylsulfonylamino, alkynylsulfonylamino, aminocarbonylamino, alkyloxycarbonylaminoimino,
@ alkylsulfonylaminoimino, alkenylsulfonylaminoimino, and alkynylsulfonylaminoimino, wherein:
(a) the amino portion of such substituents optionally is substituted with a
substituent independently selected from the group consisting of carbocyclylalkyl,
heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkenyl, alkynyl,
alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkyloxycarbonyl,
alkyloxyalkyloxycarbonyl, alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:
(1) the carbocyclyl portion of the carbocyclylalkyl and the heterocyclyl
portion of the heterocyclylalkyl optionally are substituted with one or more
substituents independently selected from the group consisting of alkyl, alkenyl,
alkynyl, carboxy, hydroxy, alkyloxy, alkenyloxy, alkynyloxy, halo, nitro, cyano,
azido, 0x0, and amino, and
(2) the amino portion of the aminocarbonylalkyl optionally is substituted
with one or two substituents independently selected fiom the group consisting of
alkyl, alkenyl, and alkynyl,
(b) the alkyl, alkenyl, and alkynyl portion of such substituents optionally is
substituted with one or more substituents independently selected from the group consisting of
carboxy, halo, 0x0, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy,
carbocyclyl, heterocyclyl, and cyano, wherein:
the amino optionally is substituted with one or two substituents independently
selected from the group consisting of alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy,
and alkynyloxy, wherein:
the alkyl optionally is substituted with one or more hydroxy;
(c) the carbocyclyl and heterocyclyl portions of such substituents optionally are
substituted with one or more substituents independently selected from the group consisting of
alkyl, alkenyl, alkynyl, carboxy, hydroxy, alkyloxy, alkenyloxy, alkynyloxy, halo, nitro,
cyano, azido, and amino, wherein:
the amino optionally is substituted with one or two substituents independently
selected from the group consisting of alkyl, alkenyl, and alkynyl; and
each R~ is independently selected from the group consisting of arninosulfonyl, alkylsulfonyl,
alkenylsulfonyl, and alkynylsulfonyl, wherein:
(a) the alkylsulfonyl, alkenylsulfonyl, and alkynylsulfonyl optionally are
substituted with one or more substituents independently selected from the group consisting of
carboxy, hydroxy, halo, amino, nitro, azido, 0x0, aminosulfonyl, alkyloxycarbonyl,
alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy,
alkynylcarbonyloxy, alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, and
aminocarbonyl, wherein:
the-amino, aminosulfonyl, and aminocarbonyl optionally are substituted with
387
one or two substituents independently selected from the group consisting of alkyl,
alkenyl, and alkynyl; and
(b) the aminosulfonyl optionally is substituted with one or two substituents
independently selected from the group consisting of alkyl, alkenyl, and alkynyl.
34. The pharmaceutical composition of claim 32, wherein the compound corresponding
in structure to formula I-LO is N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidi1n (-2 H)-y1)-2-
methoxyphenyl)naphthalen-2-yl)methanesulfonamide.
35. The pharmaceutical composition of claim 32, wherein the compound corresponding
in structure to formula I-LO is a sodium salt of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydro-pyrimidin-
1 (2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide.
36. The pharmaceutical composition of claim 32, wherein the pharmaceutical
composition further comprises one or more additional therapeutic agents.
37. The pharmaceutical composition of claim 36, wherein the one or more additional
therapeutic agents is selected from the group consisting of interferon agent, ribavirin, HCV inhibitor,
and HIV inhibitor.
38. The pharmaceutical composition of claim 37, wherein the one or more additional
therapeutic agents is an HCV inhibitor.
39. Use of the compound of claim 1 for preparing a compound corresponding in structure
to formula I-LO or a crystalline form or a salt thereof:
R '
wherein
-- -*- - i s selected from the group consisting of single carbon-carbon bond and double carboncarbon
bond;
R' is selected from the group consisting of hydrogen, methyl, and nitrogen-protecting group;
R' is selected from the group consisting of hydrogen, halo, hydroxy, methyl, cyclopropyl, and
388
R3 is selected from the group consisting of hydrogen, halo, 0x0, and methyl;
R4 is selected from the group consisting of halo, alkyl. alkenyl, alkynyl, nitro, cyano, azido,
alkyloxy, alkenyloxy, alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl, carbocyclyl,
and heterocyclyl, wherein:
(a) the amino, aminocarbonyl, and aminosulfonyl optionally are substituted with:
(1) one or two substituents independently selected from the
group consisting of alkyl, alkenyl, alkynyl, and alkylsulfonyl, or
(2) two substituents that, together with the amino nitrogen, form
a single-ring heterocyclyl, and
(b) the alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, and
alkylsulfonyl, optionally are substituted with one or more substituents independently selected
from the group consisting of halo, 0x0, nitro, cyano, azido, hydroxy, amino, alkyloxy,
trimethylsilyl, carbocyclyl, and heterocyclyl, wherein:
the amino optionally is substituted with:
(1) one or two substituents independently selected from the
group consisting of alkyl, alkenyl, alkynyl, alkylcarbonyl, alkylsulfonyl,
alkyloxycarbonyl, carbocyclyl, heterocyclyl, carbocyclylalkyl, and
heterocyclylalkyl, or
(2) two substituents that, together with the amino nitrogen, form
a single-ring heterocyclyl, and
(c) the carbocyclyl and heterocyclyl optionally are substituted with up to three
substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo,
0x0, nitro, cyano, azido, hydroxy, amino, alkyloxy, trimethylsilyl, carbocyclyl, and
heterocyclyl, wherein:
the amino optionally is substituted with:
(1) one or two substituents independently selected from the
group consisting of alkyl, alkenyl, alkynyl, alkylcarbonyl, alkylsulfonyl,
alkyloxycarbonyl, carbocyclyl, heterocyclyl, carbocyclylalkyl, and
heterocyclylalkyl, or
(2) two substituents that, together with the amino nitrogen, form
a single-ring heterocyclyl;
RS is selected from the group consisting of hydrogen, hydroxy, alkyl, alkenyl, alkynyl,
alkyloxy, alkenyloxy, alkynyloxy, alkylsulfonyloxy, carbocyclylsulfonyloxy, haloalkylsulfonyl~x~,
and halo;
is selected from the group consisting of fused Zring carbocyclyl and fused 2-ring
heterocyclyl, wherein each such substituent optionally is substituted with one or more substituents
389
independently selected from the group consisting of RE, R', RG, RH, R', RJ, and RK;
each RE is independently selected from the group consisting of halo, nitro, hydroxy, 0x0,
carboxy, cyano, amino, imino, azido, and aldehydo, wherein:
the amino optionally is substituted with one or two substituents independently
selected from the group consisting of alkyl, alkenyl, and alkynyl;
each R' is independently selected from the group consisting of alkyl, alkenyl, and alkynyl,
wherein:
each such substituent optionally is substituted with one or more substituents
independently selected from the group consisting of carboxy, hydroxy, halo, amino, imino,
nitro, azido, 0x0, aminosulfonyl, alkylsulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl,
alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy,
alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, wherein:
the amino, imino, aminosulfonyl, aminocarbonyl, carbocyclyl, and
heterocyclyl optionally are substituted with one or two substituents independently
selected from the group consisting of alkyl, alkenyl, alkynyl, alkylsulfonyl,
alkenylsulfonyl, alkynylsulfonyl, alkylsulfonylamino, hydroxy, and alkyloxy,
wherein:
amino portion of the alkylsulfonylamino optionally is substituted
with a substituent selected from the group consisting of alkyl, alkenyl, and
alkyny 1;
each RG is independently selected from the group consisting of carbocyclyl and heterocyclyl,
wherein:
each such substituent optionally is substituted with one or more substituents
independently selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy,
hydroxy, halo, amino, nitro, azido, 0x0, aminosulfonyl, alkyloxycarbonyl,
alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy,
alkynylcarbonyloxy, alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, and
aminocarbonyl, wherein:
the amino, aminosulfonyl, and aminocarbonyl optionally are substituted with
one or two substituents independently selected from the group consisting of alkyl,
alkenyl, alkynyl, alkylsulfonyl, alkenylsulfonyl, and alkynylsulfonyl;
each RH is independently selected from the group consisting of alkyloxy, alkenyloxy,
alkynyloxy, alkylsulfonyloxy, alkenylsulfonyloxy, and alkynylsulfonyloxy, wherein:
each such substituent optionally is substituted with one or more substituents
independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro,
azido, 0x0, aminosulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynjtbxycarbonyl,
alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy, alkenyloxy,
390
all alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, wherein:
the amino, aminosulfonyl, and aminocarbonyl optionally are substituted with
one or two substituents independently selected from the group consisting of alkyl,
alkenyl, alkynyl, alkylsulfonyl, alkenylsulfonyl, and alkynylsulfonyl;
1 each R' is independently selected from the group consisting of alkylcarbonyl,
I alkenylcarbonyl, alkynylcarbonyl, aminocarbonyl, alkyloxycarbonyl, carbocyclylcarbonyl, and
heterocyclylcarbonyl, wherein:
(a) the alkylcarbonyl, alkenylcarbonyl, and alkynylcarbonyl optionally are
substituted with one or more substituents independently selected from the group consisting of
carboxy, hydroxy, halo, amino, nitro, azido, 0x0, aminosulfonyl, alkyloxycarbonyl,
alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy,
alkynylcarbonyloxy, alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, and
aminocarbonyl, and
(b) the aminocarbonyl optionally is substituted with one or two substituents
independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkyloxyalkyl,
carbocyclyl, heterocyclyl, alkylsulfonyl, and alkylsulfonylamino, wherein:
the carbocyclyl and heterocyclyl optionally are substituted with one or two
substituents independently selected from the group consisting of halo, alkyl, and 0x0;
each R~ is independently selected from the group consisting of carbocyclylsulfonylamino,
heterocyclylsulfonylamino, alkylcarbonylamino, alkenylcarbonylamino, alkynylcarbonylamino,
alkyloxycarbonylamino, alkenyloxycarbonylamino, alkynyloxycarbonylarnino, alkylsulfonylamino,
alkenylsulfonylamino, alkynylsulfonylamino, aminocarbonylamino, alkyloxycarbonylaminoimino,
alkylsulfonylaminoimino, alkenylsulfonylaminoimino, and alkynylsulfonylaminoimino, wherein:
(a) the amino portion of such substituents optionally is substituted with a
substituent independently selected from the group consisting of carbocyclylalkyl,
heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkenyl, alkynyl,
alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkyloxycarbonyl,
alkyloxyalkyloxycarbonyl, alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:
(1) the carbocyclyl portion of the carbocyclylalkyl and the heterocyclyl
portion of the heterocyclylalkyl optionally are substituted with one or more
substituents independently selected from the group consisting of alkyl, alkenyl,
alkynyl, carboxy, hydroxy, alkyloxy, alkenyloxy, alkynyloxy, halo, nitro, cyano,
azido, 0x0, and amino, and
(2) the amino portion of the aminocarbonylalkyl optionally is substituted
with one or two substituents independently selected from the group consisting of
alkyl, alkenyl, and alkynyl, , ,
(b) the alkyi, alkenyl, and alkynyl portion of such substituents optionally is
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0 substituted with one or more substituents independently selected from the group consisting of
carboxy, halo, 0x0, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy,
carbocyclyl, heterocyclyl, and cyano, wherein:
the amino optionally is substituted with one or two substituents independently
selected from the group consisting of alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy,
and alkynyloxy, wherein:
the alkyl optionally is substituted with one or more hydroxy;
(c) the carbocyclyl and heterocyclyl portions of such substituents optionally are
substituted with one or more substituents independently selected from the group consisting of
alkyl, alkenyl, alkynyl, carboxy, hydroxy, alkyloxy, alkenyloxy, alkynyloxy, halo, nitro,
cyano, azido, and amino, wherein:
the amino optionally is substituted with one or two substituents independently
selected from the group consisting of alkyl, alkenyl, and alkynyl; and
each R~ is independently selected from the group consisting of aminosulfonyl, alkylsulfonyl,
alkenylsulfonyl, and alkynylsulfonyl, wherein:
(a) the alkylsulfonyl, alkenylsulfonyl, and alkynylsulfonyl optionally are
substituted with one or more substituents independently selected from the group consisting of
carboxy, hydroxy, halo, amino, nitro, azido, 0x0, aminosulfonyl, alkyloxycarbonyl,
alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy,
alkynylcarbonyloxy, alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, and
aminocarbonyl, wherein:
the amino, aminosulfonyl, and aminocarbonyl optionally are substituted with
one or two substituents independently selected from the group consisting of alkyl,
alkenyl, and alkynyl; and
(b) the aminosulfonyl optionally is substituted with one or two substituents
independently selected from the group consisting of alkyl, alkenyl, and alkynyl.
40. The use of claim 39, wherein the compound corresponding in structure to formula ILO
LO is N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin1- ( 2H)-yl)-2-methoxypheny1)naphthalen-
2-yl)methanesulfonamide.
41. The use of claim 39, wherein the compound corresponding in structure to formula ILO
is a sodium salt of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydro-pyrimidin-l(2H)-yl)-2-
methoxyphenyl)naphthalen-2-yl)methanesulfonamide.
.42. Use of the compound of claim 1 for inhibition of replication of a ribonucleic acid
(RNA) virus. . .
43. The use of claim 42, wherein the RNA virus is hepatitis C virus (HCV).
44. Use of the compound of claim 1 for treatment of hepatitis C in a mammal in need of
such treatment.
45. The use of claim 44, wherein the mammal is human.
46. Use of the compound of claim 1, for treatment of hepatitis C in a mammal, in
combination with one or more additional therapeutic agents.
47. The use of claim 46, wherein the one or more additional therapeutic agents is selected
from the group consisting of interferon agent, ribavirin, HCV inhibitor, and HIV inhibitor.
48. The use of claim 47, wherein the one or more additional therapeutic agents is an HCV
1 inhibitor.
49. Use of the compound of claim 1 for preparing a compound for inhibition of
replication of a ribonucleic acid (RNA) virus.
50. The use of claim 49, wherein the RNA virus is hepatitis C virus (HCV).
51. Use of the compound of claim 1 for preparing a compound for treatment of hepatitis
C in a mammal in need of such treatment.
1 52. The use of claim 51, wherein the mammal is human.
53. Use of the compound of claim 1, for preparing a compound for treatment of hepatitis
C in a mammal, in combination with one or more additional therapeutic agents.
54. The use of claim 53, wherein the one or more additional therapeutic agents is selected
from the group consisting of interferon agent, ribavirin, HCV inhibitor, and HIV inhibitor.
I 55. The use of claim 54, wherein the one or more additional therapeutic agents is an HCV
inhibitor.
56. A process for preparing the compound or salt of claim 1 , wherein the process
comprises reacting a compound of formula I11 (wherein R', R2, and R~ are as defined in claim 1) with
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d a compound of formula IV (wherein R4, R', and X' are as defined in claim 1; and X' is halo) in the
presence of (i) copper (I) salt catalyst and (ii) nitrogenous heteroaryl ligand
Cu(1) catalyst
4-
R' I nitrogenous '
(IV) R4 heteroaryl
ligand
57. The process of claim 56, wherein X' is selected from the group consisting of chloro,
bromo, and iodo.
58. The process of claim 56, wherein the process is conducted in the presence of a base.
59. The process of claim 58, wherein the base is selected from the group consisting of
potassium salt, sodium salt, and cesium salt.
60. The process of claim 56, wherein the nitrogenous heteroaryl ligand comprises a
I picolinamide compound corresponding in structure to formula V:
I
R'S ; and
R", R'*, R'~, R14, R1', R16, and R" are independently selected from the group consisting of
hydrogen, CM-perfluoroalkyl, C14-alkyloxy, C14-haloalkyl, chloro, and cyano.
61. The process of claim 56, wherein the nitrogenous heteroaryl ligand is selected from
the group consisting of 8-hydroxyquinoline, 2-(2-pyridy1)-benzimidazole, N-(4-cyanophenyl)
picolinamide, and N-(2-cyanopheny1)picolinamide.